Rodney P. Rocconi

Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma

PurposeAlternative and complementary therapeutic strategies need to be developed for metastatic breast cancer. Virotherapy is a novel therapeutic approach for the treatment of cancer in which the replicating virus itself is the anticancer agent. However, the success of virotherapy has been limited due to inefficient virus delivery to the tumor site. The present study addresses the utility of human mesenchymal stem cells (hMSCs) as intermediate carriers for conditionally replicating adenoviruses (CRAds) to target metastatic breast cancer in vivo.Experimental designHMSC were transduced with CRAds. We used a SCID mouse xenograft model to examine the effects of systemically injected CRAd loaded hMSC or CRAd alone on the growth of MDA-MB-231 derived pulmonary metastases (experimental metastases model) in vivo and on overall survival.ResultsIntravenous injection of CRAd loaded hMSCs into mice with established MDA-MB-231 pulmonary metastatic disease homed to the tumor site and led to extended mouse survival compared to mice treated with CRAd alone.ConclusionInjected hMSCs transduced with CRAds suppressed the growth of pulmonary metastases, presumably through viral amplification in the hMSCs. Thus, hMSCs may be an effective platform for the targeted delivery of CRAds to distant cancer sites such as metastatic breast cancer.

A prospective blinded evaluation of the accuracy of frozen section for the surgical management of endometrial cancer

OBJECTIVE: To prospectively evaluate in a blinded fashion the accuracy of frozen section in endometrial cancer. METHODS: Sixty patients with endometrial cancer or complex atypical hyperplasia were consecutively enrolled. Intraoperatively, a frozen section was obtained, processed, and stored for interpretation by blinded pathologists. Final pathologic diagnosis was conducted in the usual fashion with the pathologists blinded to frozen results. Histologic grade and myometrial invasion on frozen section was correlated with final pathology. RESULTS: Median age was 61 years (range, 39–82 years). Fifty-seven percent of patients were white, and mean body mass index was 40 mg/kg.2 Depth of invasion on frozen correlated with final pathology in 67% (95% confidence interval [CI] 55–79%). Twenty-eight percent (95% CI 17–39%) of patients were upstaged from frozen to final. Patients with no invasion on frozen were upstaged in 46% (95% CI 28–64%). Histologic grade on frozen correlated with final pathology in 58% (95% CI 46–70%); 38% (95% CI 26–50%) of patients were upgraded by final grade. Patients with frozen grade 1 histology or less were upgraded in 61% (95% CI 45–77%). Clinically relevant upstaging occurred in 11 patients (18%) (95% CI 8–28%). CONCLUSION: Frozen section for histologic grade and depth of myometrial invasion in endometrial cancer correlates poorly with final pathology. Because a large number of patients are potentially understaged with the use of frozen section with a subsequent risk of over and under treatment, we recommend consideration of comprehensive surgical staging for all patients with endometrial cancer. LEVEL OF EVIDENCE: II-2

Role of chemotherapy for patients with recurrent platinum-resistant advanced epithelial ovarian cancer: A cost-effectiveness analysis.

Current chemotherapy in platinum‐resistant ovarian cancer patients has demonstrated minimal to no improvements in survival. Despite the lack of benefit, significant resources are utilized with such therapies. Therefore, the objective in the current study was to assess the cost‐effectiveness of salvage chemotherapy for patients with platinum‐resistant epithelial ovarian cancer (EOC).

Lynch Syndrome in Women Less Than 50 Years of Age With Endometrial Cancer

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6–19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III

A multi‐institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer

While bevacizumab has shown activity in recurrent ovarian cancer, a higher than expected incidence of bowel perforations has been reported in recent trials. We sought to determine factors associated with toxicity and tumor response in patients with relapsed ovarian cancer treated with bevacizumab. A retrospective review of patients with recurrent ovarian cancer treated with bevacizumab was undertaken. Response was determined radiographically and through CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Sixty-two eligible patients were identified. The cohort had received a median of 5 prior chemotherapy regimens. Single-agent bevacizumab was administered to 12 (19%), while 50 (81%) received the drug in combination with a cytotoxic agent. Grade 3–5 toxicities occurred in 15 (24%) patients, including grade 3–4 hypertension in 4 (7%), gastrointestinal perforations in 7%, and chylous ascites in 5%. Development of chylous ascites and gastrointestinal perforations appeared to correlate with tumor response. The overall response rate was 36% (4 complete response, 17 partial response), with stable disease in 40%. A higher objective response rate was seen in the bevacizumab combination group compared to single-agent treatment (43% vs 10%) (P = 0.07). However, 29 grade 3–5 toxic episodes were seen in the combination group vs only 1 in the single-agent bevacizumab cohort (P = 0.071). We conclude that bevacizumab demonstrates promising activity in recurrent ovarian cancer. The addition of a cytotoxic agent to bevacizumab improved response rates at the cost of increased toxicity. Gastrointestinal perforations occurred in 7%. The perforations occurred in heavily pretreated patients who were responding to therapy

ALDH1A1 Maintains Ovarian Cancer Stem Cell-Like Properties by Altered Regulation of Cell Cycle Checkpoint and DNA Repair Network Signaling

Objective Aldehyde dehydrogenase (ALDH) expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. Methods Isogenic ovarian cancer cell lines for platinum sensitivity (A2780) and platinum resistant (A2780/CP70) as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. Results ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDHHIGH displayed significantly lower progression free survival than the patients with ALDHLOW cells (9 vs. 3 months, respectively p<0.01). ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ) and replication checkpoint (pS317 Chk1) were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of γ-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. Conclusion This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling.

Lipoxygenase pathway receptor expression in ovarian cancer.

Objective: To determine the expression of lipoxygenase (LOX) pathway receptors in ovarian cancer as a potential target for anti-LOX—based therapy. Study design: Paraffin-embedded tumor samples from epithelial ovarian cancer patients were used to construct tissue microarrays to stain for the proposed sites of inhibition of a LOX inhibitor (5-LOX, LTB4-BLT1, and LTB4-BLT2). Results: 245 samples were available for interpretation. Strong expression was demonstrated in 45%, 34%, and 6% of ovarian cancer for LTB4-BLT2, LTB4-BLT1, and 5-LOX, respectively. Expression of LTB4-BLT2 correlated with advanced stage III/IV disease (P = .05), suboptimal debulking (P = .07), and platinum resistance (P = .03). No correlation was seen with regard to disease-free survival. Conclusions: LOX pathway receptor expression was found in the majority of cancers evaluated. Additionally, LTB4-BLT2 expression portends worse clinical parameters for ovarian cancer. Thus, further investigation on the role of LOX pathway in ovarian cancer is warranted.

The effect of obesity on survival in patients with ovarian cancer

OBJECTIVE Data has suggested obesity as an independent prognostic factor for lower survival in patients with epithelial ovarian cancer (EOC). We sought to determine if obesity portends a disadvantage to surgical outcomes at the time of initial surgery affecting survival. METHODS A retrospective chart review of patients diagnosed with EOC was performed. All patients underwent primary cytoreductive surgery followed by taxane/platinum-based chemotherapy. Patient demographics, surgicopathologic and survival data were evaluated. Patients were compared based on body mass index (BMI) (<30 vs. > or =30) and BMI strata (underweight, normal weight, overweight, obese and morbidly obese). Survival analyses were performed with the Kaplan Meier method and compared using the log rank test, chi(2) test, and Fischers exact test. RESULTS 304 patients were identified. 71 patients (23%) were obese (BMI>30). The groups were similar in regard to stage, grade, histology, and chemotherapy administered. In regard to surgical outcomes, no difference was seen in estimated blood loss (EBL), operating room (OR) time, or operative complications excluding wound complications. Optimal debulking rates were similar in obese and non-obese patients (52% vs. 51% respectively, p=0.88). There was no statistical difference in progression free survival (17 vs. 11 months) or overall survival (48 vs. 40 months) between the two groups or across BMI strata. CONCLUSION Although obesity has been reported as an independent prognostic factor for survival, this data demonstrates that survival rates are similar between obese and non-obese patients when optimal debulking statuses are the same. Therefore, maximal effort should be directed towards optimal debulking obese patients with EOC.

Cervical intraepithelial neoplasia in adolescent women: incidence and treatment outcomes.

OBJECTIVE: We sought to estimate the incidence of cervical intraepithelial neoplasia (CIN) and treatment outcomes in adolescents with abnormal cytology. METHODS: Adolescent women (ages 14–21 years) referred to colposcopy clinic for abnormal cytology from 1992 to 2004 were identified by computerized database. Only adolescents with biopsy-proven CIN were evaluated. Demographic and risk factor data were obtained from medical records. Referral cytology, histology on biopsy and loop electrosurgical excisional procedure (LEEP), and follow-up cytology were analyzed and compared. Statistical analysis was performed by &khgr;2 or Fisher exact test, Student t tests, and logistic regression. RESULTS: Of 1,678 adolescents, 517 had biopsy-proven CIN and follow-up. Seventy-seven patients were referred with atypical squamous cells of undetermined significance (ASCUS) cytology; 174 patients were referred with low-grade squamous intraepithelial lesions (LSIL), 258 with high-grade squamous intraepithelial lesions (HSIL) and eight with atypical glandular cells (AGC). The rate of CIN 2/3 in patients with ASCUS, LSIL, and HSIL was 35% (95% confidence interval 24–46%), 36% (29–43%), and 50% (44–56%), respectively. A total of 192 patients with biopsy-proven CIN 2/3 underwent a LEEP. No patients were diagnosed with cervical carcinoma. Fifty-five percent (95% confidence interval 48–62%) of patients had abnormal cytology on follow-up, suggesting recurrence or reinfection. CONCLUSION: Adolescents with abnormal cytology have a high incidence of CIN2/3 and high rates of abnormal cytology after LEEP. Cervical intraepithelial neoplasia 2/3 is common in adolescents with abnormal cytology, yet no cases of cancer were identified. Importantly, LEEP fails to meet its therapeutic goals given a high incidence of abnormal follow-up cytology and may represent overly aggressive therapy because the majority of human papillomavirus infections are transient with high regression rates. LEVEL OF EVIDENCE: III

Re: "Outcomes of stage I/II vulvar cancer patients after negative superficial inguinal lymphadenectomy"

OBJECTIVES To investigate the patterns of recurrence associated with superficial inguinal lymphadenectomy (SupIL) and vulvectomy for patients with Stage I/II vulvar cancer. METHODS A retrospective chart review identified patients from 1990-2001 with Stage I/II vulvar cancer that underwent SupIL and vulvectomy. Survival was analyzed using the Kaplan-Meier method with Fisher Exact and Chi-square tests for comparisons between groups. RESULTS 65 patients with Stage I/II vulvar cancer with a pathologically negative SupIL were identified (30 Stage I, 35 Stage II). Three patients recurred in the inguinal region, (4.6%) and 11 patients (16.9%) recurred on the vulva. Two of the 11 patients died of disease, six patients are alive without evidence of disease after additional therapy. Five-year disease-free survival and overall survival were 66% and 97%, respectively. Risk of recurrence was not associated with smoking status, stage, or margin status. CONCLUSIONS SupIL and vulvectomy for Stage I/II vulvar cancer have a low recurrence rate in the inguinal region when nodes are negative. The local recurrence rate (17%) is acceptable, and overall survival is good using this conservative approach.