Advani, Pooja P

Background While SARS-CoV-2 vaccines are highly effective in healthy individuals, the magnitude and durability of humoral and cellular responses in patients with solid malignancies receiving chemotherapy remain understudied. Previous reports suggest that patients with cancer may not mount adequate immune response after SARS-CoV-2 vaccination. Additionally, most studies focused on humoral responses, while data regarding cellular immune responses are scarce. In this study, we evaluated humoral and cellular responses in patients with solid tumors receiving chemotherapy compared to healthy individuals up to one year after vaccinations. Methods Patients aged ≥18 who were willing to receive the SARS-CoV-2 vaccine were enrolled. Anti-SARS-CoV-2 immunoassays were used to detect antibodies against nucleocapsid and spike proteins. Human IFN-γ Fluorospot assay was used to determine antigen−specific T-cell responses. Data were compared between groups using Mann−Whitney test for continuous variables and Fisher’s exact test for categorical variables. Results A total of 67 subjects (47 patients with cancer and 20 healthy individuals) were included. 1–3 months following the second vaccine doses, 96% of patients with cancer and 100% of healthy individuals demonstrated a positive humoral response. While the positivity rate was not significantly different, patients with cancer had significantly lower spike IgG antibodies than healthy individuals. However, this difference diminished at 6 months when patients with cancer had increased antibodies compared to decreased antibodies in the healthy cohort and no difference was noticed at 12-month. Patients with cancer developed a similar antigen-specific T-cell response as healthy individuals at 1–3 months, 6 months and 12 months. There were no significant differences when comparing patients aged ≤ 55 years vs. >55 years, stages I-III vs. IV, single vs. multiple chemotherapy, and BNT162b2 vs. mRNA-1273 vaccines. There was a significant moderate correlation between neutralization and antibody levels at 12 months. However, despite patients with cancer having a significantly higher COVID risk score, there were no significant differences in COVID-19 infection and hospitalization between patients with cancer and healthy individuals. Conclusion Despite initial impaired antibody responses to SARS-CoV-2 vaccinations, patients with solid malignancies receiving chemotherapy effectively generated long-term cellular and humoral responses by 6 and 12 months, leading to similar infection and hospitalization rates compared to healthy individuals.

ABSTRACT Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 μM OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 μM DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.

NGS used to diagnose and treat NSCLC patient with initial concern for metaplastic breast cancer

Anthracyclines are one of the most widely used and effective chemotherapies in oncology, but their most important side effect is the cumulative, dose-related cardiotoxicity leading to congestive heart failure in ~5% of individuals. Methodology and pharmacogenetic studies for predicting which individuals are at high risk and subsequently the development of targeted and individualized cardioprotective plans are beginning to make progress. Here, we review current putative risk genes and variants, the strength of evidence for each genetic association and the interaction between risk genes, in the context of known clinical risk factors and potential novel cardioprotective strategies.

Purpose Significant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) –positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted. Methods NCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models. Results The 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C. Conclusion The cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.