Development of targeted therapy in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer.

Endometrial cancer (EC) is the most common female genital malignancy in the USA. Most carcinomas arising from the uterus are estrogen dependent and are associated with obesity and hypertension. They are designated type I ECs and typically, due to their early diagnosis secondary to postmenopausal bleeding, have a good prognosis. By contrast, type II ECs develop in older patients, are not hormone dependent and are responsible for most recurrences and deaths from EC. Uterine serous cancer constitutes up to 10% of all endometrial tumors, and represents the most biologically aggressive variant of type II EC. This article will describe the most salient molecular markers that have been identified in uterine serous cancer, thus far with emphasis on the use of erbB2 (HER2/neu) as the first of a series of therapeutic markers for the treatment of this highly-aggressive subset of ECs.

A survey of gynecologic oncologists regarding the end-of-life discussion: a pilot study.

OBJECTIVES: To identify the practices and attitudes of gynecologic oncologists regarding the end-of-life discussion. METHODS: A pilot survey was sent to 1105 members of the Society of Gynecologic Oncologists (SGO). The survey consisted of 20 questions and was sent via the website Survey Monkey. RESULTS: Response rate was 12.8%. Sixty percent of respondents were male, most ranged between 30 and 60 years of age and more than half performed 5-10 major surgeries per week. More than half of respondents (53.9%) deferred the End of Life discussion until the patient had sustained a major change in functional and/or medical status. Thirty percent initiated it at the first recurrence or progression of disease. Forty three percent of respondents characterized the discussion as an on-going process. Patients' age, social support, health insurance, and co-morbidities had no influence on the discussion, and neither did the tumor's site of origin or grade. More respondents initiated the discussion in advanced stage cancer (57%) and after salvage chemotherapy institution (54%). Forty four percent of respondents reported that "understanding and acceptance" was the initial response by patient when counseled about withdrawal of care. This increased to 86% when the issue was revisited. Confusion or reluctance to discuss the subject were initially reported to be 12% and 19%, respectively, but decreased to 2% and 3%, respectively, when withdrawal of care was subsequently addressed with the patient. CONCLUSIONS: This pilot survey sheds a light on attitudes and practices about the end-of-life discussion that deserve to be further studied.

Expression of αV-integrins in uterine serous papillary carcinomas; implications for targeted therapy with intetumumab (CNTO 95), a fully human antagonist anti-αV-integrin antibody.

OBJECTIVE: Uterine serous papillary carcinoma (USPC) is an aggressive variant of endometrial cancer characterized by an innate resistance to chemotherapy and poor prognosis. In this study, we evaluated the expression of αV-integrins in primary USPC cell lines and the in vitro ability of intetumumab (CNTO 95), a fully human monoclonal antibody against αV-integrins, to inhibit USPC cell adhesion and migration. MATERIALS AND METHODS: The surface expression of integrins belonging to the αV-family, including αVß3, αVß5, and αVß6, was evaluated in 6 primary USPC cell lines using flow cytometry analysis. To test the ability of intetumumab to inhibit USPC cell adhesion and migration, adhesion assays in the presence of vitronectin and migration assays through an 8.0-µm pore polycarbonate membrane also were performed. RESULTS: We found high expression of the αV-subunit on the cell surface of all 6 primary USPC cell lines tested (100% positive cells; mean fluorescence intensity range, 13.1-39.5). When the expression of single heterodimeric integrins was evaluated, αVß3, αVß5, and αVß6 were expressed on 37.5%, 32.0%, and 16.3% of cells (mean fluorescence intensity range, 6.5-16.2, 9.2-32.5, and 6.2-11.5, respectively). Importantly, in functional assays, low doses of intetumumab were effective in inhibiting adhesion (0.15 µg/mL, P = 0.003) and migration (1.25 µg/mL P = 0.02) of primary USPC cell lines. CONCLUSIONS: The αV-integrins are overexpressed on the cell surface of primary USPC cell lines. Intetumumab may significantly inhibit USPC cell adhesion and migration pathways and may therefore represent a novel treatment option for patients harboring this rare but highly aggressive variant of endometrial cancer.

Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201).

We evaluated the expression of epithelial cell adhesion molecule (EpCAM) and the potential of MT201 (adecatumumab), a human monoclonal antibody against EpCAM, in uterine serous papillary carcinoma (USPC). EpCAM expression was evaluated by real-time PCR and immunohistochemistry in a total of 56 USPC fresh-frozen biopsies and paraffin-embedded tissues. EpCAM surface expression was also evaluated by flow cytometry and immunohistochemistry in six USPC cell lines. Sensitivity to MT201 antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity was tested against a panel of primary USPC cell lines expressing different levels of EpCAM in standard 5-h (51)Cr release assays. EpCAM transcript was significantly overexpressed in fresh-frozen USPC when compared with normal endometrial cells (NEC). Median (minimum-maximum) copy number was 943.8 (31.5-1568.3) in tumor samples versus 12.9 (1.0-37.0) in NEC (P < 0.001). By immunohistochemistry, EpCAM expression was found in 96% (26 out of 27) of USPC samples with significantly higher expression compared with NECs (P < 0.001). High surface expression of EpCAM was found in 83% (five out of six) of the USPC cell lines tested by flow cytometry. EpCAM-positive cell lines were found highly sensitive to MT201-mediated antibody-dependent cellular cytotoxicity in vitro, whereas primary USPC cell lines were resistant to natural killer cell-dependent cytotoxicity. Human plasma IgG did not significantly inhibit MT201-mediated cytotoxicity against USPC. EpCAM is highly expressed in uterine serous carcinoma at mRNA and protein levels, and primary USPC are highly sensitivity to MT201-mediated cytotoxicity. MT201 might represent a novel therapeutic strategy in patients harboring advanced/recurrent or metastatic USPC refractory to standard treatment modalities.

Serum amyloid A: a novel biomarker for endometrial cancer.

BACKGROUND: The authors investigated the expression of serum amyloid A (SAA) in endometrial endometrioid carcinoma and evaluated its potential as a serum biomarker. METHODS: SAA gene and protein expression levels were evaluated in endometrial endometrioid carcinoma and normal endometrial tissues, by real-time polymerase chain reaction (PCR), immunohistochemistry (IHC), and flow cytometry. SAA concentration in 194 serum samples from 50 healthy women, 42 women with benign diseases, and 102 patients including 49 grade 1, 38 grade 2, and 15 grade 3 endometrial endometrioid carcinoma was also studied by a sensitive bead-based immunoassay. RESULTS: SAA gene expression levels were significantly higher in endometrial endometrioid carcinoma when compared with normal endometrial tissues (mean copy number by real-time PCR = 182 vs 1.9; P = .001). IHC revealed diffuse cytoplasmic SAA protein staining in poorly differentiated endometrial endometrioid carcinoma tissues. High intracellular levels of SAA were identified in primary endometrial endometrioid carcinoma cell lines evaluated by flow cytometry, and SAA was found to be actively secreted in vitro. SAA concentrations (microg/mL) had medians of 6.0 in normal healthy women and 6.0 in patients with benign disease (P = .92). In contrast, SAA values in the serum of endometrial endometrioid carcinoma patients had a median of 23.7, significantly higher than those of the healthy group (P = .001) and benign group (P = .001). Patients harboring G3 endometrial endometrioid carcinoma were found to have SAA concentrations significantly higher than those of G1/G2 patients. CONCLUSIONS: SAA is not only a liver-secreted protein, but is also an endometrial endometrioid carcinoma cell product. SAA is expressed and actively secreted by G3 endometrial endometrioid carcinoma, and it is present in high concentration in the serum of endometrial endometrioid carcinoma patients. SAA may represent a novel biomarker for endometrial endometrioid carcinoma to monitor disease recurrence and response to therapy.

Human papillomavirus type 16 (HPV-16) virus-like particle L1-specific CD8+ cytotoxic T lymphocytes (CTLs) are equally effective as E7-specific CD8+ CTLs in killing autologous HPV-16-positive tumor cells in cervical cancer patients: implications for L1 dendritic cell-based therapeutic vaccines.

Papillomavirus-like particles (VLPs) based on L1 capsid protein represent a promising prophylactic vaccine against human papillomavirus (HPV) infections. However, cell-mediated immune responses against this antigen are believed to be of limited therapeutic value in established HPV-infected cervical lesions and, for this reason, have not been intensively investigated in cervical cancer patients. In this study we analyzed and quantified by real-time PCR (RT-PCR) the RNA expression levels of E6, E7, and L1 genes in flash-frozen HPV-16 cervical carcinomas. In addition, the kinetics of expression of E6, E7, and L1 in HPV-16-infected primary cell lines established as long-term cultures in vitro was also evaluated at RNA and protein levels. Finally, in order to evaluate the therapeutic potential of L1-specific CD4(+) and CD8(+) T lymphocytes responses in cervical cancer patients, L1 VLP-loaded dendritic cells (DCs) were used to stimulate peripheral blood lymphocytes from cervical cancer patients and such responses were compared to those elicited by the E7 oncoprotein. We show that 22 of 22 (100%) flash-frozen cervical biopsy samples collected from HPV-16-positive cervical cancer patients harbor L1, in addition to E6 and E7 RNA, as detected by RT-PCR. E7 RNA copy number (mean, 176.2) was significantly higher in HPV-16-positive cervical cancers compared to the E6 RNA copy number (mean, 47.3) and the L1 copy number (mean, 58.3) (P < 0.0001 and P < 0.001, respectively). However, no significant differences in expression levels between E6 and L1 were found. Kinetic studies of E6, E7, and L1 RNA and protein expression levels in primary tumors showed a sharp reduction in L1 expression after multiple in vitro passages compared to E6 and E7. Autologous DCs pulsed with HPV-16 VLPs or recombinant full-length E7 elicited strong type 1 L1- and E7-specific responses in CD4(+) and CD8(+) T cells from cervical cancer patients. Importantly, L1 VLP-specific CD8(+) T lymphocytes expressed strong cytolytic activity against autologous tumor cells and were as effective as E7-specific cytotoxic T lymphocytes in lysing naturally HPV-16-infected autologous tumor cells. Taken together, these data demonstrate a consistent expression of L1 in primary cervical tumors and the possibility of inducing effective L1/tumor-specific CD4(+) and CD8(+) T-lymphocyte responses in patients harboring HPV-infected cervical cancer. These results may have important implications for the treatment of patients harboring established HPV-infected lesions with L1 VLPs or combined E7/L1 DC-based vaccinations.

Experience with liver dialysis in acetaminophen induced fulminant hepatic failure: a preliminary report.

BACKGROUND/AIMS: Our aim was to assess the efficacy of the liver dialysis unit (LDU) in the treatment of patients with acetaminophen-induced fulminant hepatic failure. METHODS: Seventeen patients with acetaminophen-induced fulminant hepatic failure between January 1996 and December 2001 were retrospectively studied. A liver dialysis unit became available in our Unit in July 2000, and as of December 2001, four of these 17 patients had undergone treatment with liver dialysis. RESULTS: Mean age was 29 years (range: 14-47) and 76% were women. Four of 17 patients underwent a total of 12 (range: 1-4) LDU sessions. Ammonia level tended to be lower following the LDU and all four patients recovered without a need for orthotopic liver transplantation (OLT). Prior to July 2000, eight of 13 patients survived with supportive therapy, three expired and two underwent OLT. No major bleeding episodes were observed during the LDU course. A significant difference was found between the three cases who died and the cases that survived with respect to the grade of encephalopathy (p<0.001). There was significant difference in the admission serum creatinine among survivors (p<0.05). CONCLUSION: In conclusion, the Liver Dialysis Unit treatment appeared to benefit patients with acetaminophen-induced fulminant hepatic failure by reverse of the encephalopathy and spontaneous recovery of the damaged liver in selected patients.

Unusual presentation of hepatic vascular tumors as fulminant hepatic failure.

Epithelioid hemangioendothelioma and angiosarcoma of the liver are rare neoplasms of vascular origin. They can present with nonspecific symptoms such as malaise and weight loss, as well as with liver-related symptoms such as abdominal pain, tender hepatomegaly and jaundice. Portal hypertension and rarely liver failure can occur. We hereby report two cases of fulminant hepatic failure that were eventually diagnosed with epithelioid hemangioendothelioma and angiosarcoma of the liver.