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.

Similar incidence of typhlitis in patients receiving various doses of daunorubicin or idarubicin as induction for acute myeloid leukemia.

BACKGROUND: The current standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed by abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction chemotherapy with idarubicin 12 mg/m2 (IDA), daunorubicin 60 mg/m2 (DNA60), or daunorubicin 90 mg/m2 (DNA90). METHODS: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between January 1, 2009 and June 30, 2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum only, defined as non-tumoral bowel wall thickening with or without pericolonic fat infiltration and fluid, according to CTCAE version 4.03 along with clinical symptoms. The primary endpoint was to determine the incidence of typhlitis among IDA, DNA60, and DNA90. Secondary endpoints included characterizing the variability of doses used in induction therapy and identifying any potential risk factors for the development of typhlitis. RESULTS: The overall incidence of typhlitis was 2.5%. When the definition was broadened to include the colitis, enteritis, or enterocolitis, the incidence increased. The inter-reliability ratings of the 2 radiologists' evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. In patients that developed typhlitis, all patients had clinical symptoms in addition to documented cecum inflammation on CT scan. All patients were managed conservatively with intravenous broad-spectrum antibiotics. CONCLUSION: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. The cumulative incidence of typhlitis was similar to the currently published literature, with the incidence being similar irrespective of the anthracycline chosen or dose. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy.

Periappendicitis during adalimumab treatment for ileocecal Crohn's disease in a 29-year-old male.

A 29-year-old male was diagnosed with ileocolic Crohn's disease (CD) approximately 2 years ago. Adalimumab was prescribed as CD remission induction therapy. Three months after beginning adalimumab, watery diarrhea and lower abdominal pain developed. He was admitted under a diagnosis of CD exacerbation. Despite fasting and antibiotic treatment, symptoms of acute panperitonitis appeared. He was diagnosed as acute appendicitis and we performed emergency surgery for peritoneal drainage and ileocecal resection on the fifth hospital day. We diagnosed periappendicitis based on the operative findings. This is the first report of periappendicitis with CD during adalimumab treatment.

Concomitant typhlitis and Clostridium difficile colitis developed after first R-CHOP chemotherapy in a non-Hodgkin lymphoma patient.

Typhlitis or neutropenic enterocolitis (NEC) is a life-threatening condition that occurs in neutropenic patients. Early recognition is crucial owing to high death rate. We present a case of a 54-year-old man, diagnosed with non-Hodgkin lymphoma who received a first cycle of rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), prednisolone (R-CHOP) chemotherapy 10 days prior presenting. He developed fever, mucositis, watery diarrhoea and right lower quadrant pain with rebound tenderness. He also had neutropenia, with an absolute neutrophil count of zero. CT abdomen confirmed the diagnosis of typhlitis, demonstrating characteristic terminal ileum, caecal and right-sided colon involvement. Moreover, stool PCR was also positive for toxigenic Clostridium difficile. Therefore, the patient was diagnosed with concomitant typhlitis and C difficile-associated diarrhoea (CDAD). He was empirically treated with intravenous cefepime, intravenous metronidazole and oral vancomycin. His symptoms resolved in 10 days. This case illustrated a successful medical treatment of typhlitis in concomitance with CDAD.

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.

Right lower quadrant abdominal pain in an immunocompromised patient: importance for an urgent diagnosis and treatment.

This is a case of a 34 years old male Hispanic patient with history of AIDS who presented to the ER with severe right lower quadrant abdominal pain of three days of evolution, associated with fever, chills, nausea, vomiting, watery diarrhea, weakness and general malaise. Acute appendicitis, Clostridium Difficile Colitis and Ischemic Colitis were the most important clinical conditions to consider in the differential diagnosis. Abdominal CT with IV contrast demonstrated thickening of the ascending colonic wall a finding highly suggestive of a transmural inflammatory necrotizing colitis of infectious etiology. Broad-spectrum antibiotic therapy, cancidas and ganciclovir were started with mark clinical improvement. IgG antibodies against CMV were elevated. Typhlitis is a serious illness that affects patients with impairment in immunity. It is important to include it in the differential diagnosis of an HIV/AIDS patient that presents with RLQ pain and fever. Contrast enhanced CT-Scan is mandatory to establish the diagnosis and to differentiate typhlitis from other intra-abdominal pathologies. Therapy needs to be individualized.

Effects of hydroxyethyl starch (130 kD) on brain inflammatory response and outcome during normotensive sepsis.

BACKGROUND: During sepsis, the dysfunction of blood-brain barrier (BBB) was mediated by inflammation and subsequently caused sepsis-associated encephalopathy. Hydroxyethyl starch (HES, 130/0.4) is most widely used for volume replacement to maintain or improve tissue perfusion in patients with sepsis, trauma, and shock. This study was undertaken to investigate the effects of HES on BBB permeability, brain edema, inflammatory response and clinical outcome in septic rats. METHODS: Using the cecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with 15 ml/kg HES or normal saline 4h after the operation. Two hours later, expressions of brain toll-like receptor (TLR)-2, TLR4 and intercellular adhesion molecule (ICAM)-1 mRNA was determined by real-time reverse transcription-polymerase chain reaction; inflammatory cytokines like tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 by enzyme-linked immunosorbent assay; activity of nuclear factor-kappa B (NF-kappaB) by electrophoretic mobility shift assay; BBB permeability by Evans blue extravasation method; brain edema by wet/dry weight ratio. Weight loss, and clinical symptoms were also observed. RESULTS: Without obvious influence on systemic macrohemodynamics, HES could markedly attenuate BBB dysfunction and brain edema. Meanwhile, HES could significantly reduce TNF-alpha, IL-6, and ICAM-1 mRNA, inhibit NF-kappaB activation, and down-regulate TLR2 and TLR4 expression in the brain. In addition, CLP-induced increase in weight loss, and clinical symptoms was not reduced after treatment with HES. CONCLUSIONS: HES could ameliorate BBB dysfunction and inflammation mediators by modulating brain TLR2 and TLR4 expression during sepsis. However, HES could not improve clinical outcome.

Double invasive fungal infection and typhlitis in children with acute lymphoblastic leukemia.

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.

[Typhlitis: report of a case and review of the literature]. / Typhlite: à propos d'une observation et revue de la littérature.

INTRODUCTION: Typhlitis is a rare condition, characterized by necrotizing inflammation of the colon. It occurs mainly in neutropenic patients receiving chemotherapy for leukemia. EXEGESIS: We report the case of a 64-year-old woman with T-cell lymphocytic leukaemia, who exhibited asymptomatic reactivation of cytomegalovirus infection and developed subsequently typhlitis. CONCLUSION: The pathological mechanisms of typhlitis remain unclear in neutropenic patients. The role of cytotoxic drugs as well as both bacterial overgrowth and translocation has been postulated. In our patient, asymptomatic reactivation of cytomegalovirus infection may have increased chemotherapeutic-agents-digestive toxicity.