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In this study, a four-drug combination chemotherapy regimen was associated with objective responses in more than 30% of patients and increased survival by more than 4 months, as compared with standard gemcitabine. Pancreatic adenocarcinoma was the fourth leading cause of death from cancer in the United States in 2010, 1 and it carries a grim prognosis: the 5-year survival rate is 6% in Europe and the United States. 1 , 2 Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival as compared with fluorouracil administered as an intravenous bolus (5.6 vs. 4.4 months, P=0.002). 3 In the subsequent phase 3 trials of single-agent gemcitabine, 4 the median overall survival ranged from 5.0 to 7.2 months. The combination of gemcitabine with a variety of cytotoxic and . . .

BackgroundAdipose tissue releases angiogenic factors that may promote tumour growth.ObjectiveTo determine whether body mass index (BMI), subcutaneous fat area (SFA) and visceral fat area (VFA) are associated with outcomes in patients given first-line bevacizumab-based treatment for metastatic colorectal cancer (MCC).PatientsCT was used to measure SFA and VFA in 120 patients with MCC who received bevacizumab-based treatment (bevacizumab group, n=80) or chemotherapy alone (chemotherapy group, n=40) as first-line treatment. Associations linking BMI, SFA and VFA to tumour response, time-to-progression (TTP) and overall survival (OS) were evaluated.ResultsIn the bevacizumab group, median follow-up lasted for 24 months (3–70). BMI, SFA and VFA values above the median (ie, high BMI, high VFA and high SFA) were significantly associated with absence of a response. TTP was shorter in patients with high BMI (9 vs 12 months; p=0.01) or high VFA (9 vs 14 months; p=0.0008). High VFA was associated with shorter OS (p=0.0493). By multivariate analysis, high VFA was independently associated with response, TTP and OS (HR=7.18, p=0.008, HR=5.79, p=0.005 and HR=2.88, p=0.027, respectively). In the chemotherapy group, median follow-up lasted for 30 months (4–84). BMI, SFA and VFA were not associated with response, TTP or OS. In the whole population, interaction between VFA and bevacizumab administration was significant for response (OR=3.31, p=0.005) and TTP (HR=1.64, p=0.022), thereby confirming the results.ConclusionThis study provides the first evidence that high VFA independently predicts a poorer outcome in patients given first-line bevacizumab-based treatment for MCC. However, this predictive biomarker needs to be validated in a different dataset.

In spite of the novel strategies to treat colon cancer, mortality rates associated with this disease remain consistently high. Tumour recurrence has been linked to the induction of resistance towards chemotherapy that involves cellular events that enable cancer cells to escape cell death. Treatment of colon cancer mainly implicates direct or indirect DNA-damaging agents and increased repair or tolerances towards subsequent lesions contribute to generate resistant populations. Resveratrol (RSV), a potent chemosensitising polyphenol, might share common properties with chemotherapeutic drugs through its indirect DNA-damaging effects reported in vitro . In this study, we investigated how RSV exerts its anticancer effects in models of colon cancer with a particular emphasis on the DNA-damage response (DDR; PIKKs-Chks-p53 signalling cascade) and its cellular consequences. We showed in vitro and in vivo that colon cancer models could progressively escape the repeated pharmacological treatments with RSV. We observed for the first time that this response was correlated with transient activation of the DDR, of apoptosis and senescence. In vitro , a single treatment with RSV induced a DDR correlated with S-phase delay and apoptosis, but prolonged treatments led to transient micronucleations and senescence phenotypes associated with polyploidisation. Ultimately, stable resistant populations towards RSV displaying higher degrees of ploidy and macronucleation as compared to parental cells emerged. We linked these transient effects and resistance emergence to the abilities of these cells to progressively escape RSV-induced DNA damage. Finally, we demonstrated that this DNA damage was triggered by an overproduction of reactive oxygen species (ROS) against which cancer cells could adapt under prolonged exposure to RSV. This study provides a pre-clinical analysis of the long-term effects of RSV and highlights ROS as main agents in RSV’s indirect DNA-damaging properties and consequences in terms of anticancer response and potent resistance emergence.

TNF-related apoptosis-inducing ligand or Apo2L (Apo2L/TRAIL) is a promising anti-cancer drug owing to its ability to trigger apoptosis by binding to TRAIL-R1 or TRAIL-R2, two membrane-bound receptors that are often expressed by tumor cells. TRAIL can also bind non-functional receptors such as TRAIL-R4, but controversies still exist regarding their potential to inhibit TRAIL-induced apoptosis. We show here that TRAIL-R4, expressed either endogenously or ectopically, inhibits TRAIL-induced apoptosis. Interestingly, the combination of chemotherapeutic drugs with TRAIL restores tumor cell sensitivity to apoptosis in TRAIL-R4-expressing cells. This sensitization, which mainly occurs at the death-inducing signaling complex (DISC) level, through enhanced caspase-8 recruitment and activation, is compromised by c-FLIP expression and is independent of the mitochondria. Importantly, TRAIL-R4 expression prevents TRAIL-induced tumor regression in nude mice, but tumor regression induced by TRAIL can be restored with chemotherapy. Our results clearly support a negative regulatory function for TRAIL-R4 in controlling TRAIL signaling, and unveil the ability of TRAIL-R4 to cooperate with c-FLIP to inhibit TRAIL-induced cell death.

Purpose Recurrence of glioblastoma (GB) occurs in most patients after standard concomitant temozolomide-based radiochemotherapy (CTRC). Bevacizumab (BV), an anti-VEGF antibody, has an effect on progression-free survival (PFS) but not on overall survival (OS). However, a small part of the patients experience a survival, longer than expected. This retrospective study aims to characterize long responder (LR) patients treated with BV for a first or second GBM recurrence. Methods Medical records from patients (814) who received BV for a first or second recurrence of primary glioblastoma between September 2010 and September 2015, and initially treated by CTRC were analyzed. Patients, who had at least a stable disease according to RANO criteria at 12 months from the start of BV, were included. Patients who had, a secondary GB, or received BV in neoadjuvant or adjuvant setting were excluded. Results We focused on 65 LR patients without progression 12 months after the first injection of BV (8%). Median PFS was 21.7 months [95% CI (19.3; 27.2)] and median OS was 31.1 months [95% CI (24.3; 37.5)] from the start of BV. No prognostic factor was associated with OS in multivariate analysis. Karnofsky performance status, neurological status and corticosteroid dose were stable at 12 months. Conclusions Our results highlight that among patients receiving bevacizumab in first or second recurrence, one patient out of twelve could be classified as LR. A median OS of 31.1 months from the start of BV could be expected in this subpopulation. These findings reinforce the potential benefit of the use of BV in the situation of recurrence. 256 words

An amendment to this paper has been published and can be accessed via the original article.

Background: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. Methods: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with ( n =26) or without ( n =29) epinephrine were analysed using NONMEM. Results: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity. Conclusion: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

The growing popularity of complementary and alternative medicine (CAM) both in the general population and in patients with cancer is unquestionable. However, the attitude of caregivers in this area often leads patients to hide the use of CAM to their doctors. These reasons led us to conduct a survey in the University Hospital of Amiens (France) in order to evaluate their use in patients with gynecological or breast cancer. From January 1st to august 31st 2013, we conducted a prospective study about CAM; All the patients who underwent chemotherapy for gynecological or breast cancer during the study period in Amiens University Hospital were included. 68 patients were included. CAM use rate was 27.9%. The only significant CAM use predictive factor was a high level of education (p = 0.04). The two most frequently used CAM types were homeopathy (70.6%) and acupuncture (64.7%). The aims were to reduce the side effects of conventional treatment (63.2%) and to improve the overall condition (52.6%). Patients were informed about CAM mostly from their families (57.9%). Almost 80% considered that the information provided by the hospital practitioners was inadequate. However, 88.2% wanted to receive this information from their oncologist. The CAM use rate will increase in the coming years and the French health care system, health care providers and institutions, should apply itself to support these changes rather than follow them.

Purpose Health-related quality of life (HRQoL) is assessed by self-administered questionnaires throughout the care process. Classically, two longitudinal statistical approaches were mainly used to study HRQoL: linear mixed models (LMM) or time-to-event models for time to deterioration/time until definitive deterioration (TTD/TUDD). Recently, an alternative strategy based on generalized linear mixed models for categorical data has also been proposed: the longitudinal partial credit model (LPCM). The objective of this article is to evaluate these methods and to propose recommendations to standardize longitudinal analysis of HRQoL data in cancer clinical trials. Methods The three methods are first described and compared through statistical, methodological, and practical arguments, then applied on real HRQoL data from clinical cancer trials or published prospective databases. In total, seven French studies from a collaborating group were selected with longitudinal collection of QLQ-C30. Longitudinal analyses were performed with the three approaches using SAS, Stata and R software. Results We observed concordant results between LMM and LPCM. However, discordant results were observed when we considered the TTD/TUDD approach compared to the two previous methods. According to methodological and practical arguments discussed, the approaches seem to provide additional information and complementary interpretations. LMM and LPCM are the most powerful methods on simulated data, while the TTD/TUDD approach gives more clinically understandable results. Finally, for single-item scales, LPCM is more appropriate. Conclusion These results pledge for the recommendation to use of both the LMM and TTD/TUDD longitudinal methods, except for single-item scales, establishing them as the consensual methods for publications reporting HRQoL.

Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18–75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0–3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1–14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6–29·4) in the Debio 1143 group and 24·2 months (6·6–26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39–69) of 48 patients in the Debio 1143 group versus 16 (33%; 20–48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13–6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3–4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. Debiopharm.