Sex, race, and socioeconomic distinctions in incisional hernia management.

BACKGROUND: We sought to explore the impact of sex, race, and insurance status on operative management of incisional hernias. METHODS: A retrospective cohort study was conducted to explore adult patients diagnosed with an incisional hernia. Adjusted odds for non-operative versus operative management and time to repair were queried. RESULTS: Of the 29,475 patients with an incisional hernia, 20,767 (70.5%) underwent non-operative management. In relation to private insurance, Medicaid (aOR 1.40, 95% CI 1.27-1.54), Medicare (aOR 1.53, 95% CI 1.42-1.65), and uninsured status (aOR 1.99, 95% CI 1.71-2.36) were independently associated with non-operative management. African American race (aOR 1.30, 95% CI 1.17-1.47) was associated with non-operative management while female sex (aOR 0.81, 95% CI 0.77-0.86) was predictive of elective repair. For patients who underwent elective repair, both Medicare (aOR 1.40, 95% CI 1.18-1.66) and Medicaid (aOR 1.49, 95% CI 1.29-1.71) insurance, but not race, were predictive of delayed repair (>90 days after diagnosis). CONCLUSIONS: Sex, race, and insurance status influence incisional hernia management. Development of evidence-based management guidelines may help to ensure equitable care.

Malignancy Assessment Using Gene Identification in Captured Cells Algorithm for the Prediction of Malignancy in Women With a Pelvic Mass.

OBJECTIVE: To evaluate the detection of malignancy in women with a pelvic mass by using multiplexed gene expression analysis of cells captured from peripheral blood. METHODS: This was an IRB-approved, prospective clinical study. Eligible patients had a pelvic mass and were scheduled for surgery or biopsy. Rare cells were captured from peripheral blood obtained preoperatively by using a microfluidic cell capture device. Isolated mRNA from the captured cells was analyzed for expression of 72 different gene transcripts. Serum levels for several commonly assayed biomarkers were measured. All patients had a tissue diagnosis. Univariate and multivariate logistic regression analyses for the prediction of malignancy using gene expression and serum biomarker levels were performed, and receiver operating characteristic curves were constructed and compared. RESULTS: A total of 183 evaluable patients were enrolled (average age 56 years, range 19-91 years). There were 104 benign tumors, 17 low malignant potential tumors, and 62 malignant tumors. Comparison of the area under the receiver operating characteristic curve for individual genes and various combinations of genes with or without serum biomarkers to differentiate between benign conditions (excluding low malignant potential tumors) and malignant tumors showed that a multivariate model combining the expression levels of eight genes and four serum biomarkers achieved the highest area under the curve (AUC) (95.1%, 95% CI 92.0-98.2%). The MAGIC (Malignancy Assessment using Gene Identification in Captured Cells) algorithm significantly outperformed all individual genes (AUC 50.2-65.2%; all P <.001) and a multivariate model combining 14 different genes (AUC 88.0%, 95% CI 82.9-93.0%; P =.005). Further, the MAGIC algorithm achieved an AUC of 89.5% (95% CI 81.3-97.8%) for stage I-II and 98.9% (95% CI 96.7-100%) for stage III-IV patients with epithelial ovarian cancer. CONCLUSION: Multiplexed gene expression evaluation of cells captured from blood, with or without serum biomarker levels, accurately detects malignancy in women with a pelvic mass. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02781272. FUNDING SOURCE: This study was funded by ANGLE Europe Limited (Surrey Research Park, Guildford, Surrey, United Kingdom).

HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression.

Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high- and low-expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.

Myeloid derived suppressor cells in cancer, premalignancy and inflammation: A roadmap to cancer immunoprevention.

The ultimate success of any form of cancer therapy or cancer prevention depends on its ability to engage the power of the immune system to completely eliminate a growing tumor, lower the life-time tumor risk and establish long-term memory to prevent recurrence or future tumors. For that reason, all therapies but especially immunotherapies depend on the immune health (immunocompetence) of each treated individual. Cancer and chronic illnesses, combined with a usually more advanced age of cancer patients or those at risk for cancer are known to severely suppress multiple antitumor functions of the immune system. Understanding the critical mechanisms controlling and mediating immune suppression can lead to additional therapies to alleviate the effects of those mechanisms and improve the outcome of cancer therapy and prevention. We introduce and review here a highly immunosuppressive cell population found in cancer, precancer, and chronic inflammatory diseases, myeloid derived suppressor cells (MDSC). First described in the setting of advanced cancer, their presence and immunosuppressive activity has been seen more recently in early premalignant lesions and in chronic inflammatory diseases leading to cancer. We describe the detrimental effects of their presence on cancer immunotherapy, immunosurveillance and immunoprevention and review early attempts to develop drugs to eliminate them or reduce their negative impact.

Development of Potent Forchlorfenuron Analogs and Their Cytotoxic Effect in Cancer Cell Lines.

Forchlorfenuron (FCF) is a synthetic plant cytokinin widely used in agriculture to promote fruit size, that paradoxically inhibits proliferation, migration, and invasion in human cancer cell lines. FCF has also been shown to affect HIF-1α and HER2, which are both known to play a crucial role in cancer cell survival. In this study, we have developed potent FCF analogs through structural modification of FCF, coined UR214-1, UR214-7, and UR214-9. Compared to parental FCF, these analogs are more effective in decreasing viability and proliferation in both ovarian and endometrial cancer cell lines. These FCF analogs also suppress HER2 expression at a concentration lower than that of FCF. In addition, we found that treatment with either FCF or its analogs decreases the expression of human epididymis protein 4 (HE4), which is commonly upregulated in ovarian and endometrial cancers. Given the association between cancer behavior and HE4 production in gynecologic cancers, our findings may provide insight useful in the development of new treatment strategies for gynecologic cancers.

Novel Small Molecule MEK Inhibitor URML-3881 Enhances Cisplatin Sensitivity in Clear Cell Ovarian Cancer.

Advanced clear cell ovarian cancer (CCOC) is a highly fatal malignancy with a scarcity of effective treatment options. CCOC is inherently chemotherapy resistance, but the exact mechanism of this resistance has yet to be established. Prosurvival signaling, such as through the MAPK cascade, is one way in which cancer cells can evade chemotherapy. We have determined that CCOC exhibits baseline elevated levels of MAPK activity, which increase further upon cisplatin exposure. We have developed a novel MEK inhibitor, URML-3881, to test the effect of MAPK inhibition in CCOC. URML-3881 was found to reduce in vitro CCOC viability through apoptosis and proliferation inhibition, yet it failed to induce in vivo tumor regression. Similarly, cisplatin alone had minimal impact on tumor growth, but remarkably, the combination of MEK inhibition and cisplatin led to a significant and prolonged tumor regression. These studies confirm that the combination of MEK inhibition with URML-3881 and cisplatin is superior to either agent alone in CCOC. Our data support the design of future preclinical and clinical studies into the combination of MEK inhibition and platinum-based chemotherapy as a treatment strategy for CCOC.

Index case of acute myeloid leukemia in a family harboring a novel CEBPA germ line mutation.

The persistence of a CEBPA mutation at the time of complete remission warrants germ line analysis.Not all patients harboring germ line CEBPA mutations have a family history of AML.

Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.