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.

Ileus in patients treated with immune checkpoint inhibitors: A retrospective, pharmacovigilance study using Food and Drug Administration Adverse Event Reporting System database.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been widely used in cancer treatment; however, some case reports suggested that ICIs treatment might result in ileus. This study aims to comprehensively reveal the relationship between ileus and ICIs treatment in real-world cases from Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: Reports from January 1, 2011 to December 31, 2020 were extracted from the FAERS. ICIs-related adverse events in patients were defined as related to use of anti-programmed cell death protein 1 antibodies (PD-1, nivolumab and pembrolizumab), anti-programmed cell death-ligand 1 inhibitors (PD-L1, atezolizumab, durvalumab, avelumab, and cemiplimab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab and tremelimumab). ICIs-related ileus cases were identified to characterize their clinical features. Reporting odds ratios (ROR) and information component (IC) were used to assess the relationship between ICIs and ileus. RESULTS: Among the 105 001 cases related to ICIs, 245 were reported with ICI-related ileus. The affected patients were mainly elderly (median age, 64.5 years) and male (58%, n = 143). The median onset for all cases was 36 (range 0-880) days, and no statistical difference was observed between monotherapy and combination therapy (PD-1 or PD-L1 plus CTLA-4) (p = 0.21). Most patients required drug withdrawal treatment (n = 113, 74%) and can achieve a recovered-resolved state (n = 72, 46%). All ICIs were significantly associated with ileus (ROR = 4.27, 95%Cl: 3.75-4.85; IC = 2.04, 95%Cl: 1.79-2.31). Ileus events were most commonly reported in PD-1 treatment (n = 164, ROR = 3.83, 95%Cl: 3.28-4.48; IC = 1.90, 95%Cl: 1.62-2.21). CONCLUSION: This pharmacovigilance database analysis suggested that ICIs are related to ileus. However, combination therapy may not speed up the onset of ileus.

Targin®: An effective opiate analgesia with minimal gastrointestinal side effects-An observational study.

OBJECTIVE: To examine the role of Targin® (oral oxycodone:naloxone combination) in the perioperative setting. DESIGN: A single center prospective observational pilot study at a regional hospital. SETTING: Thirty-eight eligible patients undergoing major general surgical operations were recruited. Thirty-two patients completed the study. INTERVENTIONS: Participants were given Targin twice daily from day 2 post-operatively with twice daily measures of pain scores, gut function, and mobility. MAIN OUTCOME MEASURES: The primary end points were analgesic efficacy and the rate of ileus. Secondary end points were gastrointestinal (GI) recovery and the need for opioid requirement on discharge, at 1 week and 1 month. RESULTS: Average pain score over 5 days at rest was one and on movement was four out of 10. All patients mobilized to a chair by day 3. Twenty-six participants (81.3 percent) experienced nausea at some point during the study, and four participants (12.5 percent) were diagnosed with a post-operative ileus (POI). There was no serious adverse event reported. Only two patients were on opioids at 1-month discharge. This was due to them having Orthopaedic surgery not related to this study.

Vincristine Sulfate Liposome Injection with Bendamustine and Rituximab as First-Line Therapy for B-Cell Lymphomas: A Phase I Study.

BACKGROUND: We conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma. METHODS: Participants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). RESULTS: Among 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died. CONCLUSION: Vincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.

Use of naldemedine is associated with reduced incidence of hyperactive delirium in cancer patients with opioid-induced constipation: A nationwide retrospective cohort study in Japan.

BACKGROUND: Medical benefits of peripherally acting mu-opioid receptor antagonists other than improving opioid-induced constipation remain unclear. Our aim was to evaluate the association between the use of naldemedine and incidence of hyperactive delirium in cancer patients receiving chemotherapy and opioid therapy. METHODS: We conducted a propensity score-matched analysis using a nationwide inpatient database in Japan. Cancer patients receiving both inpatient chemotherapy and opioid therapy from June 1, 2017, to March 31, 2018, were included. Patients receiving naldemedine were matched to control patients by propensity score. Our primary outcome was the incidence of hyperactive delirium during hospitalization, and secondary outcomes were the length of hospital stay, hospital costs, in-hospital mortality, and incidence of ileus. RESULTS: Of 34,031 patients receiving inpatient chemotherapy and opioid therapy, 1905 (5.6%) were included in the naldemedine group. After one-to-four propensity score matching, 1904 patients were included in the naldemedine group and 7616 in the control group. Naldemedine users had significantly reduced incidence of hyperactive delirium compared with the control patients (19.4% vs 23.3%; risk difference, -3.9 [95% confidence interval, -5.9 to -1.9]; risk ratio, 0.83 [0.75-0.92]; p<0.001; subdistribution hazard ratio, 0.85 [0.75-0.97]; p = 0.015). The median length of hospital stay was significantly shorter in the naldemedine group compared with the control group (12 days [interquartile range, 6-23] vs 14 days [6-26]; p = 0.001). The median hospital costs were also significantly lower in the naldemedine group compared with the control group (US $6179 [3351-10,026] vs US $6576 [3436-11,107]; p < 0.001). No significant differences were found for in-hospital mortality or incidence of ileus between the groups. CONCLUSIONS: Our findings suggest that the use of naldemedine may have benefits in preventing hyperactive delirium, shortening hospital stay, and decreasing hospital costs in cancer patients receiving chemotherapy and opioid therapy.

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.

Treatment of vincristine-induced ileus with metoclopramide: A case report.

INTRODUCTION: Acute lymphoblastic leukemia is an invasive malignancy which ought to be treated with several cytotoxic medications. Vincristine-based regimen is among the most commonly used regimens for the treatment of adult acute lymphoblastic leukemia. Peripheral neuropathy caused by vincristine provides a limitation in dose administration and can influence the treatment outcome and patient's quality of life. CASE PRESENTATION: Ileus and constipation occurred as a result of autonomic neuropathy in a 58-year-old man who underwent vincristine-based regimen for acute lymphoblastic leukemia treatment. Despite the administration of several laxative agents for constipation, the complication did not improve. So metoclopramide as a prokinetic agent was administered intravenously, and patient bowel movement and defecation started after 24 h. CONCLUSIONS: There is no approved protocol for vincristine-induced autonomic neuropathy treatment; thus, prokinetic agents such as metoclopramide can be considered as an option for ileus treatment after ruling out the possibility of bowel obstruction. Prophylactic stool softeners should be administrated in all patients undergoing chemotherapy with vincristine to prevent gastrointestinal motility disorders.

Decreased opioid consumption and enhance recovery with the addition of IV Acetaminophen in colorectal patients: a prospective, multi-institutional, randomized, double-blinded, placebo-controlled study (DOCIVA study).

BACKGROUND: We hypothesized that administration of IV acetaminophen alone would reduce the opioid consumption in post-operative colorectal surgery and reduce the side effects of narcotics. METHODS: Patients were randomized to receive either IV acetaminophen or placebo in addition to opioid PCA. Primary endpoints evaluated were opioid consumption and pain visual analogue scale score (PVASS) during first 48 h post-operatively. Secondary endpoints evaluated were time of return of GI function (ROGIF), time to diet ordered (TTDO), length of hospital stay (LOHS), and occurrence of ileus. RESULTS: 105 patients were enrolled and 97 remained in the study after exclusion (control group n = 50; study group n = 47). Mean ± SEs of opioid consumption in the study group was 21.5 ± 1.8 mg of morphine equivalent (ME) and 35.0 ± 3.3 mg ME at 24 and 48 h, respectively, versus 36.4 ± 4.1 mg ME and 59.7 ± 6.7 mg ME in the control group (p = 0.002 and 0.002). PVASS levels were lower in the study group at all intervals at 3, 8, 24, and 48 h (p = 0.02, 0.006, < 0.01, and 0.02). ROGIF, TTDO, and LOHS were also found to be lower in the study group (p ≤ 0.01, < 0.01, and 0.002). The rate of ileus was reduced by using IV acetaminophen (22% vs 2.1%; p = 0.004). CONCLUSIONS: IV acetaminophen helps to reduce opioid consumption for patients undergoing colorectal surgery. Additionally, there appears to be a shortened length of hospital stay, better pain control, reduced time to return of bowel function, and lower rate of post-operative ileus in patients receiving IV acetaminophen.

Postoperative complications of pediatric patients with inflammatory bowel disease treated with vedolizumab.

BACKGROUND: Vedolizumab is a biologic, which inhibits leukocyte adhesion in the gut and is used to treat ulcerative colitis (UC) and Crohn's disease (CD). Little is known of the surgical outcomes in patients treated with vedolizumab. We reviewed the postoperative complications in a cohort of pediatric UC and CD patients treated with vedolizumab. METHODS: We identified pediatric UC and CD patients treated with vedolizumab at our institution from 2014 to 2016. We compared postoperative outcomes in the vedolizumab exposed group to a cohort of vedolizumab naïve patients who required diverting ileostomy. RESULTS: Of the 31 patients who were treated with vedolizumab, 13 patients required surgery. Eight of 13 (62%) vedolizumab exposed patients had a postoperative complication, including mucocutaneous separation at the stoma (3), readmission for pain/dehydration (2), bowel obstruction at the ostomy, and intraoperative colonic perforation. In comparison, four of 16 (25%) vedolizumab naive patients had a postoperative complication, including readmission for ileus and for high stoma output with mucocutaneous separation. p=0.07. CONCLUSIONS: At our institution, patients treated with vedolizumab prior to surgery have a high prevalence of postoperative complications, notably mucocutaneous separation of the stoma. A prospective, multicenter study is needed to determine if these observed complications are attributable to vedolizumab. LEVEL OF EVIDENCE: Level III.

Comparison of the effects of patient-controlled epidural and intravenous analgesia on postoperative bowel function after laparoscopic gastrectomy: a prospective randomized study.

BACKGROUND: Although laparoscopic surgery significantly reduces surgical trauma compared to open surgery, postoperative ileus is a frequent and significant complication after abdominal surgery. Unlike laparoscopic colorectal surgery, the effects of epidural analgesia on postoperative recovery after laparoscopic gastrectomy are not well established. We compared the effects of epidural analgesia to those of conventional intravenous (IV) analgesia on the recovery of bowel function after laparoscopic gastrectomy. METHOD: Eighty-six patients undergoing laparoscopic gastrectomy randomly received either patient-controlled epidural analgesia with ropivacaine and fentanyl (Epi PCA group) or patient-controlled IV analgesia with fentanyl (IV PCA group), beginning immediately before incision and continuing for 48 h thereafter. The primary endpoint was recovery of bowel function, evaluated by the time to first flatus. The balance of the autonomic nervous system, pain scores, duration of postoperative hospital stay, and complications were assessed. RESULTS: The time to first flatus was shorter in the epidural PCA group compared with the IV PCA group (61.3 ± 11.1 vs. 70.0 ± 12.3 h, P = 0.001). Low-frequency/high-frequency power ratios during surgery were significantly higher in the IV PCA group, compared with baseline and those in the epidural PCA group. The epidural PCA group had lower pain scores during the first 1 h postoperatively and required less analgesics during the first 6 h postoperatively. CONCLUSIONS: Compared with IV PCA, epidural PCA facilitated postoperative recovery of bowel function after laparoscopic gastrectomy without increasing the length of hospital stay or PCA-related complications. This beneficial effect of epidural analgesia might be attributed to attenuation of sympathetic hyperactivation, improved analgesia, and reduced opioid use.

Opioid-related side effects: Postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature.

Opioids are widely used in clinical anesthesia. However, side effects include postoperative nausea and vomiting, shivering, ileus, and urine retention and are specifically discussed here. From the available evidence, it appears that the use of opioids is strongly associated with impaired gastrointestinal motility. Therefore, to prevent postoperative ileus, the use of opioids should be minimized and opioids should be replaced by other drugs. With regard to the risk of postoperative urinary retention, one problem is the lack of standardized definition. Nevertheless, the use of opioids is clearly an important risk factor. Postoperative nausea and vomiting have high incidences. Even if the mechanisms are partially understood, opioid-sparing strategies have been shown to decrease its incidence. Finally, the problem of postoperative shivering has been, at least partially, solved by the avoidance of (high doses) remifentanil and the use of alpha-2 agonists. In conclusion, postoperative urinary retention, postoperative ileus, nausea and vomiting, and shivering are complex problems seen after surgery. Management is possible, but prevention is possible with the avoidance of high doses of intraoperative opioids, conjointly to opioid-sparing techniques.

Toxicity of intraperitoneal chemotherapy and risk factors for severe toxicity in optimally debulked ovarian cancer patients.

OBJECTIVE: To assess the effect and toxicity of intraperitoneal (IP) chemotherapy for epithelial ovarian cancer and to determine the risk factors for severe toxicity. MATERIALS AND METHODS: Patients who received IP chemotherapy after optimal debulking surgery for ovarian cancer between 2006 and 2012 were retrospectively reviewed. Clinical characteristics were compared between patients with none/Grade 1 or Grade 2 toxicity and those with Grade 3 or Grade 4 toxicity. RESULTS: In 41 patients, the mean number of IP cycles administered was 5.6 and most patients (80.5%) completed at least six cycles. The reasons for discontinuation were catheter-related problems (30%), disease progression (20%), or drug-related adverse effects (30%). Grade 3 or Grade 4 toxicity was observed in 30 patients (73.2%). The rate of neoadjuvant chemotherapy was higher in the patients with Grade 3 or Grade 4 toxicity (37%) than in the patients without Grade 3 or Grade 4 toxicity (9%), however, this difference was not significant (p = 0.128). During a mean follow-up period of 33.6 months, tumor recurrence occurred in 20 (48.8%) patients and the median progression-free survival was 30.0 months. CONCLUSION: Despite the high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer. Toxicity should be closely monitored in patients who have received neoadjuvant chemotherapy until a large prospective study can be performed to determine its influence.

Adynamic ileus and diarrhoea: a rare adverse effect of antidepressants.

Antidepressants can cause a variety of gastrointestinal effects, including nausea, dyspepsia, anorexia, constipation, and, rarely, diarrhoea and adynamic ileus. There is a lack of cases associating antidepressants to adynamic ileus and diarrhoea. We report a case of an elderly woman in whom the use of several antidepressants apparently induced adynamic ileus with diarrhoea.

Phase I study of pegylated liposomal doxorubicin in combination with bortezomib for Japanese patients with relapsed or refractory multiple myeloma.

This phase I open-label study evaluated the tolerability of pegylated liposomal doxorubicin (PLD) and bortezomib combination in Japanese patients with relapsed or refractory multiple myeloma. Eligible patients (≥20 years) who had ≥1 line of prior chemotherapy received bortezomib 1.3 mg/m(2) rapid intravenous infusion on days 1, 4, 8 and 11 (each 21-day cycle), followed by PLD 30 mg/m(2) intravenous infusion on day 4 (each cycle), up to 6 cycles. Dose-limiting toxicity (DLT), defined as Grade 4 hematologic or Grade ≥3 non-hematologic, was evaluated through end of day 21. All three patients enrolled in the study developed DLTs [Grade 4 thrombocytopenia (n = 2) and Grade 3 ileus (n = 1)]. The study was, therefore, terminated without adding new patients, as per protocol-specified criteria. The most common Grade 3-4 adverse events (AEs) were hematologic, including thrombocytopenia, leucopenia, and neutropenia. The treatment was prematurely discontinued in all three patients due to AEs: Grade 3 bronchiolitis (serious AE), Grade 3 peripheral sensory neuropathy, and Grade 2 stomatitis. All patients achieved partial response (efficacy, secondary endpoint). In conclusion, the tolerability of PLD and bortezomib combination at dose levels approved in various countries was not confirmed in relapsed or refractory multiple myeloma patients from Japan.

[Small bowel obstruction caused by immunosuppressive therapy after a liver transplant].

This case report describes an extremely rare cause of small bowel obstruction. A female patient who was liver transplanted seven years earlier and had been in immunosuppressive therapy since then presented with clinical and radiological manifest small bowel obstruction and surgery followed. The surgical finding was a segment near the terminal ileum with three separate stenoses in which the most oral was causing the obstruction. Histology evaluation of the stenoses revealed infiltration of lymphoid tissue and the stenoses tested positive on Epstein-Barr virus. The patient was later confirmed to be suffering from post-transplant lymphoproliferative disease.

[A case of small intestinal lymphoma with ileus requiring surgery during chemotherapy].

Perforation, bleeding, and ileus are known complications of small intestinal lymphoma and can occur either at diagnosis or during the course of treatment. Surgery is an important component in the management of these gastrointestinal complications. However, there is no consensus regarding the indications for and timing of surgery in small intestinal lymphoma. We herein present our experience with a case of small intestinal lymphoma with ileus that required surgery during chemotherapy. A 69-year-old man developed abdominal pain. Computed tomography revealed lower right jaw lymphadenopathy, small intestinal wall thickening, and mesenteric lymphadenopathy. Malignant lymphoma (diffuse large B-cell type) was diagnosed on the basis of a lower jaw lymph node biopsy. The patient was initially administered chemotherapy. After the third cycle of chemotherapy, the patient developed small intestinal obstruction detected upon abdominal computed tomography. Because a stricture persisted despite medical treatment, we performed partial resection of the small intestine. The postoperative course was good, and the patient rapidly resumed chemotherapy. Currently, 6 months after the surgery, the patient is alive without any progression of the lymphoma. A multidisciplinary treatment strategy, including surgery, is desirable to achieve a safe but radical cure for small intestinal lymphoma.

Clinical and economic burden of opioid use for postsurgical pain: focus on ventilatory impairment and ileus.

Opioid-related adverse drug events (ORADEs) can have a significant impact on patient recovery after surgery. This review investigates the impact of two ORADEs, respiratory depression and postoperative ileus (POI), on clinical and economic outcomes. Opioid-induced ventilatory impairment is a potentially serious ORADE that can result in apnea and even death. The incidence of ventilatory impairment is approximately 1%, even among patients receiving opioids using patient-controlled analgesia. Costs are increased in patients treated with opioids who are at high risk of ventilatory impairment due to the need for more intensive monitoring from nursing staff and the use of alarmed monitoring equipment. Opioids, together with other factors, contribute to the development of POI through a direct effect on gut motility. Postoperative ileus has been shown to significantly increase hospital length of stay and cost of care. A key determinant of ileus development, as well as length of stay and costs, is postsurgical opioid dose. Data from a retrospective analysis show that a daily hydromorphone dose of 2 mg/day markedly increases the risk of POI. In addition, although the incidence of POI is reduced in patients who undergo laparoscopic surgery or hand-assisted laparoscopic surgery compared with open surgery, the reduction of POI can potentially be negated by excessive opioid use. Therefore, multimodal, opioid-sparing strategies should be explored and used to reduce severe ORADEs and improve outcomes in the surgical setting.