J Clin Oncol. 2022 Nov 15:JCO2200575. doi: 10.1200/JCO.22.00575. Online ahead of print.

ABSTRACT

PURPOSE: To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low gastric or gastroesophageal junction (GEJ) adenocarcinoma.

METHODS: Patients with locally advanced or metastatic HER2-low (cohort 1, immunohistochemistry 2+/in situ hybridization-negative; cohort 2, immunohistochemistry 1+) gastric/GEJ adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 therapy naive, received T-DXd 6.4 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate by independent central review.

RESULTS: Among 21 patients enrolled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received T-DXd, and had measurable tumors at baseline. The confirmed objective response rate was 26.3% (95% CI, 9.1 to 51.2) from five partial responses in cohort 1 and 9.5% (95% CI, 1.2 to 30.4) from two partial responses in cohort 2. Thirteen patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumor size. The median overall survival was 7.8 months (95% CI, 4.7 to nonevaluable) in cohort 1 and 8.5 months (95% CI, 4.3 to 10.9) in cohort 2; the median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively. The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient in each cohort (grade 1 or 2). No drug-related deaths occurred.

CONCLUSION: This study provides preliminary evidence that T-DXd has clinical activity in patients with heavily pretreated HER2-low gastric/GEJ adenocarcinoma.

PMID:36379002 | DOI:10.1200/JCO.22.00575

J Int AIDS Soc. 2022 Nov;25(11):e25970. doi: 10.1002/jia2.25970.

ABSTRACT

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years.

METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted.

RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug.

CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes.

PMID:36377082 | DOI:10.1002/jia2.25970

BMC Neurol. 2022 Nov 14;22(1):427. doi: 10.1186/s12883-022-02949-y.

ABSTRACT

BACKGROUND: Vaccination is an important public health strategy; however, many neurological adverse effects are associated with COVID-19 vaccination, being encephalitis a rare manifestation.

CASE PRESENTATION: We present the case of a 33-year-old woman who received the first dose of the BBIBP-CorV vaccine against COVID-19 on April 4 and the second dose on April 28, 2021. Three days after receiving the second dose, she experienced a subacute episode of headache, fever, insomnia, and transient episodes of environment disconnection. We obtained negative results for infectious, systemic, and oncological causes. Brain magnetic resonance imaging showed lesions in the bilateral caudate nucleus and nonspecific demyelinating lesions at the supratentorial and infratentorial compartments. The results of the neuronal autoantibodies panel were negative. She had an adequate response to immunoglobulin and methylprednisolone; however, she experienced an early clinical relapse and received a new cycle of immunosuppressive treatment followed by a satisfactory clinical evolution.

CONCLUSIONS: We report the first case of severe encephalitis associated with BBIBP-CorV (Sinopharm) vaccination in Latin America. The patient had atypical imaging patterns, with early clinical relapse and a favorable response to corticosteroid therapy.

PMID:36376863 | DOI:10.1186/s12883-022-02949-y

Sci Data. 2022 Nov 14;9(1):699. doi: 10.1038/s41597-022-01825-1.

ABSTRACT

The data currently described was generated within the EU/FP7 HeCaToS project (Hepatic and Cardiac Toxicity Systems modeling). The project aimed to develop an in silico prediction system to contribute to drug safety assessment for humans. For this purpose, multi-omics data of repeated dose toxicity were obtained for 10 hepatotoxic and 10 cardiotoxic compounds. Most data were gained from in vitro experiments in which 3D microtissues (either hepatic or cardiac) were exposed to a therapeutic (physiologically relevant concentrations calculated through PBPK-modeling) or a toxic dosing profile (IC20 after 7 days). Exposures lasted for 14 days and samples were obtained at 7 time points (therapeutic doses: 2-8-24-72-168-240-336 h; toxic doses 0-2-8-24-72-168-240 h). Transcriptomics (RNA sequencing & microRNA sequencing), proteomics (LC-MS), epigenomics (MeDIP sequencing) and metabolomics (LC-MS & NMR) data were obtained from these samples. Furthermore, functional endpoints (ATP content, Caspase3/7 and O2 consumption) were measured in exposed microtissues. Additionally, multi-omics data from human biopsies from patients are available. This data is now being released to the scientific community through the BioStudies data repository ( https://www.ebi.ac.uk/biostudies/ ).

PMID:36376331 | DOI:10.1038/s41597-022-01825-1

Am J Manag Care. 2022 Nov;28(11):566-571. doi: 10.37765/ajmc.2022.89259.

ABSTRACT

OBJECTIVES: Drug-drug interactions (DDIs) are among the most common causes of adverse drug reactions and are further complicated by genetic variants of drug-metabolizing enzymes. The aim of this study is to quantify and describe potential DDIs, drug-gene interactions (DGIs), and drug-drug-gene interactions (DDGIs) in a community-based population.

STUDY DESIGN: This was an analysis of deidentified retail pharmacy prescription data for 4761 individuals.

METHODS: Data were first assessed for DDIs, and individuals were stratified to a risk category using the logic of a commercially available digital DDGI tool. To calculate the frequency of potential DGIs and DDGIs, genotypes were imputed and randomly allocated to the cohort 100 times via Monte Carlo simulation according to each variant's frequency in the general population.

RESULTS: The probability of a DDI of any impact was 26.0% and increased to 49.6% (95% CI, 48.4%-50.7%) when drug-metabolizing phenotypes were ascribed according to the distribution of variants of 11 genes as found in a Caucasian population. There was a 7.8% probability of major DDIs, which increased to a 10.1% (95% CI, 9.5%-10.8%) probability with the addition of genetic contributions. The probability of DDGIs of any impact was correlated with the number of medications. Antidepressants, antiemetics, blood products and modifiers, analgesics, and antipsychotics had the highest probability of DDGIs.

CONCLUSIONS: The probability of drug interaction risk increased when phenotypes associated with genetic polymorphisms were attributed to the population. These data suggest that pharmacogenomic assessment may be useful in predicting drug interactions and severity when evaluating patient medication profiles.

PMID:36374614 | DOI:10.37765/ajmc.2022.89259

Reprod Sci. 2022 Nov 14. doi: 10.1007/s43032-022-01121-8. Online ahead of print.

ABSTRACT

The objective of this study is to perform a meta-analysis of all randomized controlled trials (RCTs) that surveyed the efficacy and safety of preoperative misoprostol versus placebo during abdominal hysterectomy. Six databases were screened from inception until 3 August 2022. The eligible studies were assessed for risk of bias. The outcomes were summarized as mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) in a random-effects model. Ten RCTs with 1076 patients (misoprostol = 537, placebo = 539 patients) were analyzed. Six and four RCTs had an overall low and high risk of bias (single-blinded), respectively. The mean intraoperative blood loss (n = 10 RCTs, MD = - 78.97 ml, 95% [- 130.89, - 27.06], p = 0.003), mean difference in hemoglobin drop (n = 10 RCTs, MD = - 0.42 g/dl, 95% CI [- 0.69, - 0.14], p = 0.003), and mean length of hospital stay (n = 5 RCTs, MD = - 0.2 d, 95% CI [- 0.24, - 0.16], p < 0.001) were significantly reduced in favor of the misoprostol group compared with the placebo group. However, there were no significant differences between both groups regarding the mean operative time (n = 8 RCTs, MD = - 0.63 min, 95% CI [- 5.07, 3.81], p = 0.78), rate of perioperative blood transfusion (n = 7 RCTs, RR = 0.83, 95% CI [0.53, 1.3], p = 0.42), and rate of drug-related adverse events (i.e., nausea, vomiting, diarrhea, headache, chills, and fever). Leave-one-out sensitivity analyses revealed stability for all endpoints, except hospitalization stay. There was no publication bias for all endpoints, except perioperative blood transfusion. Among patients undergoing abdominal hysterectomy, preoperative administration of misoprostol was largely safe and linked to substantial decrease in blood loss-related morbidities.

PMID:36376614 | DOI:10.1007/s43032-022-01121-8

Drug Ther Bull. 2022 Nov 14:dtb-2022-000062. doi: 10.1136/dtb.2022.000062. Online ahead of print.

ABSTRACT

Overview of: British Association of Dermatologists. Guidance on minimising risk of harm from potassium permanganate soaks. April 2022.

PMID:36376055 | DOI:10.1136/dtb.2022.000062

Drug Ther Bull. 2022 Nov 14:dtb-2022-000063. doi: 10.1136/dtb.2022.000063. Online ahead of print.

ABSTRACT

Overview of: Butler J, Anker SD, Lund LH, et al Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial. Eur Heart J 2022. doi:10.1093/eurheartj/ehac401 [Epub ahead of print, 2022 Jul 28].

PMID:36376054 | DOI:10.1136/dtb.2022.000063

Ann Pharm Fr. 2022 Nov 11:S0003-4509(22)00149-3. doi: 10.1016/j.pharma.2022.11.006. Online ahead of print.

ABSTRACT

OBJECTIVES: Proton pump inhibitors (PPI) are the most effective drugs in the treatment of acid-related gastrointestinal disorders. Yet, many studies reported potential adverse drug reactions associated with long-term use. In order to reduce the rates of inappropriate PPI prescriptions and to improve patient safety, a tool aimed at guiding pharmacists to analyze PPI prescriptions was designed. It results in a thesaurus of clinical situations designed to argue about the inappropriateness of some PPI prescriptions and to highlight the risk associated with them.

METHODS: Clinical situations in which PPIs are inappropriate were identified by four pharmacists in one gastroenterological, one surgery/liver transplantation, one internal medicine and one oncology units. A scientific literature search was performed for each clinical situation in order to corroborate the pharmacist interventions.

RESULTS: The thesaurus comprises two parts, the first one is dedicated to 12 clinical situations in which a PPI is not required (acute pancreatitis, cholecystectomy etc.), while the second one focus on 22 situations in which PPIs are associated with specific adverse drug reactions (Clostridium difficile infection, vitamin deficiency etc.). Eighty-one articles were used to support the pharmacist interventions.

CONCLUSION: This thesaurus is an analysis tool aimed at guiding pharmacists identify and argue about the inappropriateness of some PPI prescriptions in order to convince doctors to discontinue or not to initiate PPI prescriptions.

PMID:36375534 | DOI:10.1016/j.pharma.2022.11.006

Ann Pharm Fr. 2022 Nov 11:S0003-4509(22)00146-8. doi: 10.1016/j.pharma.2022.11.003. Online ahead of print.

ABSTRACT

OBJECTIVES: The objective of this study was to assess the relevance of proton pump inhibitors prescribing in patients entering a ward with a clinical pharmacist and therefore identifying inappropriate prescribing.

METHODS: A prospective study was conducted for 4 months. Patients admitted to the hospital for elective or emergency surgery, who had medication reconciliation performed by the clinical pharmacy team and who were prescribed proton pump inhibitors before admission were included. The indication for the proton pump inhibitors was collected from the patient or inferred from the medical history. The compliance of the prescriptions with the marketing authorization indications and the duration of treatment and dose was analyzed. The indications were classified into 3 groups: compliant with marketing authorization, off label but relevant use, and strictly off label use.

RESULTS: During the study period, 100 patients were included among whom only 29% had a PPI prescription that did fully comply with the recommendations. Among the twenty-three prescriptions that did not comply with the recommendations in terms of indication, 15 were not relevant at all. Among the 65 prescriptions relevant for indication, 36 were not compliant with dose or duration recommendations. 59% of the total number of patients reported that they had never tried to stop treatment.

CONCLUSIONS: Our study highlights the need for regular reassessment of proton pump inhibitors prescriptions. Multi-disciplinary collaboration on the appropriate use of this class of medication as well as increased awareness among general practitioners and hospital doctors is essential.

PMID:36375532 | DOI:10.1016/j.pharma.2022.11.003

Korean J Intern Med. 2022 Nov;37(6):1153-1166. doi: 10.3904/kjim.2021.216. Epub 2022 Nov 1.

ABSTRACT

BACKGROUND/AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly-used medications, and ailments such as arthritis or heart disease, require long-term use of these drugs, which can induce gastroenteropathy with bleeding and ulcers. This study investigated the associations between efficacy, safety, and gastrointestinal symptoms linked to rebamipide and proton pump inhibitor administration in patients requiring long-term NSAID use.

METHODS: This study was a multi-center, randomized, open-labeled, pilot design.

RESULTS: Thirty-three patients were included. Of these, 15 were included in the study group and 18 were in the control group. NSAID-induced gastric ulcers, which were the primary outcome of this study, did not occur in either the study or control group. Changes in the number of small bowel erosions and ulcers were -0.6 ± 3.06 in the study group and 1.33 ± 4.71 in the control group. The number of subjects with mucosal breaks (defined as multiple erosions and/or ulcers) was three (20%) in the study group and six (40%) in the control group (p = 0.427). No serious adverse events occurred in either group. However, dyspepsia and skin rashes occurred in six patients (31.58%) in the study group and 13 (65%) in the control group (p = 0.036).

CONCLUSION: Although statistically significant differences were not generated, possibly as a result of the small sample size, mucosal breaks observed via capsule endoscopy revealed that rebamipide was likely to be more effective than lansoprazole in preventing small intestine damage caused by NSAIDs. Furthermore, fewer side-effects emerged with rebamipide.

PMID:36375487 | DOI:10.3904/kjim.2021.216

Ann Intern Med. 2022 Nov 15. doi: 10.7326/M22-1329. Online ahead of print.

ABSTRACT

BACKGROUND: Monoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19. However, no studies have evaluated adverse events and effectiveness of mAbs in pregnant persons compared with no mAb treatment.

OBJECTIVE: To determine the frequency of drug-related adverse events and obstetric-associated safety outcomes after treatment with mAb compared with no mAb treatment of pregnant persons, and the association between mAb treatment and a composite of 28-day COVID-19-related hospital admission or emergency department (ED) visit, COVID-19-associated delivery, or mortality.

DESIGN: Retrospective, propensity score-matched, cohort study.

SETTING: UPMC Health System from 30 April 2021 to 21 January 2022.

PARTICIPANTS: Persons aged 12 years or older with a pregnancy episode and any documented positive SARS-CoV-2 test (polymerase chain reaction or antigen test).

INTERVENTION: Bamlanivimab and etesevimab, casirivimab and imdevimab, or sotrovimab treatment compared with no mAb treatment.

MEASUREMENTS: Drug-related adverse events, obstetric-associated safety outcomes among persons who delivered, and a risk-adjusted composite of 28-day COVID-19-related hospital admission or ED visit, COVID-19-associated delivery, or mortality.

RESULTS: Among 944 pregnant persons (median age [interquartile range (IQR)], 30 years [26 to 33 years]; White (79.5%; n = 750); median Charlson Comorbidity Index score [IQR], 0 [0 to 0]), 552 received mAb treatment (58%). Median gestational age at COVID-19 diagnosis or treatment was 179 days (IQR, 123 to 227), and most persons received sotrovimab (69%; n = 382). Of those with known vaccination status, 392 (62%) were fully vaccinated. Drug-related adverse events were uncommon (n = 8; 1.4%), and there were no differences in any obstetric-associated outcome among 778 persons who delivered. In the total population, the risk ratio for mAb treatment of the composite 28-day COVID-19-associated outcome was 0.71 (95% CI, 0.37 to 1.4). The propensity score-matched risk ratio was 0.61 (95% CI, 0.34 to 1.1). There were no deaths among mAb-treated patients compared with 1 death in the nontreated control patients. There were more non-COVID-19-related hospital admissions in the mAb-treated persons in the unmatched cohort (14 [2.5%] vs. 2 [0.5%]; risk ratio, 5.0; 95% CI, 1.1 to 21.7); however, there was no difference in the propensity score-matched rates, which were 2.5% mAb-treated vs. 2% untreated (risk ratio, 1.3; 95% CI, 0.58% to 2.8%).

LIMITATIONS: Drug-related adverse events were patient and provider reported and potentially underrepresented. Symptom severity at the time of SARS-CoV-2 testing was not available for nontreated patients.

CONCLUSION: In pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were mild and rare. There was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment among persons who delivered. There was no difference in 28-day COVID-19-associated outcomes and non-COVID-19-related hospital admissions for mAb treatment compared with no mAb treatment in a propensity score-matched cohort.

PRIMARY FUNDING SOURCE: No funding was received for this study.

PMID:36375150 | DOI:10.7326/M22-1329

Sci Rep. 2022 Nov 12;12(1):19409. doi: 10.1038/s41598-022-24005-y.

ABSTRACT

Drug information centers (DICs) are institutions dedicated to provide objective, independent, and up-to-date information on drugs and their rational use. To overcome the lack of recent DIC reports from central Europe, we analyzed all queries (n = 594) submitted to the DIC run by the Institute for Clinical Pharmacology of Hannover Medical School between October 2018 and April 2022. Approximately one in three queries (31.1%; 185/594) was submitted by internists. 82.8% (492/594) of the queries were patient-specific, while the remaining 17.2% (102/594) were general queries. Adverse drug reactions (ADRs), indications/contraindications, and pharmacodynamic interactions (PDIs) represented the three most frequently addressed query categories, being involved in 44.8% (266/594), 43.3% (257/594), and 34.3% (204/594) of all queries, respectively (assignment of more than one category per query was possible). As compared to general queries, patient-specific queries were statistically significantly more often related to ADRs, PDIs, and pharmacokinetic interactions (PKIs) (ADRs: 35.3% vs. 46.7%, P = 0.034; PDIs: 14.7% vs. 38.4%, P < 0.001; PKIs: 20.6% vs. 31.5%, P = 0.028). To demonstrate the complexity of queries submitted to the clinical-pharmacological DIC, we present and comment on an illustrative selection of queries.

PMID:36371467 | DOI:10.1038/s41598-022-24005-y

Lancet Haematol. 2022 Nov 9:S2352-3026(22)00292-7. doi: 10.1016/S2352-3026(22)00292-7. Online ahead of print.

ABSTRACT

BACKGROUND: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1.

METHODS: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574.

FINDINGS: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response.

INTERPRETATION: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies.

FUNDING: Forma Therapeutics.

PMID:36370742 | DOI:10.1016/S2352-3026(22)00292-7

Respir Med Res. 2022 Nov 8;82:100969. doi: 10.1016/j.resmer.2022.100969. Online ahead of print.

ABSTRACT

BACKGROUND: Anticancer immune-checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs), including interstitial pneumonitis, which is managed chiefly with systemic corticosteroids. When corticosteroids fail, second-line immunosuppressive therapy is indicated. Our objective was to evaluate the prevalence and outcomes of ICI-induced pneumonitis requiring second-line immunosuppressive therapy (IS).

METHODS: We collected data form the REISAMIC pharmacovigilance registry and the multidisciplinary immunological toxicity board at Gustave Roussy (France). No response to steroids was called steroid-refractory pneumonitis and relapse after an initial response was defined as steroid-resistant pneumonitis.

RESULTS: Of the 1187 patients screened from the REISAMIC register, 48 (4%) patients had pneumonitis treated with corticosteroids. Five of them (10%) had corticosteroid refractory/resistant disease but only 2 were treated with immunosuppressive therapy. Four additional patients requiring immunosuppressive therapy identified via the immunological toxicity board were included. Immunosuppressive therapy were cyclophosphamide (n=4 pts), infliximab (n=1 pt), intravenous immunoglobulins (n=1 pt). Five of these six patients had corticosteroid-refractory disease and one had corticosteroid-resistant pneumonitis. Five patients had severe pneumonitis (Common Terminology Criteria for Adverse Events grade ≥3) at initial pneumonitis diagnosis. Two months mortality rate in patients treated with IS was 67% (4/6). Among the patients treated with IS, the two patients alive at 5 months were treated with cyclophosphamide.

CONCLUSION: Patients with ICI-pneumonitis treated by steroids received IS in 10% of cases. High mortality at 67% of patients was observed in ICI-pneumonitis after steroid failure. Cyclophosphamide could be a treatment option for pneumonitis after corticosteroid failure that requires further investigations.

PMID:36370683 | DOI:10.1016/j.resmer.2022.100969

Eur J Cancer. 2022 Oct 19;178:1-12. doi: 10.1016/j.ejca.2022.10.004. Online ahead of print.

ABSTRACT

BACKGROUND: KN026 is a novel human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody that binds two distinct domains of HER2. We report the safety and efficacy results of the phase 2 trial in patients with advanced HER2-expressing gastric or gastroesophageal junction cancer who failed from at least one prior line of standard treatment.

MATERIAL AND METHODS: In this open-label, multicentre, phase 2 trial, eligible patients were enrolled in the high-level HER2 cohort or low-level HER2 cohort and assigned to receive KN026 10 mg/kg (once a week), 20 mg/kg (once every two weeks) or 30 mg/kg (once every three weeks) intravenously. The primary end-points were the objective response rate (ORR) and duration of response assessed according to Response Evaluation Criteria in Solid Tumours (version 1.1).

RESULTS: Between 17th June 2019 and 23rd August 2021, 45 patients were enrolled and received at least one dose of KN026, including 27 patients in the high-level HER2 cohort, 14 patients in the low-level HER2 cohort and four patients who had no HER2 expression. The ORR in the high-level HER2 cohort was 56% (95% confidence interval [CI] 35%-76%), with a durable response duration of 9.7 months (95% CI 4.2-not evaluable); while for the patients with low-level HER2, the ORR was 14% (95% CI 2%-43%). The most frequent ≥ grade 3 treatment-emergent adverse events were gastrointestinal disorders (five patients, 11%). No drug-related deaths were reported.

CONCLUSIONS: KN026 showed a favourable safety profile and promising anti-tumour activity. Our results support further studies evaluating KN026 and the combination treatment with other active drugs in patients with advanced gastric or gastroesophageal junction cancer having high-level HER2 expression.

PMID:36370604 | DOI:10.1016/j.ejca.2022.10.004

Soc Sci Med. 2022 Dec;314:115484. doi: 10.1016/j.socscimed.2022.115484. Epub 2022 Nov 3.

ABSTRACT

Recent decades' hospital closures and consolidations have been rationalized with reference to arguments of efficiency and quality returns to scale and scope. However, closures are met with public outcry from patients living in areas affected by such closures if accompanying increases in travel time are not offset by a higher quality of care. It is broadly established that increases in patients' travel time to acute care lower the probability of survival, but in non-acute and scheduled care we lack knowledge about the quality of care that patients living in closure-affected areas receive. In the non-acute setting of scheduled breast cancer surgery, this study examines how hospital clinic closures affect the quality of care that closure-affected patients receive. The effects are identified using closures of breast cancer clinics in Denmark from 2000 to 2011, during which time the number of clinics was more than halved. Using event study designs on population-wide Danish register data from 1996 to 2014, this study examine changes in surgical outcomes for 9790 patients living in municipalities where the nearest clinic has been closed. The results show that closures have reduced the number of hospitalization days and shifted surgical procedures to state-of-the-art breast-conserving techniques without generating adverse health effects and without causing crowding in non-closing clinics. An examination of the mechanisms suggests that added volume returns at non-closing clinics were of less importance than simply reallocating patients to higher-quality clinics. Closures of clinics performing scheduled surgery may be an effective policy instrument if the goal is to reduce variation in the delivery of hospital care. Increased access to state-of-the-art care may counterbalance patients' concerns of losing their local clinic. However, if the clinics to be closed are small compared to non-closing clinics then there is no potential for added economies of scale or scope in non-closing clinics.

PMID:36368239 | DOI:10.1016/j.socscimed.2022.115484

BMC Cardiovasc Disord. 2022 Nov 11;22(1):480. doi: 10.1186/s12872-022-02937-7.

ABSTRACT

BACKGROUND: Adverse drug reaction (ADR) of medications remains an obstacle to achieving optimal disease outcomes. This study aimed to assess the prevalence and associated factors of ADR among Heart failure (HF) patients hospitalized at Mbarara Regional and Referral Hospital.

METHOD: A prospective observational study was conducted among hospitalized HF patients from November 2021 to January 2022. Univariate and multivariate logistic regression was employed to determine factors associated with the ADR.

RESULT: Overall, 118 HF patients were included in the study with a median age of 43 years. A total of 164 ADRs were identified during the follow-up period of 1011 days. The incidence of new ADRs was 106 ADRs/1000 person-days. The prevalence of ADR was 59.3%. Of the 164 ADRs, 118(71.9%) were probable. The gastrointestinal system was the most frequently (27.5%) affected system. Over half (86, 52.4%) of the ADRs were mild and 96(58.5%) were preventable. Age group 19-59(AOR 0.15[0.03-0.35] at 95%CI, p = 0.013), herbal use (AOR 3.07[1.01-9.32] at 95%CI, p = 0.048), poly-pharmacy (AOR 8.7[2.4-15.77] at 95%CI, p < 0.001) and drug-drug interaction (AOR 6.06[2.79-12.5] at 95%CI, p = 0.004) were significantly associated with ADRs among HF patients.

CONCLUSION: More than half of the hospitalized HF patients experienced at least one ADR during their hospital stay. The use of herbal medicines, poly-pharmacy, and drug-drug interaction were associated with a high risk of ARDs whereas the age group 19-59 years was less likely to experience ADRs.

PMID:36368954 | DOI:10.1186/s12872-022-02937-7

Molecules. 2022 Oct 25;27(21):7242. doi: 10.3390/molecules27217242.

ABSTRACT

The liver is a crucial organ among body organs due to its wide functions, in particular, detoxification and metabolism. Exposure to detrimental chemicals or viral infections may provoke liver dysfunction and ultimately induce liver tissue damage. Finding natural substances for liver disease treatment to overcome the conventional treatments' side effects has attracted the attention of researchers worldwide. Our current work was conducted to investigate the hepato-therapeutic activities of essential oil (EO) isolated from Tagetes patula flowers. EO was extracted using the hydro-distillation (HD) technique and its chemical composition was identified by GC/MS. Then, the hepatic treatment potential of extracted EO was evaluated in vivo against CCL4 in rats. HD of T. patula flowers yielded highly chemical constituents of EO along with significant antioxidant potential. A coherent molecular network was fashioned via the Global Natural Products Social Molecular Networking (GNPS) to visualize the essential components and revealed that the sesquiterpene (E)-β-caryophyllene was the most predominant volatile constituent which accounted for 24.1%. The treatment of CCL4 led to significant induced oxidative stress markers malonaldehyde, total protein, and non-protein sulfhydryl, as well as elevated serum aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and bilirubin. In addition, it disrupted the level of lipid profile. The post-treatment using T. patula EO succeeded in relieving all toxic effects of CCl4 and recuperating the histopathological signs induced by CCL4. Silymarin was used as a standard hepatoprotective agent. The obtained results demonstrated that the extracted EO exerted high protective activities against the toxicity of CCL4. Moreover, the T. patula flowers EO can be used as a natural remedy to relieve many contemporary liver diseases related to oxidative stress.

PMID:36364067 | DOI:10.3390/molecules27217242

Medicina (Kaunas). 2022 Nov 7;58(11):1609. doi: 10.3390/medicina58111609.

ABSTRACT

Background and Objectives: Acne vulgaris is one of the most common dermatological disorders among adolescents and adults in the Kingdom of Saudi Arabia (KSA). Isotretinoin is a cost-effective way of treating severe acne patients compared to other methods used for severe forms of acne management. The present study investigated the knowledge of the use of isotretinoin and its side effects among female acne patients of the reproductive age group who were on isotretinoin. This study also assessed participants' awareness of the Saudi FDA-Pregnancy Prevention Program (SFDA-PPP). Materials and Methods: The present population-based cross-sectional survey was conducted among 768 participants using a standard and validated Arabic version questionnaire. We have applied logistic regression analysis to determine the predictors for awareness of SFDA-PPP. A Chi-square test was applied to identify the factors associated with knowledge related to isotretinoin. Results: Regarding the side effects of isotretinoin, participated female acne patients were most commonly aware of dry mouth and lips (84.5%), teratogenicity (68.2%), and headache (44.8%). Nearly 60% of the participants belonged to the low knowledge category. The present study participants' knowledge was significantly associated with education status (p = 0.007), occupation (p = 0.01), and those participants who were aware of SFDA-PPP (p = 0.001). Furthermore, we explored that only 37.5% were aware of the SFDA-PPP program implemented in Saudi Arabia. The awareness of SFDA-PPP was significantly higher among those participants belonging to health sectors (Adjusted OR (95% CI) = 1.39 (1.01-1.92), p = 0.049). Conclusion: The present survey explored inadequate knowledge among reproductive age group female acne patients regarding isotretinoin uses, precautions to be followed, and side effects, especially teratogenic effects. This survey findings suggest that improving female acne patients' knowledge of isotretinoin through health promotion activities is crucial, especially by giving them precise instructions about the teratogenic effects.

PMID:36363566 | DOI:10.3390/medicina58111609