Patricia Pautier

Malignant effusions and immunogenic tumour-derived exosomes.

BACKGROUND Exosomes derived from tumours are small vesicles released in vitro by tumour cell lines in culture supernatants. To assess the role of these exosomes in vivo, we examined malignant effusions for their presence. We also investigated whether these exosomes could induce production of tumour-specific T cells when pulsed with dendritic cells. METHODS We isolated exosomes by ultracentrifugation on sucrose and D(2)O gradients of 11 malignant effusions. We characterised exosomes with Western blot analyses, immunoelectron microscopy, and in-vitro stimulations of autologous T lymphocytes. FINDINGS Malignant effusions accumulate high numbers of membrane vesicles that have a mean diameter of 80 nm (SD 30). These vesicles have antigen-presenting molecules (MHC class-I heat-shock proteins), tetraspanins (CD81), and tumour antigens (Her2/Neu, Mart1, TRP, gp100). These criteria, including their morphological characteristics, indicate the similarities between these vesicles and exosomes. Exosomes from patients with melanoma deliver Mart1 tumour antigens to dendritic cells derived from monocytes (MD-DCs) for cross presentation to clones of cytotoxic T lymphocytes specific to Mart1. In seven of nine patients with cancer, lymphocytes specific to the tumour could be efficiently expanded from peripheral blood cells by pulsing autologous MD-DCs with autologous ascitis exosomes. In one patient tested, we successfully expanded a restricted T-cell repertoire, which could not be recovered carcinomatosis nodules. INTERPRETATION Exosomes derived from tumours accumulate in ascites from patients with cancer. Ascitis exosomes are a natural and new source of tumour-rejection antigens, opening up new avenues for immunisation against cancers.

Cutaneous side-effects of kinase inhibitors and blocking antibodies.

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.

Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors

OBJECTIVE To assess clinical outcome and fertility in patients treated conservatively for a low malignant potential (LMP) ovarian tumor. DESIGN Retrospective study. SETTING Gynecologic oncology department of a cancer care center in France. PATIENT(S) Forty-four patients treated with conservative management for a stage I (n = 32) or stage II or III (n = 12) LMP tumor. INTERVENTION(S) Thirty-three patients had unilateral adnexectomy and 11 had cystectomy. Cystectomy was bilateral in 1 patient and was done in conjunction with contralateral adnexectomy in 5 patients. MAIN OUTCOME MEASURE(S) Tumor recurrence and pregnancy rates. RESULT(S) Tumor recurrence rates after radical surgery (hysterectomy with bilateral salpingo-oophorectomy), adnexectomy, and cystectomy were 5.7%, 15.1%, and 36.3%, respectively (P<.01). Among patients who initially received conservative treatment, tumors did not recur in the form of invasive carcinoma. Five patients who had recurrence underwent repeated conservative management; these patients are alive and free of disease. Seventeen pregnancies (of which 15 were spontaneous) occurred in 14 patients; 13 pregnancies occurred in patients with stage I disease and 4 occurred in patients with stage III disease. CONCLUSION(S) Conservative management of LMP tumor significantly increases the risk of recurrence but does not affect overall survival. Such management offers even patients with advanced disease the chance to have spontaneous pregnancy. Conservative management might be proposed in young patients who wish to preserve their fertility, but careful follow-up will be required to detect tumor recurrence.

Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients

Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4(+) T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients.

Fertility results after conservative treatment of advanced stage serous borderline tumour of the ovary

Objective To assess the fertility of patients treated conservatively for a Stage II or III borderline ovarian tumour.

Prospective Multicenter Study Evaluating the Survival of Patients With Locally Advanced Cervical Cancer Undergoing Laparoscopic Para-Aortic Lymphadenectomy Before Chemoradiotherapy in the Era of Positron Emission Tomography Imaging

PURPOSE The aim of this prospective study conducted in three French comprehensive cancer centers was to evaluate the therapeutic impact on survival of laparoscopic para-aortic (PA) staging surgery in locally advanced cervical cancer (LACC) before chemoradiotherapy. PATIENTS AND METHODS We conducted a prospective multicenter study of 237 patients treated from 2004 to 2011 for LACC with negative positron emission tomography (PET) imaging of the PA area and undergoing laparoscopic PA lymphadenectomy. Radiation fields were extended to the PA area when PA nodes were involved. Chemoradiotherapy modalities were homogeneous across institutions. Patients with a poor prognosis histologic subtype or peritoneal carcinosis were excluded. RESULTS Patients had clinical International Federation of Gynecology and Obstetrics stages IB2 (n = 79), IIA (n = 10), IIB (n = 121), III (n = 22), or IVA (n = 5). One hundred ninety-nine patients had squamous carcinoma, and 38 had adenocarcinoma/adenosquamous lesions. Twenty-nine patients (12%) had nodal involvement (false-negative PET-computed tomography [CT] results)-16 with a PA nodal metastasis measuring more than 5 mm and 13 with a nodal metastasis measuring ≤ 5 mm. Event-free survival rates at 3 years in patients without PA involvement or with PA metastasis measuring ≤ or more than 5 mm were 74% (SE, 4%), 69% (SE, 21%), and 17% (SE, 14%; P < .001). CONCLUSION To our knowledge, this is the largest series of patients reported undergoing such a strategy. We obtained the same survival rate for patients with PA nodal metastasis ≤ 5 mm and patients without PA lymph node involvement, suggesting that this strategy is highly efficient in such patients. Conversely, the survival of patients with PA nodal involvement greater than 5 mm remained poor, despite the absence of extrapelvic disease on PET-CT imaging in this subgroup.

Laparoscopic ovarian transposition for pelvic malignancies: indications and functional outcomes

OBJECTIVE To assess the indications and effectiveness of laparoscopic ovarian transposition before pelvic irradiation for a gynecologic cancer. DESIGN Prospective study. SETTING A gynecologic oncology department in a French anti-cancer center. PATIENT(S) Twenty-four patients treated for pelvic cancer. INTERVENTION(S) Laparoscopic ovarian transposition to paracolic gutters. Uterine conservation in 18 patients. MAIN OUTCOME MEASURE(S) Clinical and laboratory follow-up tests of ovarian function. RESULT(S) Bilateral laparoscopic ovarian transposition was achieved in 22 patients (94%). Twelve patients were treated for clear cell adenocarcinoma of the cervix and/or upper vagina, 6 patients for invasive squamous cervical carcinoma, 3 patients for pelvic sarcoma, 1 patient for recurrent cervical cancer to the upper vagina, 1 patient for ependymoma of the cauda equina, and 1 patient for ovarian dysgerminoma. Ovarian preservation was achieved in 79%. Three pregnancies were obtained. CONCLUSION(S) Laparoscopic ovarian transposition is a safe and effective procedure for preserving ovarian function. Bilateral ovarian transposition should be performed. The main indications for laparoscopic ovarian transposition are a patient with a small invasive cervical carcinoma (<2 cm) in a patient <40 years of age who is treated by initial laparoscopically assisted vaginal radical hysterectomy and a patient with a clear cell adenocarcinoma of the cervix and upper vagina.

Accuracy of Magnetic Resonance Imaging in Predicting Residual Disease in Patients Treated for Stage IB2/II Cervical Carcinoma With Chemoradiation Therapy Correlation of Radiologic Findings With Surgicopathologic Results

The evaluation of residual disease (RD) after chemoradiation therapy (CRT) in stage IB2/II cervical carcinoma conventionally is based on a clinical examination and magnetic resonance imaging (MRI) performed 3 to 8 weeks after the end of treatment. Very few studies have correlated MRI and histologic findings specifically in cervix cancer. This was the objective of the current study.

Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.

Value and cost evaluation of routine follow-up for patients with clinical stage I/II endometrial cancer

The aim of the study was to determine the value and the costs of routine follow-up for the detection of recurrences in patients treated for endometrial cancer. Between 1986 and 1995, 390 women with clinical stage I/II endometrial carcinoma were treated with combined surgery-radiation therapy. After treatment, follow-up was based on the clinical examination, a systematic Papanicolaou (Pap) smear and radiography (chest X-ray and abdomino-pelvic ultrasonography). 27 patients relapsed: 22 patients had symptoms and 5 were asymptomatic. None of the patients had recurrence detected on the routine Pap smear nor on the systematic chest X-ray. In conclusion, the follow-up of patients treated for endometrial cancer based on routine Pap smears and systematic radiography does not permit earlier detection of recurrences. Follow-up should simply include a clinical examination whose frequency should be based on prognostic factors. Approximately two-thirds of this cost was due to systematic examinations (Pap smears and radiography). Our results indicate that such expenditure could be avoided.