Bevacizumab-Based Chemotherapy Triggers Immunological Effects in Responding Multi-Treated Recurrent Ovarian Cancer Patients by Favoring the Recruitment of Effector T Cell Subsets.

Increasing evidence strongly suggests that bevacizumab compound impacts the immunological signature of cancer patients and normalizes tumor vasculature. This study aims to investigate the correlation between the clinical response to bevacizumab-based chemotherapy and the improvement of immune fitness of multi-treated ovarian cancer patients. Peripheral blood mononuclear cells (PBMCs) of 20 consecutive recurrent ovarian cancer patients retrospectively selected to have received bevacizumab or non-bevacizumab-based chemotherapy (Bev group and Ctrl group, respectively) were analyzed. CD4, CD8, and regulatory T cell (Treg) subsets were monitored at the beginning (T0) and after three and six cycles of treatment, together with IL10 production. A lower activated and resting Treg subset was found in the Bev group compared with the Ctrl group until the third therapy cycle, suggesting a reduced immunosuppressive signature. Indeed, clinically responding patients in the Bev group showed a high percentage of non-suppressive Treg and a significant lower IL10 production compared with non-responding patients in the Bev group after three cycles. Furthermore, clinically responding patients showed a discrete population of effector T cell at T0 independent of the therapeutic regimen. This subset was maintained throughout the therapy in only the Bev group. This study evidences that bevacizumab could affect the clinical response of cancer patients, reducing the percentage of Treg and sustaining the circulation of the effector T cells. Results also provide a first rationale regarding the positive immunologic synergism of combining bevacizumab with immunotherapy in multi-treated ovarian cancer patients.

Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial.

Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homing of the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments.

Surgical treatment of an isolated omental cervical cancer recurrence: report of a case and review of the literature.

AIMS AND BACKGROUND: Recurrent cervical cancer has traditionally been associated with a dismal prognosis. Historically, patients who developed distant metastases from cervical cancer were not considered eligible for surgical resection; only palliative treatment options are available, generally consisting of chemo- and/or radiotherapy. Metastases usually appear in the liver, lung or lymph nodes. The abdominal cavity is a quite unusual site of recurrence and the disease usually has multiple foci. For this reason, peritoneal involvement by cervical cancer is considered a contraindication to local treatment. METHODS AND STUDY DESIGN: We report the first case of a 30-year-old woman with isolated intra-abdominal cervical cancer recurrence diagnosed with 18F-FDG PET/CT, successfully surgically treated. RESULTS: Histopathological analysis confirmed the tumor to be an omental relapse of squamous cervical cancer previously treated with anterior pelvic exenteration and platinum based chemotherapy. The patient underwent adjuvant treatment with 3 cycles of topotecan and has remained free of disease during the 4 years of follow-up. CONCLUSIONS: In selected cases with isolated recurrences, a surgical resection may provide a long term complete remission in recurrent cervical cancer patients.

Microvesicle cargo of tumor-associated MUC1 to dendritic cells allows cross-presentation and specific carbohydrate processing.

Tumor-associated glycoproteins are a group of antigens with high immunogenic interest: The glycoforms generated by the aberrant glycosylation are tumor-specific and the novel glycoepitopes exposed can be targets of tumor-specific immune responses. The MUC1 antigen is one of the most relevant tumor-associated glycoproteins. In cancer, MUC1 loses polarity and becomes overexpressed and hypoglycosylated. Changes in glycan moieties contribute to MUC1 immunogenicity and can modify the interactions of tumor cells with antigen-presenting cells such as dendritic cells that would affect the overall antitumor immune response. Here, we show that the form of the MUC1 antigen, i.e., soluble or as microvesicle cargo, influences MUC1 processing in dendritic cells. In fact, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment and is presented by dendritic cells to MUC1-specific CD8(+) T cells stimulating IFN-γ responses, whereas the soluble MUC1 is retained in the endolysosomal/HLA-II compartment independently by the glycan moieties and by the modality of internalization (receptor-mediated or non-receptor mediated). MUC1 translocation to the HLA-I compartment is accompanied by deglycosylation that generates novel MUC1 glycoepitopes. Microvesicle-mediated transfer of tumor-associated glycoproteins to dendritic cells may be a relevant biologic mechanism in vivo contributing to define the type of immunogenicity elicited. Furthermore, these results have important implications for the design of glycoprotein-based immunogens for cancer immunotherapy.

Effects of unilateral ovariectomy on female fertility outcome.

PURPOSE: To compare the fertility outcome among women subjected to unilateral ovariectomy and other abdominal or non-gynaecologic pelvic surgery. METHODS: In this retrospective cohort study, 113 fertile women, surgically treated between 1990 and 2001 at Sapienza University of Rome with unilateral ovariectomy (UO), appendectomy (AP) or cholecystectomy (CO) for benign disease, were analysed for fertility outcome. Patients with assessed pre-surgical fertility defects, previous abdominal or pelvic surgeries and post-surgical contraception were not included. RESULTS: Thirty-five women underwent UO, 39 were subjected to AP and 39 were treated with CO. After a minimum 10-year post-surgical interval, the overall number of successful pregnancies was 75. The rate of women who experienced at least one post-operative successful pregnancy was: 48.5 % in UO, 41 % in AP and 53.8 % in CO (UO vs. AP, P = 0.55; UO vs. CO, P = 0.99; AP vs. CO, P = 0.53). One patient (2.8 %) in UO, one patient (2.6 %) in AP and two patients (5.1 %) in CO underwent Assisted Reproductive Technology to become pregnant. The rate of women who reported at least one miscarriage was: 10/35 (28.5 %) in UO, 11/39 (28.2 %) in AP, 12/39 (30.8 %) in CO (UO vs. AP, P = 0.93; UO vs. CO, P = 0.89; AP vs. CO, P = 0.81). One ectopic pregnancy was reported in CO group and one stillbirth occurred in one AP patient. CONCLUSIONS: No statistical difference in terms of post-operative fertility outcome between patients subjected to UO, AP or CO was found, thus allowing to suppose that the removal of one ovary does not significantly worsen the female fertility outcome respect to other abdominal or pelvic procedures.

Discovery of chemotherapy-associated ovarian cancer antigens by interrogating memory T cells.

According to the immunogenic cell death hypothesis, clinical chemotherapy treatments may result in CD8(+) and CD4(+) T-cell responses against tumor cells. To discover chemotherapy-associated antigens (CAAs), T cells derived from ovarian cancer (OC) patients (who had been treated with appropriate chemotherapy protocols) were interrogated with proteins isolated from primary OC cells. We screened for immunogenicity using two-dimensional electrophoresis gel-eluted OC proteins. Only the selected immunogenic antigens were molecularly characterized by mass-spectrometry-based analysis. Memory T cells that recognized antigens associated with apoptotic (but not live) OC cells were correlated with prolonged survival in response to chemotherapy, supporting the model of chemotherapy-induced apoptosis as an adjuvant of anti-tumor immunity. The strength of both memory CD4(+) and CD8(+) T cells producing either IFN-γ or IL-17 in response to apoptotic OC antigens was also significantly greater in Responders to chemotherapy than in nonresponders. Immunogenicity of some of these antigens was confirmed using recombinant proteins in an independent set of patients. The T-cell interrogation system represents a strategy of reverse tumor immunology that proposes to identify CAAs, which may then be validated as possible prognostic tumor biomarkers or cancer vaccines.

Laparoscopically guided minilaparotomy: a minimally invasive approach for the treatment of gynaecologic diseases in morbidly obese patients.

OBJECTIVE: Obese patients are at greater risk of gynaecologic surgery. Laparotomy is generally performed, even though this approach is regarded as highly invasive, whereas laparoscopy, though minimally invasive, is relatively contraindicated because of the high conversion rates to laparotomy. In light of this, we propose laparoscopically guided transverse minilaparotomy (LGTM) as a minimally invasive alternative technique. The rationale of diagnostic laparoscopy is to evaluate the feasibility of a minimally invasive approach. We have evaluated the feasibility and compared the outcomes with a historical group treated with laparotomy (LPTM), in morbidly obese patients (MOP) subjected to gynaecologic surgery. STUDY DESIGN: From November 2004, MOPs with body mass index (BMI) ≥ 40 kg/m² and admitted for gynaecologic surgery (early stage endometrial cancer and benign disease) were enrolled in this observational study and submitted to LGTM. Patients with a uterine size greater than the umbilical transverse line and with indication for vaginal surgery were excluded operative data and outcome were prospectively recorded. RESULTS: LGTM was feasible in 34 cases (87%) out of 39. In two women, the procedure was aborted due to intraperitoneal and ovarian malignant disease spread diagnosed at laparoscopy. In three cases, conversion was necessary due to severe adhesions in one case; laparoscopically unrecognized disease spread in the parametria in the second, and in the remaining case a right common iliac vein injury during lymphadenectomy. When compared to LPTM, haemoglobin drop and postoperative stay were significantly reduced with LGTM. Complications were higher in the control group: due to a significantly higher incidence of wound dehiscence (OR 0.27, 95% CI 0.05-1.32, p<0.05). CONCLUSIONS: LGTM is feasible in the vast majority of MOPs and achieves significantly better results when compared to the standard approach.

HER2-based recombinant immunogen to target DCs through FcγRs for cancer immunotherapy.

Dendritic cell (DC)-based immunotherapy is an attractive approach to induce long lasting antitumor effector cells aiming to control cancer progression. DC targeting is a critical step in the design of DC vaccines in order to optimize delivery and processing of the antigen, and several receptors have been characterized for this purpose. In this study, we employed the FcγRs to target DCs both in vitro and in vivo. We designed a recombinant molecule (HER2-Fc) composed of the immunogenic sequence of the human tumor-associated antigen HER2 (aa 364-391) and the Fc domain of a human IgG(1). In a mouse model, HER2-Fc cDNA vaccination activated significant T cell-mediated immune responses towards HER2 peptide epitopes as detected by IFN-γ ELIspot and induced longer tumor latency as compared to Ctrl-Fc-vaccinated control mice. Human in vitro studies indicated that the recombinant HER2-Fc immunogen efficiently targeted human DCs through the FcγRs resulting in protein cross-processing and in the activation of autologous HER2-specific CD8(+) T cells from breast cancer patients.

Complete remission of ovarian cancer induced intractable malignant ascites with intraperitoneal bevacizumab. Immunological observations and a literature review.

Malignant ascites resistant to conventional drugs frequently affects ovarian cancer patients at the end of life. Here we report the case of a patient who benefited from complete resolution of ascites after low dose intraperitoneal administration of bevacizumab. Immunological analyses showed an initial increase in proportion and function of CD8(+) effector T cells and a reduction of circulating T(reg) cells. A review of the current literature regarding bevacizumab in ovarian cancer is reported. Bevacizumab has shown a high efficacy in the treatment of ovarian cancer. Intraperitoneal administration induces an immune activation and appears promising in the treatment of malignant ascites.

HPV induced triple neoplasms: a case report.

The incidence of multiple primary cancers has greatly increased in the last decade. We report the first case of a woman who suffered from 3 distinct HPV-induced neoplasms: cervical, vulvar, and head and neck carcinomas.

Neoadjuvant chemotherapy followed by radical surgery in patients affected by vaginal carcinoma.

BACKGROUND: Radiotherapy represents the standard treatment for patients affected by FIGO stage II vaginal cancer. Several authors have suggested that neoadjuvant chemotherapy followed by radical surgery might be a valid treatment option in patients affected by cervical cancer. The objective of this study was to analyse the feasibility and results obtained by neoadjuvant chemotherapy followed by surgery in patients affected by invasive vaginal cancer with paravaginal tissue involvement not reaching the pelvic side wall. METHODS: Eleven patients affected by FIGO stage II vaginal cancer were treated with paclitaxel 175 mg/m(2) and cisplatin 75 mg/m(2) every 21 days for three courses followed by radical surgery. RESULTS: All patients were subjected to the 3 planned chemotherapy courses. Three (27%) patients achieved a complete clinical response and seven (64 %) patients achieved a partial clinical response. All patients were subjected to radical hysterectomy and vaginectomy. At a median follow up of 75 months two (18%) patients suffered a disease recurrence and one of these died of disease. CONCLUSIONS: Neoadjuvant chemotherapy followed by radical surgery is a feasible therapeutic strategy with good short- and long-term results. In women affected by vaginal cancer, a larger series reporting the result of this therapeutic strategy or the results obtained by surgery alone will aid physicians to choose the best therapeutic strategy for each individual patient.