Targeted Combination of Poly(ADP-ribose) Polymerase Inhibitors and Immune Checkpoint Inhibitors Lacking Evidence of Benefit: Focus in Ovarian Cancer.

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.

Evaluation of the Quality and Comprehensiveness of YouTube Videos Discussing Pancreatic Cancer.

Pancreatic cancer is one of the most lethal diseases worldwide and incidence continues to rise, resulting in increased deaths each year. In the modern era, patients often turn to online sources like YouTube for information regarding their disease, which may be subject to a high degree of bias and misinformation; previous analyses have demonstrated low quality of other cancer-related YouTube videos. Thus, we sought to determine if patients can rely on educational YouTube videos for accurate and comprehensive information about pancreatic cancer diagnosis and treatment. We designed a search query and inclusion/exclusion criteria based on published studies evaluating YouTube user tendencies, which were used to identify videos most likely watched by patients. Videos were evaluated based on two well-known criteria, the DISCERN and JAMA tools, as well as a tool published by Sahin et al. to evaluate the comprehensiveness of YouTube videos. Statistical analyses were performed using Chi-square analysis to compare categorical variables. We used linear regression to assess for correlations between quantitative variables. Kruskal-Wallis and independent samples t-test were used to compare means between groups. We assessed inter-rater reliability using Cronbach's alpha. After the initial search query, 39 videos were retrieved that met inclusion criteria. The comprehensiveness and quality of these materials was generally low to moderate, with only 7 videos being considered comprehensive. Pearson's R demonstrated strong correlations between video length and both comprehensiveness and quality. Higher-quality videos also tended to be newer. YouTube videos regarding pancreatic cancer are generally of low to moderate quality and lack comprehensiveness, which could affect patients' perceptions of their disease or understanding of treatment options. These videos, which have collectively been viewed over 6 million times, should be subject to some form of expert review before upload, and producers of this content should consider citing the sources used in the video.

Homologous recombination proficiency in ovarian and breast cancer patients.

Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.

Direct Oral Anticoagulants Versus Warfarin in Morbidly Obese Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) have been increasingly preferred over warfarin; however, The International Society of Thrombosis and Hemostasis recommended avoiding the use of DOACs in morbidly obese patients (body mass index >40 or weight >120 kg) because of limited clinical data. STUDY QUESTION: Are DOACs effective and safe in morbidly obese patients with nonvalvular atrial fibrillation (NVAF). DATA SOURCES: We performed a comprehensive search for published studies indexed in PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials that evaluated the efficacy and safety of DOACs in morbidly obese patients with NVAF. STUDY DESIGN: Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. The primary outcome of interest was stroke or systemic embolism (SSE) rate. The secondary outcome was major bleeding (MB). RESULTS: A total of 10 studies including, 89,494 morbidly obese patients with NVAF on oral anticoagulation therapy (45,427 on DOACs vs. 44,067 on warfarin) were included in the final analysis. The SSE rate was significantly lower in DOACs group compared with warfarin group [odds ratio: 0.71; 95% confidence interval (CI): 0.62-0.81; P < 0.0001; I2 = 0%]. MB rate was also significantly lower in DOACs group compared with the warfarin group (odds ratio: 0.60; 95% CI: 0.46-0.78; P < 0.0001; I2 = 86%). On subgroup analysis, SSE and MB event rates were significantly lower in rivaroxaban and apixaban than warfarin; however, dabigatran showed noninferiority to warfarin in SSE rate but superiority in the safety outcome. CONCLUSIONS: Our meta-analysis demonstrated that DOACs are effective and safe with statistical superiority when compared with warfarin in morbidly obese patients. Large-scale randomized clinical trials are needed to further evaluate the efficacy and safety of DOACs in this cohort of patients.

BRCA1/2 signaling and homologous recombination deficiency in breast and ovarian cancer.

Patients who have mutations of the genes BRCA1 or BRCA2 are at an increased risk for developing breast and ovarian cancer. BRCA1/2 function as tumor suppressor genes, responsible for regulating DNA repair, and play an essential role in homologous recombination. Mutation of BRCA1/2 results in homologous recombination deficiency and genomic instability which drives oncogenesis and cancer proliferation. Recently, BRCA1/2 gene expression has been implicated in regulating immune response. Here we discuss the signaling pathway of BRCA1/2 in relation to breast and ovarian cancer, with emphasis on how dysregulation facilitates the path to malignancy and current treatment options.

The abscopal effect of radiation therapy.

Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.

Chimeric Antigen Receptor T-Cell Therapy: Reach to Solid Tumor Experience.

Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.

Application of machine learning for lung cancer survival prognostication-A systematic review and meta-analysis.

Introduction: Machine learning (ML) techniques have gained increasing attention in the field of healthcare, including predicting outcomes in patients with lung cancer. ML has the potential to enhance prognostication in lung cancer patients and improve clinical decision-making. In this systematic review and meta-analysis, we aimed to evaluate the performance of ML models compared to logistic regression (LR) models in predicting overall survival in patients with lung cancer. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A comprehensive search was conducted in Medline, Embase, and Cochrane databases using a predefined search query. Two independent reviewers screened abstracts and conflicts were resolved by a third reviewer. Inclusion and exclusion criteria were applied to select eligible studies. Risk of bias assessment was performed using predefined criteria. Data extraction was conducted using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) checklist. Meta-analytic analysis was performed to compare the discriminative ability of ML and LR models. Results: The literature search resulted in 3,635 studies, and 12 studies with a total of 211,068 patients were included in the analysis. Six studies reported confidence intervals and were included in the meta-analysis. The performance of ML models varied across studies, with C-statistics ranging from 0.60 to 0.85. The pooled analysis showed that ML models had higher discriminative ability compared to LR models, with a weighted average C-statistic of 0.78 for ML models compared to 0.70 for LR models. Conclusion: Machine learning models show promise in predicting overall survival in patients with lung cancer, with superior discriminative ability compared to logistic regression models. However, further validation and standardization of ML models are needed before their widespread implementation in clinical practice. Future research should focus on addressing the limitations of the current literature, such as potential bias and heterogeneity among studies, to improve the accuracy and generalizability of ML models for predicting outcomes in patients with lung cancer. Further research and development of ML models in this field may lead to improved patient outcomes and personalized treatment strategies.

Folate Receptor as a Biomarker and Therapeutic Target in Solid Tumors.

Folate is a B vitamin necessary for basic biological functions, including rapid cell turnover occurring in cancer cell proliferation. Though the role of folate as a causative versus protective agent in carcinogenesis is debated, several studies have indicated that the folate receptor (FR), notably subtype folate receptor alpha (FRα), could be a viable biomarker for diagnosis, progression, and prognosis. Several cancers, including gastrointestinal, gynecological, breast, lung, and squamous cell head and neck cancers overexpress FR and are currently under investigation to correlate receptor status to disease state. Traditional chemotherapies have included antifolate medications, such as methotrexate and pemetrexed, which generate anticancer activity during the synthesis phase of the cell cycle. Increasingly, the repertoire of pharmacotherapies is expanding to include FR as a target, with a heterogenous pool of directed therapies. Here we discuss the FR, expression and effect in cancer biology, and relevant pharmacologic inhibitors.

Post-cardiac Arrest Leukocytosis Mimicking Acute Monocytic Leukemia.

Leukocytosis is defined by an increased WBC count in the peripheral blood. This can be caused by many pathologies from benign conditions such as stress, infection, and inflammation or malignant origins such as leukemia. Although leukocytosis is regularly encountered clinically and has many etiologies making a definitive diagnosis, at times, may be difficult. A case of severe leukocytosis requires careful consideration of symptoms and confirmation with serial complete blood count (CBC) testing before pursuing further invasive testing such as bone marrow biopsy. Here, we report the case of a 78-year-old male patient who, after a cardiac arrest, presented with reactive hyperleukocytosis mimicking acute monocytic leukemia.

Small-cell breast carcinoma with response to atezolizumab: a case report.

Background: Small-cell carcinoma of the breast is a rare disease with little research outlining molecular targets or optimal therapeutic management. We summarize a young female patient with poorly differentiated high-grade carcinoma with neuroendocrine features/small-cell carcinoma. Case presentation: A 31-year-old female presented with a large left breast mass. Initial biopsy revealed small-cell, triple-negative breast carcinoma. Treatment consisted of cisplatin and etoposide but was poorly tolerated and discontinued after one cycle. Combination abraxane/atezolizumab resulted in transient partial response in tumor size with 7 months of progression-free stability. Worsening metastatic disease was found 8 months after initial biopsy on radiologic studies and the patient expired 10 months after initial biopsy. Conclusion: Transient benefit in response to combination abraxane/atezolizumab was demonstrated.

Immunotherapy is an emerging area in cancer research which utilizes the body's immune system to target cancerous cells. This offers oncologists an effective alternative to standard chemotherapy options, which often have significant side effects. Additionally, biomarkers including PD-L1 positivity to predict response to immunotherapy are currently under investigation. The patient presented with a rare type of aggressive breast cancer that previously had few treatment options. This report demonstrates the use of biomarker assessment (PD-L1) to predict immunotherapy response. The patient responded well to immunotherapy, and radiologic scans demonstrated tumor reduction. Further research into this field has the implication to improve treatments, decrease side effects of chemotherapy and improve patient outcomes for many cancers.

Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes.

BACKGROUND: First-line therapy for treatment of advanced urothelial carcinoma includes combination platinum-based chemotherapies, though resistance and long-term toxicity concerns to these regimens cause limitations in progression-free survival and overall survival. Maintenance treatment with an alternative agent such as the PD-L1 inhibitor, avelumab (Bavencio®), after initial chemotherapy has been shown to prolong overall survival. The aim of this review is to provide a landscape clinical use of avelumab in the treatment of advanced urothelial carcinoma with a focus on patient selection and outcomes. METHODS: This review includes the most up to date phases and results from clinical trials published in peer-reviewed journals. RESULTS: Three studies were included, one phase 1B trial, one phase 1B trial with 2 year follow-up, and one phase 3 trial. Patients receiving avelumab maintenance therapy at 10 mg/kg IV every two weeks had an overall better performance status, though those with an increased ECOG-PS, increased Bellmunt risk score, or failure of ≥3 chemotherapies had poorer responses. Patients over the age of 65 had a higher ORR (18-25%) compared to younger patients (13-14%). Patients with PD-L1 positive tumors had a significantly increased CR median ORR (13.8%), median PFS (5.7 months), and median 12-month OS rate (79.1%) compared to control subjects receiving best supportive care (1.2%, 2.1 months, 60.4%, respectively). TRAEs were seen in 86.7% of patients, with 32.4% of patients experiencing a ≥grade 3 AE. The most common AE was IRR (32.4%, ≥grade 3 1.01%) and irAE 25.6% of any grade, including various rashes and pruritus AEs, immune-related thyroid disorders, and immune related hepatitis. There were 3 reported treatment-related deaths (0.05%). Ongoing phases of one of the trials is investigating the use of docetaxel and avelumab together after failure of one chemotherapy. CONCLUSION: Avelumab as a maintenance therapy after platinum-based chemotherapy failure or in platinum-ineligible patients with advanced or metastatic urothelial carcinoma is an effective option with increased ORR, PFS, and OS with a similar safety profile to other chemotherapies. Ongoing studies currently in recruitment and active clinical trials will yield valuable insights into optimizing avelumab therapy in conjunction with chemotherapies and/or immunotherapies, better characterization of response for PD-L1 positive tumors, and a clearer insight into clinically validated prognostic factors to improve patient outcomes.

Subclonal landscape of cancer drives resistance to immune therapy.

Tumor mutation burden (TMB) is often used as a biomarker for immunogenicity and prerequisite for immune checkpoint inhibitor (ICI) therapy. However, it is becoming increasingly evident that not all tumors with high TMB respond to ICIs as expected. It has been shown that the ability of T-cells to infiltrate the tumor microenvironment and elicit a specific immune response is dependent not only on the TMB, but also on intra-tumor heterogeneity and the fraction of low-frequency subclonal mutations that make up the tumor. High intra-tumor heterogeneity leads to inefficient recognition of tumor neoantigens by T-cells due to their diluted frequency and spatial heterogeneity. Clinical studies have shown that tumors with a high degree of intra-tumor heterogeneity respond poorly to ICI therapy, and previous cytotoxic treatment may increase the intra-tumor heterogeneity and render second-line ICI therapy less effective. This paper reviews the role of ICI therapy when following chemotherapy or radiation to determine if they may be better suited as first-line therapy in patients with high TMB, low intra-tumor heterogeneity, and high PD-1, PD-L1, or CTLA-4 expression.

Melanoma Treatments and Mortality Rate Trends in the US, 1975 to 2019.

Importance: Melanoma accounts for most of the deaths due to skin cancer. In the past decade, effective US Food and Drug Administration (FDA)-approved therapies for melanoma have emerged. Objective: To review changes in the long-term melanoma mortality rate (MMR) trends in the US and determine whether they have any temporal association with the FDA approval of new agents. Design, Setting, and Participants: This cross-sectional study used population data from the Surveillance, Epidemiology, and End Results (SEER) database and retrospectively reviewed the age-adjusted MMR trends in adult patients (aged ≥18 years) from 1975 to 2019 in the US population. The timeline of the FDA approvals for melanoma treatment was also reviewed. Data were analyzed from March 15 to August 15, 2022. Exposures: Outcomes were assessed in association with FDA approval of drugs for the treatment of melanoma. Main Outcomes and Measures: Mortality rates are from the SEER database, reported per 100 000 population and age-adjusted to the 2000 US standard population. The annual percent change (APC) has been used to report long-term trends. Results: After the introduction of newer treatments in 2011 (most after 2013), a significant reduction in MMR was seen from 2013 to 2017 in the US for the first time in the past 40 years. Rates increased from 1975 to 1988 (APC, 1.65% [95% CI, 1.30%-2.00%]; P < .001). No statistically significant change in MMR was seen from 1988 to 2013 (APC, 0.01% [95% CI, -1.10% to 0.12%]; P = .85). The MMR decreased significantly from 2013 to 2017 (APC, -6.28% [95% CI, -8.52% to -3.97%]; P < .001). Conclusions and Relevance: These findings suggest a benefit associated with the availability of effective therapies in the past decade and further suggest that the use of new pharmacological therapies is associated with decreased MMR in the US population. These data are very encouraging and support the continued development of such therapies. Additionally, the accessibility of these treatments and the associated health care costs need to be addressed.

NF-κB Signaling in Tumor Pathways Focusing on Breast and Ovarian Cancer.

Immune disorders and cancer share a common pathway involving NF-κb signaling. Through involvement with GM-CSF, NF-κB can contribute to proliferation and activation of T- and B- cells as well as immune cell migration to sites of inflammation. In breast cancer, this signaling pathway has been linked to resistance with endocrine and chemotherapies. Similarly, in ovarian cancer, NF-κB influences angiogenesis and inflammation pathways. Further, BRCA1 signaling common to both breast and ovarian cancer also has the capability to induce NF-κB activity. Immunotherapy involving NF-κB can also be implemented to combat chemoresistance. The complex signaling pathways of NF-κB can be harnessed for developing cancer therapeutics to promote immunotherapy for improving patient outcomes.

Risk Factors Associated With Six-Month Mortality in Hospitalized COVID-19 Patients: A Single-Institution Study.

Background Coronavirus disease 2019 (COVID-19) infection can vary from asymptomatic infection to multi-organ dysfunction. The most serious complication of infection with COVID-19 is death. Various comorbid conditions and inflammatory markers have been associated with an increased risk of mortality, specifically within the immediate post-infection period; however, less is known about long-term mortality outcomes. Objectives Our objective is to determine risk factors associated with six-month mortality in hospitalized COVID-19 patients. Methods This is a single-institution, retrospective study. We included patients hospitalized with COVID-19 from the University of Toledo Medical Center in Toledo, Ohio, who were admitted from March 20, 2020, to June 30, 2021. This study was approved by a biomedical institutional review board at the University of Toledo. Patients with available pre-stored blood samples for laboratory testing were included, and hospital charts were assessed up to six months from the date of a positive COVID-19 test result. Two groups were created based on the mortality outcome at six months from COVID-19 positive test results: survivors and non-survivors. The clinical variables or outcomes and laboratory values were compared between the two groups using non-parametric methods due to the small sample size and non-normality of the data. Either the Mann-Whitney U-test for continuous variables or Fisher's exact test for categorical variables was used for statistical analysis. Results Lactate dehydrogenase (LDH) and D-dimer levels on admission were found to be significantly higher in non-survivors than in survivors. The median high D-dimer level in non-survivors was 5.96 micrograms/milliliter (µg/mL) (interquartile range (IQR): 3.95-11.29 µg/mL) vs 1.82 µg/mL (IQR 1.13-5.55 µg/mL) in survivors (p = 0.019). Median LDH levels were also higher in non-survivors vs survivors, i.e., 621.00 international units per liter (IU/L) (IQR 440.00-849.00 IU/L) vs 328.00 IU/L (IQR 274.00-529.00 IU/L), respectively (p = 0.032). The demographic profile, comorbidity profile, and laboratory data (typically associated with short-term mortality, inflammation, and organ dysfunction) were similar between survivors and non-survivors, except for LDH and D-dimer. Conclusion Higher LDH and D-dimer levels on admission were found to be associated with an increased six-month mortality rate in hospitalized COVID-19 patients. These hematologic data can serve as risk stratification tools to prevent long-term mortality outcomes and provide proactive clinical care in hospitalized COVID-19 patients.

Increased Incidence of Thrombotic Complications With Non-small Cell Lung Cancer Necessitates Consideration of Prophylactic Anticoagulation in Young Individuals.

Venous thromboembolism (VTE) is a common complication in cancer patients and is associated with increased morbidity and mortality. Lung cancer is commonly associated with VTE including pulmonary embolism. We did a retrospective analysis from the 2013 Healthcare Cost and Utilization Project data to determine the role of age as a factor in the development of VTE in this patient group. Patients were selected using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes for metastatic lung cancer and VTE. The patients were stratified by age, sex, race/ethnicity, and site of VTE. There was a total of 16,577 VTE events detected out of a total of 182,863 cases of metastatic lung cancer, representing 9% of the total cases. In patients under 65 years of age, there were 356.82 more cases of pulmonary embolism per 100,000 individuals compared to those older than 65 years (p<0.0001). The same age group also showed 374.83 more upper extremity VTE, 286.94 more non-pulmonary thoracic VTE, and 263.97 more abdominal VTE events per 100,000 individuals (p<0.0001). In conclusion, we found that patients under the age of 65 years had a significantly higher incidence of VTE, pulmonary embolism, upper extremity VTE as well as abdominal and non-pulmonary VTE.