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 metformin's 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.

We analyzed complete blood count (CBC) data obtained from neonates with Down syndrome (DS) in a primarily Hispanic population over a 10-year period to determine the incidence of hematologic abnormalities and the relationship of abnormalities to the presence of circulating blasts (CB). Hematologic values obtained during the first 10 days were analyzed. Definitions were: CB, ≥ 1% blasts manually counted on peripheral smear; elevated white blood cell count (WBC), >30,000 cells/mm(3); thrombocytopenia, platelet count < 150,000/mm(3); polycythemia, hematocrit >65%. Two hundred thirty-two neonates (88% Hispanic) with DS had 692 CBCs available for analysis. The presence of CB (11.6%) and the incidence of thrombocytopenia (60.2%) were significantly higher in DS neonates than in the reference group. Elevated WBC (33.3%) and thrombocytopenia (84.6%) were more common in DS neonates with CB versus those with no CB. No relationship between thrombocytopenia and polycythemia was observed. Unlike previous reports, we did not observe a male predominance in those DS neonates with CB. Thrombocytopenia occurred frequently in DS neonates and was significantly more likely in those with CB than in those with no CB. CBC screening should be performed routinely in DS neonates.

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5519 Background: Obesity and diabetes have been linked to poorer survival and increased recurrence rates in endometrial cancer. The anti-diabetic medication, metformin, has been shown to have anti-tumorigenic effects in vitro and in vivo, via AMPK activation and inhibition of the mTOR pathway. We conducted a pre-operative window clinical trial of metformin in obese endometrial cancer patients to evaluate short-term in vivo molecular changes. Methods: Women with endometrioid endometrial cancer who were obese (BMI>30) were recruited from a gynecologic oncology clinic. Once enrolled, patients had a repeat pre-treatment endometrial biopsy and then began metformin at a dose of 850 mg PO once daily for 1-4 weeks prior to hysterectomy/surgical staging. A tissue microarray, using triplicate cores from each specimen, was constructed from paired formalin-fixed, paraffin-embedded endometrial biopsy (pre-treatment) and hysterectomy (post-treatment) specimens. The expression of Ki-67, a marker of cell proliferation, was measured by immunohistochemistry. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. The Signed Rank Test was used for statistical analysis. Results: Sixteen patients have completed the protocol. The mean duration of treatment was 14.5 days. Percent Ki-67 staining decreased significantly with metformin treatment (mean of 19.5% decrease, p = 0.026). Two patients experienced grade 1 toxicities, including mild abdominal pain and loose stools. Ten of the 16 patients responded to metformin based on decreased proliferation from their pre- to post-treatment specimens. There were no differences in median age, BMI, HgbA1c, or number of doses taken between responders and non-responders to treatment. Pre-treatment Ki-67 levels were statistically higher in the women that responded to metformin treatment (52% versus 27.5%, p = 0.0067). Conclusions: Metformin significantly reduced proliferation in a pre-operative window study in obese endometrial cancer patients, providing further support for therapeutic clinical trials of metformin in this obesity-driven disease.

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.

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GA specific predicted risk of neonatal respiratory morbidity using LBC provides a statistical model, which can aid clinicians in individually counseling patients regarding the absolute risk of their neonate developing respiratory morbidity.

In univariate analysis, 6-month δ-BMI change was significantly associated with DFS and OS (both, P b .001): 5-year rates, ≥15% δ-BMI loss (33.5% and 59.1%), 7.5% to 14.9% loss (67.3% and 70.0%), b7.5% loss (87.8% and 95.7%), b7.5% gain (87.2% and 90.3%), 7.5% to 14.9% gain (64.6% and 67.6%), and ≥15% gain (32.5% and 66.7%). In multivariable analysis controlling for age, ethnicity, baseline BMI, histology, grade, stage, chemotherapy, and radiotherapy, 6-month δ-BMI change remained an independent prognostic factor for DFS and OS (all, P b .05): adjusted-HRs, ≥15% δ-BMI loss (3.35 and 5.39), 7.5% to 14.9% loss (2.35 and 4.19), 7.5% to 14.9% gain 2.58 and 3.33), and ≥15% gain (2.50 and 3.45) compared with b7.5% loss. (See Fig. 1.) Similar findings were observed at the 1-year time point (P b .05). Baseline BMI was not associated with survival outcome (P N .05). Conclusions: Our results demonstrated that endometrial cancer patients continued to gain weight after hysterectomy and posttreatment weight change had a bidirectional effect on survival outcome.