New drug approvals in prostate cancer and their effect on the treatment landscape.

Prostate cancer is the most frequently diagnosed non-skin cancer and the second leading cause of cancer-related mortality in men in the United States. Over the past decade, the treatment landscape for advanced prostate cancer has rapidly shifted. For decades, androgen deprivation therapy has been the cornerstone of systemic treatment for patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, more recently, we have seen the emergence of doublet and triplet combinations in the mHSPC setting. At the same time, there is an expanding list of treatments for patients with metastatic castration-resistant prostate cancer (mCRPC), including hormonal treatments, chemotherapy, immunotherapy, bone-targeted agents, radioligand therapy, and targeted therapy. The shifting of the treatment landscape for advanced prostate cancer has raised many questions regarding patient selection, therapy choice, and sequencing of different approved agents, particularly in the mCRPC setting with the earlier use of chemotherapy and androgen receptor signaling inhibitors. Since then, multiple trials have been conducted to improve the management of mHSPC and delay its progression to mCRPC. This review article discusses various clinical trials that focus on novel therapeutic targets for prostate cancer and how the initiation of newer clinical trials has affected older therapies and trials.

Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH.

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

Machine learning natural language processing for identifying venous thromboembolism: systematic review and meta-analysis.

ABSTRACT: Venous thromboembolism (VTE) is a leading cause of preventable in-hospital mortality. Monitoring VTE cases is limited by the challenges of manual medical record review and diagnosis code interpretation. Natural language processing (NLP) can automate the process. Rule-based NLP methods are effective but time consuming. Machine learning (ML)-NLP methods present a promising solution. We conducted a systematic review and meta-analysis of studies published before May 2023 that use ML-NLP to identify VTE diagnoses in the electronic health records. Four reviewers screened all manuscripts, excluding studies that only used a rule-based method. A meta-analysis evaluated the pooled performance of each study's best performing model that evaluated for pulmonary embolism and/or deep vein thrombosis. Pooled sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with confidence interval (CI) were calculated by DerSimonian and Laird method using a random-effects model. Study quality was assessed using an adapted TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) tool. Thirteen studies were included in the systematic review and 8 had data available for meta-analysis. Pooled sensitivity was 0.931 (95% CI, 0.881-0.962), specificity 0.984 (95% CI, 0.967-0.992), PPV 0.910 (95% CI, 0.865-0.941) and NPV 0.985 (95% CI, 0.977-0.990). All studies met at least 13 of the 21 NLP-modified TRIPOD items, demonstrating fair quality. The highest performing models used vectorization rather than bag-of-words and deep-learning techniques such as convolutional neural networks. There was significant heterogeneity in the studies, and only 4 validated their model on an external data set. Further standardization of ML studies can help progress this novel technology toward real-world implementation.

Isatuximab, carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed, transplantation-eligible multiple myeloma (SKylaRk): a single-arm, phase 2 trial.

BACKGROUND: Isatuximab is a CD38 monoclonal antibody approved for relapsed or refractory multiple myeloma. We aimed to evaluate the addition of isatuximab to weekly carfilzomib (K), lenalidomide (R), and dexamethasone (d; Isa-KRd) in transplant-eligible patients with newly diagnosed multiple myeloma and stratified maintenance by cytogenetic risk. METHODS: This single-arm phase 2 trial was done at three cancer centres (two hospitals and a cancer institute) in Boston (MA, USA). Eligible patients were aged at least 18 years and had transplant-eligible newly diagnosed multiple myeloma and an ECOG performance status of 2 or less. Patients received four 28-day cycles of Isa-KRd, including isatuximab 10 mg/kg intravenously weekly for 8 weeks, then every other week for 16 weeks, and every 4 weeks thereafter; carfilzomib 56 mg/m2 intravenously on days 1, 8, and 15 (20 mg/m2 for cycle 1 day 1); lenalidomide 25 mg orally on days 1-21; and dexamethasone 20 mg orally the day of and day after all doses of carfilzomib and isatuximab. Consolidation involved either upfront haematopoietic stem-cell transplantation (HSCT) with two additional cycles or deferred HSCT with four additional cycles of treatment. The primary endpoint was complete response after four cycles of treatment. Analyses were by intention-to-treat. All patients who received one dose of study drug were included in the safety analyses. This study was registered at ClinicalTrials.gov, NCT04430894, and has completed enrolment. FINDINGS: Between July 31, 2020 and Jan 31, 2022, 50 patients were enrolled. Median age was 59 years (range 40-70), 54% (27 of 50 patients) were male, and 44 (88%) were White. 46% (23 of 50) of patients had high-risk cytogenetics. Median follow-up was 26 months (IQR 20·7-30·1). 32% (16 of 50 patients) achieved a complete response after four cycles. The overall response rate (ORR) was 90% (45 patients) and 78% (39 patients) achieved a very good partial response (VGPR) or better. After completion of consolidation, 58% (29 patients) achieved a complete response; the ORR was 90% (45 patients) and 86% (43 patients) achieved a VGPR or better. The most common grade 3 or 4 side-effects (≥two patients) included neutropenia (13 [26%] of 50 patients), elevated alanine aminotransferase (six [12%] patients), fatigue (three [6%] patients), thrombocytopenia (three [6%] patients), acute kidney injury (two [4%] patients), anaemia (two [4%] patients), and febrile neutropenia (two [4%] patients). Grade 1-2 infusion-related reactions were seen in 20% (ten patients), with none grade 3. Grade 1-2 hypertension was seen in 14% (seven patients) with one grade 3 (one [2%] patient). There were two deaths assessed as unrelated to treatment. INTERPRETATION: Although the study did not achieve the prespecified complete response threshold, Isa-KRd induced deep and durable responses in transplant-eligible patients with newly diagnosed multiple myeloma. The treatment proved safe and consistent with similar regimens in this setting. FUNDING: Amgen, Sanofi, and Adaptive.

Circulating hormones in biopsy-proven steatotic liver disease and steatohepatitis: A Multicenter Observational Study.

BACKGROUND: The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated. PURPOSE: To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages. METHODS: This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited. RESULTS: We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD. CONCLUSIONS: Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.

Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18-80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (p-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08-2.25; family breast: OR: 1.68; CI: 1.08-2.60, family ovarian OR: 2.29; CI: 1.04-5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development.

Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a stress-response cytokine proposed to be associated with body weight regulation. AIMS: The primary aim was to investigate changes of circulating intact GDF-15 (wildtype, non-carrier of the rs1058587 polymorphism coding for the H2O2D mutation) and total GDF-15 (measured irrespective of the mutation) in response to liraglutide (GLP-1 receptor agonist) and lorcaserin (5-HT2C receptor agonist), two pharmacologic agents that induce food intake and weight reduction. In addition, we perform exploratory correlations of total and intact GDF-15 with clinical, hormonal and metabolo-lipidomic parameters in humans with obesity. MATERIALS AND METHODS: We utilized two studies: 1) Study 1, a randomized, double-blinded, cross-over trial of liraglutide and placebo administration for 5 weeks in subjects with obesity (n = 20; BMI = 35.6 ± 5.9 kg/m2), in escalating doses starting at 0.6 mg/day on week 1 and increased every week, up to the highest dose of 3.0 mg/day during week 5. b) Study 2, a randomized, double-blinded trial of lorcaserin 10 mg twice daily, or placebo for 12-weeks in humans with obesity (n = 34 BMI = 37.4 ± 6.1 kg/m2). Total and intact GDF-15 levels were measured with novel enzyme-linked immunosorbent assays and the metabolomics and lipidomics analysis was performed with nuclear magnetic resonance spectroscopy. RESULTS: Total and intact GDF-15 were positively correlated with diabetes risk index and trimethylamine N-oxide and negatively with eGFR. Despite significant changes in body weight, total and intact GDF-15 were not altered in response to liraglutide or lorcaserin treatment in subjects with obesity. CONCLUSIONS: Total and intact GDF-15 levels are not altered in response to liraglutide or lorcaserin therapy and are thus not directly involved in the metabolic feedback loop pathways downstream of GLP1 or 5-HT2C receptor agonists. Since neither total nor intact GDF-15 levels were altered in response to weight loss, future studies are needed to elucidate the pathways activated by GDF-15 in humans and its role, if any, in body weight regulation and energy homeostasis.

Leptin alters energy intake and fat mass but not energy expenditure in lean subjects.

Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.

Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function.

BACKGROUND: We have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. METHODS: The AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. RESULTS: The circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. CONCLUSIONS: We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.

Bullying and Sexual Discrimination in the Greek Health Care System.

INTRODUCTION: Modern medicine is based on teamwork and communication. Bullying and discrimination can have a serious effect on these, affecting the standard of medical training and patient care. AIM: To determine the incidence of bullying and sex discrimination in the Greek health care system. METHODS: An online questionnaire was designed and circulated among Greek medical professionals. RESULTS: We received 1349 completed questionnaires with a response rate of 48% and with 45% of them being female. Equal opportunities in specialty training were reported by 55% of the participants. Female doctors in medicine and in surgery reported no equal opportunities at an incidence of 15% and 30%, respectively (p < 0.001). Family obligations and lack of family support were considered as the main obstacles in female doctors' professional development by 92% and 59% of the participants, respectively. Both sexes appeared to have suffered from various forms of abusive behavior with characteristics that vary between them. Verbal abuse, threatening behavior, and sexual harassment were reported by 50%, 38%, and 20%, respectively, with women being 3 times more likely to be victims of sexual harassment (34% vs. 9%, p < 0.001). Finally, the availability of official support mechanisms was reported in only 15% of the cases, whereas friends and colleagues were the main support for 46.17% of the cases. CONCLUSION: This is the first study attempting to preliminary describe the extent of bullying and sexual discrimination in the Greek national health care system. Despite the limitations of this study, it is imperative that more research is performed on this issue from the appropriate national authorities.

The role of intravascular ultrasound in lower limb revascularization in patients with peripheral arterial disease.

INTRODUCTION: The aim of this review is to explore the safety and effectiveness of intravascular ultrasound (IVUS) during lower limb endovascular interventions in patients with peripheral arterial disease (PAD). EVIDENCE ACQUISITION: A systematic review of the PubMed and Scopus databases was performed according to PRISMA guidelines. Clinical studies evaluating IVUS as an adjunct to angiography during revascularization procedures in patients with PAD were included. EVIDENCE SYNTHESIS: Thirteen studies were identified, with a total number of 2258 patients having had IVUS for PAD intervention. Seven investigated the role of IVUS for angioplasty and stenting, with the majority being retrospective cohorts. Technical success and patency rates ranged from 90-100% and 45-100%, respectively, with a follow-up that ranged from 4.3-63 months. Three of these studies compared IVUS and non-IVUS guided angioplasty and demonstrated a significant difference in the events of amputations or re-interventions in favor of the IVUS group. Furthermore, five studies evaluated IVUS use in true-lumen re-entry, with the technical success ranging between 97-100%. In one study, where IVUS was used for atherectomy, the technical success was 100% and the long-term patency was 90% during a 12-month follow-up. Overall, no significant peri/postoperative IVUS related complications were reported, whereas, 2 studies suggested an IVUS-associated increase in procedure costs that ranged from $1080-$1333. CONCLUSIONS: There is limited and heterogeneous evidence regarding the use of IVUS for the management of PAD. Further research is required to elucidate the optimal role of IVUS in PAD as well as the cost effectiveness of this approach for routine use in the management of PAD.