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The present work is meant to show the effective capability of optimizing an unbalanced Paired-Cell Overlapping Loops of Cards with Authorization (POLCA)-controlled production system by means of a heuristic algorithm. This objective is suggested by the fact that one of the most significant issues when using card-driven production control systems is represented by the optimized setting of the large number of cards within the control loops. This is particularly true in the case of unbalanced systems, where the number of cards may vary significantly among the different loops. Little law is usually adopted in literature to infer this number from historical data, but the obtained number is usually far from the optimum. Indeed, in real-world applications, the systems to be controlled are designed to process units with very different routings, each with different probability to occur. In all these situations, they result particularly difficult to set correctly. To this aim, in the present work a Genetic Algorithm is used. The objective is that of finding the correct number of cards and to reduce the overall Total Throughput Time and the average Work In Process. The proposed approach may provide a valid support tool to overcome these limitations, making the most of POLCA capabilities in many manufacturing configurations. [ABSTRACT FROM AUTHOR]

POCKETT R.D., CASTELLANO D., MCEWAN P., OGLESBY A., BARBER B.L. & CHUNG K. (2010) European Journal of Cancer Care 19, 755-760 The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain Metastatic bone disease (MBD) is the most common cause of cancer pain and of serious skeletal-related events (SREs) reducing quality of life. Management of MBD involves a multimodal approach aimed at delaying the first SRE and reducing subsequent SREs. The objective of the study was to characterise the hospital burden of disease associated with MBD and SREs following breast, lung and prostate cancer in Spain. Patients admitted into a participating hospital, between 1 January 2003 and 31 December 2003, with one of the required cancers were identified and selected for inclusion into the study. The index admission to hospital, incidence of patients admitted and hospital length of stay were analysed. There were 28 162 patients identified with breast, lung and prostate cancer. The 3 year incidence rates of hospital admission due to MBD were 95 per 1000 for breast cancer, 156 per 1000 for lung cancer and 163 per 1000 for prostate cancer. For patients admitted following an SRE, the incidence rates were 211 per 1000 for breast cancer, 260 per 1000 for lung cancer and 150 per 1000 for prostate cancer. This study has shown that cancer patients consume progressively more hospital resources as MBD and subsequent SREs develop. [ABSTRACT FROM AUTHOR]

Pook se Bos informal settlement and the Cape Town Water & Sanitation Services Department are partnering on an urban sanitation project with a Dutch Consortium consisting of Lettinga Associates Foundation (LeAF), Landustrie Sneek and Vitens-Evides International. The aim of the project is to improve the basic sanitation services provided in informal settlements through the implementation of the MobiSan approach. The approach consists of a communal Urine-Diversion and Dehydration Toilet (UDDT) built in a former sea shipping container. The system is independent of water, electricity or sewerage connection and it is maintained by full-time community caretakers who also act as hygiene promoters. The project seeks to link sanitation services with hygiene promotion in informal settlements while enhancing user satisfaction and reducing costs in providing basic sanitation services. This paper describes the preliminary experiences and lessons learnt during the implementation and evaluation of the MobiSan prototype and discusses its potential for replication. The MobiSan has proved to be an appropriate option by means of dealing successfully with shallow groundwater table, land availability and high settlement densities. In addition it has been demonstrated to be cost-competitive in terms of operating cost compared to chemical toilets. [ABSTRACT FROM AUTHOR]

Abstract: Sanitation coverage in the informal settlements of Cape Town is severely lagging behind. A recent inventory showed that the main barriers to the implementation of proper sanitation systems are unsuitability of the location of many settlements (more than 40% of the sites are located on private land, wetlands and flooding prone areas), high settlement densities (55%), the nonpermanent status of the informal settlements and the distance to existing sewerage networks. The technical feasibility of 14 different sanitation systems was related to these general constraints. The feasibility assessment showed that only chemical toilets and container toilets were systems that could be applied on a larger scale. Both toilet systems, however, have high service and maintenance costs. Based on the evaluation, an innovative pilot project consisting of a mobile sanitation unit (MobiSan1) is being developed and will be piloted. [Copyright &y& Elsevier]

Background: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-α) treatment in patients with metastatic renal cell carcinoma (mRCC). [ABSTRACT FROM PUBLISHER]

BACKGROUND No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS A total of 886 patients underwent randomization: 442 to the enfortumab vedotin- pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.) [ABSTRACT FROM AUTHOR]

This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301. Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety. In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%. After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed. • Continued survival benefits of enfortumab vedotin over chemotherapy in treated advanced urothelial carcinoma were shown. • No new safety concerns with enfortumab vedotin were identified in the ∼2 year follow-up of patients from EV-301. • Efficacy, safety, and tolerability for enfortumab vedotin were consistent across multiple phase II/III clinical trials. [ABSTRACT FROM AUTHOR]

Background: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. Methods: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. Results: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. Conclusions: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). [ABSTRACT FROM AUTHOR]

Abstract: Chronic lymphocytic leukaemia (CLL) is a common, often incurable low-grade-B lymphoproliferative disorder. For many years, chlorambucil alone or with steroids has been the drug of choice in treatment-naive patients. Purine nucleoside analogues (PNAs) and, more recently, monoclonal antibodies (i.e. rituximab, alemtuzumab), have increased the potential for obtaining complete or even molecular remissions. Despite these advances, recurrent and/or relapsing disease remains a major concern. In this respect, new clinical and biological agents have recently been identified, which may allow a better selection for high-risk patients, who could be offered more aggressive therapies including haematopoietic stem cell transplantation (HSCT). Although autologous transplant does not appear to provide additional benefit in advanced refractory disease, allogeneic transplant may offer a chance for cure. Non-myeloablative allogeneic transplant probably has curative potential with a better toxicity profile, and it is actively being investigated. We will review the role of the current therapeutic approach to CLL, focusing on the most recent advances in chemoimmunotherapy and haematopoietic stem cell transplantation. [Copyright &y& Elsevier]

Background: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.Case Presentation: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening.Conclusions: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.Methods: We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed.Results: A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed.Conclusions: Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.). [ABSTRACT FROM AUTHOR]

Monitoring and understanding the in vitro behaviour of polyester based scaffolds both comprising the study of the hydrolytic degradation and the cell seeding viability is essential to ensure the desired functionality, according to a given biomedical purpose. As a model case to compare the performance of techniques to monitor the in vitro behaviour, poly(lactide- co -glycolide) (PLGA) scaffolds were chosen. The in vitro hydrolytic degradation of PLGA scaffolds was carried out in water and phosphate buffered saline (PBS). The evolution of the mass loss, the molar mass, the thermal properties and the surface morphology were monitored. The hydrolytic degradation media was correspondingly evaluated by means of the study of the pH, the amount of acid released and the conductivity. In addition, the in vitro biocompatibility regarding the cell culture viability was studied under physiological conditions. The cellular adhesion, cellular ability to proliferate on the scaffold, the scaffold inflammatory profile and the effect of the scaffold degradation compounds on the cells were assessed. A comparative analysis of the exploited techniques in terms of promptness of identification, depth of knowledge, simplicity of obtaining results and cost of the technique was implemented. The results showed that, depending on the balance between the interest in ascertaining the trigger of degradation or deep into the knowledge of the causes and effects of cell culture viability, an appropriate plan of analysis of the validation of polyester-based scaffolds could be designed. [ABSTRACT FROM AUTHOR]

Background: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. Patients and methods: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N=62), 600 mg apatorsen (N=60), or 1000mg apatorsen (N=61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. Results: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600mg apatorsen compared with placebo (HR=0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000- mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR=0.45 and 0.62, respectively). Higher baseline circulating tumor cells (⩾5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsentreatment arms. Conclusions: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted. [ABSTRACT FROM AUTHOR]

Background: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. Methods: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naþve and 98 postdocetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naþve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naþve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74--9.10; P<0.001 and HR 3.81; 95% CI 2.28--6.37; P<0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P=0.03, and HR 1.95; 95% CI 1.23-3.11; P=0.01, respectively) and rate of PSA decliné50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P=0.035 and OR, 5.0; 95% CI 1.70-14.91; P=0.003, respectively]. ARmutations [2105T=A (p.L702H) and 2632A➛G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naı^#245;e abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P=0.004). There was no interaction between AR and docetaxel status (P=0.83 for OS, P=0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P<0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P<0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P=0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. Conclusion: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. Clinical Trial number: NCT02288936 (PREMIERE trial). [ABSTRACT FROM AUTHOR]

Aim Very few studies have compared the epidemiological characteristics of patients with familial colorectal cancer Type X ( FCCTX) with those of sporadic colorectal cancer (S- CRC). The aim of this study was to compare clinicopathological characteristics and survival between FCCTX and S- CRC in patients from a historically isolated geographical region. Method A retrospective study was carried out of patients with S- CRC and FCCTX treated in the Canary Islands. Family and personal history of colorectal cancer ( CRC) were recorded, together with genetic (microsatellite instability), immunohistochemical and clinical variables. Results Forty-eight (10.6%) of 451 patients were classified as FCCTX and the remaining 403 (89.4%) as S- CRC. Age at the diagnosis of tumour was significantly lower in FCCTX than in S- CRC (64.06 ± 12.65 years vs 69.13 ± 10.80 years; P = 0.01; Z = −2.48). Patients with FCCTX had a larger number of synchronous tumours ( P = 0.09). Recurrence was significantly higher in FCCTX than in S- CRC (18.7% vs 8.6%; P = 0.01). Survival correlated significantly with the number of first-degree and second-degree relatives with CRC ( P = 0.04; OR: 1.368, 95% CI: 1.01-1.84, and P = 0.04; OR: 1.363, 95% CI: 1.08-1.65) and with the total number of cases of CRC in the immediate family ( P < 0.01; OR: 1.377, 95% CI: 1.17-1.61). Recurrence-free time was significantly lower in patients with FCCTX (log-rank = 0.01). Conclusion Significant differences were found in several demographic and clinicopathological variables between patients with FCCTX and patients with S- CRC. These included increased tumour presentation under the age of 50 years and a higher recurrence rate in patients with FCCTX, suggesting an increased risk of CRC in this group. [ABSTRACT FROM AUTHOR]

Background: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.Methods: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.Results: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).Conclusions: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.). [ABSTRACT FROM AUTHOR]

Background:We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.Methods:Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.Results:A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%).Conclusion:Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results. [ABSTRACT FROM AUTHOR]

A new nomogram was developed to predict disease-free survival in stage I seminoma. Rete testis invasion and tumor size resulted independent predictors of relapse in a series of 744 patients treated with a risk-adapted approach.Background We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. Patients and methods From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). Results After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). Conclusion Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted. [ABSTRACT FROM PUBLISHER]

Background Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC). Patients and methods The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib. Results High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023). Conclusions We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance. [ABSTRACT FROM PUBLISHER]

Background: A strong rationale supports the role of antiangiogenic drugs in urothelial cancer. This trial was designed to assess the activity of sunitinib as first-line treatment in patients with metastatic urothelial cancer ineligible for cisplatin and to explore molecular and imaging variables predictive of clinical benefit.Patients and methods: This was a multicenter phase II trial with sunitinib 50 mg daily in 4/2-week schedule. Eligibility criteria were as follows: creatinine clearance 30–60 ml/min, Eastern Cooperative Oncology Group Pperformance Sstatus of one or less, and adequate hepatic and hematologic function. Twelve circulating cytokines were evaluated at baseline and sequentially using Luminex xMAP® (Austin, TX). Baseline and treatment-related changes in perfusion were evaluated in a patient subgroup using contrast-enhanced computed tomography.Results: On intention-to-treat analysis, 38 patients showed 3 (8%) partial responses (PRs) and 19 (50%) presented with stable disease (SD), 17 (45%) of them ≥3 months. Clinical benefit (PR + SD) was 58%. Median time to progression (TTP) was 4.8 months and median overall survival 8.1 months. Toxicity was consistent with previous reports for sunitinib. Low interleukin-8 (IL-8) baseline levels were significantly associated with increased TTP. Baseline tumor contrast enhancement with >40 Hounsfield units was associated with clinical benefit.Conclusions: This study highlights the potential role of the angiogenic pathway as a therapy target in urothelial cancer. Baseline IL-8 serum levels and contrast enhancement of lesions warrant further study. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country. Patients and methods: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers. Results: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival. Conclusion: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries. [ABSTRACT FROM AUTHOR]

Nanofibrous scaffolds composed of polycaprolactone (PCL) and gelatin (Ge) were obtained through a hydrolytic assisted electrospinning process. The PCL-to-Ge proportion (100/0 to 20/80), as well as the dissolution time (24, 48, 72, 96, 120 h) into a 1:1 formic/acetic acid solvent before electrospinning were modified to obtain the different samples. A strong influence of these factors on the physicochemical properties of the scaffolds was observed. Higher Ge percentage reduced crystallinity, allowed a uniform morphology and increased water contact angle. The increase in the dissolution time considerably reduced the molar mass and, subsequently, fibre diameter and crystallinity were affected. During in vitro biocompatibility tests, higher cell adhesion and proliferation were found for the 60/40, 50/50 and 40/60 PCL/Ge compositions that was corroborated by MTT assay, fluorescence and microscopy. A weakened structure, more labile to the in vitro degradation in physiologic conditions was found for these compositions with higher dissolution times (72 and 96 h). Particularly, the 40/60 PCL/Ge scaffolds revealed an interesting progressive degradation behaviour as a function of the dissolution time. Moreover, these scaffolds were non-inflammatory, as revealed by the pyrogen test and after the 15-day subcutaneous in vivo implantation in mice. Finally, a reduction of the scar tissue area after infarction was found for the 40/60 PCL/Ge scaffolds electrospun after 72 h implanted in rat hearts. These results are especially interesting and represent a feasible way to avoid undesired inflammatory reactions during the scaffold assimilation. Image 1 • Tailored nanofibrous PCL/Ge scaffolds were obtained by electrospinning. • The scaffold validation revealed the relevance of composition and dissolution time. • Specific in vitro /vivo degradation and assimilation confirmed the tailoring strategy. • Similar composition of PCL/Ge and advanced dissolution time enhanced biocompatibility. • Promising results were found as a reduction of the scar tissue area after infarction. [ABSTRACT FROM AUTHOR]