Immunotherapy May Improve Tumor Sensitivity to Palliative Chemotherapy in Platinum Resistant Ovarian Cancer.

Ovarian cancer is the second most common gynecologic cancer in the US and ranks among the top 10 causes of female cancer-related deaths. Platinum-resistant disease carries a particularly poor prognosis and leaves patients with limited remaining therapeutic options. Patients with platinum-resistant disease have significantly lower response rates to additional chemotherapy, with estimates as low as 10%-25%. We hypothesize that in patients with platinum-resistant ovarian cancer, treatment with immunotherapy followed by cytotoxic chemotherapy with antiangiogenic therapy results in prolonged survival without compromising quality of life. Our experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy resulted in progression-free survival durations significantly above previously published averages. Further studies evaluating the role of immunotherapy followed by chemotherapy in combination with drugs targeting angiogenesis are needed and may provide a long-sought after breakthrough for advancing survival in platinum-resistant ovarian cancer.

A Novel Technique to Minimize Contamination for Cervical Cancer Surgery Patients.

The Laparoscopic Approach to Cervical Cancer (LACC) trial changed the surgical management of cervical cancer worldwide. It was a multinational phase III clinical trial that reported lower survival and higher rate of abdominopelvic recurrences in minimally invasive surgery (MIS) than those of open surgery after hysterectomy. It is possible that tumor exposure to the peritoneal cavity in the MIS arm may account for these differences. We propose a novel technique to minimize peritoneal contamination of malignant cells present at the cervical os by placing a vaginal cerclage abdominally to create a seal at the apex of the vagina during MIS radical hysterectomy. The 2 patients in this work remain healthy and disease-free more than 18 months after surgery using this novel technique. We intend this work to serve as a platform both for offering a safe alternative to the open approach supported by the LACC trial and, most importantly, for promoting discussion of the results of the LACC trial and further research on surgical techniques in the treatment of cervical cancer. MIS has repeatedly been shown to have lower rates of infection, fewer complications, and shorter hospital stays while providing oncologic care that is noninferior to open approach.

A comparison of quality outcome measures in patients having a hysterectomy for benign disease: robotic vs. non-robotic approaches.

STUDY OBJECTIVE: To measure procedure-related hospital readmissions within 30 days after discharge for patients who have a hysterectomy for benign disease. Secondary outcome quality measures evaluated were cost, estimated blood loss, length of stay and sum of costs associated with readmissions. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Academic community hospital. PATIENTS: Patients who underwent hysterectomy to treat benign disease from January 2008 to December 2012. INTERVENTIONS: Patients were grouped according to route of hysterectomy: robotic-assisted laparoscopic hysterectomy (robotic), laparoscopic hysterectomy (laparoscopic), abdominal hysterectomy (open via laparotomy), and vaginal hysterectomy (vaginal). MEASUREMENTS AND MAIN RESULTS: Inclusion criteria were met by 2554 patients: 601 in the robotic group, 427 in the laparoscopic group, 1194 in the abdominal group, and 332 in the vaginal group. Readmission rates in the robotic cohort were significantly less (p<.05) than in non-robotic cohorts: Robotic (1%), laparoscopic (2.5%), open (3.5%), vaginal (2.4%). Estimated blood loss, length of stay, and sum of readmission costs were also significantly less in the robotic cohort (p<.05) compared with the other 3 cohorts. CONCLUSION: Patients who undergo robotic-assisted laparoscopic hysterectomy have a significantly lower chance of readmission <30 days after surgery compared with those who undergo laparoscopic, abdominal (open) hysterectomy, and vaginal approaches. Patients in the robotics cohort also experienced a shorter length of stay, less estimated blood loss, and a cost savings associated with readmissions when compared to non-robotic approaches. Prospective registries describing quality outcomes, total sum of costs including 30 days follow-up, as well as patient-related quality of life benefits are recommended to confirm these findings and determine which surgical route offers the highest patient and societal value.

Methotrexate on a 21-day cycle for low-risk gestational trophoblastic neoplasia.

OBJECTIVE: To perform an outcome analysis of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with a 5-day intramuscular methotrexate (MTX) regimen on a 21-day cycle. STUDY DESIGN: A retrospective review of 31 patients with low-risk GTN treated with a 5-day MTX regimen. RESULTS: A total of 31 patients with low-risk GTN (WHO score < 7) received single-agent MTX at a dose of 0.4 mg/kg daily for 5 days every 21 days (mean number of cycles, 3; 83% remission). The only significant toxicity encountered was grade 2 stomatitis in 8 (26%) patients. CONCLUSION: A 5-day MTX regimen given every 21 days is convenient, well-tolerated and effective for patients with low-risk GTN.

Surgical-pathologic risk factors and immunohistochemical markers of pelvic lymph node metastasis in stage IB1 cervical cancer.

OBJECTIVE: : This study aimed to identify the surgical-pathologic risk factors and immunohistochemical markers of pelvic lymph node metastasis in stage IB1 cervical cancer. MATERIALS AND METHODS: : A retrospective review of patients with stage IB1 cervical cancer who underwent radical abdominal hysterectomy, lymph node dissection, and immunohistochemical staining for p53, bcl-2, and Ki-67 was performed. RESULTS: : A total of 29 patients with complete clinical data and pathology tissue blocks are the subjects of this study. Of these patients, 20 (69%) had squamous cell carcinoma, 8 (28%) had adenocarcinoma, and 1 (3%) adenosquamous carcinoma. The median tumor diameter as measured in the pathology laboratory was 2 cm. The median number of lymph nodes removed was 24. Four (14%) patients had positive lymph nodes. Lymphovascular invasion was noted in 10 (34%). None of the 19 patients without lymphovascular invasion had lymph node involvement. Of 29 patients, 2 (7%) had parametrial involvement. There was a statistically significant correlation between tumor diameter and depth of invasion (r = 0.43, p = .02), and between lymphovascular invasion and positive lymph nodes (r = 0.55, p = .0019). The Ki-67 immunostaining index was higher for patients with lymphovascular invasion and/or positive lymph nodes (p = .008 and p = .028, respectively). There was no association between p53 or bcl-2 expression and lymphovascular invasion or lymph node metastasis. CONCLUSIONS: : Lymph node metastasis (14 %) and parametrial involvement (7%) occurred only in patients with lymphovascular invasion and/or large tumor size. The Ki-67 staining index is associated with lymphovascular invasion and lymph node metastasis.

Resident education in principles and technique of bowel surgery using an ex-vivo porcine model.

Objective. improve competency of residents with lysis of adhesion (LOA) and bowel surgery using a porcine model. Study Design. Pig bowel was removed at time of an anatomy laboratory, cleansed, and used to demonstrate surgical techniques and principles of LOA, repair of enterotomy, bowel resection, and anastomosis. Participants were surveyed pre- and posttraining session using 10 point Likert scale. Results. Thirty one residents at varying levels of training participated. After the training session, there was a significant improvement noted in mean scores for comfort level with LOA (6.3 versus 7.7, P = .007), comfort level with enterotomy repair (2.8 versus 6.4, P < .0001), understanding principles of LOA (5.0 versus 7.7, P < .0001), understanding principles of enterotomy repair (3.5 versus 7.0, P < .0001), and familiarity with instruments used (5.8 versus 7.3, P = .01). Conclusion. Training sessions using ex-vivo porcine model improve resident perception of knowledge and comfort with LOA and enterotomy repair.

Endometrial stromal sarcoma: treatment and patterns of recurrence.

Our objective was to investigate recurrence patterns and conduct an outcome analysis of patients with endometrial stromal sarcoma (ESS).A retrospective review yielded 30 patients with ESS (20 low-grade, 10 high-grade) who underwent primary surgical resection from 1982 to 2005. Median follow-up was 42 months.All patients underwent hysterectomy, whereas pelvic (P) and paraaortic (PA) lymphadenectomy were performed in 12 and 7 patients, respectively. A median of 26 pelvic lymph nodes and 9 PA lymph nodes were removed. Pelvic or PA lymphatic disease was noted in 25% and 29% of patients, respectively. Extrauterine disease was identified in 11 (45%) of 24 patients undergoing exploratory laparotomy; 6 had no residual disease after cytoreductive surgery. None of these 6 patients experienced abdominal failure, but 1 had a hematological recurrence. Thrombotic complications were noted in 13% of patients. The 5-year overall survival was 65%. Overall survival was influenced by grade (79% vs 40%, P = 0.03) and extrauterine disease (77% vs 32%, P = 0.01). No patient who underwent a systematic lymphadenectomy had a lymphatic recurrence, irrespective of nodal status. There were 7 (23%) hematological recurrences; 2 in surgical stage I ESS. Two patients with low-grade ESS remain without evidence of disease 130 and 210 months after secondary cytoreduction. In contrast, no patient with high-grade ESS survived a recurrence.There is high prevalence of extrauterine and nodal disease in ESS. Patients are at high risk for thrombotic complications. If aggressively staged, the predominant failure risk for stage I patients is hematogenous, suggesting the need for improved systemic treatments.

Rationale for folate receptor alpha targeted therapy in "high risk" endometrial carcinomas.

Advanced and recurrent endometrial cancers account for the majority of deaths from this disease with limited therapeutic options. High grade, and nonendometrioid histology, pathologically characterize the endometrial tumors associated with adverse outcome and are classified as "high risk". The identification of molecular prognostic factors that might be targeted for therapy among "high risk" endometrial cancers is an active area of investigation. We hypothesize that the FRalpha, highly expressed in endometrial cancer cells, is a potential target for this disease. Our objectives were to determine if FRalpha overexpression is associated with adverse prognostic factors and worse outcome. Three hundred and thirty-two endometrial cancer cores were arrayed onto a tissue microarray and stained using a FRalpha-specific monoclonal antibody. Staining was scored as absent or weak and moderate or strong. Forty-one percent of 310 evaluable cases stained moderate/strong. Moderate/strong FRalpha staining was significantly associated with other poor prognostic factors including: advanced stage, nonendometrioid histology and high grade. An association was observed between moderate/strong FRalpha staining and recurrence (p < 0.0014). These findings support further exploring a role for FRalpha targeted approaches for therapy and diagnostics in endometrial cancer.

Clear cell carcinoma of the cervix: a multi-institutional review in the post-DES era.

OBJECTIVE: To conduct an outcome analysis of patients with cervical clear cell carcinoma (CCCC) in the post-DES era. METHODS: A retrospective review was conducted at 3 major gynecologic cancer centers of all primary CCCC between 1982 and 2004. RESULTS: CCCC was confirmed in 34 patients. Median age was 53 years. DES exposure was confirmed in 2 (6%) patients. A history of smoking was elicited in 22%, and of abnormal Pap smear 18% patients. Primary surgical resection was performed in all stage I or IIA patients (n=26); they displayed superior 3-year overall survival (OS) compared to advanced stage (n=8) patients (91% vs. 22%, p<0.001). Pelvic lymph node involvement was noted in 25%; all patients with positive para-aortic nodes (20% of patients sampled) had positive pelvic nodes. All node positive patients were treated with adjuvant radiation, but nevertheless displayed reduced progression free (31% vs 92%, p<0.001) and overall survival (80% vs. 100%, p=0.02). Adjuvant radiotherapy did not appear to impact OS in patients with negative lymph nodes. DISCUSSION: This series provides insight into the management of early stage CCCC in the post-DES era. Although these patients may be at slightly higher risk of nodal spread, clear cell histology by itself does not appear to portend a worse prognosis than squamous cell carcinoma of the cervix in the absence of traditional risk factors. Our data suggest that patients with low risk early stage CCCC may be managed with radical surgery alone, without the need for adjuvant chemotherapy or radiation.

Role of cytoreduction in stage III and IV uterine papillary serous carcinoma.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) frequently presents in advanced stages. The aim of this study was to assess the role of cytoreduction in stage IIIC-IV UPSC. METHODS: Retrospective review was conducted of UPSC from 1982 through 2005. Surgical treatment consisted of hysterectomy, removal of adnexae, and pelvic and paraaortic lymphadenectomy, with or without tumor cytoreduction. Median follow-up was 21 months. RESULTS: Of the 125 UPSC patients, analysis of stage IIIC-IV patients (n=70; stage IIIC 12, stage IV 58) was performed. Optimal cytoreduction was achieved in 42 of 70 (60%) patients, and optimal cytoreduction with no visible residual disease in 26 of 70 (37%) patients. Patients with no visible residual disease after cytoreduction had a better median survival (51 months) compared to optimally cytoreduced albeit with residual disease (14 months), and suboptimally cytoreduced patients (12 months) (p-value=0.002). Of the 45 patients who received CT, the median survival of patients with no residual disease vs. patients with residual disease was 52 months vs. 16 months (p<0.001) respectively. No reduction in survival was noted when radical procedures were necessary to completely remove all residual disease. Regression analysis identified absence of visible residual disease (hazard ratio (HR)=0.30, p<0.001) and CT (HR=0.56, p=0.07) as independent predictors of OS. DISCUSSION: Cytoreduction to no gross residual disease and the use of CT are associated with a significant survival benefit for patients with stage IIIC-IV UPSC. This effect persisted even in patients who underwent radical resections.

Role of systematic lymphadenectomy and adjuvant therapy in stage I uterine papillary serous carcinoma.

OBJECTIVE: To assess surgical staging with systematic lymphadenectomy (LND) and adjuvant therapy in patients with stage I uterine papillary serous carcinoma (UPSC). METHODS: A single-institution, retrospective review was conducted of all surgically treated patients with primary UPSC between 1982 and 2005. RESULTS: 42 patients (IA=15, IB=21, IC=6) were stage I. 81% (n=34) underwent LND (median 40 nodes), 69% omentectomy, and 45% peritoneal biopsies. Median follow-up was 39 months. The 5-year overall survival (OS) and progression free survival (PFS) rates were 85% and 78%. The substage 5-year OS was: IA 100%, IB 89%, IC 60%. No lymphatic recurrences (LR) were observed in 34 patients who had LND compared to 1 LR in 8 who did not undergo LND (p=NS). No recurrences were detected among the 15 patients with stage IA UPSC, irrespective of post-operative therapy. None of the 20 IB and IC patients who received radiation therapy (RT) had vaginal recurrences (VR) compared to 2 of the 7 (29%) who did not receive RT (p=0.02). A systematic LND (>20 lymph nodes) was performed in 19 stage IB and IC patients. No hematological or peritoneal recurrence (HPR) was detected in the 6 patients who received chemotherapy. In contrast, HPR were observed in 3 (23%) of 13 patients who did not receive chemotherapy. DISCUSSION: Observation is an option for patients with stage IA UPSC confirmed by systematic LND. Patients with comprehensively staged IB and IC UPSC are candidates for chemotherapy and vaginal brachytherapy to prevent HPR and VR.

Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival.

Two signaling pathways are activated by antineoplastic therapies that damage DNA and stall replication. In one pathway, double-strand breaks activate ataxia-telangiectasia mutated kinase (ATM) and checkpoint kinase 2 (Chk2), two protein kinases that regulate apoptosis, cell-cycle arrest, and DNA repair. In the second pathway, other types of DNA lesions and replication stress activate the Rad9-Hus1-Rad1 complex and the protein kinases ataxia-telangiectasia mutated and Rad3-related kinase (ATR) and checkpoint kinase 1 (Chk1), leading to changes that block cell-cycle progression, stabilize stalled replication forks, and influence DNA repair. Gemcitabine and cytarabine are two highly active chemotherapeutic agents that disrupt DNA replication. Here, we examine the roles these pathways play in tumor cell survival after treatment with these agents. Cells lacking Rad9, Chk1, or ATR were more sensitive to gemcitabine and cytarabine, consistent with the fact that these agents stall replication forks, and this sensitization was independent of p53 status. Interestingly, ATM depletion sensitized cells to gemcitabine and ionizing radiation but not cytarabine. Together, these results demonstrate that 1) gemcitabine triggers both checkpoint signaling pathways, 2) both pathways contribute to cell survival after gemcitabine-induced replication stress, and 3) although gemcitabine and cytarabine both stall replication forks, ATM plays differential roles in cell survival after treatment with these agents.