Deficient mismatch repair screening of advanced adenomas in the population screening program for colorectal cancer is not effective.

AIM: Currently, screening of colorectal cancers (CRC) by assessing mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is used to identify Lynch syndrome (LS) patients. Advanced adenomas are considered immediate precursor lesions of CRC. In this study we investigate the relevance of screening of advanced adenomas for LS in population screening. METHODS AND RESULTS: Advanced adenomas (n = 1572) were selected from the Dutch colorectal cancer population screening programme, based on one or more of the criteria: tubulovillous (n = 848, 54%) or villous adenoma (n = 118, 7.5%), diameter ≥ 1 cm (n = 1286, 82%) and/or high-grade dysplasia (n = 176, 11%). In 86 cases (5%), all three criteria were fulfilled at the same time. MMR-IHC and/or MSI analyses were performed on all cases. Only five advanced adenomas (0.3%) showed dMMR and MSI, including two cases with hypermethylation. In at least two patients a germline event was suspected based on allelic frequencies. No pathogenic explanation was found in the last case. CONCLUSION: Timely testing of precursor lesions would be preferable to detect new LS patients before CRC development. However, standard assessment of dMMR of advanced adenomas from the population screening is not effective.

Isolated cerebellar metastasis from urothelial carcinoma: A case report of a rare phenomenon.

Introduction: Although urothelial carcinoma (UC) generally is non-invasive, contrastingly in 25% of patients UC metastasizes. Isolated central nervous system (CNS) metastasis from UC without other distant metastases are considered rare. In this report we describe a patient with an isolated and solitary cerebellar metastasis from UC. Research question: In this case report we explore the value of histological analysis of CNS metastases, imaging, treatment options and survival. Material and methods: A rare case is presented of a patient diagnosed with an isolated CNS metastasis originating from UC. Through a systematic review of literature route of dissemination, current imaging and treatment options, and survival are discussed. Results: A 77-year-old male was diagnosed with a pT2N0M0 high-grade UC and treated with transurethral resection and chemoradiation therapy. Several months later, the patient presented with neurological symptoms, and radiological imaging revealed a solitary cerebellar mass. A body CT scan showed no other metastasis. After surgical resection, histology confirmed urothelial origin of the mass, matching his primary UC and the patient received post-operative stereotactic radiotherapy at the surgical site. Recurrence of the cerebellar mass occurred after 6 months for which the patient received re-resection. The patient died 5.5 months after re-resection. Discussion and conclusion: Isolated brain metastases without other distant metastases from UC are rare, so histologic confirmation of the brain metastasis is essential, particularly when the time interval between diagnosis of the UC and brain metastasis increases. Early brain CT is not recommended. PET CT may have additional value in detection of other distant metastases from UC. Despite advancements in treatments, prognosis for CNS metastasis from UC remains poor.

Detection and Yield of Colorectal Cancer Surveillance in Adults with PTEN Hamartoma Tumour Syndrome.

Colorectal cancer surveillance (CCS) with colonoscopy every five years is advised for PTEN Hamartoma Tumour Syndrome (PHTS) patients aged ≥40 due to an increased colorectal cancer (CRC) risk. However, data to support CCS guidelines are scarce and available CRC risks are low (0-5% at age 50) and likely overestimated. We aimed to assess the detection and yield of CCS for PHTS patients without a CRC history. A retrospective cohort study including PHTS patients aged ≥40 with CCS at a PHTS expertise centre between 2011 and 2022. Adenomas with a ≥10 mm size, (tubulo)villous histology, or high-grade dysplasia were considered advanced. During 67 follow-up years, 37 patients (median age 47 years) underwent 61 colonoscopies. CCS yielded no CRCs. Adenomas were diagnosed in 13/37 (35%) patients during 23/100 colonoscopies (95% CI: 14-36), including one advanced adenoma. Baseline adenoma detection rates were similar to follow-up and higher in patients aged above 50 (50/100, 95% CI: 24-76) vs. age 50 or below (11/100, 95% CI: 3-30; p = 0.021). The low CRC and advanced adenoma yield allow for a more personalised surveillance program. Following our findings combined with literature on CRC risk and progression, we suggest starting CCS at age 40 with variable follow-up intervals between 1 and 10 years depending on previous colonoscopy findings.

Is There an Optimal Definition for a Positive Circumferential Resection Margin in Locally Advanced Esophageal Cancer?

BACKGROUND: Two definitions of a positive circumferential resection margin (CRM) in esophageal cancer coexist: one by the College of American Pathologists (CAP) (CRM = 0 mm) and another by the Royal College of Pathologists (RCP) (CRM ≤ 1 mm). This study aimed to evaluate the prognostic value of both definitions in esophageal cancer and to identify a new cutoff value for the CRM to predict survival. METHODS: Patients who underwent curative esophageal resection for locally advanced (≥ pT3) adenocarcinoma or squamous cell carcinoma were selected from 2007 to 2016. The CRM was reassessed using an ocular micrometer. Overall survival (OS) and disease-free survival were estimated with uni- and multivariate analyses. RESULTS: The study enrolled 283 patients: 48 with a positive CRM according to the CAP definition and 171 with a positive CRM according to the RCP definition. In the multivariate analysis, a positive CRM according to both definitions was significantly associated with a poor OS (CAP: hazard ratio [HR], 2.26, p < 0.001; RCP: HR, 1.42, p = 0.035). A CRM of 0 mm was predictive of a worse OS and DFS than a CRM of 1 mm or less (p < 0.0001), whereas no significant difference was found between a CRM greater than 1 mm and a CRM of 1 mm or less, indicating that the CAP definition was more accurate for predicting prognosis and recurrence. New cutoff CRM values of 100 µm in squamous cell carcinoma and 200 µm in adenocarcinoma were optimal for predicting OS. CONCLUSION: The CAP definition was more accurate for predicting prognosis and recurrence. The study identified a new cutoff value of CRM according to histologic type.

The Workgroup Serrated Polyps and Polyposis (WASP) classification for optical diagnosis of colorectal diminutive polyps with iScan and the impact of the revised World Health Organization (WHO) criteria.

BACKGROUND AND AIMS: The Workgroup Serrated Polyps and Polyposis (WASP) developed criteria for optical diagnosis of colorectal polyps. The aims of this study were: (1) to improve optical diagnosis of diminutive colorectal polyps, especially SSLs, after training endoscopists in applying WASP criteria on videos of polyps obtained with iScan and (2) to evaluate if the WASP criteria are still useful when polyps are pathologically revised according to the World Health Organization (WHO) 2019 criteria. METHODS: Twenty-one endoscopists participated in a training session and predicted polyp histology on 30 videos of diminutive polyps, before and after training (T0 and T1 ). After three months, they scored another 30 videos (T2 ). Primary outcome was overall diagnostic accuracy (DA) at T0 , T1 and T2 . Polyps were histopathologically classified according to the WHO 2010 and 2019 criteria. RESULTS: Overall DA (both diminutive adenomas and SSLs) significantly improved from 0.58 (95% CI 0.55-0.62) at T0 to 0.63 (95% CI 0.60-0.66, p = 0.004) at T1 . For SSLs, DA did not change with 0.51 (95% CI 0.46-0.56) at T0 and 0.55 (95% CI 0.49-0.60, p = 0.119) at T1 . After three months, overall DA was 0.58 (95% CI 0.54-0.62, p = 0.787, relative to T0 ) while DA for SSLs was 0.48 (95% CI 0.42-0.55, p = 0.520) at T2 . After pathological revision according to the WHO 2019 criteria, DA of all polyps significantly changed at all time points. CONCLUSION: A training session in applying WASP criteria on endoscopic videos made with iScan did not improve endoscopists' long-term ability to optically diagnose diminutive polyps. The change of DA following polyp revision according to the revised WHO 2019 criteria suggests that the WASP classification may need revision.

Patient-reported outcomes after oesophagectomy in the multicentre LASER study.

BACKGROUND: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. METHODS: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. RESULTS: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. CONCLUSION: A long-term symptom burden is common after oesophageal cancer surgery.

Strain wave pathway to semiconductor-to-metal transition revealed by time-resolved X-ray powder diffraction.

One of the main challenges in ultrafast material science is to trigger phase transitions with short pulses of light. Here we show how strain waves, launched by electronic and structural precursor phenomena, determine a coherent macroscopic transformation pathway for the semiconducting-to-metal transition in bistable Ti3O5 nanocrystals. Employing femtosecond powder X-ray diffraction, we measure the lattice deformation in the phase transition as a function of time. We monitor the early intra-cell distortion around the light absorbing metal dimer and the long range deformations governed by acoustic waves propagating from the laser-exposed Ti3O5 surface. We developed a simplified elastic model demonstrating that picosecond switching in nanocrystals happens concomitantly with the propagating acoustic wavefront, several decades faster than thermal processes governed by heat diffusion.

The value of 18F-FDG positron emission tomography to differentiate benign from malignant intraductal papillary mucinous neoplasms: A prospective multicenter study.

OBJECTIVE: To assess the value of 18F-FDG PET/CT in differentiating between benign and malignant intraductal papillary mucinous neoplasms (IPMN) of the pancreas. SUMMARY BACKGROUND DATA: Malignant or high-risk IPMN require surgical resection but surgery should be avoided in patients with IPMN carrying a low risk of malignancy. 18F-FDG PET has been studied mostly in small, single center, retrospective series. METHODS: Prospective, non-comparative, multicenter French study. The primary endpoint was the specificity of PET/CT for identifying malignant IPMN (in situ or invasive carcinoma). Final diagnosis was obtained from pathological examination of the resected specimen. RESULTS: Among 120 patients analyzed, 99 had confirmed IPMN, including 24 with malignant lesions, namely 9 with carcinoma in situ and 15 with invasive carcinoma. The 18F-FDG PET/CT was positive in 44 and 31 patients in the overall and IPMN populations respectively. In the 99 IPMN patients, PET/CT showed 13 true positive, 18 false positive, 57 true negative and 11 false negative results. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for the diagnosis of malignancy were 54.2%, 76.0%, 83.8% and 41.9% respectively, versus 64.9%, 75.9%, 82.9% and 54.5% in the overall population. We could not identify a cut-off value for SUVmax to distinguish benign from malignant lesions. Conventional imaging included computed tomography, magnetic resonance cholangiopancreatography and endoscopic ultrasound. In IPMN patients who underwent the 3 techniques, sensitivity, specificity, NPV and PPV were 66.7%, 84.4%, 84.4% and 66.7% respectively. CONCLUSIONS: In this study, 18F-FDG PET/CT did not perform better than conventional imaging to differentiate malignant from benign IPMN.

Early removal of intraperitoneal drainage after pancreatoduodenectomy in patients without postoperative fistula at POD3: Results of a randomized clinical trial.

BACKGROUND: To determine whether the timing of removal of abdominal drainage (AD) after pancreatoduodenectomy (PD) influences the 30-day surgical site infection (30-day SSI) rate. METHODS: A multicenter randomized, intention-to-treat trial with two parallel arms (superiority of early vs. standard AD removal on SSI) was performed between 2011 and 2015 in patients with no pancreatic fistula (PF) on POD3 after PD (NCT01368094). The primary endpoint was the 30-day SSI rate. The secondary endpoints were specific post-PD complications (grade BC PF), postoperative morbidity and risk factor of SSI, reoperation rate, 30-day mortality, length of drainage, length of stay and postoperative infectious complications. RESULTS: One hundred and forty-one patients were randomized: 71 in the early arm, 70 in the standard arm (70.2% of pancreatic adenocarcinomas; 91.5% of pancreatojejunostomies; 66.0% of bilateral drainages; feasibility: 39.9%). Early removal of drains was not associated with a significant decrease of 30-day SSI (14.1% vs. 24.3%, P=0.12). A lower rate of deep SSI was observed in the early arm (2.8% vs. 17.1%, P=0.03), leading to a shorter length of stay (17.8±6.8 vs. 21.0±6.1, P=0.01). Grade BC PF rate (5.6%), severe morbidity (17.7%), reoperation rate (7.8%), 30-day mortality (1.4%) and wound-SSI rate (7.8%) were similar between arms. After multivariate analysis, the timing of AD removal was not associated with an increase of 30-day SSI (OR=0.74 [95% CI 0.35-1.13, P=0.38]). CONCLUSION: In selected patients with no PF on POD3, early removal of abdominal drainage does not seem to increase or decrease surgical site infection's occurrence.

Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS).

PURPOSE: The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). PATIENTS AND METHODS: E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. RESULTS: Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37-62%) and 48% (85% CI: 35-60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3-12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9-6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82-2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. CONCLUSION: CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

Correction to: Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma.

The authors would like to correct the error in the publication of the original article. The surname and given names of the authors were swapped in the "Acknowledgements". The corrected detail is given below.

Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma.

BACKGROUND AND AIMS: Clinicopathological characteristics of gastric cancer (GC) are changing, especially in the West with a decreasing incidence of distal, intestinal-type tumours and the corresponding increasing proportion of tumours with Laurén diffuse or WHO poorly cohesive (PC) including signet ring cell (SRC) histology. To accurately assess the behaviour and the prognosis of these GC subtypes, the standardization of pathological definitions is needed. METHODS: A multidisciplinary expert team belonging to the European Chapter of International Gastric Cancer Association (IGCA) identified 11 topics on pathological classifications used for PC and SRC GC. The topics were debated during a dedicated Workshop held in Verona in March 2017. Then, through a Delphi method, consensus statements for each topic were elaborated. RESULTS: A consensus was reached on the need to classify gastric carcinoma according to the most recent edition of the WHO classification which is currently WHO 2010. Moreover, to standardize the definition of SRC carcinomas, the proposal that only WHO PC carcinomas with more than 90% poorly cohesive cells having signet ring cell morphology have to be classified as SRC carcinomas was made. All other PC non-SRC types have to be further subdivided into PC carcinomas with SRC component (< 90% but > 10% SRCs) and PC carcinomas not otherwise specified (< 10% SRCs). CONCLUSION: The reported statements clarify some debated topics on pathological classifications used for PC and SRC GC. As such, this consensus classification would allow the generation of evidence on biological and prognostic differences between these GC subtypes.

Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).

Background: This open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma. Patients and methods: Patients were randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary end point was progression-free survival (PFS). Results: In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years [95% confidence interval (CI), 2.0 to not reached] with cetuximab and 2.0 years (95% CI, 1.5-2.8) with control [hazard ratio (HR), 0.79; 95% CI, 0.58-1.07; P = 0.13]. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2-4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52-1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31-0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64-1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings. Conclusion: Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma. Clinical trial information: NCT01107639.

Esophageal obstruction due to a right-sided Zenker diverticulum.

A Zenker's or pharyngoesophageal diverticulum may represent a rare cause of upper digestive obstruction, or more often, cervical dysphagia, regurgitations and cough. It develops most often on the posterior left side of cervical oesophagus in elderly patients, and depending on the severity of clinical symptoms may warrant surgical or endoscopic treatment. For large lesions with a difficult endoscopic access to the diverticular neck, surgery is recommended. In our case, we illustrate a giant right-sided Zenker's diverticulum responsible for complete aphagia in a 78-year-old male patient. Open surgery by right cervical approach, with diverticulopexy and cricopharyngeal myotomy was performed, with an uneventful recovery. This paper presents with preoperative and intraoperative illustrations of high educational value for this, often underdiagnosed, clinical entity.

A structured training program for minimally invasive esophagectomy for esophageal cancer- a Delphi consensus study in Europe.

Evidence suggests that structured training programs for laparoscopic procedures can ensure a safe standard of skill acquisition prior to independent practice. Although minimally invasive esophagectomy (MIO) is technically demanding, no consensus on requirements for training for the MIO procedure exists. The aim of this study is to determine essential steps required for a structured training program in MIO using the Delphi consensus methodology. Eighteen MIO experts from 13 European hospitals were asked to participate in this study. The consensus process consisted of two structured meetings with the expert panel, and two Delphi questionnaire rounds. A list of items required for training MIO were constructed for three key domains of MIO, including (1) requisite criteria for units wishing to be trained and (2) to proctor MIO, and (3) a framework of a MIO training program. Items were rated by the experts on a scale 1-5, where 1 signified 'not important' and 5 represented 'very important.' Consensus for each domain was defined as achieving Cronbach alpha ≥0.70. Items were considered as fundamental when ≥75% of experts rated it important (4) or very important (5). Both Delphi rounds were completed by 16 (89%) of the 18 invited experts, with a median experience of 18 years with minimally invasive surgery. Consensus was achieved for all three key domains. Following two rounds of a 107-item questionnaire, 50 items were rated as essential for training MIO. A consensus among European MIO experts on essential items required for training MIO is presented. The identified items can serve as directive principles and core standards for creating a comprehensive training program for MIO.

Resectable invasive IPMN versus sporadic pancreatic adenocarcinoma of the head of the pancreas: Should these two different diseases receive the same treatment? A matched comparison study of the French Surgical Association (AFC).

PURPOSE: To compare survival and impact of adjuvant chemotherapy in patients who underwent pancreaticoduodenectomy (PD) for invasive intraductal papillary mucinous neoplasm (IIPMN) and sporadic pancreatic ductal adenocarcinoma (PDAC). METHODS: From 2005 to 2012, 240 patients underwent pancreatectomy for IIPMN and 1327 for PDAC. Exclusion criteria included neoadjuvant treatment, pancreatic resection other than PD, vascular resection, carcinoma in situ, or <11 examined lymph nodes. Thus, 82 IIPMN and 506 PDAC were eligible for the present study. Finally, The IIPMN group was matched 1:2 to compose the PDAC group according to TNM disease stage, perineural invasion, lymph node ratio, and margin status. RESULTS: There was no difference in patient's characteristics, intraoperative parameters, postoperative outcomes, and histologic parameters. Overall survival and disease-free survival times were comparable between the 2 groups. In each group, overall survival time was significantly poorer in patients who did not achieve adjuvant chemotherapy (p = 0.03 for the IIPMN group; p = 0.03 for the PDAC group). In lymph-node negative patients of the IIPMN group, adjuvant chemotherapy did not have any significant impact on overall survival time (OR = 0.57; 95% CI [0.24-1.33]). Considering the whole population (i.e. patients with IIPMN and PDAC; n = 246), patients who did not achieve adjuvant chemotherapy had poorer survival (p < 0.01). CONCLUSIONS: The courses of IIPMN and PDAC were similar after an optimized stage-to-stage comparison. Adjuvant chemotherapy was efficient in both groups. However, in lymph node negative patients, adjuvant chemotherapy seemed not to have a significant impact.