Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint. RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.

Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe.

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.

Lymphatic ascites following pelvic and paraaortic lymphadenectomy procedures for gynecologic malignancies.

OBJECTIVE: Lymphatic ascites is an unusual complication in patients with cancer. In the gynecologic oncology patient population, the most common etiology is operative lymph node dissection. The purpose of this study was to explore the incidence, presenting symptoms, methods of diagnosis and treatment modalities utilized for lymphatic ascites in patients undergoing lymph node dissection for gynecologic cancers. METHODS: This observational study retrospectively reviewed the charts of patients who underwent lymphadenectomy as part of the surgical management for a gynecologic cancer. Patients that developed postoperative lymphatic ascites between January 2000 and December 2010 were included for analysis. Data extracted from the medical records included tumor pathology, number of harvested lymph nodes, postoperative course, method of diagnosis and treatment. RESULTS: From a total of 300 surgical staging procedures, 12 patients with lymphatic ascites were identified (4%). The most common reported symptom was leakage of clear fluid per vagina (7, 58%), followed by abdominal distension (4, 33%). The median interval from surgery to development of symptoms was 12.5 days (range 0-22 days). 5 patients had complete resolution of symptoms with dietary modifications alone while 7 patients required paracentesis. The median time from surgery to resolution of symptoms was 44 days (range 9-99). CONCLUSION: Lymphatic ascites is an under recognized and infrequently reported postoperative complication. Although it usually resolves spontaneously or with conservative management without sequelae, this condition can significantly prolong postoperative recovery and cause patient discomfort. To our knowledge this is the largest group of patients undergoing gynecologic surgical staging procedures to be reviewed for the occurrence of lymphatic ascites.

Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma.

Cyclins D1 and D3 play key roles in cell cycle progression. The downregulation of cyclin D3 was associated with phosphatase and tensin homolog deleted on chromosome ten-(PTEN)-induced cell cycle arrest. We attempted to determine whether cyclin D1 and D3 overexpression is correlated with PTEN inactivation in endometrioid endometrial cancer (EEC). The expression of PTEN, cyclin D1, and cyclin D3 were determined by immunohistochemical analysis in 105 EEC specimens. Forty-three percent of the EEC demonstrated loss of PTEN expression. Cyclin D3 was overexpressed in only 18% of the EEC specimens and was not associated with tumor grade. Cyclin D1 was overexpressed in 64% of the specimens and was more common in moderate or high-grade tumors (P = 0.002 and P = 0.02, respectively). The overexpression of cyclin D3 was not correlated with loss of PTEN in the EEC. The overexpression of cyclin D1 was much higher in grade 1 tumors with negative PTEN than tumors with positive PTEN expression (67% vs 26%). The overexpression of cyclin D3 was neither frequent nor correlated with the loss of PTEN expression. The overexpression of cyclin D1 was higher in the low-grade tumors with negative PTEN expression than tumors with positive PTEN expression. Overexpression of cyclin D1 is frequent in moderate or high-grade EECs and likely results from multiple mechanisms.

Clinicopathologic features of early adenocarcinoma of the cervix initially managed with cervical conization.

OBJECTIVE: To evaluate the clinicopathologic features of microinvasive adenocarcinoma of the cervix in order to guide the management of patients with this disease. MATERIALS AND METHODS: A retrospective review was conducted of patients diagnosed with early invasive, 1 mm and 2 mm and 3 mm and 4 mm and

Heterogeneity of stage IIIA endometrial carcinomas: implications for adjuvant therapy.

The purpose of this study was to evaluate overall survival (OS) and determine prognostic subclassifications for stage IIIA endometrial cancer. Stage IIIA endometrial cancer patients treated at M.D. Anderson Cancer Center from 1989 to 2002 were reviewed. Clinical information was obtained from the medical record. Cox regression analyses were performed to evaluate the association of pathologic criteria and OS. Patients were divided into four groups based on this analysis: E1, endometrioid/pelvic cytology only; E2, endometrioid/adnexa +/- serosal spread; NE1, nonendometrioid/pelvic cytology only; and NE2, nonendometrioid/adenexa +/- serosal spread. Forty-nine patients were identified. By multivariate analysis, histology and extent of disease were the only factors associated with OS. Five-year OS in the four subgroups based on histology and extent of disease were: E1, 79%, E2, 65%, NE1, 64%, and NE2, 13%. Histologic subtype and extent of pelvic disease are the only prognostic factors associated with OS. Patients with endometrioid tumors and extent of pelvic disease limited to positive cytology had a favorable outcome, with or without adjuvant therapy. Future prospective clinical trials should consider subclassifying patients with stage IIIA disease to better evaluate the role of adjuvant therapy.

Tumor suppressor gene, cell surface adhesion molecule, and multidrug resistance in Müllerian serous carcinomas: clinical divergence without immunophenotypic differences.

OBJECTIVES: We hypothesize that differences in the expression of selected tumor suppressor genes, cell surface adhesion molecules, and multidrug resistance glycoproteins could account for some of the reported differences between uterine serous carcinoma (USC) and extrauterine serous carcinomas (ESC), including ovarian and primary peritoneal carcinoma (OSC and PSC, respectively). METHODS: We studied the expression of the following antigens in 20 USCs, 20 OSCs, and 10 PSCs: p53 and mdm-2 (tumor suppressor genes), CD44 and CD44v6 (cell surface adhesion molecules), and the p-glycoprotein (a multidrug resistance protein recognized by two antibodies, C494 and JSB1). We further studied chemotherapeutic drug resistance by examining reports prepared using the Oncotech Extreme Drug Resistance Assay from 24 of the 50 study patients. Clinical data were obtained from medical record review. RESULTS: USC, OSC, and PSC patients were similar with respect to mean age at diagnosis, mean gravidity, mean parity, personal history of breast cancer, percentage treated with chemotherapy, and survival at 3 and 5 years postdiagnosis. Significant clinical differences included a high prevalence of nulliparity in OSC (P = 0.05), a low prevalence of Caucasian race in USC (P = 0.008), a paucity of stage I patients in OSC and PSC (P = 0.03), a high prevalence of familial breast cancer in OSC (P = 0.06), and superior 2-year survival in OSC (P = 0.02). Seventy-five percent of USCs, 52% of OSCs, and 60% of PSCs expressed p53. Five percent of USCs, 19% of OSCs, and 0% of PSCs expressed mdm-2. Forty percent of USCs, 33% of OSCs, and 10% of PSCs expressed CD44. None of the USCs, OSCs, or PSCs expressed CD44v6. Sixty-one percent of USCs and OSCs and 82% of PSCs expressed C494 while 17% of USCs, 19% of OSCs, and 20% of PSCs expressed JSB1. None of these apparent differences was statistically significant. USC, OSC, and PSCs patients did not demonstrate significant differences with respect to extreme drug resistance. However, the following trends were noted (P = 0.06): more prevalent low drug resistance for cyclophosphamide in OSC compared with USC and more prevalent extreme drug resistance for etoposide in OSC compared with USC. CONCLUSIONS: Therefore, despite significant clincial differences, the USCs and ESCs in our series do not differ significantly with respect to the expression of the tumor suppressor genes, cell surface adhesion molecules, and drug resistance proteins studied. It is premature, however, to recommend that USCs and ESCs should be treated identically.

Desmoplastic small round cell tumor with primary ovarian involvement: case report and review.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, malignant neoplasm that has recently been characterized. It has not been associated with a primary visceral organ. In women, cases are even more rare and often have some ovarian involvement. CASE: An 11-year-old girl presented with abdominal pain, nausea, and vomiting. A CT scan revealed a large heterogeneous pelvic mass with cystic components and an 8-cm midabdominal mass. During exploratory laparotomy, the patient was found to have a pelvic mass measuring 12. 9 cm replacing normal ovarian tissue. The midabdominal mass was also removed. Pathology, cytology, and immunohistochemistry confirmed a desmoplastic small round cell tumor. Even with aggressive surgical and medical intervention, the patient died 11 months after initial diagnosis. CONCLUSION: We present a rare small cell tumor that is associated with ovarian involvement. The prognosis in these patients is extremely poor and very few survivals have been reported.

The utility of venous lactate to triage injured patients in the trauma center.

BACKGROUND: Field triage criteria for trauma patients results in over-triage rates of 30% to 50% to achieve under-triage rates of 10%. This large number of patients may stress trauma center resources. Elevated arterial lactate (ALAC) levels have been shown to be a marker of serious injury but the need for arterial sampling limits the utility of the determination. The goal of this study was: 1) to determine the correlation between venous lactate (VLAC) and ALAC; 2) to determine whether VLAC could identify those patients with serious injuries; and 3) to compare an elevated VLAC level against standard triage criteria (STC) in their ability to identify major injury. STUDY DESIGN: Arterial and venous samples for blood gas and lactate analyses were obtained in 375 patients within 10 minutes of patient arrival to the trauma center. Arterial and venous samples were drawn within 2 minutes of each other, placed on ice, and analyzed within 10 minutes of sampling. The location of sampling was left to physician discretion. Data collected included injury mechanism, demographics, admission vital signs, emergency department disposition, length of stay, and injury severity scores (ISS). Admission to the ICU, need for emergency operation, length of stay, and death were noted. Emergency medical service staff were queried to determine which standard triage criteria (STC) were fulfilled. RESULTS: The mean ALAC was 3.11 mmol/L (SD 3.45, 95% confidence interval [CI] 2.67 to 3.55) and mean VLAC was 3.43 mmol/L (SD 3.41, 95% CI 2.96 to 3.90). There was no significant difference between ALAC and VLAC. The correlation between ALAC and VLAC was 0.94 (95% CI 0.94 to 0.96, p = 0.0001). An elevated VLAC predicted moderate to severe injury and there was a significant association between an increased lactate and maximum Abbreviated Injury Score (AIS) of 4 and 5 (ANOVA, F = 8.26, p < 0.001). Patients with VLAC > or =2 mmol/L had significantly increased relative risks of ISS > or = 13, death, admission to the ICU, and length of stay > 2 days. In comparison with STC, a VLAC > or = 2 mmol/L decreased undertriage in patients with ISS > or = 13 by one half (11% versus 24%) for patients with ISS > or = 13 and decreased over-triage by 28% (46% versus 64%). These data were most pronounced for patients injured in motor vehicle collisions. CONCLUSIONS: VLAC is an excellent approximation for ALAC. A VLAC > or = 2 mmol/L appears to predict an ISS > or = 13, the need for ICU resources, and prolonged hospital stays. VLAC was significantly better than STC in all patients and was most useful in victims of blunt trauma, especially motor vehicle collisions.

Validation of a hand-held lactate device in determination of blood lactate in critically injured patients.

OBJECTIVES: Admission blood lactate is an accurate predictor of injury severity and mortality in trauma patients. The purpose of this study was to evaluate a portable lactate analyzer in a clinical setting by patient care staff. DESIGN: A prospective, single-operator control solution and patient sample study, using two test devices and a reference device. SETTING: An urban Level I trauma center. PATIENTS: A convenience sample of 47 trauma patients. INTERVENTIONS: Intra-assay precision was demonstrated by performance of consecutive analyses of two lactate control solutions (high and low lactate control concentrations) by medical students and physicians. Split sample, simultaneous testing of the portable lactate analyzer was then performed on 66 whole blood specimens from a convenience sample of 47 trauma patients admitted to an urban Level 1 trauma center over 4 mos. Samples were tested simultaneously tested on two portable lactate analyzers and a reference instrument. MEASUREMENTS AND MAIN RESULTS: Acceptable intra-assay precision was achieved. Regression analysis for two test instruments demonstrated a slope of 0.920, an intercept of 0.323, an r2 of .982, and an SEM of 0.496. Regression analysis for test instrument "A" vs. the reference instrument showed a slope of 0.861, an intercept of 0.209, an r2 of .977, and an SEM of 0.598. Regression analysis for test instrument "B" vs. the reference instrument demonstrated a slope of 0.929, an intercept of -0.095, an r2 of .983, and an SEM of 0.506. CONCLUSIONS: Good correlation with a low SEM was obtained over a wide range of clinically relevant lactate values. Use of point of care lactate analysis will decrease analytic time, making an important diagnostic parameter immediately available in the critical care setting.