Impact of colorectal surgeon case volume on outcomes and applications to quality improvement.

PURPOSE: To evaluate the impact of surgeon case volumes on procedural, financial, and clinical outcomes in colorectal surgery and apply findings to improve hospital care quality. METHODS: A retrospective review was performed using 2013-2014 administrative data from a large hospital system in Southeast U.S. region; univariate and multivariable regression analyses were used to explore the impact of surgeon case volume on outcomes. RESULTS: One thousand one hundred ninety patients were included in this 2-year study. When compared with low-volume surgeons (LVS) (< 14 cases in 2 years), the high-volume surgeons (HVS) (> 34 cases) were estimated per case to have shorter cut-to-close time in the operation room by 79 min, ([95% CI 58 to 99]), lower total hospitalization cost by $4314, ([95% CI $2261 to $6367]), and shorter post-surgery and overall length of stay by 0.92 days, ([95% CI 0.50 to 1.35]) and 1.27 days ([95% CI 0.56 to 1.98]), respectively. The HVS also showed a higher tendency to choose a laparoscopic approach over an open approach, with an odds ratio of 3.16 ([95% CI 1.23 to 8.07]). When compared with medium-volume surgeons (MVS) (14-34 cases), the HVS were estimated per case to have shorter cut-to-close time in the operation room by 62 min ([95% CI 37 to 87]). Surgeon case volumes had no statistically significant impact on outcomes including in-hospital mortality, 30-day readmission, blood utilization, and surgical site infection (SSI). CONCLUSIONS: Surgeon case volume had positive impacts on procedural, financial, and clinical outcomes and this finding may be used to improve hospital's quality of care.

Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study.

BACKGROUND: Activating FGFR2 mutations are found in 10-16% of primary endometrial cancers and provide an opportunity for targeted therapy. We assessed the safety and activity of dovitinib, a potent tyrosine-kinase inhibitor of fibroblast growth factor receptors, VEGF receptors, PDGFR-ß, and c-KIT, as second-line therapy both in patients with FGFR2-mutated (FGFR2(mut)) endometrial cancer and in those with FGFR2-non-mutated (FGFR2(non-mut)) endometrial cancer. METHODS: In this phase 2, non-randomised, two-group, two-stage study, we enrolled adult women who had progressive disease after first-line chemotherapy for advanced or metastatic endometrial cancer from 46 clinical sites in seven countries. We grouped women according to FGFR2 mutation status and gave all women dovitinib (500 mg per day, orally, on a 5-days-on and 2-days-off schedule) until disease progression, unacceptable toxicity, death, or study discontinuation for any other reason. The primary endpoint was proportion of patients in each group who were progression-free at 18 weeks. For each group, the second stage of the trial (enrolment of 20 additional patients) could proceed if at least eight of the first 20 treated patients were progression free at 18 weeks. Activity was assessed in all enrolled patients and safety was assessed in all patients who received at least one dose of dovitinib. The completed study is registered with ClinicalTrials.gov, number NCT01379534. FINDINGS: Of 248 patients with FGFR2 prescreening results, 27 (11%) had FGFR2(mut) endometrial cancer. Between Feb 17, 2012, and Dec 13, 2013, we enrolled 22 patients in the FGFR2(mut) group and 31 patients in the FGFR2(non-mut) group. Seven (31·8%, 95% CI 13·9-54·9) patients in the FGFR2(mut) group and nine (29·0%, 14·2-48·0) in the FGFR2(non-mut) group were progression-free at 18 weeks. On the basis of predefined criteria, neither group continued to stage two: seven (35%) of the first 20 patients in the FGFR2(mut) group were progression free at 18 weeks, as were five (25%) of the first 20 in the FGFR2(mut) population. Rates of treatment-emergent adverse events were similar between groups and events were most frequently gastrointestinal. Overall, the most common grade 3 or 4 adverse events suspected to be related to the study drug were hypertension (nine patients; 17%) and diarrhoea (five; 9%). The most frequently reported serious adverse events suspected to be related to study drug were pulmonary embolism (four patients; 8%), vomiting (four; 8%), dehydration (three; 6%), and diarrhoea (three; 6%). Only one death was deemed to be treatment-related: one patient in the FGFR2(non-mut) group died from cardiac arrest with contributing reason of pulmonary embolism (grade 4, suspected to be study drug related) 4 days previously. INTERPRETATION: Second-line dovitinib in FGFR2(mut) and FGFR2(non-mut) advanced or metastatic endometrial cancer had single-agent activity, although it did not reach the prespecified study criteria. Observed treatment effects seemed independent of FGFR2 mutation status. These data should be considered exploratory and additional studies are needed. FUNDING: Novartis Pharmaceuticals.

Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer.

Studies have shown enhanced survival of ovarian cancer patients in which the tumors are infiltrated with tumor infiltrating lymphocytes and natural killer cells showing the importance of immune surveillance and recognition in ovarian cancer. Therefore, in this study, we tested cellular immunotherapy and varying combinations of cytokines (IL-2 and/or pegylated-IFNα-2b) in a xenograft mouse model of ovarian cancer. SKOV3-AF2 ovarian cancer cells were injected intra-peritoneally (IP) into athymic nude mice. On day 7 post-tumor cell injection, mice were injected IP with peripheral blood mononuclear cells (PBMC; 5 × 10(6) PBMC) and cytokine combinations [IL-2 ± pegylated-IFNα-2b (IFN)]. Cytokine injections were continued weekly for IFN (12,000 U/injection) and thrice weekly for IL-2 (4000 U/injection). Mice were euthanized when they became moribund due to tumor burden at which time tumor and ascitic fluid were measured and collected. Treatment efficacy was measured by improved survival at 8 weeks and overall survival by Kaplan-Meier analysis. We observed that the mice tolerated all treatment combinations without significant weight loss or other apparent illness. Mice receiving PBMC plus IL-2 showed improved median survival (7.3 weeks) compared to mice with no treatment (4.2 weeks), IL-2 (3.5 weeks), PBMC (4.0 weeks), or PBMC plus IL-2 and IFN (4.3 weeks), although PBMC plus IL-2 was not statistically different than PBMC plus IFN (5.5 weeks, p > 0.05). We demonstrate that cytokine-stimulated cellular immune therapy with PBMC and IL-2 was well tolerated and resulted in survival advantage compared to untreated controls and other cytokine combinations in the nude-mouse model.

A multicenter evaluation of adjuvant therapy in women with optimally resected stage IIIC endometrial cancer.

OBJECTIVE: To determine if there is an advantage to combination chemotherapy and radiation for optimally resected stage IIIC endometrial cancer (EC). METHODS: A multicenter retrospective analysis of patients with EC from 1991 to 2008 was conducted. Inclusion criteria were lymph node assessment and optimally resected disease. Recurrence-free (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: 265 patients with optimally resected stage IIIC EC were identified. Postoperative therapies included radiotherapy in 17% (n=45), chemotherapy in 17% (n=46), and both chemotherapy and radiation in 61% (n=161). Three-year RFS was 56% for chemotherapy alone, compared to 73% for radiation alone, and 73% for combination therapy (p=0.12). Those receiving chemotherapy alone had the worst 3-year OS (78%) compared to either radiotherapy alone (95%) or combination therapy (90%) (p=0.005). After adjustment for stage and grade those treated with chemotherapy alone were at a 2.2 fold increased risk of recurrence (95% CI, 1.2 to 4.2; p=0.02) and 4.0 fold increased risk of death (95% CI, 1.6 to 10.0; p=0.004) compared to those treated with chemotherapy and radiation. In contrast there was no significant difference in RFS [HR=1.0 (95% CI, 0.5 to 2.0; p=0.92)] or OS [HR=1.1 (95% CI, 0.3 to 3.6; p=0.91)] for those treated with radiation alone compared to those treated with chemotherapy and radiation. CONCLUSION: Adjuvant therapy with either radiation alone or chemotherapy and radiation was associated with improved outcomes for patients with optimally resected stage IIIC EC compared to those treated with chemotherapy only.

Analysis of disease recurrence and survival for women with uterine malignancies undergoing robotic surgery.

OBJECTIVES: To evaluate recurrence-free survival (RFS) and overall survival (OS) for patients who underwent robotic-assisted laparoscopic hysterectomy (RALH) for uterine malignancies. METHODS: Medical records from 372 patients with uterine malignancies who underwent RALH from 3/06 to 3/09 at two institutions were reviewed for clinico-pathologic data, adjuvant therapies, disease recurrence, and survival. Median follow-up for survival analysis was 31 ± 14 months. Thirty (8.1%) patients were lost to follow-up before 12 months and censored from the recurrence analysis. RESULTS: Mean age and BMI of 372 patients was 61.8 ± 9.8 years and 32.2 ± 8.4 kg/m(2) (range 19-70). Robotic procedures included RALH 16 (4.3%), RALH with pelvic lymphadenectomy (PL) 96 (25.8%), and RALH with pelvic-and-aortic lymphadenectomy (PAL) 252 (67.7%) cases. Histology included 319 (85.8%) endometrioid and 53 (12.6%) high-risk histologies. Mean pelvic and aortic lymph node counts were 16.8 ± 8.7 and 8.4 ± 4.5, respectively. Lymph node metastases were identified in 26 (7.3%) cases. Adjuvant therapies were prescribed for 108 (29.1%) of patients: 7.8% brachytherapy, 1.9% pelvic radiation+brachytherapy, 7.8% chemotherapy, 11.6% chemotherapy+radiation. Risk of recurrence for all patients was 8.3% and 17 (4.6%) patients died of disease. The estimated 3-year recurrence-free survival (RFS) for the entire study group was 89.3% and the estimated 5-year overall survival (OS) was 89.1%, compared to 92.5% and 93.4% for the endometrioid sub-set. CONCLUSIONS: Patients with endometrial cancer undergoing robotic hysterectomy with staging lymphadenectomies during our 3-years of robotic experience had low-risk for recurrence and excellent disease-specific survival at a median follow-up time of 31 months.

Comparison of the cytotoxic response against ovarian cancer by immune effector cells isolated and expanded from normal donors and ovarian cancer patients.

BACKGROUND/AIMS: The aim of this study was to compare the cytotoxic response against ovarian cancer (OC) cells elicited by different immune effector cells in combination with the cytokines interleukin (IL)-2 and interferon (IFN) α-2b. METHODS: OC cells were co-cultured with peripheral blood mononuclear cells (PBMC) from normal donors or OC patients and IL-2 or IFN α-2b alone or in combination, in order to determine the cytotoxicity. T cells were isolated from healthy donors to determine T cell cytotoxic activity. PBMC from healthy donors and OC patients were expanded in an IL-2/IL-7/IL-12 cocktail with and without anti-CD3 antibody, and the cytotoxic activity measured. Flow cytometry was performed on primary, selected and expanded cells to determine T, B, and natural killer- (NK) cell percentages. RESULTS: Healthy donor PBMC elicited a significant cytotoxic response (59%) compared with OC patient PBMC (7%). T cells enriched from normal donors elicited a significant cytotoxic response (18%) compared with controls lacking effector cells (1.4%); however, the cytotoxicity observed was significantly less compared with unselected PBMC. Expanded effector cells consisted primarily of T cells (98%) and the fold-expansion was significantly higher in the presence of anti-CD3 (19- versus 132-fold). No significant difference in the expansion (either fold-expansion or cell type) was observed between OC patients and healthy donors. Expanded cells from both healthy donors and OC patients elicited a significant cytotoxic response in the presence of IL-2 (19% and 22%) compared with controls. CONCLUSIONS: PBMC from OC patients do not elicit a significant cytotoxic response; however, ex vivo-expanded cells from OC patients are capable of cytotoxic killing similar to unexpanded T cells isolated from normal donors. These data provide the groundwork for further development of cellular therapy against OC.

Short- and long-term morbidity and outcomes after robotic surgery for comprehensive endometrial cancer staging.

OBJECTIVE: Although intra-operative and immediate postoperative complications of robotic surgery are relatively low, little is known about long-term morbidity. We set out to assess both short- and long-term morbidities after robotic surgery for endometrial cancer staging. METHODS: All patients who underwent robotic staging for EMCA between 2006 and 2009 from two institutions were identified. Patient charts were retrospectively reviewed for surgical complications and postoperative morbidities. RESULTS: Five hundred three patients were identified. No differences in complication rates were found between 2006-2007 and 2008-2009, even though the median BMI increased from 29.9 (range 19-52) to 32 (range 17-70) (p=0.03). 6.4% of cases were converted to laparotomy. Median length of stay was one day (range 1-46). No cystotomies, two enterotomies, one ureteric injury, and five vessel injuries occurred (1.6% intra-operative complications). Thirty-eight (7.6%) patients developed major postoperative complications, 11 (2.2%) had wound infections, and 15 (3%) required a transfusion in the 30-day peri-operative period. The total venous thromboembolism (VTE) rate for robotic cases was 1.7%. Partial cuff dehiscence managed conservatively occurred in 5 (1%) and complete dehiscence requiring closure in 7 (1.4%) patients; Sixty-three (13.4%) patients who had robotic staging developed lymphedema, with 40 (8%) requiring physical therapy. CONCLUSIONS: This study provides one of the largest cohorts of patients with robotic-assisted hysterectomy and lymphadenectomy (in 92.6%) with an assessment of morbidity. Our data demonstrates that robotic surgical staging can be safely performed with a low risk of short-term complications and lymphedema is the most frequent long-term morbidity.

A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study.

OBJECTIVES: Aflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored. METHODS: Eligible patients had measurable disease; 1-2 prior cytotoxic regimens; performance status 0-2. Aflibercept 4 mg/kg IV q14 days (28-day cycles) was administered until disease progression or prohibitive toxicity. Primary endpoints were the proportion of patients with progression-free survival at 6 months (PFS6) and tumor response rate. A flexible two-stage group sequential design to detect 20% increases in the proportion of patients responding or enduring PFS6 with 90% power (α=10%) was employed. RESULTS: Forty-nine patients were enrolled; five were excluded: wrong primary (2), second primary (1), wrong cell type (1); and never treated (1). Median age was 64 (range 48-83). Eighteen patients (41%) had two prior regimens; 27 (61%) had prior radiation. The PFS6 rate was 41%; three patients (7%, 90% CI: 2-17) had partial response. Of note, 10 patients (23%) met the PFS6 endpoint without starting a subsequent therapy; the remaining eight patients discontinued therapy for toxicity and started another therapy before 6 months elapsed. Median PFS and overall survival were 2.9 months and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23%/5%), constitutional (7%/0), hemorrhage (2%/5%), metabolic (7%/2%), and pain (18%/0). Two treatment-related deaths were recorded: GI perforation (1), and arterial rupture (1). FGF1 expression was associated with response. CONCLUSIONS: Aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population.

Phase II activity of belinostat (PXD-101), carboplatin, and paclitaxel in women with previously treated ovarian cancer.

BACKGROUND: Preclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned specifically for women with recurrent epithelial ovarian cancer (EOC). METHODS: Thirty-five women were treated on the phase 2 expansion cohort. BelCap was given as follows: belinostat, 1000 mg/m² daily for 5 days with carboplatin, AUC 5; and paclitaxel, 175 mg/m² given on day 3 of a 21-day cycle. The primary end point was overall response rate (ORR), using a Simon 2 stage design. RESULTS: The median age was 60 years (range, 39-80 years), and patients had received a median of 3 prior regimens (range, 1-4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46%) had primary platinum-resistant disease, whereas 19 patients (54%) recurred within 6 months of their most recent platinum treatment. The median number of cycles of BelCaP administered was 6 (range, 1-23). Three patients had a complete response, and 12 had a partial response, for an ORR of 43% (95% confidence interval, 26%-61%). When stratified by primary platinum status, the ORR was 44% among resistant patients and 63% among sensitive patients. The most common drug-related adverse events related to BelCaP were nausea (83%), fatigue (74%), vomiting (63%), alopecia (57%), and diarrhea (37%). With a median follow-up of 4 months (range, 0-23.3 months), 6-month progression-free survival is 48% (95% confidence interval, 31%-66%). Median overall survival was not reached during study follow-up. CONCLUSIONS: Belinostat, carboplatin, and paclitaxel combined was reasonably well tolerated and demonstrated clinical benefit in heavily-pretreated patients with EOC. The addition of belinostat to this platinum-based regimen represents a novel approach to EOC therapy and warrants further exploration.

Functional characterization of a fluorescent highly tumorigenic ovarian cancer line to test cellular therapy in experimental models.

OBJECTIVES: The objective of this study was to functionally characterize a fluorescent highly tumorigenic ovarian cancer line to test cellular therapy in combination with cytokines or chemotherapies in experimental models. METHODS: A fluorescent highly tumorigenic subline (SKOV3-AF2) was derived from the SKOV3 ovarian cancer cell line. Peripheral blood mononuclear cell (PBMC)-mediated cytotoxicity of SKOV3-AF2 in the presence of interleukin 2 (IL-2) and interferon α-2b (IFNα-2b) was assayed by lactate dehydrogenase release. Sensitivity of SKOV3-AF2 cells to polyethylene glycol-IFNα-2b and IL-2 was assayed in a xenograph nude mouse model. Histopathology was performed to determine necrosis and tumor-infiltrating lymphocytes in the solid tumors. Reverse transcriptase-polymerase chain reaction was used for gene expression analyses of E-cadherin and cysteine-rich 61 (CCN1). RESULTS: The SKOV3-AF2 subline exhibits increased cytotoxicity (up to 70%), mediated by PBMCs, IL-2, and IFNα-2b, compared with parental SKOV3-red fluorescent protein (RFP) cells. SKOV3-AF2 cells are more tumorigenic in vivo as indicated by tumor incidence, time to sacrifice, tumor weight, and ascitic fluid production. SKOV3-AF2 tumor growth was inhibited by polyethylene glycol-IFNα-2b but not low-dose IL-2. Histopathology revealed that the tumors consisted of poorly differentiated surface epithelial carcinoma. SKOV3-RFP, and -AF2 cell lines as well as -AF2 tumors expressed E-cadherin. SKOV3-AF2 derived tumors expressed CCN1; however, the SKOV3-RFP and SKOV3-AF2 cell lines did not. CONCLUSIONS: Characterization of SKOV3-AF2 cells revealed that it is more susceptible to PBMC-mediated cytotoxicity than SKOV3-RFP and highly tumorigenic in a xenograph model, and AF-2 tumors express genes that promote aggressive behavior. Collectively, our data suggest that the SKOV3-AF2 subline will be a useful tool to test cellular therapy for the treatment of ovarian cancer utilizing experimental models.

Metastatic choriocarcinoma in a viable intrauterine pregnancy treated with EMA-CO in the third trimester: a case report.

BACKGROUND: Choriocarcinoma is a highly malignant tumor arising from any gestation. Several cases of metastatic choriocarcinoma have been reported in the literature during viable intrauterine pregnancies. CASE: We present a case of choriocarcinoma metastatic to the lungs, liver and brain in a 28-year-old female who received systemic chemotherapy, consisting of etoposide-methotrexate-actinomycin D-cyclophosphamide-vincristine (EMA-CO), during pregnancy and subsequently delivered a viable female infant at 32 weeks' gestation. This case is one of only a few presented in the literature in which metastatic choriocarcinoma was treated during pregnancy with delivery during the third trimester. CONCLUSION: Most reported cases of metastatic choriocarcinoma involve immediate delivery, usually via cesarean section, of premature infants in an effort to initiate chemotherapy after delivery, avoiding inherent risks to the fetus. Our patient was successfully treated with EMA-CO regimen for high-risk gestational trophoblastic tumors and delivered a developmentally normal infant. This report details this case and the importance of early initiation of cytotoxic drugs.

ICU outcomes and survival in patients with severe COVID-19 in the largest health care system in central Florida.

BACKGROUND: Observational studies have consistently described poor clinical outcomes and increased ICU mortality in patients with severe coronavirus disease 2019 (COVID-19) who require mechanical ventilation (MV). Our study describes the clinical characteristics and outcomes of patients with severe COVID-19 admitted to ICU in the largest health care system in the state of Florida, United States. METHODS: Retrospective cohort study of patients admitted to ICU due to severe COVID-19 in AdventHealth health system in Orlando, Florida from March 11th until May 18th, 2020. Patients were characterized based on demographics, baseline comorbidities, severity of illness, medical management including experimental therapies, laboratory markers and ventilator parameters. Major clinical outcomes analyzed at the end of the study period were: hospital and ICU length of stay, MV-related mortality and overall hospital mortality of ICU patients. RESULTS: Out of total of 1283 patients with COVID-19, 131 (10.2%) met criteria for ICU admission (median age: 61 years [interquartile range (IQR), 49.5-71.5]; 35.1% female). Common comorbidities were hypertension (84; 64.1%), and diabetes (54; 41.2%). Of the 131 ICU patients, 109 (83.2%) required MV and 9 (6.9%) received ECMO. Lower positive end expiratory pressure (PEEP) were observed in survivors [9.2 (7.7-10.4)] vs non-survivors [10 (9.1-12.9] p = 0.004]. Compared to non-survivors, survivors had a longer MV length of stay (LOS) [14 (IQR 8-22) vs 8.5 (IQR 5-10.8) p< 0.001], Hospital LOS [21 (IQR 13-31) vs 10 (7-1) p< 0.001] and ICU LOS [14 (IQR 7-24) vs 9.5 (IQR 6-11), p < 0.001]. The overall hospital mortality and MV-related mortality were 19.8% and 23.8% respectively. After exclusion of hospitalized patients, the hospital and MV-related mortality rates were 21.6% and 26.5% respectively. CONCLUSIONS: Our study demonstrates an important improvement in mortality of patients with severe COVID-19 who required ICU admission and MV in comparison to previous observational reports and emphasizes the importance of standard of care measures in the management of COVID-19.

Randomized phase III study of canfosfamide in combination with pegylated liposomal doxorubicin compared with pegylated liposomal doxorubicin alone in platinum-resistant ovarian cancer.

OBJECTIVE: To evaluate the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in platinum-resistant ovarian cancer (OC). METHODS: Patients with platinum-refractory or -resistant (primary or secondary) OC were randomized to receive canfosfamide at 1000 mg/m² and PLD at 50 mg/m² intravenously or PLD alone at 50 mg/m2 intravenously on day 1 every 28 days until tumor progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Other end points were objective response rate and safety. The study was originally planned for 244 patients. The trial was temporarily placed on hold after 125 patients were randomized while the results of another trial were being reviewed and the sponsor decided not to resume enrollment. The interim analysis became the final analysis. RESULTS: The median PFS was 5.6 months for canfosfamide + PLD (n = 65) versus 3.7 months for PLD (n = 60) (hazards ratio, 0.92; P = 0.7243). A preplanned subgroup analysis showed that 75 patients with platinum-refractory or primary platinum-resistant OC had a median PFS of 5.6 months for canfosfamide + PLD versus 2.9 months for PLD (hazards ratio, 0.55; P = 0.0425). Hematologic adverse events were 66% on the canfosfamide + PLD arm versus 44% on the PLD arm, manageable with dose reductions. Nonhematologic adverse events were similar for both arms. The incidence of palmar-plantar erythrodysesthesia and stomatitiswas lower on canfosfamide + PLD(23%, 31%, respectively) versus (39%, 49%, respectively) on PLD. CONCLUSIONS: Overall median PFS showed a positive trend but was not statistically significant. The median PFS in the platinum-refractory and primary platinum-resistant OC patients was significantly longer for canfosfamide + PLD versus PLD. Canfosfamide may ameliorate the palmar-plantar erythrodysesthesia and stomatitis known to be associated with PLD. Further study of this active well-tolerated regimen in platinum-refractory and primary platinum-resistant OC is planned. This study was registered at www.clinicaltrials.gov: NCT00350948.

Robotic-assisted laparoscopic hysterectomy and lymphadenectomy for endometrial cancer: Analysis of surgical performance.

OBJECTIVES: To provide an objective analysis of surgical performance of robotic-assisted laparoscopic hysterectomy (RALH) with lymphadenectomy for endometrial cancer during the learning phase of the procedure and to assess opportunities for improvement. METHODS: From July 2006 to March 2008, 100 patients with endometrial cancer underwent RALH with lymphadenectomy using the da Vinci Robotic Surgical System. Data were analyzed for operative time (OT), estimated blood loss (EBL), length of stay (LOS), intra-operative complications, surgical-pathologic factors, and post-operative complications using an intent-to-treat analysis. A comparison of the data on a quartile (Q) basis was performed for the 100 RALH cases and separately for the 65 cases that had a complete pelvic-and-aortic lymphadenectomy (PAL). RESULTS: Age and body mass index (BMI) did not change significantly during the study. More grade 3 tumors were treated in the last 50 cases (22% vs. 10%, p<0.05). Stage III tumors were identified in 18.7% cases in Q2-4 and none in Q1 (p<0.05). The number of patients undergoing complete PAL and the number of aortic lymph nodes (LN) removed per case increased each quarter. There were 4 (4%) conversions to laparotomy. Delayed vaginal cuff healing decreased from 16% in Q1 to 0% in Q3-4. No case required blood transfusion. Comparing first 10 cases to the last 10 cases, the total LN counts increased from 15 to 21 nodes, the aortic LN counts increased from 4.7 to 8.0, and the OT decreased from 203 to 160 min. Intra-surgeon analysis revealed an improvement in the total LN yields from first 50 to second 50 cases for each surgeon. CONCLUSIONS: Operative times decreased and aortic dissections improved with increasing LN counts during the first 100 cases of RALH. Furthermore, patient safety and improvement in surgical performance was demonstrated.

Robotically assisted laparoscopic hysterectomy versus total abdominal hysterectomy and lymphadenectomy for endometrial cancer.

OBJECTIVE: To compare surgical morbidity and clinical-pathologic factors for patients with endometrial cancer (EC) undergoing robotic-assisted laparoscopic hysterectomy (RALH) versus total abdominal hysterectomy (TAH) with aortic and/or pelvic lymphadenectomy (LA). METHODS: During the first 14 months of a robotics surgical program, 56 patients with EC were scheduled to undergo RALH with LA. Cases were analyzed for operative (op) time, estimated blood loss (EBL), transfusion, intra- and post-op complications, surgical-pathologic data, patient demographics and length of stay (LOS). Data was compared to 106 serially treated patients with EC who underwent TAH with LA immediately prior to initiation of our robotics program. RESULTS: Three robotic cases (5.4%) were converted to TAH secondary to intra-op factors. FIGO stages for RALH vs. TAH were: stage I (82 vs. 69%), stage II (7 vs. 7.5%) and stage III (11 vs. 21.5%). Patients' mean age was 59+/-10 vs. 63+/-11 years (p=0.05) and body mass index (BMI) was 29+/-6.5 vs. 34+/-9 kg/m(2) (p=0.0001) for the robotic and open groups, respectively. Severe medical co-morbidities affected 5.4% of robotic patients compared to 8.5% of open cases (p>0.05). Comparing RALH and TAH, mean op time was 177+/-55 vs.79+/-17 min (p=0.0001), EBL was 105+/-77 vs. 241+/-115 ml (p<0.0001), transfusion was 0 vs. 8.5% (p=0.005), and LOS was 1.0+/-0.5 vs. 3.2+/-1.0 days (p<0.0001). Robotic patients incurred a 3.6% major peri-operative complication rate while women undergoing open procedures had an incidence of 20.8% (p=0.007). Total lymph node count was 19+/-13 nodes for robotic cases vs. 18+/-10 nodes obtained from open hysterectomy patients. CONCLUSIONS: Patients with EC who underwent RALH with LA during the first year of our robotics program were younger, thinner and had less cardio-pulmonary illness than patients previously treated with TAH and LA. LOS, EBL and peri-op complication rates were significantly lower for the robotic cohort.

Metastatic appendiceal mucinous adenocarcinoma to well-differentiated diffuse mesothelioma of the peritoneal cavity: a mimicker of florid mesothelial hyperplasia in association with neoplasms.

Atypical/florid mesothelial hyperplasia associated with another neoplastic process is not an infrequent phenomenon and has been reported in a variety of tumors. In those instances, the mesothelial proliferation might create a misdiagnosis of metastatic carcinoma but seldom raises the possibility of a well-differentiated mesothelioma seeded by metastatic neoplastic cells. Herein, we report the case of a 40-year-old woman originally diagnosed with exuberant atypical mesothelial hyperplasia after an diagnostic laparoscopy. The subsequent operation, however, demonstrated a mucinous neoplasm of the appendix with involvement of the peritoneal cavity in the form of peritoneal mucinous carcinomatosis as well as metastases to the uterine serosa and adnexal surfaces. Microscopic analysis revealed an appendiceal adenocarcinoma with signet-ring-cell features that has metastasized to a diffuse well-differentiated mesothelioma of the peritoneal cavity. In many areas, the atypical mesothelial proliferation is indistinguishable from florid mesothelial hyperplasia. The true nature of the mesothelial proliferation was only confirmed after extensive additional sampling, which showed unequivocal stromal invasion. To the best of our knowledge, this is the first report of a metastatic appendiceal mucinous adenocarcinoma to a well-differentiated diffuse mesothelioma of the peritoneal cavity. Although commonly associated with atypical/ florid mesothelial hyperplasia, a carcinoma can rarely metastasize to a well-differentiated mesothelioma, which can pose significant diagnostic difficulties because it can mimic a reactive process. This unusual case report expands the spectrum of mesothelial proliferation in conjunction with a malignant neoplasm and serves to remind pathologists that such a concomitant occurrence exists.

Clinical-pathologic and morbidity analyses of Types 2 and 3 abdominal radical hysterectomy for cervical cancer.

OBJECTIVE: To provide representative data analyses of surgical morbidity and clinical-pathologic factors for Types 2 and 3 abdominal radical hysterectomies (ARH) with pelvic+/-aortic node dissection performed in a private practice with a fellowship-training program. METHODS: From 1997 to 2005, 329 cervical cancer patients underwent ARH with lymphadenectomy. Two hundred and one cases performed at our primary institution were analyzed for operative time, blood loss, intra-operative complications, surgical-pathologic data, recurrence of disease and adjuvant therapy. RESULTS: We evaluated 201 surgical patients who underwent Type 2 (n=45) or Type 3 (n=156) ARH with node dissection. The FIGO stages were: IB1=64%, IB2=6.5%, IA=28.4%, and IIA=1%. Aortic node dissection was performed in 64% of Type 3 cases and none of Type 2 cases. Pfannenstiel incision was used in 80% (Type 2) and 76% (Type 3) cases. A suprapubic catheter was placed in 9% of Type 2 and 81% of Type 3 cases. Median age and weight were 47+/-13 years and 149+/-35 lb. Positive nodes were identified in 12% of Type 3 and 2.2% of Type 2 cases. No positive aortic nodes were found. For Types 2 and 3 ARH, median operative time was 80+/-19 vs. 99+/-23 min (p<0.001) and blood loss was 250+/-134 vs. 300+/-234 ml (p<0.001). The transfusion rate was 3%. Intra-operative complications included: 3 ureteral injuries and 1 colotomy. Tumor histology was 60% squamous, 37% adenocarcinoma, 1% adenosquamous, and 2% others. CONCLUSIONS: ARH with pelvic lymphadenectomy in modern practice is an efficient, safe procedure with low transfusion rate and shorter hospital stay than previously reported. Data will be useful as comparison when scrutinizing novel approaches to radical hysterectomy including robotic-assisted and laparoscopic techniques.

Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.

PURPOSE: To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study. PATIENTS AND METHODS: Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR). RESULTS: One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation. CONCLUSION: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.

The role of bevacizumab in recurrent, platinum-sensitive ovarian cancer.

The majority of women with ovarian cancer will experience a recurrence of their disease despite aggressive primary cytoreduction and adjuvant cytotoxic chemotherapy. Notwithstanding the high rate of recurrence, targeted and biologic agents have helped to decrease the dependence on cytotoxic chemotherapy. Bevacizumab, a vascular endothelial growth factor inhibitor, has been shown to cause regression in tumor vasculature, inhibition of angiogenesis and prevention of progenitor cell recruitment. Phase III clinical trials of bevacizumab in patients with primary epithelial ovarian cancer and in patients with platinum-sensitive ovarian cancer have shown an improvement in progression free survival without an appreciable difference in overall survival. The addition of bevacizumab to standard cytotoxic chemotherapy regimens has demonstrated improved response rates, and improved progression free survival. These results have stimulated research in additional angiogenesis inhibitors and trials to further incorporate bevacizumab into the treatment schema for patients with recurrent ovarian cancer.