Objective To establish an algorithm that incorporates sentinel lymph node (SLN) mapping to the surgical treatment of early cervical cancer, ensuring that lymph node (LN) metastases are accurately detected but minimizing the need for complete lymphadenectomy (LND). Methods A prospectively maintained database of all patients who underwent SLN procedure followed by a complete bilateral pelvic LND for cervical cancer (FIGO stages IA1 with LVI to IIA) from 03/2003 to 09/2010 was analyzed. The surgical algorithm we evaluated included the following: 1. SLN are removed and submitted to ultrastaging; 2. Any suspicious LN is removed regardless of mapping; 3. If only unilateral mapping is noted, a contralateral side-specific pelvic LND is performed (including inter-iliac nodes); 4. Parametrectomy en bloc with primary tumor resection is done in all cases. We retrospectively applied the algorithm to determine how it would have performed. Results One hundred twenty-two patients were included. Median SLN count was 3 and median total LN count was 20. At least one SLN was identified in 93% of cases (114/122), while optimal (bilateral) mapping was achieved in 75% (91/122). SLN correctly diagnosed 21 of 25 patients with nodal spread. When the algorithm was applied, all pts with LN metastasis were detected and bilateral pelvic LND could have been spared in the 75% of cases with optimal mapping. Conclusions In the surgical treatment of early cervical cancer, the algorithm we propose allows for comprehensive detection of all patients with nodal disease and spares complete LND in the majority of cases.
High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents [i.e. platinum and Poly(ADP-ribose) polymerase inhibitors (PARPis)] due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although, BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622 induces resistance to PARPis and platinum in BRCA1-mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair., Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end joining and facilitating HR-mediated DSB repair in S-phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.
The surgical management of advanced epithelial ovarian cancer involves cytoreduction, or removal of grossly-evident tumor. Residual disease after surgical cytoreduction of ovarian cancer has been shown to be strongly associated with survival. The goal of surgery is "optimal" surgical cytoreduction, which is generally defined as residual disease of 1 cm or less. However, the designation of "optimal" surgical cytoreduction has evolved to include maximal surgical effort and no gross residual disease. In order to achieve this, more aggressive surgical procedures such as rectosigmoidectomy, diaphragm peritonectomy, partial liver resection, and video-assisted thoracic surgery are reported and increasingly utilized in the surgical management of advanced ovarian cancer. The role of maximal surgical effort also extends to the recurrent setting where the goal of surgery should be complete cytoreduction. Patient selection is important in identifying appropriate candidates for surgical cytoreduction in the recurrent setting. The purpose of this article is to review the role of maximum surgical effort in primary and recurrent ovarian cancer.
Endometrial carcinomas (ECs) in young women (< or = 40 y) are usually managed conservatively in selected patients. Whether oophorectomy with total hysterectomy is mandated for patients failing hormonal therapy is controversial. Recognition of features that might discourage conservative management and ovarian preservation are currently poorly characterized. We evaluated these patients for DNA mismatch repair (MMR) protein defects to assess whether the MMR status had an impact on therapeutic decision making. Seventy ECs in women of 40 years of age or younger (n=70) were identified from review of institutional databases (1993-present). All available slides were reviewed and DNA MMR immunohistochemistry was performed using 4 markers (MLH1, PMS2, MSH2, and MSH6) in cases with available blocks (n=54). ECs were predominantly endometrioid (65/70), and most were low grade (1988 International Federation of Gynecology and Obstetrics grades 1 or 2, 83%). Five (7%) were undifferentiated carcinomas. Most patients presented at early stage (stages I to II, 90%). A significant number of patients also had synchronous ovarian carcinomas (9 of 70, 13%), predominantly endometrioid (7 of 9), whereas 2 were ovarian clear cell carcinomas. Sixty-six of the 70 patients are alive with no evidence of disease, whereas 4 patients (6%) died of disease. Immunohistochemistry for DNA MMR showed loss of at least 1 protein in 9 of 54 cases (16%) with slight predominance of MSH2/MSH6 abnormalities (5 of 9) compared with loss of MLH1/PMS2. Tumors with MMR loss frequently occurred in women with low body mass index; these tumors were of higher grade and associated with worse clinical outcomes. They frequently showed tumor characteristics associated with microsatellite instability, including tumor infiltrating lymphocytes, undifferentiated or dedifferentiated histology, and lower uterine segment origin. These tumors also showed lower estrogen receptor/progesterone receptor expression compared with tumors with retained staining for MMR proteins. None of the cases with synchronous ovarian and endometrial endometrioid carcinomas showed loss of MMR proteins, whereas 1 of 2 ECs with synchronous CCC of ovary showed loss of MSH2/MSH6.As young women with endometrioid carcinomas who show loss of mismatch proteins are at risk for high-grade tumors with worse clinical outcomes and lower estrogen receptor/progesterone receptor expression, they may not be appropriate candidates for conservative management. Although young EC patients are at increased risk for synchronous endometrioid ovarian carcinomas, this does not seem to be associated with MMR loss.
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