Trends in utilization of contralateral prophylactic mastectomy among different age, racial and ethnic groups.

Background: The use of contralateral prophylactic mastectomy (CPM) has increased over the last two decades with variations in the frequency of reconstruction. The objective of this cohort study is to elucidate the use of CPM and reconstruction among underrepresented racial and ethnic groups and women over 65 years. Methods: Women over 18 years, diagnosed with stages I to III breast cancer who underwent mastectomy from 2004-2017 were identified in the National Cancer Database (NCDB) and grouped into CPM vs. non-CPM. Multivariable analyses were used to examine the associations between CPM and reconstruction with sociodemographic and clinical factors. Results: A total of 571,649 patients were identified. Patients who underwent CPM were under 50 years (45.9%), White (88.4%) and with private insurance (73.5%). On multivariable analysis, women over 65 years [odds ratio (OR): 0.18, P<0.001], non-White (Black, OR: 0.56, P<0.001) and without private insurance (uninsured, OR: 0.50, P<0.001) had decreased odds of CPM. Women over 65 years (OR: 0.11, P<0.001), non-White (Asian/Pacific Islander, OR: 0.58, P<0.001) and without private insurance (Medicaid, OR: 0.41, P<0.001) had decreased odds of reconstruction. Conclusions: Non-White women and women over the age of 65 years were less likely to have CPM or reconstruction than their White counterparts from 2004 to 2017. Research is needed to understand factors impacting decision-making.

County characteristics associated with refusing breast cancer surgery: Evidence from the Surveillance, Epidemiology, and End Results program.

BACKGROUND: Individuals' communities impact cancer disparities and are intimately related to social determinants of health. Studies show that personal factors affect treatment refusals for a potentially curable cancer, but few studies have investigated whether community-based characteristics affect the receipt of surgery. METHODS: We used Surveillance Epidemiology and End Results Program registries from 2010 to 2015 to examine differences in rates of surgery refusal among non-Hispanic White, non-Hispanic Black, and Hispanic women diagnosed with nonmetastatic breast cancer. The community factor measures were based on county-level factors. Sociodemographic and community differences were analyzed using Pearson's χ2 tests and analysis of variance. Multivariate logistic regression of predictors of surgery refusal and the Cox proportional hazard model of disease-specific mortality were performed. RESULTS: Surgery refusers among non-Hispanic Black and Hispanic all races lived in counties with lower rates of educational attainment, median family and household income, and higher rates of poverty, unemployment, foreign-born, language isolation, urban population, and women more than 40 years old having mammography in last 2 years. Multivariate analysis shows surgery refusal rates increased in counties having a high percentage of urban population and declined in counties with an increased percentage of less than high school level education, unemployment, and median household income. Breast cancer-specific mortality increased significantly with surgery refusal. CONCLUSION: Residence in counties with the lowest socioeconomic status and disproportionately populated by racial and ethnic minorities is associated with surgery refusal. Given the high mortality associated with refusing surgery, culturally sensitive education on the benefits of care may be appropriate.

Burnout in Trauma Surgeons During the COVID-19 Pandemic: a Long-standing Problem Worsens.

Purpose of Review: Physician burnout is well-described in the literature. We analyze the effects of the COVID-19 pandemic on burnout in trauma and acute care surgeons (TACS). Recent Findings: Along with other healthcare workers and trainees, TACS faced unprecedented clinical, personal, and professional challenges in treating a novel pathogen and were uniquely affected due to their skillset as surgeons, intensivists, and leaders. The pandemic and its consequences have increased burnout and are suspected to have worsened PTSD and moral injury among TACS. The healthcare system is just beginning to grapple with these problems. Summary: COVID-19 significantly added to the pre-existing burden of burnout among TACS. We offer prevention and mitigation strategies. Furthermore, to build upon the work done by individuals and organizations, we urge that national institutions address burnout from a regulatory standpoint.

Utilization of cancer survivorship services during the COVID-19 pandemic in a tertiary referral center.

BACKGROUND: All Commission on Cancer-accredited comprehensive cancer centers offer survivorship programs (SPs) to women upon completion of treatment. These SPs can include clinical and non-clinical programming such as physical rehabilitation, emotional and psychosocial support, nutrition, and exercise programming. Concern about the availability and access to these programs during the COVID-19 pandemic has been described in recent literature. We sought to identify the impact of the COVID-19 pandemic on participation in these supportive services for breast cancer patients within a single institution. METHODS: The Ohio State University tertiary care center offers clinical and non-clinical breast cancer support services. Descriptive statistics were utilized to summarize referral and patient participation data from January 2019 through July 2021. Data from calendar year 2019 was used as a normative comparison for pre-COVID-19. In-person and telehealth use was tracked longitudinally. RESULTS: During the lockdown due to the COVID-19 pandemic (March through May 2020), provider referrals to SPs declined by 10%, while the overall total for the calendar year modestly increased from 1195 in 2019 to 1210 in 2020, representing a 1.3% increase. Psycho-oncology referrals increased from 280 to 318 (13.5%). The most significant change of participation rates in non-clinical SPs during the pandemic was utilization of exercise content, which increased by 220% from 2019 to 2020. The total proportion of breast cancer participants choosing an exercise program increased from 16.8% in 2019 to 42.2% in 2021, making it the most selected program area overall. Previously, nutrition was the most selected program area as it comprised 42.5% of overall utilization in 2019. CONCLUSION: The pandemic's potential to place barriers to participation in SPs is a legitimate concern. We found a modest decline in provider referrals to clinical services during the lockdown period, while patient-directed participation increased with more survivors engaging in exercise-based programs. Transitioning to virtual platforms served to maintain access for patients. IMPLICATIONS FOR CANCER SURVIVORS: As we grapple with the COVID-19 pandemic, patients with cancer deserve increased attention due to the expected stressors associated with the diagnosis. Those in the survivorship stage utilize services for psychosocial support, and the observed increase in utilization of SPs suggests an elevated need for connectivity. To meet this need, telehealth platforms have been expanded to allow for continued participation. It remains to be seen whether this will be sustained post-COVID-19 or whether reduced human contact will create new needs for programming.

Surgery Refusal Among Black and Hispanic Women with Non-Metastatic Breast Cancer.

BACKGROUND: Studies have shown a lower receipt of treatment among minority women with non-metastatic breast cancer. Those who refuse surgery have increased disease-specific mortality, contributing to disproportionately higher breast cancer mortality in non-Hispanic black (NHB) and Hispanic women. This study aimed to assess surgery refusal in these groups, identify factors associated with surgery refusal, and characterize the association between surgery refusal and survival. METHODS: Surveillance, Epidemiology, and End Results (SEER) Program data from 2005 to 2015 for NHB and Hispanic women with a diagnosis of non-metastatic breast cancer (n = 113,987) was divided into data of those who underwent surgery and data of those who refused surgery. Sociodemographic and tumor clinical/pathologic differences were analyzed by multivariate logistic regression of predictors of surgery refusal and Cox-proportional hazard model of disease-specific mortality. RESULTS: Of 799 patients who refused surgery, 562 were NHB and 237 were Hispanic. The percentage of patients refusing surgery increased from 0.6% in 2005 to 0.9% in 2015. The women who refused surgery were more likely to be older than 81 years, less likely to be married, and more likely to be uninsured or have Medicaid. The refusers presented with more advanced disease and more frequent estrogen receptor-positivity (ER+) and progesterone receptor-positivity (PR+) subtype on histology. Breast cancer-specific mortality increased significantly with surgery omission. Surgery refusal was independently associated with NHB race. CONCLUSION: Surgery refusal among NHB and Hispanic women with potentially curable non-metastatic breast cancer is rising, especially among NHB women, women older than 60 years, single women, and women with a later stage of disease at diagnosis. Additional studies are needed to analyze qualitative data in these populations and their underlying health beliefs, communication needs, and possible use of alternative medicine.

Inflammatory breast cancer, trimodal treatment, and mortality: Does where you live matter?

BACKGROUND: The objective of this study is to examine the associations among neighborhood socioeconomic status, trimodal treatment, and disease-specific mortality among inflammatory breast cancer patients using data from the Surveillance, Epidemiology, and End Results program. METHODS: Patients diagnosed with inflammatory breast cancer (T4d) from 2010 to 2016 were identified in the Surveillance, Epidemiology, and End Results program. The cohort was stratified into neighborhood socioeconomic status groups (low, middle, high) based on National Cancer Institute census tract-level index. Trimodal treatment was defined as receipt of modified radical mastectomy, chemotherapy, and radiation therapy. Bivariable analysis, log-rank test, and a Cox proportional hazards model (hazard ratio, 95% confidence interval) were conducted to evaluate the relationship between neighborhood socioeconomic status, trimodal treatment, and disease-specific mortality. RESULTS: In total, 4,374 patients met study criteria. There was no difference between the neighborhood socioeconomic status groups in receipt of trimodal treatment (P = .19). On multivariable analysis, there was no association between low neighborhood socioeconomic status (hazard ratio 1.13, 0.98-1.30; ref high neighborhood socioeconomic status) or middle neighborhood socioeconomic status (hazard ratio 1.01, 0.88-1.64; ref high neighborhood socioeconomic status) and disease-specific mortality. Notably, triple negative subtype (hazard ratio 2.66, 2.21-3.20; ref luminal A) and Black race (hazard ratio 1.41, 1.16-1.72; ref White) were associated with a higher disease-specific mortality. CONCLUSION: For inflammatory breast cancer patients in the Surveillance, Epidemiology, and End Results program, disease-specific mortality appears to be driven by tumor biology and patient characteristics instead of treatment disparities or neighborhood socioeconomic status.

Call to action: breast cancer screening recommendations for Black women.

African-American/Black women have more aggressive breast cancer subtypes, are diagnosed at younger ages, and have an increasing incidence rate. These disparities have resulted in Black women continuing to experience the highest mortality rate from breast cancer of any US racial or ethnic group. However, national screening mammography guidelines do not reflect the high-risk status of Black women. Here we review breast cancer screening guidelines and address the lack of inclusion of the specific needs of Black women. In order to equitably care for the health needs of Black women, high-risk designation would improve access to earlier screening and supplemental imaging including breast MRI.

Splenic macrophage phagocytosis of intravenously infused mesenchymal stromal cells attenuates tumor localization.

Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents.

Racial Differences in Response to Neoadjuvant Chemotherapy: Impact on Breast and Axillary Surgical Management.

BACKGROUND: Neoadjuvant chemotherapy (NAC), an increasingly used method for breast cancer patients, has the potential to downstage patient tumors and thereby have an impact on surgical options for treatment of the breast and axilla. Previous studies have identified racial disparities in tumor heterogeneity, nodal recurrence, and NAC completion. This report compares the effects of NAC response among non-Hispanic white women and black women in relation to surgical treatment of the breast and axilla. METHODS: A retrospective review of 85,303 women with stages 1 to 3 breast cancer in the National Cancer Database who received NAC between 1 January 2010 and 31 December 2016 was conducted. Differences in sociodemographic and clinical variables between black patients and white patients with breast cancer were tested. RESULTS: The study identified 68,880 non-Hispanic white and 16,423 non-Hispanic black women who received NAC. The average age at diagnosis was 54.8 years for the white women versus 52.5 years for the black women. A higher proportion of black women had stage 3 disease, more poorly differentiated tumors, and triple-negative subtype. The black women had lower rates of complete pathologic response, more breast-conservation surgery, and higher rates of axillary lymph node dissection, but fewer sentinel lymph node biopsies. Axillary management for the women who were downstaged showed more use of axillary lymph node dissection for black women compared with sentinel lymph node biopsy. CONCLUSIONS: The black patients were younger at diagnosis, had more advanced disease, and were more likely to have breast-conservation surgery. De-escalating axillary surgery is being adopted increasingly but used disproportionately for white women.

Intratumoral Delivery of Interferonγ-Secreting Mesenchymal Stromal Cells Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo.

Neuroblastoma, the most common extracranial solid tumor in childhood, remains a therapeutic challenge. However, one promising patient treatment strategy is the delivery of anti-tumor therapeutic agents via mesenchymal stromal cell (MSC) therapy. MSCs have been safely used to treat genetic bone diseases such as osteogenesis imperfecta, cardiovascular diseases, autoimmune diseases, and cancer. The pro-inflammatory cytokine interferon-gamma (IFNγ) has been shown to decrease tumor proliferation by altering the tumor microenvironment (TME). Despite this, clinical trials of systemic IFNγ therapy have failed due to the high blood concentration required and associated systemic toxicities. Here, we developed an intra-adrenal model of neuroblastoma, characterized by liver and lung metastases. We then engineered MSCs to deliver IFNγ directly to the TME. In vitro, these MSCs polarized murine macrophages to the M1 phenotype. In vivo, we attained a therapeutically active TME concentration of IFNγ without increased systemic concentration or toxicity. The TME-specific IFNγ reduced tumor growth rate and increased survival in two models of T cell deficient athymic nude mice. Absence of this benefit in NOD SCID gamma (NSG) immunodeficient mouse model indicates a mechanism dependent on the innate immune system. IL-17 and IL-23p19, both uniquely M1 polarization markers, transiently increased in the tumor interstitial fluid. Finally, the MSC vehicle did not promote tumor growth. These findings reveal that MSCs can deliver effective cytokine therapy directly to the tumor while avoiding systemic toxicity. This method transiently induces inflammatory M1 macrophage polarization, which reduces tumor burden in our novel neuroblastoma murine model. Stem Cells 2018;36:915-924.

Extracellular vesicles released from mesenchymal stromal cells stimulate bone growth in osteogenesis imperfecta.

BACKGROUND: Systemic infusion of mesenchymal stromal cells (MSCs) has been shown to induce acute acceleration of growth velocity in children with osteogenesis imperfecta (OI) despite minimal engraftment of infused MSCs in bones. Using an animal model of OI we have previously shown that MSC infusion stimulates chondrocyte proliferation in the growth plate and that this enhanced proliferation is also observed with infusion of MSC conditioned medium in lieu of MSCs, suggesting that bone growth is due to trophic effects of MSCs. Here we sought to identify the trophic factor secreted by MSCs that mediates this therapeutic activity. METHODS: To examine whether extracellular vesicles (EVs) released from MSCs have therapeutic activity, EVs were isolated from MSC conditioned medium by ultracentrifugation. To further characterize the trophic factor, RNA or microRNA (miRNA) within EVs was depleted by either ribonuclease (RNase) treatment or suppressing miRNA biogenesis in MSCs. The functional activity of these modified EVs was evaluated using an in vitro chondrocyte proliferation assay. Finally, bone growth was evaluated in an animal model of OI treated with EVs. RESULTS: We found that infusion of MSC-derived EVs stimulated chondrocyte proliferation in the growth plate, resulting in improved bone growth in a mouse model of OI. However, infusion of neither RNase-treated EVs nor miRNA-depleted EVs enhanced chondrocyte proliferation. CONCLUSION: MSCs exert therapeutic effects in OI by secreting EVs containing miRNA, and EV therapy has the potential to become a novel cell-free therapy for OI that will overcome some of the current limitations in MSC therapy.

Concise Review: An (Im)Penetrable Shield: How the Tumor Microenvironment Protects Cancer Stem Cells.

Cancer stem cells (CSCs) are defined by their unlimited self-renewal ability and their capacity to initiate and maintain malignancy, traits that are not found in most cells that comprise the tumor. Although current cancer treatments successfully reduce tumor burden, the tumor will likely recur unless CSCs are effectively eradicated. This challenge is made greater by the protective impact of the tumor microenvironment (TME), consisting of infiltrating immune cells, endothelial cells, extracellular matrix, and signaling molecules. The TME acts as a therapeutic barrier through immunosuppressive, and thereby tumor-promoting, actions. These factors, outside of the cancer cell lineage, work in concert to shelter CSCs from both the body's intrinsic anticancer immunity and pharmaceutical interventions to maintain cancer growth. Emerging therapies aimed at the TME offer a promising new tool in breaking through this shield to target the CSCs, yet definitive treatments remain unrealized. In this review, we summarize the mechanisms by which CSCs are protected by the TME and current efforts to overcome these barriers. Stem Cells 2017;35:1123-1130.

Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide.

BACKGROUND: Malignant gliomas (glioblastomas; GBMs) are extremely aggressive and have a median survival of approximately 15 months. Current treatment modalities, which include surgical resection, radiation and chemotherapy, have done little to prolong the lives of GBM patients. Chondroitin sulfate proteoglycans (CSPG) are critical for cell-cell and cell-extracellular matrix (ECM) interactions and are implicated in glioma growth and invasion. Chondroitinase (Chase) ABC is a bacterial enzyme that cleaves chondroitin sulfate disaccharide chains from CSPGs in the tumor ECM. Wild-type Chase ABC has limited stability and/or activity in mammalian cells; therefore, we created a mutant humanized version (Chase M) with enhanced function in mammalian cells. METHODS: We hypothesized that disruption of cell-cell and cell-ECM interactions by ChaseM and temozolomide (TMZ) will enhance the chemotherapeutic availability and sensitivity of glioma cells. RESULTS: Utilizing primary patient-derived neurospheres, we found that ChaseM decreases glioma neurosphere aggregation in vitro. Furthermore, an oncolytic HSV-1 virus expressing secreted ChaseM (OV-ChaseM) enhanced viral spread and glioma cell killing compared to OV-Control, in vitro. OV-ChaseM plus TMZ combinatorial treatment resulted in a significant synergistic enhancement of glioma cell killing accompanied by an increase in apoptotic cell death. Intracellular flow cytometric analysis revealed a significant reduction in the phosphorylation of the pro-survival AKT protein following OV-ChaseM plus TMZ treatment. Lastly, in nude mice bearing intracranial GBM30 glioma xenografts, intratumoral OV-ChaseM plus TMZ (10 mg/kg by oral gavage) combination therapy resulted in a significant (p < 0.02) enhancement of survival compared to each individual treatment alone. CONCLUSIONS: These data reveal that OV-ChaseM enhances glioma cell viral susceptibility and sensitivity to TMZ.

Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy.

PURPOSE: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)-expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy. EXPERIMENTAL DESIGN: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA-targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou-Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy. RESULTS: Combination treatment with bortezomib- and oHSV-induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy. CONCLUSIONS: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients. Clin Cancer Res; 22(21); 5265-76. ©2016 AACRSee related commentary by Suryadevara et al., p. 5164.