A case report of typhlitis during novel use of ropidoxuridine-capecitabine-radiotherapy for treatment-naïve rectal cancer.

BACKGROUND: Rectal carcinomas are tumors that arise from the last 12 cm of the large intestine closest to the anus. They generally have a modest prognosis exacerbated by a high local recurrence rate if radiosensitizing chemotherapy is not given during radiotherapy. This case report discusses the clinical trial treatment of a patient with rectal adenocarcinoma by a new ropidoxuridine-capecitabine-radiotherapy combination. This case report is novel due to the patient's participation in an accelerated titration phase I clinical trial and the resultant rare adverse event of treatment-related sigmoid typhlitis. CASE PRESENTATION: The patient was an 82-year-old female who noticed hematochezia and change in stool caliber over a period of 3 months. A rectal mass was identified by biopsy as a microsatellite stable adenocarcinoma. A planned total neoadjuvant treatment involved eight cycles of leucovorin calcium (folinic acid)-fluorouracil-oxaliplatin (mFOLFOX6) chemotherapy, followed by a clinical trial combination of ropidoxuridine-capecitabine-radiotherapy, prior to definitive surgery. The patient began daily intensity modulated pelvic radiotherapy with concurrent twice-daily oral ropidoxuridine and twice-daily oral capecitabine to be given over 6 weeks. After 14 days of ropidoxuridine-capecitabine-radiotherapy, the patient developed sigmoid typhlitis requiring a 10-day hospitalization and 14-day disruption of treatment. The patient died 27 days after the start of ropidoxuridine-capecitabine-radiotherapy. This adverse event was listed as a definite attribution to the ropidoxuridine-capecitabine treatment; pharmacokinetic and pharmacodynamic data showed low ropidoxuridine metabolite DNA incorporation and high capecitabine metabolite concentration. The accelerated titration phase I clinical trial has been subsequently closed to accrual (NCT04406857). CONCLUSIONS: We believe this case report demonstrates the decision-making process for terminating a phase I accelerated titration designed clinical trial. The report also presents the rare complication of sigmoid typhlitis as a treatment-attributed adverse event. In this case, a ropidoxuridine-capecitabine combination was used as an investigational radiosensitizing treatment now with a narrower future clinical development pathway.

Sonographic and Clinical Features of Typhlitis in Pediatric Cancer Patients on Chemotheaphy at Tikur Anbessa Specialized Hospital, Ethiopia, 2021.

Background: Typhlitis, (neutropenic enterocolitis), is a necrotizing enteropathy of the right colon, and is characterized by the clinical triad of fever, abdominal pain, neutropenia and imaging findings of right-side colonic inflammation. It is seen in the setting of severe neutropenia in immune suppressed patients who undergo treatment for malignancies, in those who have organ transplant(s) or congenital or other acquired immunosuppression. We report the clinical and imaging findings of typhlitis in pediatric cancer patients who had received chemotherapy in the largest tertiary center in Addis Ababa, Ethiopia over a period of 20 months. Methods: The medical records of hospitalized cancer patients on treatment and with suspected typhlitis and with ultrasound reports were screened (November 2018- July 2020). Retrospective analysis of the clinical and sonographic data of those with typhlitis was done. Results: Typhlitis was identified in 4.2% (12/286) of the patients on chemotherapy. 11 (91.7%) had hematologic malignancies (leukemia, lymphoma), one had a solid tumor (Head and neck embryonal RMS). Most (83.3%) had abdominal pain, diarrhea and neutropenia. Fever was identified in 67.7%. All had ultrasound evidence of typhlitis. and treated with IV antibiotics. Neither complications requiring surgical intervention nor death were seen. Conclusion: The magnitude of disease was comparable to what had previously been reported in other studies. While the presence of clinical a triad should prompt suspicion for the diagnosis, sonography can be used for confirmation and follow up obviating radiation, with good access in a resource limited setting.

Investigation of typhlitis in bone marrow transplant patients in a stem cell transplant unit.

Typhlitis is a special type of enterocolitis that specifically develops in immunosuppressive patients with hematological malignancies. Typhlitis is a common consideration after bone marrow transplantation due to high-dose chemotherapy that is used in conditioning regimens those contain high-dose cytotoxic chemotherapeutic agents. Although there are several studies about typhlitis during chemotherapy or in leukemia patients, there is not enough data evaluating its relationship between stem cell transplant in adults. Therefore, the current study aimed to analyze the possible causes that may lead to the development of typhlitis in hematopoietic stem cell recipient patients. This retrospective study included 210 adult patients who underwent bone marrow transplantation between January 2017 and December 2019. Pediatric patients (patients younger than 18 years of age) were excluded. Patients' data were evaluated to determine their effects on typhlitis and the mortality risk of the patients with typhlitis. The analysis of the variables was performed using the IBM SPSS Statistics for Windows version 26 (IBM Corp., Armonk, NY).Variables were analyzed at a 95% confidence level and a P value <0.05 was considered significant. Typhlitis developed in 23 (10.9%) transplant patients. Male sex, length of hospital stay, presence of febrile neutropenia, antibiotic and antifungal use, need for switching antibiotics, duration of neutropenia, diarrhea and antibiotic use in days were risk factors for development of typhlitis. It was observed that 100-days mortality was higher in typhlitis group reaching to a statistical significance (P < .05). In multiple logistic regression analysis, presence of mucositis and additional source of infection were determined as independent risk factors for the development of typhlitis in bone marrow transplant patients. This study provides valuable information for bone marrow transplant patients through an analysis of risk factors for the development of typhlitis. According to our results, mucositis and additional bacterial infections were found as risk factors for typhlitis therefore it would be beneficial for clinicians to consider these factors in patient follow-up. However, due to the retrospective nature of our study, prospective studies are needed to investigate risk factors and optimum treatment methods for typhlitis.

COVID-19-associated pancytopenia and typhlitis.

Neutropenic enterocolitis is also known as typhlitis, is characterized by severe inflammation in the bowel loops. It is often seen in immunosuppressed patients, and it has high morbidity and mortality. Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respiratory system and causes COVID-19 (Coronavirus Disease 2019), it may affect hematopoietic and gastrointestinal systems. Herein, we present a rare case of COVID-19-associated pancytopenia and typhlitis in a 60-year-old female who presented with abdominal pain. Contrast-enhanced abdominal computed tomography (CT) demonstrated the bowel wall thickening in the cecum and ascending colon compatible with enterocolitis. Moreover, the chest CT showed bilateral, peripheral, and multifocal ground-glass opacities, consistent with COVID-19 pneumonia. We also aimed to emphasize the laboratory, clinical, and CT findings of the patient.

Typhlitis as a complication of influenza in a patient with advanced HIV infection.

The authors report the case of an HIV-infected patient who presented with typhlitis as a complication of typical influenza. To the best of their knowledge, this is the first case reported in the literature with such an association of clinical conditions.

Typhlitis (neutropenic enterocolitis) in patients with acute leukemia: a review.

INTRODUCTION: Typhlitis is an abdominal complication of cancer chemotherapy, affecting mostly patients receiving intensive chemotherapeutic regimens with high potential to induce mucosal damage, such as patients with acute leukemia. Despite being relatively frequent, there are no randomized trials or high-quality cohort studies addressing important aspects of the diagnosis and management of the disease. Areas covered: In this review we discuss the gaps in the literature, acknowledging that the evidences for recommendations regarding the management of typhlitis are mostly expert opinion. We performed a computerized search of the MEDLINE database (PubMed version) for appropriate articles published from 1963 through July, 2016 in English language. Thereafter the reference lists of all identified studies were screened, reviewing the abstracts of all potentially pertinent articles for inclusion. Expert commentary: The diagnosis of typhlitis still relies on clinical and radiologic features consisting of fever, abdominal pain and thickness of a segment of the bowel wall, as seen by ultrasonography or CT scan. The treatment consists in antimicrobial therapy with a regimen that covers the most frequent pathogens, taking into consideration the local epidemiology. Other measures include bowel rest, and the use of G-CSF. Surgery is indicated only in selected situations.

Neutropenic enterocolitis.

Neutropenic colitis is a severe condition usually affecting immunocompromised patients. Its exact pathogenesis is not completely understood. The main elements in disease onset appear to be intestinal mucosal injury together with neutropenia and the weakened immune system of the afflicted patients. These initial conditions lead to intestinal edema, engorged vessels, and a disrupted mucosal surface, which becomes more vulnerable to bacterial intramural invasion. Chemotherapeutic agents can cause direct mucosal injury (mucositis) or can predispose to distension and necrosis, thereby altering intestinal motility. This article aims to review current concepts regarding neutropenic colitis' pathogenesis, diagnosis, and management.

Acute typhlitis caused by a caecal faecolith.

Isolated acute typhlitis caused by a caecal faecolith is extremely rare. Hereby we report such a case. A 30-year-old man presented clinically as acute appendicitis. During open surgery, an inflamed caecal mass was found. A limited colectomy including the mass and grossly health margins was performed. Histopathological examination confirmed that acute typhlitis was caused by an impacted caecal faecolith. The appendix was normal. Faecolith is an extremely rare cause of acute inflammation of the caecum presenting as a mass which is usually treated by limited right hemicolectomy.

Endogenous Acetylcholine Controls the Severity of Polymicrobial Sepsisassociated Inflammatory Response in Mice.

Acetylcholine (ACh) is the main mediator associated with the anti-inflammatory cholinergic pathway. ACh plays an inhibitory role in several inflammatory conditions. Sepsis is a severe clinical syndrome characterized by bacterial dissemination and overproduction of inflammatory mediators. The aim of the current study was to investigate the participation of endogenous ACh in the modulation of inflammatory response induced by a model of polymicrobial sepsis. Wild type (WT) and vesicular acetylcholine transporter knockdown (VAChT(KD)) mice were exposed to cecal ligation and perforation- induced sepsis. Levels of Tumor Necrosis Factor Alpha (TNF-α) and bacterial growth in peritoneal cavity and serum, and neutrophil recruitment into peritoneal cavity were assessed. The concentration of TNF-α in both compartments was higher in VAChT(KD) in comparison with WT mice. VAChT(KD) mice presented elevated burden of bacteria in peritoneum and blood, and impairment of neutrophil migration to peritoneal cavity. This phenotype was reversed by treatment with nicotine salt. These findings suggest that endogenous ACh plays a major role in the control of sepsis-associated inflammatory response.

Embolisation for caecal bleeding in a child with typhlitis.

A 16-year-old girl being treated for a relapse of promyelocytic leukaemia developed typhlitis of the caecum and ascending colon related to Klebsiella septicaemia during the neutropenic phase, 2 weeks after the start of induction treatment with chemotherapy. After 10 days of treatment with parenteral feeding and antibiotics, massive rectal blood loss occurred, causing haemodynamic instability. Contrast-enhanced abdominal CT showed contrast extravasation in the caecal lumen. This life-threatening situation prompted visceral angiography, which confirmed a contrast blush in the caecum. Subsequent embolisation resulted in haemodynamic stability.

The role of Nox2-derived ROS in the development of cognitive impairment after sepsis.

BACKGROUND: Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. METHODS: Sepsis was induced in WT and gp91(phox) knockout mice (gp91(phox-/-)) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. RESULTS: Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91(phox-/-) mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. CONCLUSIONS: Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE.

Comparison of the effects of Mg-6Zn and titanium on intestinal tract in vivo.

To evaluate the ability of Mg-6Zn to replace titanium nails in the reconstruction of the intestinal tract in general surgery, we compared the Mg-6Zn and titanium implants with respect to their effects on rat's intestinal tract by biochemical, radiological, pathological and immunohistochemical methods. The results indicated that Mg-6Zn implants started to degrade at the third week and disintegrate at the fourth week. No bubbles appeared, which may be associated with intestinal absorption of the Mg-6Zn implants. Pathological analyses (containing liver, kidney and cecum tissues) and biochemical measurements, including serum magnesium, creatinine, blood urea nitrogen, glutamic-pyruvic-transaminase and glutamic-oxaloacetic-transaminase proved that degradation of Mg-6Zn did not harm the important organs, which is an improvement over titanium implants. Immunohistochemical results showed that Mg-6Zn could enhance the expression of transforming growth factor-ß1. Mg-6Zn reduced the expression of tumor necrosis factor at different stages. In general, our study demonstrates that the Mg-6Zn alloy had good biocompatibility in vivo and performed better than titanium at promoting healing and reducing inflammation. It may be a promising candidate for stapler pins in intestinal reconstruction.

Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation.

Bacterial-induced intestinal inflammation is crucially dependent on interleukin (IL)-23 and is associated with CD4(+) T helper type 1 (Th1) and Th17 responses. However, the relative contributions of these subsets during the induction and resolution of colitis in T-cell-sufficient hosts remain unknown. We report that Helicobacter hepaticus-induced typhlocolitis in specific pathogen-free IL-10(-/-) mice is associated with elevated frequencies and numbers of large intestinal interferon (IFN)-γ(+) and IFN-γ(+)IL-17A(+) CD4(+) T cells. By assessing histone modifications and transcript levels in IFN-γ(+), IFN-γ(+)IL-17A(+), and IL-17A(+) CD4(+) T cells isolated from the inflamed intestine, we show that Th17 cells are predisposed to upregulate the Th1 program and that they express IL-23R but not IL-12R. Using IL-17A fate-reporter mice, we further demonstrate that H. hepaticus infection gives rise to Th17 cells that extinguish IL-17A secretion and turn on IFN-γ within 10 days post bacterial inoculation. Together, our results suggest that bacterial-induced Th17 cells arising in disease-susceptible hosts contribute to intestinal pathology by switching phenotype, transitioning via an IFN-γ(+)IL-17A(+) stage, to become IFN-γ(+) ex-Th17 cells.

Typhlitis in acute childhood leukemia.

OBJECTIVE: To review our experience with typhlitis among children treated for acute leukemia. MATERIAL AND METHODS: The medical records of children with acute leukemia and typhlitis between 2006 and 2009 were reviewed for demographics and symptoms, and for microbiological and imaging findings. RESULTS: In the 75 children with acute leukemia--54 with acute lymphoblastic leukemia (ALL) and 21 with acute myeloid leukemia (AML)--there were 10 episodes of typhlitis (4.5%) that developed during 221 periods of severe neutropenia. The cumulative risk of typhlitis was 7.4% in patients with ALL and 28.5% in patients with AML. Frequent symptoms were: abdominal pain and tenderness (100% each); fever and nausea (90% each); emesis (80%); diarrhea (50%), and hypotension, peritonitis and abdominal distension (10% each). The median duration of symptoms was 6 days (range: 2-11 days), and that of neutropenia 14 days (range: 3-25 days). All patients were treated medically and none surgically. Two patients died because of typhlitis and sepsis. CONCLUSIONS: In our study, the rate of typhlitis among leukemic children was 4.5%; however, the mortality rate was 20%. Thus, rapid identification and timely, aggressive medical intervention are necessary to reduce the morbidity and mortality from typhlitis.

Acute inflammation of the true cecal diverticulum--case report.

In this case report, we describe a rare event: acute inflammation of the true cecal diverticulum. Emergency surgery enabled proper diagnosis and management of this condition. Diagnostic approaches and the management of this disease are described in detail and based on literature review. In conclusion, pathologies of cecal diverticula should be considered in differential diagnosis of pain in the right iliac fossa.

Typhlitis in children with malignancy: a single center experience.

In a case-control study, medical records of all children (below 18 y of age) who were diagnosed with any malignancy between January 1988 and December 2008 were reviewed. Children who developed typhlitis during the course of their malignancy were identified. Age and sex-matched controls who were diagnosed with malignancy during the same time period but did not develop typhlitis were identified (1:4 ratio). The variables that were examined included underlying malignancy, chemotherapy, and final outcome. A total of 410 children (226 males, mean age of 87.29 ± 56.8 mo) with malignancy were recruited. Nine children (0.22%) (4 boys, mean age of 87.56 ± 60.48 mo) developed typhlitis during the course of their disease. In the control group, 36 age and sex-matched children were included (mean age of 87.67 ± 57.91 mo). Children who had Clostridium difficile infection within 8 weeks before developing typhlitis were more likely to develop typhlitis compared with controls (odds ratio 7.99, 95% confidence interval 1.46-43.7, P=0.01). One patient died from typhlitis. Clostridium difficile infection is a risk factor for developing typhlitis in children with cancer. Larger multicenter trials are needed to confirm our conclusions.