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Despite the compelling evidence for greater toxicity in female patients, sex-specific anticancer treatment strategies are missing. Increased awareness of sex differences at all stages of drug development by researchers, the pharmaceutical industry, funding institutions and regulatory agencies is needed to accurately implement precision oncology. In this Comment, Berna Özdemir summarizes the evidence for greater drug toxicity in female patients and emphasizes the need for increased awareness of sex differences at all stages of drug development to establish sex-specific anticancer treatment strategies.

The androgen receptor (AR) signalling pathway has been intensively studied in the context of prostate cancer, where androgen deprivation therapy is part of the standard of care for metastatic disease. By contrast, fewer studies have investigated the impact and translational potential of targeting AR in other cancer types where it is also expressed and functional. In this Review, we discuss the current understanding of AR in non-prostatic cancer types and summarize ongoing AR-directed clinical trials. While different androgen levels contribute to sexual dimorphism in cancer, targeting the AR system could benefit both sexes and help overcome resistance to targeted therapies. However, a bimodal function of AR signalling, which suppresses stromal changes associated with the early stages of cancer development, also needs to be considered. Future research is necessary to scrutinize cellular and molecular mechanisms of action of AR in cancer cells and the tumour microenvironment, to develop selective modulators of AR activity, and to identify patients with non-prostatic cancer who might benefit from targeting this pathway. AR-directed manipulation of host immune cells may offer a promising therapeutic approach for many types of cancers. Androgen receptor (AR) signalling plays an important role in several cancers beyond prostate cancer. This Review highlights the context-dependent functions of AR in non-prostatic malignancies, examining the intrinsic function of AR in cancer cells and the tumour microenvironment, and summarizes ongoing AR-targeted clinical trials.

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.

Female sex is associated with a higher risk for autoimmune diseases (ADs) and immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs). While the safety of ICIs in AD cohorts has been reported, sex-segregated data on patient characteristics and outcomes are lacking. In the present study, the disease and treatment characteristics of 51 patients with cancer and preexisting AD (PAD) treated with ICIs at Bern University Hospital Cancer Center (Bern, Switzerland) between January 2017 and June 2021 were analyzed by sex. Rheumatic (n=12/27, 44.4%) and endocrine (n=11/24, 45.8%) PADs were most common among male and female patients, respectively. At the time of ICI initiation, 29.6% (n=8/27) of male and 20.8% (n=5/24) of female patients received immunosuppression for their PAD. Female patients were more likely to experience an irAE (58.3 vs. 48.1%), and less likely to encounter an exacerbation of their PAD (38.5 vs. 14.3%) compared with male patients. Multiple-site irAEs (46.2 vs. 21.4%), implication of an organ specialist for irAEs (100.0 vs. 57.1%) and use of additional immunosuppressive drugs (38.4 vs. 7.7%) were more common in male patients. IrAEs were resolved and ICIs were discontinued in 69.2% (n=9/13) and 71.4% (n=10/14) of the total male and female patients, respectively. Median progression-free survival was higher in male than female patients with irAEs (19.9 vs. 10.7 months) and without irAEs (4.4 vs. 1.8 months). The median overall survival time was higher in male than female patients with irAEs (not estimable vs. 22.5 months) and without irAEs (10.1 vs. 7.4 months). Taken together, these results suggested that sex-related differences existed regarding the clinical presentation of irAEs and treatment outcome.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, characterized by its aggressive tumor biology and poor prognosis. While immune checkpoint inhibitors (ICIs) play a major part in the treatment algorithm of various solid tumors, there is still no evidence of clinical benefit from ICI in patients with metastatic PDAC (mPDAC). This might be due to several reasons, such as the inherent low immunogenicity of pancreatic cancer, the dense stroma-rich tumor microenvironment that precludes an efficient migration of antitumoral effector T cells to the cancer cells, and the increased proportion of immunosuppressive immune cells, such as regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs), facilitating tumor growth and invasion. In this review, we provide an overview of the current state of ICIs in mPDAC, report on the biological rationale to implement ICIs into the treatment strategy of pancreatic cancer, and discuss preclinical studies and clinical trials in this field. Additionally, we shed light on the challenges of implementing ICIs into the treatment strategy of PDAC and discuss potential future directions.

Background Sex- and gender-based medicine (SGBM) addresses differences between males/men and females/women with regard to clinical manifestation, diagnostics, treatment and outcomes of diseases. The implementation of SGBM in the medical curriculum varies, and data on the knowledge of lecturers and students about SGBM is scarce. This study aims to evaluate the perceived importance and knowledge of SGBM among lecturers and students. Methods This cross-sectional observational survey was conducted using a questionnaire, including ranked with a Likert Scale. Statistical analysis was performed with the Chi-squared test. All lecturers and students at the Bern University Medical School in Switzerland were invited to voluntarily participate. Results 114 (34.1%) lecturers and 903 (41.4%) students participated in the survey. Women perceived education of SGBM to be of greater importance than men in lecturer and student subgroups respectively (lecturers women vs. men median 6.0 vs. 5.0, P  = 0.011; students 6.0 vs. 5.0, P  < 0.001 ) . No significant differences between genders of self-reported knowledge of SGBM were found (lecturers women vs. men median 4.0 vs. 4.0, P  = 0.624; students 3.0 vs. 4.0, P  = 0.562). There were significant differences in the perception of the SGBM being actively addressed in lectures between lecturers and students (59.4% vs. 28.8%, P  < 0.001) and whether the curriculum should include SGBM (strongly agree 28.9% vs. 51.3%, P  < 0.001). Conclusion Women lecturers and students consider teaching of SGBM during medical studies to be more important than men. Lecturers perceived the amount of SGBM already included in the lectures to be greater compared to students.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2–3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.

The share of immune checkpoint inhibitors (ICIs) used in cancer treatment has rapidly increased in recent years. Although ICIs have the potential to provide a durable survival benefit in a subset of patients, many patients do not respond to these costly and often toxic therapies.Recent retrospective clinical data indicate that the time of day of ICI infusion may be a powerful modulator of their efficacy. These observational studies suggest an enhanced efficacy of morning over evening infusion. However, randomized trials have not confirmed in other fields findings obtained by observational studies, possibly because of selection bias and residual confounding factors. Thus, while the data are intriguing, the time dependence of the efficacy of immunotherapy needs to be confirmed in pragmatic randomized clinical trials. Here, we provide an overview of the modulation of ICI efficacy by the timing of immunotherapy infusion and critically discuss the biological rationale for chrono-immunotherapy, the circadian regulation of the immune system, and the need for pragmatic randomized clinical trials to confirm an effect of the timing of immunotherapy infusions on patient outcomes.

Approved adjuvant treatment options for stage III melanoma are the immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab, and in presence of a BRAF V600E/K mutation additionally dabrafenib in combination with trametinib (BRAFi/MEKi). This study aims to describe prescription patterns and recurrence and toxicity rates of adjuvant-treated melanoma patients from the Cancer Center of the University Hospital Bern, Switzerland. One hundred and nine patients with an indication for adjuvant treatment were identified. Five (4.6%) had contraindications and, as such, were not proposed any adjuvant treatment, while 10 patients (9.2%) declined treatment. BRAF status was known for 91 (83.5%) patients. Of 40 (36.7%) patients with BRAF V600E/K melanoma, pembrolizumab was prescribed to 18 (45.0%), nivolumab to 16 (40.0%), and dabrafenib/trametinib to three (7.5%) patients. Grade 3–4 toxicity was reported in 18.9% and 16.7% of all the patients treated with pembrolizumab and nivolumab, respectively. No toxicities were observed for dabrafenib/trametinib. Thirty-eight percent of the patients treated with pembrolizumab and 40.0% of those treated with nivolumab relapsed. No relapses were reported for dabrafenib/trametinib. Prescription patterns indicate a clear preference for adjuvant ICI treatment.