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Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours. In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m2 per day for 5 days], etoposide [100 mg/m2 per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18–21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m2 over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m2 over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m2 over 2 h on day 1), intravenous ifosfamide (2 g/m2 over 3 h on days 10, 12, and 14), plus mesna (500 mg/m2 at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10–14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676. Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49–68) in the Unfav-dose-dense group versus 48% (38–59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44–1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57–81) in the Fav-BEP group (HR 0·66, 95% CI 0·49–0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3–4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1–2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Institut National du Cancer (Programme Hospitalier de Recherche Clinique).

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE‐Japan including three clinical trials. The GALAXY study is a prospectively conducted large‐scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high‐risk stage II or low‐risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double‐blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor–positive status in the GALAXY study. Therefore, CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for ctDNA‐negative and ‐positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA‐guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management. CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for circulating tumor DNA–negative and –positive patients, respectively, and helps to answer whether measuring circulating tumor DNA postoperatively has prognostic and/or predictive value. Our circulating tumor DNA–guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy.

Background: Two recent metabolomic analyses found serum lipid, energy, and other metabolites related to aggressive prostate cancer risk up to 20 years prior to diagnosis. Methods: We conducted a serum metabolomic investigation of prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that included annual serum total prostate-specific antigen measurement and digital rectal examination. This nested study included 380 cases diagnosed post-screening and 380 controls individually matched to cases on age, race, study centre, and blood-collection date (median time to diagnosis, 10 years (range 4.4–17 years)). Sera were analysed on a high-resolution accurate mass platform of ultrahigh-performance liquid and gas chromatography/mass spectroscopy that identified 695 known metabolites. Logistic regression conditioned on the matching factors estimated odds ratios (OR) and 95% confidence intervals of risk associated with an 80th percentile increase in the log-metabolite signal. Results: Twenty-seven metabolites were associated with prostate cancer at P <0.05. Pyroglutamine, gamma-glutamylphenylalanine, phenylpyruvate, N -acetylcitrulline, and stearoylcarnitine showed the strongest metabolite-risk signals (ORs=0.53, 0.51, 0.46, 0.58, and 1.74, respectively; 0.001⩽ P ⩽0.006). Findings were similar for aggressive disease (peptide chemical class, P =0.03). None of the P -values were below the threshold of Bonferroni correction, however. Conclusions: A unique metabolomic profile associated with post-screening prostate cancer is identified that differs from that in a previously studied, unscreened population.

Novel diagnostic and prognostic biomarkers of cancers are needed to improve precision medicine. Circular RNAs act as important regulators in cancers at the transcriptional and posttranscriptional levels. The circular RNA circMAN1A2 is highly expressed in nasopharyngeal carcinoma according to our previous RNA sequencing data; however, the expression and functions of circMAN1A2 in cancers are still obscure. Therefore, in this study, we evaluated the expression of circMAN1A2 in the sera of patients with nasopharyngeal carcinoma and other malignant tumors and analyzed its correlations with clinical features and diagnostic values. The expression levels of circMAN1A2 were detected by quantitative real‐time PCR, and the correlations of clinical features with circMAN1A2 expression were analyzed by χ2 tests. Receiver operating characteristic curves were used to evaluate the clinical applications of circMAN1A2. The results showed that circMAN1A2 was upregulated in nasopharyngeal carcinoma, oral cancer, thyroid cancer, ovarian cancer, and lung cancer, with areas under the curves of 0.911, 0.779, 0.734, 0.694, and 0.645, respectively, indicating the good diagnostic value of circMAN1A2. Overall, our findings suggested that circMAN1A2 could be a serum biomarker for malignant tumors, providing important insights into diagnostic approaches for malignant tumors. Further studies are needed to elucidate the mechanisms of circMAN1A2 in the pathogenesis of cancer. We verified that circMAN1A2 was significantly upregulated in the sera of patients with NPC, oral cancer, thyroid cancer, ovarian cancer, and lung cancer and had good clinical diagnostic value. We speculate that circMAN1A2 could be a serum biomarker for malignant cancers and provide effective clues for the early diagnosis of malignant cancers.

In patients with advanced breast cancer, switching to camizestrant with a CDK4/6 inhibitor after ESR1 -mutation detection (and before disease progression) led to significantly longer progression-free survival.

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence 1 . Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations 2 – 5 . By contrast, large-scale epigenetic alterations—which are tissue- and cancer-type specific—are not similarly constrained 6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns. An immunoprecipitation-based protocol is developed to analyse DNA methylation in small quantities of circulating cell-free DNA, and can detect and classify cancers in plasma samples from several tumour types.

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3 , which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ + T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance. Stress reduces the effects of various cancer therapies, such as chemotherapy and immunotherapy, in mice; this is mediated, at least partially, through Tsc22d3 upregulation in tumor-infiltrating dendritic cells, which leads to immunosuppression.

Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33·1 months (IQR 22·3–66·8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3·2–4·1) compared with 3·5 months (2·3–4·8) in the active supportive care group (hazard ratio 0·95, 95% CI 0·73–1·20, p=0·72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.

How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75–84] vs 62% [57–67]; hazard ratio [HR] 0·50, 95% CI 0·38–0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred. Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.