Kevin Holcomb

ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis

Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.

E-cadherin expression in endometrioid, papillary serous, and clear cell carcinoma of the endometrium

OBJECTIVE To compare the frequency and pattern of E‐cadherin expression in endometrioid, papillary serous, and clear cell carcinomas of the endometrium. METHODS E‐cadherin expression was examined in 76 endometrial carcinomas by immunohistochemistry using a monoclonal antibody to E‐cadherin and was correlated with poor prognostic indicators such as depth of myometrial invasion, lymph node status, and intraperitoneal spread. The frequency of expression was compared between endometrioid, papillary serous, and clear cell carcinomas by the Fisher exact test. Logistic regression was used to examine the simultaneous effect of histological type and tumor grade on E‐cadherin expression. RESULTS Sixty‐three endometrioid, nine papillary serous, two clear cell, and two carcinomas of mixed histology were examined. E‐cadherin negative tumors were more likely to be poorly differentiated (P < .01), have cervical extension (P = .02), have positive peritoneal cytology (P < .01), and have adnexal spread (P = .01) when compared with E‐cadherin positive tumors. Papillary serous and clear cell carcinomas were significantly less likely to express E‐cadherin than endometrioid carcinoma (38% versus 95%, P < .001). Tumor grade and histological type were identified as significant predictors of E‐cadherin expression in univariable analysis; however, only histological type remained significant in multivariable analysis (P = .01). When grade was controlled, endometrioid carcinoma remained 23 times more likely to express E‐cadherin than papillary serous and clear cell carcinomas. CONCLUSION Papillary serous and clear cell carcinomas are significantly less likely to express E‐cadherin than endometrioid tumors. This difference may account for the more aggressive behavior of papillary serous and clear cell carcinomas.

Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women.

OBJECTIVE We sought to assess the ability of human epididymis protein 4 (HE4) and CA-125 to distinguish among benign, borderline, and malignant pelvic masses in premenopausal women. STUDY DESIGN We conducted a subset analysis of data from a prospective clinical trial that enrolled women undergoing surgery for an adnexal mass. Diagnostic performance of CA-125 and HE4 for epithelial ovarian cancer (EOC) detection in premenopausal women was determined. RESULTS Of 229 premenopausal patients, 195 (85%) had benign masses, 18 (8%) had EOC, and 16 (7%) had borderline ovarian tumor. The sensitivity of CA-125 and HE4 for EOC detection was 83.3% and 88.9%, respectively. The specificity of CA-125 and HE4 was 59.5% and 91.8%, respectively. A normal HE4 level ruled out invasive cancer in 98% of women with an elevated CA-125. CONCLUSION HE4 offers superior specificity compared to CA-125 for the differentiation of benign and malignant adnexal masses in premenopausal women.

Gynecologic cancer disparities: A report from the Health Disparities Taskforce of the Society of Gynecologic Oncology

OBJECTIVES To review the extent of health disparities in gynecologic cancer care and outcomes and to propose recommendations to help counteract the disparities. METHODS We searched the electronic databases PubMed and the Cochrane Library. We included studies demonstrating quantifiable differences by race and ethnicity in the incidence, treatment, and survival of gynecologic cancers in the United States (US). Most studies relied on retrospective data. We focused on differences between Black and White women, because of the limited number of studies on non-Black women. RESULTS White women have a higher incidence of ovarian cancer compared to Black women. However, the all-cause ovarian cancer mortality in Black women is 1.3 times higher than that of White women. Endometrial and cervical cancer mortality in Black women is twice that of White women. The etiology of these disparities is multifaceted. However, much of the evidence suggests that equal care leads to equal outcomes for Black women diagnosed with gynecologic cancers. Underlying molecular factors may play an additional role in aggressive tumor biology and endometrial cancer disparities. CONCLUSION Gynecologic cancer disparities exist between Black and White women. The literature is limited by the lack of large prospective trials and adequate numbers of non-Black racial and ethnic groups. We conclude with recommendations for continued research and a multifaceted approach to eliminate gynecologic cancer disparities.

Rapid progression to invasive cervix cancer in a woman infected with the human immunodeficiency virus.

Background Previous studies have shown an increased risk of cervical dysplasia in women infected with human immunodeficiency virus (HIV), as well as an increased risk of progression to higher-grade lesions. It is not known whether the rate of progression is accelerated over that in immunocompetent women. Case During September 1991, an HIV-positive woman underwent conization of the cervix showing carcinoma in situ. The surgical margins and endocervical curettings were negative for dysplasia. Papanicolaou smears 4 and 7 months after the conization also were negative. She then presented 33 months postconization with a stage Ib2 cervical carcinoma, which proved resistant to chemotherapy and pelvic radiation. Conclusion Immunosuppression caused by HIV infection may cause a more rapid progression of cervical intraepithelial lesions to carcinoma.

Is HIV infection a risk factor for advanced cervical cancer

OBJECTIVES To compare HIV-infected and HIV-negative women with invasive cervical cancer with respect to predictors of advanced disease. METHODS A retrospective analysis of 28 HIV-positive and 132 HIV-negative women with invasive cervical carcinoma was conducted and the two groups were compared with regard to stage of disease, demographic and behavioral variables, and risk factors for advanced disease. RESULTS Overall, HIV-infected women were more likely to have advanced disease, because 78% of HIV-positive women had Stage II to IV compared with 55% of HIV-negative women (odds ratio [OR] = 3.1; p = .03). Substance abuse was strongly associated with HIV infection, as were high-risk sexual variables. Although HIV infection was associated with a threefold increase in advance stage cervical cancer in a univariate analysis, only symptom duration and lack of a recent Papanicolaou smear were significant predictors of advanced disease in a multiple logistic regression analysis. CONCLUSIONS The major predictors of advanced cervical cancer are similar in HIV-positive and HIV-negative women, although the reasons for these predictors may be very different. It is likely that a large proportion of HIV-positive patients with cervical cancer acquire HIV infection after initiation of the neoplastic process.

Angiogenesis in early-invasive and low-malignant-potential epithelial ovarian carcinoma.

Objective To evaluate angiogenesis in ovaries of women with stage I invasive and low-malignant-potential epithelial ovarian carcinoma. Methods Ovarian specimens of 49 consecutive women with primary stage I invasive (n = 15) or stage I low-malignant-potential epithelial ovarian carcinoma (n = 34) were stained immunohistochemically for factor VIII–related antigen. Microvessel counts were tested for correlation with patient age, race, parity, previous oral contraceptive use, histologic type, tumor grade, tumor size, ascites, tumor excrescences, and disease-free and overall survival. Statistical analysis included multiple linear regression, Student t tests, factorial analysis of variance, and Cox proportional hazards regression, with P < .05 considered statistically significant. Results Microvessel counts of ovarian specimens of women with stage I invasive epithelial ovarian carcinoma (median 30, range 17–73) were significantly higher than those of women with stage I low-malignant-potential epithelial ovarian carcinoma (median 10, range 5–23), (P < .001). Among women with low-malignant-potential disease, microvessel counts did not differ significantly between serous and mucinous carcinomas (median 10, range 5–23 versus median 11, range 5–20, respectively, P = .78). There was no correlation between microvessel counts and age, tumor grade, tumor size, ascites, or tumor excrescences. Conclusion Angiogenesis as assessed by microvessel counts is more intense in stage I invasive ovarian epithelial carcinoma compared with stage I low-malignant-potential carcinoma, and might assist in differentiating between these histopathologic entities.

Reproductive and oncologic outcomes after progestin therapy for endometrial complex atypical hyperplasia or carcinoma.

OBJECTIVES This study evaluated fertility and oncological outcomes in women with complex atypical hyperplasia (CAH) or nonmyoinvasive grade 1 endometrioid endometrial carcinoma (EM) who desired fertility-sparing therapy. STUDY DESIGN The retrospective cohort study included women younger than 45 years with CAH or EM who desired fertility-sparing treatment at our institution. Only patients for whom both oncological treatment and pregnancy outcomes were available were included. Statistical analyses were performed using a Fisher exact test, Pearson χ(2) test, and Spearman rank correlation test, as appropriate. RESULTS Seventy-five patients were identified, and 23 (13 CAH, 10 EM) met the inclusion criteria. All 23 patients had at least 1 prior pregnancy. Treatment was split between oral progesterone only (38.5% CAH, 40% EM), levonorgestrel intrauterine device only (30.8% CAH, 20% EM), and both (30.8% CAH, 40% EM). After a median follow-up of 13 months (range, 3-74 months), 9 patients (46.2% CAH, 30% EM, P = .39) had persistent/progressive disease. Eight patients (30.8% CAH, 40% EM, P = .69) ultimately had a hysterectomy, and 3 of these (13.0%) were found to have persistent/progressive disease. Median time from diagnosis to hysterectomy was 13 months (range, 4-56 months). Fourteen of the 23 patients utilized assisted reproductive techniques (60.9%); 12 underwent IVF and 2 chose a gestation carrier. Seven clinical intrauterine pregnancies (30.4%) resulting in 6 live births (26.1%) were found in the entire cohort. CONCLUSION Fertility-sparing treatment for CAH and grade 1 endometrial cancer is feasible with progestin therapy and leads to clinically meaningful rates of pregnancy in young women who desire fertility.

Minimally invasive staging of endometrial cancer is feasible and safe in elderly women.

STUDY OBJECTIVE To compare the surgical outcome of elderly and younger patients undergoing laparoscopic or robotic surgical staging of endometrial cancer. DESIGN Retrospective analysis (Canadian Task Force classification II-2). SETTING University-affiliated hospital. PATIENTS One hundred twenty-nine patients comprised the study group. Sixty patients were aged 65 years or older (elderly group), and 69 patients were younger than 65 years (younger group). INTERVENTION Abdominal, laparoscopic, or robotic hysterectomy. MEASUREMENTS AND MAIN RESULTS Among the 109 patients who underwent laparoscopic or robotic staging, there were no differences in estimated blood loss, lymph node count, surgical time, complications, rate of blood transfusion, conversion to laparotomy, and mean postoperative stay between elderly and younger patients. CONCLUSION Minimally invasive surgical staging for endometrial cancer is both feasible and safe in the elderly population and offers similar outcomes as in younger patients.

Molecular alterations of PIK3CA in uterine carcinosarcoma, clear cell, and serous tumors.

Objectives Type II endometrial carcinomas—uterine carcinosarcomas or uterine malignant mesodermal mixed tumors (UMMMTs), clear cell carcinomas (UCCs), and uterine serous carcinomas (USCs)—are aggressive malignancies that present with advanced disease and have high mortality rates. PIK3CA mutations are commonly found in endometrial cancers. The objective of the study was to characterize molecular alterations in the PIK3CA gene in these tumors. Methods A total of 84 cases (20 UMMMTs, 18 UCCs, and 46 USCs) were selected from the surgical pathology files of Weill Cornell Medical College and Johns Hopkins Hospital. The diagnoses were confirmed by gynecologic pathologists (L.H.E. and A.Y.). DNA was extracted from paraffin-embedded tissue. Polymerase chain reaction was performed for mutational analysis. All the studies were performed in accordance with approved Institutional Review Board protocols. Results Mutations in the PIK3CA gene were identified in 3 (15%) of 20 UMMMT, 3 (16.7%) of 18 UCC, and 10 (21.7%) of 46 USC cases. We report novel mutations in PIK3CA in uterine carcinosarcoma. Conclusions A significant percentage of UMMMTs, UCCs, and USCs have mutations in PIK3CA. Further investigation is needed to develop targeted therapies for these aggressive uterine cancers.ObjectivesType II endometrial carcinomas—uterine carcinosarcomas or uterine malignant mesodermal mixed tumors (UMMMTs), clear cell carcinomas (UCCs), and uterine serous carcinomas (USCs)—are aggressive malignancies that present with advanced disease and have high mortality rates. PIK3CA mutations are commonly found in endometrial cancers. The objective of the study was to characterize molecular alterations in the PIK3CA gene in these tumors. MethodsA total of 84 cases (20 UMMMTs, 18 UCCs, and 46 USCs) were selected from the surgical pathology files of Weill Cornell Medical College and Johns Hopkins Hospital. The diagnoses were confirmed by gynecologic pathologists (L.H.E. and A.Y.). DNA was extracted from paraffin-embedded tissue. Polymerase chain reaction was performed for mutational analysis. All the studies were performed in accordance with approved Institutional Review Board protocols. ResultsMutations in the PIK3CA gene were identified in 3 (15%) of 20 UMMMT, 3 (16.7%) of 18 UCC, and 10 (21.7%) of 46 USC cases. We report novel mutations in PIK3CA in uterine carcinosarcoma. ConclusionsA significant percentage of UMMMTs, UCCs, and USCs have mutations in PIK3CA. Further investigation is needed to develop targeted therapies for these aggressive uterine cancers.