Neoadjuvant Chemoradiotherapy versus Chemotherapy for Gastroesophageal Junction Adenocarcinoma; Which Is the Optimal Treatment Option?

Background: Locally advanced gastroesophageal junction adenocarcinoma (GEJ) is treated with either perioperative chemotherapy (CT) or preoperative radiochemotherapy (RCT) followed by surgery. The aim of this study was to compare pathologic response and long-term outcomes in junction adenocarcinoma treated with neoadjuvant RCT versus CT. Methods: All patients with locally advanced GEJ adenocarcinoma treated with neoadjuvant treatment (NAT) followed by surgery between 2009 and 2018 were retrospectively analyzed. Results: A total of 94 patients were included, 67 (71.2%) RCT and 27 (28.8%) CT. Complete pathologic response was more frequent in RCT patients (13.4% vs. 7.4%, p = 0.009) with a trend to better lymph node control (ypN0) (55.2% vs. 33.3%; p = 0.057). RCT offered no benefit in R0 resection (66.7% vs. 72.1% CT, p = 0.628) and was related to higher postoperative cardiovascular complications (35.8% vs. 11.1%; p = 0.017). Long-term overall and disease-free survival were similar (5-year OS 61.1% RCT vs. 75.7% CT, p = 0.259; 5-year DFS 33.5% RCT vs. 22.8% CT; p = 0.763). NAT type was neither independently associated with pathologic response nor long-term survival. Discussion: Patients with locally advanced GEJ adenocarcinoma treated with RCT had more postoperative cardiovascular complications but higher rates of complete pathologic response and a trend to superior locoregional lymph node control. This did not translate in a survival or recurrence benefit.

Short term high-intensity interval training in patients scheduled for major abdominal surgery increases aerobic fitness.

BACKGROUND: Prehabilitation may improve postoperative clinical outcomes among patients undergoing major abdominal surgery. This study evaluated the potential effects of a high-intensity interval training (HIIT) program performed before major abdominal surgery on patients' cardiorespiratory fitness and functional ability (secondary outcomes of pilot trial NCT02953119). METHODS: Patients were included before surgery to engage in a low-volume HIIT program with 3 sessions per week for 3 weeks. Cardiopulmonary exercise and 6-min walk (6MWT) testing were performed pre- and post-prehabilitation. RESULTS: Fourteen patients completed an average of 8.6 ± 2.2 (mean ± SD) sessions during a period of 27.9 ± 6.1 days. After the program, [Formula: see text]O2 peak (+ 2.4 ml min-1 kg-1, 95% CI 0.8-3.9, p = 0.006), maximal aerobic power (+ 16.8 W, 95% CI 8.2-25.3, p = 0.001), [Formula: see text]O2 at anaerobic threshold (+ 1.2 ml min-1 kg-1, 95%CI 0.4-2.1, p = 0.009) and power at anaerobic threshold (+ 12.4 W, 95%CI 4.8-20, p = 0.004) were improved. These changes were not accompanied by improved functional capacity (6MWT: + 2.6 m, 95% CI (- 19.6) to 24.8, p = 0.800). CONCLUSION: A short low-volume HIIT program increases cardiorespiratory fitness but not walking capacity in patients scheduled for major abdominal surgery. These results need to be confirmed by larger studies.

Feasibility of a prehabilitation program before major abdominal surgery: a pilot prospective study.

OBJECTIVE: To assess the feasibility of a prehabilitation program and its effects on physical performance and outcomes after major abdominal surgery. METHODS: In this prospective pilot study, patients underwent prehabilitation involving three training sessions per week for 3 weeks preoperatively. The feasibility of delivering the intervention was assessed based on recruitment and adherence to the program. Its impacts on fitness (oxygen uptake (VO2)) and physical performance (Timed Up and Go Test, 6-Minute Walk Test) were evaluated. RESULTS: From May 2017 to January 2020, 980 patients were identified and 44 (4.5%) were invited to participate. The main obstacles to patient recruitment were insufficient time (<3 weeks) prior to scheduled surgery (n = 276, 28%) and screening failure (n = 312, 32%). Of the 44 patients, 24 (55%) declined to participate, and 20 (23%) were included. Of these, six (30%) were not adherent to the program. Among the remaining 14 patients, VO2 at ventilatory threshold significantly increased from 9.7 to 10.9 mL/min/kg. No significant difference in physical performance was observed before and after prehabilitation. CONCLUSION: Although prehabilitation seemed to have positive effects on exercise capacity, logistic and patient-related difficulties were encountered. The program is not feasible in its current form for all-comers.

Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627).

BACKGROUND: We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). METHODS: Eligibility requirements were Karnofsky performance status ≥ 60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥ 2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%. RESULTS: A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n = 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. CONCLUSIONS: Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).

Quantitative structure-permeation relationships (QSPeRs) to predict skin permeation: a critical evaluation.

PURPOSE: Development of reliable mathematical models to predict skin permeability remains a challenging objective. This article examines some of the existing algorithms and critically evaluates their statistical relevance. METHODS: Complete statistics were recalculated for a number of published models using a stepwise multiple regression procedure. The predictivity of the models was obtained by cross-validation using a "leave-one-out" deletion pattern. The relative contribution of each independent variable to the models was calculated by a standardization procedure. RESULTS: The heterogeneity of the data in terms of skin origin and experimental conditions has been shown to contribute to the residual variance in existing models. Furthermore, rigorous statistics demonstrate that some published models are based on nonsignificant parameters. As such, they afford misleading mechanistic insight and will lead to over-interpretation of the data. CONCLUSIONS: The large number of published models reflects the need for predictive tools in cutaneous drug delivery and toxicology. However, such models are more reliable when confined within well-defined chemical classes, and their applicability is often limited by the narrow property space of the set of permeants under study.

Quantitative structure-permeation relationships for solute transport across silicone membranes.

PURPOSE: The purpose of this work was to assess the molecular properties that influence solute permeation across siliconemembranes and to compare the results with transport across human skin. METHODS: The permeability coefficients (log Kp) of a series of model solutes across silicone membranes were determined from the analysis of simple transport experiments using a pseudosteady-state mathematical model of the diffusion process. Subsequently, structure permeation relationships were constructed and examined, focusing in particular on the difference between solute octanol/water and 1,2 dichloroethane/water partition coefficients (deltalog P(oct-dce)), which re ported upon H-bond donor activity, and the computationally derived molecular hydrogen-bonding potential. RESULTS: The hydrogen-bond donor acidity and the lipophilicity of the compounds examined greatly influenced their permeation across sil cone membranes. Furthermore, for a limited dataset, a significant correlation was identified between solute permeation across silicone membranes and that through human epidermis. CONCLUSION: The key molecular properties that control solute perme ation across silicone membranes have been identified. For the set of substituted phenols and other unrelated compounds examined here a similar structure-permeation relationship has been derived for their transport through human epidermis, suggesting application of the results to the prediction of flux across biological barriers.