Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ßRII (a TGF-ß "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. APPROACH AND RESULTS: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). CONCLUSIONS: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study.

BACKGROUND: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). METHODS: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. RESULTS: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. CONCLUSIONS: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC. TRIAL REGISTRATION: NCT03271047 (09/01/2017).

Treatment sequences and prognostic/predictive factors in metastatic pancreatic ductal adenocarcinoma: univariate and multivariate analyses of a real-world study in Europe.

BACKGROUND: Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and prognostic/predictive factors in patients with mPAC. METHODS: Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors. RESULTS: Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19-9 (CA 19-9) levels. CONCLUSIONS: Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future.

Light and shadow of watch-and-wait strategy in rectal cancer: oncological result, clinical outcomes, and cost-effectiveness analysis.

BACKGROUND: The watch-and-wait (WW) strategy is a potential option for patients with rectal cancer who obtain a complete clinic response after neoadjuvant therapy. The aim of this study is to analyze the long-term oncological outcomes and perform a cost-effectiveness analysis in patients undergoing this strategy for rectal cancer. MATERIAL AND METHODS: The data of patients treated with the WW strategy were prospectively collected from January 2015 to January 2020. A control group was created, matched 1:1 from a pool of 480 patients undergoing total mesorectal excision. An independent company carried out the financial analysis. Clinical and oncological outcomes were analyzed in both groups. Outcome parameters included surgical and follow-up costs, quality-adjusted life years (QALYs), and the incremental cost per QALY gained or the incremental cost-effectiveness ratio (ICER). RESULTS: Forty patients were included in the WW group, with 40 patients in the surgical group. During a median follow-up period of 36 months, metastasis-free survival (MFS) and overall survival (OS) were similar in the two groups. In the WW group, nine (22%) local regrowths were detected in the first 2 years. The permanent stoma rate was slightly higher after salvage surgery in the WW group compared to the surgical group (48.5% vs 20%, p < 0.01). The cost-effectiveness analysis was slightly better for the WW group, especially for low rectal cancer compared to medium-high rectal cancer (ICER = - 108,642.1 vs ICER = - 42,423). CONCLUSIONS: The WW strategy in locally advanced rectal cancer offers similar oncological outcomes with respect to the surgical group and excellent results in quality of life and cost outcomes, especially for low rectal cancer. Nonetheless, the complex surgical field during salvage surgery can lead to a high permanent stoma rate; therefore, the careful selection of patients is mandatory.

Efficacy and safety of dilpacimab (ABT-165) versus bevacizumab plus FOLFIRI in metastatic colorectal cancer: a phase II study.

Aim: This phase II study investigated safety and efficacy of dilpacimab or bevacizumab plus FOLFIRI in patients with previously treated metastatic colorectal cancer (mCRC). Materials & methods: Overall, 66 patients were treated (n = 34 dilpacimab + FOLFIRI; n = 32 bevacizumab + FOLFIRI). Progression-free survival, overall survival, response rates and tolerability were assessed. Results: Median progression-free survival for dilpacimab + FOLFIRI compared with bevacizumab + FOLFIRI was 3.78 months (95% CI: 2.07-7.20) versus 7.36 months (95% CI: 5.68-10.55) (hazard ratio: 3.57; 95% CI: 1.57-8.11; stratified). Median overall survival: 7.95 months for dilpacimab + FOLFIRI; not reached for bevacizumab + FOLFIRI. Objective response rates: 5.6% for dilpacimab + FOLFIRI and 14.7% for bevacizumab + FOLFIRI. Patients treated with dilpacimab + FOLFIRI experienced serious treatment-related adverse events (n = 4; 11.8%), including one case of intestinal perforation leading to death; none were reported for bevacizumab + FOLFIRI. Conclusion: Treatment with dilpacimab + FOLFIRI was not well tolerated and did not provide clinical benefit to patients with mCRC compared with bevacizumab + FOLFIRI. Clinical Trial Registration: NCT03368859 (Clinicaltrials.gov).

Developing and Validating Multi-Modal Models for Mortality Prediction in COVID-19 Patients: a Multi-center Retrospective Study.

The unprecedented global crisis brought about by the COVID-19 pandemic has sparked numerous efforts to create predictive models for the detection and prognostication of SARS-CoV-2 infections with the goal of helping health systems allocate resources. Machine learning models, in particular, hold promise for their ability to leverage patient clinical information and medical images for prediction. However, most of the published COVID-19 prediction models thus far have little clinical utility due to methodological flaws and lack of appropriate validation. In this paper, we describe our methodology to develop and validate multi-modal models for COVID-19 mortality prediction using multi-center patient data. The models for COVID-19 mortality prediction were developed using retrospective data from Madrid, Spain (N = 2547) and were externally validated in patient cohorts from a community hospital in New Jersey, USA (N = 242) and an academic center in Seoul, Republic of Korea (N = 336). The models we developed performed differently across various clinical settings, underscoring the need for a guided strategy when employing machine learning for clinical decision-making. We demonstrated that using features from both the structured electronic health records and chest X-ray imaging data resulted in better 30-day mortality prediction performance across all three datasets (areas under the receiver operating characteristic curves: 0.85 (95% confidence interval: 0.83-0.87), 0.76 (0.70-0.82), and 0.95 (0.92-0.98)). We discuss the rationale for the decisions made at every step in developing the models and have made our code available to the research community. We employed the best machine learning practices for clinical model development. Our goal is to create a toolkit that would assist investigators and organizations in building multi-modal models for prediction, classification, and/or optimization.

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

Introduction The number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer. Methods Data from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity. Results The mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7). Conclusions This retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer.

The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.

BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.

BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). METHODS: Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors.

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

Effects of sustained exercise on GH-IGFs axis in gilthead sea bream (Sparus aurata).

The endocrine system regulates growth mainly through the growth hormone (GH)/insulin-like growth factors (IGFs) axis and, although exercise promotes growth, little is known about its modulation of these factors. The aim of this work was to characterize the effects of 5 wk of moderate sustained swimming on the GH-IGFs axis in gilthead sea bream fingerlings. Plasma IGF-I/GH ratio and tissue gene expression of total IGF-I and three splice variants, IGF-II, three IGF binding proteins, two GH receptors, two IGF-I receptors, and the downstream molecules were analyzed. Fish under exercise (EX) grew more than control fish (CT), had a higher plasma IGF-I/GH ratio, and showed increased hepatic IGF-I expression (mainly IGF-Ia). Total IGF-I expression levels were similar in the anterior and caudal muscles; however, IGF-Ic expression increased with exercise, suggesting that this splice variant may be the most sensitive to mechanical action. Moreover, IGFBP-5b and IGF-II increased in the anterior and caudal muscles, respectively, supporting enhanced muscle growth. Furthermore, in EX fish, hepatic IGF-IRb was reduced together with both GHRs; GHR-II was also reduced in anterior muscle, while GHR-I showed higher expression in the two muscle regions, indicating tissue-dependent differences and responses to exercise. Exercise also increased gene and protein expression of target of rapamycin (TOR), suggesting enhanced muscle protein synthesis. Altogether, these data demonstrate that moderate sustained activity may be used to increase the plasma IGF-I/GH ratio and to potentiate growth in farmed gilthead sea bream, modulating the gene expression of different members of the GH-IGFs axis (i.e., IGF-Ic, IGF-II, IGFBP-5b, GHR-I, and TOR).

Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation.

BACKGROUND AND PURPOSE: To analyze the efficacy and safety of a new preoperative intensity-modulated radiotherapy (IMRT) and integrated-boost chemoradiation scheme. PATIENTS AND METHODS: In all, 74 patients were treated with IMRT and concurrent standard dose capecitabine. The dose of the planning target volume (PTV) encompassing the tumor, mesorectum, and pelvic lymph nodes was 46 Gy in 23 fractions; the boost PTV, at a dose of 57.5 Gy in 23 fractions, included the macroscopic primary tumor and pathological lymph nodes. The patients underwent surgery 6-8 weeks after chemoradiation. RESULTS: The complete treatment data of 72 patients were analyzed. Tumor downstaging was achieved in 55 patients (76.38 %) and node downstaging in 34 (47.2 %). In 22 patients (30.6 %), there was complete pathological response (ypCR). The circumferential resection margin was free of tumor in 70 patients (97.2 %). The 3-year estimated overall survival and disease-free survival rates were 95.4 and 85.9 % respectively, and no local relapse was found; however, ten patients (13.8 %) developed distant metastases. High pathologic tumor (pT) downstaging was shown as a favorable prognostic factor for disease-free survival. No grade 4 acute radiotherapy-related toxicity was found. CONCLUSIONS: The IMRT and integrated-boost chemoradiation scheme offered higher rates of ypCR and pT downstaging, without a significant increase in toxicity. The circumferential margins were free of tumors in the majority of patients. Primary tumor regression was associated with better disease-free survival.

New insights into fish swimming: a proteomic and isotopic approach in gilthead sea bream.

Moderate exercise enhances fish growth, although underlying physiological mechanisms are not fully known. Here we performed a proteomic and metabolic study in white (WM) and red (RM) muscle of gilthead sea bream juveniles swimming at 1.5 body lengths per second. Continuous swimming for four weeks enhanced fish growth without increasing food intake. Exercise affected muscle energy stores by decreasing lipid and glycogen contents in WM and RM, respectively. Protein synthesis capacity (RNA/protein), energy use (estimated by lipid-δ(13)C and glycogen-δ(13)C), and enzymatic aerobic capacity increased in WM, while protein turnover (expressed by δ(15)N-fractionation) did not change. RM showed no changes in any of these parameters. 2D-PAGE analysis showed that almost 15% of sarcoplasmic protein spots from WM and RM differed in response to exercise, most being over-expressed in WM and under-expressed in RM. Protein identification by MALDI-TOF/TOF-MS and LC-MS/MS revealed exercise-induced enhancement of several pathways in WM (carbohydrate catabolism, protein synthesis, muscle contraction, and detoxification) and under-expression of others in RM (energy production, muscle contraction, and homeostatic processes). The mechanism underpinning the phenotypic response to exercise sheds light on the adaptive processes of fish muscles, being the sustained-moderate swimming induced in gilthead sea bream achieved mainly by WM, thus reducing the work load of RM and improving swimming performance and food conversion efficiency.

Resected duodenal gastrointestinal stromal tumour with an affected margin and exon 9 mutation: adjuvant therapy.

We report on a 44-year-old female patient complaining of epigastric pain with an initial diagnosis of acute pancreatitis. Three months later, the symptoms reappeared and an abdomen computed tomography scan showed a mass in the third portion of the duodenum. After surgical resection, the pathologist confirmed malignant mesenchymal proliferation with a mitotic index of 2 mitoses/50 HPF. There was no tumour necrosis. The proliferation index (Ki 67) was 2%. A mutational analysis was carried out, which identified a mutation in c-KIT exon 9, with duplication of codons 502 and 503. A radical surgery was rejected by the patient and adjuvant therapy with imatinib at an initial dose of 400 mg/day was considered, with the intention of increasing the dose to 800 mg/day because of the presence of mutation in c-KIT exon 9 related to a poor response to imatinib. However, because of the adverse effects, the increase in the dose was ruled out, and the patient completed 1 year of adjuvant therapy with no evidence of disease relapse.

Watch-and-Wait policy versus robotic surgery for locally advanced rectal cancer: A cost-effectiveness study (RECCOSTE).

INTRODUCTION: Complete surgical resection for locally advanced rectal cancer is the standard treatment after a clinical complete response following chemoradiotherapy. However, some novel clinical approaches could achieve better functional results, such as Robotic Resection, or avoiding surgical procedure and incrementing surveillance intensity, called Watch-and-Wait policy. We use computational techniques to compare these clinical approaches using quality adjusted life years (QALYs). METHODS: A Markov decision analytic model was used in order to perform a cost-utility analysis, comparing standard resection (SR), Robotic Rectal Resection (RRR) and Watch-and-Wait (WW) strategies, estimating the incremental cost-effectiveness ratio per QALY to be gained from patients reaching a clinical complete response to chemoradiotherapy. Model parameter estimates were informed by previously published studies comparing WW to SR and from our database of RRR versus SR. Lifetime incremental cost-utility ratio was calculated among approaches, and a sensitivity analysis were performed in order to estimate the model uncertainty. A willingness-to-pay of per one additional QALY gained was measured to determine which strategies would be most cost-effective. RESULTS: WW is a dominating option over SR ( -75,486. 75 € and +2.04 QALYs) and RRR ( -75,486. 75 € and +0.41 QALYs). The cost-effectiveness plane shows that WW does not always dominate over RRR or SR. WW saves costs in 99.98% of the simulations when compared with either SR or RRR but only 86.9% and 55.38% (respectively) of these fall within the SR quadrant. WW is only more effective than SR 55% of the time which implies a significant uncertainty due to the high utility value assigned to cCR after chemoradiotherapy in the RRR alternative. CONCLUSION: This study provides data of cost-effectiveness differences among Standard Surgery, Watch-and-Wait and Robotic Resection approaches in clinical complete response in locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy, showing a benefit for Watch-and-Wait policy.

Synthesis of a Zinc Hydroxystannate/Sepiolite Hybrid Additive to Avoid Fire Propagation and Reduce Smoke Emission of EPDM Rubber Nanocomposites.

A zinc hydroxystannate/sepiolite (SEPZHS) hybrid additive was successfully prepared following a facile wet chemical route synthesis where zinc hydroxystannate (ZHS) nanoparticles were grown on the sepiolite's surface. SEPZHS particles have a fibrillar structure with ZHS nanoparticles homogeneously dispersed and with significantly smaller particle sizes than the synthesized ZHS nanoparticles alone. Sepiolite and SEPZHS were organically modified and introduced in a basic ethylene propylene diene monomer rubber (EPDM) formulation for cable to evaluate the nanocomposite behavior under direct fire sources. The results confirmed the synergistic effect of the hybrid SEPZHS additive in the formation of a most stable and efficient char barrier, thus improving the flame-retardant behavior of EPDM nanocomposite in terms of heat emission, with reductions of more than 40% in the peak of Heat Release Rate (cone calorimeter test), and smoke suppression, with more than 25% reduction in the Total Smoke Production and Smoke Density parameters (smoke chamber test). Moreover, the addition of sepiolite-based additives increased the mechanical properties (hardness) of the nanocomposites, as a result of the matrix reinforcement. This suggests that the SEPZHS hybrid additive may provide a promising option for a new, cost-effective, eco-friendly, yet efficient flame-retardant solution.

Characterization and Properties of Water-Blown Rigid Polyurethane Foams Reinforced with Silane-Modified Nanosepiolites Functionalized with Graphite.

In the present study, a promising flame retardant consisting of 80 wt% silane-modified nanosepiolites functionalized with 20 wt% graphite (SFG) is used to obtain a synergistic effect principally focussed on the thermal stability of water-blown rigid polyurethane (RPU) foams. Density, microcellular structure, thermal stability and thermal conductivity are examined for RPU foams reinforced with different contents of SFG (0, as reference material, 2, 4 and 6 wt%). The sample with 6 wt% SFG presents a slightly thermal stability improvement, although its cellular structure is deteriorated in comparison with the reference material. Furthermore, the influence of SFG particles on chemical reactions during the foaming process is studied by FTIR spectroscopy. The information obtained from the chemical reactions and from isocyanate consumption is used to optimize the formulation of the foam with 6 wt% SFG. Additionally, in order to determine the effects of functionalization on SFG, foams containing only silane-modified nanosepiolites, only graphite, or silane-modified nanosepiolites and graphite added separately are studied here as well. In conclusion, the inclusion of SFG in RPU foams allows the best performance to be achieved.

Surface modification of sepiolite in aqueous gels by using methoxysilanes and its impact on the nanofiber dispersion ability.

Surface modification reactions on needle-like sepiolite using alkyl and functional silanes have been carried out in the form of aqueous gels. In contrast with modifications in organic solvents, reactions in water make it possible to modify the surface of almost-individual sepiolite fibers and produce either a continuous coating or a nanotexturization of the sepiolite fiber surface, depending on the reaction conditions. This clean procedure substitutes advantageously organic solvent surface modifications and allows the tuning of surface properties such as specific surface area, wetting behavior, and chemical functionalization. A consequence of such tuning is, for example, the excellent dispersion of modified sepiolite nanofibers in a great variety of polymers by routine compounding and processing techniques.

Complete pathological response to neoadjuvant treatment is associated with better survival outcomes in patients with soft tissue sarcoma: Results of a retrospective multicenter study.

BACKGROUND: Locally advanced soft tissue sarcoma (STS) management may include neoadjuvant or adjuvant treatment by radiotherapy (RT), chemotherapy (CT) or chemoradiotherapy (CRT) followed by wide surgical excision. While pathological complete response (pCR) to preoperative treatment is prognostic for survival in osteosarcomas, its significance for STS is unclear. We aimed to evaluate the prognostic significance of pCR to pre-operative treatment on 3-year disease-free survival (3y-DFS) in STS patients. METHODS: This is an observational, retrospective, international, study of adult patients with primary non-metastatic STS of the extremities and trunk wall, any grade, diagnosed between 2008 and 2012, treated with at least neoadjuvant treatment and surgical resection and observed for a minimum of 3 years after diagnosis. The primary objective was to evaluate the effect of pCR. (≤5% viable tumor cells or ≥95% necrosis/fibrosis) on 3y-DFS. Effect on local recurrence-free survival (LRFS), distant recurrence-free survival (MFS) overall survival (OS) at 3 years was also analyzed. Statistical univariate analysis utilized chi-square independence test and odds ratio confidence interval (CI) estimate, multivariate analysis was performed using LASSO. RESULTS: A total of 330 patients (median age 56 years old, range:19-95) treated by preoperative RT (67%), CT (15%) or CRT (18%) followed by surgery were included. pCR was achieved in 74/330 (22%) of patients, of which 56/74 (76%) had received RT. 3-yr DFS was observed in 76% of patients with pCR vs 61% without pCR (p < 0.001). Multivariate analysis showed that pCR is statistically associated with better MFS (95% CI, 1.054-3.417; p = 0.033), LRFS (95% CI, 1.226-5.916; p = 0.014), DFS (95% CI, 1.165-4.040; p = 0.015) and OS at 3 years (95% CI, 1.072-5.210; p = 0.033). CONCLUSIONS: In a wide, heterogeneous STS population we showed that pCR to preoperative treatment is prognostic for survival.