Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE.

BACKGROUND: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. PATIENTS AND METHODS: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. RESULTS: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. CONCLUSIONS: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2. TRIAL REGISTRATION: NCT03812796 (registered 23rd January 2019).

Quality assessment of online patient information on upper gastrointestinal endoscopy using the modified Ensuring Quality Information for Patients tool.

INTRODUCTION: Websites and online resources are increasingly becoming patients' main source of healthcare information. It is paramount that high quality information is available online to enhance patient education and improve clinical outcomes. Upper gastrointestinal (UGI) endoscopy is the gold standard investigation for UGI symptoms and yet little is known regarding the quality of patient orientated websites. The aim of this study was to assess the quality of online patient information on UGI endoscopy using the modified Ensuring Quality Information for Patients (EQIP) tool. METHODS: Ten search terms were employed to conduct a systematic review. for each term, the top 100 websites identified via a Google search were assessed using the modified EQIP tool. High scoring websites underwent further analysis. Websites intended for professional use by clinicians as well as those containing video or marketing content were excluded. FINDINGS: A total of 378 websites were eligible for analysis. The median modified EQIP score for UGI endoscopy was 18/36 (interquartile range: 14-21). The median EQIP scores for the content, identification and structure domains were 8/18, 1/6 and 9/12 respectively. Higher modified EQIP scores were obtained for websites produced by government departments and National Health Service hospitals (p=0.007). Complication rates were documented in only a fifth (20.4%) of websites. High scoring websites were significantly more likely to provide balanced information on risks and benefits (94.6% vs 34.4%, p<0.001). CONCLUSIONS: There is an immediate need to improve the quality of online patient information regarding UGI endoscopy. The currently available resources provide minimal information on the risks associated with the procedure, potentially hindering patients' ability to make informed healthcare decisions.

Tislelizumab versus chemotherapy as second-line treatment for European and North American patients with advanced or metastatic esophageal squamous cell carcinoma: a subgroup analysis of the randomized phase III RATIONALE-302 study.

BACKGROUND: The phase III RATIONALE-302 study evaluated tislelizumab, an anti-programmed cell death protein 1 antibody, as second-line (2L) treatment for advanced/metastatic esophageal squamous cell carcinoma (ESCC). This prespecified exploratory analysis investigated outcomes in patients from Europe and North America (Europe/North America subgroup). PATIENTS AND METHODS: Patients with tumor progression during/after first-line systemic treatment were randomized 1 : 1 to open-label tislelizumab or investigator's choice of chemotherapy (paclitaxel, docetaxel, or irinotecan). RESULTS: The Europe/North America subgroup comprised 108 patients (tislelizumab: n = 55; chemotherapy: n = 53). Overall survival (OS) was prolonged with tislelizumab versus chemotherapy (median: 11.2 versus 6.3 months), with a hazard ratio (HR) of 0.55 [95% confidence interval (CI) 0.35-0.87]; HR was similar irrespective of programmed death-ligand 1 score [≥10%: 0.47 (95% CI 0.18-1.21); <10%: 0.55 (95% CI 0.30-1.01)]. Median progression-free survival was 2.3 versus 2.7 months with tislelizumab versus chemotherapy [HR: 0.97 (95% CI 0.64-1.47)]. Overall response rate was greater with tislelizumab (20.0%) versus chemotherapy (11.3%), with more durable response (median duration of response: 5.1 versus 2.1 months). Tislelizumab had a favorable safety profile versus chemotherapy, with fewer patients experiencing ≥grade 3 treatment-related adverse events (13.0% versus 51.0%). Those on tislelizumab experienced less deterioration in health-related quality of life, physical functioning, and/or disease- and treatment-related symptoms (i.e. fatigue, pain, and eating problems) as compared to those on chemotherapy, per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and QLQ-OES18 scores. CONCLUSIONS: As a 2L therapy for advanced/metastatic ESCC, tislelizumab improved OS and had a favorable safety profile as compared to chemotherapy in European/North American ESCC patients in the randomized phase III RATIONALE-302 study.

CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.

BACKGROUND: Patients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC). PATIENTS AND METHODS: This single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR). RESULTS: Between 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months). CONCLUSIONS: The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious.

Cortico-cerebellar connectivity underlying motor control in chronic post-stroke individuals.

The robust, reciprocal anatomical connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscores the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, post-stroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase-I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in subjects (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN and the their interaction as a function of motor impairment and performance. Our results indicate that 1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low-ß band, with moderately and severely impaired subjects showing desynchronization and synchronization, respectively. 2) Significant CCC was observed during isometric 'hold' period in the low-ß band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low-ß band during motor control across all impairment levels which encourages the exploitation of the cerebello-thalamo-cortical pathway as a neuromodulation target to promote rehabilitation.Significance Statement:Cerebral infarct due to stroke can lead to lasting reduction in cerebellar metabolism resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase-I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke patients performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low-ß band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

Radiology of Castleman disease: the pivotal role of imaging in diagnosis, staging, and response assessment of this rare entity.

Castleman Disease (CD) is a rare entity that typically presents as an enhancing nodal mass in the mediastinum or head and neck region on computed tomography (CT). It may manifest as unicentric or multicentric regions of lymph node enlargement. A key clinical issue in the context of CD is delayed diagnosis, which contributes adversely to patient outcome, given that accurate diagnosis facilitates earlier treatment of this curable disease. This article will address relevant imaging aspects, with reference to typical and atypical imaging features of CD, illustrated using examples from our specialist centre; the imaging journey for patients with CD; and will provide practical pointers to radiologists in differentiating CD from other benign and malignant causes of enhancing lymphadenopathy, including lymphoma and neoplastic adenopathy. We will also review current classification tools and staging challenges with reference to World Health Organization guidelines, International Working Group guidelines as well as the Lugano classification. Finally, we will discuss the potential role of additional imaging techniques in CD, highlighting novel imaging methods and expanded utilities from our specialist centre.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): a good practice guide, pictorial review, and new perspectives.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare but emerging T-cell non-Hodgkin lymphoma. It has two distinct subtypes, "effusion-only" or "mass-forming" disease, arising around implants in patients with in situ or previous history of textured-surface breast implants. The clinical, histopathological and imaging features are unique and nuanced as compared to primary breast malignancy and other lymphoma categories. Prompt recognition and diagnosis triggers referral to appropriate BIA-ALCL centres and initiation of treatment, with potential for excellent prognosis. Definitive management of both subtypes involves implant and capsule removal; systemic therapy is reserved for mass-forming disease and advanced-stage disease. There have been recent crucial advances in the diagnostic pathway, with publication of national and international guidelines: from the UK Medicines Healthcare products Regulatory Agency (MHRA) Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group (PRASEAG), and the United States National Comprehensive Cancer Network (NCCN). This review provides a practical guide to the clinical work-up of BIA-ALCL, enabling optimisation of the diagnostic imaging pathway, with representative cases.

Inguinal hernia repair: a systematic analysis of online patient information using the Modified Ensuring Quality Information for Patients tool.

BACKGROUND: Online resources are a fundamental source of healthcare information due to the increasing popularity of the internet. Ensuring accuracy and reliability of websites is crucial to improving patient education and enhancing patient outcomes. Inguinal hernia repair is the most commonly performed general surgical procedure worldwide. This study analyses the quality of online patient information about inguinal hernia repair using the Modified Ensuring Quality Information for Patients (EQIP) tool. METHODS: A systematic review of online information on inguinal hernia repair was conducted using four search terms: 'inguinal hernia', 'groin hernia', 'inguinal hernia repair' and 'inguinoscrotal hernia'. The top 100 websites for each term identified using Google were assessed using the modified EQIP tool (score 0-36). Websites for the paediatric population or intended for medical professional use were excluded from analysis. FINDINGS: A total of 142 websites were eligible for analysis, 52.8% originating from the UK. The median EQIP score for all websites was 17/36 (interquartile range 14-21). The median EQIP scores for content, identification and structure were 8/18, 2/8 and 8/12, respectively. Complications of inguinal hernia repair were included in 46.5% of websites, with only 9.2% providing complication rates and 14.1% providing information on how complications are handled. CONCLUSION: This study highlights that the current quality of online patient information on inguinal hernia repair is poor, with minimal information available on complications, hindering patients' ability to make informed decisions regarding their healthcare. To improve patient education, there is an immediate need for improved quality online resources to meet international standards.

Chronic lymphocytic leukaemia and Richter's transformation: multimodal review and new imaging paradigms.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults. It is a malignancy of CD5 B-cells characterised by small, mature-appearing lymphocytes accumulating in the blood, bone marrow, and lymphoid tissues. Richer transformation (RT) is an important adverse complication. Detection of RT is critical to allow initiation of appropriate therapy. CLL staging and response evaluation is complicated and nuanced. From our extensive tertiary centre experience of several hundred CLL cases over the last decade, we detail key computed tomography (CT) and positron-emission tomography (PET) imaging features of the natural history of CLL. The authors present an original imaging-based patient-management paradigm for the investigation of potential RT, which will inform global practice. Potential applications of whole-body diffusion weighted imaging, novel PET radiotracers, minimal residual disease, and ct-DNA are addressed.

Explosive Outbursts at School.

Explosive outbursts (EO) by students are an intensely distressing experience for that student as well as for all school staff and students present during the outburst. These EO are characterized by rapid escalations, usually far out of proportion to precipitating events, may include significant verbal and/or physical aggression, require intensive staff intervention, are often difficult for the student to process, and are typically recurrent. These explosions cross multiple psychiatric and educational diagnostic categories and require diverse interventions to address behavioral, emotional, impulsive, and sensory components. Interventions for each stage of an EO can be used to deescalate these events.

Current and future best practice in imaging, staging, and response assessment for Non-Hodgkin's lymphomas: the Specialist Integrated Haematological Malignancy Imaging Reporting (SIHMIR) paradigm shift.

Non-Hodgkin's lymphoma (NHL) encompasses over 40 different haematological malignancies, including low and high-grade neoplasms, such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) respectively. A key clinical issue in the context of NHL is delayed and inaccurate diagnosis, which contributes adversely to patient morbidity and mortality. This article will address relevant imaging aspects, with particular reference to advancements in NHL imaging, including computed tomography (CT), integrated positron-emission tomography (PET)-CT, and magnetic resonance imaging (MRI). We provide multiparametric (anato-functional) imaging display items, including histological correlation. We will also introduce our original concept of "Specialist Integrated Haematological Malignancy Imaging Reporting" (SIHMIR), a paradigm shift in lymphoma radiology.

Adjuvant therapy following oesophagectomy for adenocarcinoma in patients with a positive resection margin.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy is contentious. In UK practice, surgical resection margin status is often used to classify patients for receiving adjuvant treatment. The aim of this study was to assess the survival benefit of adjuvant therapy in patients with positive (R1) resection margins. METHODS: Two prospectively collected UK institutional databases were combined to identify eligible patients. Adjusted Cox regression analyses were used to compare overall and recurrence-free survival according to adjuvant treatment. Recurrence patterns were assessed as a secondary outcome. Propensity score-matched analysis was also performed. RESULTS: Of 616 patients included in the combined database, 242 patients who had an R1 resection were included in the study. Of these, 112 patients (46·3 per cent) received adjuvant chemoradiotherapy, 46 (19·0 per cent) were treated with adjuvant chemotherapy and 84 (34·7 per cent) had no adjuvant treatment. In adjusted analysis, adjuvant chemoradiotherapy improved recurrence-free survival (hazard ratio (HR) 0·59, 95 per cent c.i. 0·38 to 0·94; P = 0·026), with a benefit in terms of both local (HR 0·48, 0·24 to 0·99; P = 0·047) and systemic (HR 0·56, 0·33 to 0·94; P = 0·027) recurrence. In analyses stratified by tumour response to neoadjuvant chemotherapy, non-responders (Mandard tumour regression grade 4-5) treated with adjuvant chemoradiotherapy had an overall survival benefit (HR 0·61, 0·38 to 0·97; P = 0·037). In propensity score-matched analysis, an overall survival benefit (HR 0·62, 0·39 to 0·98; P = 0·042) and recurrence-free survival benefit (HR 0·51, 0·30 to 0·87; P = 0·004) were observed for adjuvant chemoradiotherapy versus no adjuvant treatment. CONCLUSION: Adjuvant therapy may improve overall survival and recurrence-free survival after margin-positive resection. This pattern seems most pronounced with adjuvant chemoradiotherapy in non-responders to neoadjuvant chemotherapy.

ANTECEDENTES: El papel del tratamiento adyuvante en pacientes con adenocarcinoma esofagogástrico tratados con quimioterapia neoadyuvante es polémico. En la práctica del Reino Unido, el estado del margen de resección quirúrgico se utiliza a menudo para identificar a los pacientes que reciben tratamiento adyuvante. El objetivo de este estudio fue evaluar el beneficio en la supervivencia del tratamiento adyuvante en pacientes con márgenes de resección positivos (R1). MÉTODOS: Se combinaron dos bases de datos de instituciones del Reino Unido que recogen información de forma prospectiva para identificar pacientes elegibles. Se utilizaron análisis de regresión de Cox ajustados para comparar la supervivencia global y la supervivencia libre de recidiva según el tratamiento adyuvante. Los patrones de recidiva se evaluaron como resultado secundario. También se realizó un análisis de emparejamiento por puntaje de propensión. RESULTADOS: De 616 pacientes incluidos en la base de datos combinada, se incluyeron en el estudio 242 pacientes con resección R1. De estos pacientes, 112 (46%) recibieron quimiorradioterapia adyuvante, 46 (19%) pacientes fueron tratados con quimioterapia adyuvante y 84 (35%) pacientes no recibieron ningún tratamiento. En el análisis ajustado, la quimiorradioterapia adyuvante mejoró la supervivencia libre de recidiva (cociente de riesgos instantáneos, hazard ratio, HR 0,59, i.c. del 95% 0,38-0,94; P = 0,026) con un beneficio tanto para la recidiva local (HR 0,48, i.c. del 95% 0,24-0,99; P = 0,047) como para la sistémica (HR 0,56, i.c. del 95% 0,33-0,94; P = 0,027). Cuando los pacientes se clasificaron según la respuesta tumoral a la quimioterapia neoadyuvante, los no respondedores (Mandard Grado 4/5) tratados con quimiorradioterapia adyuvante obtuvieron un beneficio en la supervivencia (HR 0,61, i.c. del 95% 0,38-0,97; P = 0,037). En el análisis por emparejamiento por puntaje de propensión, se observó un beneficio en la supervivencia global (HR 0,62, i.c. del 95% 0,39-0,98; P = 0,042) y en la supervivencia libre de recidiva (HR 0,51.i.c. del 95% 0,30-0,87; P = 0,004) con la quimiorradioterapia adyuvante frente a no recibir tratamiento adyuvante. CONCLUSIÓN: El tratamiento adyuvante puede mejorar la supervivencia global y la supervivencia libre de recidiva en pacientes con margen de resección positivo. Este patrón parece más pronunciado con la quimiorradioterapia adyuvante en pacientes que no responden a la quimioterapia.

Advances in local area optical data communication systems.

This paper reviews optical fibre technology for local area optical communications systems. Technologies used in local systems include single and multimode fibre, single and multimode lasers, optical modulators, photodetectors, wavelength division multiplexing, multilevel modulation formats, electronic packet switching, electronic equalization and error correction. These methods have enabled the local area optical link data rate to increase from 0.1 Gb s-1 in 1990 to nearly a Tb s-1 in 2019. The challenges to increasing link data rates further, while reducing the transmitted power per bit, at reduced cost are discussed. Potential technical solutions and newly proposed methods which might address these challenges are highlighted.

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.

BACKGROUND: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). PATIENTS AND METHODS: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. RESULTS: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. CONCLUSIONS: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. CLINICAL TRIAL IDENTIFICATION: NCT00112918.

Postoperative chemotherapy improves survival in patients with resected high-risk Stage II colorectal cancer: results of a systematic review and meta-analysis.

AIM: The aim was to assess the benefit of adjuvant chemotherapy in high-risk Stage II colorectal cancer. METHOD: A systematic literature review and meta-analysis was performed comparing survival in patients with resected Stage II colorectal cancer and high-risk features having postoperative chemotherapy vs no chemotherapy. RESULTS: Of 1031 articles screened, 29 were included, reporting on 183 749 participants. Adjuvant chemotherapy significantly improved overall survival [hazard ratio (HR) 0.61, P < 0.0001], disease-specific survival (HR = 0.73, P = 0.05) and disease-free survival (HR = 0.59, P < 0.0001) compared to no chemotherapy. Adjuvant chemotherapy significantly increased 5-year overall survival (OR = 0.53, P = 0.0008) and 5-year disease-free survival (OR = 0.50, P = 0.001). Overall survival and disease-free survival remained significantly prolonged during subgroup analysis of studies published from 2015 onwards (HR = 0.60, P < 0.0001; HR = 0.65, P = 0.0001; respectively), in patients with two or more high-risk features (HR = 0.59, P = 0.0001; HR = 0.70, P = 0.03; respectively) and in colon cancer (HR = 0.61, P < 0.0001; HR = 0.51, P = 0.0001; respectively). Overall survival, disease-specific survival and disease-free survival during subgroup analysis of individual high-risk features were T4 tumour (HR = 0.58, P < 0.0001; HR = 0.50, P = 0.003; HR = 0.75, P = 0.05), < 12 lymph nodes harvested (HR = 0.67, P = 0.0002; HR = 0.80, P = 0.17; HR = 0.72, P = 0.02), poor differentiation (HR = 0.84, P = 0.35; HR = 0.85, P = 0.23; HR = 0.61, P = 0.41), lymphovascular or perineural invasion (HR = 0.55, P = 0.05; HR = 0.59, P = 0.11; HR = 0.76, P = 0.05) and emergency surgery (HR = 0.60, P = 0.02; HR = 0.68, P = 0.19). CONCLUSION: Adjuvant chemotherapy in high-risk Stage II colorectal cancer results in a modest survival improvement and should be considered on an individual patient basis. Due to potential heterogeneity and selection bias of the included studies, and lack of separate rectal cancer data, further large randomized trials with predefined inclusion criteria and standardized chemotherapy regimens are required.

Quality assurance of surgery in the randomized ST03 trial of perioperative chemotherapy in carcinoma of the stomach and gastro-oesophageal junction.

BACKGROUND: The UK Medical Research Council ST03 trial compared perioperative epirubicin, cisplatin and capecitabine (ECX) chemotherapy with or without bevacizumab (B) in gastric and oesophagogastric junctional cancer. No difference in survival was noted between the arms of the trial. The present study reviewed the standards and performance of surgery in the context of the protocol-specified surgical criteria. METHODS: Surgical and pathological clinical report forms were reviewed to determine adherence to the surgical protocols, perioperative morbidity and mortality, and final histopathological stage for all patients treated in the study. RESULTS: Of 1063 patients randomized, 895 (84·2 per cent) underwent resection; surgical details were available for 880 (98·3 per cent). Postoperative assessment data were available for 873 patients; complications occurred in 458 (52·5 per cent) overall, of whom 71 (8·1 per cent) developed complications deemed to be life-threatening by the responsible clinician. The most common complications were respiratory (211 patients, 24·2 per cent). The anastomotic leak rate was 118 of 873 (13·5 per cent) overall; among those who underwent oesophagogastrectomy, the rate was higher in the group receiving ECX-B (23·6 per cent versus 9·9 per cent in the ECX group). Pathological assessment data were available for 845 patients. At least 15 nodes were removed in 82·5 per cent of resections and the median lymph node harvest was 24 (i.q.r. 17-34). Twenty-five or more nodes were removed in 49·0 per cent of patients. Histopathologically, the R1 rate was 24·9 per cent (208 of 834 patients). An R1 resection was more common for proximal tumours. CONCLUSION: In the ST03 trial, the performance of surgery met the protocol-stipulated criteria. Registration number: NCT00450203 ( http://www.clinicaltrials.gov).

Patient-level costs in margin re-excision for breast-conserving surgery.

BACKGROUND: High rates of reoperation following breast-conserving surgery (BCS) for positive margins are associated with costs to healthcare providers. The aim was to assess the quality of evidence on reported re-excision costs and compare the direct patient-level costs between patients undergoing successful BCS versus reoperations after BCS. METHODS: The study used data from women who had BCS with or without reoperation at a single institution between April 2015 and March 2016. A systematic review of health economic analysis in BCS was conducted and scored using the Quality of Health Economic Studies (QHES) instrument. Financial data were retrieved using the Patient-Level Information and Costing Systems (PLICS) for patients. Exchange rates used were: US $1 = £0·75, £1 = €1·14 and US $1 = €0·85. RESULTS: The median QHES score was 47 (i.q.r. 32·5-79). Only two of nine studies scored in the upper QHES quartile (score at least 75). Costs of initial lumpectomy and reoperation were in the range US $1234-11786 and $655-9136 respectively. Over a 12-month interval, 153 patients had definitive BCS and 59 patients underwent reoperation. The median cost of reoperations after BCS (59 patients) was £4511 (range 1752-18 019), representing an additional £2136 per patient compared with BCS without reoperation (P < 0·001). CONCLUSION: The systematic review demonstrated variation in methodological approach to cost estimates and a paucity of high-quality cost estimate studies for reoperations. Extrapolating local PLICS data to a national level suggests that getting BCS right first time could result in substantial savings.

A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial.

Background: Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. Patients and methods: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. Results: Regression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings. Conclusions: These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials.