Melanoma is the fifth most common cancer in the United States and accounts for the majority of all skin cancer-related deaths, making it the most lethal cutaneous malignancy. Systemic adjuvant therapy for stage IIB-IV melanoma is now approved for patients who have undergone surgical resection, given the appreciable risk of recurrence and mortality in this patient population. Despite the lower stage, high-risk stage II melanoma (stage IIB/IIC) can often exhibit an even more aggressive course when compared to stage IIIA/IIIB disease, thus justifying consideration of adjuvant therapy in these patients. In this review, we highlight the current standard of practice for the treatment of stage IIB/C melanoma, with a focus on adjuvant therapies supported by published landmark clinical trials, including anti-PD-1 therapy. Notably, adjuvant therapies approved thus far in this patient population have demonstrated an improvement in recurrence-free survival, while their impact on overall survival is pending. Finally, this review highlights currently ongoing trials and future directions for research and treatment possibilities for high-risk clinical stage II melanoma.

BACKGROUND: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, and the scarcity of scientific evidence regarding the impact of ketogenic diets on CVD risk factors necessitates urgent attention and redress.
OBJECTIVE: This meta-analysis evaluates the impact of the ketogenic diet on CVD risk factors compared with control diets through randomized controlled trials (RCTs).
METHODS: The study was registered in advance in the PROSPERO database (CRD42023491853). A systematic search was conducted across PubMed, Web of Science, EMBASE, and Cochrane Library to identify relevant RCTs. Fixed and random effects were employed to calculate the mean differences and 95% confidence intervals (CIs) for changes in CVD risk factors pre- and postketogenic diet intervention.
RESULTS: A total of 27 RCTs with 1278 participants were analyzed. The ketogenic diet intervention presented increase in total cholesterol (mean differences: 0.36 mmol/L; 95% CI: 0.15, 0.57; I2: 85.1%), low-density lipoprotein cholesterol (mean differences: 0.35 mmol/L; 95% CI: 0.20, 0.50; I2: 73.9%) and high-density lipoprotein cholesterol (mean differences: 0.16 mmol/L; 95% CI: 0.09, 0.23; I2: 86.7%) concentrations. Reductions were observed in the triglyceride (mean differences: -0.20 mmol/L; 95% CI: -0.29, -0.11; I2: 72.2%), blood glucose (mean differences: -0.18 mmol/L; 95% CI: -0.33, -0.02; I2: 76.4%), blood insulin (mean differences: -8.32 pmol/L; 95% CI: -14.52, -2.12; I2: 81.5%), diastolic blood pressure (mean differences: -1.41 mmHg; 95% CI: -2.57, -0.26; I2: 49.1%), weight (mean differences: -2.59 kg; 95% CI: -3.90, -1.28; I2: 87.4%), and body mass index (mean differences: -1.59 kg/m2; 95% CI: -2.32, -0.86; I2: 84.5%) concentrations after implementing ketogenic diets.
CONCLUSIONS: Although the ketogenic diet demonstrates benefits in terms of triglyceride, blood pressure, weight, and glycemic control, its impact on CVD risk factors, especially the elevated total cholesterol and low-density lipoprotein cholesterol concentrations, warrants a cautious approach.

BACKGROUND: This research investigates why a beneficial treatment effect reported at the first interim analysis (IA) may diminish at a subsequent analysis (SA). We examined three challenges in interpreting treatment effects from randomized clinical trials (RCTs) after the first positive IA: overestimation bias; non-proportional hazards; and heterogeneity in recruitment. We investigate how a penalized estimation method can address overestimation bias, and discuss additional factors to consider when interpreting positive IA results.
METHODS: We identified oncology RCTs reporting positive results at the initial IA and a SA for event-free (EFS) and overall survival (OS). We modeled: (1) the hazard ratio at IA (HRIA) versus its timing as measured by the information fraction (IF; i.e., events at IA versus total events sought); and (2), the ratio of HRIA to HRSA (rHR) versus the IF. This was repeated for HRIA adjusted for overestimation bias. Examples of the other two challenges were sought.
RESULTS: Amongst 71 RCTs, HRIA were positively associated with the IF (slope: EFS 0.83, 95 % CI 0.44-1.22; OS 0.25, 95 % CI 0.10-0.41). HRIA tended to exaggerate HRSA, and more so the lower the IF (slope rHR versus IF: EFS 0.10, 95 % CI - 0.22 to 0.42; OS 0.26, 95 % CI 0.07-0.46). Adjusted HRIA did not exaggerate HRSA (slope rHR versus IF: EFS - 0.14, 95 % CI - 0.67 to 0.39; OS 0.02, 95 % CI - 0.26 to 0.30). Examples of two other challenges are shown.
CONCLUSIONS: Overestimation bias, non-proportional hazards, and heterogeneity in recruitment and other important treatments should be considered when communicating estimates of treatment effects from positive IAs.

BACKGROUND: Numerous studies have assessed the efficacy and safety of fecal microbiota transplantation (FMT) as a therapy for ulcerative colitis (UC). However, the treatment processes and outcomes of these studies vary.
OBJECTIVE: To evaluate the efficacy and safety of FMT for treating UC by conducting a systematic meta-analysis.
METHODS: The inclusion criteria involved reports of adult patients with UC treated with FMT, while studies that did not report clinical outcomes or that included patients with infection were excluded. Clinical remission (CR) and endoscopic remission (ER) were the primary and secondary outcomes, respectively.
RESULTS: We included nine studies retrieved from five electronic databases. The FMT group had better CR than the control group [relative risk (RR) = 1.53; 95% confidence interval (CI): 1.19-1.94; P < 0.0008]. ER was statistically significantly different between the two groups (RR = 2.80; 95%CI: 1.93-4.05; P < 0.00001). Adverse events did not differ significantly between the two groups.
CONCLUSIONS: FMT demonstrates favorable performance and safety; however, well-designed randomized clinical trials are still needed before the widespread use of FMT can be recommended. Furthermore, standardizing the FMT process is urgently needed for improved safety and efficacy.

Irritable bowel syndrome is a persistent disturbance of the function of the gastrointestinal tract with a prevalence of about 11.2% in the population at large. While the etiology of the disorder remains unclear, there is mounting evidence that the disturbance of the gut microbiota is at least one contributing factor. This insight resulted in clinical trials investigating the therapeutic effects of products containing probiotic microorganisms. Most studies with IBS patients have evaluated the therapeutic effects of mono- and multi-strain probiotics, but only a few studies have investigated the efficacy of synbiotics (combinations of probiotic bacteria and one or more prebiotic components). This review summarizes the results from eight randomized, placebo-controlled clinical trials that investigated the efficacy of synbiotic preparations (three mono-strain and five multi-strain products) in adult IBS patients. While data remain sparse, some of the surveyed clinical trials have demonstrated interesting efficacy results in IBS patients. To allow a judgment of the role played by synbiotics in the treatment of IBS patients, more high-quality clinical trials are needed.

BACKGROUND: Integrative oncology combines conventional and complementary, or integrative, therapies for a holistic treatment of cancer patients. Yoga is increasingly used as a complementary therapy for cancer patients, but there is no direct evidence for its effect on cancer pathophysiology like tumor response, or patient outcome like overall survival.
CONCLUSIONS: In this narrative review, we present in detail published studies from randomized clinical trials on complementary yoga therapy for cancer patients, including details about the biochemical mechanisms involved. Medicinal hatha yoga with breathing, postures, meditation, and relaxation enhances the quality of life of cancer patients by providing both psychological and physiological health benefits, highlighting the interconnectedness of mind and body. Yoga therapy reduces stress levels improving heart rate variability, leading to changes in hormonal regulation (e.g., cortisol), reduced oxidative stress, and improved immune function with reduced inflammation. Still, the biochemical effects of yoga on the cancer disease itself are unrevealed.
CONCLUSIONS: More clinical and basic research is needed for further establishment of yoga as complementary therapy in oncology.
Die integrative Onkologie verbindet konventionelle und komplementäre, oder integrative, Therapien zu einem ganzheitlichen Behandlungsansatz für Menschen mit Krebs. Yoga findet zunehmend Verbreitung als Komplementärtherapie bei Krebs, doch es liegt keine direkte Evidenz für seine Wirkung auf den Verlauf der Krebserkrankung, zum Beispiel das Tumoransprechen, oder auf Patienten-Outcomes wie das Gesamtüberleben vor. In dieser narrativen Übersichtsarbeit stellen wir ausführlich Publikationen über randomisierte klinische Studien zu komplementärer Yogatherapie bei Krebspatienten vor und gehen dabei auch auf die beteiligten biochemischen Mechanismen ein. Medizinisches Hatha-Yoga mit Atmung, Stellungen, Meditation und Entspannung erhöht die Lebensqualität von Krebspatienten durch sowohl psychische als auch physische gesundheitliche Vorteile, was die Verbundenheit von Geist und Körper unterstreicht. Yogatherapie verringert die Stressbelastung und verbessert die Herzfrequenzvariabilität und führt so zu Veränderungen der hormonellen Regulation (z. B. von Cortisol), geringerem oxidativem Stress und verbesserter Immunfunktion mit vermindertem Entzündungsgeschehen. Die biochemischen Effekte von Yoga auf die Krebserkrankung selbst bleiben jedoch weiterhin ungeklärt. Weitere klinische und Grundlagenforschung ist erforderlich, um den Platz von Yoga als Komplementärtherapie in der Onkologie weiter zu festigen.

BACKGROUND: In the treatment of borderline personality disorder (BPD), there is empirical support for both dialectical behavior therapy (DBT) and schema therapy (ST); these treatments have never been compared directly. This study examines whether either of them is more effective than the other in treating patients with BPD.
METHODS: In this randomized, parallel-group, rater-blind clinical trial, outpatients aged between 18 and 65 years with a primary diagnosis of BPD were recruited in a tertiary outpatient treatment center (Lübeck, Germany). Participants were randomized to DBT or ST with one individual and one group session per week over 1.5 years. The primary outcome was the BPD symptom severity assessed with the mean score of the Borderline Personality Disorder Severity Index at 1-year naturalistic follow-up.
RESULTS: Between November 26, 2014, and December 14, 2018, we enrolled 164 patients (mean age = 33.7 [SD = 10.61] years). Of these, 81 (49.4%) were treated with ST and 83 (50.6%) with DBT, overall, 130 (79.3%) were female. Intention-to-treat analysis with generalized linear mixed models did not show a significant difference at 1-year naturalistic follow-up between DBT and ST for the BPDSI total score (mean difference 3.32 [95% CI: -0.58-7.22], p = 0.094, d = -24 [-0.69; 0.20]) with lower scores for DBT. Pre-to-follow-up effect sizes were large in both groups (DBT: d = 2.45 [1.88-3.02], ST: d = 1.78 [1.26-2.29]).
CONCLUSIONS: Patients in both treatment groups showed substantial improvements indicating that even severely affected patients with BPD and various comorbid disorders can be treated successfully with DBT and ST. An additional non-inferiority trial is needed to show if both treatments are equally effective. The trial was retrospectively registered on the German Clinical Trials Register, DRKS00011534 without protocol changes.

OBJECTIVE: This study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials.
METHODS: We searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model.
RESULTS: Proportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting \'false\' irAEs in the experiment arm (defined as \'false-irAE ratio\', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm).
RESULTS: 47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %-29.50 %) and 3.40 % (2.35 %-4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %-1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %-1.30 %) and 0.12 % (<0.01 %-0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009).
CONCLUSIONS: Our analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.

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Cardiovascular disease (CVD) is the primary cause of death and disability worldwide. Although age-standardized CVD mortality rates decreased globally by 14.5% between 2006 and 2016, the burden of CVD remains disproportionately higher in low- and middle-income countries compared to high-income countries. Even though proven, effective approaches based on multiple-drug intake aimed at the prevention and treatment of CVD are currently available, poor adherence, early discontinuation of treatment, and suboptimal daily execution of the prescribed therapeutic regimes give rise to shortfalls in drug exposure, leading to high variability in the responses to the prescribed medications. Wald and Law, in their landmark paper published in BMJ 2003, hypothesized that the use of a fixed-dose combination of statins, β-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin (classic Polypill composition) may increase adherence and decrease CVD by up to 80% when prescribed as primary prevention or in substitution of traditional protocols. Since then, many clinical trials have tested this hypothesis, with comparable results. This review aims to describe the available clinical trials performed to assess the impact of fixed-dose combinations on adherence, cost-effectiveness, and the risk factors critical to the onset of CVD.