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Copyright of BJS Open is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Previous analyses of the oesophageal circumferential resection margin (CRM) have focused on the prognostic validity of two different definitions of a positive CRM, that of the College of American Pathologists (tumour at margin) and that of the Royal College of Pathologists (tumour within 1 mm). This study aimed to analyse the validity of these definitions and explore the risk of recurrence and survival with incremental tumour distances from the CRM. Methods: This cohort study included patients who underwent resection for adenocarcinoma of the oesophagus between 2000 and 2014. Kaplan–Meier and Cox regression analyses were performed to determine the hazard ratio (HR) with 95 per cent confidence intervals for recurrence and mortality in CRM increments: tumour at the cut margin, extending to within 0·1–0·9, 1·0–1·9, 2·0–4·9 mm, and 5·0 mm or more from the margin. Results: A total of 444 patients were included in the study. Kaplan–Meier and unadjusted analyses showed a significant incremental improvement in overall survival (P < 0·001) and recurrence (P for trend < 0·001) rates with increasing distance from the CRM. Tumour distance of 2·0 mm or more remained a significant predictor of survival on multivariable analysis (HR for risk of death 0·66, 95 per cent c.i. 0·44 to 1·00). Multivariable analysis of overall survival demonstrated a significant difference between a positive and negative CRM with the Royal College of Pathologists' definition (HR 1·37, 1·01 to 1·85), but not with the College of American Pathologists' definition (HR 1·22, 0·90 to 1·65). Conclusion: This study demonstrated an incremental improvement in survival and recurrence rates with increasing tumour distance from the CRM. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the oncological outcomes of a large multicenter series of left thoracoabdominal esophagectomies, and compare these to the more widely utilized Ivor-Lewis esophagectomy. With ethics approval and an established study protocol, anonymized data from five centers were merged into a structured database. The study exposure was operative approach (ILE or LTE). The primary outcome measure was time to death. Secondary outcome measures included time to tumor recurrence, positive surgical resection margins, lymph node yield, postoperative death and hospital length of stay. Cox proportional hazards models provided hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, pathological tumor stage, tumor grade, lymphovascular invasion and neoadjuvant treatment. Among 1228 patients (598 ILE; 630 LTE), most (86%) had adenocarcinoma (AC) and were male (81%). Comparing ILE and LTE for AC patients, no difference was seen in terms of time to death (HR 0.904 95%CI 0.749-1.1090) or time to recurrence (HR 0.973 95%CI 0.768-1.232). The risk of a positive resection margin was also similar (OR 1.022 95%CI 0.731-1.429). Median lymph node yield did not differ between approaches (LTE 21; ILE 21; P = 0.426). In-hospital mortality was 2.4%, significantly lower in the LTE group (LTE 1.3%; ILE 3.6%; P = 0.004). Median hospital stay was 11 days in the LTE group and 14 days in the ILE group (P < 0.0001). In conclusion, this is the largest series of left thoracoabdominal esophagectomies to be submitted for publication and the only one to compare two different transthoracic esophagectomy strategies. It demonstrates oncological equivalence between operative approaches but possible short- term advantages to the left thoracoabdominal esophagectomy. [ABSTRACT FROM AUTHOR]

This study aims to establish the prevalence and predictors of anxiety and depression among esophageal cancer patients, post-diagnosis but prior to curatively intended surgery. This was a cross-sectional study using data from a hospital-based prospective cohort study, carried out at St Thomas' Hospital, London. Potential predictor variables were retrieved from medical charts and self-report questionnaires. Anxiety and depression were measured prior to esophageal cancer surgery, using the Hospital Anxiety and Depression Scale. Prevalence of anxiety and depression was calculated using the established cutoff (scores ≥8 on each subscale) indicating cases of 'possible-probable' anxiety or depression, and multivariable logistic regression analyses were performed to examine predictors of emotional distress. Among the 106 included patients, 36 (34%) scored above the cutoff (≥8) for anxiety and 24 (23%) for depression. Women were more likely to report anxiety than men (odds ratio 4.04, 95% confidence interval 1.45-11.16), and patients reporting limitations in their activity status had more than five times greater odds of reporting depression (odds ratio 6.07, 95% confidence interval 1.53-24.10). A substantial proportion of esophageal cancer patients report anxiety and/or depression prior to surgery, particularly women and those with limited activity status, which highlights a need for qualified emotional support. [ABSTRACT FROM AUTHOR]

The article discusses a research study on developing a Mycobacterium avium subspecies paratuberculosis (Map) infection intestinal model for evaluating systemic immunologic and mucosal pathology responses. Subjects were 40 five-week-old male dairy breed calves that were castrated and grouped randomly into high and low Map dosage and inoculated then fecal samples were cultured for necropsy. Results showed the presence of mild lymphofollicular hyperplasia of the ileal Peyer's patches and multifocal abscesses in the ileocecal crypt.

In esophageal cancer, metastatic spread to the lungs is detected in 4–9.7% of cases. During staging investigations, 22% of patients have pulmonary nodules detected on cross-sectional imaging. The purpose of this study is to elucidate the clinical importance of these incidentally found pulmonary nodules, in patients with clinically localized esophageal cancer. A retrospective cohort study was conducted from January 2008 to December 2012 in a tertiary esophagogastric referral center. One-hundred and forty-nine patients were included in the study. All patients underwent dedicated staging followed by neoadjuvant chemotherapy and surgery as indicated. Thirty-three (22.1%) patients had pulmonary nodules found in their preoperative staging. Only three (9%) patients proved to develop metastatic pulmonary disease on follow-up. Interestingly, in all three patients, the nodules were negative on initial 18−fluorodeoxyglucose positron emission tomography. Incidentally found pulmonary nodules in newly diagnosed patients with esophageal cancer during staging investigations are rarely metastases. Such nodules, in isolation, should not preclude patients from radical treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose/aims: Uptake and delivery of cancer services across the United Kingdom have been significantly impacted by the COVID-19 pandemic. This study aimed to understand the impact of the pandemic on the working practices of clinical nurse specialists and their patient interactions across different cancer specialties., Design: We performed a cross-sectional survey exploring nurses' experiences of delivering care during the pandemic, as well as their perceptions of the concerns that cancer patients were experiencing., Methods: Clinical nurse specialists working in London cancer services were invited to complete an online questionnaire. Nurses' experiences and their perceptions of patients' concerns were analyzed descriptively., Results: Fifty-four nurses participated. Almost half had been redeployed to other clinical areas during the pandemic (n = 19). COVID-19 discussions added 5 to 10 minutes on average to most consultations, with nurses either working longer/unpaid hours (34%) or spending less time talking to patients about cancer (39%) to deal with this. Approximately 50% of nurses would have liked additional information and support from their hospital., Conclusions: Clinical nurse specialist time and resources have been stretched during the COVID-19 pandemic. Hospitals need to work with nursing staff to ensure the specific information needs of cancer patients are being met., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is increasing evidence for the use of exercise in cancer patients and data supporting enhanced tumour volume reduction following chemotherapy in animal models. To date, there is no reported histopathological evidence of a similar oncological benefit in oesophageal cancer., Methods: A prospective non-randomised trial compared a structured prehabilitation exercise intervention during neoadjuvant chemotherapy and surgery versus conventional best-practice for oesophageal cancer patients. Biochemical and body composition analyses were performed at multiple time points. Outcome measures included radiological and pathological markers of disease regression. Logistic regression calculated ORs with 95% CI for the likelihood of pathological response adjusting for chemotherapy regimen and chemotherapy delivery., Results: Comparison of the Intervention (n=21) and Control (n=19) groups indicated the Intervention group had higher rates of tumour regression (Mandard TRG 1-3 Intervention n=15/20 (75%) vs Control n=7/19 (36.8%) p=0.025) including adjusted analyses (OR 6.57; 95% CI 1.52 to 28.30). Combined tumour and node downstaging (Intervention n=9 (42.9%) vs Control n=3 (15.8%) p=0.089) and Fat Free Mass index were also improved (Intervention 17.8 vs 18.7 kg/m 2 ; Control 16.3 vs 14.7 kg/m 2 , p=0.026). Differences in markers of immunity (CD-3 and CD-8) and inflammation (IL-6, VEGF, INF-y, TNFa, MCP-1 and EGF) were observed., Conclusion: The results suggest improved tumour regression and downstaging in the exercise intervention group and should prompt larger studies on this topic., Trial Registration Number: NCT03626610., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To assess the outcomes of patients with early esophageal cancer and high-grade dysplasia comparing esophagectomy, the historical treatment of choice, to endoscopic eradication therapy (EET)., Methods: Retrospective cohort study of consecutive patients with early esophageal cancer/high-grade dysplasia, treated between 2000 and 2018 at a tertiary center. Primary outcomes were all-cause and disease-specific mortality assessed by multivariable Cox regression and a propensity score matching sub analysis, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, tumor grade (G1/2 vs. G3), tumor stage, and lymphovascular invasion. Secondary outcomes included complications, hospital stay, and overall costs., Results: Among 269 patients, 133 underwent esophagectomy and 136 received EET. Adjusted survival analysis showed no difference between groups regarding all-cause mortality (HR 1.85, 95% CI 0.73, 4.72) and disease-specific mortality (HR 1.10, 95% CI 0.26, 4.65). In-hospital and 30-day mortality was 0% in both groups. The surgical group had a significantly higher rate of complications (Clavien-Dindo ≥3 26.3% vs. endoscopic therapy 0.74%), longer in-patient stay (median 14 vs. 0 days endoscopic therapy) and higher hospital costs(£16 360 vs. £8786 per patient)., Conclusion: This series of patients treated during a transition period from surgery to EET, demonstrates a primary endoscopic approach does not compromise oncological outcomes with the benefit of fewer complications, shorter hospital stays, and lower costs compared to surgery. It should be available as the gold standard treatment for patients with early esophageal cancer. Those with adverse prognostic features may still benefit from esophagectomy., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neoadjuvant chemotherapy is often used prior to surgical resection for oesophageal adenocarcinoma but remains ineffective in a high proportion of patients. The histological Mandard tumour regression grade is used to determine chemoresponse but is not available at the time of treatment decision-making. The aim of this cohort study was to identify factors that predict chemotherapy response prior to surgery., Methods: A prospectively collected database of patients undergoing surgical resection for oesophageal adenocarcinoma from a high-volume UK institution was used. Patients were subcategorised using pathological tumour response into 'responders' (Mandard grade 1-3) and 'non-responders' (Mandard grade 4 and 5). Multivariable logistic regression analysis was performed to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for responder status adjusting for a variety of parameters. Receiver operating characteristic (ROC) curves were calculated., Results: Among 315 patients included, 102 (32%) were responders and 213 (68%) non-responders. A decrease in radiological tumour volume (OR 1.92 95%CI 1.02-3.62; p  = 0.05), a 'partial response' RECIST score (OR 7.16 95%CI 1.49-34.36; p  = 0.01), a clinically improved dysphagia score (OR 2.79 95%CI 1.05-7.04; p  = 0.04) and lymphovascular invasion (OR 0.06 95%CI 0.02-0.13; p  = 0.000) influenced responder status. ROC curve analysis for responder status utilising all available parameters had an area under the curve (AUC) of 0.86., Conclusion: This study has highlighted the potential for using pre-defined factors to identify those patients who have responded to neoadjuvant chemotherapy, prior to surgical resection, potentially facilitating a more individualised therapeutic approach.

Aim: IL-33 is a potential therapeutic target but commercially available assays for the quantitation of systemic IL-33 have poor reliability. Results: In commercial IL-33 kits, interference from endogenous binding partners (e.g., soluble ST2) causes under-quantitation. Mitigating this required acid dissociation and addition of the detection reagent simultaneously with the capture step. This enabled detection of total, reduced (active) levels of IL-33 in human serum (LLOQ 6.25 pg/ml). Conclusion: Acid treatment of serum samples dissociates IL-33 from endogenous binding partners, increasing soluble ST2 tolerance to >1000 ng/ml. The modified method was specific for reduced endogenous IL-33. Analysis of over 300 samples from individuals with and without asthma and with different smoking status revealed no difference in serum IL-33.

Background: Most patients presenting with oesophageal cancer do so with advanced disease not suitable for surgery. However, there are examples of encouraging survival following surgery in highly selected patients who respond well to chemotherapy., Methods: This was a retrospective cohort study of patients who presented with advanced but nonvisceral metastatic oesophageal cancer. Consecutive patients on a prolonged primary chemotherapy pathway who underwent surgical resection following a favourable response to chemotherapy were included. Survival and recurrence rates were analysed using Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: A total of 57 patients included in the cohort operated between 2007 and 2015, the overall median survival was 44 months and the 5-year survival was 42%. Prechemotherapy cN0/cN1 (HR: 0.27, 95% CI: 0.12-0.62) conferred an independent survival advantage compared to cN2 and cN3 disease. Poor differentiation (HR: 2.46, 95% CI: 1.11-5.42), R1 resection (HR: 2.43, 95% CI: 1.14-5.19) and advanced nodal status (HR: 3.28, 95% CI: 1.44-7.47) predicted worse survival on univariable analysis. Poor differentiation (HR: 3.93, 95% CI: 1.62-9.56) was independently associated with poor survival when adjusted for other variables., Conclusion: Patients who present with advanced inoperable oesophageal cancer who have a favourable response to chemotherapy represent a limited group of patients who may benefit from surgery., (© 2021 Wiley Periodicals LLC.)

Background: Esophageal anastomoses performed following esophagectomy and total gastrectomy are technically challenging with a significant risk of anastomotic leak. A safe, reliable, and easy anastomotic technique is required to improve patient outcomes and reduce morbidity., Method: This paper analyses 328 consecutive patients who underwent transoral circular stapled esophageal anastomosis (ORVIL™) from a prospectively collected single-center database between December 2011 and February 2019., Results: Two hundred and twenty-seven esophagectomies and 101 gastrectomies were performed using OrVil™ anastomoses. The mean patient age was 63.7 years. Of 328 consecutive OrVil™-based anastomoses, there were 10 clinically significant anastomotic leaks requiring radiological or operative intervention (3.05%). Twenty-eight (8.54%) patients developed anastomotic stricture, all of which were successfully treated with endoscopic balloon dilatation (a median of 1 dilatation was required per patient)., Conclusion: The OrVil™ anastomotic technique is reliable and safe to perform. This is the largest reported series of the OrVil™ anastomotic technique to date. Leak rates and anastomotic dilations were similar to other reported series. Based on our experience, we consider the use of the OrVil™ device for reconstruction after major upper GI resection to be safe and reliable., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins., Methods: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment., Results: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06; p  .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11; p  .1.081)., Conclusions: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.

Background: Prognostication in oesophageal cancer on the basis of preoperative variables is challenging. Many of the accepted predictors of survival are only derived after surgical treatment and may be influenced by neoadjuvant therapy. This study aims to explore the relationship between pre-treatment endoscopic tumour morphology and postoperative survival., Methods: Patients with endoscopic descriptions of tumours were identified from the prospectively managed databases including the OCCAMS database. Tumours were classified as exophytic, ulcerating or stenosing. Kaplan Meier survival analysis and multivariable Cox regression analyses were performed to determine hazard ratios (HR) with 95% confidence intervals., Results: 262 patients with oesophageal adenocarcinoma undergoing potentially curative resection were pooled from St Thomas' Hospital (161) and the OCCAMS database (101). There were 70 ulcerating, 114 exophytic and 78 stenosing oesophageal adenocarcinomas. Initial tumour staging was similar across all groups (T3/4 tumours 71.4%, 70.2%, 74.4%). Median survival was 55 months, 51 months and 36 months respectively (p < 0.001). Rates of lymphovascular invasion (P = 0.0176), pathological nodal status (P = 0.0195) and pathological T stage (P = 0.0007) increased from ulcerating to exophytic to stenosing lesions. Resection margin positivity was 21.4% in ulcerating tumours compared to 54% in stenosing tumours (p < 0.001). When compared to stenosing lesions, exophytic and ulcerating lesions demonstrated a significant survival advantage on multivariable analysis (HR 0.56 95% CI 0.31-0.93, HR 0.42 95% CI 0.21-0.82)., Conclusion: This study demonstrates that endoscopic morphology may be an important pre-treatment prognostic factor in oesophageal cancer. Ulcerating, exophytic and stenosing tumours may represent different pathological processes and tumour biology., Competing Interests: Declaration of competing interest We have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Esophageal cancer surgery reduces patients' health-related quality of life (HRQoL). This study examined whether comorbidities influence HRQoL in these patients., Methods: This prospective cohort study included esophageal cancer patients having undergone curatively intended esophagectomy at St Thomas' Hospital London in 2011-2015. Clinical data were collected from patient reports and medical records. Well-validated cancer-specific and esophageal cancer-specific questionnaires (EORTC QLQ-C30 and QLQ-OG25) were used to assess HRQoL before and 6 months after esophagectomy. Number of comorbidities, American Society of Anesthesiologists physical status classification (ASA), and specific comorbidities were analyzed in relation to HRQoL aspects using multivariable linear regression models. Mean score differences with 95% confidence intervals were adjusted for potential confounders., Results: Among 136 patients, those with three or more comorbidities at the time of surgery had poorer global quality of life and physical function and more fatigue compared with those with no comorbidity. Patients with ASA III-IV reported more problems with the above HRQoL aspects and worse social function and pain compared with those with ASA I-II. Cardiac comorbidity was associated with worse global quality of life and dyspnea, while pulmonary comorbidities were related to coughing. Patients assessed both before and 6 months after surgery (n = 80) deteriorated in most HRQoL aspects regardless of comorbidity status, but patients with several comorbidities had worse physical function and fatigue and more trouble with coughing compared with those with fewer comorbidities., Conclusion: Comorbidity appears to negatively influence HRQoL before esophagectomy, but appears not to severely impact 6-month recovery of HRQoL.

Background: To evaluate the prognostic role of Positron Emission Tomography/Computed Tomography (PET/CT) and Endoscopic Ultrasound (EUS) performed before neoadjuvant chemotherapy (NAC) and surgery for oesophageal adenocarcinoma (OAC) patients, focusing on lymph node (LN) assessment. Methods: OAC patients treated in a single tertiary center during January 2008 until December 2014 were retrospectively studied. All patients had PET/CT and EUS before NAC and oesophagectomy. PET-FDG-avid local LNs and maximum standardized uptake value (SUVmax) of the primary tumour, EUS positive LNs and EUS tumour length were recorded. Univariate, multivariate and survival analyses were performed. Results: Following exclusions 151consecutive patients met the inclusion criteria, (median age 62 years). PET/CT and EUS sensitivity for local LNs metastasis was 39.2% and 88.6%, with specificities of 83.33% and 19.15% respectively. No overall survival (OS) difference was found between patients with PET/CT FDG-avid LNs and those with negative LNs (p=0.347). SUVmax uptake was divided into high and low (median cut-off value: 10) with no significant difference in OS between groups (p=0.141). EUS tumour length was not prognostic (OS, p=0.455). Conclusions: Initial LN staging in OA is inaccurate. Although PET/CT and EUS assessments may be complimentary, none independently predicted survival., (Celsius.)

Background:: observational research is increasingly important in clinical decision-making. Opt-out consent has been proposed as a more practical way to obtain participants' consent for such research. The authors evaluated patients' views on opt-out consent for observational research by identifying perceived benefits and barriers., Methods:: following a systematic literature review of research on participants' perspectives on opt-out consent, a focus group interview was conducted with oncological patients and their family members., Results:: the review identified 13 articles detailing perspectives on opt-out consent. Perceived advantages included benefitting medicine and future generations. These findings were confirmed in the focus group. The main reported barriers to opt-out consent are concerns regarding privacy and the sharing of data with third parties. Participants also demonstrated concerns on insufficient education on opt-out consent., Conclusion:: participants demonstrated willingness to participate in observational studies utilising opt-out consent. Special focus should be placed on outlining existing safeguards in research.

In recent mutation studies, analyses based on protein domain positions are gaining popularity over gene-centric approaches since the latter have limitations in considering the functional context that the position of the mutation provides. This presents a large-scale simultaneous inference problem, with hundreds of hypothesis tests to consider at the same time. This article aims to select significant mutation counts while controlling a given level of Type I error via False Discovery Rate (FDR) procedures. One main assumption is that the mutation counts follow a zero-inflated model in order to account for the true zeros in the count model and the excess zeros. The class of models considered is the Zero-inflated Generalized Poisson (ZIGP) distribution. Furthermore, we assumed that there exists a cut-off value such that smaller counts than this value are generated from the null distribution. We present several data-dependent methods to determine the cut-off value. We also consider a two-stage procedure based on screening process so that the number of mutations exceeding a certain value should be considered as significant mutations. Simulated and protein domain data sets are used to illustrate this procedure in estimation of the empirical null using a mixture of discrete distributions. Overall, while maintaining control of the FDR, the proposed two-stage testing procedure has superior empirical power., (© 2017 The Authors. Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.)