Morena Antonilli

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

SummaryMalignant 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 Treg 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.

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.

Past, Present and Future Strategies of Immunotherapy in Gynecological Malignancies

Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more effective treatments has prompted researchers to investigate and propose new therapeutic strategies. One of the most interesting approaches that are being explored is constituted by immunotherapy. Currently, immunotherapeutic strategies include vaccination with peptide, viral vectors, carbohydrates and antiidiotypic antibodies. In addition, cell based immunotherapy has been adopted in vitro activated lymphocytes and dendritic cells. Most experience has been acquired in ovarian cancer and cervical cancer. Little has been investigated in endometrial and rare gynecologic neoplasms.The clinical experiences and results achieved with immunotherapy in this setting of patients have been reviewed and the future avenues that are currently being explored have also been discussed.

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.

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 IgG1. 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.

Endometrioma-associated infertility: is surgery still the best way to go?

Purpose Endometriomas are frequently associated with female infertility. In these cases, management options include surgery and IVF. The purpose of the present review is to evaluate current literature on the treatment of endometrioma-associated infertility and to compare the pros and cons of the different therapeutic approaches. Methods Literature search of published studies on the treatment of ovarian endometriomas in infertile patients. Studies were evaluated both on the efficacy of the surgical treatment on postoperative reproductive outcome and on the effect of surgery on the ovarian reserve. Results Pregnancy rates around 50% have been consistently reported after surgery, which compare favorably with those obtained with IVF. Surgery is effective also on associated pain, and the histological evaluation of the excised specimen rules out a possible unexpected ovarian malignancy. Thorough histological analysis of the excised specimen permits the evaluation of the appropriateness of surgery. Conclusions Laparoscopic excision of the ovarian endometrioma in infertile patients should still be considered the treatment of choice, particularly in case of associated pain. Surgery should be performed following appropriate techniques, and by dedicated surgeons, in order to decrease the possible damage to the ovarian reserve that has been recently reported postoperatively.

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.

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.

Let's think twice before abandoning fibrillar oxidized regenerated cellulose.

We read with great interest the manuscript by Fagotti et al., in which the authors have reported the incidence of pelvic abscess after major gynecologic oncology surgery and have examined their series for possible risk factors. In multivariate analysis two risk factors have emerged: pelvic exenteration and the use of fibrillar oxidized regenerated cellulose. The authors hypothesized that blood, necrotic debris, fluids, and fibrillar hemostats collect in the lower abdomen and produce a simple fluid collection, which might become successively infected, turning into an abscess. Therefore, they have recommended caution in using this type of hemostat. In our opinion, it is important to note that the indication for the use of fibrillar cellulose was capillary bleeding in the pelvic region and in difficult-to-reach sites. Hemostasis is achieved by blood clotting in contact with cellulose textile. It is obvious that patients suffering from minor uncontrolled bleeding are at higher risk of developing a postoperative hematoma and consequently infection. In the presented series, the quantity and duration of the capillary bleeding have probably been reduced by the sealing agent. Hence, this natural inherited evaluation bias and the retrospective study design are enough to make a statement against fibrillar oxidized regenerated cellulose. Several unconsidered risk factors could play a major role in the genesis of abscess, such as the use and permanence of retro/intraperitoneal drainage (more or less 6 days), lymph nodal status, number of positive nodes removed with consequently lymphorrhea, and number of fibrillar oxidized regenerated cellulose patch adopted. It should be noted that the pathophysiological cascade for abscess generation described by the authors remains unchanged when the sealing agent is removed from the plot. The aphorism of the KISS principle seems particularly adequate in this peculiar case. Several other sealing agents have been introduced in general surgery and have being applied to gynecology. All of them present advantages and disadvantages (Table 1). Fibrillar oxidized regenerated cellulose has been used in surgery for several decades and it has been shown to be