Regul Toxicol Pharmacol. 2022 Aug;133:105225. doi: 10.1016/j.yrtph.2022.105225. Epub 2022 Jul 9.

ABSTRACT

Some pharmaceutical excipients may cause adverse reactions, excipient-related interactions and/or contraindications. Due to the unique characteristics of the paediatric population, adverse effects may occur to substances generally thought safe. The proportion of topical nasal medicines approved for paediatric use and the prevalence and labelling of excipients with known effect (EKE) in these products were compared in Serbia as a non-EU country and Croatia and Slovenia as EU countries. The study was designed as a post-authorization safety study and safety of excipients was considered in accordance with recommendations of the European Medicines Agency (EMA). More than 90% of topical nasal medicines registered in the three countries were approved for paediatric use and more than half of these paediatric medicines contained EKE that may cause adverse effects. Benzalkonium chloride was found in 52.38%, 55.81% and 59.09% of these products in Serbia, Croatia and Slovenia, respectively. Propylene glycol, benzyl alcohol, ethanol, methyl paraben, propyl paraben and boric acid were also present in a few analysed preparations. A significant number of EKE labelling deficiencies were detected in all three countries, hindering healthcare professionals' access to information needed for adequate patient counselling. A revision of the nasal paediatric medicines' PLs and SmPCs is recommended.

PMID:35817211 | DOI:10.1016/j.yrtph.2022.105225

Psychopharmacol Bull. 2022 Jun 27;52(3):68-71.

ABSTRACT

This case is one of the earliest to report on lurasidone-related QTc prolongation in a dose-dependent fashion in CAP population at therapeutic doses. Although these reports remain scarce, it behoves prescribers to be vigilant and mindful of these unusual but serious side effects especially in setting of cumulative risks.

PMID:35815172 | PMC:PMC9235318

Ethiop J Health Sci. 2022 May;32(3):473-484. doi: 10.4314/ejhs.v32i3.2.

ABSTRACT

BACKGROUND: The Ministry of Health of Ethiopia launched the COVID-19 vaccination campaign in March 2021, with frontline healthcare workers as first-round recipients and a goal of vaccinating 20% of the population by the end of 2021. The study aims to estimate the prevalence of COVID-19 vaccination side effects among early vaccinated healthcare workers in Adama hospital medical college.

METHODS: A cross-sectional study was carried out between March and June 2021, following the vaccination of COVID-19 vaccine among healthcare workers in Adama hospital medical college. The study used a structured self-administered questionnaire and additional telephone surveys on items covering the participants' demographic data, local and systemic manifestations after vaccination.

RESULTS: A total of 540 health care workers and supportive staff were enrolled in this study. The overall any-symptom report after the first dose of ChAdOx1 nCoV- 19 vaccine was 84.3%. The majority (39.6%) of participants had both systemic and local symptoms and 25.7% had only local and 18.9% had only systemic symptoms. Injection site pain was the most prevalent side effect symptom (64.1%), followed by fatigue (35.7%), headache (28.9%), joint pain (26.5%), and muscle pain (21.5%).

CONCLUSION: Vaccine side effects were common and found to be well-tolerated among the recipients of the first dose of ChAdOx1 nCoV-19 at Adama hospital medical college healthcare workers. The side effects were mainly mild to moderate. More side-effect profiles should be studied and disseminated to detect rare adverse reactions.

PMID:35813681 | PMC:PMC9214739 | DOI:10.4314/ejhs.v32i3.2

Front Pharmacol. 2022 Jun 22;13:878092. doi: 10.3389/fphar.2022.878092. eCollection 2022.

ABSTRACT

Introduction: Prescribing cascade refers to use of a medication to treat a drug-related adverse event. Prescribing cascades increase medication use, cost, and risk of adverse events. Objective: Our objective was to use administrative health data to identify whether use of medications from the anticholinergic cognitive burden scale was associated with proton pump inhibitor (PPI) prescribing consistent with a prescribing cascade in older adults with dementia. Method: The cohort was comprised of Nova Scotia Seniors' Pharmacare beneficiaries identified to have dementia and medication dispensation data recorded between 1 April 2010, or cohort entry and 31 March 2015. Anticholinergic medications from the anticholinergic cognitive burden scale (ACB) were abstracted. A look back period of 365 days identified if a PPI had been dispensed preceding anticholinergic dispensation. PPI initiation within 30, 60, 90, or 180 days of the anticholinergic medication was assessed. Demographic description of those dispensed anticholinergic medications or PPIs were reported. Risk factors for the prescribing cascade were investigated with logistic regression and Cox proportional hazards modelling including a sex-stratified analysis. Results: We identified 28,952 Nova Scotia Seniors' Pharmacare beneficiaries with dementia and prescription dispensation data. Anticholinergic medications were frequently dispensed with 63.4% of the cohort dispensed at least one prescription for an anticholinergic medication. The prescribing cascade defined as up to 180-days between anticholinergic medication inititation and PPI dispensation, occurred in 1,845 Nova Scotia Seniors' Pharmacare beneficiaries with dementia (incidence 6.4%). Multivariate regression showed those experiencing the prescribing cascade after initiating any anticholinergic were younger (OR 0.98, 95%CI [0.97-0.98]), less likely to live in an urban location (OR 0.82, 95%CI [0.74-0.91]), or to be men (OR 0.74, 95%CI [0.67-0.82]). Cox regression demonstrated an increased risk of starting a PPI within 180 days when initiating any medication from the ACB (HR 1.38, 95%CI [1.29-1.58]). Discussion: Regression modelling suggested that anticholinergic medications increased the risk of PPI dispensation consistent with a prescribing cascade in the cohort. The identification of the prescribing cascade in this population of older Nova Scotia Seniors' Pharmacare Program beneficiaries with dementia using administrative health data highlights how routinely collected health data can be used to identify prescribing cascades.

PMID:35814221 | PMC:PMC9257131 | DOI:10.3389/fphar.2022.878092

Cureus. 2022 Jun 9;14(6):e25797. doi: 10.7759/cureus.25797. eCollection 2022 Jun.

ABSTRACT

The incidence of amoxicillin/clavulanate (Augmentin) induced liver injury is relatively low when compared to other medications. Amoxicillin/clavulanic acid is one of the most frequently prescribed antibiotics by physicians and is used to treat various bacterial infections. However, amoxicillin/clavulanate can cause severe side effects, usually gastrointestinal like nausea and vomiting, rash, and sometimes hematologic like thrombocytopenia. Here, we present a case report where a 63-year-old male treated for a dog bite with amoxicillin/clavulanate acid four weeks ago presents to the hospital with severe cholestatic hepatitis, nausea, and pruritis.

PMID:35812609 | PMC:PMC9270929 | DOI:10.7759/cureus.25797

Cell Death Discov. 2022 Jul 9;8(1):313. doi: 10.1038/s41420-022-01109-y.

ABSTRACT

Increased medical application of psychotropic drugs raised attention concerning their toxicological effects. In fact, more than 160 psychotropic drugs including antidepressants and antipsychotics, have been shown to cause liver side effects, but the underlying mechanisms are still poorly understood. Here, we discovered that fluoxetine, a common antidepressant, was specifically sensed by NLRP3 inflammasome, whose subsequent activation resulted in the maturation of caspase-1 and IL-1β, as well as gasdermin D (GSDMD) cleavage, which could be completely abrogated by a selective NLRP3 inhibitor MCC950 or Nlrp3 knockout (Nlrp3-/-). Mechanistically, mitochondrial damage and the subsequent mitochondrial reactive oxygen species (mtROS) accumulation were crucial upstream signaling events in fluoxetine-triggered NLRP3 inflammasome activation. In fluoxetine hepatotoxicity models, mice showed the alterations of aminotransferase levels, hepatic inflammation and hepatocyte death in an NLRP3-dependent manner, and MCC950 pretreatment could reverse these side effects of fluoxetine. Notably, we also found that multiple antidepressants, such as amitriptyline, paroxetine, and imipramine, and antipsychotics, such as asenapine, could specifically trigger the NLRP3 inflammasome activation. Collectively, our findings implicate multiple psychotropic drugs may act as danger signals sensed by the NLRP3 inflammasome and result in hepatic injury.

PMID:35810159 | DOI:10.1038/s41420-022-01109-y

J Clin Med. 2022 Jun 21;11(13):3571. doi: 10.3390/jcm11133571.

ABSTRACT

Intravenous immunoglobulins (IVIGs) are widely used in the treatment of numerous diseases in both adult and pediatric populations. Higher doses of IVIGs usually serve as an immunomodulatory factor, common in therapy of children with immune thrombocytopenic purpura. Considering the broad range of IgG applications, the incidence of side effects in the course of treatment is inevitable. Aseptic meningitis, an uncommon but significant adverse reaction of IVIG therapy, can prove a diagnostic obstacle. As of April 2022, forty-four cases of intravenous immunoglobulin-induced aseptic meningitis have been reported in the English-language literature. This review aims to provide a thorough overview of the diagnostic process, pathophysiology, possible preventative measures and adequate treatment of IVIG-induced aseptic meningitis.

PMID:35806861 | DOI:10.3390/jcm11133571

J Frailty Aging. 2022;11(3):329-334. doi: 10.14283/jfa.2022.35.

ABSTRACT

Opioid use has much increased in several countries during the last two decades, accompanied by a rise in associated morbidity and mortality, especially in the United States. Data on a possible opioid crisis are scarcer in Europe. We performed a study aiming to assess the frequency of adverse drug reactions (ADR) related to opioids in patients presenting to the emergency unit (EU) of a geriatric tertiary Swiss University Hospital. This particular setting is intended for patients aged 75 and older. Our retrospective, monocentric survey of opioid use and related ADR was conducted over two months in 2018. The main and secondary outcomes were the frequency of EU visits considered due to an opioid ADR and insufficient pain relief, respectively. Current opioid use was identified in 20.3% (n=99) of the 487 included EU visits (mean age 86). An ADR was the suspected cause of the EU visit in 22 opioid users, mainly fall-related injury and gastrointestinal disorders. All these patients had at least one comorbid condition. In 19/22 cases (86%) of ADR, a drug-drug interaction might have been involved. In 12 opioid users (12%), insufficient pain relief was suspected as the cause of the EU visit. In conclusion, one-third of opioid users visiting a geriatric EU consulted for a problem related to its use mainly adverse drug-related reaction (22%) followed by insufficient pain relief (12%).

PMID:35799441 | DOI:10.14283/jfa.2022.35

Support Care Cancer. 2022 Jul 9. doi: 10.1007/s00520-022-07233-w. Online ahead of print.

ABSTRACT

PURPOSE: Supportive oncodermatology has been shown to improve several aspects of care for patients with cancer, but research showing improved diagnostic accuracy as a benefit of supportive oncodermatology is largely lacking. We thus aimed to evaluate different dermatologist groups' diagnostic accuracy for heterogenous cutaneous toxicities, using cutaneous immune-related adverse events (cirAEs) from immune checkpoint inhibitors (ICIs) as a test model.

METHODS: Billing/requisition codes were used to identify patients who initiated programmed death-1/ligand-1 (PD-1/PD-L1) ICIs between 2010 and 2019 at Dana-Farber Cancer Institute/Brigham and Women's Hospital/Massachusetts General Hospital and underwent a subsequent skin biopsy. For each biopsied cirAE, pre-biopsy clinical diagnoses and post-biopsy clinico-pathologic diagnoses were retrospectively obtained from the medical record. Each biopsy-ordering dermatology provider was categorized as a general dermatologist or supportive oncodermatologist on the basis of providing clinical care within a cancer-center or attending on a hospital/clinic service dedicated to anti-cancer drug-related skin toxicities.

RESULTS: Of 4,183 patients who initiated anti-PD-1/PD-L1 therapy between 2010 and 2019, 101 (2.4%) patients collectively had 104 biopsied cirAEs. In more than one-third of all reviewed biopsied cirAEs (n = 39, 37.5%), histopathology results frequently led to revision of the pre-biopsy clinical diagnosis. The rate of initial cirAE misclassification amongst supportive oncodermatologists was significantly lower than that amongst general dermatologists (18/66, 27.3% vs. 21/38, 55.3%; Fischer's-exact-test p = 0.006).

CONCLUSION: Experienced supportive oncodermatologists may benefit patient care through increased diagnostic accuracy for skin toxicities from ICIs. Collectively, these results underscore that both skin biopsy from any dermatology provider and oncodermatology referral (where available) are valuable resources that should be integrated into supportive cancer care.

PMID:35804176 | DOI:10.1007/s00520-022-07233-w

Eur J Obstet Gynecol Reprod Biol. 2022 Jul 3;276:38-46. doi: 10.1016/j.ejogrb.2022.06.028. Online ahead of print.

ABSTRACT

OBJECTIVE: To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated the efficacy and safety of isosorbide mononitrate (IMN) in promoting cervical ripening during labour induction.

METHODS: Six major databases were searched from inception until 22 April 2021. The risk of bias of included studies was assessed. Various endpoints (n = 21) were meta-analysed, and the endpoints were pooled as mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI).

RESULTS: In total, 23 RCTs were included in this review, comprising 26 intervention arms and a total of 4305 patients (2210 and 2095 patients were allocated to the IMN and control groups, respectively). Pertaining to obstetric-related maternal outcomes, the pooled analysis showed that admission to delivery time and rate of caesarean delivery were significantly reduced in the IMN group. Moreover, the mean Bishop score and the mean change in Bishop score were significantly increased in the IMN group. Pertaining to drug-related maternal side effect outcomes, the pooled analysis showed that the rates of headache, palpitations, nausea and flushing were significantly lower in the IMN group. Pertaining to neonatal outcomes, the pooled analysis showed no significant difference between the two groups in terms of the rates of neonatal intensive care unit admission, neonatal death, fetal distress, meconium-stained water, Apgar score < 7 at 1 and 5 min, and mean Apgar score at 1 and 5 min.

CONCLUSION: IMN correlated with several obstetric-related maternal outcomes. IMN was not associated with adverse neonatal outcomes, but was associated with substantial drug-related maternal side effects.

PMID:35803111 | DOI:10.1016/j.ejogrb.2022.06.028

Gan To Kagaku Ryoho. 2022 Jun;49(6):701-704.

ABSTRACT

Olanzapine(OLZ)is a multi-acting receptor-targeted antipsychotic drug approved in Japan in December 2017 for the treatment of anticancer drug-induced nausea and vomiting. However, the recommended doses and administration periods of OLZ in the literature and guidelines are varied. Reports on the efficacy and safety of OLZ combined with perioperative chemotherapy for breast cancer in Japanese patients are few. Moreover, the risk of nausea and vomiting during treatment with anticancer drugs in young and women patients remains to be high. In this study, we conducted an exploratory survey on the optimal duration of OLZ administration(days 1-4: 5 mg, before sleep)during perioperative breast cancer 5-fluorouracil, epirubicin, cyclophosphamide(FEC)therapy. We found that treatment with OLZ showed efficacy in improving nausea grade and maintaining relative dose intensity. Moreover, it could be used safely without interruption due to side effects, such as weight gain, elevation in blood glucose, somnolence, and insomnia. Prophylactic antiemetic therapy with OLZ administration (days 1-4: 5 mg)prior to sleep was effective in patients having FEC therapy-induced nausea and vomiting.

PMID:35799400

J Coll Physicians Surg Pak. 2022 Jul;32(7):880-884. doi: 10.29271/jcpsp.2022.07.880.

ABSTRACT

OBJECTIVE: To determine the survival endpoints and treatment-related adverse events after the use of the gemcitabine, paclitaxel, and oxaliplatin (GemPOx) protocol in relapsed/refractory germ cell tumours (GCTs) who had previously received multi-line systemic treatments including high-dose chemotherapy.

STUDY DESIGN: Observational study.

PLACE AND DURATION OF STUDY: Clinic of Medical Oncology, Gulhane School of Medicine, Ankara, Turkey, between January 2017 and August 2021.

METHODOLOGY: Clinical characteristics of adult patients with relapsed/refractory GCTs treated with the GemPOx protocol were recorded from the hospital's patient registry database. Patients without a medical record were not included in the study. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), one-year PFS rate, one-year OS rate, and treatment-related haematological side effects were determined after GemPOx.

RESULTS: Fifty-three adult patients were included (47 of them were male). Seventy-eight percent had Stage 3 at initial diagnosis. Twenty-four percent of the patients received more than four lines of systemic chemotherapy. Ninety-six percent of the patients received high-dose chemotherapy prior to GemPOx. ORR, which is the sum of the complete and partial response rates, was 69.8%. PFS was determined as 8.5 ± 5.4 months. The one-year PFS rate was 30.3%. OS was 15.9 ± 10.6 months. The one-year OS rate was 72.6%. Febrile neutropenia was observed in 15.1% of the patients.

CONCLUSION: In patients with relapsed/refractory GCTs receiving multi-line systemic chemotherapy, significant PFS and OS are achievable, and a manageable spectrum of haematological side effects is observed with GemPOx.

KEY WORDS: Gemcitabine, Paclitaxel, Oxaliplatin, Germ cell tumour.

PMID:35795936 | DOI:10.29271/jcpsp.2022.07.880

Drug Des Devel Ther. 2022 Jun 30;16:2067-2081. doi: 10.2147/DDDT.S357638. eCollection 2022.

ABSTRACT

PURPOSE: Paclitaxel-induced peripheral neuropathy (PIPN) is increasingly becoming one of the most widespread adverse effects in the treatment of cancer patients, and further precipitate neuroinflammation in the nervous system. Interestingly, Shaoyao Gancao Decoction (SGD), a traditional Chinese analgesic prescription, has emerged as a primary adjuvant to chemotherapy in relieving side effects, especially in the case of PIPN. However, the underlying mechanism of SGD functioning in PIPN remains elusive. Accordingly, the current study set out to explore the potential axis implicated in the functioning of SGD in PIPN.

METHODS: First, network pharmacology was adopted to predict the role of the transient receptor potential vanilloid type 1 (TRPV1) protein in treating PIPN with SGD. Subsequently, the effects of SGD treatment on mechanical allodynia and thermal hyperalgesia were evaluated in rat PIPN models. Based on the bioinformatics information and current literature, paclitaxel activates toll-like receptor 4 (TLR4) induces the sensitization of TRPV1 mechanistically. Thereafter, TLR4-myeloid-differentiation response gene 88 (MyD88) signaling and TRPV1 expression patterns in dorsal root ganglias (DRGs) were measured by means of Western blotting, qPCR and immunofluorescence.

RESULTS: Initial bioinformatics reared a total of 105 bioactive compounds and 1075 target genes from SGD. In addition, 40 target genes intersected with PIPN were considered as potential therapeutic genes. Based on the network analysis, SGD was found to exert its analgesic effect by reducing the expression of TRPV1. Further experimentation validated that SGD exerted an analgesic effect on thermal hyperalgesia in PIPN models, such that this protective effect was associated with the suppression of TRPV1 and TLR4-MyD88 Signaling over-expression.

CONCLUSION: Collectively, our findings indicated that SGD ameliorates PIPN by inhibiting the over-expression of TLR4-MyD88 Signaling and TRPV1, and further highlights the use of SGD as a potential alternative treatment for PIPN.

PMID:35795847 | PMC:PMC9252300 | DOI:10.2147/DDDT.S357638

BMC Med. 2022 Jul 8;20(1):219. doi: 10.1186/s12916-022-02420-2.

ABSTRACT

BACKGROUND: Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy.

METHODS: Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed.

RESULTS: Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5-25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9-2.9), and the median OS was 7.1 months (95% CI 6.1-8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3-1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40-0.50).

CONCLUSIONS: Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.

PMID:35799149 | DOI:10.1186/s12916-022-02420-2

Lancet Oncol. 2022 Jul 4:S1470-2045(22)00326-6. doi: 10.1016/S1470-2045(22)00326-6. Online ahead of print.

ABSTRACT

BACKGROUND: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma.

METHODS: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791.

FINDINGS: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage).

INTERPRETATION: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.

FUNDING: Exelixis and Ipsen.

PMID:35798016 | DOI:10.1016/S1470-2045(22)00326-6

IJU Case Rep. 2022 May 3;5(4):219-222. doi: 10.1002/iju5.12426. eCollection 2022 Jul.

ABSTRACT

INTRODUCTION: Recent introduction of immuno-oncology drugs such as pembrolizumab has resulted in improved outcomes for urothelial carcinoma patients. However, immune-related adverse events generally show great variance and are often difficult to diagnose and control.

CASE PRESENTATION: An 84-year-old Japanese male with urothelial carcinoma metastasis to the lungs after a laparoscopic left radical nephroureterectomy procedure was treated with pembrolizumab, an immuno-oncology drug, as second-line therapy. At week 6, inflammatory arthralgia involving the hands and shoulder joints, and edema of the hands were presented. The diagnosis was remitting seronegative symmetrical synovitis with pitting edema syndrome. Pembrolizumab was discontinued, and oral corticosteroid therapy was started. Two months later, pembrolizumab treatment was resumed because of a significant improvement in patient condition.

CONCLUSION: Although rare, immune-related adverse events are occasionally encountered during the use of immune-oncology drugs; thus, early diagnosis and appropriate treatment are important.

PMID:35795121 | PMC:PMC9249633 | DOI:10.1002/iju5.12426

PLoS One. 2022 Jul 6;17(7):e0269452. doi: 10.1371/journal.pone.0269452. eCollection 2022.

ABSTRACT

Work fatigue refers to physical, mental, and emotional exhaustion, resulting in the inability to work. Hitherto research indicate a close relationship between high-performance work systems and work fatigue, and there may be a double-edged sword effect of high-performance work systems on work fatigue. However, a comprehensive theoretical framework has not been developed to understand the relationship between them. Based on the challenge-hindrance stress model, this study employs role overload and job responsibility as mediating variables in a conceptual framework to understand the impact of high-performance work systems on work fatigue. Using the partial least square structural equation model and a sample of 360 employees in China, the mediating effects of role overload and job responsibility were confirmed. Further, the internal mechanisms of how high-performance work systems affect work fatigue are discussed, its adverse effects are confirmed, and its practical implications are proposed.

PMID:35793365 | PMC:PMC9258864 | DOI:10.1371/journal.pone.0269452

PLoS One. 2022 Jul 6;17(7):e0270112. doi: 10.1371/journal.pone.0270112. eCollection 2022.

ABSTRACT

BACKGROUND: The collagenase of the bacterium Clostridium histolyticum (CCH) is already an established treatment for fibroproliferative diseases like M. Dupuytren and M. Peyronie Although results are comparable to surgical intervention, skin laceration is a severe and relevant side effect. Doxycycline (DOX) recently rose interest as an inhibitor of matrix-metalloproteinases alongside its capabilities of skin accumulation. It therefore might be a potential skin protective agent in the use of CCH.

METHODS: For simulation of a fibroproliferative disease adjacent to the skin, we utilized a rodent model of capsular fibrosis involving silicone implants and subsequent fibrotic capsule formation. For in-vitro studies, fibrotic capsules were excised and incubated with 0.9 mg/ml CCH and four different doses of DOX. For in-vivo experiments, animals received 0.0, 0.3 or 0.9 mg/ml CCH injections into the fibrotic capsules with or without prior oral DOX administration. Outcome analysis included histology, immunohistochemistry, gene expression analysis, chemical collagen and DOX concentration measurements as well as μCT imaging.

RESULTS: In-vitro, DOX showed a dose-dependent inhibition of CCH activity associated with increasing capsule thickness and collagen density and content. In-vivo, oral DOX administration did neither interfere with capsule formation nor in effectiveness of CCH dissolving fibrotic capsule tissue. However, skin thickness and especially collagen density was significantly higher compared to control groups. This led to a reduced rate of clinical skin lacerations after DOX administration.

CONCLUSION: DOX inhibits CCH and accumulates in the skin. Thereby, DOX can effectively reduce skin laceration after CCH treatment.

PMID:35793344 | PMC:PMC9258873 | DOI:10.1371/journal.pone.0270112

Epileptic Disord. 2022 Oct 1;24(5):1-9. doi: 10.1684/epd.2022.1454.

ABSTRACT

OBJECTIVE: Real-world data from adolescents treated with perampanel in a routine clinical setting are lacking in Japan. We evaluated the safety and efficacy of perampanel for adolescent patients (aged 12-17 years) with drug-resistant, refractory epilepsy in real-world settings.

METHODS: This was a large-scale, prospective, observational post-marketing study, with a 104-week observation period. Safety was assessed by monitoring adverse effects (adverse drug reactions). For efficacy assessments, seizure frequency was compared between the four weeks immediately prior to the last observation and the four weeks before the commencement of perampanel.

RESULTS: In total, 519 patients were enrolled; 505 and 484 patients were included in the safety and efficacy analysis sets, respectively. The mean age was 14.4 years. The mean daily dose of perampanel was 4.4 mg/day. The main reasons for discontinuation at 104 weeks were adverse events (48.4%) and inadequate efficacy (46.8%). The retention rate at 104 weeks was 50.5%. Adverse effect and severe adverse effect incidences were 42.2% and 1.8%, respectively. The most common adverse effects were somnolence (13.5%), irritability (8.5%), dizziness (5.1%), and agitation (4.8%). There were significant differences in the occurrence of adverse effects between the initial titration interval of <2 weeks and 2-4 weeks (odds ratio=0.441, p=0.029) and 4-8 weeks (odds ratio=0.462, p=0.027). The median percent change in seizure frequency at the last observation carried forward was −50.0 for focal aware seizures with motor signs, −73.3 for focal aware seizures without motor signs, −28.6 for focal impaired awareness seizures, −62.6 for focal to bilateral tonic-clonic seizures, and −20.0 for generalized tonic-clonic seizures.

SIGNIFICANCE: In adolescent patients, perampanel was well tolerated and efficacious in reducing seizure frequency. No unexpected safety issues were observed, and slow titration may reduce the incidence of adverse effects.

PMID:35792849 | DOI:10.1684/epd.2022.1454

Lancet. 2022 Jun;399 Suppl 1:S15. doi: 10.1016/S0140-6736(22)01150-3.

ABSTRACT

BACKGROUND: Chemotherapy has several side-effects, including chemotherapy-induced peripheral neuropathy (CIPN), that can substantially reduce patients' activities of and participation in daily living. Few studies have addressed this issue. We investigated the effects that CIPN has on daily living of patients in occupied Palestinian territory.

METHODS: We did a quantitative observational cross-sectional survey of patients at the Augusta Victoria Hospital, East Jerusalem, which provides chemotherapy, and the Dunya Women's Cancer Centre, Ramallah, which provides services for women during and after chemotherapy. Eligible patients were aged 18-65 years, had received six or more cycles of chemotherapy, did not have end-stage cancer, could read and understand Arabic, and had no other illnesses that affected the nervous system or mobility. The CIPN Rasch-built overall disability scale was translated into Arabic and two questions were added. The first was to determine CIPN-associated symptoms and the second was to add the activity of cleaning with water. The questionnaire was distributed to patients via the study sites. SPSS version 22.0 was used to analyse the data with multiple tests, such as one-way ANOVA, t test, χ2, and the Tukey test. The threshold for significance was α=0·05.

FINDINGS: Of 37 eligible patients, 32 were included (10 men and 22 women) with any type of cancer. CIPN had significantly negative effects on activities and participation in daily living (α=0·008). Women were affected more than men (α=0·001) but there was no correlation between effects on daily living and age (α=0·773), place of living (α=0·092), or chemotherapy (α=0·894). The most reported symptom of CIPN was pain (n=23 [72%]) and the least reported symptom was loss of hearing (n=10 [31%]). The most affected activity was walking uphill (mean score 1·3438 [SD 0·82733]) and the least affected activity was moving a chair (2·8438 [0·3689]).

INTERPRETATION: We found that chemotherapy has notable consequences for activities of daily living. This study had several limitations: small sample size, limited number of centres that provide cancer treatments. These were due to the geographical locations of such centres and checkpoints sometimes preventing access. Additionally, the statistical data about cancer patients were limited because not all centres record chemotherapy cycle numbers, and specific cancer diagnoses and, therefore, we could not include more study sites. CIPN is, therefore, probably under-reported.

FUNDING: None.

PMID:35786249 | DOI:10.1016/S0140-6736(22)01150-3