Suicidal risk and executive functions in major depressive disorder: a study protocol.

BACKGROUND: Suicide is a serious public health concern. Depression is the main gateway to suicidal behavior. The already established relationship between depression and suicidal risk should now focus on the investigation of more specific factors: recent studies have suggested an association between vulnerability to suicidal behavior and neurocognitive alterations, a nuclear symptom of depression. This project aims to identify alterations in the Executive Functions (EF) of patients suffering a first depressive episode that might constitute a risk factor for suicidal ideation, suicidal attempts and suicide, to allow for more adequate suicide prevention. METHODS: Prospective longitudinal design involving two groups (first depressive episodes with and without alterations in their EF) and four repeated measures (0, 6, 12 and 24 months). The estimated minimum sample size is 216 subjects. The variables and measurement instruments will include socio-demographic variables, clinical variables (age of illness onset, family and personal antecedents, psychopathological and medical comorbidity, suicidal ideation, suicide attempts and completed suicides, severity of depression, including melancholic or atypical, remission of the depressive episode), and neuropsychological variables (EF and decision-making processes evaluated through the Cambridge Neuropsychological Test Automated Battery (CANTAB)). DISCUSSION: First and foremost, the identification of clinical and neuropsychological risk factors associated with suicidal behavior will open the possibility to prevent such behavior in patients with a first depressive episode in the context of clinical practice. Secondly, interventions aimed at cognitive impairment (in particular: EF) derived from the study may be incorporated into strategies for the prevention of suicidal behavior. Finally, impaired neurocognitive function (even in early stages) could become an identifiable endophenotype or "marker" in clinical and neurobiological studies about suicidal behavior in depressive patients.

Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu.

OBJECTIVE: To study the effect of trastuzumab in patients with progressive or recurrent metastatic endometrial carcinoma shown by immunohistochemistry to overexpress the HER2/neu receptor. METHODS: Disease progression was examined in 2 patients who met the study criteria, had c-erbB2 gene amplification by fluorescence in situ hybridization, and were treated with trastuzumab following radiation treatment and/or salvage chemotherapy. RESULTS: The clinical responses to trastuzumab as a single agent or in combination with chemotherapy were confirmed in both patients by serial CT scans and serum CA-125 evaluations. These patients with progressive or recurrent metastatic disease experienced relief from their symptoms and prolonged survival with no significant toxicity observed. CONCLUSION: Trastuzumab may be a viable therapeutic option as single agent or in combination with chemotherapy in patients with advanced, recurrent, and/or metastatic endometrial carcinomas overexpressing HER2/neu.

Human papillomavirus type 16 and 18 E7-pulsed dendritic cell vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial.

The safety and immunogenicity of the human papillomavirus type 16 (HPV16) or HPV18 (HPV16/18) E7 antigen-pulsed mature dendritic cell (DC) vaccination were evaluated for patients with stage IB or IIA cervical cancer. Escalating doses of autologous DC (5, 10, and 15 x 10(6) cells for injection) were pulsed with recombinant HPV16/18 E7 antigens and keyhole limpet hemocyanin (KLH; an immunological tracer molecule) and delivered in five subcutaneous injections at 21-day intervals to 10 cervical cancer patients with no evidence of disease after they underwent radical surgery. Safety, toxicity, delayed-type hypersensitivity (DTH) reaction, and induction of serological and cellular immunity against HPV16/18 E7 and KLH were monitored. DC vaccination was well tolerated, and no significant toxicities were recorded. All patients developed CD4(+) T-cell and antibody responses to DC vaccination, as detected by enzyme-linked immunosorbent spot (ELISpot) and enzyme-linked immunosorbent assays (ELISA), respectively, and 8 out of 10 patients demonstrated levels of E7-specific CD8(+) T-cell counts, detected by ELISpot during or immediately after immunization, that were increased compared to prevaccination baseline levels. The vaccine dose did not predict the magnitude of the antibody or T-cell response or the time to detection of HPV16/18 E7-specific immunity. DTH responses to intradermal injections of HPV E7 antigen and KLH were detected for all patients after vaccination. We conclude that HPV E7-loaded DC vaccination is safe and immunogenic for stage IB or IIA cervical cancer patients. Phase II E7-pulsed DC-based vaccination trials with cervical cancer patients harboring a limited tumor burden, or who are at significant risk of tumor recurrence, are warranted.

Local administration of interleukin-11 ameliorates intestinal radiation injury in rats.

Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 +/- 0.6 in the vehicle group versus 4.0 +/- 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 +/- 0.1 versus 0.5 +/- 0.03; P < 0.0001), and intestinal wall thickening (842 +/- 66 microm versus 643 +/- 54 microm; P = 0.02), reduced postradiation transforming growth factor-beta overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic.

Metastatic uterine leiomyosarcoma regression using an aromatase inhibitor.

BACKGROUND: Metastatic and disseminated uterine leiomyosarcoma has limited chemotherapeutic options. CASE: A 45-year-old nulligravida was originally diagnosed with a primary uterine leiomyosarcoma and treated with a total abdominal hysterectomy, followed by six courses of adjuvant platinum and doxorubicin chemotherapy. Three years later she developed multiple metastatic tumor nodules in the lungs. Because of the estrogen receptor positivity of the leiomyosarcoma by immunohistochemistry, she was treated with 1 mg of anastrozole daily. Progressive tumor regression was demonstrated by serial imaging in all metastatic lung tumor deposits, with an objective response lasting at least 12 months. CONCLUSION: Uterine leiomyosarcoma metastatic to the lungs regressed with the use of the anastrozole aromatase inhibitor.

Overexpression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in uterine carcinosarcomas.

PURPOSE: To evaluate the expression levels of claudin-3 and claudin-4, the low- and high-affinity receptors, respectively, for the cytotoxic Clostridium perfringens enterotoxin (CPE) in uterine carcinosarcomas and explore the potential for targeting these receptors in the treatment of this aggressive uterine tumor. EXPERIMENTAL DESIGN: We analyzed claudin-3 and claudin-4 receptor expression at mRNA and protein levels in flash frozen and formalin-fixed, paraffin-embedded carcinosarcoma specimens. Recombinant CPE was used as a novel therapy against chemotherapy-resistant carcinosarcoma cell lines in vitro. The therapeutic effect of sublethal doses of CPE was studied in severe combined immunodeficient mouse xenografts harboring large s.c. carcinosarcomas. RESULTS: All flash-frozen carcinosarcoma biopsies (12 of 12) and short-term carcinosarcoma cell lines evaluated overexpressed claudin-3 and claudin-4 by quantitative reverse transcription-PCR. Membranous immunoreactivity for claudin-4 protein expression was documented in 80% (20 of 25) of primary tumors and 100% (6 of 6) of the metastatic carcinosarcomas, whereas negligible staining was found in normal endometrial cells. Regardless of their resistance to chemotherapeutic agents, all short-term carcinosarcoma cell lines tested died within 1 h of exposure to 3.3 microg/mL of CPE in vitro. Intratumoral injections of well-tolerated doses of CPE in large s.c. carcinosarcoma xenografts led to large areas of tumor cell necrosis and tumor disappearance in all treated animals. CONCLUSIONS: Claudin-3 and claudin-4 receptors are highly overexpressed in carcinosarcoma. These proteins may offer promising targets for the use of CPE as a novel type-specific therapy against this biologically aggressive variant of endometrial cancer.

Overexpression of epidermal growth factor type-1 receptor (EGF-R1) in cervical cancer: implications for Cetuximab-mediated therapy in recurrent/metastatic disease.

OBJECTIVES: To evaluate and compare epidermal growth factor type-1 receptor (EGF-R1) expression in short term and established cervical cancer cell lines generated from primary and metastatic/recurrent sites of disease. To evaluate the sensitivity of cervical cancer cell lines to treatment with a chimeric MAb against EGFR-1 (Cetuximab). METHODS: EGFR-1 expression was evaluated by flow cytometry on 22 cervical cancer cell lines including 14 primary cervical cancer cell lines obtained from cervical biopsies (11 patients) and recurrent sites of disease (three patients) as well as eight established cell lines. Tumor cell lines were tested for sensitivity to Cetuximab-mediated complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in 51Cr release assays. Finally, Cetuximab-mediated inhibition of cell proliferation was also tested. RESULTS: Fourteen out of fourteen (100%) primary tumors and seven out of eight (87.5%) established cervical cancer cell lines expressed EGFR-1 by flow cytometry. Cell lines from recurrent/metastatic sites of disease expressed higher levels of EGFR-1 when compared to those obtained from primary sites (p>0.05). Minimal CDC was detected in the majority of cervical cancer cell lines exposed to complement+/-Cetuximab in the absence of peripheral blood lymphocytes (PBL). In contrast, cervical tumor cell lines were found highly sensitive to Cetuximab-mediated ADCC when challenged with PBL from either healthy donors or cervical cancer patients. Importantly, ADCC was further increased in the presence of complement. Finally, tumor proliferation was significantly inhibited by Cetuximab in all cervical tumors tested. CONCLUSIONS: EGFR-1 is highly expressed in primary and recurrent cervical tumors. Cetuximab might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic cervical cancer.

HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities.

OBJECTIVE: To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities. METHODS: Autologous monocyte-derived DC were pulsed with recombinant HPV16 E7 or HPV18 E7 oncoproteins and administered to 4 cervical cancer patients. Vaccinations were followed by subcutaneous administration twice daily of low doses of human recombinant interleukin-2 (1 x 10(6) IU/m2) from day 3 to day 7. Safety, toxicity, delayed type hypersensitivity reactions (DTH), clinical responses, and induction of serological and cellular immunity against HPV16/18 E7 were monitored. RESULTS: The vaccine was well-tolerated in all patients and no local or systemic side effects or toxicity were recorded. Three out of four patients were found to be significantly immunocompromised before starting the vaccination treatment, as assessed by DTH with a panel of recall antigens. Specific humoral and cellular CD4+ T cell responses to the E7 vaccine were detected in 2 patients, as detected by ELISA and by IFN-gamma ELISpot assays, respectively. Increased numbers of E7-specific IFN-gamma secreting CD8+ T cells were detected in all patients after vaccination. Swelling and induration (i.e., a positive DTH response) to the intradermal injection of HPV E7 oncoprotein and/or irradiated autologous tumor cells were detected in two patients after six vaccinations. No objective clinical responses were observed. However, both patients who developed a positive DTH to the vaccine experienced a slow tumor progression (i.e., 13 months survival) while DTH unresponsive patients died within 5 months from the beginning of therapy. CONCLUSIONS: Autologous DC pulsed with HPV16/18 E7 proteins can induce systemic B and T cell responses in patients unresponsive to standard treatment modalities. However, treatment-induced immunosuppression may impose severe limitations on the efficacy of active vaccination strategies in late stage cervical cancer patients. DC-based vaccination trials are warranted in immunocompetent cervical cancer patients with early stage disease and/or limited tumor burden, and at significant risk for tumor recurrence or disease progression.

Therapeutic vaccines for cervical cancer: dendritic cell-based immunotherapy.

Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical dysplasia and cervical cancer. Several lines of evidence suggest that cell-mediated immune responses are important in controlling both HPV infections and HPV-associated neoplasia. Since HPV E6 and E7 oncoproteins are expressed in these lesions and are necessary for the maintenance of the malignant phenotype, these proteins might be potential tumor-specific target antigens for immunotherapy of cervical cancer. The gold standard treatment for locally advanced cervical cancer is primary radiation therapy combined with chemotherapy. A potential drawback of this potentially curative treatment is a profound and long lasting negative effect on the immune system. Treatment-induced immunosuppression combined with tumor-induced subversion of the immune system may therefore impose severe limitations on the efficacy of conventional vaccination strategies in late stage cervical cancer patients. The recognition of dendritic cells (DC) as powerful antigen-presenting cells capable of inducing primary T cell responses in vitro and in vivo, has recently generated widespread interest in DC-based immunotherapy of several human malignancies. Here, we review various therapeutic HPV vaccines being developed and implemented in human clinical trials, with a particular emphasis on the use of autologous DC pulsed with full-length HPV 16 or 18 E7 oncoproteins as a novel strategy to induce HPV E7-specific and tumor-specific T cell responses in cervical cancer patients following conventional treatment.

Amplification of c-erbB2 oncogene: a major prognostic indicator in uterine serous papillary carcinoma.

BACKGROUND: Overexpression of the epidermal growth factor type II receptor HER-2/neu has been associated with resistance to chemotherapy and poor survival in several human tumors. In the current study, the authors have determined the frequency and clinical significance of HER-2/neu gene amplification in uterine serous papillary endometrial carcinoma (USPC), a highly aggressive variant of endometrial carcinoma. METHODS: Fluorescence in situ hybridization (FISH) assay was used to analyze gene amplification in paraffin blocks from 30 women harboring Stage IA-IV USPC treated at the University of Arkansas for Medical Sciences (Little Rock, AR) from 1997 to 2004. Chromosome 17 polysomy status by FISH was also assessed in all specimens. USPC patient survival in relation to HER-2/neu gene amplification was analyzed using Kaplan-Meier curves in conjunction with the log-rank test. RESULTS: Amplification of the HER-2/neu gene by FISH was observed in 14 of the 30 (47%) cases. Heterogeneity was noted in 4 of 14 cases in the amplification of the HER-2/neu gene within the same tumor samples with pockets of amplified tumor cells amidst nonamplified tumor cells. Patients with USPC harboring tumors with HER-2/neu gene amplification had a significantly shorter survival time from diagnosis to disease-related death when compared with FISH-negative patients (P = 0.0008). African-American (AA) patients were found to have a poorer prognosis compared with Caucasian (C) women (P = 0.01) and to harbor USPC with significantly higher levels of HER-2/neu gene amplification (P = 0.02). CONCLUSIONS: HER-2/neu gene amplification in USPC was found to be an important prognostic indicator for poor outcome that occurs more frequently in AA when compared with C patients. Determination of HER-2/neu gene amplification may guide clinical management of patients with USPC and may have important implications for the implementation of novel treatment strategies.