Front Endocrinol (Lausanne). 2022 Mar 23;13:794512. doi: 10.3389/fendo.2022.794512. eCollection 2022.

ABSTRACT

Tyrosine kinase inhibitors (TKIs) are nowadays a valuable treatment of desmoid tumors, a rare mesenchymal neoplasm. Although many side effects of imatinib and pazopanib, commonly or rarely occurring, have been described, reactional lymphadenopathy has not yet been reported. In this publication, we report two cases of patients with desmoid tumors, treated with pazopanib and imatinib, who developed reactional lymphadenopathy. As this side effect is presented as a newly formed mass, it can result in new diagnostic questions and added imaging tests and can even lead to discontinuation of the treatment. This report may help the clinicians facing similar problems adopt a "watch and wait" approach.

PMID:35399933 | PMC:PMC8984282 | DOI:10.3389/fendo.2022.794512

Cancer Discov. 2022 Apr 11:candisc.1615.2021. doi: 10.1158/2159-8290.CD-21-1615. Online ahead of print.

ABSTRACT

Epidermal growth factor receptor exon 20 insertion mutations (EGFR exon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to lack of effective therapy, the prognosis of these patients was poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor, showing activity against EGFR exon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase 1 clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFR exon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response (DoR) has not been reached.

PMID:35404393 | DOI:10.1158/2159-8290.CD-21-1615

J Biomater Sci Polym Ed. 2022 Apr 11:1-26. doi: 10.1080/09205063.2022.2065408. Online ahead of print.

ABSTRACT

There has been a growing interest in the scientific community to explore the complete potential of phytoconstituents, herbal or plant-based ingredients owing to a range of benefits they bring along. The herbal plants accommodate many phytoconstituents that are responsible for various activities such as anti-oxidant, antimicrobial, anticancer, anti-inflammatory, anti-allergic, hepatoprotective, etc. However, these phytoconstituents are highly sensitive to several environmental and physiological factors such as pH, oxygen, heat, temperature, humidity, stomach acid, enzymes, and light. Hence, the need is to development of a drug delivery system that can protect the phytoconstituents from both internal and external conditions. In this regard, a microparticulate drug delivery system is considered amongst the ideal choice owing to its small size, ability to protect the environment-sensitive active constituents, in achieving sustained drug delivery, targeted drug delivery, protection of the drug from physiological conditions, minimizing drug-related side effects, etc.

PMID:35404217 | DOI:10.1080/09205063.2022.2065408

Antimicrob Agents Chemother. 2022 Apr 11:e0009422. doi: 10.1128/aac.00094-22. Online ahead of print.

ABSTRACT

GST-HG131, a novel dihydroquinolizinone (DHQ) compound, has been shown to reduce circulating levels of HBsAg in animals. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetic profile of GST-HG131 in healthy Chinese subjects. This was a double-blind, randomized, placebo-controlled phase Ia clinical trial that was conducted in two parts. Part A was a single-ascending-dose (SAD; GST-HG131 10 30, 60, 100, 150, 200, 250 or 300 mg or placebo) study, which also assessed the food effect of GST-HG131 100 mg. Part B was a multiple-ascending-dose (MAD; GST-HG131 30, 60 or 100 mg or placebo BID) study. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. PK analyses were conducted in blood, urine, and fecal samples. Single doses of GST-HG131 ≤ 300 mg and multiple doses of GST-HG131 ≤ 60 mg were generally safe and well tolerated; however, multiple dosing was stopped at GST-HG131 100 mg, as pre-defined stopping rules specified in the protocol were met (Grade II drug related AEs of nausea and dizziness in >50% of subjects). In the SAD study, median tmax of GST-HG131 was 1-6 h, and t1/2 ranged from 3.88 h to 14.3 h. PK parameters were proportional to dose. Exposure was reduced after food intake. In the MAD study, steady-state was attained on day 4, and there was no apparent plasma accumulation of GST-HG131 on day 7 (Racc < 1.5). In conclusion, GST-HG131 exhibited an acceptable safety profile in healthy subjects at single doses ranging from 10-300 mg and multiple doses (BID) ranging from 30-60 mg, and the MAD doses (30 mg and 60 mg BID) that potentially meet the therapeutic AUC requirements. These findings imply GST-HG131 has potential as a therapeutic option for CHB infection. (This study has been registered at ClinicalTrials.gov under identifier NCT04499443.).

PMID:35404074 | DOI:10.1128/aac.00094-22

J Endocr Soc. 2022 Mar 10;6(5):bvac038. doi: 10.1210/jendso/bvac038. eCollection 2022 May 1.

ABSTRACT

Among the side effects of methimazole (MMI) for the treatment of Graves' disease, MMI-induced acute pancreatitis (MIP) is a rare adverse reaction, with only 7 cases being reported to date. However, 2 large-scale population-based studies recently revealed that the risk of MIP was significantly higher, ranging from 0.02% to 0.56%. Although MIP is common in middle-aged and elderly Asian women, its pathogenesis remains largely unknown. We herein present a case of a 72-year-old Japanese woman with Graves' disease who developed MIP 12 days after the initiation of MMI. The MMI was discontinued, the patient was switched to propylthiouracil (PTU) therapy, and pancreatitis gradually resolved. Serological human leukocyte antigen (HLA) typing identified HLA-DRB1*08:03:02. This HLA allele was previously detected in a patient with MIP and is one of the major risk factors for agranulocytosis induced by antithyroid drugs, including PTU as well as MMI. In cases of MIP, PTU is being considered as an alternative to MMI; however, its safety needs further investigation and patients require close monitoring after the switch to PTU. Further studies are warranted, particularly on the relationship between MIP and the presence of HLA alleles causing antithyroid drug-induced agranulocytosis.

PMID:35402762 | PMC:PMC8989154 | DOI:10.1210/jendso/bvac038

Cancer Diagn Progn. 2021 Mar 3;1(1):19-22. doi: 10.21873/cdp.10003. eCollection 2021 Mar-Apr.

ABSTRACT

BACKGROUND: The third-generation tyrosine kinase inhibitor ponatinib has demonstrated high clinical efficacy in the setting of patients with resistant chronic phase chronic myeloid leukemia (CML), also inducing deep molecular responses. However, ponatinib-related cardiovascular toxicities make management challenging, especially of those patients with CML with previous cardiovascular comorbidities.

CASE REPORT: We report on the efficacy of ponatinib treatment used as fourth-line therapy in a 55-year-old woman affected by significant comorbidities (mainly cardiovascular) present before the diagnosis of CML. Ponatinib therapy induced a rapid and excellent clinical response, with the achievement of a durable deep molecular response that allowed us to propose a strategy of treatment discontinuation in order to reduce drug-related toxicities.

CONCLUSION: A strategy of a treatment-free interval might represent a useful clinical tool in those patients with CML who achieve a durable deep molecular response but are also affected by significant comorbidities in order to minimize the risk of ponatinib-related toxicities.

PMID:35399694 | PMC:PMC8962775 | DOI:10.21873/cdp.10003

BMC Geriatr. 2022 Apr 9;22(1):307. doi: 10.1186/s12877-022-03025-3.

ABSTRACT

BACKGROUND: Medication reviews contribute to protecting long-term care (LTC) residents from drug related problems (DRPs). However, few controlled studies have examined the impact on patient-relevant outcomes so far.

OBJECTIVE: We examined the impact of a one-time, pharmacist-led medication review on medication changes (primary endpoint) including discontinued medication, the number of chronic medications, hospital admissions, falls, and deaths (secondary endpoints).

METHODS: A prospective, controlled intervention study was performed in three LTC facilities. In the intervention group (IG), after performing a medication review, a pharmacist gave recommendations for resolving DRPs to physicians, nurses and community pharmacists. The control group (CG) received usual care without a medication review. (i) We assessed the number of medication changes and the secondary endpoints in both groups before (t0) and after (t1, t2) the intervention. (ii) Additionally, the medication review was evaluated in the IG with regard to identified DRPs, the healthcare professional's feedback on the forwarded pharmacist recommendations and whether DRPs were finally resolved.

RESULTS: 107 (IG) and 104 (CG) residents were enrolled. (i) More medication changes were identified in the IG than in the CG at t1 (p = 0.001). However, no significant difference was identified at t2 (p = 0.680). Mainly, medication was discontinued in those medication changes. Chronic medications increased in the CG (p = 0.005) at t2 while hospital admissions, falls, and deaths showed no differences. (ii) Overall, 1252 DRPs (median: 10; minimum-maximum: 2-39) were identified. Recommendations for 82% of relevant DRPs were forwarded to healthcare professionals, of which 61% were accepted or clarified. 22% were not accepted, 12% required further review and 6% remained without feedback. 51% of forwarded DRPs were finally resolved.

CONCLUSIONS: We found more medication changes in the IG compared to controls. Mostly, medication was discontinued. This suggests that our intervention was successful in discontinuing unnecessary medication. Other clinical outcomes such as falls, hospitalisations, and deaths were not improved due to the one-time intervention. The medication review further identified a high prevalence of DRPs in the IG, half of which were finally resolved.

TRIAL REGISTRATION: German Clinical Trials Register, DRKS00026120 ( www.drks.de , retrospectively registered 07/09/2021).

PMID:35397527 | DOI:10.1186/s12877-022-03025-3

Int J Dermatol. 2022 Apr 10. doi: 10.1111/ijd.16222. Online ahead of print.

ABSTRACT

The Moderna COVID-19 vaccination was approved for use in the United States in December of 20201 and since that time massive public health efforts have been made to vaccinate patients against the COVID-19 infection. Adverse reactions from the vaccination are well-reported and include both local skin reactions, such as pain, swelling, and erythema at the injection site, as well as systemic reactions including fever, malaise, headache, muscle aches, drowsiness, nausea, and vomiting. While severe serious cutaneous adverse reactions, such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), remain rare; two cases of SJS/TEN related to COVID-19 vaccination have been reported. We herein review the two previously reported cases of SJS/TEN and report the first case of SJS precipitated by the Moderna Inc., MRNA 1273 COVID-19 vaccination in the United States. Although we review potential adverse reactions to vaccination, the benefits of COVID-19 vaccination outweigh the risks based on current data. Cases should be reported to the Vaccine Adverse Event Reporting System (https://vaers.hhs.gov/) to help public health officials recognize and track these severe but rare adverse events.

PMID:35398905 | DOI:10.1111/ijd.16222

Int Rev Neurobiol. 2022;162:171-184. doi: 10.1016/bs.irn.2021.12.006. Epub 2022 Mar 15.

ABSTRACT

Nonmotor symptoms of Parkinson's disease (PD) range from neuropsychiatric and cognitive to sleep, sensory, and genito-urinary disorders, and occur as a result of the disease process as well as due to side effects of drug treatment for PD. Sexual dysfunction is an important aspect of the nonmotor profile of Parkinson's but is rarely discussed. Sexual health is considered an integral element of holistic health, thus sexual dysfunction can also significantly impact quality of life in people with Parkinson's. The effect of sexual dysfunction of PD, both disease related and drug induced, on the concept of "wellness" of patients and their intimate partners is poorly understood, inadequately researched and a key unmet need in care and support. In this chapter we discuss the concept of "wellness" as applied to the treatment of PD, the ways in which nonmotor symptoms and other aspects of living may affect wellness in PD, and strategies for addressing sexual health utilizing a wellness model.

PMID:35397785 | DOI:10.1016/bs.irn.2021.12.006

Drug Ther Bull. 2022 Apr 8:dtb-2022-000022. doi: 10.1136/dtb.2022.000022. Online ahead of print.

NO ABSTRACT

PMID:35396226 | DOI:10.1136/dtb.2022.000022

BMC Cancer. 2022 Apr 7;22(1):371. doi: 10.1186/s12885-022-09480-w.

ABSTRACT

BACKGROUND: Toxicity during chemoradiotherapy (CRT) in cervical cancer patients might limit the chances of receiving an optimal treatment and to be cured. Few studies have shown relationships between acute side effects and patient's age. Here, the association between age and acute side effects such as nausea/vomiting, diarrhea and weight loss during CRT was analysed in cervical cancer patients.

METHODS: This study included 93 patients with primary cervical cancer stage IBI to IVA who received CRT from 2013 to 2019. The frequency of symptoms/toxicity grade was analysed by using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

RESULTS: Patients ≥ 52 years had a significantly higher frequency of nausea/vomiting and increased grade ≥ 3 toxicity during CRT compared to younger patients (p < 0.001, p = 0.001). Toxicity grade ≥ 3 of nausea/vomiting was associated with increased frequency of weight loss (p = 0.001), reduced ADL (p = 0.001) and dose modifications of both radiotherapy (RT) (p = 0.020) and chemotherapy (CT) (p = 0.030) compared to toxicity grade 2. The frequency of diarrhea (p = 0.015) and weight loss (p = 0.020) was higher in older patients compared to younger.

CONCLUSIONS: Older patients have an increased risk of acute side effects as nausea/vomiting, diarrhea and weight loss. Age could be useful in predicting acute side effects in primary cervical cancer patients with CRT.

PMID:35392858 | PMC:PMC8991473 | DOI:10.1186/s12885-022-09480-w

Front Endocrinol (Lausanne). 2022 Mar 22;13:779915. doi: 10.3389/fendo.2022.779915. eCollection 2022.

ABSTRACT

Immune-oncologic (IO) therapy has revolutionized the treatment and management of oncologic disease. Immunotherapy functions by enhancing the host immune-systems ability to endogenously clear malignant cells, however, this activation can also lead to immune-mediated damage to healthy native tissues. These side effects are known as immune-related adverse events or irAEs and can even present with phenotypes similar to autoimmune diseases. IrAEs are the major consequence of checkpoint inhibitors and can have a significant impact on a patient's cancer treatment and long-term quality of life. The management of these irAEs follows a similar approach to autoimmune diseases. More specifically, the management is akin to that of autoimmune disease exacerbations. While there is an array of immune-suppressing agents that can be used, steroids, immunomodulators and IO discontinuation are cornerstones of irAE management. The exact approach and dosing are based on the severity and subtype of irAE presented. Within recent years, there has been a push to better prevent and manage irAEs when they arise. There has been an additional effort to increase the number of steroid-sparing agents available for irAE treatment given the consequences of long-term steroid therapy as well as patient contraindications to steroids. The goals of this review are to summarize irAE management, highlight significant advances made in recent years and emphasize the future directions that will optimize the use of IO therapy in oncology.

PMID:35392134 | PMC:PMC8982145 | DOI:10.3389/fendo.2022.779915

Front Mol Neurosci. 2022 Mar 22;15:786632. doi: 10.3389/fnmol.2022.786632. eCollection 2022.

ABSTRACT

Interindividual variability in drug response is a major concern among patients undergoing antipsychotic drug treatment. Apart from genetic and physiological factors, this variability in drug response could also be attributed to epigenetic mechanisms. The microRNAs (miRNAs) are key epigenetic markers that play an important role in pathogenesis and drug response. Several studies have shown that miRNAs are implicated in regulating the expression of various genes involved in drug metabolism and transport. In a conventional clinical setup, it is extremely difficult to distinguish the role of miRNA in pathogenesis and drug response as it is difficult to obtain drug naïve patients. To resolve this issue, we aimed to identify the role of antipsychotic drug treatment in inducing miRNA expression under an in vitro condition using a hepatic cell line. A liver cell line was treated with a maximum tolerable drug dosage model for haloperidol, clozapine in monotherapy, and their combination in polytherapy. Genome-wide miRNA profiling was performed using 60,000 miRNA probes in the microarray format in different treatment groups. Several miRNAs were observed to be differentially expressed impacting the pharmacokinetic, pharmacodynamics, and epigenomics properties of antipsychotic drug treatment. Interestingly, some of these miRNA expression patterns were similar to reported miRNA observations on schizophrenia pathogenesis. This study unravels the potential role of miRNAs in the mechanism of action of the antipsychotic drug and could also reflect in drug-induced side effects. This study also signifies the importance of pharmacoepigenomics approach while evaluating the role of miRNAs in pathogenesis.

PMID:35392270 | PMC:PMC8980709 | DOI:10.3389/fnmol.2022.786632

Eur J Clin Pharmacol. 2022 Apr 6. doi: 10.1007/s00228-022-03317-y. Online ahead of print.

ABSTRACT

OBJECTIVE: This study evaluated the pharmacokinetic (PK) characteristics of benapenem in subjects with mild to moderate renal impairment to provide a reference for benapenem dosing regimens in this patient population.

METHODS: Eighteen subjects were enrolled in this study. Each subject received a single dose of benapenem intravenously (1.0 g in 100 ml of 0.9% saline) followed by blood and urine collection to measure the concentrations of benapenem and its major metabolite. PK analysis was performed to evaluate the effect of varying degrees of renal impairment on the PK characteristics of benapenem. The safety of benapenem was also evaluated.

RESULTS: In subjects with normal renal function, mild renal impairment, and moderate renal impairment, the maximum plasma benapenem concentrations were 163 ± 6.58 mg/L, 138 ± 17.4 mg/L, and 134 ± 0.11 mg/L, respectively (15.3% and 17.8% lower in subjects with mild and moderate renal impairment, respectively, than in subjects with normal renal function). The areas under the plasma concentration-time curve (AUC0-inf) were 1153.67 ± 143.2 mg·h/L, 1129.17 ± 241.41 mg·h/L, and 1316.46 ± 229.83 mg·h/L, respectively (P > 0.05); the cumulative urinary excretion rates at 72 h after dosing were 52.61 ± 8.58%, 39.42 ± 8.35%, and 29.84 ± 9.15%, respectively; and the metabolic ratio (AUC0-inf_KBP-3331/AUC0-inf_benapenem) were 3.96 ± 0.35%, 5.56 ± 0.82%, and 8.24 ± 0.85%, respectively. No drug-related adverse events (AEs), serious AEs, or AEs leading to withdrawal occurred in this study.

CONCLUSION: No adjustment to benapenem dosing is needed in patients with mild to moderate renal impairment.

CLINICAL TRIAL REGISTRATION: Drug clinical trial registration and information publicity platform: http://www.chinadrugtrials.org.cn/index.html .

REGISTRATION NUMBER: CTR20190760.

PMID:35385974 | DOI:10.1007/s00228-022-03317-y

Cell Rep. 2022 Apr 5;39(1):110643. doi: 10.1016/j.celrep.2022.110643.

ABSTRACT

In this study, we establish a population-based human induced pluripotent stem cell (hiPSC) drug screening platform for toxicity assessment. After recruiting 1,000 healthy donors and screening for high-frequency human leukocyte antigen (HLA) haplotypes, we identify 13 HLA-homozygous "super donors" to represent the population. These "super donors" are also expected to represent at least 477,611,135 of the global population. By differentiating these representative hiPSCs into cardiomyocytes and neurons we show their utility in a high-throughput toxicity screen. To validate hit compounds, we demonstrate dose-dependent toxicity of the hit compounds and assess functional modulation. We also show reproducible in vivo drug toxicity results using mouse models with select hit compounds. This study shows the feasibility of using a population-based hiPSC drug screening platform to assess cytotoxicity, which can be used as an innovative tool to study inter-population differences in drug toxicity and adverse drug reactions in drug discovery applications.

PMID:35385754 | DOI:10.1016/j.celrep.2022.110643

Eur J Hosp Pharm. 2022 Apr 5:ejhpharm-2021-003038. doi: 10.1136/ejhpharm-2021-003038. Online ahead of print.

ABSTRACT

OBJECTIVES: Several studies have reported the role of immune-related adverse events as a predictor of clinical benefit, but few have properly described these findings in advanced or metastatic non-small cell lung cancer treated with pembrolizumab. This study aimed to evaluate the association between immune-related adverse events development and clinical outcomes in the aforementioned group of patients.

METHODS: We conducted a retrospective study in patients with advanced or metastatic non-small cell lung cancer treated with pembrolizumab. Overall response rate, progression-free survival and overall survival were evaluated according to the appearance, subtype and number of immune-related adverse events developed. We report the results of the immune-related adverse events analysis and the potential correlation between immune-related adverse events and clinical outcomes. Univariate and multivariate analyses were performed to evaluate this relationship.

RESULTS: A total of 94 patients were analysed; 60 of them developed immune-related adverse events. Patients with immune-related adverse events had a significantly higher overall response rate compared with the non-immune-related adverse events group (34% vs 8.5%, χ2=0.005). Median progression-free survival was statistically significant in favour of patients with at least one immune-related adverse event (p=0.015). Median overall survival was not reached in patients with ≥1 immune-related adverse events, compared with 8 months (95% CI 0.6 to 15.4 months) in those without immune-related adverse events. Patients who developed ≥2 immune-related adverse events had longer median progression-free survival (11 vs 4 months, not statistically significant) and overall survival (not reached vs 11, p=0.022) compared with those with ≤1 immune-related adverse events.

CONCLUSIONS: Obtained data showed that patients with immune-related adverse events occurrence had significantly better overall response rate and longer progression-free survival and overall survival. This study highlights the role of immune-related adverse events as a predictor of survival in a real-life setting.

PMID:35383033 | DOI:10.1136/ejhpharm-2021-003038

Indian J Tuberc. 2022 Apr;69(2):250-252. doi: 10.1016/j.ijtb.2021.02.013. Epub 2021 Mar 2.

ABSTRACT

OBJECTIVE: To present an interesting case of unusual side effect of Mycobacterium W. in an adult COVID 19 positive male and discuss its assessment and management.

METHODS: - DESIGN: Case Report.

SETTING: Tertiary care hospital.

PATIENT: One.

RESULTS: 70 years male was admitted with complaints of fever, persistent dry cough since 10-12 days and progressive breathlessness since 3-4 days. Patient was found COVID-19 RTPCR positive and is known case of Type-II Diabetes with CAD (Post PTCA). Patient was managed conservatively with Oxygen support, I/V antibiotics, I/V Steroids, oral Favipiravir and other supportive treatment. Patient was also given injection Mycobacterium W. in dose of 0.3 ml per day intradermally at 3 different sites (both deltoids) consecutively for three days. 7-8 days after administration, patient developed bright red pustules which later got converted into small punched out ulcerations on all nine local sites of administration, which were managed conservatively with oral analgesics and local steroids for 8-10 days which healed without any scar formation.

CONCLUSION: Injection Mycobacterium W. is used in COVID 19 patients as an immunomodulator agent and has been proved to be safe in most of the cases but we encountered this unusual side effect of bright red pustules formation at all nine local sites of injection in our case most likely because of being administered subcutaneously instead of intradermally, making this an interesting case which is being reported to scientific fraternity.

PMID:35379411 | PMC:PMC7923955 | DOI:10.1016/j.ijtb.2021.02.013

Endokrynol Pol. 2022;73(1):110-120. doi: 10.5603/EP.a2021.0109.

ABSTRACT

INTRODUCTION: Familial hypercholesterolaemia (FH) is the most common autosomal genetic disease of cholesterol metabolism disorder. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody (mAb) is a new target lipid-regulating drug related to cholesterol metabolism that has been developed in recent years. The reported rate of reduction varies widely, and comprehensive assessments of efficacy and safety are lacking. Therefore, we conducted this study to investigate the clinical effect of PCSK9 mAbs in patients with familial hypercholesterolaemia to provide a theoretical reference for clinical practice.

MATERIAL AND METHODS: We analysed the clinical data of patients, including the percentage change in LDL-C and the incidence rates of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), from selected articles. Weighted mean differences (WMDs), risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated to compare the endpoints.

RESULTS: The results showed that, compared with placebo, the PCSK9 mAb reduced the percentage change in LDL-C in FH patients (WMD = -45.52, 95% CI: -49.70 to -41.34, I2 = 99.6%). In addition, there was no significant difference between the experimental and placebo groups in the incidence of TEAEs (RR = 1.03, 95% CI: 0.97 to 1.10, I2 = 19.1%) and SAEs (RR = 1.02, 95% CI: 0.72 to 1.44, I2 = 0.0%).

CONCLUSIONS: Overall, PSCK9 mAbs are an effective and safe method of LDL-C reduction in patients with FH.

PMID:35381104 | DOI:10.5603/EP.a2021.0109

J Immunother Cancer. 2022 Apr;10(4):e004656. doi: 10.1136/jitc-2022-004656.

ABSTRACT

OBJECTIVE: This study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy.

METHODS: Initially, 20 patients with HCC were screened and 18 patients with resectable HCC were enrolled in this open-label, single-arm, phase II clinical trial. Patients received three cycles of neoadjuvant therapy including three doses of camrelizumab concurrent with apatinib for 21 days followed by surgery. Four to 8 weeks after surgery, patients received eight cycles of adjuvant therapy with camrelizumab in combination with apatinib. Major pathological reactions (MPR), complete pathological reactions (pCR), objective response rate (ORR), relapse-free survival (RFS), and adverse events (AE) were assessed. In addition, cancer tissue and plasma samples were collected before and after treatment, and genetic differences between responding and non-responding lesions were compared by tumor immune microenvironment (TIME) analysis, circulating tumor DNA (ctDNA) analysis and proteomics analysis.

RESULTS: In 18 patients with HCC who completed neoadjuvant therapy, 3 (16.7%) and 6 (33.3%) patients with HCC reached ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and modified RECIST criteria, respectively. Of the 17 patients with HCC who received surgical resection, 3 (17.6%) patients with HCC reported MPR and 1 (5.9%) patient with HCC achieved pCR. The 1-year RFS rate of the enrolled patients was 53.85% (95% CI: 24.77% to 75.99%). Grade 3/4 AEs were reported in 3 (16.7%) of the 18 patients, with the most common AEs being rash (11.1%), hypertension (5.6%), drug-induced liver damage (5.6%), and neutropenia (5.6%) in the preoperative phase. The 289 NanoString panel RNA sequencing showed that TIME cell infiltration especially dendritic cells (DCs) infiltration was better in responding tumors than in non-responding tumors. Our results of ctDNA revealed a higher positive rate (100%) among patients with HCC with stage IIb-IIIa disease. When comparing patients with pCR/MPR and non-MPR, we observed more mutations in patients who achieved pCR/MPR at baseline (6 mutations vs 2.5 mutations, p=0.025). Patients who were ctDNA positive after adjuvant therapy presented a trend of shorter RFS than those who were ctDNA negative. Proteomic analysis suggested that abnormal glucose metabolism in patients with multifocal HCC might be related to different sensitivity of treatment in different lesions.

CONCLUSION: Perioperative camrelizumab plus apatinib displays a promising efficacy and manageable toxicity in patients with resectable HCC. DCs infiltration might be a predictive marker of response to camrelizumab and apatinib as well as patients' recurrence. ctDNA as a compose biomarker can predict pathological response and relapse. Abnormal glucose metabolism in patients with multifocal HCC may be related to different sensitivity of treatment in different lesions.

TRIAL REGISTRATION NUMBER: NCT04297202.

PMID:35379737 | DOI:10.1136/jitc-2022-004656

An Bras Dermatol. 2022 Apr 1:S0365-0596(22)00025-3. doi: 10.1016/j.abd.2021.06.008. Online ahead of print.

ABSTRACT

BACKGROUND: Adverse drug reactions are frequent, with cutaneous manifestations being the most common. In the hospital environment, the incidence of cutaneous drug reactions varies from 2% to 3%.

OBJECTIVE: To analyze the profile of cutaneous drug reactions, relating clinical forms, suspected medications, histopathological alterations, systemic repercussions, treatment and course.

METHODS: Clinical, retrospective and observational study of patients seen by the Dermatology Interconsultation team from January 2013 to December 2016.

RESULTS: The frequency of cutaneous drug reactions among the evaluated patients was 13.6%, with 219 cases diagnosed. In 65.7%, the reaction was considered mild, of which the most common was exanthema, while in 34.2%, the reaction was considered severe, with DRESS being the main form of reaction(18.2%). Antibiotics (36.5%) and anticonvulsants (10%) were the most involved drugs. In addition to drug discontinuation, systemic corticosteroids were prescribed in 47% of cases and intravenous immunoglobulin (IVIg) in 4.5%. Of the mild forms, in 62%, expectant management and/or exclusive use of symptomatic treatment was used.

STUDY LIMITATIONS: Retrospective study, with limitations inherent to this type of investigation; lack of some information in medical records; long evaluation period, with a possible change in external validity.

CONCLUSION: The most frequently identified clinical form was exanthema, and antibiotics and anticonvulsants were the most frequently involved drug classes. About one-third of the patients had severe cutaneous drug reactions, with DRESS being the main one. Cutaneous drug reactions are frequent in clinical practice, and the dermatologist should be called in as soon as possible to assist in the diagnosis and management of these cases.

PMID:35379507 | DOI:10.1016/j.abd.2021.06.008