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No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV 600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAF V600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy. SECOMBIT was a clinical trial testing different sequences of immunotherapy (ipilimumab plus nivolumab) and targeted therapy (encorafenib plus binimetinib) for untreated BRAF-mutated metastatic melanoma. Here the authors report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy, and preliminary biomarkers evaluation.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently reported adverse effect of oxaliplatin. In this study, we set out to evaluate the role of the panaceo-micro-activation (PMA) zeolite in the reduction of the incidence of CIPN and hematological and liver toxicity. The possible impact of the PMA-zeolite as an adjuvant therapeutic agent is based on its detoxification properties toward agents promoting the development of neuropathy (e.g., ammonium—recognized as a neurotoxic agent produced by tumors), as well as its positive impact on immunity and oxidative stress through its effects in the gastrointestinal tract. From April 2015 to October 2018, a total of 120 patients (pts) diagnosed with predominantly colorectal cancer requiring oxaliplatin-based chemotherapy were randomized to receive either the PMA-zeolite (Multizeo Med) or placebo while undergoing oxaliplatin-based chemotherapy. A nerve-conduction study (NCS) was planned at the baseline, after three and six months of chemotherapy, to evaluate CIPN. Furthermore, the evaluation of hematological and liver toxicity was performed during every cycle of chemotherapy. 70.6% and 64.3% of patients developed CIPN in the placebo and the PMA-zeolite group, respectively. Patients treated with the PMA-zeolite were able to undergo more cycles of chemotherapy (p = 0.03), which also indicates a significant improvement in tolerance to the therapy. The group treated with the PMA-zeolite showed a lower CIPN (although not statistically significant within the whole group of subjects) compared to patients receiving placebo. This advantage was, however, statistically significant in men (p = 0.047). In addition, supplementation with the PMA-zeolite resulted in a lower incidence of severe-grade hematological toxicity (trend toward statistical significance of p = 0.09 was observed). Cancer patients may benefit from the therapy with the appropriate certified zeolite-products (e.g., the PMA-zeolite) for human use in CIPN. The lower CIPN (statistically significant results in the male subgroup) was accompanied by a trend of lower incidence of severe-grade hematological toxicity. Furthermore, these benefits led to a better tolerance toward chemotherapy (increase in cycles) and allow an improved compliance with the oncological treatment protocol.

Following the previously published results of the clinical randomized ZeOxaNMulti trial, we evaluated the potential of the tested product PMA-ZEO (Multizeo Med) in the prevention of chemotherapy-induced side effects (especially peripheral neuropathy) within a 30-month follow-up analysis. The aim was to determine the disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) in a study-population suffering from colorectal cancer that was previously enrolled in the ZeOxaNMulti trial from April 2015 to October 2018. The participants of the study were randomized to receive either PMA-ZEO or placebo while undergoing oxaliplatin-based chemotherapy. A total of 104 patients (pts) (51% of participants randomized to the PMA-ZEO group and 49% to the placebo group), out of a total of 120 pts included in the ZeOxaNMulti trial in 2015, were followed up until March 2021 and were included in the follow-up analysis. According to the chemotherapy line, 44.2% of patients received chemotherapy in an adjuvant setting, and 55.8% of patients received chemotherapy as first-line treatment. The statistical analysis for DFS, PFS, and OS was performed by comparison of the end results with data from the PMA-ZEO/placebo-intervention start point. The analysis of OS did not show statistically significant differences in the first-line chemotherapy patients randomized to PMA-ZEO than among the placebo group ( p = 0.1) over the whole period of follow-up (30 months). However, focusing on the PMA-ZEO supplementation time point (7 months), a positive and statistically significant trend ( p = 0.004) was documented in the OS analysis for the first-line chemotherapy patients with increasing months of PMA-ZEO treatment compared to the placebo group. Furthermore, borderline statistical significance was reached for PFS at the PMA-ZEO supplementation time point (7 months) in the first-line chemotherapy patients ( p = 0.05) for cancer progression events. After stratification of the first-line chemotherapy patients, statistically relevant trends for OS for age, comorbidities, and oxaliplatin dosage (cycles) were also determined. The overall results for DFS (adjuvant patients), PFS (first-line chemotherapy patients), and OS (adjuvant and first-line chemotherapy patients) were generally slightly better in the PMA-ZEO group than in the placebo group, even though no statistically significant results were obtained between the groups within the follow-up period until 2021 (30 months). Based on this follow-up analysis, protective effects of PMA-zeolite supplementation can be deduced. A positive trend and more importantly, significant results in PFS and OS for specific patient groups during and/or after PMA-ZEO treatment were determined, which supports the use of PMA-ZEO as an oncological supportive therapy.

Coronavirus disease 2019 (COVID-19) global pandemic has created unique challenges to healthcare systems throughout the world. Ensuring subjects’ safety is mandatory especially in oncology, in consideration of cancer patients’ particular frailty. We examined the proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and/or IgG positive subjects in three different groups from Istituto Nazionale Tumori – IRCCS “Fondazione G. Pascale” in Naples (Campania region, Italy): cancer patients treated with Innovative Immunotherapy (Immune Checkpoint Inhibitors, ICIs), cancer patients undergoing standard Chemotherapies (CHTs) and healthcare providers. 9 out of 287 (3.1%) ICIs patients resulted positive, with a significant lower percentage in respect to CHTs patients (39 positive subjects out of 598, 6.5%) (p = 0.04). There was no statistically significant difference between ICIs cohort and healthcare providers, 48 out of 1050 resulting positive (4.6%). Performing a Propensity Score Matching based on gender and tumor stage, the effect of treatment on seropositivity was analyzed through a regression logistic model and the ICIs treatment resulted to be the only protective factor significantly (p = 0.03) associated with positivity (odds ratio—OR: 0.41; 95% confidence interval—CI 0.18–0.91). According to these preliminary data, ICIs would appear to be a protective factor against the onset of COVID-19 infection.

Purpose The purpose of this study was to determine the feasibility and efficacy of a United States multi-site randomized control trial (RCT) of the Schroth-based therapy program in Risser 0 patients with mild adolescent idiopathic scoliosis (AIS) curves. Methods Six sites enrolled 98 Risser 0 patients with single AIS curves between 12° and 24°. Patients were randomized to Exercise:Control group in a 2:1 ratio. Exercise group patients were instructed on the Schroth-based method and a home exercise program of 75 min/week for 1 year. Results Enrollment across 6 institutions averaged 2.2 patients per month over 45 months. Patient attrition was 42% after 1 year (41/98) and 52% after 2 years (51/98). Exercise group patients were significantly younger (11.6 vs 12.5 years) without differences in the baseline Cobb angle (16.2° vs 17.1°). Self-reported exercise adherence averaged 82% at 6 months and 63% at 1 year ( n  = 35). A significantly lower frequency of patients was braced in the Exercise group after 1 year (26% vs 55%, p  = 0.03) but not after 2 years (48% vs 63%, p  = 0.31). Curve magnitude changes between groups were not significant after 1 and 2 years. Conclusion Performing a multi-site RCT for mild AIS in the United States is challenging with slow enrollment and high attrition. Young patients with small curves have difficulty adhering to the intensive demands of Schroth-based therapy. Level of evidence II.

Introduction/BackgroundPatients (pts) with ovarian cancer experiencing a platinum-sensitive (PS) recurrence are generally re-exposed to platinum agents (PCT). The addition of bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparisons coming from randomized trials (RCTs), we have performed a network meta-analysis to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS recurrent ovarian cancer (rOC), according to BRCA status.MethodologyWe searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n=3, 1563 pts) or PARPi (n=5, 1839 pts). Only trials with PFS as primary endpoint were included. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied.ResultsIn AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR]=0.70, 95% CI 0.54–0.91). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR=0.46, 95% CI 0.36–0.59). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR=0.87, 95% CI 0.63–1.20) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV).ConclusionAccording to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts.DisclosureFabio Puglisi: Roche, AstraZeneca (honoraria and research founding). No conflict of interest is to be declared for the remaining authors. The authors receive no financial support for this study.

Background: Controversy exists regarding the optimal fellowship training experience for surgeons who perform scoliosis surgery in pediatric patients. While many studies have demonstrated that higher surgical volumes are associated with superior outcomes, the volume of scoliosis procedures performed by pediatric orthopaedic-trained surgeons as opposed to spine surgery-trained surgeons has not been reported. Methods: Validated, statewide hospital discharge databases from the states of New York and California were utilized to examine the volume of spinal fusion procedures performed for the treatment of scoliosis in patients who were eighteen years of age or less. Fellowship training of surgeons in New York who had performed more than fifty procedures from 1992 to 2001 (that is, more than five procedures per year) was determined, and the operative volumes of surgeons who had received pediatric orthopaedic as opposed to spine fellowship training were compared. Hospitals in California with either type of fellowship program were identified, and the operative volumes of hospitals and fellows with pediatric orthopaedic or spine fellowship training from 1995 to 1999 were compared. Results: Among the 228 surgeons in New York who had performed one or more spinal fusion procedures in patients eighteen years of age or less from 1992 to 2001, only 13% (thirty) had performed more than five procedures per year. However, these thirty surgeons accounted for 75% (3858) of all 5136 procedures in this age-group. Surgeons who had completed a pediatric orthopaedic fellowship had performed a mean of 14.5 procedures per physician per year, whereas those who had completed a spine fellowship had performed a mean of 10.5 procedures per physician per year. Surgeons who had not completed either type of fellowship had performed a mean of 14.4 procedures per physician per year. In California, the mean annual volume of scoliosis procedures from 1995 to 1999 was 59.0 procedures per year at hospitals with pediatric orthopaedic fellowship programs and 15.7 procedures per year at those with spine surgery programs. The mean number of procedures per fellow at hospitals with pediatric orthopaedic fellowship programs was 31.6 procedures per fellow per year, and the mean number at hospitals with spine surgery programs was 12.7 procedures per fellow per year. Over time, there was a significant increase in the number of procedures per year at hospitals with both types of fellowship programs, but the percentage increase was greater for hospitals with pediatric orthopaedic fellowship programs than for hospitals with spine surgery fellowship programs (45.2% compared with 13.5%). Conclusions: These data indicate that, on the average, a large number of surgeons in New York performed five scoliosis procedures per year or fewer. Among higher-volume surgeons in New York, those with pediatric orthopaedic fellowship training performed more scoliosis procedures on children and adolescents than those with orthopaedic spine training did. In California, the volume of scoliosis procedures at hospitals with pediatric orthopaedic fellowship programs was nearly four times greater than that at hospitals with spine fellowship programs and the volume of procedures per fellow was more than two times greater, and this disparity is widening over time. These data are an important element in establishing what type of fellowship best prepares surgeons for scoliosis surgery.

BackgroundAlthough geographic variations in the rates of orthopaedic procedures have been well documented, considerable controversy remains regarding the factors that drive these variations, particularly the role of the availability of orthopaedic surgeons. Moreover, little attention has been specifically focused on variations in the rates of commonly performed shoulder procedures. MethodsThe current study documents state-to-state variations in the rates of total shoulder replacement, humeral head replacement, and rotator cuff repair and examines factors that might account for these variations. The regional incidences of these three procedures were analyzed with use of the Health Care Financing Administration Medicare database (MEDPAR, 1992). The rates were age-adjusted, and variations were measured with use of high:low ratios, variation coefficients, and systematic components of variation. Potential causes of variation were analyzed with use of Spearman and partial correlations as well as with Poisson regression. ResultsRates for the three procedures that were studied varied from one state to another by as much as tenfold. Humeral head replacement had the lowest rate of variation according to all three measures. All three procedures were performed less often in states that were more densely populated. With the numbers available for study, no consistent, significant relationship was found between the density of orthopaedists and shoulder surgeons and the rates of any procedure. ConclusionsThe striking variations that were noted for these commonly performed procedures showed that there is a clear need for well designed clinical research to further define the factors that account for the variations and to examine the effectiveness and appropriate indications for the procedures.