Common Adverse Effects Research Articles

CTNI-68. PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR TARGETING GLIOBLASTOMA CANCER STEM CELLS

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation (Stem Cells Transl Med. 2012;1(11)). We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Patients and METHODS Patients between 20 and 74 years of age with supratentorial GBM were eligible. MF dose-escalation study was performed using a 3 + 3 design as phase I part to determine recommended phase II dose. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. After completing phase I study, we proceeded to phase II part. RESULTS The first three patients were treated with 1,500 mg/day MF from 2021 and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2 (Cancers (Basel). 2022;14(17)). Based on the phase I study, we proceeded to phase II study with 2,250 mg/day MF from April 2022 and finished recruiting patients for phase II part in May 2023. Primary endpoint of phase II trial is progression-free survival rate at 12 months compared to historical data. CONCLUSION MF dose of up to 2,250 mg/day combined with maintenance TMZ was well tolerated. We report the safety and efficacy of MF with TMZ for GBM.

NCOG-37. BELZUTIFAN IN ADULTS WITH VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA: A SINGLE-CENTER EXPERIENCE

Abstract INTRODUCTION Belzutifan is a selective inhibitor of hypoxia-inducible factor 2-alpha that has been FDA approved for Von Hippel–Lindau (VHL) syndrome-associated tumors. There is limited real-world evidence in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan. METHODS We retrospectively reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2023. RESULTS 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated. The most common adverse effect was anemia. No patients had treatment pauses or dose adjustments due to toxicity. No patients experienced hypoxia. DISCUSSION We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.

Rectum and Bladder Toxicity in Postoperative Prostate Bed Irradiation: Dose-Volume Parameters Analysis.

Although prostate cancer treatment is increasingly effective, its toxicities pose a major concern. The aim of our study was to assess the rate of adverse events (AEs) and the prognostic value of dose-volume histogram (DVH) parameters for the occurrence of treatment toxicity in patients treated with post-prostatectomy prostate bed radiotherapy (RT). The AEs were scored according to the CTCAE v.5.0. The rectum and bladder were contoured according to the RTOG Guidelines. The DVH parameters were assessed using data exported from the ECLIPSE treatment-planning system. Genitourinary (GU) and gastrointestinal (GI) toxicity were analysed using consecutive dose thresholds for the percentage of an organ at risk (OAR) receiving a given dose and the QUANTEC dose constraints. A total of 213 patients were included in the final analysis. Acute grade 2 or higher (≥G2) GU AEs occurred in 18.7% and late in 21.3% of patients. Acute ≥G2 GI toxicity occurred in 11.7% and late ≥G2 in 11.2% of the patients. Five patients experienced grade 4 AEs. The most common adverse effects were diarrhoea, proctitis, cystitis, and dysuria. The most significant predictors of acute ≥G2 GI toxicity were rectum V47 and V46 (p < 0.001 and p < 0.001) and rectum wall V46 (p = 0.001), whereas the most significant predictors of late ≥G2 GI AEs were rectum wall V47 and V48 (p = 0.019 and p = 0.021). None of the bladder or bladder wall parameters was significantly associated with the risk of acute toxicity. The minimum doses to bladder wall (p = 0.004) and bladder (p = 0.005) were the most significant predictors of late ≥G2 GU toxicity. Postoperative radiotherapy is associated with a clinically relevant risk of AEs, which is associated with DVH parameters, and remains even in patients who fulfil commonly accepted dose constraints. Considering the lack of survival benefit of postoperative adjuvant RT, our results support delaying treatment through an early salvage approach to avoid or defer toxicity.

Abstract 13481: A Rare Case of Pembrolizumab (Keytruda®) -Associated Thyrotoxicosis Causing Atrial Dysrhythmias

Introduction: Immune-Check-Point Inhibitors such as pembrolizumab (Keytruda®) are associated with the development of several immune-related adverse events. Case: 70-year-old malewith history of pleomorphic sarcoma of the right lower extremity with metastases to the lungs was started on Pembrolizumab 3 weeks before presenting to the ER with complaints of generalized weakness and palpitations. The patient was tachycardic and EKG showed atrial tachycardia at 144 beats/minute with right bundle branch block (RBBB) ( FIG 1B ). RBBB had been previously noted on EKG ( FIG 1A ). High-sensitivity-troponins were in the range of 29 to 37 ng/l. The TSH on admission was 0.01 mcu/ml with free T4 of 4.7 ng/dl (&gt; twice the upper limit of normal). Of note, TSH was normal prior to the initiation of Pembrolizumab (2.01 ng/dl). Anti-microsomal anti-thyroid peroxidase (TPO) antibodies were also elevated. US thyroid showed heterogeneous thyroid parenchyma concerning for thyroiditis. The patient received multiple doses of IV metoprolol and IV digoxin for rate control before converting spontaneously to normal sinus rhythm, and was then started on metoprolol succinate to maintain the heart rate. Decision Making: Based on the patient’s recent history of initiating Pembrolizumab therapy and normal thyroid function before, his thyroid dysfunction was attributed to the immunotherapeutic agent leading to atrial dysrhythmias. Endocrinology team was consulted, and prednisone 40 mg daily was started. Repeat free T4 after 5 days came down to 2.5 ng/dl. The patient was discharged home on oral Metoprolol and slow prednisone taper in the next few weeks and outpatient follow-up with endocrinology. Conclusion: Thyroid dysfunction is one of the most common immune-related adverse effects of Pembrolizumab that can cause multisystem dysfunction such as dysrhythmias. Therefore, clinicians should be familiar with their unique adverse effects to minimize morbidity and enable appropriate management.

A Drosophila model relevant to chemotherapy-related cognitive impairment

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model relevant to CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurologic deficits were observed with all tested chemotherapies, with doxorubicin and in particular cisplatin also resulting in memory deficits. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model relevant to CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI (and chemotherapy-induced neurotoxicity more generally) and pharmacologic screens to identify disease-modifying therapies.

Abstract 12545: Inpatient Physical Therapy Use Among US Veterans Hospitalized for Heart Failure

Background: Physical debilitation is a common adverse effect of heart failure (HF) hospitalization and is associated with adverse outcomes. Hypothesis: Inpatient physical therapy (PT) mitigates the adverse effects of HF hospitalization, and improves outcomes in patients hospitalized with HF. Methods: Patients with an index hospitalization for HF at a VA facility between January 1, 2013 to December 31, 2017 were identified. Change in PT use over time was evaluated using the Cochran-Armitage trend test. After propensity matching, the impacts of inpatient PT exposure on 90-day all-cause mortality, and a composite of all-cause mortality and readmission were assessed. Results: Of 44,299 patients admitted with HF, 11,685 (26.3%) received inpatient PT. Compared with those who did not receive PT, those who did were older (70.7 vs 75.8; P&lt;0.001), more frequently White (70.0% vs 74.0%; P&lt;0.001), and had a longer length of stay (3.9 vs 7.4; P&lt;0.001). The proportion of patients who utilized PT increased from 24.9% to 55.4% during the study period (P&lt;0.001). After propensity matching, inpatient PT use was associated with worse all-cause mortality (HR: 1.24 [1.14 - 1.36]; P&lt;0.0001) ( Figure ), and a composite outcome of death or all-cause hospitalization (HR: 1.07 [1.02 - 1.12]; P=0.0038) at 90 days. Conclusions: Inpatient PT use significantly increased from 2013 to 2017. After propensity matching, utilization of PT services was associated with adverse outcomes.

Efficacy and safety of polyethylene glycol loxenatide in type 2 diabetic patients: a systematic review and meta-analysis of randomized controlled trials

Polyethylene glycol loxenatide (PEX168) is a novel glucagon-like peptide-1 receptor agonist with a longer half-life developed by modifying the chemical structure of exenatide. This study aims to assess the efficacy and safety of PEX168 and determine the best dose. We searched PubMed, Scopus, Cochrane Library, and Web of Science databases from inception to April 25, 2023, for randomized controlled trials (RCTs) comparing PEX168 therapy alone or in combination with metformin versus other therapies. We used the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, both with 95% confidence intervals (CI). Six RCTs, including 1248 participants, were included. PEX168 added to metformin was significantly better than metformin alone regarding fasting blood glucose (MD = −1.20, 95% CI (−1.78, − 0.62), p < 0.0001), HbA1c (MD = −1.01, 95% CI (−1.48, − 0.53), p < 0.0001), and postprandial glycemia (MD = −1.94, 95% CI (−2.99, − 0.90), p = 0.0003). Similarly, for glycemic control, PEX168 monotherapy was superior to placebo (P < 0.05). No significant effects were noticed in terms of triglycerides, low-density lipoprotein, or high-density lipoprotein (p > 0.05). Body weight was significantly reduced in obese diabetic patients receiving PEX168 compared to the control group (MD = −5.46, 95% CI (−7.90, − 3.01), p < 0.0001) but not in non-obese patients (MD = 0.06, 95% CI (−0.47, 0.59), p = 0.83). People who received PEX168 alone or with metformin showed more common gastrointestinal adverse effects, especially nausea and vomiting (p < 0.05). PEX168 100, 200, and 300 ug monotherapy demonstrated comparable safety and diabetes control to metformin, but when combined with metformin, PEX168 100 and 200 ug showed significant effects on diabetes control; however, only the latter showed a significantly higher incidence of nausea and vomiting (p < 0.05). PEX168 could be a viable option for treating diabetic patients whose metformin control is inadequate or who cannot tolerate metformin. PEX168 at 100 ug in combination with metformin was found to be safe and more effective compared to metformin; however, due to the small number of trials included, these findings should be interpreted with caution, and additional trials are required.

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 Incb 39110-211 Placebo-Controlled Randomized Cohort

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Efficacy and Safety of Remdesivir in Hospitalized Pediatric COVID-19: A Retrospective Case-Controlled Study.

While most children experience mild coronavirus disease 2019 (COVID-19) infections, a minority of cases progress to severe or critical illness. This study aimed to assess the efficacy and safety of Remdesivir (RDV) therapy in children with moderate to severe COVID-19, enhancing clinical decision-making and expanding our understanding of antiviral treatments for pediatric patients. The study included 60 patients, 38 receiving RDV treatment and 22 serving as the control group. Data was collected retrospectively from January 2021 to January 2022 through electronic hospital records. Regarding the main clinical symptoms reported, most patients experienced Upper Respiratory Tract Infections (93.3%), indicating respiratory involvement. Additional symptoms included Central Nervous System (11.7%) and Gastrointestinal (10.0%). Among the 38 cases in the RDV group included in the study, the adverse effects associated with using RDV: Hypoalbuminemia in 19 cases (50.0%) and anemia in 18 cases (47.4%), making them the most common adverse effects. Only one case in the RDV group experienced non-RDV-related death with a different clinical diagnosis. The results showed that RDV treatment was well-tolerated in pediatric patients, with no significant differences in hospital stay and oxygen treatment compared to the control group with P values (0.2, 0.18), respectively. The outcomes indicate that Remdesivir may represent a safe and therapeutic choice for children with coronavirus disease 2019 (COVID-19).

Review of short-term and long-term adverse effects of covid-19 vaccination during pregnancy

BackgroundThe covid-19 pandemic sparked a debate about the safety of vaccines during pregnancy. However, pregnant women were excluded from the Pfizer-BioNTech vaccine phase 3 trials. As two years have passed since the first Covid-19 vaccine and more studies have been conducted, we want to evaluate the scientific literature to determine any actual risks in taking the vaccine during pregnancy. MethodsWe conducted literature research using PubMed and Google Scholar databases from January to April 2023. As the review considers short- and long-term adverse effects it was divided into two parts. The first part was conducted as a systematic review. The second concerning long-term negative effects due to lack of research is a literature review. The inclusion criteria for the systematic review part were singleton pregnancies, women vaccinated during pregnancy, and studies from 2020 and later. The most common short-term pregnancy adverse effects were included in the search: preterm delivery, small gestation age, intrauterine death, congenital defects, stillborn, fetal growth retardation, spontaneous abortion. Maternal immune activation was the primary concern for the long-term adverse effects and whether vaccination could cause it. The search terms included maternal immune activation, fetal neurodevelopment, neuropsychiatric disorders and the studies used were from 2019. ResultsMost studies showed no significant difference in short-term adverse effects between vaccinated and non-vaccinated women and their fetuses. However, the literature is insufficient to evaluate possible long-term adverse effects. ConclusionAvailable evidence supports the safety of administering SARS-CoV-2 vaccines to pregnant women, but further systematic reviews and meta-analyses are essential. Maternal immune activation caused by vaccination may impact a child's neurodevelopment and should be a concern for future studies.

Prevalence and determinants of adverse events following ChAdOx1 nCoV-19 vaccination (COVISHIELD) - A retrospective cohort study among healthcare workers in central Karnataka, India.

India has launched COVID vaccination program on January 16, 2021 and precautionary dose (third dose) on January 10, 2022. Our study evaluated adverse events following immunization (AEFI) among healthcare workers (HCWs) following first, second, and precautionary dose of ChAdOx1 nCoV-19 (COVISHIELD) vaccine. We also evaluated the association of AEFI with the study participants' characteristics. (1) To assess the adverse events among HCWs following first, second, and precautionary dose of COVISHIELD vaccine. (2) To determine the factors associated with adverse events of COVISHIELD vaccine. A retrospective cohort study was conducted among HCWs of a tertiary care teaching hospital in central Karnataka from January 2021 to June 2022. A semi-structured, pretested questionnaire was used to interview the HCW of tertiary care teaching hospital regarding adverse events following first, second, and precautionary dose of COVISHIELD vaccine; data collected was entered in MS Excel 2019 and analyzed using SPSS v24.0. Among 454 participants majority of them were females (231, 50.88%) and in the age group 18-27 years (151, 33.25%), and the majority were nursing staff (147, 32.37%). Adverse events were reported among 204 (44.93%) following the first dose, 149 (32.81%) after the second dose, and 230 (50.66%) participants following the precautionary dose. Generalized weakness and fever were the common adverse effects reported by participants. Majority of the study population did not report any adverse events following vaccination. Among the study participants who reported adverse events, most events were reported on the same day. Symptoms were mild in severity and short-lived.

A real-world analysis of tyrosine receptor kinase inhibitor-related toxicities in cancer treatment.

Background: This study analyzed real-world data from 2004 to 2023 to evaluate the toxicity profile of tyrosine receptor kinase (TRK) inhibitor therapy. Method: A retrospective analysis of USFDA Adverse Event Reporting System data was conducted to identify adverse events in patients receiving TRK inhibitor therapy. Result: Entrectinib demonstrated toxicities primarily in the cardiovascular and nervous systems, followed by the renal and urinary system. Common adverse effects included dizziness, renal impairment, constipation, heart failure and taste disorders. Larotrectinib induced adverse events mainly in the hepatobiliary and nervous systems, with peripheral neuropathy, myalgia, renal impairment and increased alanine aminotransferase commonly reported. Conclusion: Careful monitoring and supportive care strategies are essential for managing adverse events associated with TRK inhibitor therapy.

Real world experience on the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis in Taiwan.

Randomized controlled trials have demonstrated a reduction in the decline of lung function and a reduced risk of acute exacerbation in patients with idiopathic pulmonary fibrosis treated with the antifibrotic prifenidone. The present study aimed to investigate the real-world effectiveness and safety profile of pirfenidone treatment for patients with IPF in Taiwan. Between January 1, 2019 and December 31, 2020, we enrolled 50 patients who were newly diagnosed with IPF and had at least 12 months follow-up period after pirfenidone administration. The primary outcome of pharmacologic effect showed that the mean differences in the absolute values of forced vital capacity from baseline were 0.2 liter (n = 36), 0.13 liter (n = 32), 0.04 liter (n = 26), and - 0.004 liter (n = 26) after 3, 6, 9, and 12 months of administration, respectively. A slight improvement in quality of life, including scores of chronic obstructive pulmonary disease assessment test and St. George's respiratory questionnaire scores. The most common adverse effects were gastrointestinal upset and dermatological problems. No new safety concerns were observed in the present study. Our real-world study describe for the first time in Taiwan, the use of pirfenidone over a 12 months period. This drug preserves the lung function and improves quality of life with tolerable side effects.

The Tolerability and Safety of Psilocybin in Psychiatric and Substance-Dependence Conditions: A Systematic Review.

The objective of this systematic review is to determine the tolerability and safety of psilocybin in a variety of psychiatric and substance-dependence conditions. A systematic review was conducted using Embase, PubMed, Cochrane Central, and Web of Science through September 2023 using the following terminology: "psilocybin" AND "mental-disease" OR "substance-dependence" AND "disease-therapy," in addition to other synonymous key words. Literature reporting acute effects and safety data following the use of psilocybin as the pharmacologic intervention in a clinical trial in adult patients with a psychiatric or substance-dependence condition were included. Following the application of inclusion and exclusion criteria, 16 studies were ultimately included in this review. The most common treatment-emergent adverse effects reported were transient nausea and headache. Transient anxiety was reported as a frequent psychiatric effect, and 3 participants received a benzodiazepine for refractory anxiety during the psilocybin session. Psilocybin demonstrated modest increases in blood pressure and heart rate, and 1 participant received an antihypertensive for sustained hypertension during the psilocybin session. No cases of psilocybin-induced psychosis or Hallucinogen Persisting Perception Disorder were reported. Treatment resistance remains a concern for psychiatric patients and novel therapies are needed to help alleviate the burden of morbidity and mortality. Psilocybin demonstrates promising acute and long-term safety that may allow for its use in psychiatric or substance-dependence conditions as an alternative to standards of care or in treatment-resistant patients. Psilocybin has demonstrated tolerability and safety in recent literature that has investigated its therapeutic potential in a variety of psychiatric or substance-dependence conditions.

Development and Application of Prototype System Based on Light-Emitting Diode Arrays (660 nm) with a Top Hat Beam Profile in Order to Optimize Photobiomodulation Protocols for Treatment of Radiation-Induced Oral Mucositis in Rats.

Background: Oral mucositis (OM) is a common adverse effect of radiation to the head and neck. Recent research has shown that extra oral photobiomodulation (EO-PBM) reduces the severity of OM. However, appropriate EO-PBM therapy parameters for OM severity reduction have not been documented. Objective: This work aims to optimize EO-PBM radiation parameters for lowering the severity of radiation-induced OM in rats by establishing a photobiomodulation (PBM) treatment system based on light-emitting diode arrays with top-hat beam profile. Methods: The 36 rats are separated into 2 control groups and 4 groups receiving PBM treatment. The PBM groups are exposed to irradiance between 4 and 24 J/cm2 at 660 nm. The cheek pouch mucosa is removed after scarification for biochemical and histological examination. Student's t-test, and one-way analysis of variance (ANOVA) followed by Tukey's Multiple were applied to compare the statistical significance of differences between control groups and PBM treatment groups. Results: Statistical analysis reveals that PBM irradiation at 12 J/cm2 (200 sec) with a flatness of 0.8 and a diameter of 3 cm substantially decreased the level of inflammatory cytokines compared with the positive control group. Conclusions: Our results indicate that the designed treatment PBM system is capable of delivering the optical parameters necessary for therapeutic treatment.

Diabete mellito dopo trattamento con ocrelizumab per sclerosi multipla primariamente progressiva

Objectives: immune reconstitution therapies, which include antibody-based cell-depleting therapies targeting CD20+ (ocrelizumab, ofatumumab) or CD52+ (alemtuzumab) leukocytes, are approved for the treatment of multiple sclerosis. Autoimmune thyroid disease is the most common adverse effect of treatment with alemtuzumab, but some cases of autoimmune diabetes have been reported. To date, diabetes mellitus has not been reported after CD20-targeting monoclonal antibodies therapy. Case Report: a 41-year-old man with primary progressive multiple sclerosis was diagnosed with diabetes mellitus six months following the first ocrelizumab infusion. He experienced polyuria and polydipsia, but not other symptoms as visual loss or weight loss. We started a basal-bolus insulin therapy, with progressive and relatively rapid improvement of glycemic control. To note, C-peptide resulted indicative of a preserved beta-cell activity and autoantibodies were negative. To present date, the patient reached an excellent control with metformin. Conclusions: this is the first case of diabetes mellitus reported after ocrelizumab administration. The timing of onset and course are similar to alemtuzumab-induced autoimmune diseases, usually interpreted as an “immune reconstitution syndrome”; however, ocrelizumab cell count depletion appears inferior in duration and cell population affected. This case suggests the need for screening and follow-up of glycemic status in patients treated with ocrelizumab. As a novel therapeutic antibody, further investigation is required to elucidate the correlation between hyperglycemia and ocrelizumab.

The Role of Pharmacogenetics in the Therapeutic Response to Thiopurines in the Treatment of Inflammatory Bowel Disease: A Systematic Review.

This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients

BackgroundChimeric antigen receptor T (CAR-T) cell therapy, a new adoptive cell therapy, has been widely used to treat lymphoma patients. Immune checkpoint blockade may improve the cytotoxicity of CAR-T cells by reducing the failure of CAR-T cells and improving antitumor activity. It has shown promising efficacy.MethodWe searched PubMed, the Cochrane Library, Embase and Web of Science from January 2012 to August 2022 to find data reporting the results of CAR-T cells therapy combined with PD-1 in tumor patients. An updated search was conducted in October 2023. The partial response rate (PR), complete response rate (CR), objective response rate (ORR), mortality rate, and incidence of adverse reactions were calculated.ResultsWe analyzed 57 lymphoma patients from 5 clinical trials. The pooled partial, complete and overall response rates were 21% (95% CI 0.06–0.39, I2 = 0.37%), 27% (95% CI 0.03–0.60, I2 = 60.43%) and 65% (95% CI 0.23–0.98, I2 = 76.31%), respectively. The pooled incidence of cytokine release syndrome, neutropenia, fever, and fatigue was estimated to be 57% (95% CI 0.08–0.99, I2 = 85.20%), 47% (95% CI 0.14–0.81, I2 = 74.17%), 59% (95% CI 0.27–0.89, I2 = 60.23%), and 50% (95% CI 0.13–0.87, I2 = 73.89%), respectively.ConclusionCAR-T-cell therapy combined with anti-PD-1 immunotherapy in the treatment of lymphoma patients has efficacy, and the most common adverse effect is fever.RegistrationThe protocol was registered in prospero, with the registration number CRD42022342647.

Evaluation of Adverse Effects after the Second Dose of BNT162b2 Mrna Vaccination for COVID-19: A Survey-based Analysis among Italian Healthcare Workers

Backgrounds and Aims: Since the start of the SARS-CoV-2 pandemic, healthcare workers have been at elevated risk of contracting COVID-19. Although COVID-19 vaccines have contributed to the eradication of, or substantial decreases in, the incidence of lethal diseases, the major determinant of COVID-19 vaccine hesitancy is a fear of associated adverse effects. Here, we performed a survey assessing the reactogenicity and safety of BNT162b2 in a real-world setting. Methods: Data were collected from March 1 and June 14, 2021. A total of 206 hospital employees undergoing BNT162b2 mRNA vaccination completed the survey. These hospital workers received a questionnaire to collect the common and uncommon adverse effects developing 2–6 days after the second dose of the Pfizer-BioNTech vaccine. Results: After the second dose, female sex was found to be associated with a higher risk of vaccine-related severe systemic adverse effects than male sex (odds ratio [OR] 3.116, 95% CI 2.365–7.113). We also observed that the anti-SARS-CoV-2 receptor-binding domain titer, determined on the day when the second dose of the Pfizer-BioNTech vaccine was administered, was significantly higher in participants with severe systemic effects than those without such effects (OR 1.017, 95% CI 1.001–1.034). Conclusion: Our study suggested that healthy female healthcare workers had a three-fold higher risk than healthy male healthcare workers of developing severe adverse effects after the second dose of the Pfizer-BioNTech vaccine. Further research is warranted to determine whether a high anti-SARS-CoV-2 RBD titer determined at the time of the second vaccination might indicate a disproportionate inflammatory systemic reaction leading to severe adverse effects. Our findings might contribute to a decrease in the disappearance of COVID-19 vaccine hesitancy.

Possible therapeutic role of zinc oxide nanoparticles versus vanillic acid in testosterone-induced benign prostatic hyperplasia in adult albino rat: A histological, immunohistochemical and biochemical study

BackgroundThe search for alternative therapies for treatment of Benign prostatic hyperplasia (BPH) has been increasingly studied to avoid the common adverse effects of the usual regimens. Therefore, this study aimed at delineating possible mechanisms of benign prostatic hyperplasia (BPH) and possible therapeutic role of zinc oxide nanoparticles (ZnO-NPs) versus vanillic acid. MethodsForty rats were divided into five groups: control, sham control, Testosterone-induced BPH, BPH and Zn-NPs, and BPH and vanillic acid. Light microscopic, immune-histochemical; PCNA, Bcl-2, Bax, caspase-3, p-Akt and p-mTOR, histomorphometric analysis, MDA/SOD and GPx and were done. Gene expression of p-Akt, p-mTOR and survivin were evaluated. ResultsApplication of zinc oxide nanoparticles as well as vanillic acid significantly reduced prostatic index, epithelial thickness, stromal collagen fibers, expression of PCNA, Bcl2, p-Akt, p-mTOR and MDA tissue level (p < 0.05). Whereas expression of Bax and caspase 3, and tissue levels of SOD and GPx were significantly increased in groups treated with Zno-Nps and vanillic acid compared to that of BPH group. Zinc oxide nanoparticles showed a better effect than vanillic acid in alleviating BPH. ConclusionThese findings suggested that ZnO-NPs as well as VA ameliorated the histolo-pathological and biochemical effects of induced BPH, moreover they improved the proapoptotic and antioxidant parameters which ere induced in BPH. It is recommended to search for new agents to prevent the development and progression of BPH.