Premedication strategy in cetuximab rechallenge after Grade 2 hypersensitivity reactions.

INTRODUCTION: Cetuximab, an IgG1 monoclonal antibody, is utilized in the treatment of metastatic colorectal cancer and squamous cell head and neck cancers. Due to the risk of hypersensitivity reactions, standard premedication with a histamine-1 (H-1) antagonist is recommended prior to administration, however, there is less guidance for premedication strategies to assist with rechallenge after infusion reactions. Here, we describe two cases of successful cetuximab treatment after Grade 2 reactions, in addition to risk factors and proposed premedication strategies for successful rechallenge. CASE REPORT: Two patients who experienced Grade 2 hypersensitivity reactions were both successfully rechallenged with increased premedications 1-2 weeks after initial infusions. The first patient was a 56-year-old male diagnosed with metastatic colorectal cancer receiving cetuximab as part of a clinical trial. The second patient was a 73-year-old male diagnosed with head and neck cancer receiving cetuximab as part of standard of care concurrent with radiation. MANAGEMENT AND OUTCOME: Each patient was rechallenged with an increased premedication strategy including dexamethasone, famotidine, diphenhydramine, and acetaminophen in addition to reducing the infusion rate. Both patients either continued treatment or successfully completed therapy, without any additional infusion-related reactions. DISCUSSION: We aimed to review risk factors related to cetuximab infusion reactions and propose a premedication strategy for rechallenge postreaction. Known risk factors include male sex and the accumulation of cetuximab-specific IgE. These may be mitigated by the addition of increased premedication with dexamethasone and famotidine with concurrent reduced infusion rate.

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

AIMS: Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. METHODS: Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. RESULTS: In Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N = 28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. CONCLUSIONS: The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Xerostomia: an immunotherapy-related adverse effect in cancer patients.

PURPOSE: Xerostomia is an underrecognized adverse effect of immunotherapy (IO) that can significantly impact patients' quality of life by leading to poor nutritional status, dental caries, and oral candidiasis. The purpose of this case series was to describe the onset, severity, clinical course, and management of IO-induced xerostomia. METHODS: This was a retrospective case series conducted at an outpatient cancer center. Data collection was conducted via chart review. The severity of dry mouth symptoms was graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Six patients with advanced solid tumors who received a PD-1 inhibitor or PD-1/CTLA-4 inhibitor combination therapy were evaluated. The median time to onset of xerostomia was 4.5 months overall, though symptoms developed sooner in patients who received IO as subsequent-line therapy (median = 1.9 months). All patients developed other immune-related adverse events (IRAEs) such as hypothyroidism. Five patients (83%) had grade 2 dry mouth symptoms, and similarly, 5 patients eventually required prescription medications such as sialogogues and topical or systemic corticosteroids to alleviate symptoms. Two patients (33%) required interruptions in IO. All 3 patients who received cevimeline noticed improvement in symptoms, and one patient who received prednisone dosed at 1 mg/kg/day tapered over 5 weeks also experienced significant relief. CONCLUSION: While the optimal management of IO-induced xerostomia has not yet been established by national guidelines, increased awareness can prompt faster initiation of supportive care measures that can prevent significant discomfort and poor oral intake. Thoughtful use of over-the-counter topical agents, sialogogues, corticosteroids, and treatment interruptions can help improve tolerability of this adverse effect.

Case report of sacituzumab govitecan-hziy-induced neutropenia in a patient with metastatic triple-negative breast cancer and a uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizer genotype.

INTRODUCTION: Sacituzumab govitecan-hziy, approved in 2020 for treatment of metastatic triple-negative breast cancer, provides a new option for a population with a historically poor prognosis with standard chemotherapy. Uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers are at increased risk for profound neutropenia. This case discusses clinical implications of the uridine diphosphate glucuronosyltransferase family 1 member A1*28/*28 genotype in patients receiving sacituzumab govitecan-hziy. CASE REPORT: A 38-year-old otherwise healthy pre-menopausal female of South Asian descent was diagnosed with non-metastatic, hormone receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer. This was treated with neoadjuvant chemotherapy and multiple lines of subsequent therapies. Upon finding bone metastasis, an additional six lines of therapy ensued. In total, 3.5 years post-diagnosis, sacituzumab govitecan-hziy was started for disease transformation to triple-negative status. MANAGEMENT AND OUTCOME: Sacituzumab govitecan-hziy was initiated at the Food and Drug Administration-approved 10 mg/kg/dose on days 1 and 8 of a 21-day cycle. Grade 4 neutropenia occurred after one dose. Pharmacogenomics testing identified the patient as a uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressor. Sacituzumab govitecan-hziy was dose-reduced, and granulocyte colony-stimulating factor was administered due to the severity of neutropenia. The patient continued on sacituzumab govitecan-hziy until disease progression. DISCUSSION: Sacituzumab govitecan-hziy's propensity to cause neutropenia is multifactorial. Although incidence of all-grade neutropenia from sacituzumab govitecan-hziy is elevated for uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressors, this does not translate to increased risk for febrile neutropenia. Detailed guidance is lacking regarding empiric dose adjustments or prophylactic granulocyte colony-stimulating factor for these patients.1 Currently, pre-sacituzumab govitecan-hziy pharmacogenomics testing to identify uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers is not recommended, and the cost-effectiveness of this approach is unclear.

A Retrospective Analysis of Metronomic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) Versus Docetaxel and Cyclophosphamide (TC) as Adjuvant Treatment in Early Stage, Hormone Receptor Positive, HER2 Negative Breast Cancer.

BACKGROUND: Anthracycline and taxane-based doublets have largely replaced cyclophosphamide, methotrexate, and fluorouracil (CMF) as preferred regimens in the adjuvant treatment of breast cancer. Metronomic CMF is associated with improved tolerability over anthracycline or taxane-based regimens. Previously, there have been no direct comparisons between taxane-based regimens and CMF. MATERIALS AND METHODS: We performed a retrospective review of 98 breast cancer patients treated at the Seattle Cancer Care Alliance from February 2015 through December 2018 that received either metronomic CMF or docetaxel and cyclophosphamide (TC) as adjuvant therapy for early-stage, hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2-) breast cancer. The primary outcome assessed was disease-free survival (DFS). Secondary outcomes included overall survival (OS), dose intensity, and adverse effects. RESULTS: With an average follow-up of 35.9 and 28.2 months for CMF and TC, respectively, there was no significant difference in DFS or OS between the chemotherapy regimens. DFS at 3 years was 96.7% vs. 94.3% and OS 96.7% vs. 100% for CMF and TC, respectively. There were more dose delays in the CMF group, but on average, patients receiving either regimen achieved a dose intensity ≥85%. There was a trend towards increased hospitalization or emergency department utilization (23.1% vs. 10.6%) and Grade 4 toxicities (9.6% vs. 4.3%) with TC vs. CMF. CONCLUSION: Metronomic CMF offers equivalent survival outcomes to TC and remains a viable option in the adjuvant treatment of HR+/HER2- breast cancer. There was a trend towards increased Grade 4 toxicities and hospitalizations with TC, suggesting that metronomic CMF may offer a more tolerable treatment option while maintaining excellent disease outcomes.

Comparison of Binding Site of Remdesivir and Its Metabolites with NSP12-NSP7-NSP8, and NSP3 of SARS CoV-2 Virus and Alternative Potential Drugs for COVID-19 Treatment.

Remdesivir was approved by the U.S.A. Food and Drug administration for emergency use to interfere with the replication of SARS CoV-2 virus (the agent that causes COVID-19) in adults and children hospitalized with severe disease. The crystal structure of the metabolite of remdesivir (Monophosphate of GS-441524) and NSP12-NSP8-NSP7 of SARS CoV-2 virus was recently reported. The crystal structures of ADP-Ribose or AMP and NSP3 of SARS CoV-2 virus were also released, recently. This study compared their binding sites and suggests the crystal structure of NSP3 of SARS CoV-2 virus as an alternative binding site of AMP or ADP-ribose to treat COVID-19. We virtually screened 682 FDA-approved compounds, and the top 10 compounds were selected by analysis of docking scores, (G-score, D-score, and Chemscore) and visual analysis using a structure-based docking approach of NSP3 of SARS CoV-2 virus. All immunization approaches are based on the SARS-CoV-2 virus spike protein. A recent study reported that the D614G mutation in the SARS-CoV-2 virus spike protein reduces S1 shedding and increases infectivity of SARS COV-2 virus. Therefore, if there is a severe change in the spike protein of a modified Coronavirus, all developed vaccines can lose their efficacy, necessitating the need for an alternative treatment method. The top 10 compounds (FDA-approved) in this study are selected based on NSP 3 binding site, and therefore are a potential viable treatment because they will show potential activity for all mutations in the SARS-CoV-2 virus spike protein.

Design and Preliminary Findings From a New Electronic Cohort Embedded in the Framingham Heart Study.

BACKGROUND: New models of scalable population-based data collection that integrate digital and mobile health (mHealth) data are necessary. OBJECTIVE: The aim of this study was to describe a cardiovascular digital and mHealth electronic cohort (e-cohort) embedded in a traditional longitudinal cohort study, the Framingham Heart Study (FHS). METHODS: We invited eligible and consenting FHS Generation 3 and Omni participants to download the electronic Framingham Heart Study (eFHS) app onto their mobile phones and co-deployed a digital blood pressure (BP) cuff. Thereafter, participants were also offered a smartwatch (Apple Watch). Participants are invited to complete surveys through the eFHS app, to perform weekly BP measurements, and to wear the smartwatch daily. RESULTS: Up to July 2017, we enrolled 790 eFHS participants, representing 76% (790/1044) of potentially eligible FHS participants. eFHS participants were, on average, 53±8 years of age and 57% were women. A total of 85% (675/790) of eFHS participants completed all of the baseline survey and 59% (470/790) completed the 3-month survey. A total of 42% (241/573) and 76% (306/405) of eFHS participants adhered to weekly digital BP and heart rate (HR) uploads, respectively, over 12 weeks. CONCLUSIONS: We have designed an e-cohort focused on identifying novel cardiovascular disease risk factors using a new smartphone app, a digital BP cuff, and a smartwatch. Despite minimal training and support, preliminary findings over a 3-month follow-up period show that uptake is high and adherence to periodic app-based surveys, weekly digital BP assessments, and smartwatch HR measures is acceptable.

Evaluation of the Association Between Genetic Variants in Circadian Rhythm Genes and Posttraumatic Stress Symptoms Identifies a Potential Functional Allele in the Transcription Factor TEF.

Previous studies suggest that genetic variants within genes affecting the circadian rhythm influence the development of posttraumatic stress symptoms (PTSS). In the present study, we used data from three emergency care-based cohorts to search genetic variants in circadian pathway genes previously associated with neuropsychiatric disorders for variants that influence PTSS severity. The three cohorts used included a discovery cohort of African American men and women enrolled following motor vehicle collision (n = 907) and two replication cohorts: one of multi-ethnic women enrolled following sexual assault (n = 274) and one of multi-ethnic men and women enrolled following major thermal burn injury (n = 68). DNA and RNA were collected from trauma survivors at the time of initial assessment. Validated questionnaires were used to assess peritraumatic distress severity and to assess PTSS severity 6 weeks, 6 months, and 1 year following trauma exposure. Thirty-one genetic variants from circadian rhythm genes were selected for analyses, and main effect and potential gene*stress and gene*sex interactions were evaluated. Secondary analyses assessed whether associated genetic variants affected mRNA expression levels. We found that six genetic variants across five circadian rhythm-associated genes predicted PTSS outcomes following motor vehicle collision (p < 0.05), but only two of these variants survived adjustment for multiple comparisons (False Discovery Rate < 5%). The strongest of these associations, an interaction between the PAR-zip transcription factor, thyrotroph embryonic factor (TEF) variant rs5758324 and peritraumatic distress, predicted PTSS development in all three cohorts. Further analysis of genetic variants in the genetic region surrounding TEFrs5758324 (±125,000 nucleotides) indicated that this allele showed the strongest association. Further, TEF RNA expression levels (determined via RNA-seq) were positively associated with PTSS severity in distressed individuals with at least one copy of the TEFrs5758324 minor allele. These results suggest that rs5758324 genetic variant in TEF, a regulator of clock-controlled genes and key mediator of the core circadian rhythm, influence PTSS severity in a stress-dependent manner.

Supervised learning reveals circulating biomarker levels diagnostic of hepatocellular carcinoma in a clinically relevant model of non-alcoholic steatohepatitis; An OAD to NASH.

Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH) HCC manifests in the absence of cirrhosis. Given the sheer size of the ongoing non-alcoholic fatty liver disease (NAFLD) epidemic and the dismal prognosis associated with late-stage primary liver cancer there is an urgent need for HCC surveillance in the NASH population. Using serum levels of HCC biomarkers as vectors and biopsy-proven HCC or no HCC as outputs / binary classifier, a supervised learning campaign was undertaken to develop a minimally invasive technique for making a diagnosis of HCC in a clinically relevant model of NASH. Adult mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. In this training set, receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of ≥ 0.89. Serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) diagnostic for HCC were confirmed in a test set comprising mice on control diet or FFD and mice subjected to hepatic ischemia-reperfusion injury. These data suggest that levels of circulating OPN, AFP and DKK1 can be used to make a diagnosis of HCC in a clinically relevant model of NASH.