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Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18–75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0–1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1–14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4–61·6), 3-year disease-free survival rates were 76% (95% CI 69–81) in the neoadjuvant chemotherapy group and 69% (62–74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49–0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3–4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3–4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3–4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

Background FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. Methods This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. Results We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /− CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively ( p  < 0.0001). Conclusions FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in “real-life” patients now have to be confirmed in a Phase 3 randomised trial.

Increased dissolved inorganic nitrogen (DIN) concentrations in sea water have been linked to a reduction of the temperature threshold at which corals bleach, however, the mechanism underlying this change is not known. This phenomenon is now explained in terms of increased phosphatase activities and imbalanced DIN supply resulting in phosphate starvation of algael symbionts. Mass coral bleaching, resulting from the breakdown of coral–algal symbiosis has been identified as the most severe threat to coral reef survival on a global scale 1 . Regionally, nutrient enrichment of reef waters is often associated with a significant loss of coral cover and diversity 2 . Recently, increased dissolved inorganic nitrogen concentrations have been linked to a reduction of the temperature threshold of coral bleaching 3 , a phenomenon for which no mechanistic explanation is available. Here we show that increased levels of dissolved inorganic nitrogen in combination with limited phosphate concentrations result in an increased susceptibility of corals to temperature- and light-induced bleaching. Mass spectrometric analyses of the algal lipidome revealed a marked accumulation of sulpholipids under these conditions. Together with increased phosphatase activities, this change indicates that the imbalanced supply of dissolved inorganic nitrogen results in phosphate starvation of the symbiotic algae. Based on these findings we introduce a conceptual model that links unfavourable ratios of dissolved inorganic nutrients in the water column with established mechanisms of coral bleaching. Notably, this model improves the understanding of the detrimental effects of coastal nutrient enrichment on coral reefs, which is urgently required to support knowledge-based management strategies to mitigate the effects of climate change.

Background Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution. Methods Lymphocytic DPD activity was assessed in a group of 136 patients receiving FP-based chemotherapy from 2004 to 2016. There were 105 digestive (77.2%), 24 breast (17.6%) and 7 head and neck cancers (5.2%). Cox or logistic regression models were applied with adjustment on all confounding factors that could modify OS, PFS or response. All models were stratified on the three cancer locations. A cut-off for DPD activity was assessed graphically and analytically. Results An optimal cut-off for DPD activity at 0.30 nmol/min/mg protein was identified as the best value for discriminating survivals and response. In multivariate analysis, individual lymphocytic DPD activity was significantly related to overall survival ( p  = 0.013; HR: 3.35 CI95%[1.27–8.86]), progression-free survival ( p  < 0.001; HR: 3.15 CI95%[1.75–5.66]) and response rate ( p  = 0.033; HR: 0.33 CI95%[0.12–0.92]) with a marked detrimental effect associated with high DPD activity. Conclusions DPD status screening should result in a two-pronged approach with FP dose reduction in case of low intrinsic DPD and, inversely, an increased FP dose for high intrinsic DPD. In a context of personalized FP-based treatment, this innovative strategy needs to be prospectively validated.

Background Fiber length is one of the primary quality parameters for the cotton industry when considering the textile performance and end-use quality of cotton. Currently, many decisions regarding cotton fiber length utilize the industry standard measurement device, i.e., the High Volume Instrument (HVI). However, it is documented that complete fiber length distributions hold more information than the currently reported HVI length parameters, i.e., upper half mean length (UHML) and uniformity index (UI). An alternative measurement device, the Advanced Fiber Information System (AFIS), is able to capture additional information about fiber length distribution. What is currently not known is how much additional information the AFIS length distribution holds. Results The stability of differences in within-sample variation in fiber length captured by the AFIS length distribution by number characterizing differences between samples was deemed stable across the extended testing period. A diverse breeding population was evaluated and four significant sources of within sample variation in length were identified. A comparison of the ability between HVI length parameters and AFIS fiber length distribution to correctly categorize breeding lines to their family was performed. In all cases, the AFIS fiber length distribution more accurately identified germplasm families. Conclusions The long-term stability test of the AFIS fiber length distribution by number shows that the measurement is stable and can be used to assess differences across samples. However, more information about within-sample variation in fiber length than that can be captured by length parameters is needed to assess differences across samples in many applications. Four length parameters outperform two length parameters when trying to identify the familial background of the samples in this set. These parameters characterize distributional shape differences that are not captured by the standard AFIS length parameters, UQL and short fiber content by number (SFCn). These findings suggest that additional types of variation in cotton fiber length are not captured and are therefore not currently used in most cotton breeding programs.

The assessment and treatment of chronic pain rely heavily on patient self-report, making linguistically and culturally appropriate tools essential. However, no well-validated Arabic language measures of pain-related disability are widely available. The objective of this study was to create and validate a Modern Standard Arabic (MSA) version of the Pain Disability Index (PDI). This prospective cross-sectional study was conducted in a pain management clinic in a tertiary care center in the United Arab Emirates (UAE). The MSA PDI was developed using a forward–backward translation protocol by a team of native Arabic speakers from diverse backgrounds, reviewed by a professional translation company, and pilot-tested with a small sample of patients. Participants completed the MSA PDI along with measures of depression (PHQ-8), anxiety (GAD-7), and current pain severity. A total of 423 Arabic-speaking adults participated (54.84%) women, mean age of 43.71 ± 13.53, most of whom were UAE nationals (88.41%). The mean PDI score was 31.29 (±17.64), indicating moderate pain-related disability. Over half of the sample met screening thresholds for moderate to severe pain (50.83%), depression (57.21%), or anxiety (38.77%). Factor analysis of the MSA PDI supported a unidimensional structure. The MSA PDI also demonstrated excellent internal consistency (α = .91). Construct validity was supported through a tiered multi-method approach (correlation, regression, and structural equation modeling), which showed moderate positive associations between pain severity, depression, anxiety, and pain-related disability. Overall, the MSA PDI showed strong psychometric properties and provides a reliable, standardized tool for assessing pain-related disability in Arabic-speaking populations.

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

Background Metastatic squamous cell carcinomas (SCC) of the anal canal are rare and there is no international consensus on their second‐line management. 5‐Fluorouracil (5‐FU) and mitomycin in combination with radiotherapy is the standard for locally advanced forms but its efficacy in metastatic stage has never been evaluated. Patients and methods We report a retrospective analysis of patients treated with 5‐FU and mitomycin from 2000 to 2017 in our institution for a metastatic SCC of the anal canal after failure of platinum‐based regimen. The main outcome was progression‐free survival (PFS) and the secondary outcomes were overall survival (OS), response rate, and toxicity. Results Nineteen patients, 15 women and four men, with a median age of 57 years were identified (range, 40‐79 years). Patients received a median of three cycles (1‐7) of mitomycin 5‐FU. A dose reduction was necessary in six patients (31.6%), one patient had to discontinue treatment following toxicity and no death was due to treatment toxicity was reported. An objective response was observed in five patients (26.4%, 95% CI 6.6‐46.2) including one complete response, six patients (31.6%, 95% CI 10.7‐52.5) showed tumor stabilization. Median PFS and OS were 3 months [95% CI 1‐5] and 7 months [95% CI 2.2‐11.8]. Responder had a median duration of response of 4 months [95% CI 1.8‐6.1] and one patient had 23 months duration of response. No significant difference was noted for PFS and OS for patients previously treated with mitomycin and 5‐FU at a local stage. Conclusion Mitomycin and 5‐FU regimen provides tumor control with acceptable tolerance. It is an option for patients with metastatic SCC of the anal canal after failure of platinum‐based chemotherapy. [Correction added on 9 October 2019, after first online publication: '5‐FU' was inadvertently removed from the Results and Conclusion and has now been added to the text.] 5‐Fluorouracil and mitomycin in combination with radiotherapy is the standard for locally advanced squamous cell carcinomas of the anal canal and we have evaluated its efficacy in metastatic stage. This study is a retrospective analysis of patients treated with and mitomycin from 2000 to 2017 in our institution for a metastatic SCC of the anal canal after failure of platinum‐based regimen. Mitomycin and 5‐FU provides a Response Evaluation Criteria in Solid Tumors response in nearly a quarter of patients with acceptable toxicity. It is a reasonable therapeutic option after failure of a first‐line chemotherapy in the absence of other therapeutic option.

Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer. We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I–IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0–2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m2 per day for 4 days and cisplatin 75 mg/m2 on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094. 134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9–36·4). Median progression-free survival was 9·7 months (95% CI 8·1–14·5) in the FOLFOX group and 9·4 months (8·1–10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70–1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil–cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin–fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group. Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery. UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer.