Evaluation of factors associated with clinically problematic hiccups in cisplatin-containing treatment with dexamethasone and neurokinin 1 receptor antagonists.

Trifluridine/tipiracil (FTD/TPI) frequently induces chemotherapy-induced nausea and vomiting (CINV). As evidence of factors associated with CINV in oral chemotherapeutic agents is limited, we aimed to assess factors for nausea development in a real-world FTD/TPI-containing treatment for metastatic colorectal cancer (mCRC). Patients with mCRC receiving FTD/TPI with or without bevacizumab (n = 104) were retrospectively evaluated. Nausea occurred in 40.4% of the patients, and the severity was grade 1 for 23.1%, grade 2 for 15.4%, and grade 3 for 1.9%. Multivariable logistic regression analysis suggested that female sex (adjusted odds ratio 2.74, 95% confidence interval 1.02–7.33, p = 0.045) and concomitant bevacizumab (2.68, 1.13–6.37, p = 0.03) were independent risk factors for all-grade nausea during the first cycle as a primary endpoint. Particularly, among patients with FTD/TPI monotherapy, females significantly exhibited nausea compared to males. Our study revealed that concomitant bevacizumab and female sex are independent risk factors for nausea in FTD/TPI-containing treatment for mCRC.

To identify mortality trends and risk factors associated with stillbirths and neonatal deaths 1982-2011. Population-based cross-sectional study based on reported pregnancy history in Iganga-Mayuge Health and Demographic Surveillance Site (HDSS) in Uganda. A pregnancy history survey was conducted among women aged 15-49 years living in the HDSS during May-July 2011 (n = 10 540). Time trends were analysed with cubic splines and linear regression. Potential risk factors were examined with multilevel logistic regression with adjusted odds ratios (AOR) and 95% confidence intervals (CI). 34 073 births from 1982 to 2011 were analysed. The annual rate of decrease was 0.9% for stillbirths and 1.8% for neonatal mortality. Stillbirths were associated with several risk factors: multiple births (AOR 2.57, CI 1.66-3.99), previous adverse outcome (AOR 6.16, CI 4.26-8.88) and grand multiparity among 35- to 49-year-olds (AOR 1.97, CI 1.32-2.89). Neonatal deaths were associated with multiple births (AOR 6.16, CI 4.80-7.92) and advanced maternal age linked with parity of 1-4 (AOR 2.34, CI 1.28-4.25) and grand multiparity (AOR 1.44, CI 1.09-1.90). Education, marital status and household wealth were not associated with the outcomes. The slow decline in mortality rates and easily identifiable risk factors calls for improving quality of care at birth and a rethinking of how to address obstetric risks, potentially a revival of the risk approach in antenatal care.

This Month in Gastroenterology

Regorafenib, a multikinase inhibitor for treating metastatic colorectal cancer (mCRC), induces fatigue in 40-50% of administered patients, including approximately 10% of grade ≥ 3 cases. Additionally, hypoalbuminemia is associated with cancer- and chemotherapy-induced fatigue and frequently observed in patients with advanced cancers. This study aimed to assess the impact of baseline hypoalbuminemia on the development of clinically problematic fatigue in a real-world regorafenib treatment for mCRC. Patients with mCRC who underwent regorafenib (n = 102) were divided into the control (baseline serum albumin levels ≥ 3.5g/dL) and hypoalbuminemia (baseline serum albumin levels < 3.5g/dL) groups, and retrospectively evaluated. The primary endpoint was comparison of grade ≥ 2 fatigue incidence during all treatment cycles. We also assessed the impact of grade ≥ 2 symptoms on the treatment efficacy. Incidence of grade ≥ 2 fatigue in all treatment cycles in the hypoalbuminemia group was 41.7%, which was significantly higher than that in the control group (14.1%, P = 0.008). In addition, grade ≥ 2 fatigue within the first cycle was significantly more confirmed in the hypoalbuminemia group than in the control group (37.5% vs. 11.5%, P = 0.01). Additionally, patients with early grade ≥ 2 fatigue within 14days from treatment initiation had a significantly shorter time to treatment failure or overall survival than those without the symptoms. Patients with baseline hypoalbuminemia developed clinically problematic fatigue after regorafenib monotherapy for mCRC. Because regorafenib is a later-line mCRC treatment, successful management of emerging fatigue is crucial and requires further evaluation.

P1.12-04 The FLARE score and circulating neutrophils are associated with poor Covid-19 outcomes in patients with thoracic cancers

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Chapter 12. Neurokinin Receptor Antagonists

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials

COVID-19 outcomes in patients waitlisted for kidney transplantation and kidney transplant recipients.

Tonic immobility (TI) is considered to be an innate fear response characterized by a temporary state of profound and reversible motor inhibition. TI occurs in a wide range of species in a predator-prey confrontation and is hypothesized to be a terminal defence response occurring when there is physical contact between prey and predator. The objective of the present study was to investigate the validity of the TI model in guinea pigs for detection of anxiolytic and/or antidepressant drug activity. Compounds that reduced TI include the serotonin (5-HT) releaser fenfluramine, the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, the 5-HT(2C/2B) receptor antagonist SB206553, the 5-HT(2A) receptor antagonist MDL 100.151 -- but only at doses thought also to inhibit 5-HT(2C) receptors--the noradrenaline (NA) reuptake inhibitor desipramine, the benzodiazepine inverse agonist FG-7142, the alpha(2)-adrenergic receptor antagonist yohimbine, the neurokinin (NK)(1) receptor antagonist L-733.060, and the NK(2) receptor antagonist SR-48968. Compounds that increased TI include the benzodiazepine agonists diazepam and alprazolam, and the alpha(2)-adrenergic receptor agonist clonidine. The selective 5-HT reuptake inhibitors citalopram, paroxetine and fluoxetine, the 5-HT(1A) receptor antagonist WAY100.635, the 5-HT(2C) receptor agonist MK-212, the 5-HT/NA reuptake inhibitor imipramine, the NA reuptake inhibitor talopram, the benzodiazepine antagonist flumazenil, the alpha(2)-adrenergic receptor antagonist idazoxan and the psychostimulant amphetamine did not have any effect. These findings indicate that the serotonergic, noradrenergic and neurokinin systems are involved in mediating or modulating TI behaviour in guinea pigs. The potential of TI as a behaviour for detecting anxiolytic-like effect may be questioned due to the contradictory effect of the benzodiazepine ligands, which may be attributed to the sedative and/or ataxic effects of the compounds. Nevertheless, there is preclinical evidence suggesting that 5-HT(1A) receptor agonists, 5-HT(2C) receptor antagonists and NK(1) and NK(2) receptor antagonists possess anxiolytic potential. Only when results of clinical investigations of the anxiolytic potential of non-benzodiazepine ligands (for example the NK receptor antagonists) are available, will it be possible to determine fully the predictive validity of the TI model.

Previous upper abdominal surgery is a risk factor for nasogastric tube reinsertion after pancreaticoduodenectomy

Evaluation of Risk Factors and Survival Effect of Delayed Excretion of High-Dose Methotrexate in Patients with Leukemia and Lymphoma

1. Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature. 2. A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK2 receptor antagonist (SR48968, 1 mM) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation. 3. Post-treatment through the microdialysis fibre with the NK1 receptor antagonist (0.01-10 mM) was effective in reversing the heat hyperalgesia. In contrast, post-treatment spinally with the NK2 receptor antagonist (0.01-1 mM) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 4. Pretreatment systemically with the NK1 receptor antagonist (30 mg kg-1) had no effect on the heat hyperalgesia or pain-related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK2 receptor antagonist (10 mg kg-1) systemically prevented the heat hyperalgesia and pain-related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 5. Post-treatment systemically with either the NK1 (0.1-30 mg kg-1) or the NK2 (0.1-10 mg kg-1) receptor antagonist resulted in a dose-dependent reversal of the heat hyperalgesia. Pain-related behaviour ratings were reduced by post-treatment only with the NK1 receptor antagonist. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses. 6. Direct pretreatment of the knee joint with either the NK1 (30 mg) or the NK2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 7. There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK2 receptors appear to be activated early in the development of the heat hyperalgesia and NK1 receptors are involved in the maintenance of the heat hyperalgesia. 8. Peripherally, both NK1 and NK2 receptors are involved in the development of heat hyperalgesia and pain-related behaviour ratings induced by acute inflammation.

Retrospective study of prospectively collected data. To determine if postoperative morbidity for patients undergoing spinal deformity surgery varies by sex. Influence of sex has been investigated in other surgical procedures but has not yet been studied in adult spinal deformity surgery. The American College of Surgeons National Surgical Quality Improvement Program is a large multicenter clinical registry that prospectively collects preoperative risk factors, intraoperative variables, and 30-day postoperative morbidity and mortality outcomes from about 400 hospitals nationwide. Current Procedural Terminology codes were used to query the database for adults who underwent fusion for spinal deformity. Patients were separated into groups of male and female sex. Univariate analysis and multivariate logistic regression were used to analyze the effect of sex on the incidence of postoperative morbidity and mortality. Female sex was found to be a predictor of any complication[odds ratio (OR): 1.4, 95% confidence interval (CI) 1.2-1.7, P < 0.0001], intra- or postoperative RBC transfusion (OR: 1.6, 95% CI 1.4-1.9, P < .0001), urinary tract infection (OR: 2.0, 95% CI 1.2-3.3, P = 0.0046), and length of stay >5 days (OR: 1.3, 95% CI 1.1-1.5, P = 0.0015). Male sex was associated with higher rate of pulmonary (2.9% vs. 2.0%, P = 0.0344) and cardiac complications (0.9% vs. 0.5%, P = 0.0497). However, male sex as an independent risk factor for pulmonary (OR: 1.4, 95% CI 1.0-2.1, P = 0.0715) and cardiac complications (OR: 1.9, 95% CI 0.9-4.0, P = 0.1076) did not reach significance. Female sex was found to increase overall morbidity, particularly for urinary tract infection, transfusion, and length of stay >5 days. Male sex was associated with greater incidence of pulmonary and cardiac complications. Thus, sex and other patient characteristics highlighted must be considered as part of surgical risk planning and patient counseling. 3.

We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.