Megan J. DiFurio

Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki‐67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate‐activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre‐ and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre‐ and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki‐67 staining in their endometrial tumors post‐treatment. Metformin decreased expression of phosphorylated (p)‐AMPK (P = 0.00001), p‐Akt (P = 0.0002), p‐S6 (51.2%, P = 0.0002), p‐4E‐BP‐1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformins effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre‐operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer.

OBJECTIVES Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer. METHODS We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice. RESULTS At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51g versus 31g, p=0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7cm(2) versus 1.2cm(2), p=0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways.

Obesity is associated with worse overall survival in women with low-grade papillary serous epithelial ovarian cancer.

Objective The objective of this study was to evaluate prognostic risk factors for survival in women with low-grade serous epithelial ovarian cancer (LGSC). Methods A multicenter retrospective analysis of patients with LGSC was conducted. Potential epidemiologic risk factors evaluated included obesity, age, parity, race, smoking, oral contraceptive pill and/or hormonal replacement therapy use, and previous hysterectomy or surgery on fallopian tubes and/or ovaries. Additional factors included stage, extent of debulking, residual disease, and disease status. Results Eighty-one patients were identified, and pathologic diagnosis was independently confirmed. Median age at diagnosis was 56 years (range, 21–86 years). Thirty-four percent were obese, and 80% had optimally debulked disease. Forty-six percent were alive, 14% with disease, whereas 25% were dead of disease, 2% died of intercurrent disease, and 27% had an unknown status. In a univariate analysis, optimal surgical debulking was associated with improved progression-free survival (P = 0.01), disease-specific survival (P = 0.03), and overall survival (OS) (P < 0.001) and body mass index with worse OS (P = 0.05). On multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval, 1.05–7.3; P = 0.04) and optimal tumor debulking (hazard ratio, 0.05; 95% confidence interval, 0.008–0.29; P = 0.001) were a significant predictor of OS. Conclusions In a multivariate analysis, obesity and optimal tumor cytoreduction were significant predictors of OS. However, obesity was not associated with worse disease-specific survival, suggesting that mortality of obese patients with LGSC may result from other comorbidities. Interventions addressing obesity may improve survival for women diagnosed with LGSC, and further study is warranted to address the role of obesity in LGSC.

Displaced granulosa cells in the fallopian tube mistaken for metastatic granulosa cell tumor.

A 44-yr-old woman underwent a total hysterectomy and bilateral salpingectomy secondary to uterine leiomyomas. Gross examination of the fallopian tubes revealed no masses or lesions; however, 2 small foci of granulosa cells were identified microscopically within one of the fallopian tubes. These foci were suspicious for granulosa cell tumor metastases. The patient subsequently underwent a bilateral oophorectomy, which revealed no primary granulosa cell tumor. Immunohistochemical studies were used to help support the benign nature of the granulosa cells within the fallopian tube. A review of the literature revealed only 1 similar case report of displaced benign granulosa cells within the fallopian tubes. The ovaries in both this case and the previous case report were found to contain multiple cystic follicles, suggesting ovulation as the likely mechanism of displacement. Knowledge of this rare occurrence and the use of immunohistochemical staining are paramount to making a correct diagnosis, thus preventing a misdiagnosis of malignancy and possible unnecessary treatment.

Accuracy of Ultrasonography-Guided Fine-Needle Aspiration in Detecting Persistent Nodal Disease After Chemoradiotherapy

IMPORTANCE Few patients with persistent adenopathy following chemoradiotherapy (CRT) for head and neck squamous cell carcinoma harbor viable disease. Improved selectivity for surgical salvage is needed to prevent unnecessary salvage neck dissection. OBJECTIVE To determine whether ultrasonography-guided fine-needle aspiration (FNA) can be used to identify viable cancer cells in the lymph nodes of patients with persistent radiographic adenopathy following CRT. DESIGN, SETTING, AND PARTICIPANTS A pilot study included patients undergoing preoperative ultrasonography-guided FNA of lymph nodes considered suspicious on radiography prior to planned neck dissection at a quaternary care facility from February 28, 2011, to March 18, 2013. Data analysis was performed from April 28 to December 24, 2013. Patients treated for head and neck squamous cell carcinoma with CRT who were determined to have persistent neck disease on a 6-week posttreatment computed tomographic scan of the neck and scheduled for salvage neck dissection were considered candidates for this pilot study. All patients enrolled in the study underwent ultrasonography-guided FNA of the suspicious lymph nodes within 2 weeks of the planned neck dissection. The cytopathologist reading the samples was blinded to the patients identity. EXPOSURES Fine-needle aspiration with a 23- to 25-gauge needle following CRT. MAIN OUTCOMES AND MEASURES The accuracy of ultrasonography-guided FNA cytologic results was compared with the standard of surgical pathologic examination of neck dissection specimens. RESULTS Fourteen patients (11 [79%] men; mean [SD] age, 57.8 [11.2] years) were enrolled in this pilot study; data were collected on 17 lymph nodes. Among these 14 patients with incomplete radiographic clinical response, 17 lymph node aspirations were performed. Ultrasonography-guided FNA identified squamous cell carcinoma in the aspirates of 4 (80%) of the 5 nodes with squamous cell carcinoma identified on pathologic testing and confirmed the absence of disease in the remaining 12 (71%) lymph nodes. The statistical analysis of these results revealed a sensitivity of 80%; specificity, 100%; positive predictive value, 100%; and negative predictive value, 92.3%. The diagnostic accuracy of ultrasonography-guided FNA at detecting residual persistent cancer was 88%. CONCLUSIONS AND RELEVANCE This pilot study suggests that ultrasonography-guided FNA may be a feasible ancillary diagnostic imaging tool to imaging to assess patients with radiographic persistent disease prior to consideration of salvage neck dissection.

Discussion: ‘Tumor diameter as a predictor in endometrial cancer surgery’ by Yanazume et al

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Yanazume S, Saito T, Eto T, et al. Reassessment of the utility of frozen sections in endometrial cancer surgery using tumor diameter as an additional factor. Am J Obstet Gynecol 2011;204:531.e1-7.