Huyen Q. Pham

Predictive model of venous thromboembolism in endometrial cancer.

OBJECTIVE To profile characteristics and survival of endometrial cancer patients who develop venous thromboembolism (VTE) and to establish a predictive model of VTE in endometrial cancer. METHODS Cases were identified using an institutional database between 2000 and 2011. VTE was correlated to clinico-pathological information and survival outcomes. Frequency and odds ratio (OR) of VTE were examined in a predictive model based on combination patterns of independent risk factors for VTE. RESULTS VTE was seen in 42 (8.1%, 95% CI 5.8-10.5) out of 516 cases subsequent to the diagnosis of endometrial cancer. Multivariate analysis identified 4 independent risk factors for VTE: elevated CA-125 (hazard ratio [HR] 5.38, p<0.001), extrauterine disease (HR 2.87, p=0.019), thrombocytosis (HR 2.11, p=0.04), and high risk histology (serous and clear cell, HR 2.09, p=0.049). VTE was the strongest variable for decreased progression-free survival (HR 4.28) and the second strongest variable for decreased overall survival (HR 5.65) in multivariate analysis. In a predictive model of VTE, the presence of multiple risk factors was associated with significantly increased risk of VTE: frequency of VTE, 1.4% if no risk factors, 0-9.3% (OR 1.0-4.2) if a single risk factor, 11.1-25.0% (OR 9.0-24.0) if two risk factors, and 42.9-46.2% (OR 54.0-61.7) if ≥3 risk factors. CONCLUSION VTE represents a surrogate for aggressive disease in endometrial cancer. Multiple risk factors of VTE in our predictive model demonstrated exceedingly high risk of VTE, suggesting that there may be a certain population of endometrial cancer patients who would benefit from long-term anti-coagulant prophylaxis to improve survival outcome.

Pemetrexed and cisplatin for the treatment of advanced, persistent, or recurrent carcinoma of the cervix: A limited access phase II trial of the Gynecologic Oncology Group

PURPOSE To estimate the antitumor activity of pemetrexed and cisplatin with objective tumor response (partial and complete) in patients with advanced, persistent, or recurrent carcinoma of the cervix and to determine the nature and degree of toxicity of this regimen. Secondarily, this study will determine the effects of this regimen on progression-free survival and overall survival. PATIENTS AND METHODS Eligible, consenting patients received pemetrexed 500 mg/m(2) and cisplatin 50 mg/m(2) intravenously repeated every 21 days until disease progression or adverse events prohibited further therapy. Patients received no prior therapeutic chemotherapy, except when administered concurrently with primary radiation therapy. Subsequent doses were adjusted according to observed toxicity and protocol guidelines. Adverse events were assessed with Common Terminology Criteria for Adverse Events v 3.0. The primary measure of efficacy was tumor response according to Response Evaluation Criteria in Solid Tumors. The study was stratified by prior radiation therapy. RESULTS From September 2008 to November 2011, 55 patients were enrolled by five Gynecologic Oncology Group member institutions; of those, 54 patients were eligible and assessable. The regimen was well tolerated with 26% receiving more than nine cycles. The most common greater than grade 2 toxicities were neutropenia 35%, leukopenia 28%, and metabolic 28%. The overall response rate was 31% (one complete and 16 partial). The median progression-free survival was 5.7 months, and overall survival was 12.3 months. CONCLUSION Pemetrexed in combination with cisplatin demonstrates activity in the treatment of advanced, persistent, or recurrent carcinoma of the cervix.

Immunohistochemical panel to differentiate endometrial stromal sarcoma, uterine leiomyosarcoma and leiomyoma: something old and something new

Aims To evaluate an immunohistochemical panel differentiating endometrial stromal sarcoma (ESS) from uterine leiomyosarcoma (ULMS) and leiomyoma (LM). Methods 94 cases (28 ESS, 41 ULMS, 25 LM) were retrieved and arrayed. 10 immunomarkers (estrogen receptor (ER), progesterone receptor (PR), CD10, smooth muscle actin, desmin, h-caldesmon, transgelin, GEM, ASC1, stathmin1) were used. A predictive model was constructed and examined by receiver operating characteristics curve analysis to determine area under the curve (AUC). Results The combination of ER+/PR+/CD10+/GEM−/h-caldesmon−/transgelin− can predict ESS versus ULMS with AUC predictive value of 0.872 (95% CI 0.784 to 0.961, p<0.0001). The combination of ER+/PR+/CD10+/h-caldesmon−/transgelin− can predict low grade (LG) ESS from ‘LG’ ULMS with AUC predictive value of 0.914 (95% CI 0.832 to 0.995, p<0.0001). Finally, ULMS and ESS, including the LGs, were more likely to be stathmin1+ than LM. Conclusions Due to the different clinical course and management, adding novel antibodies (GEM, transgelin) to the well established immunohistochemistry panel seemed to be useful in distinguishing ESS from ULMS and LG ESS from ‘LG’ ULMS. Finally, stathmin1 expression could be of value in differentiating LM from uterine sarcomas.

Phase II Study of Gemcitabine and Docetaxel in Recurrent Platinum Resistant Ovarian Cancer

To evaluate the activity of gemcitabine and docetaxel in patients with recurrent ovarian cancer. Methods: Patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with docetaxel on day 1 and gemcitabine on days 1 and 8, repeated every three weeks. Results: Twenty patients, with a platinum-free interval of three months, were enrolled. Overall response rate was 25%. Treatment was associated with significant myelosuppression. Conclusions: In chemotherapy-resistant patients, this regimen exhibited encouraging activity. Excessive myelosuppression led to early closure. This was prevented by administering docetaxel on day 8 (instead of day 1) and prophylactic use of G-CSF.

Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C.

Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8(+) T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting that s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection.

Extent of pelvic lymphadenectomy and use of adjuvant vaginal brachytherapy for early-stage endometrial cancer

OBJECTIVE To examine trends of adjuvant radiotherapy choice and to examine associations between pelvic lymphadenectomy and radiotherapy choice for women with early-stage endometrial cancer. METHODS The Surveillance, Epidemiology, and End Results Program was used to identify surgically treated stage I-II endometrial cancer between 1983 and 2012 (type 1 n=79,474, and type 2 n=25,020). Piecewise linear regression models were used to examine temporal trends of intracavitary brachytherapy (ICBT) and whole pelvic radiotherapy (WPRT) use, pelvic lymphadenectomy rate, and sampled node counts. Multivariable binary logistic regression models were used to identify independent predictors for ICBT use. RESULTS There was a significant increase in ICBT use and decrease in WPRT use during the study period. ICBT use exceeded WPRT use in 2003 for type 1 stage IA, and in 2007 for type 1 stage IB and type 2 stage IA diseases. In addition, number of sampled pelvic nodes significantly increased over time in type 1-2 stage I-II diseases (mean, 7.0-12.7 in 1988 to 15.2-17.6 in 2012, all P<0.001). On multivariable analysis, extent of sampled pelvic nodes was significantly associated with ICBT use for type 1 cancer: adjusted-odds ratios for 1-10 and >10 nodes versus no lymphadenectomy in stage IA (1.38/2.40), IB (2.75/6.32), and II (1.36/2.91) diseases. Similar trends were observed for type 2 cancer: adjusted-odds ratios for stage IA (1.69/3.73), IB (2.25/5.65), and II (1.36/2.19) diseases. CONCLUSION Our results suggest that surgeons and radiation oncologists are evaluating the extent of pelvic lymphadenectomy when counseling women with early-stage endometrial cancer for adjuvant radiotherapy.

Microfocus of Anaplastic Carcinoma Arising in Mural Nodule of Ovarian Mucinous Borderline Tumor With Very Rapid and Fatal Outcome.

A 36-yr-old woman presented with abdominal discomfort. A computed tomography scan revealed a large left cystic and solid pelvic mass without evidence of metastatic disease. Total hysterectomy with bilateral salpingo-oophorectomy and tumor staging was performed. Grossly, the ovarian mass measured 20×18 cm and the cut surface was multiloculated with 1 single mural nodule measuring 2×1.5 cm. The histologic diagnosis of ovarian mucinous borderline tumor with a microfocus of anaplastic carcinoma arising in sarcoma-like mural nodule, FIGO Stage IA was rendered. After 3 mo, the patient returned with symptomatic anemia. A computed tomography scan showed enlarged retroperitoneal and pelvic lymph nodes. Image-guided biopsy of the pelvic lymph node showed a metastatic anaplastic carcinoma from her primary ovarian carcinoma. Chemotherapy was initiated, but the patient developed fulminant disseminated intravascular coagulation within <1 wk of her presentation which was fatal.

Single Marital Status and Infectious Mortality in Women With Cervical Cancer in the United States

Objective Unmarried status including single marital status is associated with increased mortality in women bearing malignancy. Infectious disease weights a significant proportion of mortality in patients with malignancy. Here, we examined an association of single marital status and infectious mortality in cervical cancer. Methods This is a retrospective observational study examining 86,555 women with invasive cervical cancer identified in the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Characteristics of 18,324 single women were compared with 38,713 married women in multivariable binary logistic regression models. Propensity score matching was performed to examine cumulative risk of all-cause and infectious mortality between the 2 groups. Results Single marital status was significantly associated with young age, black/Hispanic ethnicity, Western US residents, uninsured status, high-grade tumor, squamous histology, and advanced-stage disease on multivariable analysis (all, P < 0.05). In a prematched model, single marital status was significantly associated with increased cumulative risk of all-cause mortality (5-year rate: 32.9% vs 29.7%, P < 0.001) and infectious mortality (0.5% vs 0.3%, P < 0.001) compared with the married status. After propensity score matching, single marital status remained an independent prognostic factor for increased cumulative risk of all-cause mortality (adjusted hazards ratio [HR], 1.15; 95% confidence interval [CI], 1.11–1.20; P < 0.001) and those of infectious mortality on multivariable analysis (adjusted HR, 1.71; 95% CI, 1.27–2.32; P < 0.001). In a sensitivity analysis for stage I disease, single marital status remained significantly increased risk of infectious mortality after propensity score matching (adjusted HR, 2.24; 95% CI, 1.34–3.73; P = 0.002). Conclusions Single marital status was associated with increased infectious mortality in women with invasive cervical cancer.

Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series

Tumors deficient in DNA mismatch repair are known to display increased susceptibility to immune checkpoint inhibitors due to accumulation of DNA damage and increased neoantigen load. This suggests that deficiency in the BRCA-related DNA repair mechanism may also be a surrogate marker for immunotherapy response. The aim of this study was to examine the efficacy of the immune checkpoint inhibitor, nivolumab, in women with BRCA gene mutations and recurrent müllerian cancer. This retrospective case series followed six BRCA carriers who received nivolumab monotherapy (3.0 mg/kg, intravenous, day 1 and 15, every 4 weeks) as salvage therapy for recurrent epithelial ovarian (n = 5) and fallopian tubal (n = 1) cancers. Toxicity, treatment response, and survival were examined. Median age was 57 (range 51–64). BRCA1 and 2 mutations were equally distributed. All had high-grade serous histology, and all but one had advanced-stage disease at initial diagnosis. The majority had platinum-resistant disease (n = 4). All received salvage therapy prior to nivolumab therapy (median 3 lines), including PARP inhibitors (n = 3). The median number of nivolumab treatment cycles was 9, including 2 women receiving 18 cycles. Three women developed nivolumab-related toxicities, most commonly grade 2 hypothyroidism (n = 2). Median follow-up time was 13.4 months, and there were 3 complete responses, 1 partial response, and 2 patients with progressive disease. Objective response rate was 67% (4 out of 6). In conclusion, our study suggests that nivolumab monotherapy is well-tolerated and may be an effective salvage therapy for BRCA mutation carriers with recurrent epithelial ovarian, fallopian tubal, and primary peritoneal cancers.

Endoplasmic reticulum stress in complex atypical hyperplasia as a possible predictor of occult carcinoma and progestin response

Glucose-regulated protein (GRP)-78, the key regulator of endoplasmic reticulum (ER) stress, is associated with endometrial cancer (EC) development and progression. However, its role in the continuum from complex atypical hyperplasia (CAH) to EC is unknown and the focus of this study. METHODS 252 formalin-fixed, paraffin-embedded endometrial biopsies from patients with CAH diagnosed between 2003 and 2011 were evaluated for GRP78 expression by immunohistochemistry. Expression was also evaluated in subsequent biopsies from those patients treated with progestins. Differences in GRP78 expression were assessed using standard statistical methods. RESULTS GRP78 expression was undetectable in 45(18%) patients with CAH, while 120(48%) CAH cases showed moderate/strong expression. Among women who ultimately underwent hysterectomy for CAH (n=134), 54(40%) had occult EC while 57(43%) had persistent CAH. Those with occult EC upon hysterectomy had significantly stronger GRP78 expression than those who did not have occult EC (p=0.007). Greater GRP78 expression within CAH remained independently associated with the presence of an occult EC (p=0.017). Thirty-four of 54 (63%) patients with occult EC had moderate/strong GRP78 expression compared to 36 of 80 (45%) patients with persistent CAH, benign or non-atypical hyperplastic endometrium. In those treated with progestins, samples with persistent CAH and EC were more likely to have high levels of GRP78 expression in the initial biopsies than those who responded (p=0.014). CONCLUSIONS Increased GRP78 expression in untreated CAH correlates with the presence of an occult EC. In addition, CAH specimens with greater GRP78 expression may identify patients who are less likely to respond to progestin therapy.