Laparoscopic surgery for adrenocortical carcinoma: Estimating the risk of margin-positive resection.

BACKGROUND: Over recent years, there has been increasing adoption of minimally invasive surgery (MIS) in the treatment of adrenocortical carcinoma (ACC). However, MIS has been associated with noncurative resection and locoregional recurrence. We aimed to identify risk factors for margin-positivity among patients who undergo MIS resection for ACC. We hypothesized that a simple nomogram can accurately identify patients most suitable for curative MIS resection. METHODS: Curative-intent resections for ACC were identified through the National Cancer Database spanning 2010-2018. Trends in MIS utilization were reported using Pearson correlation coefficients. Factors associated with margin-positive resection were identified among preoperatively available variables using multivariable logistic regression, then incorporated into a predictive model. Model quality was cross validated using an 80% training data set and 20% test data set. RESULTS: Among 1260 ACC cases, 38.6% (486) underwent MIS resection. MIS utilization increased over time at nonacademic centers (R = 0.818, p = 0.007), but not at academic centers (R = 0.009, p = 0.982). Factors associated with margin-positive MIS resection were increasing age, nonacademic center (odds ratio [OR]: 1.8, p = 0.006), cT3 (OR: 4.7, p < 0.001) or cT4 tumors (OR: 14.6, p < 0.001), and right-sided tumors (OR: 2.0, p = 0.006). A predictive model incorporating these four factors produced favorable c-statistics of 0.75 in the training data set and 0.72 in the test data set. A pragmatic nomogram was created to enable bedside risk stratification. CONCLUSIONS: An increasing proportion of ACC are resected via minimally invasive operations, particularly at nonacademic centers. Patient selection based on a few key factors can minimize the risk of noncurative surgery.

Insurance Coverage of Prophylactic Mastectomies: A National Review of the United States.

BACKGROUND: Breast cancer is associated with a multitude of risk factors, such as genetic predisposition and mutations, family history, personal medical history, or previous radiotherapy. A prophylactic mastectomy (PM) may be considered a suitable risk-reducing procedure in some cases. However, there are significant discrepancies between national society recommendations and insurance company requirements for PM. MATERIALS AND METHODS: The authors conducted a cross-sectional analysis of insurance policies for a PM. One-hundred companies were selected based on the greatest state enrolment and market share. Their policies were identified through a Web-based search and telephone interviews, and their medical necessity criteria were extracted. RESULTS: Preauthorized coverage of PMs was provided by 39% of insurance policies (n = 39) and 5 indications were identified. There was consensus amongst these policies to cover a PM for BRCA1/2 mutations (n = 39, 100%), but was more variable for other genetic mutations (15%-90%). Coverage of PM for the remaining indications varied among insurers: previous radiotherapy (92%), pathological changes in the breast (3%-92%), personal history of cancer (64%) and family history risk factors (39%-51%). CONCLUSION: There is a marked level of variability in both the indications and medical necessity criteria for PM insurance policies. The decision to undergo a PM must be carefully considered with a patient's care team and should not be affected by insurance coverage status.

Treat Now or Treat Later: Comparative Effectiveness of Adjuvant Therapy in Resected Stage IIIA Melanoma.

BACKGROUND: Adjuvant therapy for most sentinel-node-positive (stage IIIA) melanoma may have limited clinical benefit for older patients given the competing risk of non-cancer death. The objective of this study is to model the clinical effect and cost of adjuvant therapy in stage IIIA melanoma across age groups. STUDY DESIGN: A Markov decision analysis model simulated the overall survival of patients with resected stage IIIA melanoma treated with adjuvant therapy vs observation. In the adjuvant approach, patients are modeled to receive adjuvant pembrolizumab (BRAF wild type) or dabrafenib/trametinib (BRAF mutant). In the observation approach, treatment is deferred until recurrence. Transition variables were derived from landmark randomized trials in adjuvant and salvage therapy. The model was analyzed for age groups spanning 40 to 89 years. The primary outcome was the number needed to treat (NNT) to prevent one melanoma-related death at 10 years. Cost per mortality avoided was estimated using Medicare reimbursement rates. RESULTS: Projections for NNT among BRAF wild type patients increased by age from 14.71 (age 40 to 44) to 142.86 (age 85 to 89), with patients in cohorts over the age of 75 having an NNT over 25. The cost per mortality avoided ranged from $2.75 million (M) (age 40 to 44) to $27.57M (age 85 to 89). Corresponding values for BRAF mutant patients were as follows: NNT 18.18 to 333.33; cost per mortality avoided ranged from $2.75M to $54.70M. CONCLUSION: Universal adjuvant therapy for stage IIIA melanoma is costly and provides limited clinical benefit in patients older than 75 years.

Contralateral prophylactic mastectomy in the setting of breast cancer diagnosis and their insurance coverage in the United States.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) is more common in the United States than the rest of the world. However, the benefit of this procedure is still under question in many breast cancer scenarios. CPM utilization in the United States is in part dependent on a patient's health insurance coverage of breast oncology surgery and any desired reconstruction. However, there are great discrepancies in the coverage provided by insurers. METHODS: The authors conducted a cross-sectional analysis of insurance policies for a CPM in the setting of diagnosed breast cancer. One hundred companies were selected based on their state enrollment and market share. Their policies were identified through a Web-based search and telephone interviews, and their medical necessity criteria were extracted. RESULTS: Of the 100 companies assessed, 36 (36%) had a policy for CPM. Within those, significantly more provided coverage than denied the procedure (72% vs. 25%, p < 0.0001), with the remainder providing case-by-case coverage. Eleven criteria were identified from preauthorized policies, the most common prerequisite was breast cancer diagnosis under 45 years old (n = 9, 35%). Most policies did not differentiate between gender in their policies (n = 25, 69%), but of those that did, 100% (n = 11) provided coverage for men and women, with 82% (n = 9) requiring further criteria from the female patients. CONCLUSION: The coverage of CPM in the United States varies from complete denial to unrestricted approval. This may be due to conflicting reports in the literature as to the utility of the procedure. The decision to undergo this procedure must be taken with thoughtful consideration and the support of a multidisciplinary approach.

Access to maternity and prenatal care services in rural Michigan.

BACKGROUND: The United States physician shortages affect rural health care access, including maternity care. Project aims were to identify and characterize prenatal and delivery care in Michigan's rural counties and to explore access to trial of labor after cesarean (TOLAC) services for women in rural Michigan. METHODS: Descriptive, cross-sectional design used 2015 Medicaid claims data and public health plan information to identify maternity care services provided within Michigan's rural counties. Publicly available health plan information was used to identify rural maternity hospitals and prenatal care practitioners; findings were verified by Internet searches and telephone interviews. Medicaid claims data were used to determine services provided. High-risk geographic areas were defined as those where women needed to travel >30 miles for maternity-related care. Expected TOLAC rate was determined based on published national birth data; rural hospitals were stratified based on whether they met the expected TOLAC rate, delivered 20%-60% of expected rate, or billed ≤1 TOLAC birth to Medicaid in 2015. RESULTS: In Michigan's 57 rural counties, only 29 hospitals provide maternity care. Geographic high-risk areas were identified in the Upper Peninsula and northeast Lower Peninsula of Michigan. Only two rural hospitals billed for the expected rate of TOLAC births; six delivered at a lower rate, and the remaining 21 hospitals provided no TOLAC services, resulting in large areas of the state where women were not offered this option locally. CONCLUSIONS: Maternity care services are limited for many rural Michigan women. Findings can be used to target specific strategies to improve access to care for these women. Similar analyses, exploring patterns of maternity care delivery in other rural regions worldwide, may uncover similar or additional inequities.

Wolffian tumor (female adnexal tumor of Wolffian origin) presenting as a pelvic side wall mass: Report of a case.

The Wolffian tumor, previously identified as "female adnexal tumor of probable Wolffian origin," is a rare tumor first described in 1973. The tumor is usually benign and is characterized by diffuse and tubular patterns, accentuated by reticulum and periodic acid-Schiff stains. Immunohistochemistry is used to further identify and classify these tumors, which are positive for cytokeratins, vimentin, inhibin, calretinin, and CD10 and negative for cytokeratin 20, epithelial membrane antigen, estrogen receptor, progesterone receptor, 34betaE12, and glutathione S-transferase. We report the case of a 47-year-old female with Wolffian tumor arising from the pelvic sidewall, separate from all reproductive organs. This is the first reported case of Wolffian tumor in this location.

Preoperative Thrombocytosis Predicts Shortened Survival in Patients with Malignant Peritoneal Mesothelioma Undergoing Operative Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: This study was designed to determine the clinical significance of preoperative thrombocytosis in patients with malignant peritoneal mesothelioma (MPM) undergoing operative cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). CRS and HIPEC have been associated with prolonged survival in patients with MPM and is the preferred treatment in select patients. However, patient selection criteria remain ill-defined for this operation that is also associated with significant morbidity and mortality. Preoperative thrombocytosis has been associated with poor outcomes in various malignancies but never studied in MPM. METHODS: Between January 2006 and December 2015, 100 patients with high-grade epithelioid MPM were evaluated and selected for CRS and HIPEC at our center (M: 53, F: 47; mean age: 54 years [range 17-81 years]). We analyzed various patient and treatment related factors potentially associated with overall survival (OS). RESULTS: The median actuarial overall survival was 32.8 months; the actuarial 1-, 3-, 5-year survivals were 70, 49, and 36%, respectively. On multivariate analysis, suboptimal resection (CCR > 1), high tumor burden (PCI > 20), and elevated preoperative platelet count (>367,000/mm3) were independently associated with shortened OS (P < 0.05). Median OS in patients with elevated versus normal platelet counts were 13 and 58 months, respectively (P < 0.001). Compared with patients with normal platelet counts, patients with elevated counts had significantly greater residual disease after operation (P = 0.008). CONCLUSIONS: Elevated preoperative platelet count is independently associated with poor outcome. Notably, thrombocytosis reflects aggressive tumor biology and should be considered a factor in patient selection for CRS and HIPEC.

Intraductal papillary mucinous neoplasm in a neonate with congenital hyperinsulinism and a de novo germline SKIL gene mutation.

A 3 day old infant with persistent severe hypoglycemia was found to have a cystic pancreatic tumor. Cessation of glucose infusion led to severe hypoglycemia. Pancreaticoduodenectomy was performed and revealed an intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia. Sequencing of the IPMN revealed a KRAS gene mutation not present in surrounding normal tissues. Deep sequencing of the patient's blood for KRAS mutations showed no evidence of mosaicism. Whole exome sequencing of the blood of the patient and both parents revealed a de novo germline SKIL mutation in the child that was not present in either parent. This suggests a possible role for SKIL in the pathogenesis of pancreatic tumors.

Optimizing dendritic cell-based approaches for cancer immunotherapy.

Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent "next-generation" DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes.

Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy.

The success of cellular immunotherapies against cancer requires the generation of activated CD4⁺ and CD8⁺ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial. While some studies have shown a pro-cancerous role for IL-17, other studies have shown an anti-tumor function. The induction of polarized T-cell responses can be regulated by dendritic cells (DCs). DCs are key regulators of the immune system with the ability to affect both innate and adaptive immune responses. These properties have led many researchers to study the use of ex vivo manipulated DCs for the treatment of various diseases, such as cancer and autoimmune diseases. While Th1/Tc1 cells are traditionally used for their potent anti-tumor responses, mounting evidence suggests Th17/Tc17 cells should be utilized by themselves or for the induction of optimal Th1 responses. It is therefore important to understand the factors involved in the induction of both type-1 and type-17 T-cell responses by DCs.

Induction of reactive oxygen species by human T-cell leukemia virus type 1 tax correlates with DNA damage and expression of cellular senescence marker.

Human T-cell leukemia virus type 1 (HTLV-1) Tax affects cellular genomic stability and senescence. As yet, the mechanism(s) for these events caused by Tax is incompletely understood. Here, we show that Tax expression in primary human cells induces reactive oxygen species (ROS), which elicits DNA damage and the expression of senescence marker. Treatment with a ROS scavenger or knockdown of Tax expression by small interfering RNA (siRNA) abrogated Tax-induced DNA damage and the expression of senescence marker. Our data suggest that ROS induction explains Tax-induced cellular DNA damage and cellular senescence.