Biomedical imaging modalities such as magnetic resonance imaging (MRI) have revolutionized the ability to detect and track the progress of many cancer types. However, the difficulty of obtaining detailed images of cancer cells buried deep within normal tissues has slowed the usefulness of imaging technology for improved, personalized cancer care.
An approach biomedical engineers are pursuing to overcome this limitation involves building nanoprobes that are designed to travel throughout the body, accumulate in cancer cells, and send a signal that illuminates the tumor.
NIBIB-supported researchers at Johns Hopkins University have developed a smart nanoprobe designed to infiltrate prostate tumors and send back a signal using an optical imaging technique known as Raman spectroscopy. The new probe, reported in Advanced Science, has the potential to determine tumor aggressiveness and could also enable sequential monitoring of tumors during therapy to quickly determine if a treatment strategy is working.
“We are excited about the potential for improving diagnosis and treatment of many common cancers,” explained the project leaders Jeff Bulte, PhD, and Ishan Barman, PhD. “We are combining self-assembling nanoprobes with Raman spectroscopy to achieve precise, single-cell resolution images required for eventual practical use in the clinic.”
The engineering team constructed a nanoprobe that is sensitive to its local microenvironment: it is activated only after it encounters legumain, a tumor-associated enzyme that is produced by aggressive prostate cancer cells. Once it encounters the nanoprobe, legumain splits it into pieces that can self-assemble to create an optically active nanoparticle. These nanoparticles emit specific wavelengths of light that can be detected with Raman spectroscopy to visualize the tumor.
Postdoctoral fellows Swati Tanwar, PhD, and Behnaz Ghaemi, PhD, spearheaded the design and synthesis of the nanoprobe, called nanoSABER (for Self-Assembling Bioorthogonal Enzyme Recognition)—an apt name that reflects the surgical precision of the smart molecule.
“We have chosen Raman reporters that are specifically active in the ‘cell silent’ region of the near-infrared spectrum to avoid interference with the signal from normal tissue,” explained Barman. “This selective activity is crucial for our imaging technique, as it allows for precise detection by Raman spectroscopy without reacting with or being obscured by the surrounding biological material.”
The researchers used two prostate cancer cell lines exhibiting varying levels of legumain expression—one high and one low—alongside a non-cancerous prostate epithelial cell line, which produces a negligible amount of the enzyme.
NanoSABER was tested in laboratory cell cultures and in an experimental mouse model. In both settings, the prostate cells expressing legumain activated the nanoprobe and emitted a signal with an intensity that corresponded to the amount of legumain produced by the cancer cells. The non-legumain cell type did not activate the nanoprobe, demonstrating that the nanoSABER system performed as designed, emitting a signal that correctly indicated the presence and amount of the cancer-associated enzyme.
“The work by this group is a significant step towards better care for men afflicted with prostate cancer,” explained Tatjana Atanasijevic, PhD, a program director in the Division of Applied Science & Technology at NIBIB. “It is an excellent example of the type of innovative technologies NIBIB supports that have the potential to dramatically impact health care.”
The team believes they have engineered a molecular system with the potential to not only identify tumors using optical imaging but to also rapidly assess tumor aggressiveness—potentially without the need for painful biopsies that are the current standard of care. In addition, as profiles of enzyme secretion by different types of cancers are discovered, additional nanoSABER probes can be synthesized that will allow a level of precise diagnosis of tumor types and characteristics that is not currently possible, including sequential imaging of tumors to determine whether therapies are working in real time.
SYNC-T, an investigational therapy that combines a device-induced vaccination at the tumor site with intratumoral infusion of a multitarget biologic drug, led to numerous clinical responses in patients with metastatic castrate-resistant prostate cancer (mCRPC). The results were reported at the American Association for Cancer Research (AACR) Annual Meeting 2024.
Patients with mCRPC—prostate cancer that does not respond to hormone therapies—have few treatment options and a high mortality rate, according to Charles Link, MD, an adjunct professor at Lankenau Institute for Medical Research, part of Main Line Health, and a cofounder and executive chairman of Syncromune. Prostate cancer has an immunologically “cold” tumor microenvironment. This has presented challenges for existing immunotherapies, which have exhibited low response rates and high toxicity in patients with prostate cancer.
Link and colleagues developed a novel treatment approach to stimulate a systemic antitumor immune response for mCRPC. Their therapy, called SYNC-T, first uses a probe that is inserted directly into the primary or metastatic tumor to freeze a portion of the tumor, which causes the tumor cells to fracture (oncolysis) and release immune-stimulating neoantigens. In essence, this method generates a personalized in situ neoantigen cancer vaccine that serves to activate the immune system, Link explained.
Link added that the imaging and procedural techniques for inserting a probe into the prostate are similar to the methods routinely used by urologists to conduct prostate biopsies. Immediately following the oncolysis step, an investigational multitarget biologic drug called SV-102—which is a fixed-dose drug comprised of active pharmaceutical ingredients: an anti-PD-1 antibody, an anti-CTLA4 antibody, a CD40 agonist, and a TLR9 agonist—is infused into the area of lysis in the tumor.
“SV-102 simultaneously blocks two distinct mechanisms of immune suppression and activates two distinct mechanisms of immune enhancement, allowing the vaccine-induced T cells to activate and mount a systemic antitumor immune response,” said Link.
The safety and efficacy of SYNC-T were evaluated in a phase I clinical trial, which enrolled 15 patients (12 patients with mCRPC and three patients with metastatic prostate cancer who opted out of hormone therapy), 13 of which have been evaluated for response. Sixty percent of patients identified as white, 33% as Hispanic, and 7% as Black. The median age was 61 years.
Of the 13 evaluable patients, 11 experienced an objective response, with five complete responses and six partial responses). The other two evaluable patients had stable disease at the time of data analysis. Six patients experienced mild to moderate treatment-related adverse events, including fever, rigors, fatigue, diaphoresis, hematuria, urinary tract infection, acute urinary retention, and hepatic enzyme elevation.
“The toxicity of SYNC-T appears to be much lower than what has been observed previously with intravenous immunotherapy for prostate cancer,” Link noted.
“Our results indicate that SYNC-T is associated with a high response rate without generating severe toxicity in this initial group of patients, which opens up opportunities to expand the role of immunotherapy in mCRPC,” he summarized. “Further, this approach uses standard procedures already employed by urologists and radiologists, which means the treatment could potentially be rapidly adopted by treating physicians.”
Limitations of the study include the small sample size, short follow-up time, and the single-arm design.
In patients with newly diagnosed prostate cancer patients, radioguided surgery can detect and remove metastatic pelvic lymph nodes, according to research published in the March issue of The Journal of Nuclear Medicine. Targeting the prostate-specific membrane antigen (PSMA), which is overexpressed in most prostate cancer patients, radioguided surgery can improve nodal staging to guide treatment recommendations for this important patient population.
In newly diagnosed prostate cancer patients, nodal involvement correlates with recurrence, and determining if lymph node metastases are present and where they are located is crucial for clinical decision making and treatment planning. For example, patients with nodal involvement can benefit from adjuvant therapies, such as radiation and chemotherapies, which can improve outcomes.
To date, extended pelvic lymph node dissection (ePLND), a procedure in which as many metastatic lymph nodes as possible are removed from the pelvic area, is considered the best tool for nodal staging. Although the therapeutic effect of ePLND in prostate cancer patients is controversial, evidence suggests that removal of all nodal metastases could maximize locoregional disease control.
“PSMA-radioguided surgery can aid the surgeon in accurately finding and removing all metastatic lymph nodes in newly diagnosed prostate cancer patients. This is specifically important to detect positive lymph nodes just outside the standard pelvic surgical area, or in surgically challenging regions, that would have been missed otherwise,” said Diederik M. Somford, MD, PhD, urologist and principal investigator at the Canisius Wilhelmina Hospital in Nijmegen, Netherlands.
The study included 20 newly diagnosed prostate cancer patients with at least one suggestive lymph node visible on a preoperative 18F-PSMA PET/CT scan. 111In-PSMA-radioguided surgery was performed to remove metastatic lymph nodes, and a postoperative 18F-PSMA PET/CT scan was performed to verify successful removal of suggestive lesions. The safety and feasibility of 111In-PSMA-radioguided surgery was assessed, as well as its accuracy in determining metastatic lymph nodes.
No adverse events related to 111In-PSMA-radioguided surgery were reported. 111In-PSMA radioguided surgery identified and removed 29 of 49 lesions, of which 28 (97 percent) contained lymph node metastases. Another 14 of 49 (29 percent) removed lymph nodes were not detected with 111In-PSMA radioguided surgery, of which two contained metastases.
“Although previous studies have reported on the feasibility of PSMA-radioguided pelvic lymph node surgery, this study is among the first trials to investigate this technique in a larger number newly diagnosed patients,” said Melline G.M. Schilham, MD, executive researcher at the Radboud University Medical Centre in Nijmegen, Netherlands. “The study shows that this novel surgical technique is safe and feasible. Furthermore, each patient underwent postoperative imaging to check whether the lymph nodes were truly removed, which is important to substantiate the reliability of the results.”
“The current results demonstrate the great potential for radioguided surgery in prostate cancer and highlight the expanding role of molecular imaging at the operating room,” noted Mark Rijpkema, PhD, principal investigator at the Radboud University Medical Centre. “Optimization of tracers and larger clinical trials may further improve surgical outcomes in the future by implementing both measurements of removed tissue, as well as real-time measurements during surgery.”
Changes in gut microbiota abundance have been linked to prostate cancer development. However, the causality of the gut-prostate axis remains unclear.
Methods
The genome-wide association study (GWAS) data for gut microbiota sourced from MiBioGen (n = 14,306), alongside prostate cancer summary data from PRACTICAL (n = 140,254) and FinnGen Consortium (n = 133,164). Inverse-variance-weighted (IVW) was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl), after diligently scrutinizing potential sources of heterogeneity and horizontal pleiotropy via the rigorous utilization of Cochran’s Q test, the MR-PRESSO method, and MR-Egger. We used meta-analysis methods in random effects to combine the Mendelian randomization (MR) estimates from the two sources.
Results
The pooled analyses of MR results show that genus Eubacterium fissicatena (OR = 1.07, 95% CI 1.01 to 1.13, P = 0.011) and genus Odoribacter (OR = 1.14, 95% CI 1.01 to 1.27, P = 0.025) were positively associated with prostate cancer. However, genus Adlercreutzia (OR = 0.89, 95% CI 0.83 to 0.96, P = 0.002), Roseburia (OR = 0.90, 95% CI 0.83 to 0.99, P = 0.03), Holdemania (OR = 0.92, 95% CI 0.86 to 0.97, P = 0.005), Flavonifractor (OR = 0.85, 95% CI 0.74 to 0.98, P = 0.024) and Allisonella (OR = 0.93, 95% CI 0.89 to 0.98, P = 0.011) seems to be a protective factor for prostate cancer. Sensitivity analysis found no significant heterogeneity, horizontal pleiotropy, or reverse causal links in all causal associations.
Conclusion
This MR study lends support to a causal relationship between genetically predicted gut microbiota and prostate cancer. Research on the gut-prostate axis, along with further multi-omics analyses, holds significant implications for the prevention and treatment of prostate cancer.
Introduction
In men globally, prostate cancer represents 7% of all new cancer diagnoses, with a pronounced prevalence in Western nations [1]. Notably, it emerges as the second leading cause of cancer-associated mortality in this demographic, culminating in over 350,000 deaths annually [2]. Given this, the urgency of early detection in potentially high-risk individuals, accompanied by swift therapeutic interventions, becomes paramount in curbing both the incidence and mortality rates linked to this malignancy.
The gut microbiota, a diverse collection of microorganisms in the digestive tract, is vital in determining and sustaining the host’s health via interactions like nutrient processing and immune system modulation. Obesity and high-fat consumption are linked to Prostate cancer risks, with lifestyle, particularly dietary habits, influencing the gut microbiome [3]. It’s long been believed that certain bacteria can cause persistent, mild inflammation, potentially triggering prostate cancer. Although the current positive correlation between prostatitis and prostate cancer rates may be the result of detection bias [4]. Poutahidis et al. [5] demonstrated that gastrointestinal bacterial infections can enhance prostatic intraepithelial neoplasia (PIN) and microinvasive carcinoma in vivo. Additionally, individuals diagnosed with prostate cancer showed significant increases in proinflammatory Bacteroides and Streptococcus species. Antibiotics promote selection for resistant bacteria by enhancing the proliferation of pathogenic strains. Research indicates that antibiotic use elevates the risk of infections from Clostridium difficile and methicillin-resistant Staphylococcus aureus [6]. Tulstrup et al. [7] found that changes in the microbiota due to antibiotics can alter intestinal permeability, thereby heightening the risk of neoplastic alterations. Earlier research has demonstrated that prostate cancer patients exhibiting elevated oestrogen levels may possess intestinal bacterial genes capable of oestrogen metabolism. Such metabolic activity can expedite carcinogenesis by activating polycyclic aromatic hydrocarbons (PAHs) [8,9,10]. Escherichia coli commonly resides in the human gut. Murine studies have indicated a potential link between E. coli and prostatitis development [11]. Moreover, Campylobacter jejuni has been identified as an inducer of cell cycle arrest and cellular death through its toxin production. Notably, Clostridium can transform gut glucocorticoids into androgens through side chain cleavage, contributing synergistically to the progression of prostate cancer [12]. While numerous studies have investigated the link between specific gut microbes and prostate cancer, the causal relationship between them remains unclear [13, 14].
Mendelian randomization (MR) emerges as a method of instrumental variable (IV) analysis that harnesses single nucleotide polymorphisms (SNPs) derived from genome-wide association studies (GWAS) as tools to deduce causal associations between two traits [15]. MR approximates the inherent attributes of a RCT and exhibits a reduced susceptibility to the impact of covariates. Moreover, its operational simplicity and cost-effectiveness enhance its appeal [16]. Consequently, we conducted a two-sample MR utilizing aggregated data from accessible GWAS repositories. This approach facilitated an exploration of the conceivable etiological correlation between gut microbiota and the risk of Prostate cancer through a comprehensive meta-analysis.
Discussion
In this study, large-scale GWAS data using European ancestry, combined with MR and meta-analyses demonstrated a potential causal link between gut microbiome and prostate cancer.
Despite the anatomical distance between the prostate and the gut, a substantial body of research suggests a potential link between the gut microbiome and both prostate cancer development and drug resistance. Liss et al. [30] conducted a study utilizing 16S rRNA sequencing to analyze the gut microbiota of 133 American men who underwent prostate biopsies. Their findings indicated elevated levels of Streptococcus and Bacteroides species in men diagnosed with prostate cancer. Further genome studies indicate that alterations in folate and arginine pathways, possibly influenced by gut microbes, may play a role in prostate cancer risk. Golombos et al. [13] observed a greater prevalence of Bacteroides massiliensis in individuals with prostate cancer in comparison to the healthy control group. Conversely, Faecalibacterium prausnitzii and Eubacterium rectalie exhibited higher relative abundances among the control group. Elevation of F.prausnitzii and E.rectalie is associated with the formation of anti-inflammatory butyrate, resulting in a symbiotic and protective effect [31, 32].
The results of data pooled from the PRACTICAL and FinnGen consortiums indicate that the genus Eubacterium fissicatena and Odoribacter are associated with an increased risk of prostate cancer. Conversely, the genus Adlercreutzia, Roseburia, Holdemania, Flavonifractor, and Allisonella are potential protective factors against prostate cancer. In fact, the gut microbiome tends to be influenced by host genetics. Xu et al. [33] demonstrated that Odoribacter had nominally significant heritability estimates (0.476), implying its potential role as a genetic carcinogenic factor for prostate cancer. The Eubacterium fissicatena group may be associated with in vivo metabolism. Nutritional investigations have shown a significant increase in the abundance of the E. fissicatena group in populations following a low-calorie diet for 6 days a week [34]. Despite the absence of specific studies on the relationship between the E. fissicatena group and prostate cancer, Zang et al. discovered a causal relationship between E. fissicatena and psoriasis. This finding suggests that gut microbes play a role in mediating the modulation of relevant immune responses [35].
Equol, a secondary metabolite of daidzein produced by the intestinal microbiota, is significantly associated with a reduced risk of prostate cancer in Japanese men, as indicated by plasma equol levels in a study [36]. Additionally, a positive correlation was detected between the genus Adlercreutzia and S-equol concentration [37]. Roseburia, a Gram-positive anaerobic bacterium, induces cancer cell apoptosis through the inhibition of histone deacetylases and related signaling pathways. It also contributes to immune homeostasis and has anti-inflammatory properties by producing short-chain fatty acids [38]. While research on the role of Holdemania, Flavonifractor, and Allisonella in prostate cancer is limited, their correlation with colorectal cancer and metabolism suggests potential roles in immune function, inflammation, and hormone levels. These factors have been implicated in the development and progression of prostate cancer [39, 40]. The effects of bacteria on prostate cancer risk are likely multifactorial, involving a combination of specific microbial activities, host responses, and interactions within the broader microbiome [41]. Eubacteriales from the same order may have different effects on prostate cancer, which is related to the fact that different species in the same bacterial order may have different metabolic pathways and produce different metabolites. Secondly, the functions of bacteria will vary according to the host and environment, and finally we cannot ignore the interactions between bacterial groups [42]. As research in this field progresses, a more nuanced understanding of these complexities will likely emerge.
4.1 Strength and limitation
Our MR analysis has the following advantages. Firstly, the sample size in the GWAS was large and the study strictly adhered to the three assumptions of MR, thus reducing confounders and reverse bias. Secondly, the study population included only individuals of European origin, minimizing population stratification interference. Finally, sensitivity analyses and different model estimations were used to ensure the reliability of the results.
However, certain limitations are unavoidable. Firstly, we assumed of a linear relationship between gut microbiota and prostate cancer risk, disregarding the potential presence of U-shaped associations. Furthermore, the generalizability of our results to different racial groups and various subtypes of prostate cancer is uncertain. Additionally, data limitations such as individual dietary habits and environmental factors may lead to confounding factors. Consequently, further molecular experiments are imperative to corroborate the findings of this study.
5 Conclusion
This MR study unveils genetic evidence supporting a causal link between gut microbiota and prostate cancer. The multi-omics-based platform is anticipated to offer fresh perspectives on prostate cancer diagnosis and treatment by delving into the pathogenic mechanisms and potential bacterial biomarkers.
Prostate-specific membrane antigen (PSMA)–targeted radioguided surgery (RGS) aims to optimize the peroperative detection and removal of PSMA-avid lymph node (LN) metastases (LNMs) and has been described in patients with recurrent prostate cancer (PCa). In newly diagnosed PCa patients undergoing pelvic LN dissections, PSMA RGS could guide the urologist toward PSMA-expressing LNMs as identified on preoperative 18F-PSMA PET/CT imaging. The objective was to evaluate the safety and feasibility of 111In-PSMA RGS in primary PCa patients with one or more suggestive LNs on preoperative 18F-PSMA PET/CT. Methods: This prospective, phase I/II study included 20 newly diagnosed PCa patients with at least 1 suggestive LN on preoperative 18F-PSMA PET/CT. PSMA RGS was performed 24 h after 111In-PSMA-I&T administration, and postoperative 18F-PSMA PET/CT was performed to verify successful removal of the suggestive lesions. The primary endpoint was determination of the safety and feasibility of 111In-PSMA RGS. Safety was assessed by monitoring adverse events. Feasibility was described as the possibility to peroperatively detect suggestive LNs as identified on preoperative imaging. Secondary outcomes included the accuracy of 111In-PSMA RGS compared with histopathology, tumor- and lesion-to-background ratios, and biochemical recurrence. Results: No tracer-related adverse events were reported. In 20 patients, 43 of 49 (88%) 18F-PSMA PET–suggestive lesions were successfully removed. 111In-PSMA RGS facilitated peroperative identification and resection of 29 of 49 (59%) RGS-target lesions, of which 28 (97%) contained LNMs. Another 14 of 49 (29%) resected LNs were not detected with 111In-PSMA RGS, of which 2 contained metastases. Conclusion:111In-PSMA RGS is a safe and feasible procedure that allows peroperative detection of 18F-PSMA PET/CT–suggestive lesions in newly diagnosed PCa patients. The use of a radioactive PSMA tracer and a detection device (γ-probe) during surgery helps in identifying LNs that were suggestive of PCa metastases on the 18F-PSMA PET/CT before surgery and thus may improve the peroperative identification and removal of these LNs.
Several misconceptions surround the relationship between physical activity and prostate cancer, leading to confusion and misinformation. One common misconception is that engaging in intense physical activity increases the risk of developing prostate cancer. In reality, several studies suggest that regular, moderate exercise may have a protective effect against prostate cancer. Sedentary lifestyles, on the other hand, have been associated with a higher risk.
Another misconception is the belief that only vigorous exercise provides benefits. While vigorous activities can be beneficial, even light to moderate physical activity, such as brisk walking, gardening, or cycling, has been linked to a reduced risk of prostate cancer. It’s important for individuals to understand that incorporating any form of regular physical activity into their routine can contribute to overall health and potentially lower the risk of prostate cancer.
Some may also believe that age is a barrier to the positive effects of physical activity on prostate health. However, research suggests that older men who engage in regular exercise still experience health benefits, including a potential reduction in the risk of developing prostate cancer. Exercise can also play a crucial role in improving the quality of life for prostate cancer survivors, helping manage treatment side effects and promoting overall well-being.
Lastly, there is a misconception that physical activity is only relevant after a prostate cancer diagnosis. While exercise is beneficial during and after treatment, maintaining an active lifestyle before diagnosis may contribute to a lower risk of developing prostate cancer in the first place. It’s crucial to dispel the notion that the benefits of physical activity are limited to specific stages of life or health conditions.
In summary, regular physical activity, even at moderate intensity, is associated with a lower risk of prostate cancer. Dispelling misconceptions and promoting awareness of the positive impact of exercise on prostate health can contribute to better-informed lifestyle choices and ultimately help reduce the incidence of this common cancer.
Prostate health has long been a subject of scientific scrutiny, and researchers have explored various factors that may influence it, including the role of masturbation. Contrary to common misconceptions, the relationship between frequent masturbation and prostate health is a complex and debated topic within the scientific community.
Studies on prostate health have shown a nuanced connection with sexual activity, with some research suggesting potential benefits. One study led by Dr. Jennifer Rider, published in the journal JAMA, found that frequent ejaculation, either through sexual intercourse or masturbation, was associated with a lower risk of prostate cancer in men. The study proposed that the release of toxins and potentially carcinogenic substances through ejaculation could contribute to this protective effect.
However, it is crucial to acknowledge the existing uncertainties and limitations within the realm of medical studies. The evidence supporting the positive link between masturbation frequency and prostate health is not universal, and some studies have failed to establish a significant correlation. This divergence in findings often stems from methodological differences, varying sample sizes, and the complexity of human sexual behavior, making it challenging to draw definitive conclusions.
Benefits: A Pleasurable Perspective on Men’s Wellness
Examining the potential benefits of frequent masturbation opens the door to a broader discussion on men’s overall wellness. Beyond its association with reduced prostate cancer risk, masturbation has been linked to several health advantages. Regular sexual activity, including masturbation, has been shown to contribute to the release of endorphins, commonly known as “feel-good” hormones. This hormonal response may play a role in improving mental well-being, reducing stress, and enhancing sleep quality.
Moreover, the positive impact of masturbation on hormonal balance should not be overlooked. Dr. Mark Hamilton, an endocrinologist specializing in reproductive health, notes that ejaculation triggers hormonal changes, including the release of oxytocin and testosterone. These hormones play crucial roles in stress relief, mood regulation, and maintaining overall hormonal equilibrium.
Risks: Navigating Uncertainties in Sexual Health
While exploring the potential benefits of masturbation, it is essential to address the existing uncertainties and potential risks associated with this aspect of sexual health. Some studies have suggested a link between excessive sexual activity and an increased risk of prostate-specific antigen (PSA) elevation, a potential marker for prostate issues. However, these findings are inconclusive, and the medical community remains divided on the interpretation of such results.
Furthermore, concerns about the impact of frequent ejaculation on the immune system and cardiovascular health have been raised. Dr. Emily Chen, a cardiologist with a focus on sexual health, emphasizes the need for comprehensive research in this area. While some studies suggest potential immune-boosting effects of sexual activity, conflicting evidence exists, underscoring the need for further investigation.
Reproductive Health: Balancing Act for Ejaculatory Function
The relationship between masturbation frequency and male reproductive health involves a delicate balance. Ejaculation is a crucial aspect of reproductive function, playing a role in sperm quality and motility. However, excessive ejaculation may raise concerns about sperm depletion and its potential impact on fertility. Dr. Sarah Martinez, a reproductive endocrinologist, highlights that while occasional masturbation is unlikely to affect fertility, those actively trying to conceive may consider moderation.
Conclusion: Navigating the Seas of Sexual Science
In conclusion, the intricate interplay between sexual satisfaction, mental well-being, and overall health underscores the need for a holistic perspective on the role of masturbation in men’s lives. While certain studies suggest potential benefits for prostate health and overall well-being, the scientific community is far from reaching a unanimous consensus. The divergent findings across various studies highlight the challenges inherent in researching such intimate and complex aspects of human behavior.
As we navigate the seas of sexual science, it is crucial to approach the topic with an open mind, acknowledging the limitations of existing research and the evolving nature of scientific understanding. Rather than offering prescriptive recommendations, health professionals should encourage individuals to maintain a balanced approach to sexual activity, considering both the potential benefits and risks associated with frequent masturbation.
Ultimately, fostering a healthy attitude towards one’s sexuality, informed by scientific knowledge and personal comfort, is paramount. As the scientific community continues to unravel the mysteries surrounding masturbation and men’s health, individuals are encouraged to stay attuned to their bodies, prioritize holistic well-being, and engage in open, informed conversations with healthcare professionals.
While HPV has been directly linked to cervical and some head and neck cancers, emerging evidence suggests new associations with other types of cancers.
Viruses play a significant role in the development of certain types of cancers. They can alter normal cell function by integrating their genetic material into human DNA, leading to mutations and disruptions in cell growth and division. This can cause uncontrolled cell proliferation, a hallmark of cancer.
Some viruses, like the human papillomavirus (HPV), are directly linked to specific cancers such as cervical and some head and neck cancers. As cancer research continuously evolves, new correlations between known viruses and various cancers are emerging.
Evolving Role of HPV
HPV is a contagious pathogen primarily transmitted through sexual contact, leading to HPV-related cancers in both genders. The vast majority of cervical cancers have a connection to HPV, and a growing body of evidence suggests a similar association with some head and neck cancers, particularly oropharyngeal cancer. Additionally, a range of anogenital cancers, such as vaginal, vulvar, penile, and anal cancers, also fall under the category of malignancies associated with HPV.
Recent studies have revealed a potential link between HPV infections and more significant forms of cancer. These insights challenge our current understanding of these diseases and open new avenues for prevention and treatment strategies.
HPV’s link to cervical, head, and neck cancers is well-established and supported by decades of research and clinical evidence. The virus is a significant cause of these cancers, with a clear and direct connection. However, emerging research is exploring the potential role of HPV in other cancers, such as prostate and thyroid cancers.
While initial studies suggest a possible link, the research is still in the early stages.
Prostate Cancer: The Leading Cancer in Men
The prostate is a small gland located just below the bladder in men, near the rectum. It’s shaped like a walnut and surrounds the urethra, the tube that carries urine from the bladder out through the penis. Its primary function is to produce seminal fluid, which is a component of semen. This location and function make it a vital part of the male reproductive system.
Globally, prostate cancer is the most common cancer diagnosis among men. In 2015, it accounted for around 1.6 million new cases. Over the period from 2014 to 2019, the incidence of prostate cancer exhibited a consistent annual increase of 3 percent.
U.S. projections for 2023 anticipated 288,300 new cases of prostate cancer, solidifying its status as the most prevalent cancer among males in the country. This would constitute 15 percent of all new cancer diagnoses and is associated with an estimated 34,700 deaths within the same year.
In its early stages, prostate cancer may not cause noticeable symptoms. More advanced cases can lead to issues like trouble urinating, decreased force in the urine stream, blood in urine or semen, bone pain, unintentional weight loss, and erectile dysfunction. Approximately half of the cancers were advanced.
Risk factors include older age, being black, a family history of prostate cancer, and obesity. The mortality rate of prostate cancer in blacks is two to four times higher than in other racial and ethnic groups.
HPV and Prostate Cancer
A December 2023 study published in the Nature journal Prostate Cancer and Prostatic Diseases has shed light on HPV as a new risk factor for prostate cancer.
The study utilized data from Taiwan’s Longitudinal Health Insurance Database 2010, analyzing cases of 5,137 patients with prostate cancer and 15,411 matched controls.
The findings were significant, with data indicating a markedly higher incidence (2.3 times higher) of previous HPV infections among individuals with prostate cancer compared with their control counterparts. This means that the risk of developing prostate cancer is more than double after a previous HPV infection compared with those who were never infected. Individuals diagnosed with chronic prostatitis were also at a higher risk for subsequently developing prostate cancer.
Adjustments were made for other common risk factors, including age, monthly income, geographic location, urbanization level of the patient’s residence, as well as hyperlipidemia, diabetes, hypertension and chronic prostatitis, tobacco use, and alcohol abuse.
These findings suggest that HPV might play a more fundamental role in the development of prostate cancer than previously thought.
HPV and Thyroid Cancer
More surprisingly, thyroid cancer, a less common but still potentially lethal cancer, was also related to HPV.
The thyroid is a small, butterfly-shaped gland located at the base of the neck, just below the “Adam’s apple,” the thyroid cartilage surrounding the larynx, which is typically more prominent in men than women. It plays a crucial role in the body’s metabolism, growth, and development. The thyroid gland produces thyroid hormones that regulate various bodily functions, including heart rate, body temperature, and how the body uses energy. These hormones are essential for the proper functioning of nearly every body part.
Thyroid cancer is the most prevalent cancer of the endocrine system. In recent years, the incidence of thyroid cancer in the United States has significantly increased, tripling over the past 30 years. Currently, around 45,000 new cases are diagnosed each year.
Another groundbreaking study in Nature published in January focused on the association between HPV and thyroid cancer.
This research involved a comprehensive case-control study using Taiwan’s Longitudinal Health Insurance Database 2010, including 3,062 patients with thyroid cancer and 9,186 propensity-scored matched controls. The propensity score balances an observational study by using some of the study characteristics to mimic a randomized controlled trial.
The study’s results were startling: The research suggests a significant link between HPV and the development of thyroid cancer. People with a prior HPV infection have almost twice the chance of developing thyroid cancer compared with those without a prior infection, with similar findings in males and females.
The results remained the same regardless of age, sex, income, and other key attributes, suggesting a fundamental biological association between the virus and its cancer-inducing outcome.
Cancer-Causing Mechanisms
While these studies provide compelling evidence of the association between HPV and both prostate and thyroid cancers, it’s essential to understand the underlying mechanisms. There are several mechanisms through which HPV contributes to the development of these cancers.
Harmful genetic and environmental elements can increase the risk of developing cancer. However, our immune system can monitor and kill cancer cells as soon as the malignant cells appear. Ultimately, the strength of our immune system determines if we contract cancer or not and how fast it will spread if we do, which depends on our body’s ability to fight cancer cells effectively.
Genetic mutations in specific cancer-related genes commonly lead to abnormal cell growth and tumor formation. Environmental risk factors include ionizing radiation. Nutritional factors, including iodine deficiency or excess, can increase the risk of developing thyroid cancer.
The role of HPV in causing cancer is primarily due to its critical cancer-inducing proteins, E6 and E7. These proteins break down the body’s tumor-fighting proteins (p53 and pRb). This breakdown interferes with the standard control of cell growth, leading to rapid and uncontrolled cell multiplication.
Additionally, E6 and E7 interfere with other cell functions, such as DNA repair and blood vessel growth, and hinder the cell’s natural self-destruction, termed “apoptosis,” which can lead to increased genetic instability and potential cancer.
Can the HPV Vaccine Prevent These Cancers?
The potential link between HPV and these cancers has profound implications. Exploring possible preventive measures could be a significant step forward in cancer prevention.
Some people have proposed expanding the use of HPV vaccines to include protection against these types of cancers. While this may appear to be a reasonable assumption given the current belief that the HPV vaccine adequately prevents cervical cancer, the battle between the virus and vaccine technology has proven to be more complex than most people realize. Viruses are a group of microscope organisms with a profound ability to escapeeven our most advanced vaccine technology.
For example, in the case of cervical cancer, the HPV vaccine does not cover all high-risk HPV types. Of the over 200 HPV strains, 22 pose a high risk for cervical cancer, yet Gardasil 9 targets less than half of these high-risk strains. This limitation may lead to the prevalence of other dangerous strains. Studies have observed shifts in HPV strain prevalence post-vaccination, with some non-vaccine high-risk strains becoming more common, particularly in vaccinated individuals.
Furthermore, the vaccine bypasses our mucosal immunity, resulting in an unbalanced stimulation of our immune system which may not favor our body’s holistic fight against cancer.
HPV vaccines do not cover all HPV strains that cause cervical cancer and will induce changes in cervical HPV strains. (Illustration by The Epoch Times)
The Role of Natural Immunity in Eradicating Cancer
Our body’s natural immunity serves to combat viruses and, therefore, plays a crucial role in fighting against cancer.
This natural defense mechanism is equipped to detect and eliminate cancer cells. Enhancing our natural immunity strengthens our ability to recognize and respond to cancerous cells early, thereby preventing the development of cancer.
Eating healthy food, maintaining quality sleep and a healthy weight, exercising, and using stress-reduction techniques, including mindfulness and meditation, all help enhance our natural immunity and reduce cancer risks.
Controlled Sexual Behavior Reduces Cancer Risk
Controlled sexual behaviors are known to be protective against cervical cancer, including older age at first sexual activity and limited sexual partners.
Engaging in sex for the first time on or before age 16 or between 17 to 20 years of age increased the risk of developing invasive cervical cancer by 2.3 and 1.8 times, respectively, compared with women over age 21. (Illustration by The Epoch Times)
In the case of prostate cancer, research also suggests a possible link between sexual activity and increased cancer risk.
A systematic review analyzing 21 case-control studies and one cohort study of 55,490 male participants (14,976 patients and 40,514 controls) explored how prostate cancer risk was affected by the number of female sexual partners, the age at first sexual intercourse, and the ejaculation frequency.
The researchers found that having more female sexual partners slightly increased the risk of prostate cancer. Delaying the age of first intercourse reduced this risk by 4 percent for every five-year delay. Moderate frequency of ejaculation, defined as two to four times per week, was significantly associated with a lower risk of prostate cancer.
For thyroid cancer, there is no biomedical study that directly establishes a link between sexual behavior and the risk of developing this type of cancer. However, limiting the number of sexual partners and delaying the age of first sex would reduce the risk of HPV infection. As HPV is carcinogenic, the less HPV we have in our body, the less likely we will develop a related cancer.
Sexual behavior, including the age of first sexual activity and the number of sexual partners, is relevant in cancer prevention in theory based on the established research findings regarding the interplay between HPV, sexual activity, and cancer.
Future Perspective on HPV and Cancer
The revelations from these newly published studies suggest that the impact of HPV infection extends far beyond the commonly known associations with cervical and head or neck cancers.
By shedding light on its potential role in prostate and thyroid cancers, these findings challenge the medical community to broaden its perspective on HPV. It’s possible that other cancers may also be influenced by HPV and sexual behavior. Future research may reveal more profound underlying mechanisms.
As research continues to unveil the multifaceted nature of HPV, it becomes increasingly clear that our understanding and management of this virus are crucial to the broader fight against cancer. This could lead to the development of comprehensive educational health programs that ultimately contribute to reducing the incidence and mortality rates associated with these and other cancers.
Last but not least, our choices matter; traditional values can help us live healthier.
PSMA PET is more accurate than CT and bone scans for staging patients with prostate cancer and in recent years has become the standard imaging modality at initial staging. Nearly all prostate cancer trials have used CT and bone scans for staging, however, and the best way to apply those data to patients staged with PSMA PET remains unclear. “Most research to date has focused on the increased sensitivity of PSMA PET versus conventional imaging such as bone scans and CT,” said Thomas Hope, MD, vice chair of clinical operations and strategy in the Department of Radiology and Director of Molecular Therapy at the University of California in San Francisco. “In this study, my colleagues and I took the opposite approach and looked at where PSMA PET was negative when bone scans were positive.”
Rather than receiving definitive radiation treatment for localized disease, these patients may have received treatment aimed at preventing the further spread of what was incorrectly identified as metastatic diseaseThomas Hope
The multicenter retrospective diagnostic study included 167 prostate cancer patients at various disease states who were imaged with bone scans and PSMA PET within 100 days. Each study was interpreted by three blinded readers. Using PSMA PET scans as the reference standard, researchers evaluated positive predictive value, negative predictive value, and specificity for bone scans as well as inter-reader reproducibility, positivity rate, uptake on PSMA PET, and number of lesions.
While the specificity of bone scans was found to be high and similar across disease states, the positive predictive value of bone scans at initial staging was found to be much lower than in the overall population. When compared to PSMA PET, more than half (57%) of bone scans at initial staging were found to contain false-positive metastases.
“Rather than receiving definitive radiation treatment for localized disease, these patients may have received treatment aimed at preventing the further spread of what was incorrectly identified as metastatic disease,” said Hope. “These results bring into question how to apply data from clinical trials that are based on bone scans to patients who receive PSMA PET. Looking at the big picture, this study highlights the importance of understanding how test characteristics impact patient management.”
With the expanded approval of enzalutamide (Xtandi), oncologists have a new treatment option to offer some patients with prostate cancer who have had a biochemical recurrence.
The number of treatment options for prostate cancer has exploded over the last decade. That trend is showing no signs of letting up, with the Food and Drug Administration’s (FDA) recent decision to expand the approved uses of enzalutamide (Xtandi) to treat people with prostate cancer that hasn’t spread, or metastasized, to other parts of the body.
Under this new approval, announced on November 16, enzalutamide can now be used alone, or in combination with leuprolide, to treat nonmetastatic prostate cancer that is castration sensitive.
The new approval also requires that the patient have had an increase in their blood PSA levels after earlier surgery or radiation, known as a biochemical recurrence. However, the approval only applies to those considered to be at high-risk of their cancer spreading.
Trial participants treated only with enzalutamide also had better metastasis-free survival than those treated with leuprolide alone.
But the extent to which this new approval and the EMBARK results will, or should, change patient care is still unclear, explained Fatima Karzai, M.D., of NCI’s Center for Cancer Research, who specializes in treating prostate cancer but was not involved in the trial.
For example, Dr. Karzai said, more time is needed to know whether trial participants treated with enzalutamide alone or in combination with leuprolide live longer overall. As a result, this new approval “will garner different treatment approaches” that oncologists recommend to their patients.
Other experts believe the approval will have a substantial impact on patient care. One of the trial’s lead researchers, Stephen Freedland, M.D., of Cedars-Sinai in Los Angeles, said many patients with these high-risk biochemical recurrences will now be treated with the enzalutamide and leuprolide combination.
Dr. Freedland acknowledged that side effects are a concern. “But there are a lot of benefits” to using both drugs together, he added, including “delaying metastasis.” The development of metastases not only requires immediate treatment but also can cause significant pain, particularly when the cancer has spread to the bones.
In addition, Dr. Freedland noted that other analyses from the trial suggests that, overall, treatment with both drugs doesn’t harm people’s quality of life.
From castration-resistant to castration-sensitive localized prostate cancer
Enzalutamide works by disrupting testosterone’s interaction with cancer cells. It’s already approved by FDA to treat nonmetastatic and metastatic prostate cancer, including when the cancer can no longer be controlled with drugs that block testosterone production (like leuprolide), known as castration-resistant disease.
In up to half of people with castration-sensitive localized prostate cancer who previously had surgery or radiation to eliminate the tumor, their PSA levels start to creep up, sometimes rapidly, within 10 years. When any such uptick happens, it may mean that the cancer is starting to grow again in the prostate or that there are small tumors somewhere else in the body.
A key measure that oncologists use to judge whether rising PSA levels are a concern is how long it takes for the levels to double from the time they became detectable again.
When the PSA doubling time is rapid, around 9 months or less, studies have suggested it means those patients are at high-risk of having their cancer spread to other organs.
But how to best address biochemical recurrences—even those with rapid PSA doubling times—has been “a gray zone,” Dr. Karzai explained.
Should treatment begin immediately to prevent the cancer from gaining steam? Or should treatment wait until the patient is experiencing symptoms or for confirmation from imaging scans that the cancer has spread?
Currently, many people with a biochemical recurrence with a PSA doubling time of 9 months or less are started on leuprolide or similar drugs, she said.
The EMBARK trial was designed to try to bring some clarity to the question.
In large clinical trials, enzalutamide improved how long men with castration-sensitive prostate cancer that has already spread live overall. So, with the EMBARK trial, researchers wanted to see if enzalutamide might also improve outcomes in people with prostate cancer that hasn’t spread but that—based on rising PSA levels—may be poised to.
Better metastasis-free survival, time with no treatment
Funded by Pfizer and Astellas Pharma, the manufacturers of enzalutamide, the trial enrolled nearly 1,100 participants who had been treated for localized prostate cancer. All participants had PSA levels that had returned and doubled within 9 months, but with no signs that their cancer had spread.
EMBARK participants were randomly assigned to treatment with both enzalutamide and leuprolide or with either drug alone.
After starting treatment, participants had full-body CT scans and bone scans every 6 months to look for signs that their cancer had returned. Participants whose PSA levels decreased to undetectable levels within 37 weeks could pause treatment. Such breaks are often called “treatment holidays.” Treatment resumed if their PSA levels started to rise again.
Five years after starting treatment, Dr. Freedland and his colleagues reported, about 87% of participants treated with enzalutamide and leuprolide were still alive with no evidence of metastasis, compared with 80% of people treated with only enzalutamide and 71% with only leuprolide. The findings were published in October in The New England Journal of Medicine.
Dr. Freedland noted that, to date, there is a strong statistical trend suggesting that people treated with both drugs also will live longer overall than those treated with leuprolide alone. But participants will have to be followed longer before it’s known for sure.
About 91% of people in the combination treatment group were able to pause treatment because of undetectable PSA levels, compared with 86% in the enzalutamide-only group and 68% in the leuprolide group.
Many patients in all three groups were able to pause treatment for 2 years or more, although the median length of treatment suspension was longest in the combination treatment group (20 months versus 17 and 11 months, respectively).
Side effects and quality of life
There were no surprises in terms of the side effects seen in the trial in people treated with enzalutamide alone or with leuprolide. That said, side effects were common and sometimes serious in all three treatment groups.
In the enzalutamide–leuprolide group, the most common side effects were hot flashes, fatigue, and muscle aches, although many of these were also common in the leuprolide alone group. In the enzalutamide–alone group, the most common side effects include hot flashes, fatigue, and enlarged breasts. Severe side effects were not frequent in any of the groups and were generally higher in those treated with enzalutamide.
In an editorial that accompanied the trial resultsExit Disclaimer, Ana Aparicio, M.D., who specializes in treating prostate cancer at the University of Texas M.D. Anderson Cancer Center, noted that of the trial participants who died, potentially up to 60% were from causes other than prostate cancer.
The large number of noncancer deaths can point to a problem called overtreatment—that is, treatment that was not likely to extend or improve a person’s life.
“The extent to which the cancer treatments contributed to these deaths is unknown,” Dr. Aparicio wrote. “But even if there was no association, their frequency arguably diminishes [the treatments’] potential benefit.”
Nevertheless, she concluded, the results show that, at least for some patients, the upside of “early cancer control” with enzalutamide alone or combined with leuprolide “outweigh[s] its risks.”
According to a separate analysis from EMBARK published in October in NEJM Evidence, treatment with enzalutamide and leuprolide did not appear to decrease EMBARK participants’ quality of life, Dr. Freedland noted.
The prospect of a prolonged treatment holiday is also an important consideration, he continued.
“After 8 or 9 months of therapy, if you do really well, we stop [treatment],” he said. “It’s not years and years of treatment. We’re going to be very aggressive for a period, and if you do well, chances are really high you’ll reach that [suspension] threshold.”
Use of PSMA-PET has expanded rapidly in the United States, so questions have been raised about how it should alter how people interpret the EMBARK results and—with this new approval—apply its findings in everyday patient care.
Although PSMA-PET scans can find small tumors missed by standard imaging (PET and bone scans), Dr. Karzai said, “it remains unclear whether early identification will alter the course of a patient’s disease.” In other words, a small tumor somewhere in the body may not grow or spread soon, if ever.
More research is needed on how to apply PSMA-PET imaging findings to decisions about treatment, Dr. Freedland said.
But, even in the absence of PSMA-PET results, he added, factors such as patient age, their overall health, and how they weigh the potential benefits of different treatments versus their risk will all come into play.
“While we don’t expect 100% of patients will go on [the combination treatment], it’ll be interesting to see how physicians and patients interpret these data and make decisions in the real world,” Dr. Freedland said.
For the time being at least, Dr. Karzai said, good doctor–patient communication about treatment options will be important.
“Clinicians will need to have balanced conversations with patients about the benefits of treatment when compared to the side effects” of both drugs, she said.
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