IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies.

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Oligometastatic recurrence of an oesophageal adenocarcinoma at a chest drain site following radical treatment: palliative treatment or resection?

A 62-year-old female patient diagnosed with oesophageal adenocarcinoma underwent radical treatment consisting of neoadjuvant chemotherapy and oesophagectomy with no major complications. Eleven months later, she re-presented with a mass at one of the chest drain sites. A PET-CT scan and biopsy demonstrated this to be a single recurrence of the oesophageal adenocarcinoma. Excision of the metastatic lesion was considered as per metachronous single site metastasis. However, the operation was postponed due to acute kidney injury. Restaging after 6 weeks revealed progressive metastatic disease. The patient underwent palliative therapy and passed away soon after. Oesophageal cancer recurrence has a very poor prognosis, and factors such as the disease-free interval, site of recurrence and tumour pathological factors must be considered when stratifying for suitability for metastasectomy. A period of watchful waiting followed by restaging is essential to rule out patients with indolent metastatic disease.

Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project.

PURPOSE: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. METHODS: We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. RESULTS: We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 °C or 65 °C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). CONCLUSION: We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy.

This corrects the article DOI: 10.1038/bjc.2017.188.

Diagnostic Lessons from a Complex Case of Postintestinal Transplantation Enteropathy.

Recent advances in the field of intestinal transplantation have been mitigated by the incidence of allograft rejection. In such events, early identification and appropriate timing of antirejection therapy are crucial in retaining graft function. We present the case of a patient who suffered severe postintestinal transplantation allograft enteropathy, primarily characterized by extensive mucosal ulcerations, and was refractory to all conventional therapy. This progressed as chronic rejection; however crucially this was not definitively diagnosed until allograft function had irreversibly diminished. We argue that the difficulties encountered in this case can be attributed to the inability of our current array of investigative studies and diagnostic guidelines to provide adequate clinical guidance. This case illustrates the importance of developing reliable and specific markers for guiding the diagnosis of rejection and the use of antirejection therapeutics in this rapidly evolving field of transplant surgery.

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy.

BACKGROUND: The majority of anal cancers (84-95%) are driven by infection with human papillomavirus (HPV). HPV-positive tumours show significantly better responses to chemo-radiotherapy when compared with HPV-negative tumours. HPV infection is linked to alterations in DNA damage response proteins, including MRE11. MRE11 is a potential predictive biomarker for response to radiotherapy in muscle-invasive bladder cancer and may hold predictive power in other cancers. METHODS: Using a previously reported cohort, we evaluated the levels of MRE11 in anal cancer and assessed its predictive value in this disease. RESULTS: We found no association between the level of MRE11 and relapse-free survival following chemo-radiotherapy. CONCLUSIONS: MRE11 has no predictive value in the analysis of relapse-free survival after chemo-radiotherapy in anal cancer and does not add to the prognostic value of p16 and tumour-infiltrating lymphocyte scores. Further investigation into the role of DNA repair proteins in anal cancer is required.

Primary Squamous Cell Carcinoma of the Stomach.

Squamous cell carcinoma (SCC) of the stomach is a rare entity. There are several theories regarding the development of this tumor, but its pathogenesis remains obscure. Fewer than 100 cases of primary SCC of the stomach have been published in the literature. Due to advanced stage at the time of diagnosis in most of these cases, the prognosis is generally poor. In the case presented here, endoscopy revealed a vegetative tumor in the stomach described as SCC by biopsy. Following curative surgery, adjuvant chemotherapy was administered; however, the patient died 3 years and 4 months after surgery after recurrence was diagnosed.

A template for a clinico-pathological audit of medical liver biopsies.

AIMS: With changing indications for performing medical liver biopsies, we aimed to develop a tool to allow pathologists to evaluate the current usefulness, value and impact of their medical liver biopsy service. METHODS: We designed and piloted a questionnaire-based clinico-pathological audit for medical liver biopsies. RESULTS: The audit tool was simple to implement and provided useful information about our service. Hepatologists felt that 96% of reports were clinically useful. 56% of biopsies confirmed clinical diagnoses, 46% helped differentiate between diagnoses and 42% were able to exclude possible diagnoses. 74% resulted in a change of management and 27% of liver biopsies resulted in a diagnosis which was not clinically suspected. CONCLUSIONS: We demonstrate the usefulness of an audit tool in providing evidence of the value of the liver pathology service in a large UK regional centre.

Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature.

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of "possible" relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended.

Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer.

p38 MAPK signaling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association remains largely unknown. The related p38αMAPK (MAPK14) proteins p38γ (MAPK12) and p38δ (MAPK13) were recently shown to modulate the immune response, although their role in tumorigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analyzed the role of p38γ and p38δ in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38γ-, p38δ-, and p38γ/δ-deficient (p38γ/δ(-/-)) mice. We found that p38γ/δ deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38γ/δ(-/-) mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38γ/δ(-/-) bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38γ/δ(-/-) chimeric mice with WT bone marrow compared with p38γ/δ(-/-) mice transplanted with p38γ/δ(-/-) bone marrow. Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.

Cutaneous graft versus host disease in pediatric multivisceral transplantation.

Multivisceral transplantation (MvTx) is the concurrent transplantation of the stomach, pancreaticoduodenal complex, and intestine, with or without the liver. Its use is increasing worldwide as it has been considered as a therapy for patients with functional disturbance of several organs. Graft-versus-host disease (GvHD) has been a relevant clinical problem in MvTx ever since the procedure was first performed, but little has been reported about its specific cutaneous features. Our study included all pediatric patients with clinical and histopathologic evidence of cutaneous GvHD who received MvTx between October 1999 and December 2010 in University Hospital La Paz. Seventeen children underwent MvTx at our center during this period of time. Five patients developed cutaneous GvHD (29.4%). The median onset was 45.2 days after transplantation. Acute cutaneous GvHD, consisting of symmetrical maculopapular exanthema with prominent acral erythema and accentuated lesions on the face and pinnae, was clinically suspected and pathologically confirmed in four patients (80%). Three children (60%) experienced disease progression to a formation and a positive Nikolsky sign. Only one girl (20%) showed lichenoid GvHD. The first therapeutic approach was steroids and tacrolimus adjustment; many other drugs were used in refractory cases. Three of the five patients (60%) died with concomitant GvHD, the immediate cause of death being another comorbid disease. Knowledge of the features of cutaneous GvHD in MvTx allows clinicians early recognition and prompt therapeutic intervention that may prevent progression to higher-grade disease and improve outcomes for these patients.

Misregulation of suppressors of cytokine signaling in eosinophilic esophagitis.

BACKGROUND: Several findings suggest that eosinophilic esophagitis (EoE) is strongly associated with atopy and allergen-driven, Th2-type immune responses, indicating the association of EoE with immune dysregulation. The objective of this study is to ascertain the molecular mechanism involved in EoE disease development a Th2 condition. METHODS: 25 patients with diagnosis of EoE and 17 non-EoE controls were recruited by the gastroenterology and allergy departments from three different hospitals. Transcription analysis of suppressors of cytokine signaling 1, 3, 5 (SOCS), interleukin-5 (IL), IL-13, eotaxin (CCL26), eoataxin receptor (CCR3), and mitogen-activated protein kinase 1 (MAPK1) was performed in esophageal biopsies by real time PCR. Western blot of ERK esophageal protein and additional measures of IL-5 and VEGF levels in serum were performed. RESULTS: The esophagus of EoE patients expresses and synthesizes high levels of SOCS1 and SOCS3 proteins (P < 0.05), and these expression correlated with levels of IL-5, IL-13, CCL26, CCR3, and MAPK1 genes. In addition, we demonstrate the implication of the ERK pathway (P < 0.001). CONCLUSIONS: SOCS proteins probably contribute to EoE pathogenesis by directly or indirectly inducing the Th2 profile, as well as by promoting the production of Th2 cytokines. All these findings further enhance our understanding of the mechanism of EoE, and accumulating evidence suggests that EoE pathogenesis is likely to be due to misregulation of immunological pathways.

NIH-3T3 fibroblasts cultured with plasma from colorectal cancer patients generate poorly differentiated carcinomas in mice.

The ability of cells to undergo cellular transitions, in particular, to switch between epithelial and mesenchymal states, might be highly advantageous during the progression of carcinoma. Using histological and immunohistochemical techniques, we here show that the injection into mice of spontaneously transformed NIH-3T3 cells generated fusocellular sarcomas, whereas NIH-3T3 cells that had been transformed by culturing with plasma from colorectal cancer patients gave rise to tumors that phenotypically resembled the carcinomas of the original cancer patients. Thus, plasma from cancer patients is able to transform NIH-3T3 fibroblasts into malignant epithelial-like cells, suggesting that such cells might undergo mesenchymal to epithelial transition during plasma-induced transformation.