Robot-assisted laparoscopic removal of an extraperitoneal pelvic solitary fibrous tumor.

•Pelvic SFTs are rare, typically benign soft tissue neoplasms that pose a diagnostic challenge for gynecologists.•Retroperitoneal pelvic SFTs can mimic gynecologic malignancies and should be considered in diagnosis of a solitary pelvic mass.•Pathologic diagnosis is typically confirmed by immunohistochemistry staining positively for CD34 and STAT6.•Complete surgical excision is recommended for these tumors and can be completed with a minimally invasive approach.•Close long-term follow-up is necessary due to possible recurrence or metastasis, especially for high-risk pathologic features.

Impact of Race and Ethnicity on Perioperative Outcomes During Hysterectomy for Endometriosis.

STUDY OBJECTIVE: To assess whether complications incurred during hysterectomy for the treatment of endometriosis differ among racial-ethnic groups. DESIGN: Retrospective cohort study. SETTING: American College of Surgeons National Surgical Quality Improvement Program database from 2014 to 2019. This database is a robust, comprehensive, multi-institutional database with nearly 700 participating hospitals. PATIENTS: Patients with a diagnosis of endometriosis or with an endometriosis-associated symptom as the primary indication for surgery and surgical intraoperative documentation of endometriosis. INTERVENTIONS: Compare perioperative complications based on patient race and ethnicity. MEASUREMENTS AND MAIN RESULTS: A total of 5639 patients underwent hysterectomy for endometriosis; of these, 4368 were White patients (77.5%), 528 Black patients (9.4%), 491 Hispanic patients (8.7%), 252 Asian patients (4.5%). There was no association between location of endometriosis and patient race and ethnicity. However, White patients had highest rate, and Asian patients had the lowest rate of laparoscopic hysterectomy, 85.3% vs 69.8%, respectively (p <.01). In addition, there were differences in concomitant procedures performed at time of hysterectomy based on race and ethnicity, with White patients having the highest rates of adnexal/peritoneal surgery at 12.5% (p <.01) compared with patients of the other racial and ethnic groups. Asian patients had the highest rate of ureteral surgery at 6.8% (p <.01) and highest rate of intestinal surgery at 16.3% (p <.01) compared with patients of other racial and ethnic groups. There was no association of rates of concomitant bladder surgery, appendectomy, or rectal surgery with patient race and ethnicity. Black patients had the highest rate of minor complications at 13.5% (p <.01) and the highest rate of major complications at 6.6% (p <.01) compared with patients of other racial and ethnic groups. After multivariable analysis, Black patients still had increased odds of having a major complication compared with patients of other racial and ethnic groups even after controlling for patient characteristics and perioperative factors such as endometriosis lesion location, surgical approach, and concomitant procedures (odds ratio 1.64; 95% confidence interval, 1.10-2.45). CONCLUSION: Endometriosis lesion location did not differ with patient race and ethnicity. However, patient race and ethnicity did have an impact on the surgical approach and the concomitant surgical procedures performed at time of hysterectomy. Black patients had the highest odds of major complications.

Perioperative Myomectomy Outcomes Based on the Current Coding Rules: Comparing Leiomyoma Burden and Surgical Approach.

OBJECTIVE: To assess postoperative outcomes based on surgical approach for myomectomies with increasing leiomyoma burden. METHODS: We conducted a retrospective analysis using the American College of Surgeons National Surgical Quality Improvement Program database from 2014 to 2019 of benign myomectomy procedures. These cases were categorized into "smaller" and "larger" procedures based on leiomyoma burden. Smaller myomectomies included leiomyomas weighing less than 250 g or with one-four leiomyomas (Current Procedural Terminology [CPT] codes 58545 and 58140); larger myomectomies included leiomyomas weighing 250 g or more or with five or more leiomyomas (CPT codes 58546 and 58146). Postoperative complications estimated using the Clavien-Dindo classification system were compared based on surgical approach. RESULTS: Of 8,363 total myomectomy procedures, 3,117 (37.3%) were performed using minimally invasive surgery (MIS) and 5,246 (62.7%) were performed using laparotomy. Among MIS cases, 2,080 (66.7%) were categorized as smaller myomectomies and 1,037 (33.3%) cases as larger myomectomies. Among laparotomy cases, 2,587 (49.3%) were smaller myomectomies, and 2,659 (50.7%) were larger myomectomies. Regardless of myomectomy size, MIS was associated with a lower perioperative blood transfusion rate than laparotomy (1.63% vs 8.93%, respectively, P<.01). Laparotomy was associated with an increased rate of minor complications (adjusted odds ratio [aOR] 2.86 (95% CI 2.24-3.67) for smaller leiomyoma burden (11.91% vs 4.28%) and for larger leiomyoma burden (21.59% vs 6.75%, aOR 3.43, 95% CI 2.64-4.47) cases. Laparotomy demonstrated an increased cumulative major complication rate (3.31% vs 1.25%) (aOR 2.45, 95% CI 1.35-4.45) for larger myomectomies. CONCLUSION: A minimally invasive surgical approach for both smaller and larger myomectomies was associated with fewer minor complications compared with laparotomy. Minimally invasive surgery for larger myomectomies was associated with fewer cumulative major complications compared with laparotomy.

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies.

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERß), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

A New Strategy to Control and Eradicate "Undruggable" Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology.

Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future.

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer.

BACKGROUND: Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS "pathway" activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. METHODS: In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. FINDINGS: SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. INTERPRETATION: The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. FUNDING: This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

RAS pathway biomarkers for breast cancer prognosis.

Metastatic breast cancer is a highly heterogeneous, rapidly evolving and devastating disease that challenges our ability to find curative therapies. RAS pathway activation is an understudied research area in breast cancer. EGFR/RAS pathway activation is prevalent in breast cancer with poor prognosis. The prognostic RAS pathway biomarkers can be used to identify resistant tumour clones, stratify patients and guide therapies.

Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat.

SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered.