[show abstract][hide abstract] ABSTRACT: Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women, and there has been no substantial decrease in the death rates due to EOC in the last three decades. Thus, basic knowledge regarding ovarian tumor cell biology is urgently needed to allow the development of innovative treatments for EOC. Traditionally, EOC has not been considered an immunogenic tumor, but there is evidence of an immune response to EOC in patients. Clinical data demonstrate that an antitumor immune response and immune evasion mechanisms are correlated with a better and lower survival, respectively, providing evidence for the immunoediting hypothesis in EOC. This review focuses on the immune response and immune suppression in EOC. The immunological roles of chemotherapy and surgery in EOC are also described. Finally, we detail pilot data supporting the efficiency of immunotherapy in the treatment of EOC and the emerging concept that immunomodulation aimed at counteracting the immunosuppressive microenvironment must be associated with immunotherapy strategies.
Journal of Translational Medicine 06/2013; 11(1):147. · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vγ9Vδ2 cells are cytotoxic T cells that are able to recognize epithelial ovarian carcinoma (EOC) cells. Therefore, Vγ9Vδ2 cell-based adoptive transfer is an attractive therapy for EOC. However, the inefficient ex vivo expansion after specific stimulation of Vγ9Vδ2 cells from some patients and the relationships between Vγ9Vδ2 cells and clinical course of EOC are issues that remain to be clarified. Herein, peripheral blood mononuclear cells (PBMCs) from 60 EOC patients were stimulated with bromohydrin pyrophosphate (BrHPP) or zoledronate, which are specific agonists of Vγ9Vδ2 cells. The compounds differed in their efficacies to induce ex vivo Vγ9Vδ2 PBMC expansion, but 16/60 samples remained inefficiently expanded with both stimuli. Interestingly, the Vγ9Vδ2 cells in these low-responding PBMCs displayed before expansion (ex vivo PBMCs) an altered production of the pro-inflammatory cytokines IFN-γ and TNF-α, a decreased naive fraction and a reduced frequency. No evidence of an involvement of CD4(+)CD25(+)Foxp3(+) regulatory cells was observed. Importantly, our data also demonstrate that a Vγ9Vδ2 cell frequency of 0.35% or less in EOC PBMCs could be used to predict low responses to both BrHPP and zoledronate. Moreover, our data highlight that such a deficiency is not correlated with advanced EOC stages but is associated with more refractory states to platinum-based chemotherapy and is an independent predictor of shorter disease-free survival after treatment. These results are the first to suggest a potential contribution of Vγ9Vδ2 cells to the anti-tumor effects of chemotherapeutic agents and they strengthen interest in strategies that might increase Vγ9Vδ2 cells in cancer patients.
PLoS ONE 01/2013; 8(5):e63322. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ITI (inter-trypsine inhibitor) gene family includes five genes (ITIH1 to ITIH5) that encode proteins involved in the dynamics of the extracellular matrix (ECM). ITIH5 was found inactivated by partial deletion in a case of congenital uterovaginal aplasia, a human rare disease also called Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. The aim of the present study was to analyze the expression of ITIH5 in the uterus in adult life and during embryogenesis in order to establish the involvement of this gene in both normal and pathological conditions of uterus development. This was achieved in mice by reverse transcription-quantitative PCR, whole-mount hybridization, and Western blot analysis. Itih5 expression was much stronger in female genital tract primordia (Müllerian ducts) and derivatives than elsewhere in the body. This gene was strongly expressed during pregnancy and development of the female genital tract, indicating that the encoded protein probably had an important function in the uterus during these periods. Two different specific isoforms of the protein were detected in Müllerian derivatives during embryogenesis and in adults. Although ITIH genes are expected to be predominantly expressed in the liver, ITIH5 is mainly expressed in the uterus during development and adult life. This tends to indicate an additional and specific role of this gene in the female reproductive tract, and furthermore reinforces ITIH5 as a putative candidate gene for MRKH syndrome.
[show abstract][hide abstract] ABSTRACT: Epithelial ovarian cancer (EOC) usually spreads into the peritoneal cavity, thereby providing an opportunity for intraperitoneal adoptive immunotherapy with Vγ9Vδ2 T lymphocytes, a T cell subpopulation endowed with high lytic properties against tumor cells. However, previous studies have reported that Vγ9Vδ2 T cells fail to expand from peripheral blood mononuclear cells in one-third of patients with cancer. Here, from a cohort of 37 patients with EOC, a multiple correspondence analysis identified three populations, one of which was not suitable for Vγ9Vδ2 T-cell adoptive therapy. Interestingly, the ineligible patients were identified based on the frequency of Vγ9Vδ2 T cells in their peripheral blood and the patients' age. The average time to tumor recurrence was also found to be significantly different between the three populations, suggesting that the innate immune response is involved in EOC prognosis. A dramatic decrease in the lytic properties of Vγ9Vδ2 T cells occurred following incubation with ascitic supernatant and was found to be associated with reduced perforin/granzyme degranulation. Prostaglandin E2, but not IL-6, IL-10, VEGF or TGF-β, showed immunosuppressive effects in Vγ9Vδ2 T cells. Interestingly, our results emphasize that pretreating ovarian tumor cells with zoledronate partially reverses the immunosuppressive effects of ovarian cancer-associated ascites and restores a high level of lytic activity. These data sustain that optimal Vγ9Vδ2 T-cell adoptive immunotherapy previously requires counteracting the tumor immunosuppressive microenvironment. Altogether, our findings provide a rationale for clinically evaluating Vγ9Vδ2 T-cell adoptive immunotherapy with intraperitoneal carcinomatosis presensitization by zoledronate in patients with EOC.
International Journal of Cancer 11/2011; 131(4):E449-62. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: The authors analyzed the outcome of patients with Isolated Skin Recurrence After Salvage Mastectomy (ISRASM) performed after conservative treatment for breast carcinoma, taking into account initial tumor characteristics, intramammary recurrence (first recurrence) characteristics, local skin recurrence (second recurrence) characteristics, and the type of treatment at each stage of the breast cancer continuum.
Forty-two patients who had ISRASM between 1976 and 2007 were included in this retrospective study. Twenty-six factors were studied in univariate and multivariate analyses.
Mean Overall Survival (OS) was 70.3 (±4.1) months. The 5-year OS rate was 66.6%. 31% of patients did not present any recurrence, 52% had locoregional recurrence and 14% metastatic recurrence following ISRASM. Univariate analysis showed that 4 prognostic factors were significantly related to OS and/or Disease-Free Survival (DFS): (1) initial chemotherapy after primary breast cancer (P = 0.09 and 0.01 respectively), (2) presence of emboli at the site of intramammary recurrence (first recurrence) (P = 0.02 and 0.03), (3) interval between first and second surgery of less than 3 years (P = 0.09 and 0.0003), and (4) inflammatory skin involvement at ISRASM (P = 0.005 and 0.17). Multivariate analysis showed that presence of emboli at the site of intramammary recurrence was significantly related to OS and that an interval between first and second recurrence of less than 3 years was significantly related to DFS.
Our results show that ISRASM affects a group of breast cancer patients with predominantly local rather than metastatic disease. Prognostic factors depend on characteristics at initial breast cancer, first recurrence and second recurrence. Evidence-based guidelines are still required for ISRASM management.
Breast (Edinburgh, Scotland) 02/2011; 20(4):380-4. · 2.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is estimated that nearly 15% of breast cancers occur in women at the age where motherhood is possible, and only 7% of them will become pregnant. The ovarian toxicity of the chemotherapy is particularly evident after 40 years, and preserving fertility in patients undergoing treatment becomes a concern due to advances in therapeutic techniques: in vitro fertilization and embryo freezing are currently widely used. Pregnancy does not appear to affect the prognosis of breast cancer, with the reservations one may have regarding the medical literature, whatever the stage of disease, the number and outcome of pregnancy. Some questions exist about the delay recommended for this pregnancy: from to two years for consensual forms of good prognosis, up to five years in case of more pejorative prognosis. Pregnancy must be carefully monitored, as complications are more frequent, while breastfeeding is possible. Pregnancy is at a risk period for BRCA mutation carriers without it seeming to be a major risk factor (breastfeeding being possible). Hormonal contraceptives increase the risk of breast cancer especially in patients currently using them, with a promoter effect. The composition of pills (dosage, type of progestin) may affect the risk of breast cancer even if the available studies are biased (Levonorgestrel IUDs raise the same problems and cannot be indicated). The absence of scientific evidence against the potential risk of pregnancy and hormonal contraception should lead the practitioner to an attitude of listening and consulting on a case by case basis.
[show abstract][hide abstract] ABSTRACT: Flat epithelial atypia (FEA) is recognized as a precursor of breast cancer and its management (surgical excision or intensive follow-up) remains unclear after diagnosis on core needle biopsy (CNB). The aim of this study was to determine the underestimation rate of pure FEA on CNB and clinical, radiological, and pathological factors of underestimation. 4,062 CNBs from 5 breast cancer centers, performed over a 5-year period, were evaluated. A CNB diagnosis of pure FEA was made in 60 cases (1.5%) (the presence of atypical ductal hyperplasia, lobular neoplasia, radial scars, phyllodes tumor, papillary lesions, ductal carcinoma in situ or invasive carcinoma at CNB were exclusion criteria), and subsequent surgical excision was systematically performed. The histological diagnosis was retrospectively reviewed using standardized criteria and the precise terminology of the World Health Organization by two pathologist physicians. At surgical excision, 6 (10%) ductal carcinoma in situ and 2 (3%) invasive carcinoma were diagnosed. The total underestimation rate was 13%. FEA was associated with atypical ductal hyperplasia in 10 (17%) cases and with lobular neoplasia in 2 (3%) at final pathology. Residual FEA was found in 14 (23%) cases. No clinical, radiological or pathological factors were significantly associated with underestimation. Our data highlight the importance of recognizing and diagnosing FEA in core needle biopsies. Thus, the presence of FEA on CNB, even in isolation, warrants follow-up excision.
Breast Cancer Research and Treatment 10/2010; 125(1):121-6. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Three models have been developed to predict four or more involved axillary lymph nodes (ALNs) in patients with breast cancer with one to three involved sentinel lymph nodes (SLNs). Two scores were developed by Chagpar et al (Louisville scores excluding or including method of detection), and a nomogram was developed by Katz et al. The purpose of our investigation was to compare these models in a prospective, multicenter study.
Our study involved a cohort of 536 patients having one to three involved SLNs who underwent ALN dissection. We evaluated the area under the receiver operating characteristic curve (AUC), calibration (for the Katz nomogram only), false-negative (FN) rate, and clinical utility of the three models. Results were compared with the optimal logistic regression (OLR) model that was developed from the validation cohort.
Among the 536 patients, 57 patients (10.6%) had > or = four involved ALNs. The AUC for the Katz nomogram was 0.84 (95% CI, 0.81 to 0.86). The Louisville score excluding method of detection was 0.75 (95% CI, 0.72 to 0.78). The Louisville score including method of detection was 0.77 (95% CI, 0.74 to 0.79). The FN rates were 2.5% (eight of 321 patients), 1.8% (two of 109 patients), and 0% (zero of 27 patients) for the Katz nomogram and the Louisville scores excluding and including method of detection, respectively. The Katz nomogram was well calibrated. Optimism-corrected bootstrap estimate AUC of the OLR model was 0.86. Using this result as a reasonable target for an external model, the performance of the Katz nomogram was remarkable.
We validated the three models for their use in clinical practice. The Katz nomogram outperformed the two other models.
Journal of Clinical Oncology 10/2009; 27(34):5707-12. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several lines of chemotherapy can be proposed for patients with metastatic breast cancer, but beyond the second line, agreement is lacking concerning the most appropriate therapeutic strategy.
We conducted a retrospective analysis of the files of 162 patients, who had received at least 3 lines of chemotherapy (CT3) for metastatic breast cancer during a 5-year period (2000-2004), in order to analyze management practices and search for factors affecting survival from CT3 and predictive factors of non-progressive disease (NPD) after CT3.
Multivariate analysis identified seven factors which had a positive influence on survival from CT3 (SBR grade I, absence of adjuvant hormone therapy, free interval >or=2 years, absence of cerebromeningeal metastasis before CT, unique focus at initiation of CT3, use of polychemotherapy for CT2, and complete response to CT1 or CT2) and two predictive factors of NPD (histology and drug group used for CT3).
These factors should help determine the appropriate strategy for proposing a third line of chemotherapy.
Cancer Chemotherapy and Pharmacology 09/2009; 66(1):113-20. · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine factors predictive of the presence of residual tumor on the specimen from mastectomy performed after conservative treatment for breast cancer in order to limit potentially unnecessary mastectomies (free of residual lesions).
294 patients treated in 2 expert centers for breast cancer with breast-conserving therapy (BCT) followed by mastectomy, according to French recommendations, were investigated between January 1, 1998 and January 1, 2005. Patients with residual tumor on the mastectomy specimen were compared with patients whose mastectomy specimens did not reveal any residual tumor. All the clinical risk factors (age, previous history of breast cancer, tumor focality) and histological risk factors (tumor size, histological type, positive margins, estrogen and progesterone receptor expression, histological grade) for residual tumor after BCT were compared between the 2 patient groups.
Of the 294 patients studied, 202 (68.71%) mastectomies had residual tumor and 92 (31.29%) were tumor-free. Four predictive factors for residual tumor were found in the univariate analysis: age under 45 years (p=0.01), absence of estrogen receptor expression (p=0.05), positive margins (p=0.01), and presence of lymph node metastases (p=0.05). The multivariate analysis revealed only 2 independent risk factors that were significantly associated with increased risk of residual tumor on the mastectomy specimen: age under 45 years (p=0.05) and presence of positive margins on the lumpectomy specimen (p=0.05).
Young age of patients (under 45-years-old) and presence of positive margins on the operative specimen are independent risk factors of residual tumor after conservative treatment of breast cancer.
Breast (Edinburgh, Scotland) 08/2009; 18(4):233-7. · 2.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Achieving negative margins is essential in conservative treatment for breast cancer. The conventional method for intra-operative assessment of resection margins is gross or histological examination of frozen sections. We describe and evaluate the contribution of an original intra-operative touch preparation cytology (IOTPC) technique (400 procedures) performed on 396 patients.
IOTPC consists of touching glass slides to the surfaces of interest after gently pressing the spatially localized specimen taken according to predetermined conditions. The result is conveyed to the surgeon immediately and compared with the conventional histological findings after embedding in paraffin.
The average response time is 10min, which renders the technique compatible with standard operating room procedures and its cost is reasonable. The method has a sensitivity of 88.6%, specificity of 92.2%, positive predictive value of 73.6%, negative predictive value of 97%, and correlation with paraffin section histology of 91.5%. Only 5 true false negatives were found in this series and the technique prevented 11.75% of secondary re-excision procedures for positive margins.
IOTPC is a reliable extemporaneous method for assessing surgical margins in conservative treatment for breast cancer and a useful tool for surgeons.
Breast (Edinburgh, Scotland) 07/2009; 18(4):248-53. · 2.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several models have been developed to predict nonsentinel lymph node (non-SN) status in patients with breast cancer with sentinel lymph node (SN) metastasis. The purpose of our investigation was to compare available models in a prospective, multicenter study.
In a cohort of 561 positive-SN patients who underwent axillary lymph node dissection, we evaluated the areas under the receiver operating characteristic curves (AUCs), calibration, rates of false negatives (FN), and number of patients in the group at low risk for non-SN calculated from nine models. We also evaluated these parameters in the subgroup of patients with micrometastasis or isolated tumor cells (ITC) in the SN.
At least one non-SN was metastatic in 147 patients (26.2%). Only two of nine models had an AUC greater than 0.75. Three models were well calibrated. Two models yielded an FN rate less than 5%. Three models were able to assign more than a third of patients in the low-risk group. Overall, the Memorial Sloan-Kettering Cancer Center nomogram and Tenon score outperform other methods for all patients, including the subgroup of patients with only SN micrometastases or ITC.
Our study suggests that all models do not perform equally, especially for the subgroup of patients with only micrometastasis or ITC in the SN. We point out available evaluation methods to assess their performance and provide guidance for clinical practice.
Journal of Clinical Oncology 05/2009; 27(17):2800-8. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: A 66-year-old woman was diagnosed with vaginal melanoma. Sentinel node mapping was performed using Tc sulfur colloid. Planar scintigraphic acquisitions detected 2 sentinel nodes in the right external iliac region, which were laparoscopically removed with an anterior vaginectomy. Sentinel node mapping is feasible in cases of vaginal melanoma.
[show abstract][hide abstract] ABSTRACT: Lobular neoplasia (LN) is a risk factor for bilateral breast cancer without consensus as to its appropriate management. The authors report on a retrospective multi-institutional study concerning 52 patients in whom a diagnosis of LN was made after core needle biopsy (CNB) and who subsequently underwent surgical excision. The excision specimens revealed seven cases of invasive carcinoma and three cases of ductal carcinoma in situ, indicating an underestimation of lesions at CNB in 19% of cases, and in particular in those patients with pleomorphic LN, and when clinical, radiological masses were detected. This lesion is increasingly being diagnosed by CNB due to widespread screening. Follow-up surgical excision should be performed in order to examine the whole lesion in the case of masses or when the histologic specimen reveals a pleomorphic subtype. In other cases, annual mammographic surveillance should be undertaken due to the persistent long-term risk of developing bilateral breast cancer.
The Breast 11/2007; 16(5):533-9. · 2.49 Impact Factor
[show abstract][hide abstract] ABSTRACT: Terminal deletions of the long arm of chromosome 4 are associated with a recognizable phenotype consisting of dysmorphic facial features, cleft palate, upper and lower limb malformations, cardiac defects and growth and mental retardation. Here we report on two female patients, a mother and her daughter, carrying the same 4q34-->qter deletion but presenting with a different phenotype. The mother's presentation is consistent with previous findings in patients with terminal deletions of the long arm of chromosome 4. However, she presented at the age of 54years with bilateral serous carcinoma of the Fallopian tubes, a rare gynaecologic cancer that might be attributed to the haploinsufficiency of the tumor suppressor gene FAT. The daughter presented isolated congenital aplasia of the uterus and vagina, the prime feature of the MRKH syndrome. This has not been described before in association with a 46,XX,del(4)(q34qter).
European Journal of Medical Genetics 01/2007; 50(1):66-72. · 1.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective
To report a case of rupture of the uterine broad ligaments occurring during the third trimester of pregnancy.
The patient was admitted for a painful pelvic syndrome at the end of the pregnancy initially treated as a premature birth. The appearance of a hemoperitoneum led to a laparotomy with caesarean section allowing the diagnosis and the treatment of a bilateral rupture of the broad ligaments.
Tears of the uterine broad ligaments is responsible for an acute surgical abdomen with hemoperitoneum in the pregnant woman without fetal suffering nor maternal genital hemorrhage warranting exploratory laparotomy.
The diagnosis of this affection is a difficult task in particular in the absence of previous notion of trauma generally evocated a posteriori during surgical exploration.
[show abstract][hide abstract] ABSTRACT: Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs.
The IL-4/GM-CSF (granulocyte-macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells.
Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR-Lin- cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-gamma production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR-Lin- cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid.
These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest.
Breast cancer research: BCR 02/2005; 7(3):R326-35. · 5.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Retrospective study of 8 medical files of nodular PASH removed with histological and radiological assessment.
Patients were 39 years old. The mean size of the tumors was 4 cm and the clinical and mammographic pattern was typical of a benign palpable lesion; ultrasound showed a hypoechoic well cicumscribed mass sometimes with anechoic areas. Histologically, the tumor was uncapped, fibrous, containing a false network of vascular slits; immunohistochemical ruled out the diagnosis of angiosarcoma.
PASH is a benign mesenchymal tumor of the breast observed in premenopausal women. A complete surgical tumorectomy is needed with medical follow up in relation to the risk of recurrence in 20% of cases.
[show abstract][hide abstract] ABSTRACT: Low-grade endometrial sarcoma is a rare gynecological tumor (0.2% of female genital tract tumors) mainly observed in women before their 50's.
The authors present a series of 10 patients followed in two institutions and describe the treatment administered (cytoreductive surgery, i.e. bilateral annexectomy and total hysterectomy, and medical treatments) and the follow-up.
Local recurrence occurred in 70% of cases, whereas metastasis was rare even after suboptimal surgical removal of the tumor. Adjuvant progestin therapy is currently the most effective treatment for curing and preventing local recurrence. The use of aromatase inhibitors is a promising research approach.
Anticancer research 28(5B):2869-74. · 1.71 Impact Factor