Highly variable timing renders immunotherapy efficacy and toxicity impractical biomarkers of one another in clinical practice.

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Prophylaxis Against Thromboembolic Events During Chemotherapy for Germ Cell Cancer.

INTRODUCTION: Patients with advanced germ cell tumors (GCT) receiving cisplatin-based chemotherapy have high rates of thromboembolic events (TEE) which can negatively affect their overall survival. While primary TEE prophylaxis during chemotherapy may prevent these events, it is unclear which patients will benefit in this setting. MATERIALS AND METHODS: A review of PubMed/Medline was conducted in December 2020 and all pertinent articles were evaluated for relevancy and quality of data for inclusion in the review. RESULTS: Studies on patients receiving initial cisplatin-based chemotherapy for advanced GCT have reported up to a 19% rate of TEE. This high rate may be associated with multiple factors including retroperitoneal lymphadenopathy, advanced clinical stage, high risk Khorana scores and presence of a central line. Large phase III clinical trials have demonstrated the benefit of low-molecular-weight-heparin and direct oral anticoagulants for primary prophylaxis and against recurrent TEE. However, primary prophylaxis is currently underutilized with GCT patients starting chemotherapy. CONCLUSION: Precise models to predict TEE risk and consideration of anticoagulation are difficult to develop owing to the relatively uncommon nature of GCT and lack of representation in primary TEE prophylaxis clinical trials. Despite these limitations, we believe that the benefits of prophylactic anticoagulation outweigh the risk of major bleeding in select GCT patients with higher risk of TEE. We have developed a simple algorithm to help guide TEE prophylaxis selection based on patient factors and route of chemotherapy administration. Given the high rate of TEE in GCT patients, we believe better utilization of primary prophylaxis in patient starting cisplatin-based chemotherapy will have clinical benefit.

Association between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors.

BACKGROUND: Increased body mass index (BMI) has been associated with improved response to immune checkpoint inhibitors (ICIs) in multiple cancer types. We evaluated associations between BMI, ICI dosing strategy, and clinical outcomes. METHODS: We abstracted clinical data on patients with cancer treated with ICI, including age, sex, cancer type, BMI, ICI type, dosing strategy (weight-based or fixed), radiographic response, overall survival (OS), and progression-free survival (PFS). We compared clinical outcomes between low-BMI and high-BMI populations using Kaplan-Meier curves, Cox regressions, and Pearson product-moment correlation coefficients. RESULTS: A total of 297 patients were enrolled, of whom 40% were women and 59% were overweight (BMI≥25). Of these, 204 (69%) received fixed and 93 (31%) received weight-based ICI dosing. In the overall cohort, overweight BMI was associated with improved PFS (HR 0.69; 95% CI 0.51 to 0.94; p=0.02) and had a trend toward improved OS (HR 0.77; 95% CI 0.57 to 1.04; p=0.08). For both endpoints, improved outcomes in the overweight population were limited to patients who received weight-based ICI dosing (PFS HR 0.53; p=0.04 for weight-based; vs HR 0.79; p=0.2 for fixed dosing) (OS HR 0.56; p=0.03 for weight-based; vs HR 0.89; p=0.54 for fixed dosing). In multivariable analysis, BMI was not associated with PFS or OS. However, the interaction of BMI≥25 and weight-based dosing had a trend toward association with PFS (HR 0.53; 95% CI 0.26 to 1.10; p=0.09) and was associated with OS (HR 0.50; 95% CI 0.25 to 0.99; p=0.05). Patients with BMI<25 tended to have better outcomes with fixed-dose compared with weight-based ICI, while patients with BMI≥25 tended to have better outcomes with weight-based ICI, although these differences did not achieve statistical significance. There was no association between radiographic response and BMI with fixed-dose ICI (p=0.97), but a near-significant trend with weight-based ICI (p=0.1). In subset analyses, the association between BMI, ICI dosing strategy, and clinical outcomes appeared limited to men. CONCLUSIONS: The clinical benefit of ICI in high-BMI populations appears limited to individuals receiving weight-based ICI dosing. Further research into optimal ICI dosing strategies may be warranted.

Statin Intolerance, Anti-HMGCR Antibodies, and Immune Checkpoint Inhibitor-Associated Myositis: A "Two-Hit" Autoimmune Toxicity or Clinical Predisposition?

Immune-related adverse events induced by immune checkpoint inhibitor (ICI) therapy may affect diverse organ systems, including skeletal and cardiac muscle. ICI-associated myositis may result in substantial morbidity and occasional mortality. We present a case of a patient with advanced non-small cell lung cancer who developed grade 4 myositis with concurrent myocarditis early after initiation of anti-programmed death ligand 1 therapy (durvalumab). Autoantibody analysis revealed marked increases in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody levels that preceded clinical toxicity, and further increased during toxicity. Notably, the patient had a history of intolerable statin myopathy, which had resolved clinically after statin discontinuation and prior to ICI initiation. This case demonstrates a potential association between statin exposure, autoantibodies, and ICI-associated myositis.

Lack of Association Between Radiographic Tumor Burden and Efficacy of Immune Checkpoint Inhibitors in Advanced Lung Cancer.

BACKGROUND: Historically, tumor burden has been considered an impediment to efficacy of immunotherapeutic agents, including vaccines, stem cell transplant, cytokine therapy, and intravesical bacillus Calmette-Guérin. This effect has been attributed to hypoxic zones in the tumor core contributing to poor T-cell infiltration, formation of immunosuppressive stromal cells, and development of therapy-resistant cell populations. However, the association between tumor burden and efficacy of immune checkpoint inhibitors is unknown. We sought to determine the association between radiographic tumor burden parameters and efficacy of immune checkpoint inhibitors in advanced lung cancer. MATERIALS AND METHODS: We performed a retrospective analysis of patients with advanced lung cancer treated with immune checkpoint inhibitors. Demographic, disease, and treatment data were collected. Serial tumor dimensions were recorded according to RECIST version 1.1. Associations between radiographic tumor burden (baseline sum of longest diameters, longest single diameter) and clinical outcomes (radiographic response, progression-free survival, and overall survival) were determined using log-rank tests, Cox proportional-hazard regression, and logistic regression. RESULTS: Among 105 patients, the median baseline sum of longest diameters (BSLD) was 6.4 cm; median longest single diameter was 3.6 cm. BSLD was not associated with best radiographic, progression-free survival, or overall survival. In univariate and multivariate analyses, no significant associations were observed for the other radiographic parameters and outcomes when considered as categorical or continuous variables. CONCLUSION: Although tumor burden has been considered a mediator of efficacy of earlier immunotherapies, in advanced lung cancer it does not appear to affect outcomes from immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: Historically, tumor burden has been considered an impediment to the efficacy of various immunotherapies, including vaccines, cytokines, allogeneic stem cell transplant, and intravesical bacillus Calmette-Guérin. However, in the present study, no association was found between tumor burden and efficacy (response rate, progression-free survival, overall survival) of immune checkpoint inhibitors in advanced lung cancer. These findings suggest that immune checkpoint inhibitors may provide benefit across a range of disease burden, including bulky tumors considered resistant to other categories of immunotherapy.

GCNA Preserves Genome Integrity and Fertility Across Species.

The propagation of species depends on the ability of germ cells to protect their genome from numerous exogenous and endogenous threats. While these cells employ ubiquitous repair pathways, specialized mechanisms that ensure high-fidelity replication, chromosome segregation, and repair of germ cell genomes remain incompletely understood. We identified Germ Cell Nuclear Acidic Peptidase (GCNA) as a conserved regulator of genome stability in flies, worms, zebrafish, and human germ cell tumors. GCNA contains an acidic intrinsically disordered region (IDR) and a protease-like SprT domain. In addition to chromosomal instability and replication stress, Gcna mutants accumulate DNA-protein crosslinks (DPCs). GCNA acts in parallel with the SprT domain protein Spartan. Structural analysis reveals that while the SprT domain is needed to limit DNA damage, the IDR imparts significant function. This work shows that GCNA protects germ cells from various sources of damage, providing insights into conserved mechanisms that promote genome integrity across generations.

Analysis Of Level Of Satisfaction Of Postgraduate Trainees On Surgical Floor.

BACKGROUND: Organizations flourish with a satisfied workforce. There is little known information on demographic characteristics and motivators for job satisfaction among Pakistani postgraduate trainees in surgery. Job satisfaction is predicted by intrinsic motivators (personal growth and perceived ability to work) and extrinsic motivators (perceived social support). Work family interference/enhancement and job stressors (workload and long working hours) also impacts job satisfaction; predicting overall life satisfaction. This study aims at examining life satisfaction predicted by personal and professional characteristics.. METHODS: The postgraduate trainees in the public and private hospitals of Rawalpindi and Islamabad were surveyed using validated measures of life satisfaction, personal growth, perceived social support, perceived ability to work, work family interference/enhancement, job stressors, co-workers support, supervisors support, and job satisfaction from September 15 to December 28, 2017. RESULTS: Personal growth, perceived ability to work, availability of social support, and work family enhancement positively correlate to job and life satisfaction. Work life interference and job stressors negatively relate to job and life satisfaction. Job satisfaction is also partially mediated by intrinsic and extrinsic motivators on life satisfaction, whereas job stressors weakened the relationship between job satisfaction and life satisfaction. Long working hours is negatively related to job satisfaction and life satisfaction. CONCLUSIONS: Life satisfaction is predicted by job satisfaction that is characterized intrinsic and extrinsic motivators. Healthcare organizations face challenge of providing reduced working hours, increased salaries, supportive working environment, and increased supervision to enhance the job satisfaction of employees and to improve the functioning of the healthcare environment.

Affect on survival per increase in each millimeter of tumor depth in tongue cancer.

The critical tumor depth at which the risk of occult metastasis increases in tongue cancer has been demonstrated as ≥4-5 mm. Conventional T staging might not be an accurate predictor for survival in situations wherein infiltrative growth pattern is easily overlooked. Thus risk of death associated with increase in tumor depth per millimeter might be useful to understand patient's disease status during follow up. Historical cohorts of patients with pT1N0 and pT2N0 primary squamous cell carcinoma of tongue treated between January 2010 and December 2011 were selected and analyzed in univariate and multivariate cox-regression model to indicate the risk of death associated with an increase in each millimeter of tumor depth. The median period of follow up was 34 months. Total 67 patients fulfilled the above mentioned criteria, among them 11 patients died by the end of study period. The mean (SD) age of the patients studied was 49.7 (12.7) years and their age ranged from 21 to 74 years. Among these 66 % (n = 44) were males. In the univariate log-rank test, margin status (p = 0.016), t-stage (p = 0.018) and increased tumor depth (p < 0.0001) were risk factors for occurrence of death. When adjusted for other risk factors in the multivariate cox-regression model, per one unit increase of tumor depth (mm) there was 1.07 (95 % CI 0.95, 1.21) units increased risk of death. Depth of tumor with increase in each millimeter in tongue cancer appears to be associated with risk of death irrespective of regional lymphatic spread.

Association between infant- and child-feeding index and nutritional status: results from a cross-sectional study among children attending an urban hospital in Bangladesh.

Integration of infant- and child-feeding index (ICFI) addressing the multidimensional child-feeding practices into one age-specific summary index is gaining importance. This cross-sectional study was aimed at understanding the association between the ICFI and the nutritional status of 259 children, aged 6-23 months, who attended the paediatric outpatient department of the Dhaka Medical College Hospital in Bangladesh. The mean length-for-age z-score (LAZ) of children aged 12-23 months was significantly (p < 0.05) higher among those who were at the upper ICFI tercile compared to those who were at the middle or lower ICFI tercile (-2.01 and -3.20 respectively). A significant correlation was found between the ICFI and the LAZ (r = 0.24, p = 0.01 and r = 0.29, p = 0.01) in children aged 6-8-months and 12-23-months. Multivariable analysis, after adjusting for potential confounders, also found a significant association between the ICFI and the LAZ (beta = 0.13, p = 0.03). The predictive capability of the proposed ICFI on nutritional status of children, especially length-for-age, needs to be further evaluated prospectively among healthy children in the community.