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Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008–000625–19, and ClinicalTrials.gov, number NCT01288794. From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40–0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3–4 non-liver related adverse events. In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. Italian Medicine Agency.

Background Thiazide or thiazide-like diuretics associated hyponatremia (TAH) has a high prevalence in hospitalized patients. Patients might present either with hypovolemic hyponatremia due to volume loss as a diuretic effect of thiazide or with a thiazide-induced syndrome of inadequate antidiuresis-like hyponatremia in need of fluid restriction. Sodium-based urine indices are usually not able to differentiate these two, being directly influenced by thiazide itself. Current guidelines suggest the use of clinical hydration status assessment in patients with TAH, but this approach has a poor diagnostic performance. In a retrospective analysis, we found apparent strong ion difference (aSID) as well as chloride and potassium levels in urine (ChU) to be helpful in the differential diagnosis of TAH. Methods This is a randomized (1:1 ratio) controlled, superiority, parallel-group single-center trial. In total, 136 participants with TAH < 130 mmol/l will be enrolled and randomly assigned to undergo either aSID/ChU-guided therapy of TAH or standard of care during hospitalization. At baseline, hydration status will be assessed by history/clinical examination and ultrasound. The primary outcome is the percentage of patients with an increase in serum sodium level > 4 mmol/l at day 1 or > 134 mmol/l in a maximum of 3 days in the aSID/ChU guided therapy group as compared to the standard care group. Discussion This study will prospectively investigate whether the implementation of 2 new diagnostic indices (aSID and, if inconclusive, ChU) allows for a correct treatment of TAH. As a secondary outcome, the performance of clinical and ultrasound-guided hydration status assessment will be investigated. Trial registration ClinicalTrials.gov, identifier: NCT06381934 . Registered on 19 April 2024. www.kofam.ch , identifier: SNCTP 000005848/BASEC2024-00335.

Introduction The prevalence of epilepsy increases in elderly patients aged > 65 years, and treatment is challenging because clinical data are limited. Objective Our objective was to evaluate the safety of eslicarbazepine acetate (ESL) in patients aged ≥ 65 years versus non-elderly patients with focal seizures. Methods The safety data of seven phase II and III, double-blind, open-label, randomized clinical studies of ESL in adults were pooled. At least possibly related treatmentemergent adverse events (TEAEs) and ESL post-marketing adverse drug reactions (ADRs) were analyzed separately by age categories. Results The most frequently reported at least possibly related TEAEs in elderly ( N  = 120) versus non-elderly patients ( N  = 1863) were dizziness (10.8 vs. 20.3%), somnolence (9.2 vs. 12.6%), and hyponatremia (6.7 vs. 1.5%). Elderly patients presented a higher incidence of serious TEAEs (22.5 vs. 7.6%) and at least possibly related serious TEAEs (6.7 vs. 2.5%), probably because treatment was complicated by comorbidities and comedications. After an estimated cumulative exposure of over 2 million patient-months worldwide and 8 years of post-marketing surveillance, hyponatremia was the most frequently reported ADR ( n  = 232), accounting for 14.6% and 6.8% of the ADRs reported in elderly ( n  = 473) and non-elderly patients ( n  = 2406), respectively. This was followed by ADR/safety information such as drug–dose titration not performed (7.0 vs. 5.4%), product use in unapproved indication (4.9 vs. 1.9%), off-label use (3.4 vs. 2.2%), dizziness (3.4 vs. 3.5%), and seizure (2.1 vs. 5.8%). Conclusion No specific safety issue was identified from the pooled studies for elderly compared with non-elderly patients. After 8 years of post-marketing surveillance, the qualitative safety of ESL remains similar to that observed in the clinical studies.

Purpose To compare the toxicity and clinical efficacy of TL (docetaxel + lobaplatin) induction chemotherapy combined with lobaplatin concurrent chemoradiotherapy and TPF (docetaxel + cisplatin + 5-fluorouracil) induction chemotherapy combined with cisplatin concurrent chemoradiotherapy in the treatment of locally advanced head and neck squamous cell carcinoma. Methods and patients In total, 128 patients with locally advanced head and neck cancer were prospectively enrolled between August 2016 and April 2021. They were randomly divided into trial group and control group, all using chronological dosage mode. The trial group used TL regimen induction chemotherapy combined with lobaplatin concurrent chemoradiotherapy; the control group used TPF regimen induction chemotherapy and cisplatin concurrent chemotherapy. The endpoints were adverse events and survival rates at 1, 3 and 5 years. Results Median follow-up was 42 months (20–71 months). (1) Adverse events: During induction chemotherapy, compared with TPF group, grade 3–4 leukocytes and neutrophils, diarrhea, 1–2 hyperbilirubinemia, nausea / vomiting, oral mucositis, fatigue, anorexia, hyponatremia were significantly lower in TL group ( p <0. 05): 6% vs. 35%, 14% vs. 53%, 0% vs. 6%, 15% vs. 40%, 9% vs. 56%, 0% vs. 10%, 3% vs. 13%, 2% vs. 23%, 15% vs. 74%. During chemoradiotherapy, the incidence of hyponatremia, hypokalaemia and grade 1–2 nausea was significantly lower in the TL group ( p <0. 05), with 24% vs. 69%, 20% vs. 65% and 24% vs. 44%, respectively. However, more grade 3–4 thrombocytopenia were observed in the TL group (15% vs. 3%, p <0. 05). (2) There was no significant difference in the recent objective response rate (ORR) between patients with TL group and TPF group ( p =0.961). (3) There was no statistical difference in 1, 3 and 5 years OS between TL group and TPF group, respectively, (71.0% vs. 67.5%, p =0.573), (56.6% vs. 56.9%, p =0.814), (52.5% vs. 52.9%, p =0.841); 1, 3 and 5 years PFS are: (63.4% vs. 64.0%, p =0.883), (51.1% vs. 54.0%, p =0.705) and (47.3% vs. 45.9%, p =0.887), None of them were significantly different. Multivariate analysis of COX regression showed that T stage ( p =0.01) and surgery ( p =0.046) were independent factors affecting PFS and OS, respectively. OS subgroup analysis shows that people receiving the TL regimen in postoperative and nodal stage N1 and N2 patients tended to survive longer than those receiving the TPF regimen. Conclusion Patients with postoperative, N1 or N2 stage locally advanced head and neck squamous cell carcinoma (HNSCC) may have more significant clinical benefits when treated with TL regimen. TL regimen has advantages in reducing toxic side effects and can be used as one of the first-line treatment options. Trial registration ClinicalTrials.gov (No. NCT03117257).

Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40–60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m2 on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40–60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m2 on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3–57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7–79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4–60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3–4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. Taiho Pharmaceutical.

PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose, describe dose-limiting toxicities (DLT) and characterize the pharmacokinetic profile of PTC299 in children with recurrent CNS tumors. PTC299 was administered orally twice or three times daily, depending on the regimen. Four regimens were evaluated using the rolling 6 design, starting with 1.2 mg/kg/dose twice daily and escalating to 2 mg/kg/dose three times daily. Pharmacokinetic studies were performed during the first two courses. Twenty-seven children (14 male, median age 11.2, range 5.5–21 years) with recurrent brain tumors were treated; 21 were fully evaluable for toxicity assessment. Therapy was well-tolerated, and the only DLT was grade 3 hyponatremia. Grade three and grade four toxicities were uncommon in subsequent cycles. Median AUC 0–Tlast values at the 2 mg/kg were similar to those observed in adults. The study was terminated while patients were being treated at the highest planned dose, due to hepatotoxicity encountered in the ongoing adult phase I studies. No complete or partial responses were observed. Two patients with low-grade gliomas were noted to have minor responses, and at the time of the study’s closure, 5 children with low-grade gliomas had been on therapy for 8 or more courses (range 8–16). PTC299 was well-tolerated at the highest dose level tested (2 mg/kg/dose TID) in children with recurrent brain tumors and prolonged disease stabilization was seen in children with low-grade gliomas.

It is a common practice to administer 4.3% dextrose in 0.18% saline peri-operatively and for routine fluid maintenance in the paediatric age group. Concerns have been expressed about the risk of hyponatraemia associated with the administration of hypotonic intravenous fluids, hence the need to re-evaluate our practice. This study aims to evaluate the relative incidence of intra-operative hyponatraemia following the use of isotonic and hyopotonic intravenous fluids. This randomised double-blind clinical trial recruited consecutive American Society of Anaesthesiologists physical status Class I and II children aged between 6 months and 17 years scheduled for various minor elective surgical procedures. The patients received one of 3 intravenous infusions for intra-operative fluid management. Group I received 4.3% dextrose in 0.18 saline (n = 25), Group II received normal saline (n = 20) and Group III received Ringer's lactate (n = 20). Blood samples were collected before the surgery and at the end of surgery for serum electrolytes. One patient in each group developed moderate hyponatraemia intraoperatively. This constituted a 4% (1/25) incidence of intra-operative hyponatraemia among patients who had hypotonic maintenance fluid and a 5% (2/40) incidence in the isotonic maintenance groups. The incidence of hyponatraemia was therefore comparable between patients who had hypotonic and isotonic intra-operative maintenance fluids (P = 1.000). We conclude that healthy children who have intraoperative hypotonic maintenance fluids during minor elective surgeries are not exposed to the additional risk of hyponatraemia compared to those who have isotonic fluids. The study of a larger sample size is recommended to further validate our findings.

Purpose The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer. Methods Patients received continuous, once-daily oral doses of cediranib 20 mg in combination with either cisplatin (60 mg/m 2 iv day 1) plus S-1 (40–60 mg bid, days 1–21) every 5 weeks for a maximum of eight cycles [Arm A]; or cisplatin (80 mg/m 2 iv, day 1) plus capecitabine (1,000 mg/m 2 bid, days 1–14) every 3 weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21 days of cycle 1. Results Fourteen patients (Arm A, n  = 6; Arm B, n  = 8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n  = 13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n  = 1; Arm B, n  = 2) partial responses that were ongoing at data cut-off. Conclusions Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.

Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer. We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9–14·3). 11 (17%, 95% CI 10–28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths. Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. Ono Pharmaceutical, Bristol-Myers Squibb.

Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1–2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.