Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care.

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors.

BACKGROUND: The risk of incident atrial fibrillation (AF) among breast cancer survivors, especially for younger women, and cancer treatment effects on the association remain unclear. This study aimed to investigate the risk of AF among breast cancer survivors and evaluate the association by age group, length of follow-up, and cancer treatment. METHODS: Using data from the Korean Health Insurance Service database (2010-2017), 113,232 women newly diagnosed with breast cancer (aged ≥ 18 years) without prior AF history who underwent breast cancer surgery were individually matched 1:5 by birth year to a sample female population without cancer (n = 566,160) (mean[SD] follow-up, 5.1[2.1] years). Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) considering death as a competing risk were estimated, adjusting for sociodemographic factors and cardiovascular/non-cardiovascular comorbidities. RESULTS: BCS had a slightly increased AF risk compared to their cancer-free counterparts (sHR 1.06; 95% CI 1.00-1.13), but the association disappeared over time. Younger BCS (age < 40 years) had more than a 2-fold increase in AF risk (sHR 2.79; 95% CI 1.98-3.94), with the association remaining similar over 5 years of follow-up. The increased risk was not observed among older BCS, especially those aged > 65 years. Use of anthracyclines was associated with increased AF risk among BCS (sHR 1.57; 95% CI 1.28-1.92), which was more robust in younger BCS (sHR 1.94; 95% CI 1.40-2.69 in those aged ≤ 50 years). CONCLUSIONS: Our findings suggest that younger BCS had an elevated risk of incident AF, regardless of the length of follow-up. Use of anthracyclines may be associated with increased mid-to-long-term AF risk among BCS.

Parent Penalty: Parental Leave Experiences of Trainees and Early-Career Faculty in Oncology Subspecialties.

PURPOSE: Prime childbearing years occur during medical training and early career, leaving physicians with tough choices between family planning and career growth. Restrictive workplace parental leave (PL) policies may negatively affect physician well-being. We evaluate existing PL and lactation policies, as well as return-to-work experiences, among oncology trainees and early-career faculty. METHODS: An anonymous 43-question cross-sectional survey was distributed via e-mail and social media channels between May and June 2021 to oncology trainees and physicians within 5 years of terminal training in the United States. The survey was administered through SurveyMonkey. Descriptive statistics were used to analyze data. Two hundred seventy-five participants were recruited via social media and outreach to program directors and coordinators in adult hematology/oncology and radiation oncology program directors. RESULTS: The average duration of PL was <6 weeks for most participants. Among those who used PL, 50% felt pressured to work while on PL, 60% felt guilty asking coworkers for help, and 79% were overwhelmed with demands of work and home, whereas only 27% had resources available at workplace to assist with transition back to work. Among those who breastfed at return to work, 31% did not have access to a lactation room, 56% did not have adequate pumping breaks, and 66% did not have pumping breaks mandated in contract. CONCLUSION: Our findings underline the immense magnitude of problems surrounding inadequate PL and support for lactating mothers among trainees and early-career physicians in oncology subspecialities. Policies and practices around PL and lactation should be restructured to meet the needs of the evolving oncology workforce.

Consistency Between State's Cancer Registry and All-Payer Claims Database in Documented Radiation Therapy Among Patients Who Received Breast Conservative Surgery.

PURPOSE: Arkansas is one of only four known states that have linked All-Payer Claims Database (APCD) to state's cancer registry (Arkansas Cancer Registry [ACR]). We evaluated the reporting consistency of radiation therapy (RT) between the two sources. METHODS: Women age ≥ 18 years diagnosed in 2013-2017 with early-stage hormone receptor-positive breast cancer who received breast-conserving surgery were identified. Patients must have continuous insurance coverage (any private plans, Medicaid, and Medicare) in the 13 months (month of diagnosis and 12 months after). Receipt of RT was identified independently from ACR and APCD. We calculated sensitivity, specificity, positive predictive value, and negative predictive value for receipt of RT coded by the registry compared with APCD billing claims as the gold standard. We assessed the degree of concordance between the data sources by Cohen's kappa statistics. RESULTS: The final sample included 2,695 patients who were in both databases and satisfied our inclusion/exclusion criteria. Using APCD as the gold standard, there were high sensitivity (88.1%) and positive predictive value (87.7%) and moderate specificity (71.1%) and negative predictive value (71.8%). The overall agreement between the two sources was 83.0%, with a kappa statistic of 0.59 (95% CI, 0.56 to 0.63). Consistency measures varied by age, stage, and insurance type with Medicare fee-for-service coverage only having the best and private insurance only the worse consistency. CONCLUSION: In patients with early-stage hormone receptor-positive breast cancer who received breast-conserving surgery, recording of RT receipt was moderately consistent between Arkansas APCD and ACR. Future studies are needed to identify factors affecting reporting consistency to better use this unique resource in addressing population health problems.

Stem Cell Theory of Cancer: Implications for Translational Research from Bedside to Bench.

A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.

The Hispanic Paradox in Non-Small Cell Lung Cancer.

OBJECTIVE/BACKGROUND: According to the U.S. Census Bureau, 18% of the total population in the United States identified themselves as Hispanic in 2016 making it the largest minority group. This study aimed to evaluate the effect of Hispanic ethnicity on the overall survival of patients with non-small cell lung cancer (NSCLC) using a large national cancer database. METHODS: We used the National Cancer Database to identify patients diagnosed with NSCLC between 2010 and 2015. The two comparative groups for this study were non-Hispanic Whites (NHWs) and Hispanics. The primary outcome was overall survival. RESULTS: Of the 555,475 patients included in the study, 96.9% and 3.1% were NHWs and Hispanics with a median follow up of 12.6 months (interquartile range 4.1-30.6) and 12.1 months (interquartile range 3.8-29.5), respectively. Hispanics were more likely to be uninsured, and live in areas with lower median household income or education level. In the age-, sex-, and comorbidities-adjusted Cox model, the overall survival was significantly better in Hispanics compared with NHWs (hazard ratio [HR] 0.92, 95% confidence interval 0.90-0.93, p < .001). In a demographic, socioeconomic, clinical, and facility characteristics adjusted Cox model, Hispanics had further improvement in survival (HR 0.79, 95% confidence interval 0.78-0.81, p < .001). The survival advantage was seen in all cancer stages: Stage I-HR 0.76 (0.71-0.80), Stage II-HR 0.85 (0.79-0.92), Stage III-HR 0.81 (0.77-0.85), and Stage IV-HR 0.79 (0.77-0.81). CONCLUSION: Hispanic ethnicity was associated with better survival in NSCLC. This survival advantage is likely the result of complex interactions amongst several physical, social, cultural, genomic, and environmental factors.

NCDB Analysis of Melanoma 2004-2015: Epidemiology and Outcomes by Subtype, Sociodemographic Factors Impacting Clinical Presentation, and Real-World Survival Benefit of Immunotherapy Approval.

Background: The incidence of invasive melanoma is rising, and approval for the first immune checkpoint inhibitor (ICI) to treat metastatic melanoma occurred in 2011. We aim to describe the epidemiology and outcomes in recent years, sociodemographic factors associated with the presence of metastasis at diagnosis, and the real-world impact of ICI approval on survival based on melanoma subtype and race. Methods: This is a retrospective analysis of the National Cancer Database (NCDB) from the years 2004-2015. The primary outcome was the overall survival of metastatic melanoma by subtype. Secondary outcomes included sociodemographic factors associated with the presence of metastasis at diagnosis and the impact of treatment facility type and ICI approval on the survival of metastatic melanoma. Results: Of the 419,773 invasive melanoma cases, 93.80% were cutaneous, and 4.92% were metastatic at presentation. The odds of presenting with metastatic disease were higher in African Americans (AA) compared to Caucasians (OR 2.37; 95% CI 2.11-2.66, p < 0.001). Treatment of metastatic melanoma at an academic/research facility was associated with lower mortality versus community cancer programs (OR 0.75, 95 % CI 0.69-0.81, p-value < 0.001). Improvement in survival of metastatic melanoma was noted for Caucasians after the introduction of ICI (adjusted HR 0.80, 95% CI 0.78-0.83, p < 0.001); however, this was not statistically significant for AA (adjusted HR 0.80, 95% CI 0.62-1.02, p-value = 0.073) or ocular cases (HR 1.03, 95% CI 0.81-1.31, p-value = 0.797). Conclusion: Real-world data suggest a 20% improvement in survival of metastatic melanoma since the introduction of ICI. The disproportionately high odds of metastatic disease at presentation in AA patients with melanoma suggest the need for a better understanding of the disease and improvement in care delivery.

Outcomes of in-hospital cardiopulmonary resuscitation for cardiac arrest in adult patients with metastatic solid cancers: A Nationwide Inpatient Sample database analysis from 2012 to 2014.

BACKGROUND: Cardiopulmonary arrest is known to have a poor prognosis, further worsened by preexisting comorbidities. With improved treatment, the prevalence of metastatic cancers is rapidly increasing; however, the outcomes of in-hospital cardiopulmonary resuscitation (ICPR) remain to be well described. This study examines the epidemiology, associations, and outcomes of ICPR in these patients. METHODS: This is a retrospective cohort analysis of the Nationwide Inpatient Sample database (2012-2014) including patients aged ≥18 years with metastatic cancers. Primary outcome was inpatient mortality following ICPR. Factors associated with the primary outcome were analyzed using univariate/multivariate logistic regression analysis. RESULTS: Among all admissions with metastatic cancers (n = 5,500,684), 0.47% (n = 26,070) received ICPR. Inpatient mortality was 81.77% (n = 8905) versus 68.90% among those without metastatic solid cancers and receiving ICPR. Inpatient palliative care encounter was documented in 18.95% of patients with metastatic cancer who received ICPR. On multivariate logistic regression, some of the notable factors associated with higher mortality included being of African American or Hispanic race and hospital admission over the weekend. Factors associated with lower mortality included female sex, elective admission, and head and neck as the primary site. Admissions with ICPR were associated with higher mean total charge of hospitalization (by $48,670) compared with admissions without ICPR. Of those who survived ICPR, 43.82% were transferred to another facility after discharge. CONCLUSIONS: Among adult patients with metastatic solid cancers having ICPR, 81.8% died within the same hospital admission. Race and admission type predicted mortality. Despite known poor prognosis, only a minority had palliative care. LAY SUMMARY: Cardiopulmonary resuscitation during hospitalization for patients who have metastatic cancer has a very poor outcome with a mortality rate of 81.77%. Inpatient cardiopulmonary resuscitation in these patients is also associated with a significantly higher cost of care, longer length of stay, and high rate of transfer to a different health care facility upon discharge. Knowledge of these outcomes is helpful in discussing the pros and cons of pursuing aggressive resuscitative interventions with patients and families.

Incidence and outcomes of heparin-induced thrombocytopenia in solid malignancy: an analysis of the National Inpatient Sample Database.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction to heparin products characterized by thrombocytopenia with or without thrombosis. This study aimed to determine the incidence, morbidity, mortality and economic burden of HIT in solid-malignancy-related hospitalizations. We analyzed the National Inpatient Sample Database (NIS), the largest public database of hospital admissions in the United States, from January 2012 to September 2015. The primary outcome of the study was the incidence of HIT. Secondary outcomes included incidence of venous thrombosis (acute deep venous thrombosis and pulmonary embolism), arterial thrombosis (thrombotic stroke, myocardial infarctions and other arterial thromboembolism), mortality associated with HIT, length of stay, total hospital charges and disposition. During the study period, 7 437 049 hospitalizations had an associated diagnosis of solid malignancy. Approximately 0·08% (n = 6225) hospitalizations had a secondary diagnosis of HIT in this population. The standardized incidence of total thrombotic events was higher in the solid malignancy with HIT compared to the solid malignancy without HIT group (24·7% vs. 6·8%, P < 0·001). The standardized mortality rate was 4·8% in solid malignancy with HIT compared to 3·4% in the without HIT group (OR, 1·53; 95% CI, 1·25-1·89; P < 0·001). HIT in solid malignancy is a rare condition but associated with increased morbidity and mortality.

Extended duration of thromboprophylaxis for medically ill patients: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The benefit of extended-duration thromboprophylaxis in patients hospitalised for acute medical illness beyond hospital stay remains controversial. AIMS: To perform a meta-analysis of randomised controlled trials (RCT) in order to examine the efficacy and safety of extended-duration anticoagulation for venous-thromboembolism (VTE) prophylaxis in this high-risk population. METHODS: An electronic database search was conducted to include all RCT comparing between extended-duration versus short-duration prophylactic anticoagulation in medically ill patients. The primary efficacy outcome was the composite events of asymptomatic deep vein thrombosis (DVT), symptomatic VTE and death from VTE-related causes. RESULTS: Five RCT were included totalling 40 124 patients, with a mean age of 71 years and 51% were male. In comparison to standard-duration therapy, extended-duration thromboprophylaxis was associated with a significant reduction in the primary efficacy outcome (risk ratio (RR) 0.75; 95% confidence interval (CI) 0.67-0.85; P < 0.01), symptomatic VTE (RR 0.53; 95% CI 0.33-0.84; P < 0.01) and asymptomatic DVT (RR 0.81; 95% CI 0.71-0.94; P < 0.01). However, there were no significant differences between both groups with regard to VTE-related death (RR 0.81; 95% CI 0.60-1.10; P = 0.18) or all-cause death (RR 0.97; 95% CI 0.88-1.08; P = 0.64). In contrast, extended-duration thromboprophylaxis was associated with an increased risk of major bleeding (RR 2.04; 95% CI 1.42-2.91; P < 0.01) and non-major clinically relevant bleeding (RR 1.81; 95% CI 1.29-2.53; P < 0.01). CONCLUSIONS: Among hospitalised medically ill patients, prolonging venous thromboprophylaxis was associated with a decreased risk of composite events of the primary efficacy outcome and increased risk of bleeding with no significant difference in VTE-related death.