The death of laparoscopy.

BACKGROUND: The introduction of laparoscopy in 1989 revolutionized surgical practices, reducing post-operative complications, and enhancing outcomes. Despite its benefits, limitations in laparoscopic tools have led to continued use of open surgery. Robotic-assisted surgery emerged to address these limitations, but its adoption trends and potential impact on open and laparoscopic surgery require analysis. METHODS: A retrospective analysis used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) databases from 2012 to 2021. The study encompassed various abdominal procedures, employing Vector Autoregressive (VAR) models to analyze the dynamic relationships between surgical techniques. The models predicted future trends in open, laparoscopic, and robotic surgery until Q2 of 2025. RESULTS: The analysis included 360,171 patients across diverse procedures. In urology, robotic surgery dominated prostatectomies (83.1% in 2021) and nephrectomies (55.1% in 2021), while the open approach remained the predominant surgical technique for cystectomies (72.5% in 2021). In general surgery, robotic colectomies were forecasted to surpass laparoscopy, becoming the primary approach by 2024 (45.7% in 2025). Proctectomies also showed a shift towards robotic surgery, predicted to surpass laparoscopy and open surgery by 2025 (32.3%). Pancreatectomies witnessed a steady growth in robotic surgery, surpassing laparoscopy in 2021, with forecasts indicating further increase. While hepatectomies remained predominantly open (70.0% in 2025), esophagectomies saw a rise in robotic surgery, predicted to become the primary approach by 2025 (52.3%). CONCLUSIONS: The study suggests a transformative shift towards robotic-assisted surgery, poised to dominate various minimally invasive procedures. The forecasts indicate that robotic surgery may surpass laparoscopy and open surgery in colectomies, proctectomies, pancreatectomies, and esophagectomies by 2025. This anticipated change emphasizes the need for proactive adjustments in surgical training programs to align with evolving surgical practices. The findings have substantial implications for future healthcare practices, necessitating a balance between traditional laparoscopy and the burgeoning role of robotic-assisted surgery.

Poor Diagnostic Reproducibility in the Identification of Nonconventional Dysplasia in Colitis Impacts the Application of Histologic Stratification Tools.

Due to their increased cancer risk, patients with longstanding inflammatory bowel disease are offered endoscopic surveillance with concomitant histopathologic assessments, aimed at identifying dysplasia as a precursor lesion of colitis-associated colorectal cancer. However, this strategy is beset with difficulties and limitations. Recently, a novel classification criterion for colitis-associated low-grade dysplasia has been proposed, and an association between nonconventional dysplasia and progression was reported, suggesting the possibility of histology-based stratification of patients with colitis-associated lesions. Here, a cohort of colitis-associated lesions was assessed by a panel of 6 experienced pathologists to test the applicability of the published classification criteria and try and validate the association between nonconventional dysplasia and progression. While confirming the presence of different morphologic patterns of colitis-associated dysplasia, the study demonstrated difficulties concerning diagnostic reproducibility between pathologists and was unable to validate the association of nonconventional dysplasia with cancer progression. Our study highlights the overall difficulty of using histologic assessment of precursor lesions for cancer risk prediction in inflammatory bowel disease patients and suggests the need for a different diagnostic strategy that can objectively identify high-risk phenotypes.

Suppression of tumour growth from transplanted astrocytoma cells transfected with luciferase in mice by bioluminescence mediated, systemic, photodynamic therapy.

BACKGROUND: Grade 4 astrocytomas are usually incurable due to their diffusely infiltrative nature. Photodynamic therapy (PDT) is a promising therapeutic option, but external light delivery is impractical when cancer cells infiltrate unknown areas of normal brain. Hence the search for endogenous sources to generate light at cancer cells. In vitro, astrocytoma cells, transfected with firefly luciferase, can be killed by bioluminescence-mediated PDT (bPDT). This study asks if bPDT can suppress tumour growth In vivo, when all components of treatment are administered systemically. METHODS: Transfected astrocytoma cells were injected subcutaneously or intra-cranially in athymic CD1 nu/nu mice. bPDT required ip bolus of mTHPC (photosensitiser) and delivery of the d-luciferin substrate over 7 days via an implanted osmotic pump. Control animals had no treatment, photosensitiser only or d-luciferin only. For subcutaneous tumours, size and BLI (light emitted after d-luciferin bolus) were measured before and every 2 days after PDT. For intracranial tumours, monitoring was weekly BLI. RESULTS: For subcutaneous tumours, there was significant suppression of the tumour growth rate (P<0.05), and absolute tumour size (P<0.01) after bPDT. Proliferation of subcutaneous and intracranial tumours (monitored by BrdU uptake) was significantly reduced in treated mice. (P<0.001) CONCLUSIONS: This study reports bPDT suppression of tumour growth from luciferase transfected astrocytoma cells with all components of treatment given systemically, as required for effective management of recurrent astrocytomas in unknown sites. However, research on systemic bPDT is needed to establish whether effects on non-transfected tumours can be achieved without any unacceptable effects on normal tissues.

Simulated annealing for balancing covariates.

Covariate balance is one of the fundamental issues in designing experiments for treatment comparisons, especially in randomized clinical trials. In this article, we introduce a new class of covariate-adaptive procedures based on the Simulated Annealing algorithm aimed at balancing the allocations of two competing treatments across a set of pre-specified covariates. Due to the nature of the simulated annealing, these designs are intrinsically randomized, thus completely unpredictable, and very flexible: they can manage both quantitative and qualitative factors and be implemented in a static version as well as sequentially. The properties of the suggested proposal are described, showing a significant improvement in terms of covariate balance and inferential accuracy with respect to all the other procedures proposed in the literature. An illustrative example based on real data is also discussed.

A clinical decision support system optimising adjuvant chemotherapy for colorectal cancers by integrating deep learning and pathological staging markers: a development and validation study.

BACKGROUND: The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment. METHODS: We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT<4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or >12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectal cancer from the QUASAR 2 trial was used for validation; these patients were treated with single-agent capecitabine. The proposed risk stratification system was evaluated using Cox regression analysis. We similarly evaluated a risk stratification system intended to reflect current guidelines and clinical practice. The primary outcome was cancer-specific survival. FINDINGS: The new risk stratification system provided a hazard ratio of 10·71 (95% CI 6·39-17·93; p<0·0001) for high-risk versus low-risk patients and 3·06 (1·73-5·42; p=0·0001) for intermediate versus low risk in the primary analysis of the validation cohort. Estimated 3-year cancer-specific survival was 97·2% (95% CI 95·1-98·4; n=445 [41%]) for the low-risk group, 94·8% (91·7-96·7; n=339 [32%]) for the intermediate-risk group, and 77·6% (72·1-82·1; n=291 [27%]) for the high-risk group. The guideline-based risk grouping was observed to be less prognostic and informative (the low-risk group comprised only 142 [13%] of the 1075 patients). INTERPRETATION: Integrating DoMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs. FUNDING: The Research Council of Norway.

British Society of Gastroenterology (BSG) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) joint consensus guidelines on the diagnosis and management of eosinophilic oesophagitis in children and adults.

BACKGROUND: Eosinophilic oesophagitis (EoE) is an increasingly common cause of dysphagia in both children and adults, as well as one of the most prevalent oesophageal diseases with a significant impact on physical health and quality of life. We have provided a single comprehensive guideline for both paediatric and adult gastroenterologists on current best practice for the evaluation and management of EoE. METHODS: The Oesophageal Section of the British Society of Gastroenterology was commissioned by the Clinical Standards Service Committee to develop these guidelines. The Guideline Development Group included adult and paediatric gastroenterologists, surgeons, dietitians, allergists, pathologists and patient representatives. The Population, Intervention, Comparator and Outcomes process was used to generate questions for a systematic review of the evidence. Published evidence was reviewed and updated to June 2021. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to assess the evidence and make recommendations. Two rounds of voting were held to assess the level of agreement and the strength of recommendations, with 80% consensus required for acceptance. RESULTS: Fifty-seven statements on EoE presentation, diagnosis, investigation, management and complications were produced with further statements created on areas for future research. CONCLUSIONS: These comprehensive adult and paediatric guidelines of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition are based on evidence and expert consensus from a multidisciplinary group of healthcare professionals, including patient advocates and patient support groups, to help clinicians with the management patients with EoE and its complications.

Endoscopic eradication therapy for Barrett's esophagus-related neoplasia: a final 10-year report from the UK National HALO Radiofrequency Ablation Registry.

BACKGROUND AND AIMS: Long-term durability data for effectiveness of radiofrequency ablation (RFA) to prevent esophageal adenocarcinoma in patients with dysplastic Barrett's esophagus (BE) are lacking. METHODS: We prospectively collected data from 2535 patients with BE (mean length, 5.2 cm; range, 1-20) and neoplasia (20% low-grade dysplasia, 54% high-grade dysplasia, 26% intramucosal carcinoma) who underwent RFA therapy across 28 UK hospitals. We assessed rates of invasive cancer and performed detailed analyses of 1175 patients to assess clearance rates of dysplasia (CR-D) and intestinal metaplasia (CR-IM) within 2 years of starting RFA therapy. We assessed relapses and rates of return to CR-D (CR-D2) and CR-IM (CR-IM2) after further therapy. CR-D and CR-IM were confirmed by an absence of dysplasia and intestinal metaplasia on biopsy samples taken at 2 consecutive endoscopies. RESULTS: Ten years after starting treatment, the Kaplan-Meier (KM) cancer rate was 4.1% with a crude incidence rate of .52 per 100 patient-years. CR-D and CR-IM after 2 years of therapy were 88% and 62.6%, respectively. KM relapse rates were 5.9% from CR-D and 18.7% from CR-IM at 8 years, with most occurring in the first 2 years. Both were successfully retreated with rates of CR-D2 of 63.4% and CR-IM2 of 70.0% 2 years after retreatment. EMR before RFA increased the likelihood of rescue EMR from 17.2% to 41.7% but did not affect the rate of CR-D, whereas rescue EMR after RFA commenced reduced CR-D from 91.4% to 79.7% (χ2P < .001). CONCLUSIONS: RFA treatment is effective and durable to prevent esophageal adenocarcinoma. Most treatment relapses occur early and can be successfully retreated.

Image-Enhanced Endoscopy and Molecular Biomarkers Vs Seattle Protocol to Diagnose Dysplasia in Barrett's Esophagus.

BACKGROUND & AIMS: Dysplasia in Barrett's esophagus often is invisible on high-resolution white-light endoscopy (HRWLE). We compared the diagnostic accuracy for inconspicuous dysplasia of the combination of autofluorescence imaging (AFI)-guided probe-based confocal laser endomicroscopy (pCLE) and molecular biomarkers vs HRWLE with Seattle protocol biopsies. METHODS: Barrett's esophagus patients with no dysplastic lesions were block-randomized to standard endoscopy (HRWLE with the Seattle protocol) or AFI-guided pCLE with targeted biopsies for molecular biomarkers (p53 and cyclin A by immunohistochemistry; aneuploidy by image cytometry), with crossover to the other arm after 6 to 12 weeks. The primary end point was the histologic diagnosis from all study biopsies (trial histology). A sensitivity analysis was performed for overall histology, which included diagnoses within 12 months from the first study endoscopy. Endoscopists were blinded to the referral endoscopy and histology results. The primary outcome was diagnostic accuracy for dysplasia by real-time pCLE vs HRWLE biopsies. RESULTS: Of 154 patients recruited, 134 completed both arms. In the primary outcome analysis (trial histology analysis), AFI-guided pCLE had similar sensitivity for dysplasia compared with standard endoscopy (74.3%; 95% CI, 56.7-87.5 vs 80.0%; 95% CI, 63.1-91.6; P = .48). Multivariate logistic regression showed pCLE optical dysplasia, aberrant p53, and aneuploidy had the strongest correlation with dysplasia (secondary outcome). This 3-biomarker panel had higher sensitivity for any grade of dysplasia than the Seattle protocol (81.5% vs 51.9%; P < .001) in the overall histology analysis, but not in the trial histology analysis (91.4% vs 80.0%; P = .16), with an area under the receiver operating curve of 0.83. CONCLUSIONS: Seattle protocol biopsies miss dysplasia in approximately half of patients with inconspicuous neoplasia. AFI-guided pCLE has similar accuracy to the current gold standard. The addition of molecular biomarkers could improve diagnostic accuracy.

The Bowel Cancer Screening Programme Expert Board: an analysis of activity during 2017-2020.

AIMS: The inception of the National Health Service Bowel Cancer Screening Programme in England in 2006 highlighted the fact that the differential diagnosis between the presence of epithelial misplacement and adenocarcinoma occurring in colorectal adenomas is problematic. The pathology Expert Board (EB) was created to facilitate the review of difficult cases by a panel of three experienced gastrointestinal pathologists. This article describes a review of the work of the EB over a 4-year period (2017-2020). METHODS AND RESULTS: Four hundred and thirty polyps were referred to the EB from 193 pathologists and 76 hospitals during this time. The EB diagnosis was benign for 67%, malignant for 28%, and equivocal for 2% (with no consensus in the remainder). The most common diagnosis change made by the EB was from malignant to benign-made in 50% of polyps referred with an initially malignant diagnosis. The level of agreement between the individual EB members was 'good' (kappa score of 0.619) but that between the EB and the referring diagnosis was 'poor' (kappa score of 0.149). Data from one EB member indicated that the presence of lamina propria, features of torsion and cytological similarity between the superficial and deep glands were predictors of a benign diagnosis, whereas the presence of irregular neoplastic glands, a desmoplastic reaction and lymphovascular invasion were commonly observed features in polyps with a malignant diagnosis. CONCLUSION: Diagnostic agreement between EB members is better than that between the EB and referring pathologists. There was a consistent trend for the EB to change diagnoses from malignant to benign.

The natural history of low-grade dysplasia in Barrett's esophagus and risk factors for progression.

BACKGROUND AND AIM: Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma. The optimal management of low-grade dysplasia arising in Barrett's esophagus remains controversial. We performed a retrospective study from a tertiary referral center for Barrett's esophagus neoplasia, to estimate time to progression to high-grade dysplasia/esophageal adenocarcinoma in patients with confirmed low-grade dysplasia compared with those with downstaged low-grade dysplasia from index presentation and referral. We analyzed risk factors for progression. METHODS: We analyzed consecutive patients with low-grade dysplasia in Barrett's esophagus referred to a single tertiary center (July 2006-October 2018). Biopsies were reviewed by at least two expert pathologists. RESULTS: One hundred and forty-seven patients referred with suspected low-grade dysplasia were included. Forty-two of 133 (32%) of all external referrals had confirmed low-grade dysplasia after expert histopathology review. Multivariable analysis showed nodularity at index endoscopy (P < 0.05), location of dysplasia (P = 0.05), and endoscopic therapy after referral (P = 0.09) were associated with progression risk. At 5 years, 59% of patients with confirmed low-grade dysplasia had not progressed versus 74% of patients in the cohort downstaged to non-dysplastic Barrett's esophagus. CONCLUSION: Our data show variability in the diagnosis of low-grade dysplasia. The cumulative incidence of progression and time to progression varied across subgroups. Confirmed low-grade dysplasia had a shorter progression time compared with the downstaged group. Nodularity at index endoscopy and multifocal low-grade dysplasia were significant risk factors for progression. It is important to differentiate these high-risk subgroups so that decisions on surveillance/endotherapy can be personalized.

Consensus recommendations for the standardized histopathological evaluation and reporting after radical oesophago-gastrectomy (HERO consensus).

BACKGROUND: Variation in the approach, radicality, and quality of gastroesophageal surgery impacts patient outcomes. Pathological outcomes such as lymph node yield are routinely used as surrogate markers of surgical quality, but are subject to significant variations in histopathological evaluation and reporting. A multi-society consensus group was convened to develop evidence-based recommendations for the standardized assessment of gastroesophageal cancer specimens. METHODS: A consensus group comprised of surgeons, pathologists, and oncologists was convened on behalf of the Association of Upper Gastrointestinal Surgery of Great Britain & Ireland. Literature was reviewed for 17 key questions. Draft recommendations were voted upon via an anonymous Delphi process. Consensus was considered achieved where >70% of participants were in agreement. RESULTS: Consensus was achieved on 18 statements for all 17 questions. Twelve strong recommendations regarding preparation and assessment of lymph nodes, margins, and reporting methods were made. Importantly, there was 100% agreement that the all specimens should be reported using the Royal College of Pathologists Guidelines as the minimum acceptable dataset. In addition, two weak recommendations regarding method and duration of specimen fixation were made. Four topics lacked sufficient evidence and no recommendation was made. CONCLUSIONS: These consensus recommendations provide explicit guidance for gastroesophageal cancer specimen preparation and assessment, to provide maximum benefit for patient care and standardize reporting to allow benchmarking and improvement of surgical quality.

Dataset for the reporting of carcinoma of the esophagus in resection specimens: recommendations from the International Collaboration on Cancer Reporting.

BACKGROUND AND OBJECTIVES: A standardized data set for esophageal carcinoma pathology reporting was developed based on the approach of the International Collaboration on Cancer Reporting (ICCR) for the purpose of improving cancer patient outcomes and international benchmarking in cancer management. MATERIALS AND METHODS: The ICCR convened a multidisciplinary international expert panel to identify the best evidence-based clinical and pathological parameters for inclusion in the data set for esophageal carcinoma. The data set incorporated the current edition of the World Health Organization Classification of Tumours of the Digestive System, and Tumour-Node-Metastasis staging systems. RESULTS: The scope of the data set encompassed resection specimens of the esophagus and esophagogastric junction with tumor epicenter ≤20 mm into the proximal stomach. Core reporting elements included information on neoadjuvant therapy, operative procedure used, tumor focality, tumor site, tumor dimensions, distance of tumor to resection margins, histological tumor type, presence and type of dysplasia, tumor grade, extent of invasion in the esophagus, lymphovascular invasion, response to neoadjuvant therapy, status of resection margin, ancillary studies, lymph node status, distant metastases, and pathological staging. Additional non-core elements considered useful to report included clinical information, specimen dimensions, macroscopic appearance of tumor, and coexistent pathology. CONCLUSIONS: This is the first international peer-reviewed structured reporting data set for surgically resected specimens of the esophagus. The ICCR carcinoma of the esophagus data set is recommended for routine use globally and is a valuable tool to support standardized reporting, to benefit patient care by providing diagnostic and prognostic best-practice parameters.

Reporting only relative effect measures was potentially misleading: some good practices for improving the soundness of epidemiological results.

OBJECTIVE: In the medical and epidemiological literature there is a growing tendency to report an excessive number of decimal digits (often three, sometimes four), especially when measures of relative occurrence are small; this can be misleading. STUDY DESIGN AND SETTING: We combined mathematical and statistical reasoning about the precision of relative risks with the meaning of the decimal part of the same measures from biological and public health perspectives. RESULTS: We identified a general rule for minimizing the mathematical error due to rounding of relative risks, depending on the background absolute rate, which justifies the use of one or more decimal digits for estimates close to 1. CONCLUSIONS: We suggest that both relative and absolute risk measures (expressed as a rates) should be reported, and two decimal digits should be used for relative risk close to 1 only if the background rate is at least 1/1,000 py. The use of more than two decimal digits is justified only when the background rate is high (ie, 1/10 py).

Current dilemmas in the pathological staging of colorectal cancer: the results of a national survey.

AIMS: Accurate and consistent pathological staging of colorectal carcinoma (CRC) in resection specimens is especially crucial to guide adjuvant therapy. The aim of this study was to assess whether certain staging scenarios yield discordant opinions in the setting of current international and UK national guidelines. METHODS AND RESULTS: Members of the UK Gastrointestinal Pathology External Quality Assurance Scheme were invited to complete an anonymous, on-line survey that presented 15 scenarios related to pT or pR staging of CRC, and three questions about the respondent. The survey invitation was e-mailed to 405 pathologists, and 184 (45%) responses were received. The respondents had discordant opinions on whether and how CRC pT or pR staging is affected by: acellular mucin lakes and duration after short-course radiotherapy; the nature of the carcinoma at a resection margin or peritoneal surface; and microscopic evidence of perforation. This discordance was rarely related to the respondent's occupation type, and was not related to duration of work as a consultant or the staging guidelines used. CONCLUSIONS: This survey confirms that there remain several clinically critical but unresolved pT and pR staging issues for CRC. These issues therefore deserve attention in future versions of international and national staging guidelines.

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis.

BACKGROUND: Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs). METHODS: Eligible studies included RCTs assessing standard dose REG versus placebo. Outcomes of interest included: AE-related permanent discontinuation, dose interruptions and dose reductions. RESULTS: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library and EMBASE: 7 eligible studies involving a total of 2099 patients (Regorafenib: 1362; placebo: 737) were included in our analysis. The use of REG was associated with higher incidence and risk of all outcomes of interest when compared with placebo. The incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving REG were 9.7%, 57.2% and 47%, respectively, versus 3.3%, 16.7% and 7.7% of placebo group; compared with placebo, the summary relative risks (RRs) of permanent discontinuation, dose interruptions and dose reductions in REG arm were 2.80 (95% CI 1.85-4.22), 3.21 (95% CI 2.59-3.99) and 6.02 (95% CI 3.28-11.03), respectively. CONCLUSIONS: Treatment with REG at the standard dose of 160 mg is associated with a significant increase in AE-related permanent discontinuation, dose interruptions and dose reductions. Prompt identification and management of AEs seem mandatory to obtain maximal benefit from REG treatment. In the current landscape, dose personalization of REG may have the potential to improve quality of life, minimize treatment discontinuation and maximize patient outcomes.

Cryoballoon ablation for treatment of patients with refractory esophageal neoplasia after first line endoscopic eradication therapy.

Background and study aims Cryoablation with the Cryoballoon device is a novel ablative therapy that uses cycles of freezing and thawing to induce cell death. This single-center prospective study evaluated the feasibility of the focal cryoablation device for the treatment of areas of refractory esophageal neoplasia in patients who had undergone first line endoscopic eradication therapy (EET). Complete remission of dysplasia (CR-D) and complete remission of intestinal metaplasia (CR-IM) at first follow-up endoscopy, durability of disease reversal, rates of stenosis and adverse events were studied. Patients and methods Eighteen cases were treated. At baseline, nine patients had low-grade dysplasia (LGD), six had high-grade dysplasia (HGD) and three had intramucosal carcinoma (IMC). Median length of dysplastic Barrett's esophagus (BE) treated was 3 cm. The median number of ablations per patient was 11. Each selected area of visible dysplasia received 10 seconds of ablation. One session of cryoablation was performed per patient. Biopsies were performed at around 3 months post-ablation. Results CR-D was achieved in 78 % and CR-IM in 39 % of patients. There were no device malfunction or adverse events. Stenosis was noted in 11 % of cases. At a median follow up of 19-months, CR-D was maintained in 72 % of patients and CR-IM in 33 %. Conclusions Cryoablation appears to be a viable rescue strategy in patients with refractory neoplasia. It is well tolerated and successful in obtaining CR-D and CR-IM in patients with treatment-refractory BE. Further trials of dosimetry, efficacy and safety in treatment-naïve patients are underway.

Compound optimal allocations for survival clinical trials.

The aim of the present paper is to provide optimal allocations for comparative clinical trials with survival outcomes. The suggested targets are derived adopting a compound optimization strategy based on a subjective weighting of the relative importance of inferential demands and ethical concerns. The ensuing compound optimal targets are continuous functions of the treatment effects, so we provide the conditions under which they can be approached by standard response-adaptive randomization procedures, also guaranteeing the applicability of the classical asymptotic inference. The operating characteristics of the suggested methodology are verified both theoretically and by simulation, including the robustness to model misspecification. With respect to the other available proposals, our strategy always assigns more patients to the best treatment without compromising inference, taking into account estimation efficiency and power as well. We illustrate our procedure by redesigning two real oncological trials.

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.

Development and validation of a risk prediction model to diagnose Barrett's oesophagus (MARK-BE): a case-control machine learning approach.

Background: Screening for Barrett's Oesophagus (BE) relies on endoscopy which is invasive and has a low yield. This study aimed to develop and externally validate a simple symptom and risk-factor questionnaire to screen for patients with BE. Methods: Questionnaires from 1299 patients in the BEST2 case-controlled study were analysed: 880 had BE including 40 with invasive oesophageal adenocarcinoma (OAC) and 419 were controls. This was randomly split into a training cohort of 776 patients and an internal validation cohort of 523 patients. External validation included 398 patients from the BOOST case-controlled study: 198 with BE (23 with OAC) and 200 controls. Identification of independently important diagnostic features was undertaken using machine learning techniques information gain (IG) and correlation based feature selection (CFS). Multiple classification tools were assessed to create a multi-variable risk prediction model. Internal validation was followed by external validation in the independent dataset. Findings: The BEST2 study included 40 features. Of these, 24 added IG but following CFS, only 8 demonstrated independent diagnostic value including age, gender, smoking, waist circumference, frequency of stomach pain, duration of heartburn and acid taste and taking of acid suppression medicines. Logistic regression offered the highest prediction quality with AUC (area under the receiver operator curve) of 0.87. In the internal validation set, AUC was 0.86. In the BOOST external validation set, AUC was 0.81. Interpretation: The diagnostic model offers valid predictions of diagnosis of BE in patients with symptomatic gastroesophageal reflux, assisting in identifying who should go forward to invasive testing. Overweight men who have been taking stomach medicines for a long time may merit particular consideration for further testing. The risk prediction tool is quick and simple to administer but will need further calibration and validation in a prospective study in primary care. Funding: Charles Wolfson Trust and Guts UK.

Specific Toxicity of Maintenance Olaparib Versus Placebo in Advanced Malignancies: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: We performed a systematic review and meta-analysis to investigate the safety of maintenance with olaparib after platinum-based chemotherapy in cancer patients. MATERIALS AND METHODS: Eligible studies included randomized controlled trials (RCTs) regarding the clinical role of olaparib maintenance therapy versus placebo in BRCA-mutated, advanced cancers. Safety profile from each selected study was investigated for all-grade and G3-G4 haematological and non-haematological adverse drug events (ADEs). RESULTS: Four RTCs that involved 1099 patients were included in the analysis. Overall incidences of all-grade and G3-4 ADEs in olaparib group were 97.6% and 41%, respectively. Patients treated with maintenance olaparib showed higher risk of all-grade and G3-G4 anaemia, all-grade neutropenia and thrombocytopenia. Moreover, all-grade and G3-G4 fatigue, all-grade vomiting, diarrhoea, nausea and decreased appetite were more common in the olaparib group compared to placebo. CONCLUSION: Despite an increased risk and incidence of several haematological and non-haematological toxicities, olaparib is a relatively safe agent for the treatment of advanced solid tumors. Prompt identification of ADEs is mandatory to avoid therapy discontinuation and optimize treatment.