Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer - Multi-centre study.

Background and purpose: Radical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery. Materials and methods: This retrospective multi-centre study (2009-2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer. Results: With a median follow-up of 26(IQR:12-49) months, initial clinical Complete Response (cCR) was 82(70-93)% with rates of local regrowth 18(8-29)%, 3-year actuarial local control (LC) 84(75-95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48-78)% and 58(44-75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients. Conclusion: CXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery.

Sequence of Contact X-ray Brachytherapy (CXB) and External Beam Radiation (EBRT) in organ-preserving treatment for small rectal cancer.

BACKGROUND AND PURPOSE: External Beam Radiotherapy (EBRT) followed by Contact X-ray Brachytherapy (CXB) and vice versa are viable alternatives to surgery for selected rectal cancer patients who have small tumours (≤3 cm). However, the optimal sequence of treatment needs to be established. We compared two approaches using Propensity Score (PS) matching and inverse probability treatment weighting (IPTW) analyses to investigate whether the sequence of treatment affected patient outcomes. MATERIALS AND METHODS: This retrospective analysis (2008-2019) included patients with rectal adenocarcinoma (cT1-3,N0-1,M0, grade 1-2, size ≤ 3 cm) who received both EBRT and CXB, irrespective of treatment sequence. PS matching and IPTW were conducted to balance covariate standardised mean differences between groups. Oncological outcomes and rate of post-treatment rectal bleeding were assessed. RESULTS: Following PS matching and IPTW analyses from 251 eligible patients; 103 starting with EBRT (median follow-up: 37 [IQR:18-56] months) and 148 with CXB (median follow-up: 32 [IQR:16-54] months, a significant improvement in 3-year overall survival (77% vs 85%, p = 0.02, [HR:0.58 (95% CI:0.37-0.91)]) and a higher risk of post-treatment rectal bleeding (grade 1 (26%) and grade 2 (6%)) were found in patients who started with CXB (p = 0.08). No significant differences were observed in local regrowth (18% vs 12%, p = 0.47), distant relapse (10% vs 6%, p = 0.53), 3-year organ preservation rates (70% vs 75%, p = 0.20, [HR:0.66 (95% CI: 0.35-1.26)]), or disease-free survival (78% vs 82%, p = 0.17, [HR: 0.47 (95% CI: 0.16-1.38)]) CONCLUSION: In patients with rectal cancer (≤3 cm), commencing with CXB rather than EBRT, was associated with improved overall survival, but had a higher risk of G1/2 rectal bleeding. No statistically significant differences were observed in other oncological outcomes.

Contact X-ray brachytherapy (CXB) as a salvage treatment for rectal cancer patients who developed local tumor re-growth after watch-and-wait approach.

Purpose: A watch-and-wait approach is an alternative to surgery for rectal cancer patients who have achieved a clinical complete response (cCR) following neoadjuvant (chemo)radiotherapy. However, approximately 25-38% of patients experience subsequent local tumor re-growth that requires salvage surgery. We evaluated the effectiveness of contact X-ray brachytherapy (CXB) as an alternative method of salvage therapy for those patients who were either unfit for or refused surgery. Oncological outcomes, tolerability, and feasibility of subsequent surgery for local treatment failure following CXB were reported. Material and methods: From 2009-2021, all patients treated with CXB as salvage therapy for local rectal cancer re-growth after watch-and-wait approach at our center were analyzed. Results: Contact X-ray brachytherapy as a salvage treatment (range, 90-110 Gy) was offered to 56 patients who experienced tumor re-growth following (chemo)radiation and watch-and-wait protocol. Median age was 76 (IQR = 66-83) years. Most patients (82%) had early-stage re-growth (ycT1/ycT2, ycN0), and 18% had more advanced stages (ycT3/ycT4, ycN0). After a median of 37-month follow-up (IQR = 19-53), 48% of patients who had early-stage re-growth achieved a sustained complete remission after CXB compared with 20% of those who had more advanced tumor stages. Disease-free and overall survivals for the whole cohort were 69% and 100% at 1-year, 51% and 82% at 3-year, and 51% and 65% at 5-years. CXB effectively controlled local re-growth-related symptoms. Mild post-CXB side effects occurred in 18% of cases. All (100%) eight patients who developed further local relapse, and 29% of those who had residual disease post-CXB salvage were successfully managed with subsequent surgery. Conclusions: Contact X-ray brachytherapy offers a new treatment option for patients in this situation whose other therapy options are not suitable for or refused initial surgery. Early local tumor re-growth responded best with minimal treatment-related toxicity and excellent symptom control. Disease-free and overall survival rates were acceptable, and delaying surgical salvage for local re-growth did not compromise patients' eventual long-term outcomes.

Neuroendocrine neoplasms: Consensus on a patient care pathway.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

PREF-NET: a patient preference and experience study of lanreotide autogel administered in the home versus hospital setting among patients with gastroenteropancreatic neuroendocrine tumours in the UK.

PURPOSE: PREF-NET reported patients' experience of Somatuline® (lanreotide) Autogel® (LAN) administration at home and in hospital among patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). METHODS: PREF-NET was a multicentre, cross-sectional study of UK adults (aged ≥ 18 years) with GEP-NETs receiving a stable dose of LAN, which comprised of (1) a quantitative online survey, and (2) qualitative semi-structured interviews conducted with a subgroup of survey respondents. The primary objective was the description of overall patient preference for home versus hospital administration of LAN. Secondary objectives included describing patient-reported opinions on the experience and associated preference for each administration setting, and the impact on healthcare utilisation, societal cost, activities of daily living and health-related quality of life (HRQoL). RESULTS: In the primary analysis (80 patients; mean age 63.9 years), 98.7% (95% confidence interval [CI]: 96.1-100.0) of patients preferred to receive LAN at home, compared with 1.3% (95% CI: 0.0-3.9) who preferred the hospital setting. Among participants, over half (60.3%) received their injection from a non-healthcare professional. Most patients (79.5% [95% CI: 70.5-88.4]) reported a positive effect on HRQoL after the switch from hospital to home administration. Qualitative interviews (20 patients; mean age 63.6 years) highlighted that patients preferred home administration because it improved overall convenience; saved time and costs; made them feel more comfortable and relaxed, and less stressed; and increased confidence in their ability to self-manage their treatment. CONCLUSION: Almost all patients preferred to receive LAN treatment at home rather than in hospital with increased convenience and psychological benefits reported as key reasons for this preference.

The history and evolution of HLA typing external proficiency testing schemes in UK NEQAS for H&I.

The UK National External Quality Assessment Service (NEQAS) provide an external proficiency testing (EPT) service for clinical laboratories. UK NEQAS for Histocompatibility and Immunogenetics (H&I) has been providing EPT schemes for over 45 years and has grown during this time to provide 19 EPT schemes. Accurate human leucocyte antigen (HLA) typing is critical to support safe clinical services, including transplantation, therefore high quality, relevant EPT schemes are required as part of a laboratory's quality assurance. This article reviews the development of the HLA typing EPT schemes, from the first HLA phenotyping scheme in 1975, via the first HLA genotyping scheme in 1992, through to the introduction in 2017 of HLA third field assessment results from next-generation sequencing technology. In addition, the introduction of EPT schemes to cover HLA associated diseases and pharmacogenetic reactions, including HLA-B27, HLA*B*57:01 and HLA-DQ for coeliac disease are discussed. The accuracy of laboratory EPT results for HLA phenotyping are >96% (2018-2022), HLA genotyping >99% (2020-2022), HLA-B27 testing >99% (2018-2022) and B*57:01 testing >99% (2017-2022). However, for HLA genotyping for coeliac disease 22%-46% of laboratories made errors in 2020-2022. On investigation, the high rate of unsatisfactory performance was attributed to laboratories lacking specific knowledge to interpret HLA genotyping results and accurately report HLA types for coeliac disease. A misleading commercial kit insert was also identified. The assessment of scheme results has uncovered several issues which have been addressed with the intention of educating participants and improving clinical services. The UK NEQAS for H&I EPT schemes have evolved over the past four decades to reflect changes in HLA typing technology, laboratory clinical practice and to cover post-analytical interpretative elements of HLA typing.

A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity.

We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic-induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial-related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse-specific version of the model to quantify doxorubicin and 5-fluorouracil (5-FU)-induced toxicity, which included pharmacokinetics and 5-FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose-dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk, and transcriptional induction of the p53 pathway. Using a human-specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5-FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific-molecularly targeted therapy, the mice failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modeling approach, preclinical experimental settings have to be suitable to quantify drug-induced clinical toxicity with precision at the structural scale of the model. Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross-settings differences in toxicity when building these approaches.

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1-G3.

The aim of the present guidance paper was to update the previous ENETS guidelines on well-differentiated gastric and duodenal neuroendocrine tumours (NETs), providing practical guidance for specialists in the diagnosis and management of gastroduodenal NETs. Type II gastric NETs, neuroendocrine carcinomas (NECs), and functioning duodenal NETs are not covered, since they will be discussed in other ENETS guidance papers.

Mouse organoids as an in vitro tool to study the in vivo intestinal response to cytotoxicants.

Cross-species comparison of drug responses at the organoid level could help to determine the human relevance of findings from animal studies. To this end, we first need to evaluate the in vitro to in vivo translatability of preclinical organoids. Here, we used 5-fluorouracil (5-FU) as an exemplar drug to test whether the in vivo gut response to this cytotoxicant was preserved in murine intestinal organoids. Mice treated with 5-FU at 20 or 50 mg/kg IV (low and high dose, respectively) displayed diarrhea at clinically relevant exposures. 5-FU also induced intestinal lesions, increased epithelial apoptosis, and decreased proliferation in a dose-dependent manner. To enable comparison between the in vitro and in vivo response, top nominal in vitro drug concentrations that caused significant cytotoxicity were chosen (dose range 1-1000 µM). The inferred intracellular concentration in organoids at 1000 µM was within the tissue exposure range related to intestinal toxicity in vivo. 5-FU at ≥ 100 µM decreased ATP levels and increased Caspase-3 activity in intestinal organoids. In keeping with the in vivo findings, 5-FU increased the percentage of Caspase-3-positive cells and reduced Ki67 staining. At the transcriptome level, there was an overlap in the activity of pathways related to 5-FU's mode of action, lipid and cholesterol metabolism and integrin signaling across in vivo gut and organoids. The predicted activity state of upstream regulators was generally well preserved between setups. Collectively, our results suggest that despite their inherent limitations, organoids represent an adequate tool to explore the intestinal response to cytotoxicants.

Clinical prediction models assessing response to radiotherapy for rectal cancer: protocol for a systematic review.

BACKGROUND: Rectal cancer has a high prevalence. The standard of care for management of localised disease involves major surgery and/or chemoradiotherapy, but these modalities are sometimes associated with mortality and morbidity. The notion of 'watch and wait' has therefore emerged and offers an organ-sparing approach to patients after administering a less invasive initial treatment, such as X-ray brachytherapy (Papillon technique). It is thus important to evaluate how likely patients are to respond to such therapies, to develop patient-tailored treatment pathways. We propose a systematic review to identify published clinical prediction models of the response of rectal cancer to treatment that includes radiotherapy and here present our protocol. METHODS: Included studies will develop multivariable clinical prediction models which assess response to treatment and overall survival of adult patients who have been diagnosed with any stage of rectal cancer and have received radiotherapy treatment with curative intent. Cohort studies and randomised controlled trials will be included. The primary outcome will be the occurrence of salvage surgery at 1 year after treatment. Secondary outcomes include salavage surgery at at any reported time point, the predictive accuracy of models, the quality of the developed models and the feasibility of using the model in clinical practice. Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL will be searched from inception to 24 February 2022. Keywords and phrases related to rectal cancer, radiotherapy and prediction models will be used. Studies will be selected once the deduplication, title, abstract and full-text screening process have been completed by two independent reviewers. The PRISMA-P checklist will be followed. A third reviewer will resolve any disagreement. The data extraction form will be pilot-tested using a representative 5% sample of the studies reviewed. The CHARMS checklist will be implemented. Risk of bias in each study will be assessed using the PROBAST tool. A narrative synthesis will be performed and if sufficient data are identified, meta-analysis will be undertaken as described in Debray et al. DISCUSSION: This systematic review will identify factors that predict response to the treatment protocol. Any gaps for potential development of new clinical prediction models will be highlighted. TRIAL REGISTRATION: CRD42022277704.

Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa.

The alternative (noncanonical) nuclear factor-κB (NF-κB) signaling pathway predominantly regulates the function of the p52/RelB heterodimer. Germline Nfkb2 deficiency in mice leads to loss of p100/p52 protein and offers protection against a variety of gastrointestinal conditions, including azoxymethane/dextran sulfate sodium (DSS)-induced colitis-associated cancer and lipopolysaccharide (LPS)-induced small intestinal epithelial apoptosis. However, the common underlying protective mechanisms have not yet been fully elucidated. We applied high-throughput RNA-Seq and proteomic analyses to characterize the transcriptional and protein signatures of the small intestinal mucosa of naïve adult Nfkb2-/- mice. Those data were validated by immunohistochemistry and quantitative ELISA using both small intestinal tissue lysates and serum. We identified a B-lymphocyte defect as a major transcriptional signature in the small intestinal mucosa and immunoglobulin A as the most downregulated protein by proteomic analysis in Nfkb2-/- mice. Small intestinal immunoglobulins were dramatically dysregulated, with undetectable levels of immunoglobulin A and greatly increased amounts of immunoglobulin M being detected. The numbers of IgA-producing, cluster of differentiation (CD)138-positive plasma cells were also reduced in the lamina propria of the small intestinal villi of Nfkb2-/- mice. This phenotype was even more striking in the small intestinal mucosa of RelB-/- mice, although these mice were equally sensitive to LPS-induced intestinal apoptosis as their RelB+/+ wild-type counterparts. NF-κB2/p52 deficiency confers resistance to LPS-induced small intestinal apoptosis and also appears to regulate the plasma cell population and immunoglobulin levels within the gut.NEW & NOTEWORTHY Novel transcriptomic analysis of murine proximal intestinal mucosa revealed an unexpected B cell signature in Nfkb2-/- mice. In-depth analysis revealed a defect in the CD38+ B cell population and a gut-specific dysregulation of immunoglobulin levels.

Endoscopic surveillance alone is feasible and safe in type I gastric neuroendocrine neoplasms less than 10 mm in diameter.

PURPOSE: Type I gastric neuroendocrine neoplasms (g-NENs) have a low risk of metastasis and a generally favourable prognosis. Patients with small type I g-NENs (≤10 mm) frequently require no treatment, whereas those with larger polyps usually undergo resection. We evaluated the safety and outcomes of endoscopic surveillance after no initial treatment in selected patients with type I g-NENs. METHODS: Retrospective analysis of type I g-NEN patients across two European Neuroendocrine Tumour Society Centers of Excellence 2003-2019. RESULTS: Following initial assessment, 87 of 115 patients with type I g-NEN (75 with polyps ≤10 mm) received no initial treatment and underwent endoscopic surveillance. 79/87 (91%) demonstrated no clinically meaningful change in tumour size or grade over a median 62 month follow up. Only two patients developed NEN progression that required a change in management and two other patients developed gastric adenocarcinoma/high grade dysplasia; all four initially had ≥11 mm g-NENs. CONCLUSIONS: Patients with ≤10 mm type I g-NENs were unlikely to develop clinically significant tumour progression and in most cases, resection was not needed. The endoscopic surveillance interval could therefore potentially be safely increased to every 2-3 years in such patients. However, lifelong surveillance is still advocated due to the additional risk of developing gastric adenocarcinoma.

Dental procedures in children with or without intellectual disability and autism spectrum disorder in a hospital setting.

BACKGROUND: This population-based cohort study investigated dental procedures in the hospital setting in Western Australian children with or without intellectual disability (ID) and/or autism spectrum disorder (ASD) aged up to 18 years. Considering previously reported disparities in dental disease between Indigenous and non-Indigenous Australian children, this study also investigated the effect of Indigenous status on dental procedures. METHODS: Data on Western Australian live births from 1983 to 2010 from the Midwives Notification System were linked to the Intellectual Disability Exploring Answers database and the Hospital Morbidity Data collection. Primary admissions for relevant dental diagnoses were identified, and treatment procedures for dental hospitalization were investigated. Descriptive statistics and Pearson's chi-squared test of independence were used for analysis. RESULTS: Overall, 76 065 episodes of dental hospitalization were recorded. Amongst children with ID and/or ASD, Indigenous children experienced more extractions and fewer restorations (68.7% and 16.2%) compared to non-Indigenous children (51.5% and 25.9%). After 6 years, extraction occurred less often in children with ID and/or ASD than in those without, where most surgical dental extractions were in the age group of 13-18 years. CONCLUSIONS: This study indicates a need for further improvements in access to dental services and the quality of care provided in hospitals for children with ID/ASD. There is also concern that more vulnerable Indigenous and all disadvantaged children are receiving an inadequate level of dental services resulting in more emergency dental hospitalization and invasive treatment.

Myths and misconceptions in the management of Helicobacter pylori infection.

The discovery of Helicobacter pylori infection in 1984 revolutionised the management of several common upper gastrointestinal diseases. However, some of the clinical practices that were adopted following discovery of this organism have become less appropriate over the intervening years. This article discusses five 'myths and misconceptions' that we believe have now emerged and which we argue need re-evaluation. Although the prevalence of H. pylori infection is decreasing in some developed countries, it remains a huge global problem and the most serious consequence of infection, gastric adenocarcinoma, is still a major cause of mortality. The epidemiology of H. pylori-related diseases is also changing and careful testing remains crucially important, especially in patients with peptic ulceration. Eradication of H. pylori infection has also become much more difficult over recent years as a result of the widespread acquisition of antibiotic resistance. Routine assessment of the success of eradication should therefore now be performed. Finally, there has been increased awareness about the role of H. pylori in the multistep pathway of gastric carcinogenesis, about the opportunities to prevent cancer development by eradicating this infection in some individuals and about detecting high-risk preneoplastic changes via endoscopic surveillance. The discovery of H. pylori was rightly honoured by the award of the Nobel prize for Physiology and Medicine in 2005. However, unless we re-evaluate and update the ways in which we manage H. pylori infection, much of the fantastic progress that has been made in this field of medicine may tragically be lost once again.

New Developments in Gastric Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: Gastric neuroendocrine neoplasms (g-NENs) are a rare type of stomach cancer. The three main subtypes have different pathogeneses, biological behaviours and clinical characteristics, so they require different management strategies. This article will provide an overview of g-NENs and highlight recent advances in the field. RECENT FINDINGS: Molecular profiling has revealed differences between indolent and aggressive g-NENs, as well as a new somatic mutation responsible for some familial type I g-NENs. Novel biomarkers have been developed which will hopefully improve diagnosis, treatment, risk stratification and follow-up. Patient treatment is also changing, as evidence supports the use of less aggressive options (e.g. endoscopic surveillance or resection) in some patients with more indolent tumours. g-NEN heterogeneity poses challenges in understanding and managing this rare disease. More basic science research is needed to investigate molecular pathogenesis, and future larger clinical studies will hopefully also further improve treatment and patient outcomes.

Neuroendocrine tumours: what gastroenterologists need to know.

Gastroenterologists are intermittently involved in diagnosing and managing patients who have neuroendocrine tumours (NETs). However, few UK gastroenterologists have received extensive training about this topic. This article aims to provide a brief introduction to NETs; it is aimed at a general gastroenterologist audience. NETs present in diverse ways and many symptomatic patients unfortunately experience significant delays in diagnosis. Comprehensive evaluation of a patient with a possible NET involves assessing their symptoms, the tumour's primary organ of origin, its differentiation status, grade and stage, whether the NET is secreting hormones and whether there is any underlying hereditary predisposition. Such assessment often needs specialist investigations such as nuclear medicine scans. All these factors influence patient management and prognosis, so a patient's case and investigations should always be discussed by a fully constituted NET multidisciplinary team. Most localised tumours are considered for resection, but there are multiple treatment options for metastatic disease and many patients receive several different therapies during the course of their illness. The most common first line treatment in patients who have metastatic low grade NETs is monthly long acting somatostatin analogue injections. Prognosis is highly variable, but some patients who have inoperable metastases survive for many years on treatment with good quality of life. Gastroenterologists may also be involved in managing the non-tumour associated chronic gastrointestinal problems that some patients experience. Their involvement has been shown to improve patient-reported outcomes and quality of life.