Gastroparesis as a significant gastrointestinal adverse event during intensive chemotherapy for solid cancer

Proper management of chemotherapy-related gastrointestinal toxicities is essential to maximize therapeutic outcome for malignancies. Gastroparesis is characterized by delayed gastric emptying without gastrointestinal obstruction. Although it has not been well recognized as a complication of chemotherapy for solid malignancies, we here report a case of gastroparesis apparently due to neurotoxicity of high-intensity taxane- and platinum-based chemotherapy for a solid tumor. The patient experienced late-onset gastric dysmotility as evidenced by an abnormally dilated stomach even after cessation of feeding for several days. The gastroparesis was successfully controlled with a 5-HT4 receptor agonist, resulting in recovery of gastric motility and allowing completion of curative anticancer treatment. Despite its rarity in patients with solid cancers, gastroparesis should be recognized as a potential cause of persistent upper abdominal symptoms during neurotoxic chemotherapy in such individuals, given that a delay in its management may be detrimental to survival outcome.

Outcomes of Non-anesthesiologist-Administered Propofol in Pediatric Gastroenterology Procedures

Background and Aims: Non-anesthesiologist-administered propofol (NAAP) has been found to have an acceptable safety profile in adult endoscopy, but its use remains controversial and pediatric data is limited. Our aim was to examine the safety and efficacy of NAAP provided by pediatric hospitalists in pediatric endoscopy.Methods: We retrospectively reviewed 929 esophagogastroduodenoscopy (EGD), colonoscopy, and combined EGD/colonoscopy cases in children aged 5–20 years between April 2015 and December 2016 at a large children's hospital. We analyzed the data for adverse events in relation to demographics and anthropometrics, American Society of Anesthesiologists physical classification score, presence of a trainee, comorbid conditions, and procedure time.Results: A total of 929 cases were included of which 496 (53%) were completed with NAAP. Seventeen (3.4%) of NAAP cases had an adverse event including the following: 12 cases of hypoxia, 2 cardiac, and 3 gastrointestinal adverse events. General anesthesia cases had 62 (14.3%) adverse events including the following: 54 cases of hypoxia, 1 cardiac, 7 gastrointestinal, and 1 urologic adverse event. No adverse events in either group required major resuscitation. NAAP vs. general anesthesia had a lower overall adverse event rate (3.4 vs. 14.3%, p < 0.0004) and respiratory adverse event rate (2.4% vs. 12.5%, p < 0.0004). Overall, cardiac and gastrointestinal adverse event rates between the two groups were comparable. When accounting for all captured factors via logistic regression, both younger age (P < 0.001) and general anesthesia (P < 0.0001) remained risk factors for an adverse event.Conclusion: The overall adverse event rate of NAAP was low (3.4%) with none requiring major resuscitation or hospitalization. This is comparable to studies of NAAP in adult endoscopy and suggests that NAAP provided by pediatric hospitalists has an acceptable safety profile.

The Efficacy and Safety of Bisphosphonates for Osteoporosis in Women Older Than 65 Years: A Meta-Analysis

Background: Osteoporosis presents a major threat to the health of women older than 65 years. Bisphosphonates (BPs) are now the principal class of medications for osteoporosis. Objective: To evaluate the efficacy and safety of BPs in women older than 65 years. Methods: A comprehensive search in the PubMed, EMBASE, Web of Science and Cochrane Central databases was undertaken for randomized controlled trials (RCTs) on the efficacy and safety of BPs in women older than 65 years. The primary outcome measures were the change in bone mass density (BMD), serum bone turnover marker levels, fracture rate and the adverse effect (AE) rate. The final search was performed in August 2019. Results: Seven RCTs were included. A total of 23287 patients met the inclusion criteria. BPs significantly increased the BMD of the posteroanterior (PA) spine, lateral spine and femoral neck, and reduced the fracture, vertebrate fracture and hip fracture rates in women older than 65 years. In addition, BPs increased the risks for pyrexia, myalgia, arthralgia, headache and influenza-like symptoms and had no statistical effect on any AEs, any serious AEs, discontinuation due to AEs, oesophagitis, any upper gastrointestinal adverse event, atrial fibrillation and myocardial infarction occurrence in women older than 65 years. Finally, intravenous BPs reduced hip fracture risk but increased AEs in women older than 65 years. Conclusion: Despite the fact that AEs significantly increased after drug delivery, BPs are highly effective and safe for managing osteoporosis in women older than 65 years. Zoledronic acid caused an increased rate of AEs in women older than 65 years, but these AEs seemed to be mild to moderate. In addition, the hip fracture rate in women older than 80 years old treated with BPs was different than that in the other included patients. Therefore, doctors may prescribe BPs for women older than 65 years in order to increase BMD, and AEs and hip fractures in women older than 80 years should be given attention.

Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study

Background This study evaluated the efficacy, safety and tolerability of the novel inhaled phosphodiesterase-4 inhibitor CHF6001 added-on to formoterol in patients with chronic obstructive pulmonary disease (COPD). Methods Randomised, double-blind, placebo- and active-controlled, parallel-group study. Eligible patients had symptomatic COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 30–70% predicted, and history of ≥1 moderate/severe exacerbation. Patients were randomised to extrafine CHF6001 400, 800, 1200 or 1600 μg twice daily (BID), budesonide, or placebo for 24 weeks. Primary objectives: To investigate CHF6001 dose-response for pre-dose FEV1 after 12 weeks, and to identify the optimal dose. Moderate-to-severe exacerbations were a secondary endpoint. Results Of 1130 patients randomised, 91.9% completed. Changes from baseline in pre-dose FEV1 at Week 12 were small in all groups (including budesonide), with no CHF6001 dose-response, and no significant treatment–placebo differences. For moderate-to-severe exacerbations, CHF6001 rate reductions versus placebo were 13–28% (non-significant). In post-hoc analyses, CHF6001 effects were larger in patients with a chronic bronchitis phenotype (rate reductions versus placebo 24–37%; non-significant), and were further increased in patients with chronic bronchitis and eosinophil count ≥150 cells/μL (49–73%, statistically significant for CHF6001 800 and 1600 μg BID). CHF6001 was well tolerated with no safety signal (including in terms of gastrointestinal adverse events). Conclusions CHF6001 had no effect in the primary lung function analysis, although was well-tolerated with no gastrointestinal adverse event signal. Post-hoc analyses focused on exacerbation risk indicate specific patient subgroups who may receive particular benefit from CHF6001. Trial registration ClinicalTrials.gov (NCT02986321). Registered 8 Dec 2016.

ARISTOTLE: A phase III trial comparing concurrent capecitabine with capecitabine and irinotecan (Ir) chemoradiation as preoperative treatment for MRI-defined locally advanced rectal cancer (LARC).

4101 Background: Phase II studies reported high pathological complete response (pCR) rates and acceptable toxicity using irinotecan and fluoropyrimidine chemoradiation in LARC (ISRCTN:09351447). Methods: This phase III, multicentre, open-label trial funded by Cancer Research UK, randomly assigned (1:1) patients with MRI defined LARC threatening or involving resection margins without metastases, to pre-operative radiotherapy (RT) 45Gy/25 fractions combined with either capecitabine 900mg/m2(CRT) or 650 mg/m2 bd weekdays with Irinotecan iv once-weekly 60mg/m2 weeks 1-4 (IrCRT). The primary endpoint is disease-free survival (DFS). Secondary endpoints include treatment compliance, safety and pCR. Results: 75 UK sites randomised 564 eligible patients from Oct/11 to July/18; 284 to CRT and 280 to IrCRT. 370 (66%) male; median age 61 years (range:29-83). Staging in both arms was similar: mrT3 (432/564(77%), mrT4 (89/564(16%); mrCRM involved (275/564(49%); threatened ≤1mm (215/564(38%). Compared with CRT, IrCRT patients were less likely to receive 45Gy RT (207/276(75%) vs 251/283(89%), p < 0.001) or receive ≥90% capecitabine dose in 188/276(68%) vs 253/283(89.4%)p < 0.001). A total of 204/276(74%) received ≥90% irinotecan dose. The grade 3-4 gastrointestinal adverse event rate was 21%(58/276) with IrCRT and 12%(34/283) with CRT (p = 0.004). Patients receiving IrCRT had significantly more diarrhoea 38/276(13.8%) vs 10/283(3.5%)p < 0.001) and neutropenia 27/276(9.8%) vs 3/283 (1.1%) p < 0.001). Two CRT and three IrCRT patients experienced a treatment related death. 237/276(86%) IrCRT and 241/283(85%) CRT patients had surgery. The median time from end of RT to surgery(10.6 weeks), the surgical procedure APE 262/478(55%), AR 189/478(40%), Hartmann’s 10/478(2%); and the surgical complications(any event) 38%(181/478) were similar in both arms. The pCR rate is available in > 95% patients and is 20.2%(46/228) for IrCRTvs.17.4%(40/230) for CRT (p = 0.45), A > 84% CRM-ve resection rate is similar in both arms. Conclusions: For patients with MRI defined high risk LARC low rates of CRM involvement were observed in both arms reflecting high quality multidisciplinary care. The addition of irinotecan did not significantly improve the pCR rate, was associated with a decrease in the RT and capecitabine compliance and a higher rate of adverse events. Surgical procedure or complications were unaffected. Longer follow-up is required to assess DFS and translational data. Clinical trial information: 09351447 .

Lymphocytic colitis in the setting of teriflunomide use for relapsing multiple sclerosis

Teriflunomide is an oral monotherapy used to treat relapsing multiple sclerosis. Although teriflunomide may be associated with gastrointestinal symptoms, these events are mild and self-limiting. We present a 39-year-old female who developed severe diarrhea and lost 20 pounds within 3 weeks of starting teriflunomide. Despite discontinuing teriflunomide and undergoing cholestyramine washout, her symptoms persisted. Celiac disease on genetic testing was positive, but no anti-transglutaminase and anti-endomysial antibodies were detected. She underwent colonoscopy and biopsy was consistent with lymphocytic colitis. Remission was achieved within days of starting budenoside. Our case describes a rare, but serious, gastrointestinal adverse event of teriflunomide.

1371. Safety, Tolerability, and Pharmacokinetics of Multiple Doses of TP-6076, a Novel, Fully Synthetic Tetracycline, in a Phase 1 Study

Background TP-6076 is a novel, fully synthetic tetracycline being developed for the treatment of serious bacterial infections, including those caused by multidrug-resistant Acinetobacter baumannii. TP-6076 has demonstrated potent activity in vitro against carbapenem-resistant strains of A. baumannii, with MIC90 64 times lower compared with tigecycline and 256 times lower compared with minocycline. We now report the results of a multiple ascending dose study in normal healthy volunteers. Methods This was a phase 1, single-site, randomized, double-blind, placebo-controlled dose-escalating, multiple dose study in healthy adults who met the inclusion/exclusion criteria and provided informed consent prior to any study procedure. Cohorts of eight subjects each (six active and two placebo) received daily doses of 6.0 to 40.0 mg TP-6076 or placebo for 7 days. Plasma and urine samples for pharmacokinetic (PK) analyses were collected starting immediately prior to dosing until 96 hours after the last dose. Safety was assessed through collection of adverse events (AEs), clinical laboratories, vital signs, ECG, and physical examination data. Results The geometric mean derived PK parameters for TP-6076 were: There were no serious or severe AEs reported. The most frequently reported AEs were gastrointestinal events, including nausea and vomiting, and localized infusion site reactions. There were no clinically significant changes in clinical laboratory values, ECG parameters, or physical examination findings. Conclusion Following multiple IV doses of TP-6076, plasma exposure increased as dose increased. Multiple IV doses of TP-6076 were generally well tolerated, with higher gastrointestinal adverse event rates in the higher dose groups. Disclosures L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. A. Moore, Tetraphase Pharmaceuticals: Employee, Salary.