Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

Intestinal obstruction as a result of intra-abdominal hematoma: a complication of low molecular weight heparin in pediatric patients. / Obstrucción intestinal por hematoma intraabdominal: una complicación de la heparina de bajo peso molecular en el paciente pediátrico.

INTRODUCTION: Hematomas are a rare cause of intestinal obstruction. Subcutaneous heparin can bring about direct punctures on small bowel loops, potentially leading to traumatic hematoma and intestinal obstruction. CASE REPORTS: We present three cases of pediatric patients with clinical signs of intestinal obstruction treated with subcutaneous heparin. Two cases had increased acute-phase reactants and radiological signs of intestinal suffering, so surgical treatment was decided upon, with intramural hematoma emerging as an intraoperative finding. The third case was conservatively managed with anticoagulant discontinuation and gut rest, since the patient had an adequate general condition and no findings compatible with ischemia or necrosis were noted in the complementary tests. DISCUSSION: The administration of subcutaneous heparin may cause intestinal wall hematomas due to its anticoagulating effect and to the risk of inadvertent punctures on small bowel loops.

INTRODUCCION: Los hematomas son una causa poco frecuente de obstrucción intestinal. La heparina subcutánea tiene riesgo de producir la punción directa de un asa intestinal, provocando un hematoma traumático que genere una obstrucción intestinal. CASOS CLINICOS: Se describen tres casos de pacientes pediátricos con clínica de obstrucción intestinal en tratamiento con heparina subcutánea. Dos casos presentaron elevación de reactantes de fase aguda y signos radiológicos de sufrimiento intestinal por lo que se optó por tratamiento quirúrgico, con el hallazgo intraoperatorio de hematoma intramural. El tercer caso fue manejado de manera conservadora con supresión de la anticoagulación y reposo intestinal, dado el adecuado estado general y ausencia de hallazgos compatibles con isquemia o necrosis en las pruebas complementarias. COMENTARIOS: La administración de heparina subcutánea puede provocar la aparición de hematomas de pared intestinal, tanto por su efecto anticoagulante, como por el riesgo de punción inadvertida de un asa intestinal.

Possible case of bortezomib-induced ileus paralytic.

This report describes a case of a patient with active multiple myeloma who was started on bortezomib, cyclophosphamide and dexamethasone and subsequently presented to the emergency department with acute intestinal obstruction one week later. The patient underwent exploratory laparotomy, but no mechanical cause of the obstruction was found. The patient later developed sepsis and eventually died. The possible cause of the intestinal obstruction was attributed to bortezomib, and the paper discusses the potential mechanism of this side effect and its management based on available literature.

Gastrointestinal perforation associated with bevacizumab in metastatic colorectal cancer.

OBJECTIVE: To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab. METHODS: We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation. RESULTS: All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. CONCLUSIONS: Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation.

Lower Risks of Gastrointestinal Perforation and Intestinal Obstruction in Patients with Atypical Antipsychotics in Comparison with Typical Antipsychotics Based on Real-World Data from the MID-NET® in Japan.

Intestinal perforation and obstruction are known to be one of the adverse events caused by antipsychotics; however, warning information on package inserts varies among antipsychotics. To investigate the risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics compared with those in patients prescribed typical antipsychotics, a nested case-control study was conducted utilizing real-world data from the MID-NET® medical information database in Japan. The study period spanned from January 1, 2009, to December 31, 2018. We found that the risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics were significantly lower than those in patients prescribed typical antipsychotics (adjusted odds ratio, 0.48; 95% confidence interval, 0.29-0.80). This finding was supported with prolonged periods for the exposure definition in the sensitivity analyses. In addition, no major differences in the risks of atypical antipsychotics, such as risperidone, quetiapine, olanzapine, and aripiprazole, were identified in this study. The safety profile regarding the lower risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics should be considered when choosing antipsychotics in clinical practice in terms of the proper use of such drugs.

Anaplastic lymphoma kinase tyrosine kinase inhibitors associated gastrointestinal obstruction, perforation, and ulceration: an analysis of the FDA adverse event reporting system database (FAERS).

BACKGROUND : There have been cases reporting anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) and associated serious gastrointestinal (GI) adverse drug reactions (gastrointestinal obstruction, perforation, and ulceration). These adverse drug reactions are not in the drug package inserts, and the drug relationships are not proven in the literature.  AIM: We aimed to examine the potential association between GI obstruction, perforation, and ulceration, and ALK-TKIs by data mining of the US FDA Adverse Event Reporting System (FAERS). METHOD  : We conducted a disproportionality analysis of GI obstruction, perforation, and ulceration by estimating the reporting odds ratios (ROR) and the information component (IC) with 95% confidence intervals. RESULTS : A total of 279 cases of ALK-TKI-associated GI obstruction, perforation, and ulceration from January 1, 2011, to December 31, 2020, were identified. GI obstruction, perforation, and ulceration cause 16% of cases of death. A significantly increased reporting rate for GI obstruction [ROR 1.77 (1.45-2.15); IC 0.82 (0.53-2.03)] and perforation [ROR 1.61 (1.28-2.02); IC 0.68 (0.35-1.92)] was observed for ALK-TKIs as a drug class. The signal of GI ulceration was detected only in crizotinib [ROR 1.23 (1.01-1.50); IC 0.29 (0.01-1.51)]. A statistically significant ROR and IC emerged for the site of the esophagus.  CONCLUSION : Overall, the pharmacovigilance study of the FAERS indicates slightly increased reporting of GI obstruction and perforation, which may cause severe or even fatal outcomes among ALK-TKIs users.

Prenatal therapy with magnesium sulphate and intestinal obstruction due to meconium in preterm newborns.

INTRODUCTION: Magnesium sulphate (MgSO4) therapy has shown to be useful as a neurological protector in the preterm newborn below 32 weeks of gestation. The most documented adverse effect is cardiorespiratory failure, whereas its relationship with meconium obstruction is controversial. The main objective of this study was to analyse the possible association between prenatal MgSO4 therapy and meconium obstruction. PATIENTS AND METHODS: An analytical retrospective study was conducted on <32 weeks preterm babies admitted to a tertiary-level hospital (January 2016-December 2017). Epidemiological, prenatal and postnatal data on the outcomes were obtained, analysed and compared in both groups (exposed to MgSO4 and not exposed). RESULTS: The study included 201 patients (146 exposed and 55 non-exposed). There were no significant differences in the mean gestational age (28.4 ±â€¯2.2 vs. 28.7 ±â€¯2.8 weeks, respectively), or in the rest of epidemiological and perinatal variables. Prenatal corticosteroid therapy was more frequent in the MgSO4 group (75.9 vs. 53.7%; p = .002), and in the non-exposed group there were more multiple pregnancies (52.7 vs. 36.6%; p = .027), and female gender (56.4 vs. 37%; p = .013). There were no statistically significant differences in the presence of meconium obstruction (75.9% in exposed vs. 67.3% in non-exposed; p = .23), although repeated rectal stimulation was more frequent in the exposed group (43.2 vs. 27.9%; p = .08). Furthermore, there were no significant differences in the main cardiorespiratory variables: 1-min Apgar score (6.2 in MgSO4- exposed vs. 5.6 in non-exposed; p = .75), 5-min Apgar score (7.9 vs. 7.6; p = .31), advanced newborn resuscitation (26 vs. 31.5%; p = .44), maximum FiO2 (45.5 vs. 48; p = .58), and initial inotropic requirements (10.3 vs. 20.8%; p = .55). CONCLUSIONS: This study found no correlations between MgSO4 therapy and meconium obstruction or cardiorespiratory failure.

Incretin-Based Drugs and Risk of Intestinal Obstruction Among Patients With Type 2 Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

ACE inhibitor-induced angioedema causing small bowel obstruction.

Mucosal angioedema of the face, lips, tongue, and throat is a well-recognized adverse reaction to angiotensin-converting enzyme (ACE) inhibitors that is experienced by a minority of patients. Rarely, this angioedema can involve the small bowel, and patients commonly present with abdominal pain and small bowel obstruction. Due to the increasing number of patients being treated for hypertension, clinicians should consider the diagnosis of small bowel angioedema secondary to ACE inhibitor use in all patients with this presentation who are using this class of medications.

Incretin-based drugs and intestinal obstruction: A pharmacovigilance study.

AIMS: To investigate the risk of intestinal obstruction associated with incretin-based drugs by performing a disproportionality analysis of adverse reaction reports in a global pharmacovigilance database. METHODS: We conducted a case/non-case analysis using VigiBase, the World Health Organization's adverse drug reactions (ADR) database, to assess intestinal obstruction reporting associated with incretin-based drugs (glucagon-like peptide 1 analogues [GLP-1a] and dipeptidyl peptidase 4 inhibitors [DPP-4i]. Cases were defined as reports of gastrointestinal stenosis and obstruction (MedDRA High Level Group Term) and non-cases were all other reactions recorded. Disproportionality analysis were performed by computing reporting odds ratios (ROR) with their 95% confidence interval (95%CI) within all ADR reports concerning diabetes drugs from January 2007 to January 2018 and in a restricted sample including only serious reports. RESULTS: A total of 501,244 ADR with diabetes drugs were reported in VigiBase during the study period. We identified 452 intestinal obstructions involving an incretin-based drug. In disproportionality analyses, intestinal obstructions were more than 4.5 times more frequently reported with incretin-based drugs than with other diabetes drugs (ROR 4.52, 95% CI: 3.87-5.28) with a higher signal for serious cases and for DPP-4i (ROR 8.66, 95% CI: 7.27-10.32) compared to GLP-1a (ROR 3.05, 95% CI: 2.54-3.66). CONCLUSIONS: We identified a pharmacovigilance signal that suggests a risk of potentially serious intestinal obstruction associated with incretin-based drugs, as a class and with a greater signal for DPP4-i. Other studies are needed to confirm and better understand the potential risk of intestinal obstruction associated with incretin-based drugs.

Diaphragm disease in emergency surgery.

BACKGROUND/AIMS: Diaphragm disease of the small bowel has been described in the literature over the last three decades. The pathognomonic characteristic of multiple circumferential stenosis is noted on gross examination of the bowel. It is a severe form of non-steroidal anti-inflammatory drug-induced enteropathy, often presenting as acute small bowel obstruction. A systematic review was performed to identify risk factors and patient outcomes in histologically-proven diaphragm disease of the small intestine in patients undergoing emergency operation for small bowel obstruction. METHODS: A comprehensive search was performed between January 1975 and March 2019 using relevant MeSH terms. Studies were chosen based on predefined inclusion criteria. Diaphragm disease of the small intestine was defined as macroscopically detected thin diaphragm-like mucosal folding inside the lumen of the bowel. The parameters assessed included patient characteristics, duration of use of non-steroidal anti-inflammatory drugs, type of emergency surgery performed, complications, recurrence, presentation and diagnosis of diaphragm disease. RESULTS: A total of 21 studies were analysed which included 17 case reports, one case series, and three retrospective comparative studies. Overall 29 patients with diaphragm disease of the small bowel were reported following emergency laparotomy for small bowel obstruction. Use of non-steroidal anti-inflammatory drugs was noted in all cases with an average duration of 3-5 years. All patients presented acutely with features of small bowel obstruction and had emergency laparotomy, except one who underwent laparoscopic resection. In the comparative studies patients were more likely to be female and to have been taking non-steroidal anti-inflammatory drugs for more than 7 years. CONCLUSIONS: This is a rare disease, difficult to diagnose and often confirmed by the intra-operative macroscopic appearance of circumferential stenosis of the bowel. Risk factors for developing small bowel diaphragm disease include long-term use of non-steroidal anti-inflammatory drugs, and female gender. Patients with this disease are at increased risk of developing acute small bowel obstruction, so early identification is important.

Nivolumab-induced small bowel obstruction and perforation: a rare but life-threatening side effect of immunotherapy.

We present a case of a 58-year-old female with anti-PD-1 immunotherapy-related small bowel perforation. The patient was on long-term therapy with nivolumab for metastatic non-small cell lung cancer. She presented to the emergency department with acute abdominal pain, in which the CT revealed a short segment of dilated distal ileum proximal to a very short segment of bowel with mural thickening and a perforation near the transition point. The patient underwent subsequent laparotomy, which confirmed the CT findings and revealed a short-segment of friable and dilated loop of distal ileum proximal to a stricture and a small perforation at the transition point. Pathological analysis revealed mural thickening at the site of stricture without evidence of malignancy with focal necrosis and perforation at the transition point. Bowel perforation in the setting of anti-PD-1 immunotherapy is rare, but life-threatening complication, and should be considered in oncology patients on immunotherapy presenting with severe abdominal pain.

Small bowel diaphragm disease from long-term non-steroidal anti-inflammatory use.

Small bowel diaphragm disease (SBDD) is characterised by circumferential lesions of short length (<5 mm), causing intrinsic stenosis of the small bowel lumen. A 63-year-old women with a history of long-term non-steroidal anti-inflammatory use, presented with a 12-month history of intermittent episodes of colicky abdominal pain, nausea and vomiting. Her only past surgery was a laparoscopic hysterectomy. Abdominal CT demonstrated an area of thickening in the mid small bowel, however a diagnostic laparoscopy failed to demonstrate adhesions or any external abnormality. A capsule endoscope did not progress beyond the mid small bowel at the site of a suspected diaphragm. The patient underwent a laparotomy and using the retained capsule as a marker, the area of bowel affected by SBDD was identified. With an ageing population and the widespread use of non-steroidalanti-inflammatory drugs, general surgeons may see an increase in the incidence of SBDD.

Iatrogenic Kaposi sarcoma of the terminal ileum following short-term treatment with immunomodulators for Crohn disease: A case report.

RATIONALE: Kaposi sarcoma (KS) is a mesenchymal neoplasm associated with human herpes virus-8. It is often found in patients with primary or secondary immunodeficiency. An iatrogenic form of KS is detectable in patients who have received immunosuppressive therapy. To date, there are few reported cases of patients with KS treated with immunosuppressants for inflammatory bowel disease. PATIENT CONCERNS: We report the case of a 45-year-old young woman with abdominal pain, episodic diarrhea and a mild weight loss. The patient was treated with immunosuppressive therapy for a parietal thickening of the terminal ileum, wrongly diagnosed as Crohn disease. After 9 months after the beginning of antitumor necrosis factor-α, the patient was admitted for obstructive symptoms. A computed tomography suspected neoplasia of ileocecal region. The patient underwent an uneventful ileocecal surgical resection. DIAGNOSES: The histopathology showed endometriosis of the ileal wall and an irrefutable diagnosis of KS by immunohistochemistry-positive staining for human herpes virus-8. INTERVENTIONS AND OUTCOMES: The patient underwent surgical resection and is disease free at 6 years follow-up. LESSONS: This case underlines the interaction of immunosuppressive therapy with the possible consequent development of visceral KS.

Anti-TNF biologic therapy does not increase postoperative morbidity in pediatric Crohn's patients.

INTRODUCTION: Limited knowledge exists as to what impact preoperative biologic therapy has on postoperative complications in pediatric patients undergoing abdominal surgery for Crohn's disease (CD). Therefore, we sought to determine the 30-day postoperative infectious complication rate among pediatric CD patients who received biologic therapy within 12 weeks of an abdominal operation. METHODS: A retrospective chart review was performed on pediatric (<18 years of age) CD patients who underwent an abdominal operation between 1/1/2008 and 12/31/2017. Patients were grouped according to whether they received an anti-TNF (infliximab, adalimumab, certolizumab pegol) or no biologic therapy within 12 weeks prior to the operation. The primary outcome was the overall 30-day postoperative infectious complication rate. Secondary outcomes included 30-day readmission rate and return to the operating room (ROR). RESULTS: A total of 69 pediatric CD patients met inclusion criteria (n = 54 anti-TNF therapy, n = 15 received no biologic therapy). There were no differences between the anti-TNF and no biologic cohorts with respect to demographics or CD characteristics. No significant differences in overall 30-day postoperative infectious complications existed between patients exposed to anti-TNF agents and those with no preoperative exposure, or in its subcategories of surgical infectious complications and nonsurgical infectious complications. There was also no difference in the rate of ileus, readmission, or ROR. CONCLUSIONS: Preoperative exposure to anti-TNF biologic therapy does not add to overall or infectious 30-day postoperative morbidity in pediatric CD patients. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective review.