Jo Marie Tran Janco

Tumor-Infiltrating Dendritic Cells in Cancer Pathogenesis

Dendritic cells (DCs) play a pivotal role in the tumor microenvironment, which is known to affect disease progression in many human malignancies. Infiltration by mature, active DCs into the tumors confers an increase in immune activation and recruitment of disease-fighting immune effector cells and pathways. DCs are the preferential target of infiltrating T cells. However, tumor cells have means of suppressing DC function or of altering the tumor microenvironment in such a way that immune-suppressive DCs are recruited. Advances in understanding these changes have led to promising developments in cancer-therapeutic strategies targeting tumor-infiltrating DCs to subdue their immunosuppressive functions and enhance their immune-stimulatory capacity.

Vulvar and vaginal melanoma: Case series and review of current management options including neoadjuvant chemotherapy

OBJECTIVE We report our experience with vulvar (Vu) and vaginal (Va) melanoma, with review of surgical and adjuvant therapy guidelines and description of our use of neoadjuvant therapy in selected cases. METHODS We reviewed patients seen at Mayo Clinic for management of Vu or Va melanoma, January 1993-February 2012. Surgical treatment, pathologic and outcome data were abstracted. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method, and compared between subgroups using the log-rank test. RESULTS 50 patients underwent surgery for primary or recurrent melanoma (Vu=36, Va=14). The 5-year OS rate was 30.9%, with median OS of 3.3 years. Adjuvant therapy was given to 30.6% of Vu cases with varying combinations of agents. Among Vu patients, after adjusting for node status and depth of invasion, adjuvant therapy was not associated with improved OS (p=0.39) or RFS (p=0.31). Preoperative chemotherapy was used in 2 Va cases. Despite temozolomide followed by exenteration for a 4 cm multi-focal lesion, one patient died within 3 months. The second patient, with a 2 cm vaginal lesion, demonstrated a partial response to carboplatin and paclitaxel (CP). After local excision and lymphadenectomy she received additional CP with bevacizumab and remains disease free at 5 years. CP with bevacizumab was also used in 1 Vu case with a solitary 5 cm midline lesion. She underwent vulvectomy after a partial response, received additional CP and bevacizumab postoperatively, and remains without disease at 2 years. CONCLUSION Preoperative chemotherapy with CP and bevacizumab may improve treatment outcomes, particularly for Va and large Vu lesions.

Development of a prediction model for residual disease in newly diagnosed advanced ovarian cancer.

OBJECTIVES To construct a tool, using computed tomography (CT) imaging and preoperative clinical variables, to estimate successful primary cytoreduction for advanced epithelial ovarian cancer (EOC). METHODS Women who underwent primary cytoreductive surgery for stage IIIC/IV EOC at Mayo Clinic between 1/2/2003 and 12/30/2011 and had preoperative CT images of the abdomen and pelvis within 90days prior to their surgery available for review were included. CT images were reviewed for large-volume ascites, diffuse peritoneal thickening (DPT), omental cake, lymphadenopathy (LP), and spleen or liver involvement. Preoperative factors included age, body mass index (BMI), Eastern Cooperative Oncology Group performance status (ECOG PS), American Society of Anesthesiologists (ASA) score, albumin, CA-125, and thrombocytosis. Two prediction models were developed to estimate the probability of (i) complete and (ii) suboptimal cytoreduction (residual disease (RD) >1cm) using multivariable logistic analysis with backward and stepwise variable selection methods. Internal validation was assessed using bootstrap resampling to derive an optimism-corrected estimate of the c-index. RESULTS 279 patients met inclusion criteria: 143 had complete cytoreduction, 26 had suboptimal cytoreduction (RD>1cm), and 110 had measurable RD ≤1cm. On multivariable analysis, age, absence of ascites, omental cake, and DPT on CT imaging independently predicted complete cytoreduction (c-index=0.748). Conversely, predictors of suboptimal cytoreduction were ECOG PS, DPT, and LP on preoperative CT imaging (c-index=0.685). CONCLUSIONS The generated models serve as preoperative evaluation tools that may improve counseling and selection for primary surgery, but need to be externally validated.

PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB.

The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.

Risk-prediction model of severe postoperative complications after primary debulking surgery for advanced ovarian cancer

OBJECTIVES To refine models to predict surgical morbidity and 90-day mortality after primary debulking surgery (PDS) for advanced epithelial ovarian cancer (EOC). METHODS Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/2/2003 and 12/30/2011 were included. Patient characteristics, intraoperative and postoperative outcomes, and vital status were abstracted. Complications were graded using the Accordion classification. Nomograms were generated based on multivariate modeling. RESULTS 138 (22.3%) of the 620 patients who underwent PDS experienced a grade≥3 complication. Age (OR 1.21 per 10 years increase in age), BMI (OR 1.35 for BMI<25 kg/m2 versus reference, OR 2.83 for BMI≥40 kg/m2 versus reference), ASA score≥3 (OR 1.49), stage (OR 1.69 stage IV) and surgical complexity (OR 2.32 high complexity versus intermediate) were predictive of an accordion grade≥3 complication Within 90 days of surgery, 55 (8.9%) patients died. A multivariable model included age (OR 1.76 per 10 year increase in age), ASA score≥3 (OR 3.28), preoperative albumin<3.5 (OR 4.31), and BMI (OR 2.04 for BMI<25 kg/m2 versus reference, OR 3.64 for BMI≥ 40 kg/m2 versus reference) was predictive of 90-day mortality. CONCLUSION Using an independent cohort we report the importance of age, ASA score, preoperative albumin, FIGO stage, and surgical complexity, and BMI, to refine a prediction model for complications after PDS for advanced EOC. This information is useful in preoperative counseling and can be utilized to aid in patient-centered decision making and risk stratification.

Lymphatic mapping and ligation for persistent ascites after surgery for gynecologic malignancy.

BACKGROUND: Ascites after lymphatic dissection, usually amenable to conservative management, may require surgery. We describe a technique in the context of treatment for gynecologic malignancy to localize and ligate lymphatic leaks. CASE: The patient was a 37-year-old woman with recurrent ovarian carcinoma, who developed recurrent chylous and lymphatic ascites after secondary cytoreduction surgery including lymph node resection in multiple basins. Ascites were refractory despite paracenteses, dietary modification, and octreotide therapy. Sclerotherapy was unsuccessful. Surgical ligation of the lymphatic leak was accomplished with injection of isosulfan blue dye into groin nodes to assist with localization. CONCLUSION: Select cases of persistent ascites after surgery for gynecologic malignancy will require surgery after conservative measures are attempted. Awareness of options for management is important for those caring for women with gynecologic cancer.

Short-term outcomes after incontinent conduit for gynecologic cancer: Comparison of ileal, sigmoid, and transverse colon

OBJECTIVE The aim of this study is to estimate the overall rates of significant incontinent conduit-related complications and compare rates between conduit types. METHODS This was a retrospective review of 166 patients who underwent incontinent urinary diversion from April 1993 through April 2013. Patients were categorized by conduit type-ileal, sigmoid colon, and transverse colon. Significant conduit-related complications were assessed at 30 and 90days after surgery. Significant conduit-related complication was defined as any of the following: ureteral stricture, conduit leak, conduit obstruction, conduit ischemia, ureteral anastomotic leak, stent obstruction requiring intervention via interventional radiology procedure or reoperation, and renal failure. RESULTS A total of 166 patients underwent formation of an incontinent urinary conduit, most commonly during exenteration for gynecologic malignancy. There were 129 ileal, 11 transverse colon, and 26 sigmoid conduits. The overall significant conduit-related complication rate within 30days was 15.1%. Complication rates for ileal, transverse and sigmoid conduits were 14.7%, 0%, and 23.1%, respectively (Fishers exact test, p=0.24). By 90days, the Kaplan-Meier estimated rates of significant complications were 21.8% overall, and 22.3%, 0%, and 28.9%, respectively, by conduit type (log-rank test, p=0.19). The most common significant conduit-related complications were conduit or ureteral anastomotic leaks and conduit obstructions. By 1 and 2years following surgery, the Kaplan-Meier estimated overall rate of significant conduit-related complication increased to 26.5% and 30.1%, respectively. CONCLUSIONS Our study suggests that there are multiple appropriate tissue sites for use in incontinent conduit formation, and surgical approach should be individualized. Most significant conduit-related complications occur within 90days after surgery.

Extraperitoneal Laparoscopic Para-aortic Lymphadenectomy in Endometrial Cancer: Rationale and Surgical Technique

Extraperitoneal laparoscopic para-aortic lymphadenectomy is an increasingly utilized procedure in gynecologic oncology, with advantages over open or traditional laparoscopic surgery, namely, decreased propensity for postoperative adhesions and ability to complete thorough surgical staging in a minimally invasive fashion. For patients with endometrial carcinoma who are at high risk for dissemination to the para-aortic lymph nodes, this technique provides reliable access up to the level of the renal vessels and can be particularly helpful in obese patients.