Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Artificial Intelligence and Cancer Control: Toward Prioritizing Justice, Equity, Diversity, and Inclusion (JEDI) in Emerging Decision Support Technologies.

PURPOSE FOR REVIEW: This perspective piece has two goals: first, to describe issues related to artificial intelligence-based applications for cancer control as they may impact health inequities or disparities; and second, to report on a review of systematic reviews and meta-analyses of artificial intelligence-based tools for cancer control to ascertain the extent to which discussions of justice, equity, diversity, inclusion, or health disparities manifest in syntheses of the field's best evidence. RECENT FINDINGS: We found that, while a significant proportion of existing syntheses of research on AI-based tools in cancer control use formal bias assessment tools, the fairness or equitability of models is not yet systematically analyzable across studies. Issues related to real-world use of AI-based tools for cancer control, such as workflow considerations, measures of usability and acceptance, or tool architecture, are more visible in the literature, but still addressed only in a minority of reviews. Artificial intelligence is poised to bring significant benefits to a wide range of applications in cancer control, but more thorough and standardized evaluations and reporting of model fairness are required to build the evidence base for AI-based tool design for cancer and to ensure that these emerging technologies promote equitable healthcare.

Disparities in Breast-Conserving Therapy for Non-Hispanic American Indian/Alaska Native Women Compared with Non-Hispanic White Women.

BACKGROUND: Little is known about the surgical patterns of American Indian/Alaska Native (AI/AN) breast cancer patients. The purpose of this study is to determine whether there are disparities in breast cancer surgery and radiation therapy between non-Hispanic AI/AN (NH-AI/AN) women and non-Hispanic White (NHW) women. METHODS: Data from the National Program of Cancer Registries of the Centers for Disease Control and Surveillance, Epidemiology, and End Results were used for this cross-sectional study. Female patients with invasive breast cancer diagnosed 2010-2015 were stratified by race/ethnicity, surgical procedure, radiation, and region. Percentage distributions of mastectomy and lumpectomy were compared overall and by region and stage. RESULTS: From 2010 to 2015 there were 3292 NH-AI/AN women and 165,225 NHW women diagnosed with breast cancer. For early stage (AJCC stage 1 and 2), NH-AI/AN women had overall significantly higher percentage of mastectomy (41% vs 34.4%, p < 0.001) and significantly lower percentage of lumpectomy (59% vs 65.6%) compared with NHW women, without significant differences in post-lumpectomy radiation (71% vs 70%). There were regional variations, notably in the Northern Plains, where the percentage of mastectomy for early-stage disease was 48.9% for NH-AI/AN women versus 35.9% for NHW women, and in Alaska with 47% for NH-AI/AN women versus 33.3% for NHW women (p < 0.001). There were no overall significant differences in type of surgery or radiation for late-stage disease between groups. CONCLUSION: This is the first study to show disparities in surgical management of NH-AI/AN women with breast cancer. For early-stage disease, NH-AI/AN women undergo a higher percentage of mastectomy. Future clinical directions could focus on the factors that drive awareness, decision-making, and access to breast conservation.

Four Immune Modulating Genes in Primary Melanoma That Predict Metastatic Potential.

INTRODUCTION: Histologic characteristics cannot adequately predict which patients are at risk of developing metastatic disease after excision of primary cutaneous melanoma. The aim of this study was to identify immunomodulatory genes in primary tumors associated with development of distant metastases. MATERIALS AND METHODS: Thirty-seven patients with primary melanoma underwent surgical excision. RNA was extracted from the primary tumor specimens. cDNA was synthesized and used with Human Gene Expression microarray. Differential expression of 74 immunomodulatory genes was compared between patients who developed distant metastases and those who did not. RESULTS: Six of 37 patients developed distant metastases during the time of the study. Differential expression of microarray data showed upregulation of four immunomodulatory genes in this group. These four genes-c-CBL, CD276, CXCL1, and CXCL2-were all significantly overexpressed in the metastatic group with differential expression fold change of 1.15 (P = 0.01), 1.16 (P = 0.04), 2.51 (P < 0.001), and 1.68 (P < 0.02), respectively. CXCL1 had particularly high predictive value with an area under the curve of 0.80. Multivariate analysis showed only expression of CXCL1 (P = 0.01) remains predictive of distant metastases in melanoma patients. This result was confirmed using quantitative real-time polymerase chain reaction. CONCLUSIONS: CXCL1, CXCL2, c-CBL, and CD276 are immunomodulatory genes present in primary melanoma that are strongly associated with development of metastatic disease. Identification of their presence, particularly CXCL1, in the primary tumor could be used as a predictor of future risk of metastatic disease and thereby to identify patients who might benefit early from immunotherapy.

Incidence of primary liver cancer in American Indians and Alaska Natives, US, 1999-2009.

PURPOSE: To evaluate liver cancer incidence rates and risk factor correlations in non-Hispanic AI/AN populations for the years 1999-2009. METHODS: We linked data from 51 central cancer registries with the Indian Health Service patient registration databases to improve identification of the AI/AN population. Analyses were restricted to non-Hispanic persons living in Contract Health Service Delivery Area counties. We compared age-adjusted liver cancer incidence rates (per 100,000) for AI/AN to white populations using rate ratios. Annual percent changes (APCs) and trends were estimated using joinpoint regression analyses. We evaluated correlations between regional liver cancer incidence rates and risk factors using Pearson correlation coefficients. RESULTS: AI/AN persons had higher liver cancer incidence rates than whites overall (11.5 versus 4.8, RR = 2.4, 95% CI 2.3-2.6). Rate ratios ranged from 1.6 (Southwest) to 3.4 (Northern Plains and Alaska). We observed an increasing trend among AI/AN persons (APC 1999-2009 = 5%). Rates of distant disease were higher in the AI/AN versus white population for all regions except Alaska. Alcohol use (r = 0.84) and obesity (r = 0.79) were correlated with liver cancer incidence by region. CONCLUSIONS: Findings highlight disparities in liver cancer incidence between AI/AN and white populations and emphasize opportunities to decrease liver cancer risk factor prevalence.

Prevalence and Predictors of Preoperative Venous Thromboembolism in Asymptomatic Patients Undergoing Major Oncologic Surgery.

BACKGROUND: Postoperative venous thromboembolism (VTE) is a leading cause of in-hospital mortality for cancer patients; however, the prevalence of preoperative VTE remains unclear. OBJECTIVE: The aim of this study was to evaluate the prevalence and risk factors associated with preoperative VTE in asymptomatic patients undergoing major oncologic surgery. METHODS: Retrospective analysis of 346 patients identified from our prospectively maintained database of patients undergoing abdominopelvic oncologic surgery from 2009 to 2016. RESULTS: The prevalence of preoperative VTE found on screening venous duplex scan was 10.1%. Patients with a history of prior VTE were more likely to have a preoperative deep vein thrombosis (DVT) versus those with no prior VTE (42.9% vs. 4.5%, p < 0.01). Relative risk for prior VTE was 8.2 [95% confidence interval (CI) 4.7-14.3]. Older age was also associated with preoperative VTE. Regression modeling determined that patients were 1.24-fold as likely to have a preoperative DVT for every 5-year increase in age (relative risk 1.24, 95% CI 1.09-1.42). Patients with preoperative DVT were more likely to have been diagnosed with sepsis 1 month prior to surgery (8.6% vs. 1.6%, p = 0.04). There were no postoperative pulmonary emboli. The overall postoperative complication rate was higher in those with a preoperative DVT (25.7% vs. 13.2%, p = 0.071). CONCLUSION: Asymptomatic patients undergoing major oncologic surgery have a 10.1% prevalence of preoperative DVT. Increasing age, recent diagnosis of sepsis, and a history of prior VTE are significantly associated with preoperative DVTs. This suggests high-risk oncologic patients may benefit from screening lower extremity venous duplex ultrasound prior to Surgery.

Proportion of colon cancer attributable to lifestyle in a cohort of US women.

BACKGROUND: Many modifiable lifestyle factors have been associated with colon cancer risk, but less is known about their effect on disease when considered together. Estimating the proportion of colon cancer cases that could be prevented by the adoption of combined modifiable lifestyle behaviors will provide important insights into disease prevention. METHODS: In the Nurses' Health Study, we defined a low-risk group according to a combination of six factors: body mass index < 25 kg/m(2), physical activity of ≥ 21 metabolic equivalent of task per week, alcohol consumption ≤ 30 g/day, cigarette smoking <10 pack-years before the age of 30, current use of multivitamins for ≥ 15 years, and total calcium intake ≥ 700 mg/day. A composite risk score index was created and the population attributable risk (PAR%) was calculated after accounting for other known risk or protective factors. RESULTS: We documented 1,127 colon cancer cases among 81,092 over 24 years of follow-up. Compared with women in the lowest risk category, the women at all other exposure levels had a hazard ratio of colon cancer of 1.81 (95% confidence interval 1.15-2.85). The score index was significantly and linearly related to an increasing risk of colon cancer (p value for trend <0.0001). The PAR% of the six risk factors considered together in relation to colon cancer was 0.37 (95% CI 0.09-0.60). When regular aspirin use (two tablets/week for six or more years) was included with the other low-risk behaviors, the PAR% increased to 0.43 (95% CI 0.14-0.65). CONCLUSIONS: Beyond the known benefit from colonoscopy/sigmoidoscopy, key behavior modifications and adherence to a healthy lifestyle could avoid approximately 37% of colon cancer cases among women.

Health Behavior Change Intervention Preferences Expressed by American Indian Cancer Survivors From a Southwest Tribal Community: Semistructured Interview Study.

BACKGROUND: While many factors, including social determinants of health, affect cancer mortality, one modifiable risk factor that may contribute to cancer disparities is obesity. The prevalence of obesity in the American Indian/Alaska Native population is 48.1% per the Centers for Disease Control and Prevention. The overall cancer mortality for the American Indian/Alaska Native population is 18% higher than the White population as reported by the American Cancer Society. Interventions tailored to American Indian/Alaska Native communities that promote healthy lifestyle behaviors after cancer diagnosis and prior to cancer surgery (prehab) might improve cancer outcomes for this population. OBJECTIVE: The aim of the study is to characterize the lifestyle behaviors of San Carlos Apache cancer survivors and identify preferences for the adaption of a prehab intervention. METHODS: Semistructured interviews and validated questionnaires were completed with San Carlos Apache cancer survivors (N=4), exploring their viewpoints on healthy lifestyle and cancer risk and preferences for program development. A thematic content analysis was conducted. RESULTS: Participants had an average BMI of 31 kg/m2 and walked 53 minutes daily. The majority of participants reported a high willingness to change eating habits (n=3, 75%). All 4 reported willingness to participate in a diet and exercise program. Important themes and subthemes were identified: (1) cancer is perceived as a serious health condition in the community (N=4, 100%); (2) environmental exposures are perceived as cancer-causing threats (n=3, 75%); (3) healthy diet, exercise, and avoiding harmful substances are perceived as mitigating cancer risk (n=3, 75%); (4) barriers to healthy habits include distance to affordable groceries (n=3, 75%) and lack of transportation (n=2, 50%); (5) there is high interest in a prehab program geared toward patients with cancer (N=4, 100%); and (6) standard monitoring practiced in published prehab programs showed early acceptability with participants (N=4, 100%). CONCLUSIONS: Collaboration with tribal partners provided important insight that can help inform the adaptation of a culturally appropriate prehab program for San Carlos Apache patients diagnosed with cancer.

The Influence of Statin Use on Chemotherapeutic Efficacy in Studies of Mouse Models: A Systematic Review.

BACKGROUND/AIM: Using statins as antitumor agents is an approach to cancer therapy that has been explored extensively in specific cancer types. Reframing the query to how a statin interacts with the treatment regimen instead might provide new insight. Given that cell-cycle regulation influences tumorigenesis, it is possible that the cell-cycle phase which a given chemotherapy acts on influences the synergistic effects with adjuvant statin use. In this review, we outline the effect of statins in combination with chemotherapeutic drugs in in vivo animal model studies based on the class of chemotherapy and its relation to the cell cycle. MATERIALS AND METHODS: This systematic review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 with 23 articles deemed eligible to be included. RESULTS: Our review suggests that statins influence the success of chemotherapy treatments. Furthermore, enhanced efficacy was demonstrated with chemotherapeutic drugs that act at every phase of the cell cycle. CONCLUSION: This type of compilation departs from the norm of describing statin influence on named cancer subtypes and instead catalogs how statins interact with categorical chemotherapy agents which might be beneficial for broader therapeutic decision-making across cancer subtypes, possibly contributing to pharmaceutical development, and thereby helping to maximize patient outcomes.

Sphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy.

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.

Subclavian Vein Stenosis Imitating Inflammatory Breast Cancer.

Unilateral breast erythema, edema, and peau d'orange are classically associated with inflammatory breast cancer. However, occasionally this constellation of symptoms is seen with other causes. Maintaining a broad differential can therefore save a prospective patient from months of worry about a possible cancer diagnosis, untreated symptoms, and unnecessary and expensive tests. Here we present the case of a 75-year-old woman with a history of pacemaker placement complicated by left upper extremity deep venous thrombosis (DVT) who subsequently developed left breast peau d'orange, swelling, and erythema. After initially being worked up for inflammatory breast cancer, including multiple breast biopsies, she was then referred to specialists in cardiology, allergy, pulmonology, rheumatology, dermatology, lymphedema therapy, and vascular surgery undergoing an exhaustive workup that spanned nearly a year. Eventually, a venogram was performed, which revealed complete occlusion of her left subclavian vein. After undergoing angioplasty and stenting, her symptoms resolved.

The Link Between Statins and Breast Cancer in Mouse Models: A Systematic Review.

Statins, a class of cholesterol-lowering drugs, have consistently demonstrated pleiotropic effects in both preclinical and clinical studies. Outside of inhibiting the production of cholesterol in cells, statins have shown antineoplastic properties most commonly in breast cancer. Clinical and epidemiological studies, however, are less definitive than preclinical studies regarding statins as potential adjuvant oncologic therapy. Our objective is to summarize mouse model studies that investigate the link between statins and breast cancer using a cancer care continuum framework to provide a clinically relevant picture of the potential use of statins in breast cancer. A systematic review of the PubMed database was performed to identify studies published between January 2007 and July 2022 that investigated the effects of statins on breast cancer prevention, treatment, and survivorship in mouse models. Overall, 58 studies were identified using our search strategy. Based on our inclusion and exclusion criteria, 26 mouse model studies were eligible to be included in our systematic review. In breast cancer mouse models, statins alone and in combination with anti-cancer therapies demonstrate proven antineoplastic effects across the cancer care continuum. The antineoplastic benefit of statins as single agents in mouse model studies helps inform their synergistic benefit that future clinical studies can test. Parameters such as statin timing, dose, and breast cancer subtype are key stepping stones in defining how statins could be used in the treatment of breast cancer.

Native and Indigenous Populations and Gastric Cancer: A Worldwide Review.

Gastric cancer is a worldwide concern, particularly for Indigenous populations who face greater disparities in healthcare. With decreased access to screening and critical treatment delays, this group is experiencing adverse health effects. To determine what factors drive these disparities, a systematic review was performed in PubMed. This revealed a lack of research on gastric cancer specific to this population. The literature primarily focused on subset analyses and biological aspects with sparse focus on determinants of health. The results informed this presentation on factors related to Indigenous gastric cancer, which are influenced by colonialism. Indigenous populations encounter high rates of food shortage, exposure to harmful environmental agents, structural racism in the built environment, H. pylori, and compromised healthcare quality as an effect of colonialism, which all contribute to the gastric cancer burden. Putting gastric cancer into a cultural context is a potential means to respond to colonial perspectives and their negative impact on Indigenous patients. The objective of this manuscript is to examine the current state of gastric cancer literature from a global perspective, describe what is currently known based on this literature review, supplemented with additional resources due to lack of published works in PubMed, and to present a model of gastric cancer through the lens of a modified medicine wheel as a potential tool to counter colonial healthcare perspectives and to honor Indigenous culture.

How Should Health Professions Schools Partner With AI/AN Communities?

Many health professions education institutions exist on land once inhabited by American Indians and Alaska Natives (AI/AN). Land acknowledgment by these academic organizations is helpful, but collaborative support of AI/AN health is also needed. Because tribal-university partnerships in education are fewer than in research but just as important, this article considers health professions schools' responsibilities to offer students clinical rotations on tribal lands and to recruit AI/AN students. Such investment expands student educational opportunity, diversifies clinical workforces, and helps tribes improve health infrastructure and sustainability. This article also offers an adaptable roadmap for building such partnerships.

Cutaneous Metastasis in the Setting of Both Colon and Breast Primary Malignancies.

Colorectal cancer (CRC) is the third most diagnosed cancer in the United States, and many patients unfortunately have metastases at the time of their diagnosis. Cutaneous metastases of CRC have been reported in few journals and primarily as case reports due to their rarity. Here, we present the case of an 83-year-old woman with recently resected colon cancer, T4aN1bMx stage IIIB. She presented to our clinic for evaluation of a right midback mass, and a punch biopsy revealed dermal involvement by invasive, poorly differentiated carcinoma with epidermoid features. The mass was excised, and we ordered a PET scan in search of the primary tumor, which at that time was suspected to be of skin cancer origin. Surprisingly, this revealed a second malignancy triple-negative invasive ductal carcinoma of the left breast. The back mass stained positive for CK20, which was compatible with a metastasis from a colonic primary. After initially declining adjuvant therapy, the patient completed one cycle of capecitabine and oxaliplatin, which she tolerated poorly. She continued to further decline, developed widespread cutaneous metastases, and went home on hospice. Cutaneous lesions are an exceedingly rare site of metastasis for colon adenocarcinoma, and their clinical presentation can vary widely. It is important for providers to investigate any new skin lesion in a patient with a recent or remote history of malignancy, even if there were no sites of distant metastasis at initial diagnosis.

What Should Physicians Consider About American Indian/Alaska Native Women's Reproductive Freedom?

Historically, American Indians and Alaska Natives (AI/AN) have been subjected to a lack of control over various aspects of their lives, including their reproductive health. In discussions of family planning with AI/AN patients, clinicians must consider past violations of reproductive rights and the need for transparent consent. This article explores the following questions: What were historical violations of AI/AN women's reproductive rights? How should physicians express respect for this history and for the autonomy of AI/AN female patients regarding surgical sterilization procedures today?

Surgical and molecular characterization of primary and metastatic disease in a neuroendocrine tumor arising in a tailgut cyst.

Neuroendocrine tumors (NETs) arising from tailgut cysts are a rare but increasingly reported entity with gene expression profiles that may be indicative of the gastrointestinal cell of origin. We present a case report describing the unique pathological and genomic characteristics of a tailgut cyst NET that metastasized to liver. The histologic and immunohistochemical findings were consistent with a well-differentiated NET. Genomic testing indicates a germline frameshift in BRCA1 and a few somatic mutations of unknown significance. Transcriptomic analysis suggests an enteroendocrine L cell in the tailgut as a putative cell of origin. Genomic profiling of a rare NET and metastasis provides insight into its origin, development, and potential therapeutic options.