San Antonio

Exercise Preserves CV Function in Breast Cancer Patients

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SAN ANTONIO — A year-long structured exercise program initiated 3 weeks after surgery for breast cancer significantly attenuated expected declines in cardiovascular (CV) function as patients continued through treatment, a Norwegian randomized, placebo-controlled study found.

The program, which took place outdoors and incorporated aerobics, weight bearing movement, and stretching, enabled almost full recovery of CV function at 12 months.

The study was presented here during the San Antonio Breast Cancer Symposium (SABCS) 2018.

“It is striking that for all [patient] groups — whether they received chemotherapy or not — there was a really good effect of being in the physical activity program,” said lead author Inger Thune, MD, PhD, Oslo University Hospital, Norway.

“Our study supports incorporation of supervised clinical exercise programs into breast cancer treatment guidelines,” Thune told Medscape Medical News at a meeting press briefing.

“CV function during treatment is a reflection of a patient’s physical function later on in life, because [poor CV function] is a marker of susceptibility to comorbidity and to overall survivorship, so its loss can be a very important issue in daily life,” she added.

Kent Osborne, MD, of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, wholeheartedly agreed with the idea of patients exercising throughout treatment as much as possible.

“You’d be surprised how little activity patients get after their diagnosis, and this is partly related to their families telling them, ‘You need to rest because you are on this chemotherapy,’ ” he told reporters.

“But patients need to be as active as they can. They will tolerate chemotherapy better and have better outcomes, so we have to convince the family not to treat the patient as if they are sick,” emphasized Osborne, who moderated the press event.

Study Details

The Energy Balance and Breast Cancer Aspect (EBBA-II) trial enrolled 545 women with stage I or II breast cancer following surgical excision of their tumor.

The mean age of patients was 55 years, and the mean body mass index was approximately 25 kg/m2. More than 70% of both groups had invasive breast cancer.

Approximately 22% of both groups also had lymph node metastases, and about 70% of women in both groups underwent breast-conserving surgery.

Slightly more than half of both groups underwent chemotherapy. About half of these patients received an anthracycline-based regimen, and some 40% received a taxane.

Of both groups, 80% also underwent radiotherapy, and almost 60% were treated with some form of endocrine therapy.

Three weeks after undergoing breast cancer surgery, patients were randomly assigned either to participate in a 12-month exercise program or to receive standard care.

Patients performed aerobic exercises of moderate to high intensity; there was also a weight-bearing and stretching component to the program.

The exercise program was tailored to an individual’s maximal oxygen uptake (VO2max), as assessed prior to their undergoing surgery. VO2max is a common measure of CV fitness.

Patients exercised together twice a week for 60 minutes per session and were instructed to exercise at home for another 120 minutes a week to achieve a total of 240 minutes a week of activity.

“CV capacity was assessed before surgery, at 6 months, and again at 12 months,” Thune noted.

“And at a mean of 31 mL/kg/min, the VO2max in both groups was basically identical at baseline,” she said.

Focus on Chemo Recipients

At 6 months, “the intervention group did much better at preserving their CV function than the control group, among whom there was an 8.9% decrease in VO2max,” Thune reported.

By way of comparison, VO2max in the intervention group dropped by only 2.7% at 6 months, the investigators noted.

At 12 months, CV function among those who participated in the exercise program had rebounded to almost the same VO2max levels as prior to surgery. On the other hand, those who received standard care had a 3.8% decrease in VO2max at 12 months relative to presurgical baseline levels (P < .001).

When investigators assessed VO2 levels among 242 patients who had not undergone chemotherapy, findings were again significantly in favor of the intervention group.

After 6 months of exercise, “patients in the intervention group had a 1.6% increase in the level of their VO2max, which was maintained at 12 months of follow-up,” Thune noted.

In contrast, patients in the control group had a 2.7% decrease in VO2max at 6 months. This loss persisted to 12 months, she added.

The researchers also analyzed changes in CV function for patients who had received any kind of chemotherapy as well as those who had been treated with a taxane.

Among 295 patients who received some form of chemotherapy, exercise participants experienced a 9% decrease in VO2max at 6 months, compared with a 14.2% decrease among control patients who received standard care.

Again by 12 months, VO2max had almost rebounded to presurgical baseline levels among those who exercised, whereas for control patients, VO2max was 6.4% lower than at baseline (P < .001).

A separate analysis was conducted for 212 patients who had received a taxane as part of their chemotherapy regimen.

For these patients, treatment effects were most pronounced. There was a 17.5% drop in VO2max at 6 months among control patients and a significant, though slightly less pronounced, drop among exercise participants.

However, at 12 months, VO2max had rebounded to only about 1.4% below presurgical baseline levels among exercise participants. For the control group, there was a 7.3% decrement in VO2max (P < .05).

“It is striking that for all these groups — whether they received chemotherapy or not — there was a really good effect of being in the physical activity program,” Thune noted.

“We believe that breast cancer patients receiving chemotherapy should be offered a tailored exercise program based on pretreatment levels of physical function,” she concluded.

‘It’s Going to Be a Useful Agent’: Oxybutynin for Hot Flashes

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SAN ANTONIO — Oxybutynin (multiple brands), an anticholinergic widely used to treat urinary incontinence caused by an overactive bladder, is surprisingly effective in the treatment of hot flashes in breast cancer survivors, new research shows.

It was also effective in study patients who did not have breast cancer but who were bothered by frequent or severe menopausal symptoms, according to a presentation here at the San Antonio Breast Cancer Symposium (SABCS) 2018.

“Hot flashes are a big problem across the general population, but breast cancer survivors are at higher risk for experiencing either more severe or longer-lasting hot flushes, often as a consequence of our therapies,” lead author Roberto Leon-Ferre, MD, assistant professor of oncology, Mayo Clinic, Rochester, Minnesota, told a press briefing here.

Hot flashes can affect breast cancer outcomes — symptoms can be so severe that patients will discontinue endocrine therapy prematurely, he added.

In the new study, oxybutynin significantly reduced the frequency and severity of hot flashes, and its use had a positive impact on several quality-of-life metrics.

“If you are dealing with a patient who does not have a lot of other comorbidities and who doesn’t take a lot of other medications that could interact with the drug, this is a good option,” Leon-Ferre concluded.

To qualify for the study, at baseline, women had to have been experiencing 28 or more hot flashes a week for at least 30 days.

Nearly two thirds of 150 patients enrolled in the trial took either tamoxifen (multiple brands) or an aromatase inhibitor for breast cancer for the duration of the study. The remaining women were not breast cancer patients.

Concurrent use of antidepressants, gabapentin (multiple brands), or pregabalin (Lyrica, PF Prism), which are all used to treat hot flashes, was allowed.

Almost half of the women in each group reported having 10 or more hot flashes a day, and more than three quarters of them reported that their hot flashes had persisted for 9 months or longer.

Oxybutynin was administered at a dosage of either 2.5 mg twice a day or 5 mg twice a day for 6 weeks.

“A baseline questionnaire was given to establish the degree of hot flushes women were experiencing as well as quality of life metrics,” Leon-Ferre noted.

The investigators also administered the Hot Flash—Related Daily Interference Scale (HFRDIS) — a weekly “hot-flash diary” — to establish the degree to which hot flashes were interfering with various aspects of a patient’s life, he added.

Approximately 50 patients were enrolled in each of the three treatment arms; 35 to 40 evaluable patients remained in each arm at study endpoint.

The investigators evaluated change in individual patient symptoms over 6 weeks from baseline.

Leon-Ferre and colleagues observed that for women who received oxybutynin 5 mg bid, hot flash scores at week 6 were reduced by nearly 80%.

The 2.5-mg bid dosage had a similar though slightly less pronounced effect on hot flash scores at study endpoint.

“Patients on both oxybutynin doses had a significantly greater reduction in their hot flash score and frequency compared with placebo (P < .01),” the investigators summarized.

For the patients who received oxybutynin at either of the two dosages, reductions in hot flash scores compared favorably to the 30% reduction experienced by patients who received placebo. This “is consistent with what we see in other placebo-controlled studies, so placebo does have an effect in controlling hot flashes,” Leon-Ferre observed.

Mean frequency of hot flashes was reduced from baseline by about the same magnitude as was seen for reductions in the hot flash score in each of the three treatment arms.

Table. Mean Changes in Endpoints From baseline to Week 6

Oxybutynin 2.5 mg bid Oxybutynin, 5 mg bid Placebo
Hot flash score -10.6 -16.9 -5.7
Hot flash frequency 4.8 fewer hot flashes per day 7.5 fewer hot flashes per day 2.6 fewer hot flashes per day

For women who received either of the two dosages of oxybutynin, most HFRDIS measures, including measures related to sleep, leisure activities, work, and relationships, were significantly better in comparison with women who received placebo.

However, neither dosage of oxybutynin offset the effect that hot flushes had on patients’ ability to concentrate or on their sexuality. At the lower dosage, oxybutynin did not improve mood or enjoyment of life; at the higher dosage, improvements were seen for these measures.

Side effects were as expected with any anticholinergic and included dry mouth, abdominal pain, and difficulty urinating with both dosages.

At the higher dosage, oxybutynin also increased the risk of developing dry eyes, as well as risk for episodes of confusion, diarrhea, and headaches.

New Therapies

Leon-Ferre’s home institution, the Mayo Clinic, has long been involved in the exploration of new therapies for hot flashes in women who cannot take hormone replacement therapy — the most effective treatment for menopausal symptoms — because they have either had breast cancer or are at high risk for it.

Among the agents studied in this regard have been two antidepressants, venlafaxine (multiple brands) and citalopram (multiple brands).

Results from these trials show that venlafaxine reduced hot flash scores by approximately 60%. Citalopram was slightly less effective than venlafaxine.

“We have to be cautious, as these are cross-trial comparisons, but oxybutynin shows a more significant decrease in hot flash score [than anything else so far], so with the results of this particular study, we will be more keen on using oxybutynin now,” he said.

Asked to comment on the findings, Ken Osborne, MD, SABCS codirector and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, told Medscape Medical News that he personally is now going to start using oxybutynin for more patients because it is at least as effective as venlafaxine and it has some other advantages.

You have to pick the right patientT Dr Ken Osborne

For example, oxybutynin does not interfere with the metabolism of tamoxifen, an important consideration for breast cancer survivors.

In contrast, it is thought that some antidepressants used to treat hot flashes have the potential to decrease the efficacy of tamoxifen.

“You have to pick the right patient,” Osborne elaborated.

“If you have a patient with a lot of anxiety or depression, then you are going to use venlafaxine; if not, you might want to use oxybutynin,” he noted.

The fact that some of the patients enrolled in the current study were already taking an antidepressant or other agents presumably to treat their hot flashes suggests that these other medications were not fully working for them, Osborne also pointed out.

“When they added oxybutynin into that mix, they showed that it can help here too,” he said.

“So I think it’s going to be a useful agent,” Osborne concluded.

Hot flashes not only affect patients who have estrogen-dependent cancer, which is treated with therapies that block estrogen production. They also affect patients with estrogen-independent cancer that is treated with chemotherapy; chemotherapy itself can induce early menopause, which will trigger hot flashes as well.

Major Trial: Partial Breast Radiation Good for Early Breast Cancer

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SAN ANTONIO — Accelerated partial breast irradiation (PBI), although not 100% equivalent to whole-breast irradiation (WBI) for disease control in patients with early- stage breast cancer, yields outcomes so similar that it may be considered a viable treatment option for many patients, a long-term follow-up of the largest trial of its kind indicates.

“In an effort to improve quality of life for our patients, we studied whether or not we could reduce overall treatment times significantly down to a week or less by doing a technique known as partial breast irradiation, meaning limiting radiation only to the lumpectomy cavity region and accelerating treatment down to 5 days or less,” Frank Vicini, MD, MPH, Radiation Oncology Institute, Pontiac, Michigan, told a press briefing held here during the San Antonio Breast Cancer Symposium (SABCS) 2018.

“And while [we] cannot declare that WBI and PBI are equivalent in controlling local-in-breast tumor recurrence…the absolute difference in the 10-year cumulative incidence of IBTR [ipsilateral breast tumor recurrence] was only 0.7%…. So PBI may be an acceptable alternative to WBI for a proportion of women who undergo breast-conserving surgery,” he concluded.

The NRG (NSABP B-39/RTOG 0413) trial randomly assigned 4216 women who had recently undergone lumpectomy to receive either WBI or accelerated PBI. Women enrolled in the study had zero to three positive axillary nodes on study entry.

Twenty-five percent of the group had ductal carcinoma in situ (DCIS), 65% had stage I breast cancer, and 10% had stage II disease. The majority of women also had hormone receptor—positive tumors.

Women who were assigned to the WBI arm following adjuvant chemotherapy received daily treatment with 2.0 Gy/fraction of radiation totaling 50 Gy with a sequential boost to the surgical site.

Duration of WBI was 5 to 6 weeks, which was the standard of care at the time the trial was designed.

Those assigned to accelerated PBI prior to adjuvant chemotherapy received twice-daily treatment with 3.4 to 3.85 Gy given as either brachytherapy or 3D external-beam radiation.

Patients who underwent accelerated PBI received a total of 10 treatments over 5 to 10 days.

“The primary endpoint was to determine whether or not PBI results in IBTR — both DCIS and invasive breast cancer — was the same as it was for WBI,” Vicini noted.

At a median follow-up of 10.2 years, Vicini and colleagues documented a total of 161 IBTRs as first events — 90 among women treated with accelerated PBI, and 71 for those treated with WBI.

On the basis of the upper limit of the hazard ratio confidence interval, “PBI did not meet the criteria for equivalence to WBI in controlling IBTR,” Vicini reported.

On the other hand, the 10-year cumulative incidence of IBTR was very low in both groups, at 4.6% for patients in the accelerated PBI arm vs 3.9% for those in the WBI arm.

Furthermore, the difference in recurrence-free interval rates between the two arms — 91.8% in the accelerated PBI group vs 93.4% in the WBI group — was also negligible, at only 1.6%, Vicini added.

There were no differences in distant disease-free interval (DDFI), overall survival (OS), or disease-free survival (DSF).

For example, at 10 years, 96.7% of patients in the accelerated PBI arm were free of distant disease, as were 97.1% of patients in the WBI arm.

At the same follow-up point, 90.6% of patients in the accelerated PBI arm were still alive, as were 91.3% of those treated with WBI.

DSF rates were also very similar between the two treatment arms, Vicini noted.

Rates of grade 3 toxicity were similar between the two treatment groups, at 9.6% in the accelerated PBI group and 7.1% for those who received WBI. Rates of higher-grade toxicities were also very low and were similar between the two treatment groups.

Additional analyses are currently underway to evaluate secondary endpoints, including quality of life and cosmetic outcomes, Vicini noted.

“There have been many studies looking at quality of life [after radiotherapy], and you can imagine that quality of life is better with PBI — it’s pretty intuitive,” Vicini noted.

“And there is a pretty dramatic difference in the treatment interval from 5 to 7 weeks [with WBI] down to a week or less [with PBI], so as long as the control rates are the same, the trend in oncology now is ‘less is better,’ ” he added.

Furthermore, DDFI, OS, and DFS were not different between the two arms. Arguably, these endpoints are more important than recurrence, Vicini suggested, even though recurrence is an important event for patients.

“These findings suggest that the less burdensome radiation method of accelerated PBI may be an acceptable choice for many women,” Vicini said.

“So I think this is a very important study and it certainly is important to patients,” he concluded.

PBI Not Commonly Used

Asked by Medscape Medical News to comment on the findings, press briefing moderator Virginia Kaklamani, MD, University of Texas Health, San Antonio, noted that the majority of patients in the United States who are similar to those in the current study are still undergoing WBI. “PBI is not as common as it should be,” she noted.

“In the end, this is detrimental to patients, because if they have WBI, they have to come in for radiation therapy for at least 5 and sometimes 7 weeks, whereas otherwise [with PBI], they would be coming in for 5 to 10 days,” Kaklamani added.

She felt that findings from the current study “absolutely” should provide reassurance that radiation oncologists can offer accelerated PBI to patients who meet the same criteria as those included in the current study.

“We have many trials evaluating shorter radiation intervals,” Kaklamani noted.

“And the medical community needs to be implementing more PBI, and patients should also be asking for it,” she suggested.

Reshma Jagsi, MD, DPhil, professor and deputy chair, Department or Radiation Oncology, University of Michigan in Ann Arbor, felt that high-quality randomized trials such as this one in which shorter courses of accelerated PBI were compared to WBI are “critically important” to help inform treatment decisions that women who are diagnosed with breast cancer must make each year.

“These decisions depend on the patient’s own values and preferences,” Jagsi told Medscape Medical News in an email.

For example, some women might prefer to come in twice a day for a week rather than daily for many weeks to minimize disruption of their work schedule or because of problems involving transportation, whereas others might quite reasonably decide otherwise.

“The contribution of trials like these is to arm each woman with the precise risk information she needs to make the decision that is right for her,” Jagsi wrote.

“These trialists have made an enormous contribution through this work,” he concluded.

Prophylaxis May Cut Cardiotoxicity Risk in HER+ Breast Cancer

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Clear benefit for anthracycline treatment, not trastuzumab

SAN ANTONIO — The frequency of cardiotoxicity declined significantly with prophylactic antihypertensive medication for patients with early HER2-positive breast cancer treated with anthracycline-containing chemotherapy, but not trastuzumab (Herceptin), a randomized trial showed.

Although the trial did not meet the primary endpoint of cardiotoxicity in all treated patients, the incidence decreased by about half in patients who received anthracycline-containing adjuvant or neoadjuvant therapy and cardiovascular prophylaxis with a beta-blocker or angiotensin converting enzyme (ACE) inhibitor. Patients who received trastuzumab (Herceptin) without an anthracycline had a similar rate of cardiotoxicity whether they received one of the antihypertensive drugs or placebo, reported Pamela M. Munster, MD, of the University of California San Francisco, and colleagues.

“Our primary endpoint was similar for all cohorts,” Munster said at the San Antonio Breast Cancer Symposium (SABCS). “However, cardiotoxicity-free survival [CFS versus placebo] is comparable, with a hazard ratio of 0.71 for carvedilol and 0.74 for lisinopril, with a nonsignificant P-value.”

“Cardiotoxicity-free survival was longer with carvedilol or lisinopril than with placebo in patients who received anthracycline-containing regimens, but no differences were seen with the non-anthracycline regimens,” she added. “In patients with HER2-positive breast cancer treated with trastuzumab and anthracyclines, the addition of lisinopril or carvedilol should be considered.”

Two separate studies presented at the 2018 American College of Cardiology meeting in Orlando reported that cardiotoxicity from breast cancer drugs was about half as likely with prophylactic use of heart drugs in higher-risk patients, as well as an early trend for less cardiac damage.

‘Nice,’ but Not Enough?

The results are “very nice” but did not address the key issue for patients with breast cancer treated with anthracyclines and/or trastuzumab, said Steven Vogl, MD, a medical oncologist who practices in the Bronx in New York City.

“You’ve shown that you have fewer decreases in [left ventricular ejection fraction, LVEF], so you can give more trastuzumab, but did these interventions prevent dyspnea, heart failure — something that bothered the patient?” Vogl asked.

Acknowledging that his point was well taken, Munster said investigators struggled over the selection of the primary endpoint and ultimately decided that LVEF was more practical to assess than “subjective symptoms” in a community-based clinical trial involving 127 practices across the U.S.

“We will now analyze, do we in the long term actually have symptomatic changes, or is it just left ventricular ejection fraction?” she added.

Vogl continued, “There is considerable controversy about whether longer trastuzumab is better than shorter, but the bulk of the data suggest, at least for patients with the worse prognosis — positive nodes or bigger tumors — longer is better. In that situation, if that’s correct, then it’s good to give these [cardiovascular drugs] because then you get to give longer trastuzumab, regardless of whether they prevent symptoms or severe congestive heart failure — if you’re going to do the echocardiograms.”

Background and Results

Adjuvant trastuzumab remains standard of care for patients with early-stage HER2-positive breast cancer. The drug’s potential for cardiotoxicity requires monitoring and often leads to dose interruption and/or discontinuation, Munster noted. Results of several small studies suggested that treatment-induced cardiotoxicity might be prevented by prophylaxis with an ACE inhibitor or beta blocker, which are widely used to treat hypertension and heart failure.

Designing a randomized, multicenter, community-based trial of cardiovascular prevention posed several challenges, she continued. Reports about the frequency and severity of cardiotoxicity with HER2-targeted regimens varied widely. Evolving changes in practice pattern preferences for adjuvant neoadjuvant regimens have led to variation by geography and practice setting. Selection of regimens might be influenced by perceived or actual cardiac risk factors of patients with HER2-positive tumors.

Ultimately, investigators designed a randomized, double-blind, placebo controlled community-based trial involving patients with early HER2-positive breast cancer treated with trastuzumab. The design included stratification by use of anthracycline-containing chemotherapy. Patients were randomized to lisinopril (Zestril), carvedilol (Coreg and Coreg CR), or placebo, beginning day 1 of trastuzumab treatment and continuing for 52 weeks.

The trial had a primary endpoint of cardiotoxicity, defined as an absolute 10% decrease in LVEF from baseline or a 5% absolute decrease if LVEF fell below 50%. Eligible patients had early HER2-positive breast cancer and planned treatment with trastuzumab for 1 year, adjuvant or neoadjuvant cytotoxic therapy, LVEF ≥50, systolic blood pressure ≥90 mm Hg, and pulse ≥60 bpm.

Investigators randomized 468 patients 1:1:1 to placebo, lisinopril 10 mg, or carvedilol 10 mg. A total of 193 patients discontinued treatment before 52 weeks, including 86 patients who had a decrease in cardiac function. The patients remained in follow-up and 181 were eligible for efficacy analysis. Munster said 189 of 468 patients received anthracycline-containing chemotherapy in addition to trastuzumab.

The primary analysis showed similar rates of cardiotoxicity for the three treatment arms: 32% for placebo, 29% for carvedilol, and 30% for lisinopril. The carvedilol and lisinopril groups had nonsignificant trends toward better CFS, but neither difference achieved statistical significance:

  • Carvedilol: HR 0.71 (95% CI 0.47-1.07, P=0.052)
  • Lisinopril: HR 0.74 (95% CI 0.48-1.12, P=0.076)

The prespecified analysis by anthracycline use showed significant advantages for treatment with either cardiovascular agent versus placebo. Patients who received anthracycline-containing chemotherapy in addition to trastuzumab had a 51% reduction in the CFS hazard with carvedilol (95% CI 0.27-0.89, P=0.009) and a 47% reduction with lisinopril (95% CI 0.30-0.94, P=0.015). Cardiovascular prophylaxis did not affect CFS in the patients who received trastuzumab without an anthracycline.

Interruption of trastuzumab therapy occurred significantly more often in the placebo group (26.3% vs 15.4% with carvedilol and 17.3% with lisinopril, P=0.01). Anthracycline use accounted for most of the difference, as trastuzumab interruption occurred in 40.3% of the placebo group versus 19.7% of the carvedilol group and 23.0% of the lisinopril group.

Adverse events associated with carvedilol and lisinopril were consistent with their known safety profiles. Fatigue, dizziness, headache, cough, and hypertension were more common with lisinopril than with carvedilol.

SABCS session moderator Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology in Milan, called the findings “provocative and potentially practice changing.”

Team develops compact, high-power terahertz source at room temperature

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Terahertz (THz) radiation—radiation in the wavelength range of 30 to 300 microns—is gaining attention due to its applications in security screening, medical and industrial imaging, agricultural inspection, astronomical research, and other areas. Traditional methods of generating terahertz radiation, however, usually involve large and expensive instruments, some of which also require cryogenic cooling. A compact terahertz source—similar to the laser diode found in a DVD player —operating at room temperature with high power has been a dream device in the terahertz community for decades.

Manijeh Razeghi, Walter P. Murphy Professor of Electrical Engineering and Computer Science at Northwestern University‘s McCormick School of Engineering and Applied Science, and her group has brought this dream device closer to reality by developing a compact, room-temperature source with an of 215 microwatts.

Razeghi presented the research October 7 at the International Conference and Exhibition on Lasers, Optics & Photonics in San Antonio, and will also present at the European Cooperation in Science and Technology conference in Sheffield, England on October 10. The findings were published July 1 in the journal Applied Physics Letters and was presented at the SPIE Optics + Photonics conference in August in San Diego.

Razeghi’s group is a world leader in developing quantum cascade lasers (QCL), compact semiconductor lasers typically emitting in the mid-infrared spectrum ( of 3 to 16 microns).

Terahertz radiation is generated through nonlinear mixing of two mid-infrared wavelengths at 9.3 microns and 10.4 microns inside a single quantum cascade laser. By stacking two different QCL emitters in a single laser, the researchers created a monolithic nonlinear mixer to convert the mid-infrared signals into , using a process called difference frequency generation. The size is similar to standard , and a wide spectral range has already been demonstrated (1 to 4.6 THz).

“Using a room-temperature mid-infrared laser to generate terahertz light bypasses the temperature barrier, and all we need to do is to make the output power high enough for practical applications,” said Razeghi, who leads Northwestern’s Center for Quantum Devices (CQD). “Most applications require a minimum of microwatt power levels, but, of course, the higher the better.”

The achieved output power, 215 microwatts, is more than three times higher than earlier demonstrations. This dramatic boost is due to a number of novelties, including Cherenkov phase matching, epilayer down mounting, symmetric current injection, and anti-reflection coating.

Statins and Musculoskeletal Conditions, Arthropathies, and Injuries.

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ABSTRACT

Importance  Statin use may be associated with increased musculoskeletal adverse events, especially in physically active individuals.

Objective  To determine whether statin use is associated with musculoskeletal conditions, including arthropathy and injury, in a military health care system.

Design  A retrospective cohort study with propensity score matching.

Setting  San Antonio Military Multi-Market.

Participants  Tricare Prime/Plus beneficiaries evaluated from October 1, 2003, to March 1, 2010.

Interventions  Statin use during fiscal year 2005. On the basis of medication fills, patients were divided into 2 groups: statin users (received a statin for at least 90 days) and nonusers (never received a statin throughout the study period).

Main Outcomes and Measures  Using patients’ baseline characteristics, we generated a propensity score that was used to match statin users and nonusers; odds ratios (ORs) were determined for each outcome measure. Secondary analyses determined adjusted ORs for all patients who met study criteria and a subgroup of patients with no comorbidities identified using the Charlson Comorbidity Index. Sensitivity analysis further determined adjusted ORs for a subgroup of patients with no musculoskeletal diseases at baseline and a subgroup of patients who continued statin therapy for 2 years or more. The occurrence of musculoskeletal conditions was determined using prespecified groups of International Classification of Diseases, Ninth Revision, ClinicalModification codes: Msk1, all musculoskeletal diseases; Msk1a, arthropathies and related diseases; Msk1b, injury-related diseases (dislocation, sprain, strain); and Msk2, drug-associated musculoskeletal pain.

Results  A total of 46 249 individuals met study criteria (13 626 statin users and 32 623 nonusers). Of these, we propensity score–matched 6967 statin users with 6967 nonusers. Among matched pairs, statin users had a higher OR for Msk1 (OR, 1.19; 95% CI, 1.08-1.30), Msk1b (1.13; 1.05-1.21), and Msk2 (1.09; 1.02-1.18); the OR for Msk1a was 1.07 (0.99-1.16; P = .07). Secondary and sensitivity analyses revealed higher adjusted ORs for statin users in all outcome groups.

Conclusions and Relevance  Musculoskeletal conditions, arthropathies, injuries, and pain are more common among statin users than among similar nonusers. The full spectrum of statins’ musculoskeletal adverse events may not be fully explored, and further studies are warranted, especially in physically active individuals.

Source: JAMA

The 2011 San Antonio Breast Cancer Symposium.

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Highlights include adjuvant bisphosphonates, endocrine therapy, treatment of HER2-positive breast cancer, and genomic scores for predicting risk for recurrence of ductal carcinoma in situ.

Presentations at the 2011 San Antonio Breast Cancer Symposium (SABCS; December 6–10, 2011) encompassed bisphosphonates as adjuvant therapy, use of biological mechanisms to enhance endocrine therapy, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and genomic assays for ductal carcinoma in situ (DCIS). Key findings are summarized below; for more information, readers are encouraged to visit the SABCS website.

Benefits of Bisphosphonates
Several reports focused on the role of bisphosphonates for lowering recurrence risk in patients with early breast cancer. The ABSCG-12 trial of adjuvant endocrine therapy (ovarian suppression plus tamoxifen or anastrozole) with or without zoledronic acid (ZA) was updated with long-term follow-up . At initial publication of the study showed that ZA provided no overall survival (OS) benefit but did confer disease-free survival (DFS) benefit in postmenopausal patients (probably because of their low estrogen levels). Now, at median follow-up of 84 months, DFS was improved in patients who received ZA (hazard ratio, 0.71; P=0.011) as was OS (HR, 0.63; P=0.049). The added benefit of ZA occurred regardless of primary tumor size, axillary nodal status, or whether patients received tamoxifen or anastrozole. The effect of ZA was most striking in women older than 40.

The ZO-FAST trial  designed to determine whether ZA has greater benefit for bone-mineral density (BMD) when given immediately versus after a delay (duration determined based on postbaseline bone health) in postmenopausal patients with early breast cancer. The initial report showed that immediate use of ZA had greater beneficial effects on BMD than did delayed use. Now, 5-year follow-up has confirmed these findings and also showed a 34% improvement in DFS with immediate ZA versus delayed ZA (absolute difference in risk for a DFS event, 3.6%). The greater benefit of immediate therapy was observed in patients with low estrogen levels resulting from ovarian suppression, in those who were older than 60, and in those who were naturally postmenopausal at study entry.

The NSABP B-34 trial  involved oral clodronate rather than ZA in patients with early breast cancer, but findings were similar to those of the ABSCG-12 and ZO-FAST trials: Results showed no benefit for DFS or OS with clodronate in the overall study population, but benefit was seen in postmenopausal participants (risk for distant metastases was lowered by 20% to 39% in women 50 or older). Although results of other trials have been inconsistent, the body of evidence points to an anticancer effect from bisphosphonate therapy, leading clinicians to reconsider this class of agents as a component of adjuvant therapy.

Honing Endocrine Therapy
Our better understanding of downstream signaling pathways in hormone receptor–positive breast cancer has yielded new agents that are effective against hormone-resistant disease. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that enhances the activity of preoperative endocrine therapy. The BOLERO-2 trial of exemestane plus everolimus or placebo involved postmenopausal patients with metastatic breast cancer whose disease had progressed on letrozole or anastrozole. Now, updated results  showed that median progression-free survival more than doubled with the addition of everolimus (3.2 months vs. 7.4 months by investigator assessment; 11.0 months vs. 4.1 months by independent radiologic review). All subgroups of patients benefited from everolimus; however, adverse events included stomatitis, rash, diarrhea, hyperglycemia, fatigue, and pnuemonitis. The clinical benefit of adding everolimus to exemestane seems clear, but the adverse events associated with this doublet move the experience of receiving endocrine therapy closer to that of chemotherapy.

A New Agent, Pertuzumab, Joins Trastuzumab
The number of options for treating HER2-positive breast cancer continues to grow, leveraged by elucidation of the underlying biology of tumor-cell receptors and downstream signaling pathways. Investigators presented the results of the CLEOPATRA study phase III trial involvong 800 patients with HER2-positive, metastatic breast cancer who were randomized to receive docetaxel plus trastuzumab with or without pertuzumab (a monoclonal antibody that prevents HER2 from dimerizing with other HER subtypes, particularly the most potent signaling partner, HER3). A full report of these findings was recently published, results are expected to lead to regulatory approval of pertuzumab in 2012.

Predictive Value of Genomic Assays for DCIS
In a biomarker validation study , researchers reported that the Oncotype DX DCIS Score (calculated based on a 12-gene subset of the 21-gene Oncotype DX assay for invasive breast cancer) can predict risk for an ipsilateral breast event (either a new invasive breast cancer or a DCIS recurrence) in women who have undergone breast-conserving surgery. DCIS scores from 0 to 100 were generated and were classified as predictive of low (<39), intermediate (39–54), and high (55) risk for recurrence. The assay’s predictive value was assessed in 327 participants in the prospective ECOG E5194 study. Rates of any ipsilateral breast event and of invasive breast cancer were directly related to DCIS risk scores. The Oncotype DX DCIS assay is now commercially available and could inform clinical decision making about the need for radiation therapy, additional surgery, or both treatments.

Source:Journal Watch Oncology and Hematology.