Thomas A. Caputo

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.

Postoperative high dose-rate intravaginal brachytherapy combined with external irradiation for early stage endometrial cancer: A long-term follow-up

PURPOSE To evaluate the long-term control of disease and cure rate, complications, second malignancy, and survival of early-stage endometrial cancer patients treated with surgery, high dose-rate brachytherapy, and external beam radiation therapy. METHODS AND MATERIALS From 1969 through 1979, 300 patients with clinically staged Stage I-II endometrial cancer underwent total abdominal hysterectomy and bilateral salpingo-oopherectomy, followed by high dose-rate intravaginal radiation, 7 Gy x 3 to 0.5 cm from the mucosal surface, using a remote afterloading technique. External beam radiation therapy, 40 Gy to midplane in 4 weeks, was delivered to high risk patients through AP/PA and lateral fields. RESULTS The patients were followed for 5-24 years (median 12). The actuarial progression-free survival rate was 96.6%. Post-treatment grade 1-2 actuarial complication rate was 9.5%, including cystitis (4.5%), vaginal stenosis (2.5%), proctitis (1.5%), vaginal necrosis (0.5%), and partial bowel obstruction (0.5%). Neither grade 3-4 complications nor additional late complications were observed in any of our patients. Relapse rate was only 3.7%, of which 45.5% were local, 45.5% were distant, and 9% were mixed. All the patients with relapse were postmenopausal, age range of 58-77 years, with tumor grade 2-3 in 64%. Second primary cancer rate was 12.8% (mostly breast and colon). Factors that were associated with improved prognosis were young age, premenopausal, low grade, no extrauterine disease, and a histology of adenocarcinoma (adenocarcinoma with squamous metaplasia). CONCLUSION High dose rate intravaginal radiation therapy combined with surgery and external beam radiation therapy achieved a high cure rate small number of minor complications. No long-term treatment-related complications were noted in any of the patients. This treatment combination may be safely applied to patients with early stage endometrial cancer.

A comparative analysis of 57 serous borderline tumors with and without a noninvasive micropapillary component.

The literature concerning serous borderline tumors with a noninvasive micropapillary component suggests an association with invasive implants. We compared the clinicopathologic features of micropapillary serous borderline tumors (MSBTs) with typical SBTs to determine the following: 1) the importance of focal micropapillary architecture in an otherwise typical SBT, 2) the behavior of low-stage MSBTs, 3) whether high-stage MSBTs are inherently more aggressive than high-stage SBTs, and 4) whether invasive implants are prevalent in an MSBT cohort without referral selection bias. The 57 borderline tumors studied were diagnosed at a university hospital between 1981 and 1998; they included 14 MSBTs, 35 SBTs, and 8 SBTs with focal micropapillary features. None of the specimens were referrals for expert pathologic consultation, thus distinguishing our study group from most of those previously reported. Neither MSBTs nor SBTs were associated with invasive implants at diagnosis (0 of 14 and 0 of 43, respectively). They also did not differ with respect to overall stage at diagnosis, but MSBTs were more frequently bilateral than SBTs (71% versus 23%, p = 0.001). There was an increased risk of recurrence in MSBT versus SBT (3 of 14 versus 1 of 43, p = 0.035), but this was stage related; there was no difference between groups when evaluating recurrence in stage I disease (0 of 8 versus 0 of 27). There was no difference in recurrence or stage at diagnosis between SBTs with focal micropapillary features and other SBTs. There was 100% survival in all groups. We conclude that high-stage MSBTs with noninvasive implants should be considered a subtype of SBTs with an increased risk of recurrence. Stage I MSBTs demonstrate clinical features that are similar to low-stage SBTs. Focal micropapillary architecture (<5 mm) has no bearing on outcome. MSBTs in the general population are not strongly associated with invasive implants.

Smoking, body weight, and early‐stage endometrial cancer

The effect of cigarette smoking on the risk of early‐stage endometrial cancer was evaluated in a population‐based case‐control study of women aged 40 to 69 years from upstate New York. Two hundred women with early‐stage endometrial cancer diagnosed between 1979 and 1981, and 200 matched community controls were interviewed in person and asked about smoking habits and other risk factors. Statistical analysis revealed a significant decline in relative risk with increased smoking (P < 0.05). This effect strongly modified the well‐known increase in risk with body weight. Among smokers risk did not increase with body weight, whereas among nonsmokers risk increased rapidly with body weight, especially among nonsmokers in whom the peripheral conversion of androgens was the primary source of serum estrogen. Despite this apparent reduced risk for endometrial cancer, smoking remains a major health hazard for women as well as men.

Dietary Antioxidants, Supplements, and Risk of Epithelial Ovarian Cancer

Several studies of dietary and serum antioxidant micronutrients (vitamins A, C, and E and β-carotene) suggest that higher levels may be protective for ovarian cancer. None of these has examined supplements. We used a food frequency questionnaire and additional questions on supplements to study 168 histologically confirmed epithelial ovarian cancer cases, 159 community controls, and 92 hospital-based controls. Antioxidant consumption from diet or supplements was calculated in milligrams or international units per day. In multivariate analyses using only community controls, the highest levels of intake of vitamins C and E from supplements were protective: odds ratio (OR) = 0.40 [95% confidence interval (CI) = 0.21-0.78] and OR = 0.33 (95% CI = 0.18-0.60), respectively. Consumption of antioxidants from diet was unrelated to risk. In analyses combining antioxidant intake from diet and supplements, vitamins C (>363 mg/day) and E (>75 mg/day) were associated with reduced risks: OR = 0.45 (95% CI = 0.22-0.91) and OR = 0.44 (95% CI = 0.21-0.94), respectively. Results were similar, with some attenuation toward the null, in analyses combining both control groups. The levels of vitamins C and E associated with the protective effect were well above the current US Recommended Dietary Allowances. These findings support the hypothesis that antioxidant vitamins C and E from supplements are related to a reduced risk of ovarian cancer.

IgA ANTIBODIES TO THE 27-kDa HEAT-SHOCK PROTEIN IN THE GENITAL TRACTS OF WOMEN WITH GYNECOLOGIC CANCERS

Heat‐shock proteins promote cell survival under adverse environmental conditions. Synthesis of the 27‐kDa (HSP27), 70‐kDa (HSP70), and 90‐kDa (HSP90) heat‐shock proteins is increased in malignantly transformed cells and has been associated with tumor proliferation, metastasis, and resistance to chemotherapeutic agents. The increased expression of heat‐shock proteins and their association with tumor‐specific antigens may result in local immunity to the heat‐shock proteins. We examined the occurrence of IgA antibodies to HSP27, HSP70, and HSP90 in the lower genital tracts of women with possible gynecologic cancers. Cervical samples were obtained from 119 consecutive women being evaluated for a gynecologic malignancy or returning for a follow‐up examination following cancer treatment. Aliquots were tested for IgA anti‐heat‐shock protein antibodies by ELISA. Aliquots were also tested for IgG antibodies to HSP27 as well as for human papillomavirus. Anti‐HSP27 IgA was detected in 85.7% of 21 women with endometrial cancer tested prior to diagnosis and in 41.1% of 17 women tested after treatment. In women with ovarian cancer, 77.8% of 9 women tested prior to diagnosis and 75.0% of 24 women evaluated after treatment were anti‐HSP27 IgA‐positive. Of 6 women with cervical cancer tested prior to diagnosis, 5 were positive for this antibody. None of 25 women with benign diagnoses or 46 healthy women were cervical IgA anti‐HSP27‐positive (P < 0.0001). In contrast, anti‐HSP27 IgG was not associated with a gynecologic malignancy. HSP27 cervical antibodies were not associated with the presence of human papillomavirus. Cervical IgA antibodies to HSP90 were associated with ovarian cancer; antibodies to HSP70 were not cancer‐associated. We conclude that cervical IgA antibodies to HSP27 may be indicators of a gynecologic malignancy. Int. J. Cancer 87:824–828, 2000.

Intravenous leiomyomatosis with intracardiac extension: a single-institution experience

OBJECTIVE The aim of this study was to outline the surgical management and outcomes for patients diagnosed with intravenous leiomyomatosis with intracardiac extension at a single institution. STUDY DESIGN This was a retrospective review of patients diagnosed with intravenous leiomyomatosis with intracardiac extension between 2002-2008. RESULTS Four patients were identified. The surgical approach in 3 (75%) patients was a single-stage operation. Four (100%) patients presented with cardiac symptoms: 3 (75%) with syncope and 1 (25%) with an abnormal electrocardiogram. Mean age at presentation was 48 years (range, 42-58 years). Complete resection of tumor was obtained in 1 (25%) patient and 3 (75%) patients experienced incomplete resection. Mean follow-up, including surveillance imaging, was 25.5 months (range, 8-57 months) and all 4 patients (100%) are currently free of recurrence. CONCLUSION Surgical excision remains an effective therapy for treating patients with benign metastasizing leiomyomatosis. Incomplete surgical resection may result in favorable response.

Infrared spectroscopic study of cervical smears in patients with HIV: implications for cervical carcinogenesis.

Patients with HIV have an increased incidence of cervical cancer, necessitating increased surveillance. Infrared spectroscopy (IRS) has the potential of aiding the diagnosis of cervical neoplasia and also of providing clues into its pathogenesis. We studied by IRS cervical scrapings from 22 HIV-infected and 23 control women; 8 of the former and none of the latter had dysplasia. The infrared spectra followed three patterns, designated pattern I (similar to that previously associated with normal cervical samples), pattern II (intermediate between patterns I and III), and pattern III (associated with cervical neoplasia). Compared with HIV-negative controls, HIV-infected women had a higher prevalence of pattern III and a lower prevalence of pattern II; these differences were statistically significant (P = .015 by chi2 analysis). Similar spectroscopic changes were present even when only the cytologically normal samples from HIV-positive and HIV-negative women were analyzed. We speculate that these changes may reflect early structural changes associated with cervical neoplasia that are not detectable cytologically. The infrared spectra in the region 950 to 1,300 cm(-1) could not differentiate cervical samples from HIV-infected and uninfected patients. The potential practical applications of IRS in HIV cervical disease are discussed.

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.

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.