Isolated Area Postrema Syndrome Preceding the Diagnosis of Giant Cell Arteritis: A Case Report.

OBJECTIVE: We report a case of biopsy-proven giant cell arteritis after an initial presentation of area postrema syndrome. METHODS: A 65-year-old man was evaluated using MRI, temporal artery biopsy, and ultrasound. RESULTS: The patient presented with refractory nausea, vomiting, and hiccups that caused weight loss without any other neurologic or clinical symptoms. His MRI scan 15 days later revealed a hyperintense sign on the area postrema with no abnormal diffusion or contrast enhancement, compatible with isolated area postrema syndrome. An extensive workup for inflammation and other etiologies including neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody disorder, and multiple sclerosis (MS) showed negative results. The patient responded to treatment with methylprednisolone. Two months after the initial clinical manifestation, the patient developed fatigue, headache, and scalp tenderness. He was diagnosed with giant cell arteritis after ultrasonography and biopsy were performed. He responded well to oral glucocorticoids and had only 1 relapse during tapering. He has not had arteritic ischemic optic neuropathy or any new episodes of area postrema syndrome. DISCUSSION: This case demonstrates the importance of expanding the differential diagnosis in patients with area postrema syndrome and no other signs of NMOSD.

Safety of office-based flexible endoscopic procedures of the pharynx and larynx under topical anesthesia.

INTRODUCTION: Flexible endoscopic procedures (FEP) using a working channel allowed otolaryngologists to perform more procedures on the pharynx and the larynx under local anesthesia. The purpose of this work is to demonstrate the feasibility and safety of this technique by studying the adverse effects of this practice in an office-based setting. METHODS: This is a monocentric retrospective cohort study. We searched the database using the French procedural code for FEP performed in an outpatient setting between January 2005 and December 2020. Data regarding the patient's characteristics, indications, and periprocedural complications were extracted. RESULTS: In total, we included 231 patients with a total of 308 FEP: 36% biopsy, 20% hyaluronic acid injection (including 3.5% at the level of the cavum), 20% injection of other substances (in descending order: botulinum toxin, cidofovir, physiological serum, cortisone), 20% exploration for an occult tumor, 3% samples for microbiological analysis, 1% other procedures. Of the 308 FEP included in this study, 24 patients (10.3%) had complications corresponding to 7.8% of the procedures performed. During the procedures, reported complications include minor laryngeal bleeding (n = 5), vasovagal syncope (n = 5), laryngospasm (n = 1) or nausea (n = 3), dysphagia (n = 3), and voice disorders (n = 3). Post-procedural complications were hypertensive crisis (n = 1), asthma attack (n = 1), pneumonia (n = 1), laryngitis (n = 1). Using the Clavien-Dindo classification system, these complications could be defined as grade I (laryngeal bleeding, vasovagal syncope, laryngospasm, dysphagia, nausea, voice disorders, and laryngitis) and grade II (hypertensive crisis, asthma attack, pneumonia) in 9.1% and 1.2% of cases, respectively. Most of these complications were self-limiting, while asthma attacks, pneumonia, laryngitis, and voice disorders required a medical intervention. All complications were managed without sequelae. There was no serious complication grade (no grade III, IV or V). CONCLUSIONS: FEP, which is now well standardized in our institution, makes it possible to carry out a wide range of interventions with little morbidity. These results are in line with those of literature but this technique remains out of nomenclature in France. Our experience led to the development of an evidence-based standard of care that can serve as a framework for practitioners on a nationwide level, while the work to establish official guidelines by the French society of phoniatrics and laryngology is in progress.

Efficacy and Side Effects of Irinotecan Combined with Nedaplatin versus Paclitaxel Combined with Cisplatin in Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer and Tumor Marker Analysis: Based on a Retrospective Analysis.

Objective: A case-control study was adopted to investigate the efficacy and side effects of irinotecan combined with nedaplatin (NP) versus paclitaxel combined with cisplatin for locally advanced cervical cancer (CC) neoadjuvant chemotherapy (NACT) and to analyze the changes in tumor marker levels. Methods: A total of 96 patients with locally advanced CC who were treated from October 2019 to October 2021 were enrolled in our hospital as the research subjects, and their clinical data were collected for retrospective analysis and grouped according to their treatment regimens. Among them, 53 patients received paclitaxel combined with cisplatin as the control group, and the other 43 patients received irinotecan combined with NP as the observation group. The clinical effectiveness of neoadjuvant chemotherapy and alterations in tumor markers (CEA, AFP, CA125, and SCCA) were compared between the two groups. The incidence of common chemotherapy side effects was observed and compared between the two groups, including nausea and vomiting, abdominal pain and diarrhea, liver function impairment, bone marrow suppression, transient hyperglycemia, rash, ECG abnormalities, peripheral neurotoxicity, and muscle aches and pains. Results: The clinical efficiency of neoadjuvant chemotherapy was 97.67% in the observation group and 81.13% in the control group, with no statistically significant difference between the groups (P > 0.05). There was no significant difference in CEA, AFP, and CA125 between the two groups before and after chemotherapy, but the decrease of SCCA before and after chemotherapy was statistically significant. There was no significant difference in the incidence of liver function damage, myelosuppression, abnormal ECG, and rash between the two groups (P > 0.05). There are statistically significant differences in the incidence of nausea and vomiting, transient hyperglycemia, peripheral neurotoxicity, and muscle aches between the observation and control groups (P < 0.05). The incidence of nausea and vomiting, transient hyperglycemia, peripheral neurotoxicity, and muscle aches was higher in the control group than in the observation group, with statistically significant differences (P < 0.05). The difference in the incidence of diarrhea and abdominal pain between the observation group and the control group was statistically significant (P < 0.05), and the incidence of diarrhea and abdominal pain in the observation group was higher than that in the control group. Conclusion: Irinotecan in combination with nedaplatin can be an effective neoadjuvant chemotherapy regimen for advanced localized cervical cancer, particularly in patients with combined diabetes.

SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2021)

Among the side effects of anticancer treatment, chemotherapy-induced nausea and vomiting (CINV) is one of the most feared given its high prevalence, affecting up to 40% of patients. It can impair patient’s quality of life and provoke low adherence to cancer treatment or chemotherapy dose reductions that can comprise treatment efficacy. Suffering CINV depends on factors related to the intrinsic emetogenicity of antineoplastic drugs and on patient characteristics. CINV can appear at different times regarding the administration of antitumor treatment and the variability of risk according to the different antitumor regimens has, as a consequence, the need for a different and adapted antiemetic treatment prophylaxis to achieve the desired objective of complete protection of the patient in the acute phase, in the late phase and in the global phase of emesis. As a basis for the recommendations, the level of emetogenicity of anticancer treatment is considered and they are classified as high, moderate, low and minimal emetogenicity and these recommendations are based on the use of antiemetic drugs with a high therapeutic index: anti 5-HT, anti-NK and steroids. Despite having highly effective treatments, clinical reality shows that they are not applied enough, so evidence-based recommendations are needed to show the best options and help in decision-making. To cover all the antiemetic prophylaxis options, we have also included recommendations for oral treatments, multiday regimens and radiation-induced emesis prevention.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

TRough versus AUC Monitoring of cyclosporine: A randomized comparison of adverse drug reactions in adult allogeneic stem cell recipients (TRAM study).

OBJECTIVE: To investigate the incidence and severity of adverse drug reactions of cyclosporine using AUC-targeted therapeutic drug monitoring (TDM) compared to trough level (Ctrough )-targeted TDM in adult allogeneic stem cell recipients. METHODS: Blind, monocenter, intervention study. Subjects were 1:1 randomized into either an AUC group or a Ctrough group. Adverse drug reactions were accessed two and four weeks after start of treatment. RESULTS: Forty patients were included, resulting in 15 evaluable subjects (AUC group) and 13 evaluable subjects (Ctrough group). Grade two/three toxicity was observed in 46% (Ctrough group) versus 60% of subjects (AUC group) (P = .463). There was no significant difference between two and four weeks after start of cyclosporine for nausea (P = .142 resp. P = .122), renal dysfunction (P = .464 resp. P = 1.000), and hypomagnesemia (P = 1.000 resp. P = .411). Subjects in the AUC group reached the therapeutic goal earlier (72,7% versus 43,0% at third sampling point, P = .332) and were within the target range more consistently. CONCLUSION: This study showed no reduction in incidence and severity of cyclosporine-induced toxicity with AUC- versus trough level-targeted TDM. Although modeled dosing based on AUC led to faster optimal target attainment, this did not result in less toxicity in the early days after transplantation.

Incidence of chemotherapy-induced nausea and vomiting among cancer patients receiving moderately to highly emetogenic chemotherapy in cancer centers in Sichuan, China.

PURPOSE: Nausea and vomiting are the most painful and feared side effects for patients during chemotherapy. Currently, most studies focus on the occurrence of CINV during the risk phase. We initiated this real-world study to understand the actual occurrence of CINV throughout all phases, to provide a basis to prevent CINV in patients during chemotherapy and improve their quality of life. METHODS: This prospective real-world study was conducted at 17 major cancer centers in Sichuan, China. Cancer patients who were about to receive moderately/highly emetogenic chemotherapy were included in the study. Occurrences of nausea and vomiting were recorded using patient diaries, and physicians are responsible for recording patient clinical data. RESULTS: A total of 1,139 patients were included in this study between August 2018 and April 2019. In this study, the incidence of acute CINV was 55.3%, delayed CINV was 62.3%, and CINV beyond the risk period was 36%. All phases overall, the overall complete control (CC) rate of CINV was 30.1 and 32.1% for highly and moderately emetogenic chemotherapy regimens, respectively. The median CC time for CINV was 7 days, but only 21.5% of these patients used antiemetic regimens according to the NCCN guideline. CONCLUSION: In the real world, the incidence of CINV is high in patients receiving chemotherapy, and nausea and vomiting may occur beyond the risk period; the low level of standardized antiemetic treatment in compliance with the guideline might have been the main reason for unsatisfactory prevention and control of CINV in this study.

The gut microbiome: a missing link in understanding the gastrointestinal manifestations of COVID-19?

Coronavirus disease 2019 (COVID-19), which is caused by infection with SARS-CoV-2, presents with a broad constellation of both respiratory and nonrespiratory symptoms, although it is primarily considered a respiratory disease. Gastrointestinal symptoms-including nausea, abdominal pain, vomiting, and diarrhea-rank chief among these. When coupled with the presence of viral RNA in fecal samples, the presence of gastrointestinal symptoms raises relevant questions regarding whether SARS-CoV-2 can productively infect the upper or lower gastrointestinal tract. Despite the well-documented prevalence of gastrointestinal symptoms and the high rate of SARS-CoV-2 fecal RNA shedding, the biological, clinical, and epidemiological relevance of these findings is unclear. Furthermore, the isolation of replication-competent virus from fecal samples has not been reproducibly and rigorously demonstrated. Although SARS-CoV-2 shedding likely occurs in a high proportion of patients, gastrointestinal symptoms affect only a subset of individuals. Herein, we summarize what is known about gastrointestinal symptoms and fecal viral shedding in COVID-19, explore the role of the gut microbiome in other respiratory diseases, speculate on the role of the gut microbiota in COVID-19, and discuss potential future directions. Taking these concepts together, we propose that studying gut microbiota perturbations in COVID-19 will enhance our understanding of the symptomology and pathophysiology of this novel devastating disease.

Adherence to ASCO for Prophylaxis of Acute Chemotherapy- Induced Nausea and Vomiting in Iran.

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) is one of the scariest chemotherapy-induced adverse effects. We evaluated the adherence to the 2017 American Society of Clinical Oncology (ASCO), the latest guideline recommendations, for the management of acute CINV at our institute. METHODS: During a 6-months cross-sectional study on outpatient's cancer patients, we collected data from the prescription documents during temporary hospitalization and compared the results with ASCO guideline recommendations. RESULTS: The most prescribed prophylactic regimens for the management of CINV were combination of aprepitant, granisetron, and dexamethasone and metoclopramide (51.8%). Regarding prescription compatibility in our center with ASCO guideline recommnedations, selection of different regimens for prophylaxis of acute CINV in our institute was compliant in 0 %, 22%, 4%, and 40% of high, moderate, low, and minimal emetogenic potential of chemotherapy regimen groupss, respectively. CONCLUSION: Although our hospital is a referral and university-affiliated center, adherence to the ASCO guideline recommendations for prophylaxis of CINV was poor.

Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.

Antiemetics: types, actions and uses.

Nausea and vomiting are common symptoms in the hospital setting, with numerous causes. Common precipitants leading to or complicating inpatient hospital admissions include nausea and vomiting secondary to drugs, gastrointestinal disturbances, metabolic aberrancies, and vestibular pathologies. Appropriate selection and prescribing of antiemetic drugs is therefore important for healthcare professionals. There are numerous antiemetics available to physicians, ranging from muscarinic, dopaminergic and serotoninergic drugs, each acting on a different part of the nausea-vomiting cascade. This review describes the main pathophysiological processes involved in the development of symptomatic nausea and vomiting, and gives an overview of how common antiemetic drugs function to alleviate symptoms, alongside cautions and contraindications in their usage.

Acute treatment-related toxicity in elderly patients with good performance status compared to young patients in locally advanced esophageal carcinoma treated by definitive chemoradiation: A retrospective comparative study.

INTRODUCTION: The benefit of definitive chemoradiotherapy (CRT) in elderly patients with locally advanced esophageal cancer is not well established. We perform a single institutional retrospective study of CRT in terms of toxicity in elderly patients (age more than 60 years) as compared with young cohort (age <60 years) in locally advanced nonmetastatic esophageal cancer. PATIENTS AND METHODS: A total 145 of patients, 79 in young age (Group A) and 66 patients of elder age (Group B) with Stage II and III squamous cell carcinoma of the esophagus with ECOG PS of 0-1, who had undergone definitive CRT at our institute from January 2015 to November 2018 were selected for this analysis. Chemotherapy was cisplatin (40 mg/m2) given concurrently on weekly basis with radiotherapy (RT). Total prescribed dose of RT was 50.4 Gy at the rate of 1.8 Gy per fraction. Median age was 40 years (25-60 years) and 65 years (60-75 years) in young and elderly group, respectively. Follow-up is done at median of 28 months (1-48 months) after treatment. RESULTS: Acute Grade 2-3 esophagitis was seen in 48.10% in young cohort, while it was 60.6% in older group. Grade 2-3 nausea and vomiting was seen in 32.91% in young age patients, while it was 45.5% in elder patients. No statistically significant difference is seen in acute treatment-related toxicity in young and elderly group. CONCLUSION: Our conclusion is that patients with adequate functional status should not be excluded from curative CRT based on age alone.

Quantitative electroencephalogram analysis of frontal cortex functional changes in patients with migraine.

The functional abnormality of brain areas accounting for the migraine remains to be elucidated. Most related studies have used functional magnetic resonance imaging to investigate brain areas involved in migraine. However, the results are heterogeneous. In this study, we used a convenient tool to explore the brain regions involved in migraine. In this study, 40 children with migraine and 40 sex- and age-matched health controls were enrolled, and electroencephalogram was used to explore the functional abnormal areas of migraine through electroencephalogram bands and low-resolution electromagnetic tomography analysis. The results revealed that spectrum edge frequency 50 in all electroencephalogram channels in patients with migraine were lower than those in controls. Significant differences were discovered over frontal areas. In addition, significantly higher current density over the frontopolar prefrontal cortex and orbitofrontal cortex and higher connectivity over the left prefrontal cortex were observed in patients with migraine. We suggest that functional disturbance of the prefrontal cortex may play a potential role in children with migraine, and that low-resolution electromagnetic tomography is a reliable and convenient tool for studying the functional disturbance of migraine.

Ramosetron versus Palonosetron in Combination with Aprepitant and Dexamethasone for the Control of Highly-Emetogenic Chemotherapy-Induced Nausea and Vomiting.

PURPOSE: The purpose of this study was to compare ramosetron (RAM), aprepitant (APR), and dexamethasone (DEX) [RAD] with palonosetron (PAL), APR, and DEX [PAD] in controlling highly-emetogenic chemotherapy (HEC)-induced nausea and vomiting. MATERIALS AND METHODS: Patients were randomly assigned (1:1) to receive RAD or PAD:RAM (0.3 mg intravenously) or PAL (0.25 mg intravenously) D1, combined with APR (125 mg orally, D1 and 80 mg orally, D2-3) and DEX (12 mg orally or intravenously, D1 and 8 mg orally, D2-4). Patients were stratified by sex, cisplatin-based chemotherapy, and administration schedule. The primary endpoint was overall complete response (CR), defined as no emesis and no rescue regimen during 5 days of HEC. Secondary endpoints were overall complete protection (CP; CR+nausea score < 25 mm) and total control (TC; CR+nausea score < 5 mm). Quality of life was assessed by Functional Living Index Emesis (FLIE) questionnaire on D0 and D6. RESULTS: A total of 279 patients receiving RAD (n=137) or PAD (n=142) were evaluated. Overall CR rates in RAD and PAD recipients were 81.8% and 79.6% (risk difference [RD], 2.2%; 95% confidence interval [CI], -7.1 to 11.4), respectively. Overall CP and TC rates for RAD and PAD were 56.2% and 58.5% (RD, -2.3%; 95% CI, -13.9 to 9.4) and 47.5% vs. 43.7% (RD, 3.8%; 95% CI, -7.9 to 15.5), respectively. FLIE total score ≥ 108 (no impact on daily life) was comparable between RAD and PAD (73.9% vs. 73.4%, respectively). Adverse events were similar between the two groups. CONCLUSION: In all aspects of efficacy, safety and QOL, RAD is non-inferior to PAD for the control of CINV in cancer patients receiving HEC.

Cannabinoids use in adolescents and young adults with cancer: a single-center survey.

OBJECTIVE: To present an investigation into the intake of cannabinoids in a population of adolescents and young adults with cancer. METHODS: Sixty-six patients took part in the research: 27 reported having used cannabinoids, 21 before diagnosis; among the latter, 10 increased use during treatment. RESULTS: Benefits were reported by 19% of responders regarding anxiety control, 24% for nausea, 29% for pain control and improvement of sleep, and 48% for appetite improvement. CONCLUSIONS: Cannabis use by patients may often be unknown to caregivers. Studying this subject may help to better define important therapeutic aspects of these substances.

Nausea and Vomiting: a Palliative Care Imperative.

PURPOSE OF REVIEW: This review was undertaken to survey recent literature for research reports and comprehensive clinical reviews addressing the pharmacologic management of nausea and vomiting (N&V) in advanced cancer. The goal was to integrate findings in a comprehensive article that incorporates palliative care concepts into antiemetic treatment. RECENT FINDINGS: There are few published studies of N&V in advanced cancer; such research may be limited by the multicausal nature of N&V and participant burden to patients with life-limiting disease. Most articles are written by oncologists who also specialize in palliative care, and those addressing adverse effects of drugs used as antiemetics are found in other literature. Articles addressing more novel therapies, like cannabinoids and medical marijuana, are uncommon in the oncology literature. N&V in patients with progressive or advanced cancer is often multicausal. Nausea is more common and persistent, and even mild nausea is bothersome and may cause anxiety or depression. The mechanisms of nausea and vomiting overlap, but different neural pathways constitute the final pathway for each-the brainstem for vomiting and higher brain regions for nausea. Common causes of N&V in advanced cancer include constipation, opioids, and malignant bowel obstruction. About 40% have undetermined causes and may be exacerbated by impaired gastric emptying, chemical imbalances, or other factors. Several drugs that have antiemetic effects and act at different receptors are used to palliate N&V. There is a paucity of research that supports palliative antiemetic choices, and other research is needed to define potential therapeutic strategies that capitalize on differences between nausea and vomiting.

Analyzing Apomorphine-Mediated Effects in a Cell Model for Parkinson's Disease with Partial Least Squares Structure Equation Modeling.

Genome-wide gene expression data for cell model of Parkinson's disease (PD) have considerably improved our understanding of the underlying molecular mechanisms involved in cell death during PD neurodegeneration. Apomorphine (APOM), a nonselective dopamine agonist, has been used to treat patients with advanced PD showing no response to levodopa or other dopamine agonists. Although APOM plays a role as a free radical scavenger with neuroprotective effect, it has been reported that long-term use of APOM in PD treatment brings about side effects such as nausea and orthostatic hypotension. For safe use of APOM in PD treatment, it is crucial to understand the underlying molecular mechanisms of APOM in PD. In this study, two groups of microarray data including PD cell model and APOM added PD cell model were used to survey mediation effects of APOM in PD cell model. Mediation analysis between disease genes obtained from PD cell model and drug genes obtained from APOM added PD cell model was carried out with shortest path model on KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and partial least squares structure equation modeling. Our results suggest that drug genes responding to APOM might contribute to negative regulation of disease genes by direct or indirect ways.

Spray-Dried Silica Xerogel Nanoparticles as a Promising Gastroretentive Carrier System for the Management of Chemotherapy-Induced Nausea and Vomiting.

PURPOSE: The current work aimed to develop spray-dried silica xerogel nanoparticles (SXNs) as a gastroretentive carrier for the dual delivery of chlorambucil (CHL) and granisetron hydrochloride (GR). As a low-density system, it was proposed to float over gastric fluids; allowing for the retention of CHL in the acidic medium where it is more stable while ensuring the solubility of GR. METHODS: Silica xerogels were developed by sol-gel process, using Tetraethyl orthosilicate (TEOS) water and acetic acid, followed by spray drying. SXNs were evaluated for particle size, zeta potential, entrapment efficiency (EE%), CHL and GR release after 1 hr (P1h) and after 8 hrs (P8h). The best achieved system (SXN4) was evaluated for morphology, pore diameter, total porosity, bulk density, wetting time, floating characteristics. Furthermore, the pharmacokinetics of the loaded drugs were evaluated in rats; relative to an aqueous CHL suspension containing GR. RESULTS: SXN4 system had the highest desirability (0.69); showing spherical nanoparticles (181.63 nm), negative zeta potential (-5.18 mV), promising EE% of 59.39% and 73.94% (for CHL and GR, respectively) and sustained CHL and GR release profiles characterized by low P1h (22.75% and 30.74%) and high P8h (60.36% and 99.33%), respectively. It had a mean pore diameter of 8.622 nm, a total porosity of 62.27%, a bulk density of 0.605 g/mL, a wetting time of 292 sec, zero lag time and a floating duration of at least 8 h. CONCLUSION: The prolongation in the mean residence time (MRT(0-∞)) and the promotion of the relative oral bioavailabilities of both drugs could unravel the potential of this system for the management of chemotherapy-induced nausea and vomiting.

Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Impact of age and gender on the safety and efficacy of chemotherapy plus bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies.

BACKGROUND: The phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS = 0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender. PATIENTS AND METHODS: Subgroup analyses according to age (<70 versus 70-75 years) and gender were carried out for overall response rate (ORR), progression-free survival (PFS), and AE rates. RESULTS: Of 1187 patients, 1005 (85%) were aged <70 years and 182 (15%) 70-75 years; 693 (58%) were males and 494 (42%) females. There was no evidence of interaction between age or gender and the benefit provided by the intensification of the upfront chemotherapy in terms of ORR and PFS, or the increased risk of experiencing G3/4 AEs. Elderly patients and females experienced higher rates of overall G3/4 AEs (73% versus 60%, P < 0.01 and 69% versus 57%, P < 0.01, respectively). Notably, in the FOLFOXIRI/bevacizumab subgroup, G3/4 diarrhea and febrile neutropenia occurred in 27% and 16% of elderly patients, respectively, while females reported high incidences of any grade nausea (67%) and vomiting (50%). CONCLUSIONS: The improvements in terms of ORR and PFS of FOLFOXIRI/bevacizumab versus doublets/bevacizumab are independent of gender and age, with a similar relative increase in AEs among elderly patients and females. Initial dose reductions and possibly primary G-CSF prophylaxis should be recommended for patients between 70 and 75 years old treated with FOLFOXIRI/bevacizumab, and a careful management of antiemetic prophylaxis should be considered among females.