Association Between Neighborhood Opportunity, Allostatic Load, and All-Cause Mortality in Patients With Breast Cancer.

PURPOSE: Adverse neighborhood contextual factors may affect breast cancer outcomes through environmental, psychosocial, and biological pathways. The objective of this study is to examine the relationship between allostatic load (AL), neighborhood opportunity, and all-cause mortality among patients with breast cancer. METHODS: Women age 18 years and older with newly diagnosed stage I-III breast cancer who received surgical treatment between January 1, 2012, and December 31, 2020, at a National Cancer Institute Comprehensive Cancer Center were identified. Neighborhood opportunity was operationalized using the 2014-2018 Ohio Opportunity Index (OOI), a composite measure derived from neighborhood level transportation, education, employment, health, housing, crime, and environment. Logistic and Cox regression models tested associations between the OOI, AL, and all-cause mortality. RESULTS: The study cohort included 4,089 patients. Residence in neighborhoods with low OOI was associated with high AL (adjusted odds ratio, 1.21 [95% CI, 1.05 to 1.40]). On adjusted analysis, low OOI was associated with greater risk of all-cause mortality (adjusted hazard ratio [aHR], 1.45 [95% CI, 1.11 to 1.89]). Relative to the highest (99th percentile) level of opportunity, risk of all-cause mortality steeply increased up to the 70th percentile, at which point the rate of increase plateaued. There was no interaction between the composite OOI and AL on all-cause mortality (P = .12). However, there was a higher mortality risk among patients with high AL residing in lower-opportunity environments (aHR, 1.96), but not in higher-opportunity environments (aHR, 1.02; P interaction = .02). CONCLUSION: Lower neighborhood opportunity was associated with higher AL and greater risk of all-cause mortality among patients with breast cancer. Additionally, environmental factors and AL interacted to influence all-cause mortality. Future studies should focus on interventions at the neighborhood and individual level to address socioeconomically based disparities in breast cancer.

Association of Allostatic Load With All-Cause Mortality in Patients With Breast Cancer.

Importance: Elevated allostatic load (AL) has been associated with adverse socioenvironmental stressors and tumor characteristics that convey poor prognosis in patients with breast cancer. Currently, the association between AL and all-cause mortality in patients with breast cancer is unknown. Objective: To examine the association between AL and all-cause mortality in patients with breast cancer. Design, Setting, and Participants: This cohort study used data from an institutional electronic medical record and cancer registry at the National Cancer Institute Comprehensive Cancer Center. Participants were patients with breast cancer diagnoses (stage I-III) between January 1, 2012, through December 31, 2020. Data were analyzed from April 2022 through November 2022. Exposure: AL was expressed as a summary score calculated by assigning 1 point for biomarkers in the worst sample quartile. High AL was defined as AL greater than the median. Main Outcomes and Measures: The main outcome was all-cause mortality. A Cox proportional hazard models with robust variance tested the association between AL and all-cause mortality. Results: There were 4459 patients (median [IQR] age, 59 [49-67] years) with an ethnoracial distribution of 3 Hispanic Black patients (0.1%), 381 non-Hispanic Black patients (8.5%), 23 Hispanic White patients (0.5%), 3861 non-Hispanic White patients (86.6%), 27 Hispanic patients with other race (0.6%), and 164 non-Hispanic patients with other race (3.7%). The mean (SD) AL was 2.6 (1.7). Black patients (adjusted relative ratio [aRR], those with 1.11; 95% CI, 1.04-1.18), single marital status (aRR, 1.06; 95% CI, 1.00-1.12), and those with government-supplied insured (Medicaid aRR, 1.14; 95% CI, 1.07-1.21; Medicare aRR, 1.11; 95% CI, 1.03-1.19) had a higher adjusted mean AL than those who were White, married/living as married, or privately insured, respectively. Adjusting for sociodemographic, clinical, and treatment factors, high AL was associated with a 46% increase in mortality risk (hazard ratio [HR], 1.46; 95% CI, 1.11-1.93) over low AL. Similarly, compared with patients in the first AL quartile, those in the third quartile (HR, 1.53; 95% CI, 1.07-2.18) and the fourth quartile (HR, 1.79; 95% CI, 1.16-2.75) had significantly increased risks of mortality. There was a significant dose-dependent association between increased AL and a higher risk of all-cause mortality. Furthermore, AL remained significantly associated with higher all-cause mortality after adjusting for the Charlson Comorbidity Index. Conclusions and Relevance: These findings suggest increased AL is reflective of socioeconomic marginalization and associated with all-cause mortality in patients with breast cancer.

Ulcerated Cutaneous Melanoma: A Review of the Clinical, Histologic, and Molecular Features Associated with a Clinically Aggressive Histologic Phenotype.

The presence of ulceration in melanoma is associated with poor clinical outcomes and is the third most powerful predictor of survival in the AJCC Melanoma Staging System after tumor thickness and mitotic activity. The aggressive biological behavior associated with ulceration has been hypothesized to be the result of an intrinsic biological attribute that favors dissemination and presents locally with the loss of epidermal integrity. Among the features of ulcerated melanoma, many show promise as potential prognostic tools, markers of differential immunogenicity and indicators of oncogenic drivers of invasion and metastasis. The incidence of ulcerated melanoma is greater in males, increases with age and with systemic inflammatory risk factors (diabetes, smoking, low vitamin D, elevated body mass index). Patients with ulcerated primary tumors seem to exclusively benefit from adjuvant interferon (IFN) therapy, which is likely the consequence of an altered tumor microenvironment. When ulceration is present, there is a higher density of macrophages and dendritic cells and enhanced expression of pro-inflammatory cytokines, such as IL-6. There is also an increased expression of proteins involved in tumor antigen presentation in ulcerated melanomas. Histologically, vascular density, vasculogenic mimicry and angiotropism are all significantly correlated with ulceration in melanoma. The presence of ulceration is associated with reduced protein expression of E-cadherin and PTEN and elevated levels of N-cadherin and the matrix metalloproteinases. Differential microRNA expression also holds promise as a potential prognostic biomarker of malignancy and disease spread within the setting of ulceration. However, the molecular and cellular differences associated with the ulcerated state are complex and further study will aid in determining how these differences can be harnessed to improve care for patients with melanoma.

Association of Allostatic Load With Overall Mortality Among Patients With Metastatic Non-Small Cell Lung Cancer.

Importance: Adverse social determinants of health (SDHs) (eg, poverty) are associated with poor oncologic outcomes among patients with lung cancer. However, no studies have evaluated biological correlates of adverse SDHs, operationalized as allostatic load (AL), with mortality due to lung cancer. Objective: To examine the association among AL, SDHs, and mortality among patients with metastatic non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This cross-sectional study of an observational cohort was performed at a National Cancer Institute-designated comprehensive cancer center with data accrued from June 1, 2017, to August 31, 2019. Patients with metastatic (stage IV) NSCLC enrolled at diagnosis into a prospective observational cohort study were included in the present analysis if they had all the biomarkers to calculate an AL score (N = 143). Follow-up was completed on August 31, 2021, and data were analyzed from July 1 to September 30, 2021. Exposures: Social determinants of health. Main Outcomes and Measures: Overall mortality and AL. Results: A total of 143 patients met the study criteria with a median age of 63 (IQR, 55-71) years (89 men [62.2%] and 54 women [37.8%]). In terms of race and ethnicity, 1 patient (0.7%) was Asian, 7 (4.9%) were Black, 117 (81.8%) were White, 17 (11.9%) were of multiple races, and 1 (0.7%) was of other race or ethnicity. The mean (SD) AL was 2.90 (1.37). Elevated AL covaried with lower educational level (r = -0.26; P = .002), male sex (r = 0.19; P = .02), limited mobility (r = 0.19; P = .04), worsening self-care (r = 0.30; P < .001), problems engaging in usual activities (r = 0.21; P = .01), depressive symptoms (r = 0.23; P = .005), and a high number of stressful life events (r = 0.30; P < .001). Multivariable analysis found only increasing difficulty with mobility (r = 0.37 [95% CI, 0.13-0.60]; P = .002) and male sex (r = 0.63 [95% CI, 0.19-1.08]; P = .005) associated with higher AL. On adjusted analysis, elevated AL (hazard ratio, 1.43 [95% CI, 1.16-1.79]; P = .001) and low educational level (hazard ratio, 2.11 [95% CI, 1.03-4.34]; P = .04) were associated with worse overall mortality. Conclusions and Relevance: The findings of this cross-sectional study suggest that higher AL was associated with adverse SDHs and worse overall mortality among patients with advanced NSCLC. These results provide a framework for replication and further studies of AL as a biological correlate for SDH and future prognostic marker.

Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a cancer predisposing syndrome. Studies suggest that women < 50 years old (y.o.) with NF1 have an increased breast cancer (BC) incidence and BC associated mortality. However, this has not been widely recognized secondary to small study populations. METHODS: A systematic literature review was conducted through database searches for BC and NF1: 3456 articles identified, 166 reviewed, 58 used for descriptive analysis and 4 utilized for meta-analysis. Fisher's exact tests, Kaplan-Meier curves and random-effects meta-analysis models were used for analysis. RESULTS: Two hundred eighty-six cases of NF1 and female BC were identified with a median age of 46 years at diagnosis; 53% were <  50. Peak age of BC diagnosis was between 34 to 44 years. Women < 50 y.o. presented with more advanced disease vs. those ≥50 (56% vs. 22% stage III-IV, respectively; p = 0.005). Median survival for the entire cohort was 5 years vs. the reported median BC survival of over 20 years in the general population using the SEER database. Median age at BC death was 48.5 years; 64% of deceased patients were <  50. Meta-analysis of a total of 4178 women with NF1 revealed a BC standardized incidence ratio (SIR) of 3.07 (95%CI 2.16-4.38) for women with NF1 vs. the general population. Women < 50 y.o. demonstrated a higher SIR of 5.08 (95%CI 3.77-6.81) compared to 1.92 (95%CI 1.40-2.63) if ≥50 y.o. CONCLUSIONS: This systematic literature review and meta-analysis suggests that women with NF1 <  50 y.o. have a five-fold increased risk of BC, present with more advanced disease, and may have an increased BC related mortality. Increased awareness and implementation of recent National Comprehensive Cancer Network early BC screening guidelines for this high-risk patient population is essential. Additional evaluation on the influence of NF1 gene mutations identified in patients undergoing hereditary cancer genetic testing on breast cancer risk in individuals without clinical evidence of NF1 is needed.

Effect of topical microporous polysaccharide hemospheres on the duration and amount of fluid drainage following mastectomy: a prospective randomized clinical trial.

BACKGROUND: Seroma formation is the most common complication after mastectomy and places patients at risk of associated morbidities. Microporous polysaccharide hemospheres (MPH) consists of hydrophilic, plant based, polysaccharide particles and is currently used as an absorbable hemostatic agent. An animal model evaluating MPH and seroma formation after mastectomy with axillary lymph node dissection showed a significant decrease in seroma volume. Study aim was to evaluate topical MPH on the risk of post-mastectomy seroma formation as measured by total drain output and total drain days. METHODS: Prospective randomized single-blinded clinical trial of patients undergoing mastectomy for the treatment of breast cancer. MPH was applied to the surgical site in the study group and no application in the control group. RESULTS: Fifty patients were enrolled; eight were excluded due to missing data. Forty-two patients were evaluated, control (n = 21) vs. MPH (n = 21). No difference was identified between the two groups regarding demographics, tumor stage, total drain days, total drain output, number of clinic visits, or complication rates. On a subset analysis, body mass index (BMI) greater than 30 was identified as an independent risk factor for high drain output. Post hoc analyses of MPH controlling for BMI also revealed no statistical difference. CONCLUSIONS: Unlike the data presented in an animal model, no difference was demonstrated in the duration and quantity of serosanguinous drainage related to the use of MPH in patients undergoing mastectomy for the treatment of breast cancer. BMI greater than 30 was identified as an independent risk factor for high drain output and this risk was not affected by MPH use. NCT03647930, retrospectively registered 08/2018.

A Comprehensive Program for the Enhancement of Accrual to Clinical Trials.

BACKGROUND: The Ohio State University Comprehensive Cancer Center (OSUCCC) embarked on a single institution campaign over 2 years to enhance the enrollment of cancer patients into therapeutic clinical trials. The goal of this campaign was to achieve a 40 % increase in accrual over a 2-year period. METHODS: The entire process of accruing patients to clinical trials at the OSUCCC was carefully evaluated and broken down into several interlocking components. The four key areas of emphasis were as follows: (i) tasking of OSUCCC leadership with increased oversight of the entire process; (ii) education of all stakeholders [patients, their families, nurses and staff, physicians (both internal and external), Disease-Specific Committees (DSCs), and the OSUCCC leadership] as to the purpose, advantages, and availability of clinical trials, with an emphasis on accrual to cancer clinical trials (CCTs) being a critical function of all OSUCCC employees; (iii) increased oversight of the portfolio of clinical trials by DSCs; and (iv) optimization of accrual operations and infrastructure center-wide. RESULTS: The accrual goal was achieved a full 4 months ahead of schedule. In total, 2327 patients were accrued to therapeutic clinical trials over the course of this 2-year campaign. Prior to implementation of the accrual program, the accrual rate was consistently below 15 %. From 2009 onwards, the therapeutic accrual rate was always greater than 25 %. CONCLUSIONS: A campaign to educate key stakeholders in the clinical trials accrual process was successful in its goal of increasing accrual to therapeutic trials.

Attachment anxiety is related to Epstein-Barr virus latency.

Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress. Attachment anxiety, a type of relationship insecurity characterized by worry about rejection and abandonment, is a chronic interpersonal stressor. Stress impacts cellular immunity, including herpesvirus reactivation. We investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein-Barr virus (EBV), when individuals were being tested for breast or colon cancer and approximately 1 year later. Participants (N=183) completed a standard attachment questionnaire and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Individuals with more attachment anxiety had higher EBV VCA IgG antibody titers than those with less attachment anxiety. The strength of the association between attachment anxiety and antibody titers was the same at both assessments. This study is the first to show an association between latent herpesvirus reactivation and attachment anxiety. Because elevated herpesvirus antibody titers reflect poorer cellular immune system control over the latent virus, these data suggest that high attachment anxiety is associated with cellular immune dysregulation.

A phase I study of high-dose interleukin-2 with sorafenib in patients with metastatic renal cell carcinoma and melanoma.

This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h × 8-12 doses) was administered on days 1-5 and 15-19, followed by sorafenib on days 29-82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.

Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis.

PURPOSE: Practice guidelines recommend that patients who receive neoadjuvant chemotherapy and radiation for locally advanced rectal cancer complete postoperative adjuvant systemic chemotherapy, irrespective of tumor downstaging. PATIENTS AND METHODS: The National Comprehensive Cancer Network (NCCN) Colorectal Cancer Database tracks longitudinal care for patients treated at eight specialty cancer centers across the United States and was used to evaluate how frequently patients with rectal cancer who were treated with neoadjuvant chemotherapy also received postoperative systemic chemotherapy. Patient and tumor characteristics were examined in a multivariable logistic regression model. RESULTS: Between September 2005 and December 2010, 2,073 patients with stage II/III rectal cancer were enrolled in the database. Of these, 1,193 patients receiving neoadjuvant chemoradiotherapy were in the analysis, including 203 patients not receiving any adjuvant chemotherapy. For those seen by a medical oncologist, the most frequent reason chemotherapy was not recommended was comorbid illness (25 of 50, 50%); the most frequent reason chemotherapy was not received even though it was recommended or discussed was patient refusal (54 of 74, 73%). After controlling for NCCN Cancer Center and clinical TNM stage in a multivariable logistic model, factors significantly associated with not receiving adjuvant chemotherapy were age, Eastern Cooperative Oncology Group performance status ≥ 1, on Medicaid or indigent compared with private insurance, complete pathologic response, presence of re-operation/wound infection, and no closure of ileostomy/colostomy. CONCLUSION: Even at specialty cancer centers, a sizeable minority of patients with rectal cancer treated with curative-intent neoadjuvant chemoradiotherapy do not complete postoperative chemotherapy. Strategies to facilitate the ability to complete this third and final component of curative intent treatment are necessary.

Review of complementary and alternative medicine and selected nutraceuticals: background for a pilot study on nutrigenomic intervention in patients with advanced cancer.

As commonly defined, complementary and alternative medicine (CAM) is a broad category that includes biologically based practices, mind-body medicine, manipulative and bodybased practices, and energy medicine as well as complete medical systems such as naturopathy, homeopathy, Ayurvedic medicine, and traditional Chinese medicine. Several CAM methodologies show promise for the treatment of chronic conditions such as depression and pain disorders or have demonstrated effects upon the immune response in experimental studies. There is growing interest in the use of integrative medicine the combination of CAM methodologies with a conventional medical approach-for the optimization of treatment of various cancers. The Ohio State University Center for Integrative Medicine has developed a specialized nutrigenomic protocol for integrative cancer care. The center uses a comprehensive nutritional and medical evaluation, including a panel of proinflammatory molecules and physiologic parameters, to guide a program of individualized dietary interventions. Dietary supplementation is a current focus of study, including: (1) Omega-3 fatty acids and B vitamins, which are thought to play important roles in immunomodulation; (2) Magnesium oxide, which has been shown to decrease inflammation and improve insulin resistance and lipid profiles; and (3) Cinnamon extract, which reportedly decreases serum glucose levels. This article presents a brief overview of CAM and integrative medicine and a discussion of the relevant nutraceuticals.

Braking bad: blockade of inhibitory pathways improves interleukin-15 therapy.

Blockade of the CTLA-4 and PD-1 inhibitory pathways in T cells via the administration of neutralizing antibodies at the time of interleukin (IL)-15 therapy markedly enhanced the survival of tumor-bearing mice as compared with those receiving IL-15 alone or IL-15 in combination with just one of the antibodies.

Meeting report: The 13th Annual Meeting of the Translational Research Cancer Centers Consortium (TrC3); Immune Suppression and the Tumor Microenvironment, Columbus, Ohio; March 1-2, 2010.

The Translational Research Cancer Centers Consortium (TrC3) is a cancer immunotherapy network, established to promote biologic therapeutics in the Midwestern and Northeastern regions of The United States. The 13th Annual Meeting of the TrC3 was hosted by The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and took place at The Blackwell Hotel and Conference Center in Columbus, OH on March 1-2, 2010 (http://www.osuccc.osu.edu/TrC3/index.htm). This year's theme was "Immune Suppression and the Tumor Microenvironment." The meeting consisted of 21 oral presentations, a roundtable discussion focused on enhancing collaborative relationships within the consortium, and a poster session with 54 abstracts from predoctoral or postdoctoral researchers. This annual meeting brought together more than 170 investigators from 9 regional cancer centers including: Abramson Cancer Center at The University of Pennsylvania, Barbara Ann Karmanos Cancer Institute at Wayne State University, Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Center, James P. Wilmot Cancer Center, Mary Babb Randolph Cancer Center at West Virginia University, The Ohio State University Comprehensive Cancer Center, Penn State Cancer Institute, Roswell Park Cancer Institute, and University of Pittsburgh Cancer Institute. The proceedings of this year's meeting are summarized in this report.

Distress reduction from a psychological intervention contributes to improved health for cancer patients.

PURPOSE: Psychological interventions are efficacious in reducing emotional distress for cancer patients. However, it is not clear whether psychological improvements are, in turn, related to improved health. A clinical trial tests whether a psychological intervention for cancer patients can do so, and also tests two routes to achieve better health: (a) reducing patients' Emotional Distress, and/or (b) enhancing their functional immunity. METHODS: Post-surgery, 227 breast cancer patients were randomized to intervention or assessment only Study Arms. Conducted in small groups, intervention sessions were offered weekly for 4 months and followed by monthly sessions for 8 months. Measures included psychological (distress), biological (immune), and health outcomes (performance status and evaluations of patient's symptomatology, including toxicity from cancer treatment, lab values) collected at baseline, 4 months, and 12 months. RESULTS: A path model revealed that intervention participation directly improved health (p<.05) at 12 months. These effects remained when statistically controlling for baseline levels of distress, immunity, and health as well as sociodemographic, disease, and cancer treatment variables. Regarding the mechanisms for achieving better health, support was found for an indirect effect of distress reduction. That is, by specifically lowering intervention patients' distress at 4 months, their health was improved at 12 months (p<.05). Although the intervention simultaneously improved patients' T-cell blastogenesis in response to phytohemagglutinin (PHA), the latter increases were unrelated to improved health. CONCLUSION: A convergence of biobehavioral effects and health improvements were observed. Behavioral change, rather than immunity change, was influential in achieving lower levels of symptomatology and higher functional status. Distress reduction is highlighted as an important mechanism by which health can be improved.

Individual trajectories in stress covary with immunity during recovery from cancer diagnosis and treatments.

Research connects stressful events with altered immune regulation, but the role of subjective stress is uncertain. Using a longitudinal design, we provide a statistically powerful test of the relationship between subjective stress (perceived stress, emotional distress) and immunity (T cell blastogenesis, natural killer cell cytotoxicity, [NKCC]) as individuals adjust to a severe stressor, a cancer diagnosis and its treatments. Women with regional breast cancer (N=113) were assessed at diagnosis/surgery and reassessed 4, 8, 12, and 18 months later. Latent growth curve analysis tested two hypotheses: (1) initial levels of subjective stress will correlate inversely with initial levels of immunity, and (2) rate of change in subjective stress will correlate inversely with rate of change in immunity. As predicted by Hypothesis 1, participants with high initial subjective stress showed poor initial blastogenesis. As predicted by Hypothesis 2, participants exhibiting an early, rapid decline in subjective stress also showed rapid improvement in NKCC. Follow-up analyses revealed perceived stress to be strongly related to immune function, while emotional distress was not. This is the first study to investigate trajectories in stress and immunity during recovery from a major stressor. Results imply that NK and T cells are sensitive to different aspects of the stress response. While T cell blastogenesis correlated with initial (peak) subjective stress, NKCC correlated with change (improvement) in subjective stress. These data highlight the importance of subjective stress, particularly stress appraisals, in the immune response to a major stressor.