[Oncological results of active surveillance in prostate cancer: A retrospective multicentric cohort]. / Résultats oncologiques de la surveillance active dans le cancer de la prostate : série rétrospective multicentrique.

PURPOSE: To report oncological outcomes of patients with prostate cancer undergoing active surveillance according to SURACAP criteria. METHODS: This multicentric study included patients who were initially treated with active surveillance for localized prostate cancer according to the SURACAP criteria. The duration of active surveillance as well as the causes of discontinuing the protocol and the definitive pathological results of patients who further underwent radical prostatectomy were retrospectively evaluated. The predictors of discontinuing active surveillance were assessed using a univariable Cox Model. In addition, the predictive value of initial MRI was assessed for patients who performed such imagery. RESULTS: Between 2007 and 2013, 80 patients were included, with a median age of 64 years [47-74]. Median follow-up was 52.9 months [24-108]. At 5 years follow-up, 43.4% patients were still under surveillance. Among patients that underwent surgery, 17.8% had an extra-capsular extension. The risk of discontinuing was not significantly greater for patients with tumor size of 2 or 3mm versus 1mm (HR=0.9 [0.46-1.75], P=0.763), 2 positives cores versus 1 (HR=0.98 [0.48-2.02], P=0.967), T2a vs. T1c stage (HR=2.18 [0.77-6.18], P=0.133), increased PSA level (HR=1 [0.96-1.15], P=0.975) or the patient's age (HR=1 [0.93-1.16], P=0.966). Among the 50 patients who performed initial MRI, the results of such imagery was not significantly associated to the risk of discontinuing active surveillance MRI (HR=1.49 [0.63-3.52], P=0.36). CONCLUSION: Although this study reveals a high rate of release from active surveillance at 5 years, the rate of extra-capsular tumors reported in the group of patients that underwent surgery is among the lowest in literature. LEVEL OF EVIDENCE: 4.

Impact of the extent of extraprostatic extension defined by Epstein's method in patients with negative surgical margins and negative lymph node invasion.

BACKGROUND: To assess the impact of the degree of extraprostatic extension (EPE) on biochemical recurrence (BCR) and utility of the original Epstein's criteria to define EPE in a cohort of pT3aN0 without positive surgical margin (PSM). METHODS: A two-center retrospective analysis was performed on data from 490 pT3aN0 patients who underwent radical prostatectomy between 2000 and 2012. Patients with neoadjuvant and/or adjuvant therapy, detectable PSA and PSM were excluded. Our pathologists used Epstein's criteria to report the degree of EPE. When pathology reports did not reflect the terms 'focal' or 'established' (non-focal), slides were analyzed by a single genitourinary pathologist for final evaluation. The end point was defined by BCR. RESULTS: Selection criteria yielded 247 patients. Mean follow-up was 56.3±4.6 months; mean age at surgery was 62.5 years. Sixty-one (24.7%) patients experienced BCR during follow-up. Patients with focal extension had a 5-year recurrence-free survival of 89% versus 80% for those with non-focal extension (P=0.0018). In multivariate analysis, both pathologic Gleason score (hazard ratio 2.5; 95% confidence interval 1.4-4.5; P=0.002) and the extent of EPE (hazard ratio 1.8; 95% confidence interval 1.1-3.5; P=0.029) were significant predictors of BCR. CONCLUSIONS: The extent of EPE is an independent predictor of BCR in pT3aN0 prostate cancer without PSM. This study reinforces the utility of the subjective Epstein approach already adopted by most pathologists for quantification of the extent of EPE.

[Head to head comparison of two currently used nomograms predicting the risk of side specific extra capsular extension to indicate nerve sparing during radical prostatectomy for treatment of prostate cancer]. / Validation externe des nomogrammes de prédiction de l'extension extra-prostatique spécifiquement au côté pour des patients atteints de cancer de prostate traités par prostatectomie totale.

OBJECTIVE: To perform a head to head comparison of these two nomograms by an external validation combined with an identification of probability cut-offs when to indicate NS. METHODS: The full models of the nomograms of Ohori et al. and Steuber et al. were used to calculate the risk of ECE based on PSA and side specific information on clinical stage, biopsy Gleason score, % positive cores, and % cancer in cores. A dataset of 968 prostate half lobes was used retrospectively for analysis. All patients underwent laparoscopic robot-assisted or open radical prostatectomy for localized prostate cancer. RESULTS: The predictive accuracy of the Ohori nomogram was at 0.80 and for the Steuber Nomogram at 0.78 (comparison P > 0.05). In the calibration plot, the Ohori nomogram showed less departures from ideal predictions than the Steuber nomogram. The best probability cut-off to allow NS for the Ohori nomogram seemed to be ≤ 10%, permitting NS in 59.7% of all cases and being associated with a false negative rate of 10%. The best cut-off for the Steuber nomogram seemed to be ≤ 8%, permitting NS in 44% and associated with a false negative rate 12.5%. CONCLUSIONS: The Ohori et al. and the Steuber et al. nomograms allow highly accurate and comparable predictions of the risk of side specific ECE. LEVEL OF EVIDENCE: 4.

[The French mesothelioma network from 1998 to 2013]. / Mésothéliome: les dispositifs en place en France « le réseau mésothéliome ¼ 1998-2013.

Mesothelioma is a rare disease less than 0.3% of cancers in France, very aggressive and resistant to the majority of conventional therapies. Asbestos exposure is nearly the only recognized cause of mesothelioma in men observed in 80% of case. In 1990, the projections based on mortality predicted a raise of incidence in mesothelioma for the next three decades. Nowadays, the diagnosis of this cancer is based on pathology, but the histological presentation frequently heterogeneous, is responsible for numerous pitfalls and major problems of early detection toward effective therapy. Facing such a diagnostic, epidemiological and medico-legal context, a national and international multidisciplinary network has been progressively set up in order to answer to epidemiological survey, translational or academic research questions. Moreover, in response to the action of the French Cancer Program (action 23.1) a network of pathologists was organized for expert pathological second opinion using a standardized procedure of certification for mesothelioma diagnosis. We describe the network organization and show the results during this last 15years period of time from 1998-2013. These results show the major impact on patient's management, and confirm the interest of this second opinion to provide accuracy of epidemiological data, quality of medico-legal acknowledgement and accuracy of clinical diagnostic for the benefit of patients. We also show the impact of these collaborative efforts for creating a high quality clinicobiological, epidemiological and therapeutic data collection for improvement of the knowledge of this dramatic disease.

[Value of MRI in detection of extracapsular extension in prostate cancer: a prospective study comparing imaging and histology]. / Performances de l'IRM pour la détection de l'extension extracapsulaire dans le cancer de la prostate: étude prospective de confrontation radiopathologique.

OBJECTIVE: To establish MRI's performances for the detection of extracapsular progression of prostate carcinoma, in a single center, analyzing the correlation between MRI imaging and histological analysis of prostate specimen. METHODS: From February 2008 to June 2012, all the patients selected for prostatectomy had a pre-operative MRI. Diffusion, T2 and dynamic T1 with gadolinium injection sequences were realized on a 1.5T-MRI with external antenna. All imaging data was analyzed by a specialized radiologist. Prostate specimens were histologically analyzed throughout large blades for utmost topographic comparison. The histological TNM was compared to the MRI data. MRI's capacity in determining the existence and the size of extracapsular progression was studied. RESULTS: One hundred and fifty-eight patients (median age 62 years old, mean PSA 8.6 ng/mL) were included, among which 45% of d'Amico low risk and 55% of intermediate and high risk. Histological results were 63% of pT2 and 37% of pT3. MRI's sensibility and specificity for detecting extracapsular progression were 0.30 and 0.85 respectively (PPV 0.54; NPV 0.67), with a 65% accuracy. In the low risk group, sensibility equaled to 0.16. CONCLUSION: In our experience, MRI results were not reliable to influence the choice of treatment. It should be executed by expert radiologists, who are still very few.

[Pseudotumoral pulmonary AL amyloidosis]. / Amylose AL pulmonaire de forme pseudo-tumorale.

INTRODUCTION: Thoracic involvement in amyloidosis is rare. An isolated pseudotumor without extra-thoracic disease suggests a malignant process. We present the case of a patient with pseudonodular AL amyloidosis, confirmed by lobar lung resection. CASE REPORT: A 57-year-old woman, with a 25-pack-year smoking history, presented with a nodular opacity on chest x-ray. Physical examination was normal. Thoracic CT-scan revealed an isolated spiculated nodule in the right upper lobe. A whole body positron emission tomography (PET) scan revealed high FDG activity in this nodule, without evidence of metastatic disease. Bronchoscopy was negative. Lobectomy revealed lambda L-chain amyloidosis. Investigation for systemic extension was negative. Follow up has been unremarkable. CONCLUSION: A spiculated lung nodule on conventional imaging (radiography, scanner) is cancer until proven otherwise. The use of PET scan in this context is sensitive but not specific. Definitive diagnosis must be obtained by histological examination. Nodular lung amyloidosis must be included in the differential diagnosis of lung nodules and false-positive FDG PET.

Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction.

Epithelial-to-mesenchymal transition (EMT) is closely linked to conversion of early-stage tumours into invasive malignancies. Many signalling pathways are involved in EMT, but the key regulatory kinases in this important process have not been clearly identified. Protein kinase CK2 is a multi-subunit protein kinase, which, when overexpressed, has been linked to disease progression and poor prognosis in various cancers. Specifically, overexpression of CK2α in human breast cancers is correlated with metastatic risk. In this article, we show that an imbalance of CK2 subunits reflected by a decrease in the CK2ß regulatory subunit in a subset of breast tumour samples is correlated with induction of EMT-related markers. CK2ß-depleted epithelial cells displayed EMT-like morphological changes, enhanced migration, and anchorage-independent growth, all of which require Snail1 induction. In epithelial cells, Snail1 stability is negatively regulated by CK2 and GSK3ß through synergistic hierarchal phosphorylation. This process depends strongly on CK2ß, thus confirming that CK2 functions upstream of Snail1. In primary breast tumours, CK2ß underexpression also correlates strongly with expression of EMT markers, emphasizing the link between asymmetric expression of CK2 subunits and EMT in vivo. Our results therefore highlight the importance of CK2ß in controlling epithelial cell plasticity. They show that CK2 holoenzyme activity is essential to suppress EMT, and that it contributes to maintaining a normal epithelial morphology. This study also suggests that unbalanced expression of CK2 subunits may drive EMT, thereby contributing to tumour progression.

OGX-427 inhibits tumor progression and enhances gemcitabine chemotherapy in pancreatic cancer.

Despite many advances in oncology, almost all patients with pancreatic cancer (PC) die of the disease. Molecularly targeted agents are offering hope for their potential role in helping translate the improved activity of combination chemotherapy into improved survival. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes such as cancer. Further, Hsp27 expression becomes highly upregulated in cancer cells after chemotherapy. Recently, a modified antisense oligonucleotide that is complementary to Hsp27 (OGX-427) has been developed, which inhibits Hsp27 expression and enhances drug efficacy in cancer xenograft models. Phase II clinical trials using OGX-427 in different cancers like breast, ovarian, bladder, prostate and lung are in progress in the United States and Canada. In this study, we demonstrate using TMA of 181 patients that Hsp27 expression and phosphorylation levels increase in moderately differentiated tumors to become uniformly highly expressed in metastatic samples. Using MiaPaCa-2 cells grown both in vitro and xenografted in mice, we demonstrate that OGX-427 inhibits proliferation, induces apoptosis and also enhances gemcitabine chemosensitivity via a mechanism involving the eukaryotic translation initiation factor 4E. Collectively, these findings suggest that the combination of Hsp27 knockdown with OGX-427 and chemotherapeutic agents such as gemcitabine can be a novel strategy to inhibit the progression of pancreas cancer.

[Diffuse xanthogranulomatous pyelonephritis in infant]. / Pyélonéphrite xanthogranulomateuse diffuse du nourrisson.

We report a case of a renal mass in a 4-month boy, which occured during the assessment of a pelvi-calyceal dilatation diagnosed at 23 weeks of gestational age. There was no history of urinary infection, fever or weight loss. Physical examination revealed a mass of the left flank with significant flank tenderness. Laboratory test showed a biological inflammatory syndrome and urine culture was negative. Investigations including ultrasound and computed tomography scan were suggestive of diffuse xanthogranulomatous pyelonephritis with a non-functioning left kidney. Left total nephrectomy was performed through a lumbar incision with an extraperitoneal approach. The kidney was enlarged with a dilated pelvis containing pus upstream of a proximal ureteral atretic segment. Pathological examination of the kidney confirmed the diagnosis of diffuse xanthogranulomatous pyelonephritis. The boy remains well at 1 year follow-up. Xanthogranulomatous pyelonephritis is very rare in infants. It is an uncommon severe progressive renal infection resulting in destruction of renal parenchyma, histologically replaced by xanthomatous cells and granulomatous reaction. Pathogenesis of xanthogranulomatous pyelonephritis remains unclear. But it is well known that urinary tract obstruction and renal lithiasis are determining factors. It can occur in variant clinical forms but its symptoms remain non-specific. Curative treatment consists in nephrectomy and definitive diagnosis is made on histological examination of the kidney. This diagnosis should be discussed when a renal mass occurs in a context of malformative uropathy and xanthogranulomatous pyelonephritis have to be included in the differential diagnosis of renal mass in infants and children.

Tumor protein p53-induced nuclear protein (TP53INP1) expression in medullary thyroid carcinoma: a molecular guide to the optimal extent of surgery?

BACKGROUND: Medullary thyroid cancer (MTC) is characterized by early regional lymph node metastasis, the presence of which represents a critical obstacle to cure. At present no molecular markers have been successfully integrated into the clinical care of sporadic MTC. The present study was designed to evaluate TP53INP1 expression in MTC and to assess its ability to guide the surgeon to the optimal extent of surgery performed with curative intent. METHODS: Thirty-eight patients with sporadic MTC were evaluated. TP53INP1 immunoexpression was studied on embedded paraffin material and on cytological smears. RESULTS: TP53INP1 was expressed in normal C cells, in C-cell hyperplasia, and in 57.9% of MTC. It was possible to identify two groups of MTC according to the proportion of TP53INP1 expressing tumor cells: group 1 from 0% to <50% and group 2 from 50% to 100% of positive cells. Patients with a decreased expression of TP53INP1 (group 1) had a lower rate of nodal metastasis (18.8% versus 63.4% in group 2; P = 0.009), with only minimal lymph node involvement per N1 patient (2.7% of positive lymph nodes versus 22.9%; P < 0.001) and better outcomes (100% of biochemical cure versus 55.5%; P < 0.001). Patients with distant metastases were only observed in group 2. Cytological samples exhibit similar results to their embedded counterparts. CONCLUSIONS: TP53INP1 immunoexpression appears to be a clinical predictor of lymph node metastasis in MTC. The evaluation of TP53INP1 expression may guide the extent of lymph node dissection in the clinically node-negative neck. These findings require prospective validation.

Development of a biochip-based assay integrated in a global strategy for identification of fusion transcripts in acute myeloid leukemia: a work flow for acute myeloid leukemia diagnosis.

Three major types of rearrangements are involved in acute myeloid leukemias (AML): t(8;21)(q22;q22), inv(16)(p13q22), and 11q23/MLL abnormalities. Their precise identification becomes essential for diagnosis, prognosis, and therapeutic choices. Resulting fusion transcripts (FT) are also powerful markers for monitoring the efficacy of treatment, the minimal residual disease (MRD) and could become therapeutic targets. Today, the challenge is to propose an individual follow-up for each patient even for those with a rare fusion event. In this study, we propose a biochip-based assay integrated in a global strategy for identification of rare FT in AML, after fluorescence in situ hybridization detection, as described by the World Health Organization classification. Using cell lines, we developed and validated a biochip-based assay called the AMLFusionChip that identifies every FT of AML1-ETO, CBFbeta-MYH11 as well as MLL-AF9, MLL-ENL, MLL-AF6, and MLL-AF10. The original design of our AMLFusionChip.v01 enables the identification of these FT wherever the breakpoint on the partner gene may be. In case of biochip negative result, our 3'RACE amplification strategy enables to clone and then sequence the new translocation partner. This AMLFusionChip strategy fits into the concept of personalized medicine for the largest number of patients.

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome.

BACKGROUND: c Kit (CD117) expression in tissues has been reported as a relevant target for specific therapy in some human malignancies, but has been poorly documented in breast carcinomas. METHODS: The prognostic significance of c Kit in a series of 924 breast carcinomas (mean follow-up, 79 months) was investigated using standardised high-throughput quantitative densitometry of immunohistochemical precipitates in tissue microarrays. RESULTS: c Kit was expressed in 14.7% breast carcinomas (and in 42 out of 586 node-negative tumours). In univariate analysis, (log-rank test) the score of c Kit expression correlated with poor patient outcome P=0.02 and particularly in node-negative cases (P=0.002). In multivariate Cox analysis, c Kit was an indicator of metastasis independent of 25 other concomitantly evaluated markers of prognosis. Logistic regression showed that c Kit ranked 10 out of 25 (P=0.041), and was included in a 10-marker signature that allowed 79.2% of the patients to be correctly classified in the metastatic or metastasis-free categories independently of hormone receptors and HER-2 status. Interestingly, c Kit was also a significant predictor of metastasis in node-negative tumours (2 out of 25 ranking, P<0.0001) and included in a six-marker signature of prognosis, correctly classifying 88.6% of the patients (P<0.0001). CONCLUSION: We concluded that, as assessed by quantitative immunohistochemistry, c Kit is an independent prognostic indicator that could also potentially serve as a target for specific therapy in breast carcinomas.