Lobar or Sublobar Resection for Peripheral Stage IA Non–Small-Cell Lung Cancer

Posted by zedie

Abstract

Background

The increased detection of small-sized peripheral non–small-cell lung cancer (NSCLC) has renewed interest in sublobar resection in lieu of lobectomy.

Methods

We conducted a multicenter, noninferiority, phase 3 trial in which patients with NSCLC clinically staged as T1aN0 (tumor size, ≤2 cm) were randomly assigned to undergo sublobar resection or lobar resection after intraoperative confirmation of node-negative disease. The primary end point was disease-free survival, defined as the time between randomization and disease recurrence or death from any cause. Secondary end points were overall survival, locoregional and systemic recurrence, and pulmonary functions.

Results

From June 2007 through March 2017, a total of 697 patients were assigned to undergo sublobar resection (340 patients) or lobar resection (357 patients). After a median follow-up of 7 years, sublobar resection was noninferior to lobar resection for disease-free survival (hazard ratio for disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24). In addition, overall survival after sublobar resection was similar to that after lobar resection (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection and 64.1% (95% CI, 58.5 to 69.0) after lobar resection. The 5-year overall survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9% (95% CI, 74.1 to 82.9) after lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, a between-group difference of 2 percentage points was measured in the median percentage of predicted forced expiratory volume in 1 second, favoring the sublobar-resection group.

Conclusions

In patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, sublobar resection was not inferior to lobectomy with respect to disease-free survival. Overall survival was similar with the two procedures. (Funded by the National Cancer Institute and others; CALGB 140503 ClinicalTrials.gov number, NCT00499330. opens in new tab.)

QUICK TAKELobar vs. Sublobar Resection for Peripheral Stage IA NSCLC 01:46

In 1995, the Lung Cancer Study Group reported the results of a randomized trial comparing lobectomy with sublobar resection in patients with clinical T1N0 non–small-cell lung cancer (NSCLC).¹ The frequency of local recurrence was three times as high with sublobar resection as with lobectomy, and lung cancer–related mortality was 50% higher with sublobar resection. These results established lobectomy as the standard of surgical care for patients with clinical T1N0 NSCLC. In the decades since, advances in imaging and staging methods have allowed the detection of smaller and earlier tumors, a situation that has rekindled interest in sublobar resection for patients with clinical stage IA NSCLC who might otherwise be candidates for lobectomy.^2-5 Japanese investigators recently reported the results of a large, randomized trial (JCOG0802) comparing lobectomy with anatomical segmentectomy in patients with clinical stage IA NSCLC with a tumor size of 2 cm or less.⁶ After a median follow-up of approximately 7 years, anatomical segmentectomy was superior to lobectomy for overall survival (primary end point) and noninferior to lobectomy for relapse-free survival. Here, we report the results of a randomized international trial comparing sublobar resection (wedge resection or segmentectomy) with lobectomy in patients with clinical stage IA NSCLC with a tumor size of 2 cm or less.

Methods

Trial Design and Patients

Cancer and Leukemia Group B (CALGB) 140503 was a multicenter, international, randomized, noninferiority, phase 3 trial involving patients with NSCLC clinically staged as T1aN0. CALGB is now part of the Alliance for Clinical Trials in Oncology (hereafter referred to as the Alliance). Clinical staging was based on the seventh edition of the tumor–node–metastasis staging system. Patients were recruited from 83 academic and community-based institutions in the United States, Canada, and Australia. Patients were registered to the trial if they had met the preoperative eligibility criteria, and they underwent randomization after meeting the intraoperative eligibility criteria. Preoperative eligibility criteria included the presence of a peripheral lung nodule with a solid component measuring 2 cm or less on preoperative computed tomography (CT) that was presumed or confirmed to be NSCLC; a center of the tumor, as seen on CT, that was located in the outer third of the lung and a tumor location that was suitable for either sublobar resection (wedge or segment) or lobar resection; an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0, 1, or 2 (on a 5-point scale in which higher numbers indicate greater disability); no malignant disease within the past 3 years other than nonmelanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix; no previous chemotherapy or radiation therapy for the index lung cancer; no evidence of locally advanced or metastatic disease; and an age of 18 years or older. Patients with pure ground-glass opacities or pathologically confirmed N1 or N2 disease were not eligible.

Intraoperative eligibility criteria included histologic confirmation of NSCLC (if not already obtained) and confirmation of N0 status by means of frozen-section examination (for tumors on the right side, node levels 4, 7, and 10; for tumors on the left side, node levels 5 or 6, 7, and 10). Nodes that were previously sampled by means of mediastinoscopy, endobronchial ultrasonography, or endoscopic ultrasonography within 6 weeks before the definitive surgical procedure did not need to be resampled.

Trial Oversight

The trial was conducted according to the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines. The protocol was approved by the CALGB/Alliance central institutional review board and the institutional review board at each participating institution and is available with full text of this article at NEJM.org. All the patients provided written informed consent before trial enrollment. Since activation of CALGB/Alliance 140503, the trial has been monitored by the Alliance data and safety monitoring board twice a year.

The first two authors developed the trial design, had full access to the raw data, and analyzed the data. The first author wrote the first draft of the manuscript. All the authors had the opportunity to revise the manuscript and vouch for the completeness and accuracy of the data and for the adherence of the trial to the protocol. The primary funder (National Cancer Institute) approved the trial design but had no role in the collection, interpretation, or analysis of the data or in the writing of the manuscript. There were no agreements concerning confidentiality of the data between the primary funder and the authors or the participating institutions.

Randomization and Procedures

Eligible patients were preregistered to the trial with the use of the Oncology Patient Enrollment Network registration system, a Web-based system for patients’ enrollment into National Cancer Institute–sponsored cooperative group clinical trials. Once intraoperative eligibility (as described above) was confirmed, patients underwent randomization (in a 1:1 ratio) to either sublobar resection or lobar resection on the basis of a permuted-block randomization scheme with stratification according to radiographic tumor size (<1 cm, 1 to 1.5 cm, or >1.5 to 2.0 cm), histologic type (squamous-cell carcinoma, adenocarcinoma, or other), and smoking status (never, former, or current). Trial-group assignments were not concealed to patients, surgeons, nurses, data managers, or statisticians. The type of sublobar resection (wedge resection or segmentectomy) and the choice of surgical approach (thoracotomy vs. video- or robotic-assisted thoracoscopic surgery) was at the surgeon’s discretion.

End Points

The primary end point was disease-free survival, defined as the time between randomization and disease recurrence or death from any cause, whichever occurred first. The primary objective was to determine whether sublobar resection (segmentectomy or wedge resection) is noninferior to lobectomy with respect to disease-free survival among patients with small NSCLC (tumor size, ≤2 cm) exclusive of second primary lung cancer.

Secondary end points were overall survival, locoregional and systemic recurrence, and expiratory flow rates 6 months postoperatively. Overall survival was defined as the time between randomization and death from any cause. Locoregional recurrence was defined as recurrent disease in the lung or the hilar nodes of the index lobe. Regional recurrence was defined as isolated mediastinal nodal recurrence. All other recurrence was deemed to be systemic.

Statistical Analysis

The trial was designed to have approximately 80% power with 351 events of disease recurrence or death to reject the null hypothesis that the hazard ratio after sublobar resection as compared with after lobectomy is less than 1.306 by stratified log-rank test for noninferiority at a one-sided significance level of 5% when the true hazard ratio is 1. With a prespecified noninferiority margin of 1.306, there is a 5% chance that the null hypothesis will be rejected when the hazard ratio after sublobar resection is 30.6% higher than after lobectomy. A justification of the noninferiority margin is provided in the Supplementary Appendix, available at NEJM.org. Interim analyses with early stopping boundaries were planned for noninferiority (i.e., early evidence that sublobar resection is not inferior to lobectomy) and futility (i.e., low probability of showing that sublobar resection is not inferior to lobectomy at the planned final analysis). The critical values of early stopping for noninferiority were calculated on the basis of a Lan–DeMets alpha-spending function for O’Brien–Fleming–like boundaries.^7,8 The trial enrolled 697 patients from June 2007 through March 2017. On the basis of interim analyses conducted up to November 2021 and a validation analysis in March 2022, the Alliance data and safety monitoring board recommended unanimously to release the data and terminate further monitoring of the trial by the data and safety monitoring board, noting that there was minimal chance that the trial may yield a different conclusion at the planned final analysis.

The primary analysis of efficacy end points was based on the intention-to-treat population, which included all the patients who had undergone randomization according to their randomly assigned treatments. In the analysis of disease-free survival, data for patients who were alive without disease recurrence were censored at the time of the last follow-up. In the analysis of overall survival, data for patients who were alive were censored at the time of the last follow-up. Survival end points were characterized with the use of the Kaplan–Meier estimator. The P value for testing the noninferiority of sublobar resection to lobar resection for disease-free survival was obtained from a stratified log-rank test with tumor size, histologic type, and smoking status as stratification factors. Hazard ratios and their confidence intervals were estimated with the use of stratified Cox proportional-hazards models. Violation of the proportional-hazards assumption was evaluated by the method of Schoenfeld residuals. We calculated 90% confidence intervals for disease-free survival and its derived variables so that they are consistent with the one-sided significance level of 5% used for the primary noninferiority test of sublobar resection as compared with lobectomy.

After randomization and on review of source documents, 27 patients were deemed to have not met all intraoperative eligibility criteria (15 assigned to sublobar resection and 12 assigned to lobar resection). In addition, 5 patients were converted from their assigned lobar resection to sublobar resection and 10 from their assigned sublobar resection to lobar resection. Therefore, in addition to the intention-to-treat analysis, we conducted a sensitivity per-protocol analysis based only on patients who met all intraoperative eligibility and who had undergone their assigned surgical procedure. A post hoc analysis on the heterogeneity of treatment effects for disease-free and overall survival across patient subgroups, including race, sex, age group, ECOG performance-status score, tumor location, tumor size, histologic type, and smoking status, was summarized with forest plots, and the hazard ratios and confidence intervals therein were estimated from unstratified Cox proportional-hazards models fitted to the subgroups. To examine consistency of treatment effect across trial sites, we classified sites on the basis of total enrollment into high-enrolling sites (>30 patients), medium-enrolling sites (10 to 30 patients), and low-enrolling sites (<10 patients). We obtained site-adjusted hazard ratios and confidence intervals with the use of a Cox proportional-hazards mixed-effects model, with trial sites as a random effect. In another post hoc analysis, we explored the treatment effect on recurrence-free survival (for which all deaths were censored) and on lung cancer–related death as compared with other causes of death, with cumulative incidence functions estimated with the use of the Gray method⁹ and the associated hazard ratios and confidence intervals estimated by means of the Fine–Gray subdistribution hazard model.¹⁰

The incidences of disease recurrence were summarized according to treatment group, and the confidence intervals of the differences in incidences were estimated with the use of the Miettinen and Nurminen method.¹¹ The changes in pulmonary functions (forced expiratory volume in 1 second [FEV₁] and forced vital capacity [FVC]) between baseline and 6 months postoperatively were summarized according to treatment group, and the confidence intervals of median difference were estimated with the use of the bootstrap bias-corrected and accelerated method with 2000 bootstrapped samples.¹² Other than the confidence interval of the primary end point, all reported confidence intervals were computed at a 95% confidence level. The widths of confidence intervals were not adjusted for multiple testing and may not be used in place of hypothesis testing. Short-term morbidity and mortality for this trial had been reported previously.¹³

Data quality was ensured by review of data by the Alliance Statistical and Data Management Center (SDMC) and the trial chairperson (first author), in accordance with Alliance policies. The analyses of the efficacy end points, including disease-free and overall survival, have been independently validated by an Alliance SDMC statistician, who is not associated with the trial. All statistical analyses were conducted by the trial statisticians and statistical programmers with the data locked on June 21, 2022. Data management and statistical analysis were performed with SAS software, version 9.4, and graphs were generated in R software, version 3.6.3.

Results

Patients

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.

Between June 15, 2007, and March 13, 2017, a total of 1080 patients with suspected or confirmed T1aN0 NSCLC were preregistered to the trial by 125 surgeons at 83 participating institutions. A total of 697 patients (64.5%) met preoperative and intraoperative eligibility criteria and were randomly assigned to undergo either sublobar resection (340 patients) or lobar resection (357 patients) (Fig. S1 in the Supplementary Appendix). Of the 340 patients assigned to sublobar resection, 201 (59.1%) underwent wedge resection and 129 (37.9%) underwent an anatomical segmental resection. In a previously reported subgroup analysis, failure to proceed with intraoperative randomization was attributable to undiagnosed benign disease (50.0%), a higher stage of NSCLC that was discovered at the time of surgery (22.6%), or malignant disease other than NSCLC (7.7%).¹⁴ The demographic and clinical characteristics of the randomly assigned patients at baseline are shown in Table 1.

Survival

Figure 1. Disease-free and Overall Survival.Figure 2. Exploratory Subgroup Analysis of Disease-free Survival.

After a median follow-up of 7 years, sublobar resection was not inferior to lobectomy for disease-free survival (hazard ratio for disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24). The 5-year disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection and 64.1% (95% CI, 58.5 to 69.0) after lobar resection (Figure 1A). The treatment effect was similar across trial sites (Table S2), with a hazard ratio of 0.99 (90% CI, 0.80 to 1.21) after adjustment for trial sites as a random effect. In a post hoc exploratory analysis, results were generally consistent between the overall analysis and subgroup analyses defined by key demographic and clinical variables, including age group, sex, tumor location, histologic type, smoking history, tumor size, and ECOG performance-status score (Figure 2). Overall survival (key secondary end point) was similar in the sublobar-resection group and the lobar-resection group (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year overall survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9% (95% CI, 74.1 to 82.9) after lobectomy (Figure 1B). The per-protocol sensitivity analysis yielded similar findings to the intention-to-treat analysis for both disease-free and overall survival (Fig. S2). The post hoc subgroup analysis showed no substantial between-group difference in overall survival across all key demographic and clinical variables (Fig. S3).

Recurrence

Table 2. Patterns of Recurrence.Figure 3. Recurrence-free Survival and Cause of Death.

After the exclusion of 10 patients (4 in the sublobar-resection group and 6 in the lobar-resection group) who had died of treatment-related events within 90 days after their surgical procedure, 687 patients were available for assessment of disease recurrence (336 in the sublobar-resection group and 351 in the lobar-resection group). Disease recurrence developed in 102 patients (30.4%) after sublobar resection and 103 (29.3%) after lobectomy (Table 2). Locoregional recurrence occurred in 45 patients (13.4%) after sublobar resection and 35 (10.0%) after lobectomy. More than 50% of the recurrences in each group were systemic in nature. In a post hoc exploratory analysis, recurrence-free survival was similar in the sublobar-resection group and the lobar-resection group (hazard ratio for disease recurrence, 1.05; 95% CI, 0.80 to 1.39) (Figure 3A). The 5-year recurrence-free survival was 70.2% (95% CI, 64.6 to 75.1) after sublobar resection and 71.2% (95% CI, 65.8 to 75.9) after lobar resection. A total of 101 lung cancer–related deaths were noted (46 in the sublobar-resection group and 55 in the lobar-resection group), as were 93 deaths from other causes (48 and 45 in the respective groups). The cumulative incidence of deaths from lung cancer and other causes of death was similar in the two groups (Figure 3B).

Expiratory Flow Rates

At 6 months postoperatively, the magnitude of reduction from baseline in the percentage of predicted FEV₁ was greater after lobar resection (−6.0; 95% CI, −8.0 to −5.0) than after sublobar resection (−4.0; 95% CI, −5.0 to −2.0) (Table S1). Similarly, the magnitude of reduction in the percentage of predicted FVC was greater after lobectomy (−5.0; 95% CI, −7.0 to −3.0) than after sublobar resection (−3.0; 95% CI, −4.0 to −1.0).

Discussion

In this large, randomized trial, we found that in patients with peripheral clinical stage T1aN0 (≤2 cm) NSCLC, sublobar resection was noninferior to lobectomy with respect to disease-free survival (primary end point). We also found that overall survival (secondary end point) was similar with the two procedures. The results of post hoc exploratory analyses that examined the association between relevant demographic and clinical variables and disease-free and overall survival were consistent with the overall results of the trial. However, given the small sample size and few events in each subgroup, these findings should be interpreted with caution. In addition, no substantial difference between the two groups was seen in the incidences or patterns of disease recurrence. Locoregional recurrences were slightly numerically higher after sublobar resection than after lobectomy (13.4% vs. 10.0%), but the difference was not clinically meaningful. Although we did not mandate the extent of lymph-node dissection beyond sampling of major hilar and two mediastinal nodal stations, regional recurrence occurred in 1.8% of the patients after sublobar resection and 2.6% of the patients after lobectomy.

It is important that these results are interpreted strictly within the constraints of the eligibility criteria mandated by the trial. Specifically, the results are applicable only to a highly selected group of patients with peripherally located NSCLC who are deemed to have clinical T1aN0 disease (tumor size, ≤2 cm) according to imaging criteria and in whom the absence of metastases to hilar and mediastinal lymph nodes is pathologically confirmed. We had previously reported that among patients with clinically node-negative disease who were registered for the trial, 6.4% had positive major hilar or mediastinal nodes precluding randomization.¹⁴ These results will become increasingly relevant as the proportion of patients with early-stage lung cancer increases with expanded implementation of lung cancer screening and as the number of older persons with early-stage disease in whom sublobar resection may be the preferred surgical option increases.^15,16 We had previously reported 30-day mortality of 0.6% and 90-day mortality of 1.2% after sublobar resection.¹³ These values compared favorably with 30-day mortality of 1.1% and 90-day mortality of 1.7% after lobectomy. We would note that 80% of all the resections in both groups of this trial were performed in a minimally invasive fashion.

Another proposed benefit of sublobar resection is preservation of pulmonary function as measured by expiratory flow rates. In this trial, we observed a lower decrement in forced expiratory flow after sublobar resection than after lobectomy. However, the absolute difference between the two groups was only 2 percentage points for both FEV₁ and FVC. Although this difference is arguably not clinically meaningful in this patient population with normal baseline pulmonary functions, it may be more clinically relevant in patients with compromised pulmonary functions or in those with lower-lobe disease in whom lobar resection may be associated with greater impairment of pulmonary function. In addition, a single measurement at 6 months may not be predictive of potential further reductions or perhaps improvements in flow rates at 12 or 18 months postoperatively. More likely, however, proof of preservation of pulmonary function may be best shown with the use of functional tests, such as the 6-minute walk test or pulmonary exercise testing.

Our trial results are consistent with recently reported results by investigators of the Japanese Clinical Oncology Group. Saji and colleagues reported the results of JCOG0802, a randomized noninferiority trial comparing lobectomy with anatomical segmentectomy in a similar cohort of patients.⁶ The results showed that anatomical segmentectomy was noninferior to lobar resection for overall and relapse-free survival. Although these results are generally similar to those reported in the current trial, several critical methodologic differences exist between the two trials. An important difference is that anatomical segmentectomy, a procedure considered by most surgeons to be more oncologically sound than wedge resection, was the only method of sublobar resection allowed in the JCOG0802 trial. In the current trial, both anatomical segmentectomy and wedge resection were considered to be acceptable methods of sublobar resection. Wedge resection was allowed in the current trial because it is the most frequently practiced method of sublobar resection in North America and Europe; thus, its inclusion would make the trial more representative of a “real world” setting.^17,18 Surgical details of both methods of sublobar resection, including margin status, are being analyzed. Another important difference between the two trials is that in JCOG0802 more than 90% of the patients had adenocarcinoma, of whom 45% had an associated ground-glass component. These part-solid tumors are generally thought to be associated with better survival than a completely solid adenocarcinoma. The high proportion of patients who had part-solid tumors may have contributed to the outstanding 5-year survival of more than 90% reported in each group of that trial. It is also consistent with the reported low incidence of distant metastases, which was 4.8% in the lobectomy group and 4.9% in the segmentectomy group. In contrast, distant metastases developed in 16.0% of all the patients in the current trial, which accounted for more than 50% of all recurrences.

Regardless of these differences in trial design, the concordance of results between the two trials is reassuring. Together, these findings affirm that sublobar resection for patients with clinical T1aN0 disease by either anatomical segmentectomy or wedge resection is an effective management approach for this subgroup of patients with NSCLC.

Source: NEJM

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer

Posted by zedie

Abstract

Background

Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor–positive early breast cancer receiving adjuvant endocrine therapy.

Methods

We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor–positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and overall survival were also assessed.

Results

A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.

Conclusions

Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor–positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329. opens in new tab.)

QUICK TAKEOmission of Radiotherapy in Early Breast Cancer 01:40

In the United States, 26% of breast cancer diagnoses are in women 65 to 74 years of age.¹ The prevalence of breast cancer among older adults is rising.² Underrepresentation of older patients with breast cancer in clinical trials has led to undertreatment and overtreatment.³ A meta-analysis by the Early Breast Cancer Trialists’ Cooperative Group⁴ showed that radiotherapy after breast-conserving therapy, although it reduces the overall cumulative incidence of recurrence among node-negative patients, confers only a modest survival benefit. Omission of radiotherapy after breast-conserving therapy in low-risk, older patients with smaller hormone receptor (HR)–positive tumors remains controversial,^5-7 with only limited long-term level 1 evidence available to guide treatment decisions.^2,8-12 The 5-year results of the PRIME II trial showed that among women 65 years of age or older who had HR-positive T1 or T2 primary tumors (≤3 cm in the largest dimension) and no lymph-node involvement and who were treated with breast-conserving therapy and adjuvant endocrine therapy, radiotherapy was associated with a lower percentage of patients having local breast cancer recurrence (4.1% without radiotherapy vs. 1.3% with radiotherapy).⁹ Despite guidelines supporting the omission of radiotherapy in women 70 years of age or older with T1^10,11 or small selected T2¹² estrogen-receptor (ER)–positive tumors treated with breast-conserving therapy and adjuvant endocrine therapy, the use of radiotherapy in the United States in this clinical context remains common.¹³ Here we report the 10-year outcomes of the PRIME II trial.

Methods

Oversight

We conducted PRIME II, a phase 3 randomized clinical trial that was designed by the Scottish Cancer Trials Breast Group (SCTBG). The methods have been described previously.⁹ The trial was conducted in 76 centers in the United Kingdom, Greece, Australia, and Serbia. The protocol (available with the full text of this article at NEJM.org) received U.K. ethics approval. All the patients provided written informed consent. Two of the authors designed the trial with the SCTBG. The authors wrote the article and vouch for the accuracy and completeness of the data for the adherence to the protocol. The funders of the trial had no role in its design or conduct, no access to the data, and no role in the analysis or publication of the data.

Patient Selection

Women 65 years of age or older were eligible to participate if they had T1 or T2 primary breast cancer (tumor size, ≤3 cm in the largest dimension) that had been treated with breast-conserving therapy plus axillary staging (four-node lower axillary sample, sentinel-node biopsy, or axillary-node clearance) and was node-negative, estrogen receptor (ER)–positive or progesterone receptor–positive (or both), and had clear excision margins (≥1 mm); they also needed to have received adjuvant or neoadjuvant endocrine therapy. Patients were eligible if they had either cancer with grade 3 histologic features or lymphovascular invasion but not both. Patients were excluded if they were younger than 65 years of age, had a history of in situ or invasive carcinoma of either breast, or had had malignant disease within the previous 5 years (except nonmelanomatous skin cancer or carcinoma in situ of the cervix). Neither HER2 status (since it was not routinely measured at the initiation of the trial) nor coexisting conditions were recorded. All patients had to have a health status that would make treatment and follow-up possible.

Treatment

At trial entry, a computerized randomization service was used to randomly assign patients in a 1:1 ratio to receive either whole-breast irradiation or no irradiation. Guidelines were given for irradiation (40 to 50 Gy in total; 2.66 to 2.00 Gy per fraction in 20 to 25 fractions), which was administered over a period of 3 to 5 weeks. Boost irradiation of the breast was allowed with electrons (10 to 15 Gy) or with an iridium implant (e.g., 20 Gy to the 85% reference isodose volume). We recommended tamoxifen at a dose of 20 mg per day for 5 years as standard adjuvant endocrine therapy. Follow-up was performed through annual clinical visits for at least 5 years and subsequently through clinic visits or telephone calls to the patient or a community doctor to determine each patient’s health status. Annual mammography of both breasts was recommended, but mammography performed at the first, third, and fifth years after surgery was acceptable.

Trial End Points

The primary end point was local breast cancer recurrence. The secondary end points were regional recurrence, contralateral breast cancer, distant metastases, disease-free survival, and overall survival. Local recurrence was defined as any cancer in the scar or in the same breast. Regional recurrence was defined as disease in the ipsilateral axillary or supraclavicular lymph nodes. The end points were assessed by the local investigator and were not centrally assessed.

Statistical Analysis

Our null hypothesis was that there would be no difference between the radiotherapy and no-radiotherapy groups in terms of local recurrence at 5 years. The trial was originally powered to detect a difference at 5 years of at least 5 percentage points (i.e., recurrence in 5% of patients in the radiotherapy group and in 10% of those in the no-radiotherapy group) with 80% power at a significance level of 5% with a target of enrolling 1000 patients. Ethics approval was granted on November 14, 2008, to increase the sample size to 1294, because both randomized and nonrandomized studies¹⁴ suggested that our initial estimate of the local recurrence rate was excessive. Our revised estimates enabled the detection of a difference of at least 3 percentage points (2% in the radiotherapy group and 5% in the no-radiotherapy group) at 5 years with 80% power at a significance level of 5% and with a 10% allowance for loss to follow-up. Our planned statistical analysis of primary and secondary end points of the trial was documented on March 3, 2020, before the analysis was performed. Adherence to adjuvant endocrine therapy was included as an additional secondary end point.

Data were analyzed with Kaplan–Meier plots and by log-rank testing (Mantel–Cox statistic for the equality of survival distributions between the two groups). Hazard ratios and 95% confidence intervals were estimated with the Cox proportional-hazards model, with the proportional-hazards assumption tested for each model with the use of the graphical and numeric methods described by Lin et al.¹⁵ All the analyses were performed on an intention-to-treat basis with two-tailed tests. Because no procedure for type I error control was implemented for secondary end points, the results for these end points are reported as point estimates and confidence intervals only, without hypothesis testing. The widths of the confidence intervals have not been adjusted for multiple testing and therefore may not be used in place of hypothesis testing. The effect of the duration of endocrine therapy and the level of tumor ER on outcomes were prespecified exploratory end points.

Clinicians were asked to note on the annual clinical research form whether a patient was still taking adjuvant endocrine therapy, and if not, when the patient had stopped. This allowed an analysis of the data with adjuvant endocrine therapy as a time-varying covariate, in which the risk of local recurrence at time t for patients taking adjuvant endocrine therapy was compared with the risk for patients not taking adjuvant endocrine therapy at time t.

Post hoc subgroup analysis of local recurrence according to ER score was performed. Patients were classified as having either ER-high or ER-low tumors. Tumors were defined as ER-high if they had an Allred score of 7 or 8 (on a scale from 0 to 8, with higher scores indicating greater staining for ER), an ER level of at least 20 fmol per milligram of protein, or more than 50% of cells staining positive for ER, or when the only information available on the case-report form was classification as “+++” (indicating strong staining for ER), “strongly positive,” or “ER-positive.” Tumors without these characteristics were defined as ER-low. Data were analyzed with SPSS software, version 22 (IBM), and SAS software, version 9.4, for Windows (SAS Institute).

Results

Patients

Figure 1. Randomization and Follow-up.Table 1. Demographic and Clinical Characteristics of the Patients.

From April 16, 2003, to December 22, 2009, a total of 1326 patients underwent randomization; 658 were randomly assigned to receive postoperative irradiation, and 668 were assigned to receive no postoperative irradiation (Fig. 1). Patients were recruited from the United Kingdom (1263 patients), Greece (22 patients), Australia (16 patients), and Serbia (25 patients). Table 1 shows the baseline characteristics of the trial population, which were similar in the two treatment groups. The median age of the patients at trial entry was 70 years (interquartile range, 67 to 74), and less than 10% of patients had ER-low tumors. Of the 584 patients for whom radiotherapy data were available, 91 (15.6%) received a tumor-bed boost after whole-breast irradiation.

End Points

Figure 2. Local Recurrence, Distant Recurrence as the First Event, Breast Cancer–Specific Survival, and Overall Survival.

After 10 years of follow-up, the cumulative incidence of local recurrence was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (Fig. 2A). The hazard ratio for local recurrence (no radiotherapy vs. radiotherapy) was 10.4 (95% CI, 4.1 to 26.1; P<0.001) (full data, not censored at 10 years). Local recurrence of breast cancer developed in 51 patients assigned to no radiotherapy and in 5 patients assigned to radiotherapy. In the no-radiotherapy group, 48 of 51 local recurrences occurred as the first event, including 37 in patients who had only local recurrence.

The 10-year cumulative incidence of distant recurrence as the first event was 1.6% (95% CI, 0.4 to 2.8) without radiotherapy and 3.0% (95% CI, 1.4 to 4.5) with radiotherapy (Fig. 2B). No substantial differences at 10 years were noted in the cumulative incidence of regional recurrence, contralateral breast cancer (data not shown), or new cancers or in survival free from new cancer (Table S1 and Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

Disease-free survival at 10 years was 68.9% (95% CI, 64.7 to 73.0) in the no-radiotherapy group and 76.3% (95% CI, 72.5 to 80.2) in the radiotherapy group (Fig. S2). Breast cancer–specific survival at 10 years was 97.4% (95% CI, 96.0 to 98.8) among patients assigned to no radiotherapy and 97.9% (95% CI, 96.5 to 99.2) among patients assigned to radiotherapy (Fig. 2C). Sixteen deaths in the no-radiotherapy group and 15 deaths in the radiotherapy group were due to breast cancer (Table S2). Most causes of death were not breast cancer; 25% of all deaths (59 of 231) were due to cancers other than breast cancer. Overall survival at 10 years was 80.8% (95% CI, 77.2 to 84.3) in the no-radiotherapy group and 80.7% (95% CI, 76.9 to 84.3) in the radiotherapy group (Fig. 2D).

Subgroup Analysis

Figure 3. Local Recurrence According to Estrogen Receptor (ER) Status and Receipt of Radiotherapy.

In a subgroup analysis of local recurrence according to ER status, the cumulative incidence of local recurrence was lower among patients with ER-high cancers than in the overall trial population (Fig. 3). The 10-year cumulative incidence of local recurrence among patients with ER-high tumors was 8.6% (95% CI, 5.7 to 11.4) in the no-radiotherapy group and 1.0% (95% CI, 0.1 to 1.9) in the radiotherapy group (hazard ratio, 8.23; 95% CI, 3.24 to 20.85). The 10-year cumulative incidence of local recurrence among patients with ER-low tumors in the no-radiotherapy group was 19.1% (95% CI, 8.2 to 29.9) (hazard ratio [vs. patients with ER-high tumors in the radiotherapy group], 23.93; 95% CI, 8.43 to 67.93). No local recurrence was observed among patients with ER-low tumors in the radiotherapy group, but the sample was very small (53 patients). Data were collected on the duration of adjuvant endocrine therapy, and the time-dependent analysis showed an increased risk of local recurrence among patients in the no-radiotherapy group who were no longer taking endocrine therapy (hazard ratio [vs. patients who continued to take endocrine therapy], 4.66; 95% CI, 1.77 to 12.25). Other studies¹⁶ have shown that less than 80% adherence is associated with significantly decreased benefit from adjuvant endocrine therapy.

Discussion

In this trial involving older women with HR-positive breast cancer treated with adjuvant endocrine therapy, the 10-year incidence of local cancer recurrence after breast-conserving surgery was significantly lower among patients who received whole-breast irradiation than among those who did not receive irradiation. The incidence of local recurrence up to 10 years among patients who received radiotherapy remained low, whereas that among patients who did not receive radiotherapy continued to increase with no apparent plateau. However, the absolute difference in the incidence of local recurrence at 10 years was modest (8.6 percentage points). Despite this difference, irradiation had no substantial effect on the incidence of regional or distant metastases or on breast cancer–specific or overall survival. The low cumulative incidence of local recurrence at 10 years after breast-conserving surgery and irradiation is consistent with the results of the earlier Cancer and Leukemia Group B (CALGB) 9343 trial, which involved patients 70 years of age or older who had T1, node-negative, HR-positive tumors treated with breast-conserving surgery and tamoxifen⁸; in that trial, the incidence of local recurrence within 10 years was 7 percentage points lower among patients who received irradiation than among those who did not. Our observations in a higher-risk population show a similar between-group difference in the incidence of local recurrence. Earlier trials of irradiation after breast-conserving surgery,^17-23 apart from the Italian trial,²³ were not exclusive to older patients, which limited their generalizability to an older population.

The 9.5% cumulative incidence of local recurrence at 10 years among the patients who did not receive radiotherapy in our trial lies within range from the European Society of Mastology (EUSOMA) guidelines, which cited a maximum rate of locoregional recurrence of 10% at 10 years.²⁴ Our results are also consistent with the small benefit from irradiation that was found in the low-risk group of older patients in a meta-analysis of trials of adjuvant radiotherapy after breast-conserving surgery.⁴ EUSOMA guidelines recommend that patients older than 70 years of age receiving adjuvant endocrine therapy for low-risk tumors may be treated without irradiation,²⁵ similar to the recommendations of the U.K. National Institute for Health and Care Excellence²⁶ and the National Comprehensive Cancer Network guidelines, which allow omission of irradiation in women 65 years of age or older²⁶ or 70 years of age or older¹¹ with stage 1, ER-positive breast cancer after breast-conserving surgery. Our findings provide additional data indicating that although the omission of irradiation increases the cumulative incidence of local recurrence, it does not have a similar effect on distant disease–free or overall survival.

The applicability of these results to clinical practice will be influenced by the balance of the risks and benefits of radiation as compared with those of adjuvant endocrine therapy. Irradiation has associated complications, including cardiac events and second cancers.^27,28 We did not collect data on toxic effects of radiation in our trial. However, an analysis of treatment-related complications in the PRIME I trial, in which patients were also randomly assigned to receive or not receive irradiation after breast-conserving surgery, showed no difference in global quality of life between the two groups.^29,30 An increased risk of cardiovascular events has been reported in association with tamoxifen and aromatase inhibitors.³¹ In contemporary practice, higher-risk patients (i.e., those with T2 or grade 3 HR-positive tumors) are likely to be treated with an aromatase inhibitor as endocrine therapy rather than with tamoxifen. The results of the current trial are similar to those of the British Association of Surgical Oncology II trial,²⁰ in which local disease was controlled with tamoxifen or irradiation given alone. Viable options for patients who meet the entry criteria for our current trial are a short course of irradiation or adjuvant endocrine therapy. The advantage of endocrine therapy is that it also reduces the risk of cancer recurrence in the contralateral breast.

The risk–benefit ratio of irradiation and endocrine therapy in older patients with low-risk, ER-positive disease has become more nuanced,³² with hypofractionated dose schedules,³³ accelerated partial breast irradiation,³⁴ and improved delivery techniques.³⁵ Given the limitations of partial-breast irradiation (which demands localization of the treatment site and associated quality assurance) as compared with whole-breast irradiation, we concur with the view³⁶ that adjuvant endocrine therapy without irradiation is the principal competitor to whole-breast irradiation. For patients who do not receive irradiation and do have subsequent development of local recurrence, the option of further breast-conserving therapy and irradiation is available, so recurrence does not necessarily mean loss of the breast.

Women in either group in the current trial were more likely to die from other causes than from breast cancer. Of the 231 deaths that occurred, only 31 (13%) were due to breast cancer. Patients and clinicians can balance the harms and benefits of irradiation knowing that avoiding it does not increase the risk of death from breast cancer.

Few patients in the trial had grade 3 cancers (36 patients) or lymphovascular invasion (39 patients), and therefore whether radiotherapy can be avoided in these patients is not clear. On the basis of studies of neoadjuvant endocrine therapy (Dixon JM and Turnbull A: personal communication), ER-high grade 3 tumors do not respond less well than lower-grade tumors. However, the current trial was underpowered to detect any difference in local recurrence between grade 3 and grade 1 or 2 tumors. For grade 3 tumors and lymphovascular invasion, our estimates of effect size are not very precise as a result of low numbers. We can speculate that in selecting suitable patients for the trial, clinicians were cautious in enrolling patients with grade 3 tumors or lymphovascular invasion because the risk of local recurrence is doubled in patients who have cancer with grade 3 histologic features or lymphovascular invasion,^37,38 although the relevance of these characteristics as risk factors in older patients is unclear. Confining the option of omission of irradiation to grade 1 and 2 tumors is also in line with current European guidelines.^24,25 No grade 3 tumors were included in the CALGB 9343 trial.⁸

Our data are consistent with an earlier observation⁹ that patients with ER-high cancers have a lower cumulative incidence of local recurrence at 10 years than do patients with ER-low cancers (Fig. 3). The percentage of patients who completed 5 years of endocrine therapy was between 60% and 70%. Patients who are less than 80% adherent to endocrine therapy are thought to have poorer outcomes.^16,39 We did not collect data on adherence. Instead, using the reported end of endocrine therapy as a surrogate measure, we found a risk of local recurrence that was 4 times as high among patients who were not taking endocrine therapy as among those who continued the therapy in the no-radiotherapy group.

Our trial has some limitations. We did not collect data on coexisting conditions or monitor adherence to endocrine therapy prospectively. Omission of postoperative irradiation after breast-conserving surgery and adjuvant endocrine therapy for ER-positive tumors varies and is influenced by coexisting conditions. Relatively high levels of use of irradiation for such patients have been reported from nonrandomized studies conducted in the United States.¹³

Our trial provides robust evidence indicating that irradiation can be safely omitted in women 65 years of age or older who have grade 1 or 2, ER-high cancers treated by breast-conserving therapy, provided that they receive 5 years of adjuvant endocrine therapy.

Source: NEJM

Diagnosis and management of patients with polyneuropathy

Posted by zedie

KEY POINTS

Polyneuropathy is a common neurologic condition with a variety of subtypes that involve the motor, sensory or autonomic fibres.
Distal symmetric polyneuropathy is the most common subtype of polyneuropathy; it classically presents with sensory-predominant, length-dependent symptoms and signs.
Clinical features such as acute-to-subacute onset, asymmetry, non–length dependence, motor-predominant signs and associated systemic features should prompt urgent neuromuscular referral for investigation of polyneuropathy.
Most causes of distal symmetric polyneuropathy can be identified through evaluation of a patient’s medical history; some causes are identified with screening laboratory tests.
First-line oral treatment options for the symptoms of painful diabetic neuropathy are tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, sodium-channel blockers, and gabapentinoids, which all appear to be similarly effective.

Polyneuropathy is a common neurologic condition with an overall prevalence in the general population of about 1%–3%, increasing to roughly 7% among people older than 65 years.1 Polyneuropathy has many causes, and can present in many different ways; thus, it requires a logical clinical approach for evaluation, diagnosis and management. We review the approach to evaluating a patient with polyneuropathy by highlighting important aspects of the history and neurologic examination. We focus on the role of diagnostic investigations for distal symmetric polyneuropathy (DSP), the most common subtype, and an approach to the symptomatic treatment of painful diabetic polyneuropathy (PDN). We draw on practice-based guidelines, meta-analyses and systematic reviews, where possible, as they represent the highest levels of evidence (Box 1).

Box 1: Search strategy for this review

Using PubMed, we screened all publications from the last 10 years that pertained to the management of polyneuropathy in the primary or urgent care setting, using the search terms “polyneuropathy,” “peripheral neuropathy,” and “management.” We reviewed those that were relevant to the subject, and emphasized practice guidelines, meta-analyses and reviews. For practice guidelines, we extended this search to the last 20 years and reviewed the references of each included guideline for potential inclusion.

What are the clinical features of a polyneuropathy?

Symptoms of polyneuropathy can be categorized by whether they involve sensory, motor or autonomic fibres. Sensory fibres include large-diameter fibres, which mediate vibratory sensation and proprioception, and small-diameter fibres, which mediate pain and temperature sensation. Both modalities should be examined because their relative impairment is a clue to the cause. Dysfunction of either type of sensory fibre can result in sensory alteration, which can range from paresthesias, described as “pins and needles” (positive sensory symptoms), to substantial or complete loss of sensation, known respectively as hypoesthesia and anesthesia (negative sensory symptoms). Large fibre sensory dysfunction may result in gait impairment caused by loss of proprioception (sensory ataxia). Small fibre sensory dysfunction most often causes pain, with some patients having hyperesthesia, an accentuated sensation of tactile stimulation, or allodynia, the perception of normally nonpainful stimuli as painful. Spontaneous episodes of pain can be accompanied by redness and swelling of the affected skin owing to the transmission of unprovoked pain signals by damaged sensory C-fibres, which also release vasoactive substances that cause neurogenic inflammation.2 Additional small-fibre sensory symptoms include deep aching, postexertional malaise and neuropathic itch.3 In contrast, patients with involvement of the motor fibres will primarily describe weakness, which may manifest as loss of dexterity, gait disturbance or both. Autonomic symptoms caused by neuropathy may be underrecognized because these symptoms may have many other causes. Common autonomic symptoms include orthostatic intolerance, gastroparesis, constipation, diarrhea, neurogenic bladder, sexual dysfunction, pupillomotor (i.e., blurry vision) symptoms and vasomotor symptoms, which can lead to dry eyes, mouth or skin, or burning and flushing of the skin.4

Distal symmetric polyneuropathy is the most common subtype of polyneuropathy and is characterized by a length-dependent process whereby the longest nerves are affected first. Findings include symmetric distal weakness with sensory loss (small fibres, large fibres or both) and diminished or absent ankle reflexes.5 Sensory loss begins in the feet, in a nondermatomal, multiple nerve distribution.5 When sensory symptoms or signs reach the upper calf, the fingertips become affected as the nerve lengths in these areas are roughly equivalent; this is known as the glove and stocking pattern of sensory loss.6 In severe cases, this pattern is followed by sensory loss in the midline anterior chest and abdomen, owing to distal degeneration of the thoracic intercostal nerves. Weakness occurs after sensory loss, first affecting toe extension, then ankle dorsiflexion.6 Autonomic symptoms may occur if small sensory fibres are also affected, and typically begin distally, with sweating abnormalities or circulatory instability of the feet.5

Clinicians should be aware of conditions that may mimic polyneuropathy, particularly cervical myelopathy, which can present with a pyramidal distribution of weakness (i.e., preferential weakness of upper limb extensors and lower limb flexors), hyperreflexia below the level of the lesion, a sensory level, and bladder and bowel dysfunction. Acute causes of myelopathy, including cord compression or ischemic infarction, can present with loss of reflexes at and below the level of the lesion.

How should patients be assessed?

An approach to the clinical assessment of a patient with possible polyneuropathy, and a guide for which patients to refer urgently to a specialist, is provided in Figure 1. Patients with certain symptoms and signs require urgent onward referral, and recognizing subtypes of polyneuropathy and important differential diagnoses is important to direct management.

Figure 1:

Approach to assessing a patient with suspected polyneuropathy. *Screening positive on ODS increases likelihood of an inflammatory cause or other treatable neuropathy. Note: ODS = onset, distribution and systemic features tool.

Patients with neuropathies with an acute (evolving over days) to subacute (evolving over weeks) onset, with plateauing of symptoms (stability of accrued neurological deficits) within 8 weeks from symptom onset, require urgent referral to a neuromuscular specialist.7 This also applies to peripheral neuropathies with hyperacute onset of symptoms (e.g., wrist or foot drop) as they raise concern for a vasculitic process. Patients with acute neuropathy who have substantial pain or associated trauma may require urgent management via the emergency department.

Additional patterns that are highly suggestive of vasculitic neuropathy include rapidly progressive, painful polyneuropathy and multiple concurrent mononeuropathies (mononeuritis multiplex), where mononeuropathy is defined as signs or symptoms attributable to 1 nerve.8 A non–length-dependent pattern with both proximal and distal weakness may indicate an inflammatory demyelinating process, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), particularly if motor deficits are comparable to or greater than sensory deficits. A less common diabetic neuropathy, diabetic lumbosacral radiculoplexus neuropathy, is a painful, rapidly evolving, asymmetric lower limb neuropathy that can cause severe morbidity.

The differential diagnoses for subtypes of polyneuropathy are listed in Table 1. A patient with diffuse areflexia without other neurologic deficits on neurologic examination, may require referral given the possibility of a hereditary cause. Isolated, asymmetric reflexes, such as the loss of only 1 ankle reflex, may suggest a mononeuropathy or radiculopathy, for which non-urgent referral for neuromuscular evaluation is appropriate. Distal calf atrophy, hammer toes and pes cavus (high-arched feet) are characteristic of a long-standing neuropathy, often seen in hereditary neuropathies (Figure 2).

Table 1:

Differential diagnoses for subtypes of polyneuropathy9

Figure 2:

Photographs of a patient with chronic polyneuropathy from Charcot–Marie–Tooth disease, with findings of (A) atrophy of the distal leg and foot musculature; (B) pes cavus (high arch), hammer toes and skin discolouration on the feet; and (C) severe atrophy of intrinsic hand muscles (including the lumbricals) with relative preservation of forearm muscles, resulting in metacarpophalangeal hyperextension and proximal interphalangeal and distal interphalangeal flexion, referred to as “claw hands.”

A diagnostic screening tool using onset, distribution and systemic features can be used to accurately identify patients with inflammatory neuropathies. Patients who screen positive using this tool have 1 or more of the following features: acute or subacute onset (< 8 wk to reach plateau), non–length-dependent distribution or at least 1 systemic sign (skin changes, weight loss, autonomic symptoms, fever and chills, or joint inflammation).7 The screening tool is 96% sensitive and 85% specific in identifying inflammatory neuropathies, including Guillain–Barré syndrome, CIDP (and its subtypes), multifocal motor neuropathies, vasculitic neuropathies and paraneoplastic neuropathies.7 Systemic findings in a patient with an axonal neuropathy would also prompt referral to a neuromuscular specialist. Prompt recognition and treatment is important as prolonged duration of disease without adequate treatment of these neuropathies can lead to serious morbidity.

Electrophysiological studies can assist with diagnosis and guide management and clinical follow-up. In many parts of Canada, it is difficult to access a neuromuscular subspecialist in a timely manner and the patient should be referred to a general neurologist. Patients with suspected Guillain–Barré syndrome should be referred to their local emergency department for evaluation and consideration of admission to the hospital because of the possibility of progressive weakness, respiratory failure and dysautonomia. Urgent electrodiagnostic evaluation is indicated, as testing can confirm the diagnosis and lead to specific and definitive management.10

What tests aid in the diagnosis of distal symmetric polyneuropathy?

The presence of neuropathic symptoms and signs, and of electrodiagnostic findings provide the highest level of accuracy for the diagnosis of DSP.5 Findings on physical examination include decreased or absent ankle reflexes, decreased distal sensation, and distal muscle weakness or atrophy. Neuropathic symptoms alone have relatively poor diagnostic accuracy; signs are better predictors and should be weighed more heavily.5 Electrodiagnostic studies provide a higher level of specificity to the clinical diagnosis.11^,12

Whether all patients with suspected DSP should receive electrodiagnostic evaluation is unclear. Four observational studies found that electrodiagnostic evaluation was associated with a change in diagnosis, management or both for more than 40% of patients, but only 1 study was focused on patients referred for DSP.13^–16 However, a retrospective cohort study found a change in management in fewer than 1% of patients with DSP seen by community neurologists.17 These disparate findings likely reflect the exclusion of many other types of neuropathies in this study, as more than 80% of study patients had a neuropathy attributed to abnormal glucose metabolism.18

We suggest performing electrodiagnostic evaluation for most patients who present with polyneuropathy, including DSP, especially if the cause is not established. Nerve conduction studies and electromyography allow the electromyographer to categorize the polyneuropathy as primary axonal or demyelinating; motor, sensory or both; or acquired or inherited. All of these categories have important implications for determinining cause and management.9 For example, distal acquired demyelinating symmetric polyneuropathy, a variant of CIDP, presents like DSP but requires relevant investigations for mimics and often requires treatment with immunotherapy.19 Additional valuable information obtained from nerve conduction studies and electromyography includes chronicity, prognosis and, in some circumstances, response to therapy.

Patients with exclusively small-fibre sensory neuropathy will have normal findings on electrodiagnostic studies because these tests evaluate function of only motor and large sensory fibres. Skin biopsy with measurement of the intraepidermal nerve fibre density is a validated, reproducible marker of small-fibre sensory pathology.20 This is the gold standard test for the diagnosis of small-fibre neuropathy, as recommended by the American Academy of Neurology (AAN), with a sensitivity of 45%–90% and specificity of 95%–97%.21 However, its availability and reimbursement vary widely across Canada, thereby limiting its use. The AAN practice guideline also recommends that clinicians consider autonomic testing (i.e., sudomotor, cardiovagal and vasomotor adrenergic testing) in the evaluation of patients with suspected autonomic neuropathies and in those with small-fibre sensory neuropathies.21 Nerve biopsy is useful when vasculitis, sarcoidosis and infiltrative disorders (such as malignant disease or amyloidosis) are suspected.

How is the cause of an acquired distal symmetric polyneuropathy determined?

The history and neurologic examination are paramount in determining the cause of DSP. Overall, nearly 60% of patients will have an identified cause after history and physical examination for DSP; screening laboratory tests can be used to discover a cause in an additional 10% of patients, leaving around 30% of cases as idiopathic.6^,22^,23 Chronic idiopathic axonal neuropathy is the term reserved for ambulatory patients who have a slowly progressive polyneuropathy, typically after the age of 60 years.24

Common causes of DSP include diabetes, history of alcohol use disorder, renal impairment and medications, including chemotherapy, with diabetes being the most common (Table 2).26 About 40%–50% of patients with diabetes mellitus will develop a detectable neuropathy within 10 years after onset.27 However, other treatable causes for DSP should still be considered among patients with diabetes.27^–29 Alcohol-related neuropathy is an irreversible, slowly progressive DSP that is likely mediated by a combination of direct toxic effects and secondary vitamin deficiency, such as a B₁ or B₁₂ deficiency.25 Uremic neuropathy occurs in as many as 90% of patients with a glomerular filtration rate below 6 mL/min/1.73 m².30 Medications and chemotherapy agents can also cause DSP (Table 2).

Table 2:

Common medications associated with polyneuropathy25

Screening laboratory tests are routinely used for patients with DSP to test for treatable causes. The AAN practice guideline recommends high-yield screening laboratory tests for all patients with DSP (summarized in Box 2).31

Box 2: High-yield screening laboratory tests for distal symmetric polyneuropathy

Complete blood cell count
Serum sodium, potassium, chloride and bicarbonate
Serum urea and creatinine
Liver function tests
Fasting blood glucose and hemoglobin A_1c*
Serum protein electrophoresis
Vitamin B₁₂ with or without methylmalonic acid†

↵* Two-hour glucose tolerance test is recommended if hemoglobin A_1c is 6.0%–6.4%.31
↵† Methylmalonic acid (normal range 0.1–0.4 μmol/L) is recommended if vitamin B₁₂ level is 150–300 (normal range 145–569) pmol/L.

What is the approach to symptomatic treatment of painful neuropathy?

In general, the treatment of chronic neuropathic pain is not influenced by the cause, as limited evidence exists to suggest that specific medications are more effective for specific disorder.32 Notable exceptions include trigeminal neuralgia and cancer-related neuropathic pain. The Special Interest Group on Neuropathic Pain published an international guideline on pharmacotherapy for neuropathic pain.32 A more recent comprehensive guideline from France provides recommendations on pharmacological and nonpharmacological treatment for focal, central or diffuse peripheral neuropathic pain.33

Much of the literature for the symptomatic treatment of painful neuropathy is derived from studies on patients with PDN. Neuropathic pain is one of the most disabling symptoms for these patients.34 It occurs in about 40%–60% of patients with diabetes and neuropathy, yet few patients are treated for pain despite the availability of effective treatments.35^,36

The AAN practice guideline on symptomatic treatment of PDN was derived from a meta-analysis that included only randomized controlled trials with a maximum duration of active treatment of 16 weeks.37 Most clinical trials quantified successful treatment as a 30% reduction in pain,37 and few patients achieve more than a 50% reduction with any single drug.38 Patients should therefore be counselled that the goal of therapy is to reduce, not eliminate, pain to align patients’ expectations with the expected efficacy of interventions.38 Evidence from this meta-analysis showed that 4 classes of oral medications reduce pain, namely tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors (SNRIs), sodium-channel blockers and gabapentinoids. The effect sizes were similar among the 4 classes of medications and all are options for first-line monotherapy among patients with PDN.37 Given the similar efficacy of these medications, clinicians should consider their adverse effect profile and cost, as well as patient comorbidities to determine the first-line oral agent.

Opioids can provide short-term pain reduction in patients with PDN, but the evidence that they are effective in the long term is weak.39^,40 Opioids and opioids combined with SNRIs are discouraged for long-term management owing to lack of efficacy, high dependence rates and dose-dependent risk of serious adverse effects.27^,37^,38 Cannabis-based medicines, including nabilone, a synthetic cannabinoid, may help improve neuropathic pain; however, more studies are needed as their benefits may be outweighed by their potential harms.37^,41^,42

Clinicians should assess the efficacy of first-line therapy after the medication has been titrated to an efficacious dose for 6–12 weeks.37^,43 The OPTION-DM trial, a multicentre, randomized, double-blind trial, compared the efficacy of combination therapies (amitriptyline with pregabalin, pregabalin with amitriptyline or duloxetine with pregabalin) for the primary outcome of pain relief and for secondary outcomes (including quality of life, mood and sleep) among patients with PDN. Combination therapies for patients who did not respond to monotherapy at 6 weeks had similar efficacy across primary and secondary outcomes.43 This trial provides evidence for using combination therapy of first-line medications for patients with PDN if they have suboptimal response to monotherapy. It is also important to assess and treat comorbid mood and sleep disorders, and consider topical or nonpharmacological interventions.37

Conclusion

The diagnosis and management of patients who present with polyneuropathy requires a systematic approach. Distal symmetric polyneuropathy, the most common subtype, is characterized by a combination of neuropathic symptoms and findings on physical examination and electrodiagnostic testing. Most causes of DSP can be identified after an evaluation of a patient’s medical history and completion of high-yield screening laboratory tests, but some patients will be classified as idiopathic. Patients with diabetic neuropathic pain should be offered symptomatic pharmacological options, which are effective at reducing pain but not eliminating it. Future research should address key gaps in our current knowledge of symptomatic treatment of neuropathic pain caused by polyneuropathy (Box 3).

Box 3: Unanswered questions

Should all patients with symptoms and signs consistent with distal symmetric polyneuropathy and a known cause be referred for nerve conduction studies and electromyography for diagnostic confirmation?
What is the threshold for additional laboratory testing beyond high-yield screening tests among patients with progressive symptoms and signs of polyneuropathy?
Do all patients with only symptoms of isolated small-fibre neuropathy require a skin biopsy, given its wide differential diagnosis?
What management strategies are best for neuropathic pain caused by polyneuropathy?

The compatibility of oxytocin and tranexamic acid injection products when mixed for co-administration by infusion for the treatment of postpartum haemorrhage: An in vitro investigation

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Abstract

Objective

To investigate the compatibility of oxytocin and tranexamic acid injection products when mixed for the purpose of co-administration by intravenous infusion.

Design

Compatibility testing.

Setting

Hospitals taking part in a multicentre postpartum haemorrhage treatment (E-MOTIVE) trial in Kenya, Nigeria, Tanzania and South Africa.

Sample

Oxytocin and tranexamic acid products.

Methods

The compatibility of two sentinel products of oxytocin injection and tranexamic acid injection in 200-mL infusion bags of both 0.9% w/v saline and Ringer’s lactate solution was assessed. We analysed all tranexamic acid–oxytocin combinations, and each evaluation was conducted for up to 3 h. Subsequently, the compatibility of multiple tranexamic acid products with reference oxytocin products when mixed in 0.9% w/v saline over a period of 1 h was investigated.

Main outcome measures

Concentration of oxytocin over time after mixing with tranexamic acid products.

Results

We found significant interaction between certain oxytocin and tranexamic acid products after mixing them in vitro and observing for 1 h. The interaction substantially impacted oxytocin content leading to reduction in concentration (14.8%–29.0%) immediately on mixing (t = 0 min). In some combinations, the concentration continued to decline throughout the stability assessment period. Oxytocin loss was observed in 7 out of 22 (32%) of combinations tested.

Conclusions

In a clinical setting, mixing certain oxytocin and tranexamic acid products before administration may result in an underdosing of oxytocin, compromising care in an emergency life-threatening situation. The mixing of oxytocin and tranexamic acid injection products for co-administration with intravenous infusion fluids should be avoided until the exact nature of the observed interaction and its implications are understood.

1 INTRODUCTION

The World Health Organization (WHO) has defined a postpartum haemorrhage (PPH) ‘first-response’ treatment bundle based on evidence, current recommendations and international consensus.¹ The bundle comprises four key elements: uterotonic drugs, tranexamic acid (TXA), intravenous (IV) fluids and uterine massage. This treatment bundle has been developed further with the introduction of the E-MOTIVE intervention to improve the detection and first-response management of PPH, which consists of: (1) early PPH detection using a calibrated drape; (2) massage of the uterus; (3) oxytocic drugs; (4) TXA; (5) IV fluids; and (6) an examination of the genital tract and escalation, when necessary.² The E-MOTIVE intervention is currently being evaluated in Kenya, Nigeria, Pakistan, South Africa and Tanzania.

A key implementation approach that we have explored for the use of the E-MOTIVE bundle is the co-administration (infusion) of the oxytocin (OXY) and TXA components with IV fluids. This approach could simplify administration, which may be particularly important in resource-constrained settings with limited numbers of healthcare practitioners to attend a PPH emergency. Following an extensive literature review, no reports were identified providing evidence of the compatibility of OXY and TXA when mixed for intravenous administration. Therefore, the aim of this study was to conduct a preliminary investigation of the compatibility of OXY and TXA injection products when mixed for the purpose of co-administration by IV infusion as part of the treatment bundle for PPH. We used products collected from clinical sites supporting the E-MOTIVE implementation research project. We previously reported on the quality of individual OXY and TXA injection products, sampled from E-MOTIVE sites in Kenya, Nigeria, South Africa and Tanzania.³ All samples selected for the study were tested for assay and related substances according to the British Pharmacopoeia (BP). For part 1, both OXY products and one TXA product met the BP assay and related substances specifications, and one TXA product had a significant level of impurities. For part 2, all OXY samples met BP assay and related substances specifications. Five TXA samples showed a significant level of impurities, one of which was out of specification for TXA potency and one sample was quality assured (originator product).

2 METHODS

The study was conducted in two stages. First, we developed an analytical methodology to assess the compatibility of the two sentinel products of OXY injection (10 IU/mL) and TXA injection (100 mg/mL) in 200-mL infusion bags of both 0.9% w/v saline IV bags (1-L freeflex®; Fresenius Kabi, Bad Homburg, Germany) and Hartmann’s (Ringer’s) lactate solution IV bags (1-L freeflex®; Fresenius Kabi). We analysed all TXA–OXY combinations, and each evaluation was conducted for up to 3 h. Based on the results from these investigations, the second stage screened the compatibility of multiple TXA products with reference OXY products (5 and 10 IU/mL) when mixed in 0.9% w/v saline in glass vials over a period of 1 h.

2.1 Sample collection

Samples were collected from health facilities in Kenya, Nigeria, South Africa, and Tanzania that had participated in the E-MOTIVE study. Local ethical approvals for the study, including the shipment and quality measurement of the OXY and TXA samples, were acquired. The facilities provided ten ampoules of OXY (one package) and, if available, ten ampoules of TXA (two packages). Ampoules came from the same batch, in their original packaging, not opened and with at least 6 months left before the expiry date. After local collection in each country, the samples were then shipped to Monash University, Australia, at 2–8°C in the presence of a temperature logger. The quality of all OXY and TXA samples collected is described by Ammerdorffer et al.,³ and a subset of these samples were used in the current study.

In total, four samples of OXY and 20 samples of TXA were tested:

two OXY samples and two TXA samples were tested during study 1, resulting in two different OXY–TXA combinations;
two OXY samples and 18 TXA samples were tested during study 2, resulting in 19 different OXY–TXA combinations.

2.2 Analytical methodology

2.2.1 OXY analysis

Analysis of OXY was conducted using a validated reversed-phase liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Reversed-phase chromatography was performed using an XSelect CSH C18 column (2.1 × 50 mm, 2.5 μm particle size; Waters, Milford, MA, USA) and a 0.1% formic acid/acetonitrile gradient at a flow rate of 0.5 mL/min. The injection volume was 8 μL and the total run time was 6 min. The analyses were performed on an LCMS-8060 instrument (Shimadzu, Kyoto, Japan) in positive electrospray ionization (ESI) mode using multiple reaction monitoring (MRM). Parent/daughter transitions acquired for quantitation were 1007.4 → 723.3 (single charge) and 504.3 → 285.2 (double charge). The validated range was 20–100 ng/mL OXY using external standard quantitation. It should be noted that an LC-MS/MS method was used in preference to pharmacopoeial methods to provide the necessary sensitivity to quantify the low concentrations of OXY present when ampoules are further diluted in preparations for infusion use.

2.2.2 TXA analysis

Analysis of TXA was conducted using a high-performance liquid chromatography (HPLC) assay based on the BP 2019 method. Briefly, chromatography was performed on a Shimadzu Nexera UHPLC system using an Agilent Zorbax Eclipse Plus C18 column (4.6 × 250 mm, 5 μm particle size). The mobile phase comprised 0.1 M anhydrous sodium dihydrogen phosphate dissolved in 60:40 water:methanol and adjusted to pH 2.5 with phosphoric acid. Sodium dodecyl sulphate (SDS, 5 mM) was added as an ion-pairing reagent and separation was performed in isocratic mode at a flow rate of 0.9 mL/min using a 20-μL injection volume. TXA for injection samples (100 mg/mL) were diluted 1:20 to bring them within the validated range of the method (2.5–6.0 mg/mL).

2.2.3 Method verification

Prior to commencing the study, both methods were evaluated to verify that the presence of each active substance did not interfere with the quantitation of the other in both 0.9% w/v saline and Ringer’s lactate solutions (selectivity). Additional method verification was undertaken to demonstrate that the validated parameters, accuracy, precision, linearity, carry-over and matrix effect were not affected by the mixing of OXY and TXA.

2.3 Study methods

2.3.1 Study methods (part 1)

Materials

Two batches of each OXY injection 10 IU/mL and TXA injection 100 mg/mL were used in part 1 of the study, as shown in Table 1. These batches were collected from sites in Kenya and Nigeria supporting the E-MOTIVE trial. Prior analysis of these batches of product had shown that all batches were within their expiry date. Both OXY products and one TXA product met the BP assay and related substances specifications, and one TXA product had a significant level of impurities. Neither the OXY nor TXA products were quality assured, under the definition of having been assessed and listed by WHO under the prequalification of medicines programme or approved by a stringent regulatory authority (SRA). TABLE 1. Product details of the 1-mL ampoules of OXY and 5-mL ampoules of TXA used in part 1 of the study.

Batch ID	Product conc.	Expiry date	Assayed potency (%)	Related substances	Country of manufacture
OXY A	10 IU/mL	01/2022	104.6–105.35	Complies with BP	China
OXY B	10 IU/mL	01/2022	100.7–100.9	Complies with BP	India
TXA A	100 mg/mL	04/2023	100.9–102.1	4 unknown impurities > 0.1% Total impurities = 477% (peak area)^a	Pakistan
TXA B	100 mg/mL	06/2022	98.6–100.0	Complies with BP^b	India

^a Representative chromatogram is included in Figure 1D.
^b Representative chromatogram is included in Figure 1E.

Methods

In each experiment, duplicate glass volumetric flasks containing 200 mL of either 0.9% w/v saline solution or Ringer’s lactate solution were accurately prepared. A 200-mL volume was selected as this was reported to be the smallest volume of IV fluids used at the E-MOTIVE implementation sites. Therefore, this volume is likely to represent the greatest risk if compatibility issues exist, as it will lead to the highest concentration of active compounds once added to the IV solution.

Into each flask, one 1-mL ampoule of OXY (10 IU, approx. 17 μg) and two 5-mL ampoules of TXA injection (1000 mg) were added and the bulk solution mixed vigorously. These doses are the ‘standard of care’ and are used at the E-MOTIVE implementation sites. Upon completion of mixing, 1 mL of solution was immediately removed for analysis from the duplicate solutions and the remaining bulk solutions were transferred to an empty IV infusion bag. The bag was stored under ambient conditions and further duplicate samples were taken over a period of 3 h.

The following two combinations of products were evaluated in these experiment: OXY A with TXA A and OXY B with TXA B.

Based on the results of these experiments, the compatibility of the reverse combinations of products was then evaluated, specifically OXY A with TXA B and OXY B with TXA A. However, in these experiments, the bulk solutions, once mixed, were not transferred into IV infusion bags, but were stored under ambient conditions in the glass volumetric flasks in which they were prepared. This change was made to eliminate the possibility of surface effects (e.g. adhesion, adsorption, etc.) within the bags. In addition, the stability of the solutions in terms of the OXY concentration only was evaluated for a reduced period of approximately 30 min, reflecting the results observed in the first experimental series.

2.3.2 Study methods (part 2)

The second part of the study involved a comprehensive screening of a wider range of TXA injection products collected from the E-MOTIVE implementation sites in Kenya, Nigeria, South Africa and Tanzania. Compatibility was assessed against two OXY injection products, one collected from South Africa and one available in-house.

Materials

Individual batches of two OXY products and 18 TXA products of 100 mg/mL were used in part 2 of the study, as shown in Table 2. All batches were tested for quality against the BP specifications for assay and related substances prior to starting the study. Both OXY products passed quality testing against the BP specification in terms of assay and related substances, but neither was quality assured through a listing under the WHO prequalification programme or through approval by an SRA. The TXA products marked with a single asterisk failed quality testing in terms of TXA content, whereas TXA products marked with two asterisks failed total impurity specifications. One TXA product (TXA 8) was quality assured and had been manufactured by the innovator company. TABLE 2. Product details of the 1-mL ampoules of OXY and 5-mL ampoules of TXA used in part 2 of the study.

Batch ID	Product conc	Expiry date	Assayed potency (%)	Related substances	Country of manufacture
OXY 1	5 IU/mL	September 22	100.4–100.5	Complies with BP	India
OXY 2	10 IU/mL	September 24	95.7–96.0	Complies with BP	South Africa
TXA 1	100 mg/mL	May 23	98.3–98.6	Complies with BP	India
TXA 2	100 mg/mL	June 23	99.9–100.2	Complies with BP	India
TXA 3	100 mg/mL	June 22	102.7–103.3	Complies with BP	India
TXA 4	100 mg/mL	August 24	98.1–98.5^a	4 unknown impurities > 0.1% Total impurities = 466% (peak area)	Pakistan
TXA 5	100 mg/mL	March 23	98.2–98.7	Complies with BP	Pakistan
TXA 6	100 mg/mL	July 23	99.0–99.7	Complies with BP	India
TXA 7	100 mg/mL	March 24	96.5–97.8	Complies with BP	India
TXA 8	100 mg/mL	August 23	97.9–98.4	Complies with BP	South Africa
TXA 9	100 mg/mL	February 24	97.6–98.4	Complies with BP	India
TXA 10	100 mg/mL	June 23	97.6–98.0	Complies with BP	Cyprus
TXA 11	100 mg/mL	December 22	97.4–102.0^a	6 unknown impurities > 0.1% Total impurities = 153% (peak area)	India
TXA 12	100 mg/mL	August 24	103.8–104.7^a	5 unknown impurities > 0.1% Total impurities = 161% (peak area)	India
TXA 13	100 mg/mL	February 24	103.2–104.3	Complies with BP	India
TXA 14	100 mg/mL	June 24	98.9–99.7^a	3 unknown impurities > 0.1% Total impurities = 1.3% (peak area)	India
TXA 15	100 mg/mL	June 24	99.1–99.4^a	2 unknown impurities > 0.1% Total impurities = 1.2% (peak area)	India
TXA 16	100 mg/mL	November 23	101.6–102.6^a	Related Cpd A > 0.1% 2 unknown impurities > 0.1% Total impurities = 1.0% (peak area)	Pakistan
TXA 17	100 mg/mL	June 24	98.8–99.3^a	2 unknown impurities > 0.1% Total impurities = 1.2% (peak area)	India
TXA 18	100 mg/mL	July 24	93.6–99.3^b	Complies with BP	India

^a Failed total impurity specifications.
^b Failed quality testing in terms of TXA content.

Methods

In part 2 of the study, the following adaptations were made to the study methodology.

Mixing was conducted in a deactivated glass HPLC vial to minimise the possibility of surface interactions and accommodate limited sample quantities.
Test mixtures were prepared in 0.9% w/v saline only, as no differences between saline solution and Ringer’s lactate solution were observed in the first part of the study.
Only OXY concentration was assayed, as the results from part 1 had provided no indication that TXA concentration is compromised by co-mixing.
With the limited availability of the product, only single samples of product combinations prepared in saline were analysed.

A 1.0-mL volume of 0.9% w/v saline solution was accurately pipetted into a deactivated glass HPLC vial. An accurately pipetted aliquot of OXY injection solution was added to the saline solution in the HPLC vial and the solution vortex mixed. The volume of OXY injection solution added was 20 μL for experiments using OXY 1 (5 IU/mL) and 10 μL for OXY 2 (10 IU/mL), to accommodate the different concentration strengths of the two products. Following the addition of OXY, a 100-μL aliquot of TXA injection solution was accurately measured into the HPLC vial and the solution vortex mixed. This provides solution concentrations for both active compounds comparable with those used in part 1 of the study. Upon completion of mixing, the HPLC vial was placed immediately into the LC-MS/MS equipment and the assay process started with samples analysed at t = 0 min and every 10 min thereafter over a 1-h period.

In total, 19 combinations of OXY and TXA in saline solution were evaluated. All 18 TXA products were assessed in combination with the OXY 1 product, whereas a combination of TXA 8 and OXY 2 was assessed to evaluate a specific combination of interest to the E-MOTIVE trial.

3 RESULTS

3.1 Study part 1

The results derived from the initial combinations evaluated (OXY A/TXA A and OXY B.TXA B) were inconsistent in terms of OXY concentration over the time evaluated. In the OXY A/TXA A combination solutions, using both diluents, the OXY concentration was observed to decline rapidly, becoming undetectable by the assay method within 1 h (Figure 1A). The experiment was stopped upon observation of this phenomenon and did not continue to 3 h as originally planned. No significant change in TXA concentration was observed across the duration of the study.

Details are in the caption following the image — **FIGURE 1**Open in figure viewer PowerPoint OXY concentration over time (three combinations) and HPLC chromatograms of TXA A and TXA B (results, part 1). (A) OXY concentration over time (OXY A/TXA A combination) in duplicate samples prepared in 0.9% w/v saline solution and Ringer’s lactate solution. (B) OXY concentration over time (OXY B/TXA B combination) in duplicate samples prepared in 0.9% w/v saline solution and Ringer’s lactate solution. (C) OXY concentration over time (OXY A/TXA B and OXY B/TXA A) in duplicate samples prepared in 0.9% w/v saline solution. The axis of 1(A), 1(B) and 1(C) are OXY concentration (ng/mL) and time after mixing. (D) HPLC chromatogram of TXA A, with the unknown excipient/impurity components observed in this formulation encircled in red. (E) HPLC chromatogram of TXA B. The axis of 1(D) and 1(E) are Peak Height (mAU) and Time.

It is noted that the OXY concentrations at t = 0 showed significant variation between experiments. This warrants further investigation; however, it should be noted that although samples ate t = 0 are taken immediately upon completion of mixing, there is necessarily a time period to prepare and transfer the sample for LC-MS/MS analysis in which any interaction will continue to occur, and this may vary between samples.

The second combination evaluated (OXY B/TXA B) showed a modest drop in OXY concentration immediately after the addition of the mixed solution to the IV infusion bag; however, unlike the first combination, the OXY concentration remained stable thereafter (Figure 1B). The TXA concentration across samples in this second experiment remained stable throughout.

The compatibility of the reverse combinations (OXY A/TXA B and OXY B/TXA A) was evaluated in terms of OXY concentration when mixed in glass vials over a period of 30 min. The results show that the OXY B/TXA A combination showed a similar rapid decline in OXY concentration to that observed with OXY A/TXA A, whereas the OXY concentration remained stable in OXY A/TXA B (Figure 1C).

The HPLC chromatograms of TXA A and TXA B were reviewed to look for differences that might correlate with these observations. These chromatograms are shown in Figure 1D,E. Although both TXA products met BP assay and related substances specifications, it is clear that TXA A contains significantly more impurities than TXA B. In particular, a pair of early eluting peaks observed at approx. 5.5 and approx. 7.5 min (circled in Figure 1D) were several times larger than the main TXA peak by area. This offers one possible line of enquiry to explain the results observed, specifically that these impurities in TXA A, and possibly other impurities not detected by the HPLC method, interact with OXY on mixing to reduce its solution concentration.

3.2 Study part 2

The results for the 19 combinations of OXY and TXA injection products evaluated over a period of 1 h are shown in Table 3. Five of the 19 combinations of products showed a significant decrease in OXY concentration immediately on mixing, such that the OXY concentration at the start of the stability assessment (t = 0 min) was >10% (14.8%–29.0%) below the nominal concentration of the solution (i.e. outside the BP assay limits for the OXY injection product). In two of these combinations (OXY 1/TXA 4 and OXY 1/TXA 18) the OXY concentration continued to decline during the stability period, resulting in solutions at t = 60 min post-mixing containing 1.9% and 29.5% of the nominal initial OXY concentration respectively. The three remaining combinations, where losses were observed immediately on mixing (OXY 1/TXA 11, OXY 1/TXA 16 and OXY 2/TXA 8), showed no further significant change in OXY concentration during the period of stability assessment. All other combinations showed no significant losses on mixing and remained stable throughout the study. TABLE 3. Concentration of OXY over time after mixing with different tranexamic acid products in 0.9% w/v saline solution.

	OXY/TXA combination
	OXY1/TXA1	OXY1/TXA2	OXY1/TXA3	OXY1/TXA4	OXY1/TXA5	OXY1/TXA6	OXY1/TXA7	OXY1/TXA8	OXY1/TXA9	OXY1/TXA10	OXY1/TXA11	OXY1/TXA12	OXY1/TXA13	OXY1/TXA14	OXY1/TXA15	OXY1/TXA16	OXY1/TXA17	OXY1/TXA18	OXY2/TXA8
Time after mixing (min)
0	144.4	149.1	137.6	116.9	157.6	149.6	136.4	157.9	139.4	137.5	127.0	155.7	139.5	138.9	136.4	116.9	143.5	105.8	117.1
10	146.1	144.8	140.2	20.2	170.5	151.7	140.2	149.7	140.6	134.2	131.0	155.8	136.0	134.6	141.6	113.1	144.2	66.5	118.4
20	150.1	150.4	148.1	8.0^a	171.4	147.2	140.1	155.5	144.5	135.5	127.7	152.8	136.2	133.9	143.1	118.7	148.5	54.2	113.9
30	149.8	146.1	147.5	5.1^a	168.4	145.7	136.9	149.5	142.4	135.2	128.5	149.6	132.5	135.3	145.9	117.6	141.7	49.0	118.6
40	147.9	145.4	149.8	3.8^a	158.0	148.7	134.2	150.9	139.6	129.9	130.0	150.6	132.4	135.5	140.2	116.5	142.0	46.7	115.9
50	149.3	147.1	147.3	3.3^a	154.7	141.8	132.1	140.6	142.8	131.0	136.0	155.1	131.9	136.6	144.4	114.8	141.6	42.6	114.7
60	149.5	142.8	140.6	2.9^a	160.9	139.5	130.9	145.6	135.5	126.0	129.8	151.4	140.2	133.3	143.4	113.4	144.3	44.0	111.9
Average conc (ng/mL)	148.2	146.5	144.4	22.9	163.1	146.3	135.8	149.9	140.7	132.8	130.0	153.0	135.5	135.4	142.1	115.9	143.7	58.0	115.8
%RSD^b	1.5	1.8	3.3	183.0	4.2	3.0	2.7	3.9	2.1	3.0	2.3	1.7	2.5	1.4	2.2	1.9	1.7	38.4	2.2
Time-0 conc. as % of target conc.	96.9	100.0	92.3	78.4	105.7	100.3	91.5	105.9	93.5	92.2	85.2	104.4	93.6	93.1	91.5	78.4	96.2	71.0	77.8

^a Below lower limit of quantitation.
^b The target OXY concentration was 150 ng/mL. %RSD is the standard deviation expressed as a percentage of the population average (% relative standard deviation).

4 DISCUSSION

4.1 Main findings

We found an unexpected interaction between certain OXY and TXA products after mixing them in vitro and observing for up to 60 min. The interaction significantly impacted the OXY content, leading to a reduction in concentration within a short period of time.

The results of the two experiments indicate that mixing some combinations of OXY and TXA injection in 0.9% w/v saline solution or Ringer’s lactate solution results in an immediate and significant (14.8%–29.0%) loss of OXY, as measured against the target concentration. In a subset of the combinations where losses are observed, the concentration continues to decline after mixing and throughout the stability assessment period (up to 3 h). These results were observed across both infusion fluids.

The initial exploratory investigation (part 1) suggested some indications as to the possible causes for this phenomenon. Specifically, the presence of impurities in the TXA product that, when combined with each of the two OXY products, showed a loss of OXY on mixing and throughout the stability period. Also, the possibility of surface adhesion of OXY within the infusion bag cannot be ruled out as contributing to the observations upon mixing. However, the subsequent screen of multiple OXY–TXA injection combinations in 0.9% w/v saline (part 2) indicates that other factors may be contributing to the effects observed. First, these experiments were conducted in deactivated amber glass HPLC vials, selected to minimise surface effects, and yet a similar phenomenon was observed. Second, the combinations where OXY losses were observed did not correlate completely with TXA products where significant impurity content was observed on the HPLC chromatograms. We have previously reported quality issues with samples of TXA collected from the clinical sites involved in the E-MOTIVE trial,³ in terms of excessive impurity content. Although seven of the 18 TXA products used in this study showed similar deficiencies, only four of five affected combinations in part 2 of the study contained TXA products with significant impurity profiles. However, it should be noted that the methods used in this study would only detect organic impurities and further work would be required to understand whether inorganic impurities are present. Finally, one quality-assured TXA product (TXA 8) was evaluated with two OXY products (OXY 1 and OXY 2) and a loss of OXY upon mixing was observed only in combination with one OXY product (OXY 2). This may indicate that some characteristic of the OXY product contributes to these effects.

It is worth noting that the ratio of the OXY injection product (10 IU, 17 μg/mL) concentration to the TXA injection product (500 mg/5 mL) is very small. Consequently, reactive species present at a proportionally low level within the TXA product, although meeting all quality specifications for the TXA product, might be present at concentrations of the same order as OXY, and could feasibly lead to a substantial loss of OXY if an interaction were to occur.

In summary, this study did not identify any single characteristic of the products evaluated or the experimental design that would reasonably explain the observed results, and the possibility of multiple contributory factors must be considered.

Source: BJOG

Artificial intelligence and automation in endoscopy and surgery

Posted by zedie

Abstract

Modern endoscopy relies on digital technology, from high-resolution imaging sensors and displays to electronics connecting configurable illumination and actuation systems for robotic articulation. In addition to enabling more effective diagnostic and therapeutic interventions, the digitization of the procedural toolset enables video data capture of the internal human anatomy at unprecedented levels. Interventional video data encapsulate functional and structural information about a patient’s anatomy as well as events, activity and action logs about the surgical process. This detailed but difficult-to-interpret record from endoscopic procedures can be linked to preoperative and postoperative records or patient imaging information. Rapid advances in artificial intelligence, especially in supervised deep learning, can utilize data from endoscopic procedures to develop systems for assisting procedures leading to computer-assisted interventions that can enable better navigation during procedures, automation of image interpretation and robotically assisted tool manipulation. In this Perspective, we summarize state-of-the-art artificial intelligence for computer-assisted interventions in gastroenterology and surgery.

Source: NATURE

Are Most Fish Oil Products Synthetic?

Posted by zedie

Medical journals and mass media swear by it, so it’s easy to get the idea fish oil is something any sensible person should use. Yet, certain supplements use industrial solvents, don’t contain “a single milligram” of the omega-3s found in fish, and may cause more harm than good.

STORY AT-A-GLANCE

A chemical process leaves many fish oil supplements lacking in actual EPA and DHA omega-3s.
Trans-esterification transforms most fish oil into a synthetic product that’s far removed from the natural fish oil you’d get when eating sardines or other fatty fish.
A class-action lawsuit filed against The Bountiful Company and its subsidiary Nature’s Bounty alleges consumers are being misled, as the supplements contain “not a single milligram” of the omega-3 fats found in fish.
In fish, DHA, and EPA occur in the form of triglycerides, which are the most bioavailable; in most fish oil supplements, the omega-3 fats are in ethyl ester form.
Ideally, consume omega-3 fats by eating fatty, cold-water fish such as wild-caught Alaskan salmon, sardines, anchovies, mackerel, and herring—if you choose to use a supplement, krill oil provides a superior alternative to fish oil.

Reading medical journals and following the mass media, it’s easy to get the idea that fish oil is something any sensible person should use. It’s rare to see anything suggesting that it could be dangerous.

The omega-3 fats, including those with long chains found in fish oils, are said to make babies more intelligent, to be necessary for good vision, and to prevent cancer, heart disease, obesity, arthritis, depression, epilepsy, psychosis, dementia, ulcers, eczema, and dry skin.

Certain fish oil supplements contain “not a single milligram” of the omega-3 fats found in fish, according to a class-action lawsuit filed against The Bountiful Company and its subsidiary Nature’s Bounty.¹ As a result, people consuming these supplements in the hopes of gaining omega-3’s many beneficial effects may be being misled.

Wild-caught salmon, sardines, and certain other fish are an excellent source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), two omega-3 fats known for their role in brain health, heart health, and more. It’s been shown, for instance, that eating fatty fish two to three times a week reduces the risk of heart disease and stroke.²

However, because most Americans do not consume much seafood, many rely on fish oil supplements instead. But Nature’s Bounty fish oil contains no EPA or DHA, the suit alleges.³

Are Consumers Wasting Billions on Synthetic Fish Oil?

Fish oil is among the most popular supplements in the United States. Globally, the fish oil market was valued at $1.9 billion in 2019, with estimates suggesting this will rise to $2.8 billion by 2027.⁴ Many of these dollars may be wasted, however, due to a chemical process that leaves many fish oil supplements lacking in actual EPA and DHA. According to the suit, which was filed in September 2021:⁵

“Defendants manufacture, label and sell a Product which they claim to be 1400 mg. of Fish Oil containing of 647 mg. of Eicosapentaenoic Acid (“EPA”) and 253 mg. of Docosahexaenoic Acid (“DHA”)—the essential omega-3 fatty acids that naturally occur in fish …

“They also proudly claim that the contents are USP verified, which, among other things, assures consumers that the Product “contains the ingredients listed on the label, in the declared potency and amounts” … Contrary to what is represented on the label, however, this Product is not fish oil, nor does it contain a single milligram of EPA or DHA.”

Most Fish Oil Supplements Contain Omega-3 Ethyl Esters

The issue with most fish oil supplements is the chemical process used—trans-esterification—which transforms the oil into a synthetic product that’s far removed from the oil you’d get when eating sardines or other fatty fish. The suit explains:⁶

“What was once a low-grade oil derived from fish offal, has been subjected to a chemical process by which its molecular structure and constituent parts have been substantially transformed and irrevocably altered into a synthesized product that does not otherwise exist in fish, or nature.

“Through this chemical process, known as trans-esterification, an industrial solvent is introduced into the fish oil in order to break its natural triglyceride bonds and cleave the glycerol backbone from fatty acid molecules.

“Thereafter, ethanol is introduced to which the newly freed fatty acids bond to form fatty acid ethyl esters. Fish oil is stripped of hundreds of its constituent sub-ingredients, and the Omega-3s, which include DHA and EPA, are converted into ethyl esters.

“Critically, these newly formed Omega-3s are different molecules than the Omega-3s which exist naturally in fish oil. The new chemical by-products are universally recognized by their common or usual name — Fatty Acid Ethyl Esters (‘FAEE’).”

Dietary supplement labels should use the product’s common name in order to inform consumers of what they’re purchasing. But fish oil is trans-esterified, it becomes FAEE, the lawsuit alleges, and therefore can no longer be called fish oil on labels.

“To do so, as NBI [Nature’s Bounty Inc] has done, is false, misleading, deceptive, unlawful and perpetrates an actionable fraud on the consuming public,” according to the suit, which added, “Defendants falsely represented the fundamental nature of their product, and as a result of this false and misleading labeling, were able to sell these products to tens of thousands of unsuspecting consumers throughout New York and the United States.”⁷

Synthetic ‘Fish Oil’–’Found Nowhere in Any Fish–Ever’

Nature’s Bounty and The Bountiful Company filed a motion to dismiss the lawsuit in February 2022. They denied that labeling their fatty acid ethyl esters “fish oil” was misleading and also suggested their label complies with federal law. In January 2023, U.S. Magistrate Judge Anne Shields recommended granting the motion to dismiss, writing:⁸

“If it has not already been made clear, the court states clearly here that there is nothing false about labeling the product as fish oil. Describing the product this way denotes nothing more than a statement of fact that the OM3’s [omega-3 fats] therein are derived from fish oil. It says nothing about the process by which crude fish oil makes its way to the OM3s found in each capsule.

“Plaintiffs do not, and cannot, argue that other supplements containing OM3’S derived from fish oil are properly named only if they are derived via a different process. All such products get their OM3s from fish oil. To suggest that molecular differences between such products make a difference to a reasonable consumer is plainly implausible.”

The plaintiffs’ attorneys, Michael Braun and Mai Kats, pushed back, urging the district court judge overseeing the lawsuit to not take Shields’ recommendation, stating:⁹

“In short, under Second Circuit precedent, plaintiffs are entitled to proceed with their claim that when purchasing defendants’ product, they read the label and believed the product to be comprised of authentic fish oil — that is, oil 1) derived from pressing fresh fish and 2) containing both DHA and EPA.

“Additionally, plaintiffs are entitled to show, through discovery and expert testimony, that reasonable consumers attribute a higher value to the marketed product—a clean product—than to the product they received, which is a lab-created, artificial concoction, comprised of intensely and chemically-processed fish waste (offal) that lacks both DHA and EPA and consists instead of unnatural ethel ester compounds found nowhere in any fish ever.”

Ethyl Ester Versus Triglyceride Forms of Omega-3 Fat

While the judge suggested a “reasonable consumer” won’t care whether their omega-3 fats are in ethyl ester form, I’d suggest most will absolutely care—if they’re informed about the difference. In fish, DHA and EPA occur in the form of triglycerides,¹⁰ which are the most bioavailable.

A triglyceride consists of a three-carbon molecule that forms a “backbone” for the fatty acids to latch onto. Each carbon molecule is linked to a fatty acid, so in total, a triglyceride is composed of three carbons bonded to three fatty acids. In most commercial fish oil supplements, however, the DHA and EPA are delivered in the form of ethyl esters.

Ethyl esters are essentially a synthetic substrate, created through the micro-distillation process of crude fish oil, in which ethanol and/or industrial alcohol is added. This mix is heat distilled in a vacuum chamber, resulting in a concentrated omega-3 ethyl ester condensate.

Not only does this molecular distillation process remove vital resolvins and protectins that are important in reducing inflammation, but it also concentrates the EPA and DHA. You can tell the concentration of these two fats in any given supplement by looking at the label. In fish, the oil consists of 20 percent to 30 percent EPA and DHA, whereas purified fish oil concentrate typically contains between 60 percent and 85 percent EPA and DHA.¹¹

Most corporations produce ethyl ester fish oil because it’s far less expensive to produce than the triglyceride form. Ethyl esters are also easier to work with during processing, as they have a higher boiling point, which becomes important when the oils are heated and purified of environmental pollutants.

Ethyl Esters Are the Least Bioavailable Form

The problem with ethyl esters is they’re the least bioavailable form of omega-3. Manufacturers could convert them back into the triglyceride form by detaching the ethyl alcohol molecule and reattaching a glycerol molecule in a process known as re-esterification,¹² but most don’t because it’s so costly.

This is unfortunate, as your body metabolizes the triglyceride and ethyl ester forms differently, and this is when the issues arise. Since the glycerol backbone is missing in the ethyl ester form, the EPA and DHA will scavenge for available triglycerides or steal a glycerol molecule from somewhere.

One way or another, the fatty acids need to be converted back into triglyceride form or your gut epithelium will not be able to process them. When the ethyl ester form of EPA or DHA ends up stealing glycerol molecules, the molecule that lost its glycerol will then go searching for a replacement, creating a negative domino effect. Further, the fatty acids cannot be transported through your blood unless they’re in triglyceride form.

On the other hand, when you consume omega-3s in triglyceride form, the fatty acids are first separated from the glycerol backbone. All of the individual parts are then absorbed by gut epithelial cells, where they’re reattached to form triglyceride.

When you consume ethyl esters, they must be processed in your liver. There, the ethanol backbone is separated from the free fatty acids, and your body must then reattach the free fatty acids to glycerol to form triglyceride. Your liver must also process the ethyl alcohol, which may release free radicals and cause oxidative stress — the opposite of what you’re trying to achieve when you consume fish oil.

Synthetic Fish Oil May Cause More Harm Than Good

Many are aware of the fact that omega-3s are also PUFAs [polyunsaturated fatty acids] just like omega-6s which are so dangerous when consumed in excess quantities. But most don’t know that omega-3 fats are actually ten times more perishable than omega-6 fats and far more susceptible to oxidative damage. Fish oils are also generally much more immunosuppressive than omega-6 seed oils.

This is important to know because of all of the processing that occurs in processed fish oil. Invariably these highly perishable fats will be damaged and cause far more harm than good. I personally would never take processed fish oil in the ethyl ester form and strongly encourage you to seriously reconsider your choice if you are taking them.

Even if you were able to get unoxidized ethyl ester fish oils, absorption is also an issue. Free fatty acids of fish oil have an absorption rate of at least 95 percent. EPA in its natural triglyceride form had a 69 percent absorption rate in one study, while ethyl ester forms absorbed only about 20 percent.¹³

Importantly, unstable molecules are also more prone to oxidative damage and thus rancidity, which means consuming synthetic fish oil could potentially cause more harm than good. As explained by Douglas MacKay, N.D., senior vice president of scientific and regulatory affairs for the Council for Responsible Nutrition:¹⁴

“The potential negative health effects of consuming rancid fish oils have not been fully elucidated. However, it has been shown that oxidized by-products of polyunsaturated fatty acids, including DHA, are elevated in patients with neurodegenerative conditions.

“The triglyceride structure is the natural “resting” state for lipid molecules. The inherent structure of three fatty acids attached to one glycerol backbone provides protection to the double bonds in the long-chain PUFAs from being exposed to free radicals.

“An ethyl ester fatty acid, on the other hand, exists as a single strand and is exposed on all sides to free radicals. Although there is little data that directly compares the stability of EE [ethyl ester] fish oils to TG [triglyceride] fish oils, such basic biochemistry suggests the superior stability of TG fish oils both inside a capsule or liquid as well as within the body.”

The Best Way to Get Your Omega-3s

Ideally, it is best to get your omega-3 fats from whole-food forms. This includes wild-caught Alaskan salmon, sardines, anchovies, mackerel, and herring. If you choose to use a supplement, krill oil provides a superior alternative to fish oil.

Krill oil contains less EPA and DHA per gram of supplement than fish oil does. However, krill oil is more bioavailable as the EPA and DHA are bound in a phospholipid form, allowing you to take lower doses while still reaping similar results.

Vagus Nerve: What It Is and How to Make It Better

Posted by zedie

Getting this critical nerve into better ‘shape’ can have far reaching effects on how you feel

Your body relies on tight communication between senses, organs, muscles, brain, and more—and one of the most critical communication lines is the vagus nerve.

The vagus nerve is the longest cranial nerve in the body, traveling from the brain stem down through the spinal cord to the abdominal area. Along the way, it reaches out and affects many organs.

Also known as cranial nerve X and the pneumogastric nerve, the vagus nerve is the primary component of the parasympathetic nervous system, which is part of the autonomic nervous system. The autonomic nervous system also includes the sympathetic nervous system.

While the sympathetic nervous system triggers the fight-or-flight response, the parasympathetic nervous system sets off a calming response after the danger has passed. Feelings of safety trigger the front (ventral) part of the vagus nerve while danger activates the back (dorsal). When a vagus nerve is healthy, it leads an individual to respond in an appropriate or mindful way.

What the Vagus Nerve Does

The vagus nerve is named after the Latin word for “wandering,” which is appropriate because it affects so many organs and functions in the body. It performs two types of functions:

Sensory: involved in sensations on the skin, in muscles, and in organs
Motor: includes activities such as swallowing, digestion, breathing, coughing, vomiting, and heart rate variability

This versatile nerve is also involved in the fight/flight response and how the body responds in a healthy way to stress. A healthy vagal tone, that is, the activity of the vagus nerve, would indicate generally healthy emotional regulation and physical health as well.

How to Stimulate Your Vagus Nerve

All of these important functions indicate that you should strive to maintain a healthy vagus nerve (good vagal tone). You can do this by stimulating your vagus nerve, which then results in feelings of calm and relaxation, a decrease in heart rate, and slowed breathing. Here are some ways to stimulate your vagus nerve at home.

Exercise: Physical activity has many health benefits, and better vagal tone is one of them. In research involving individuals with heart problems, exercise therapy improved heart rate variability by increasing vagal tone and reducing the activity of the sympathetic nervous system.

Meditation: A 2020 study found that practicing mindfulness meditation can improve heart rate variability as well as sleep quality. In another study, individuals who participated in a six-week loving-kindness-meditation program showed an improvement in vagal tone while those who were on a waiting list for the program didn’t.

Singing or humming: When you sing or hum, it’s been shown you are activating your parasympathetic nervous system, slowing breathing, and increasing heart rate variability. Chanting also results in the same benefits.

Yoga: This activity activates the parasympathetic nervous system and can help with blood flow, digestion, and heart rate.

Deep slow breathing: Research shows that practicing deep, slow breathing can improve vagal tone and reduce anxiety.

Relaxing (chillin’ out): Activities that are relaxing and calming help improve vagal tone, whether it’s Tai Chi, socializing with friends, kicking back with a book, or some of the stress-reducing recommendations already noted here.

Gargling: The benefit from gargling is similar to that achieved by singing or humming.

According to clinical psychologist Dr. Glenn Doyle, “The vagus nerve is deeply plugged into our heart, our guts, and our voice. … When we speak, shout, sing, the vagus nerve is lit up like a Christmas tree—which is one of the reasons why those activities can be so cathartic and emotional for so many of us.”

Bottom Line

A healthy vagus nerve is essential for optimal function of many organ systems and overall good health. Take care of yours by engaging in stimulating activities as much as possible!

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure

Posted by zedie

Abstract

Background

Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF).

Objectives

This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF.

Methods

This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity.

Results

The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L).

Conclusions

The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.

Discussion

DREAM-HF is the largest clinical trial of cell therapy in HFrEF to date. The primary endpoint of a reduction in recurrent nonfatal hospitalization or urgent care events because of decompensated heart failure or successfully resuscitated high-grade symptomatic ventricular arrhythmias and its associated key secondary endpoint (time-to-first TCE) were negative in our study. However, our findings suggest novel hypothesis-generating insights into how cardiac cell therapy using MPCs may have a significant benefit on the natural history of HFrEF. MPC therapy resulted in significant reductions in TTFE for MI or stroke over a mean follow-up of 30 months with the most benefit seen in patients with evidence of systemic inflammation (baseline hsCRP ≥2 mg/L). These findings raise the possibility that treating patients with HFrEF with MPCs may improve outcomes by targeting local cardiac and systemic inflammatory changes that cause macrovascular and microvascular abnormalities in patients with heart failure

FDA Approves New Immunotherapy Combination To Treat Advanced Liver Cancer

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Medical oncologist Ghassan Abou-Alfa led the clinical trial that resulted in the FDA’s approval of a new combination therapy for hepatocellular cancer. — MSK’s gastrointestinal medical oncologist Ghassan Abou-Alfa led the clinical trial that resulted in the FDA’s approval of a promising new combination therapy for hepatocellular cancer.

Patients with inoperable advanced liver cancer have a new option for treatment to extend their lives. Today the U.S. Food and Drug Administration (FDA) approved a combination of the immunotherapy drugs durvalumab (Imfinzi®) plus the experimental drug tremelimumab for people with unresectable hepatocellular cancer, the most common type of liver cancer.

The FDA approval was based on results of the clinical trial HIMALAYA involving 1,117 patients, led by gastrointestinal medical oncologist Ghassan Abou-Alfa at Memorial Sloan Kettering Cancer Center (MSK).

“This new therapy significantly improved overall survival for patients compared to what had been the standard of treatment,” says Dr. Abou-Alfa. “The prognosis for liver cancer has been a difficult challenge for doctors and our patients.”

There are an estimated 42,000 adults diagnosed with primary liver cancer every year.
Approximately 30,000 people die from the disease.
The 5-year survival rate is 20.2%, based on 2012–2018 data.

The results from the international study showed after three years, about 30.7% of the patients who received the new combination immunotherapy were still alive, compared with 20.2% of the people who received only the kinase inhibitor drug sorafenib (Nexavar®). In the group given durvalumab alone, 24.7% were still alive.

In other words, the combination immunotherapy lowered the risk of death by 22%, according to the study.

This new therapy significantly improved overall survival for patients compared to what had been the standard of treatment.

Ghassan K. Abou-Alfa Medical Oncologist

How the New Combination Immunotherapy for Liver Cancer Works

Both immunotherapy drugs are checkpoint inhibitors — which means they help release the brakes cancer cells put on the immune system to prevent them from being destroyed.

Tremelimumab targets the CTLA-4 checkpoint. Durvalumab targets the PD-1 checkpoint. Patients received one dose of tremelimumab, followed by durvalumab, given intravenously every four weeks.

“The single dose of tremelimumab given at the beginning of the treatment theoretically jump-starts the immune system and improves the response to the durvalumab given once a month,” says Dr. Abou-Alfa.

About 25% of patients on the combination therapy experienced serious side effects, including skin problems, reduced liver function, and digestive issues. Patients taking sorafenib reported significantly more side effects. Those who took durvalumab alone had fewer.

Dr. Abou-Alfa first presented the results of the randomized phase 3 trial at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in June 2022.

The name for this new FDA-approved regimen is STRIDE. “It’s certainly a step in the right direction,” says Dr. Abou-Alfa. “While there is a heartbreaking need for more effective liver cancer treatments, this new immunotherapy combination can help more patients live longer and have a better quality of life.”

FDA Approves Promising Therapy for Advanced Prostate Cancer: Targets a Protein Called PSMA

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Man in his 70s (prostate cancer patient) smiling for camera — In 2019, Michael Rosenblum received an experimental new prostate cancer treatment after the disease spread to his bones. Since then, he has been symptom-free. The treatment is now FDA-approved.

Prostate cancer treatment took a major step forward today as the U.S. Food and Drug Administration approved a new therapy that zeros in on cancer cells to destroy them. The treatment, called ¹⁷⁷Lu-PSMA-617, uses a molecule that selectively seeks out and attaches to a specific protein on the cancer cell surface called PSMA (prostate-specific membrane antigen). The technology delivers radiation that damages DNA and destroys the cancer cell.

“This type of precision medicine is a game changer for people whose prostate cancer has spread despite receiving multiple treatments,” says Memorial Sloan Kettering Cancer Center medical oncologist Michael Morris. He helped design, execute, and analyze a clinical trial showing the effectiveness of ¹⁷⁷Lu-PSMA-617. “FDA approval of this therapy will enable even more people who had essentially been given death sentences to survive and live well.”

This treatment, developed by the pharmaceutical company Novartis, could be a breakthrough for treating prostate cancer after it has spread and grown resistant to other drugs. Prostate cancer is the second leading cause of cancer death in American males and kills 34,000 people in the U.S. every year.

The FDA approval is the latest bold advance in the emerging field of theranostics, which uses radioactive substances to visualize cancer cells and destroy them without harming normal cells. It also enables doctors to determine how well a treatment is actually working.

“We have a theranostic motto, which is ‘We see what we treat, and we treat what we see,’ ” says nuclear medicine physician Lisa Bodei, Director of Targeted Radionuclide Therapy at MSK. She is an expert specializing in using radioactive materials to diagnose and treat cancer and played a key role in the treatment of MSK participants in the trial.

The clinical trial, called VISION, showed that adding the drug to standard treatment slowed progression of prostate cancer. Dr. Morris presented results from this trial in June 2021 at the annual meeting of the American Society of Clinical Oncology. The results also were reported in The New England Journal of Medicine.

A New Lifeline

The new therapy could be a lifeline for many people with metastatic prostate cancer. Just ask Michael Rosenblum. In 2019, his prostate cancer was resistant to chemotherapy and other treatments and had spread. PET scans showed dark clusters of cancer cells in bones throughout his body. His PSA levels — a marker that normally should be in the single-digit range — had soared to more than 100.

Dr. Morris enrolled Michael in the VISION clinical trial. Michael began treatment in July 2019 and ended in February 2020. After six doses of the therapy, follow-up scans showed the metastatic cancer was no longer visible. The 76-year-old continues to be disease-free, with a PSA that is undetectable.

“I had no side effects either on the day of the procedures or afterward,” Michael says. “My PSA went right down, and my blood tests have been really good. From how I feel today, you would never think I had cancer a few years ago.”

PET scans of patient with metastatic cancer before and after treatment. — PSMA-PET scans of Michael Rosenblum before treatment (left) show prostate cancer metastases (small dark spots) throughout his body. After treatment (right), metastatic cancer is no longer visible.

How PSMA Lights Up Cancer Cells

In 2021, the U.S. Food and Drug Administration issued national approval to two new prostate cancer imaging tests based on similar technology. On a PET scan, the test lights up the cancerous cells that would otherwise be hidden, enabling doctors to precisely target treatment.

Both advances in imaging and therapy rely on targeting PSMA, which is not found on most normal cells but is overexpressed in cancer cells, especially those that have spread. The PSMA molecule was cloned at MSK in the early 1990s.

The Molecular Imaging and Therapy Service, led by Heiko Schöder, played a key role in the development and testing of a slightly different PSMA-directed imaging technology at MSK.

“This advance is the result of years of work by the community of physicians promoting the use of PSMA agents,” Dr. Schöder says. “It’s gratifying to see a collaborative effort result in a breakthrough that has the potential to make a difference for so many patients with advanced prostate cancer.”

Finding Hidden Cancer Cells: FDA Approval of New Imaging Tool Could Transform Treatment Decisions for Advanced Prostate Cancer

A newly approved imaging technology can identify the location of prostate cancer cells, allowing doctors to choose the best treatment.

Before receiving the therapy, patients in the VISION trial were scanned with PSMA-directed PET imaging to make sure enough PSMA was present in the cells to make them likely to respond to the treatment. If so, they received the radioactive drug by injection over four to six sessions, spaced six weeks apart.

Those who received the new treatment along with standard therapy had a 38% reduction in risk of death compared with those who received standard therapy alone — with a difference in median survival of 15.3 months versus 11.3 months. Also, the length of progression-free survival (the period when the disease didn’t get worse) for those receiving the new treatment more than doubled from a median of 3.4 months to a median of 8.7 months. Side effects were more common in people receiving the new treatment but were well tolerated. The most common was dry mouth.

As a next step, Dr. Morris and colleagues are looking into using the PSMA-directed therapy earlier — rather than only after the prostate cancer has spread.

“I have been involved in the PSMA research since the end of my fellowship at MSK in the late 1990s,” says Dr. Morris, whose research has been supported by the philanthropy of John and Susan Magnier and Peter and Jean Scannell. “It’s amazing to see it all come to fruition this year. The benefits these advances will bring to men with this common disease cannot be overstated.”

What Lies Ahead: Leading the Way With Alpha Therapies

The coming years will see even more powerful forms of radioactive therapy. The MSK laboratory of radiochemist Jason Lewis and other researchers are investigating the use of alpha particles, which have a much higher energy — hundreds of times more potent — than the photons used in conventional radiation or beta particles. Not only do alpha particles cause more damage when they slam into cancer cells but their path of destruction is more tightly focused, sparing normal cells.

MSK is building one of the nation’s first dedicated alpha particle GMP labs at a U.S. academic institution. (GMP means “Good Manufacturing Practices,” which are regulated and enforced by the FDA.)

“These radiopharmaceuticals that we are creating translate very well from bench to bedside,” says Dr. Lewis, Chief of the Radiochemistry and Imaging Sciences Service and Director of the Radiochemistry and Molecular Imaging Probe Core Facility. “When you see these striking responses to treatment, it brings real hope for the future and our patients.”

Advances in radiotheranostics are supported by The Tow Foundation, long-time contributors to MSK’s mission.

Key Takeaways

A new FDA-approved drug could be an effective treatment against prostate cancer that has spread.
The treatment uses a molecule that seeks out and attaches to a specific protein on the cancer cell surface called PSMA
The technology delivers radiation that damages DNA and destroys the cancer cell..

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Abstract

Background

Methods

Results

Conclusions

Methods

Trial Design and Patients

Trial Oversight

Randomization and Procedures

End Points

Statistical Analysis

Results

Patients

Survival

Recurrence

Expiratory Flow Rates

Discussion

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Abstract

Background

Methods

Results

Conclusions

Methods

Oversight

Patient Selection

Treatment

Trial End Points

Statistical Analysis

Results

Patients

End Points

Subgroup Analysis

Discussion

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Box 1: Search strategy for this review

What are the clinical features of a polyneuropathy?

How should patients be assessed?

What tests aid in the diagnosis of distal symmetric polyneuropathy?

How is the cause of an acquired distal symmetric polyneuropathy determined?

Box 2: High-yield screening laboratory tests for distal symmetric polyneuropathy

What is the approach to symptomatic treatment of painful neuropathy?

Conclusion

Box 3: Unanswered questions

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Abstract

Objective

Design

Setting

Sample

Methods

Main outcome measures

Results

Conclusions

1 INTRODUCTION

2 METHODS

2.1 Sample collection

2.2 Analytical methodology

2.2.1 OXY analysis

2.2.2 TXA analysis

2.2.3 Method verification

2.3 Study methods

2.3.1 Study methods (part 1)

Materials

Methods

2.3.2 Study methods (part 2)

Materials

Methods

3 RESULTS

3.1 Study part 1

3.2 Study part 2

4 DISCUSSION

4.1 Main findings

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Abstract

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STORY AT-A-GLANCE

Are Consumers Wasting Billions on Synthetic Fish Oil?

Most Fish Oil Supplements Contain Omega-3 Ethyl Esters

Synthetic ‘Fish Oil’–’Found Nowhere in Any Fish–Ever’