Timing of genetic testing in BRCA1/2 and PALB2-Associated breast cancer: Preoperative result disclosure increases uptake of risk-reducing mastectomy and reduces unnecessary exposure to radiotherapy.

INTRODUCTION: The impact of timing of genetic testing on uptake of risk reducing mastectomy (RRM) in affected female BRCA1/2 or PALB2 carriers remains an area of evolving interest, particularly with the introduction of mainstream genetic testing initiatives. METHODS: Women with stage I-III breast cancer and a confirmed germline pathogenic variant in BRCA1/2 or PALB2 between 2000 and 2023 were identified from an institutional genetics database. Uptake of RRM was evaluated according to disclosure of genetic testing results before or after index surgery for a first diagnosis of breast cancer. RESULTS: The cohort included 287 female BRCA1/2 or PALB2 carriers with a median age of 44 years (IQR, 36-52). Overall, 155 (54 %) carriers received genetic testing results before and 132 (46 %) after index breast surgery. Receipt of genetic testing results before surgery was associated with a higher rate of index bilateral mastectomy (58.7 % vs. 7.6 %, p < 0.001) and a commensurate decrease in adjuvant radiation (41.9 % vs. 74.2 %, p < 0.001). At a median follow up of 4.4 years after genetic testing, 219 (76.3 %) affected carriers had undergone bilateral RRM, including 83.9 % with preoperative knowledge and 67.4 % of patients with postoperative knowledge of their germline pathogenic variant (log rank, p < 0.001). On multivariate regression, disclosure of genetic testing results before index breast surgery was independently associated with long-term uptake of bilateral mastectomy (HR 1.69, 95 % CI 1.21-2.38). CONCLUSION: Genetic testing results delivered prior to index breast surgery increase uptake of bilateral RRM in affected BRCA1/2 and PALB2 carriers. Efforts to mainstream genetic testing would help optimize surgical decision-making.

Awareness and Candidacy for Endocrine Prevention and Risk Reducing Mastectomy in Unaffected High-Risk Women Referred for Breast Cancer Risk Assessment.

INTRODUCTION: Primary prevention of breast cancer in women at elevated risk includes several strategies such as endocrine prevention and risk-reducing mastectomy (RRM). The objective of this study was to evaluate awareness of different preventive strategies across high-risk subgroups. PATIENTS AND METHODS: Women referred for high risk evaluation between 2020 and 2023 completed an initial risk-assessment questionnaire that included questions around perceived lifetime risk and consideration of preventive strategies. One-way analysis of variance (ANOVA) and chi-squared tests were used to compare differences across different high-risk subgroups. RESULTS: 482 women with a median age of 43 years (20-79 years) met inclusion criteria; 183 (38.0%) germline pathogenic variant carriers (GPV), 90 (18.7%) with high-risk lesions (HRL) on breast biopsy, and 209 (43.4%) with strong family history (FH) without a known genetic predisposition. Most high-risk women reported that they had considered increased screening and surveillance (83.7%) and lifestyle strategies (80.6%), while fewer patients had considered RRM (39.8%) and endocrine prevention (27.0%). Prior to initial consultation, RRM was more commonly considered in GPV carriers (59.4%) relative to those with HRL (33.3%) or strong FH (26.3%, p < 0.001). Based on current guidelines, 206 (43%) patients were deemed eligible for endocrine prevention, including 80.5% with HRL and 39.0% with strong FH. Prior consideration of endocrine prevention was highest in patients with HRL and significantly lower in those with strong FH (47.2% HRL versus 31.1% GPV versus 18.7% FH, p = 0.001). CONCLUSIONS: Endocrine prevention is the least considered preventive option for high-risk women, despite eligibility in a significant proportion of those presenting with HRL or strong FH.

Surgical Decision Making in Genetically High-Risk Women: Quantifying Postoperative Complications and Long-Term Risks of Supplemental Surgery After Risk-Reducing Mastectomy.

BACKGROUND: Risk-reducing mastectomy (RRM) helps prevent breast cancer in high-risk women but also carries a risk of unanticipated supplemental surgeries. We sought to determine the likelihood of supplemental surgeries following RRM. METHODS: We performed a retrospective cohort study of female patients with a confirmed germline pathogenic variant (GPV) in a breast cancer susceptibility gene (BRCA1/2, PALB2 and others) who underwent bilateral or contralateral RRM at our institution between 2006 and 2022. Supplemental surgeries were defined as any operation requiring general or local anesthesia performed outside of the initially planned procedure(s). The Kaplan-Meier method was used to estimate the 5-years cumulative incidence of supplemental surgery. RESULTS: Of 560 GPV carriers, RRMs were performed in 258 (46.1%) women. The median age of the cohort was 44 years (interquartile range 37-52 years), with 33 (12.8%) patients undergoing RRM without reconstruction and 225 (87.2%) undergoing RRM with reconstruction. Following surgery, 34 patients (13.2%) developed early (< 30 days) postoperative complications, including infection, hematoma, seroma, loss of the nipple areola complex, flap necrosis, implant exposure and/or prosthesis removal. At a median follow-up of 3.8 years, 94 (36.4%) GPV carriers underwent at least one reoperation. Participants who experienced an early postoperative complication had the highest rate of reoperation (85.3% vs. 29.0%; p < 0.001) and a significantly higher likelihood of multiple additional surgical interventions (41.2% vs. 10.7%; p < 0.001). The 5-years rate of supplemental surgery was 39.2% [95% confidence interval (CI) 32.7-46.5] in the overall cohort and 31.5% (95% CI 24.9-39.3) in patients without an early postoperative complication. CONCLUSIONS: Unanticipated supplemental surgeries occur in 40% of GPV carriers following RRM and in nearly one-third of patients without early postoperative complications.

Incidence of Occult Breast Cancer in Carriers of BRCA1/2 or Other High-Penetrance Pathogenic Variants Undergoing Prophylactic Mastectomy: When is Sentinel Lymph Node Biopsy Indicated?

BACKGROUND: This study sought to determine the likelihood of occult malignancy during risk-reducing mastectomy in high-penetrance pathogenic variant carriers to help refine axillary staging recommendations. METHODS: The authors performed a retrospective cohort study analyzing all female carriers of pathogenic variants in BRCA1/2, PALB2 or other genes who underwent prophylactic surgery at their institution between 2006 and 2021. Occult breast cancer was defined as the unanticipated presence of in situ or invasive malignancy on pathologic evaluation of prophylactic mastectomy specimens. RESULTS: Of 523 women, 243 carriers met the inclusion criteria for the study including 124 BRCA1 (51.0%), 108 BRCA2 (44.4%), and 11 PALB2, TP53, CDH1, or PTEN (4.6%) carriers. The median age was 44 years (interquartile range, 37-52 years). Overall, 128 women (52.7%) underwent bilateral prophylactic mastectomies, and 115 (47.3%) underwent contralateral prophylactic mastectomy. In the 371 mastectomies performed, 16 (4.3%) occult malignancies were diagnosed. Most of the occult malignancies were ductal carcinoma in situ (13 mastectomies, 3.5%), whereas 3 mastectomies (0.8%) contained invasive breast cancer. If Breast Imaging Reporting and Data System (BIRADS) 1-2 or BIRADS 3 findings were reported on preoperative magnetic resonance imaging (MRI), the rate of occult malignancy decreased to 3.0 and 2.8%, respectively, per mastectomy. The patient-level factors associated with a likelihood of occult breast cancer greater than 10% included a history of prior breast cancer, age exceeding 60 years, and BIRADS 4 findings on preoperative imaging. CONCLUSIONS: Occult invasive malignancy was detected in less than 1% of the risk-reducing mastectomies performed for women with BRCA1/2 or PALB2 pathogenic variants. Sentinel lymph node biopsy can be safely avoided when BIRADS 1-3 findings are reported on preoperative MRI.

Perforated mucocele of the appendix in the left upper quadrant: A challenging anatomy and an improvised surgical technique.

INTRODUCTION: Pseudomyxoma peritonei (PMP) is a feared complication of appendicular mucocele perforation. Although a rare disease, its major sequel mandates recognition and early intervention. Intestinal malrotation is mostly asymptomatic in adults. Its significance arises when it complicates another coinciding condition by confusing the presentation, leading to delay in diagnosis and treatment. PMP and incidental finding of gut malrotation in adults are two rare events, and the chance of both occurring in the same patient is very slim. This can complicate the clinical picture and lead to devastating outcomes. PRESENTATION OF THE CASE: We present a case of PMP in a patient with gut malrotation, managed with cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). DISCUSSION: Management with CRS/HIPEC has been found to improve outcomes for patients with PMP. However, the extensive disease and abnormal anatomy of the patient in our report proposed unique intraoperative challenges. Preserving part of the colon was possible with an improvised surgical technique that we used which proved to be safe and effective. CONCLUSION: Early recognition and consideration of uncommon but serious surgical conditions are essential for improved patient outcomes. To our knowledge, this is the first report in the English literature that describes the use of CRS/HIPEC for PMP in a case of intestinal malrotation. This improvised surgical technique was found to be safe and can provide a surgical solution for preserving part of the colon in selected patients.

The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction.

C. difficile is a Gram-positive spore-forming anaerobic bacterium that is the leading cause of nosocomial diarrhea in the developed world. The pathogenesis of C. difficile infections (CDI) is driven by toxin A (TcdA) and toxin B (TcdB), secreted factors that trigger the release of inflammatory mediators and contribute to disruption of the intestinal epithelial barrier. Neutrophils play a key role in the inflammatory response and the induction of pseudomembranous colitis in CDI. TcdA and TcdB alter cytoskeletal signaling and trigger the release of CXCL8/IL-8, a potent neutrophil chemoattractant, from intestinal epithelial cells; however, little is known about the surface receptor(s) that mediate these events. In the current study, we sought to assess whether toxin-induced CXCL8/IL-8 release and barrier dysfunction are driven by the activation of the P2Y6 receptor following the release of UDP, a danger signal, from intoxicated Caco-2 cells. Caco-2 cells express a functional P2Y6 receptor and release measurable amounts of UDP upon exposure to TcdA/B. Toxin-induced CXCL8/IL-8 production and release were attenuated in the presence of a selective P2Y6 inhibitor (MRS2578). This was associated with inhibition of TcdA/B-induced activation of NFκB. Blockade of the P2Y6 receptor also attenuated toxin-induced barrier dysfunction in polarized Caco-2 cells. Lastly, pretreating mice with the P2Y6 receptor antagonists (MSR2578) attenuated TcdA/B-induced inflammation and intestinal permeability in an intrarectal toxin exposure model. Taken together these data outline a novel role for the P2Y6 receptor in the induction of CXCL8/IL-8 production and barrier dysfunction in response to C. difficile toxin exposure and may provide a new therapeutic target for the treatment of CDI.