Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol

Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP– Renal Tumour Study Group (SIOP–RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. Methods and materials: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. Results: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1–151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. Conclusions: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP–RTSG 2016 UMBRELLA protocol

Negative Survival Impact of High Radiation Doses to Neural Stem Cells Niches in an IDH-Wild-Type Glioblastoma Population

Aims: Assess the impact of radiation doses to neural stem cell (NSC) niches in patients with IDH-wild-type glioblastoma.Materials and Methods: Fifty patients were included in the study. NSC niches [SubVentricular Zone (SVZ) and Sub Granular Zone (SGZ)] were contoured by fusing CT scans and pre-therapy MRI, Tumor location defined ipsilateral and contralateral SVZ and SGZ. Prognostic significance of clinical, biological and dosimetric parameters were examined. We generated a Recursive Partitioning Analysis (RPA) model with independent prognostic classes.Results: Median follow-up: 23.8 months. Event free and overall survival (OS): 10 and 19.1 months. Incomplete surgery, PTV (planning target volume), ipsilateral SVZ or NSC niche mean dose > 57.4 Gy, contralateral NSC niche mean dose > 35 Gy and bilateral NSC niche mean dose > 44 Gy were significantly correlated with reduced OS. Only EGFR amplification was an independent prognostic factor (p = 0.019) for OS. RPA generated independent risk groups: 1 (low risk): [ipsilateral NSC mean dose (INMD) < 58.01 Gy and methylated MGMT promoter], 2: (INMD < 58.01 Gy and unmethylated MGMT promoter and contralateral SVZ mean dose < 18.6 Gy; p = 0.43), 3: (INMD < 58.01 Gy and unmethylated MGMT promoter and contralateral SVZ mean dose > 18.6 Gy; p = 0.002) and 4: (very high risk) (INMD > 58.01 Gy; p < 0.001).Conclusion: High radiation doses to ipsilateral NSC and contralateral SVZ could have a negative impact on overall survival in IDH-wild-type glioblastoma population

A mechanistic model for prediction of metastatic relapse in early-stage breast cancer using routine clinical features

International audienceEstimation of the risk of metastatic relapse is a major challenge to decide treatment options for early-stage breast cancer patients. To date, metastasis free survival (MFS) analysis mainly relies on classical - agnostic - statistical models (e.g., Cox regression). Instead, we propose to derive mechanistic models to predict MFS.The data consisted of patients who did not receive adjuvant systemic therapy from two databases: one (data 1, N = 163) with routine clinical features and the PAI-1 and uPA biomarkers and two (data 2, N = 692) with 11 routine clinical features. The mathematical models are based on a partial differential equation describing a size-structured population of metastases. They predict MFS from the size of the tumor at diagnosis and two mathematical parameters, α and μ describing respectively the tumor growth speed and metastatic dissemination potential. Using mixed-effects modeling, the population distributions of α and μ were assumed to be lognormal and to depend on routine clinical variables, whereas the observation error was assumed lognormal on the time-to-relapse. Variable selection consisted first in a univariate Wald test for all covariates with effect either on α or μ. We then used a backward elimination procedure. Significance of the covariates in the final model was assessed by a multivariable Wald test. Concordance indexes (c-index) were computed to assess the predictive power in cross-validation procedures as well as test sets.The model was implemented as an R package using optimized C++ code for the mechanistic part and enabling parallelization, resulting in a 4-fold reduction of the computing compared to a former python implementation. Nevertheless, over 4 hours are still needed to run a 100 samples bootstrap on a distributed computing cluster. The model selection procedure on data 1 revealed an association of PAI1 and age with μ, and of Estrogen receptor level with alpha, consistent with the established biological link between PAI-1 and tumor invasiveness. The resulting model achieved good prediction performances with a c-index of 0.72 in 5 folds cross-validation. Using only routine clinical markers, the algorithm on data 2 selected a model with the grade and Progesterone Receptors in α, Ki67 and node status in μ. These were able to adequately describe the data on calibration plots but performed poorly in prediction with a cross validated c-index of 0.60.Mechanistic modeling was able to unravel the biological and predictive role of PAI-1 but showed limited predictive power when using only on routine clinical features

The outcomes of a second and third Gamma Knife radiosurgery for recurrent essential glossopharyngeal neuralgia.

Gamma Knife radiosurgery (GKR) is a minimally invasive surgical option for drug-resistant essential glossopharyngeal neuralgia (GPN). The authors reviewed pain outcomes and complications in GPN patients who underwent a second or a third GKR for recurrent or persistent pain. A retrospective review of all patients treated in a single center (Marseille, France) since 2004 was performed. Median prescribed dose was 85 Gy (range 70-90 Gy) at second GKR and 85 Gy at third GKR. Clinical outcome was evaluated using the Barrow Neurological Institute (BNI) scale. Six patients (4 males, 2 females) underwent second or third GKR. The median age was 70.2 years (range 64-83 years) at second GKR and 79.8 years at third GKR. No patient had any previous surgery but GKR. Five cases had a neurovascular conflict. Median follow-up period was 12 months (range 10-94 months) after second GKR and 16 months after third GKR. The median delay to initial pain freedom response was 30 days (range 3-120 days). One patient experienced pharyngeal hypoesthesia after second GKR. After a third GKR, up to 16 months, no side effects were encountered. At the last follow-up, 3 patients were BNI I, 2 were BNI IIIa, and one did not have any improvement. Second GKR resulted in pain reduction with low risk of additional morbidity. In patients unsuitable for microvascular decompression, GKR as a repeat or third treatment for intractable GPN is safe and effective. Third GKR was not associated with any side effects up to 16 months after the procedure

Mechanistic modeling of metastatic relapse in early breast cancer to investigate the biological impact of prognostic biomarkers

International audienceEstimating the risk of metastatic relapse is a major challenge to decide adjuvant treatment options in early-stage breast cancer (eBC). To date, distant metastasis-free survival (DMFS) analysis mainly relies on classical, agnostic, statistical models (e.g., Cox regression). Instead, we propose here to derive mechanistic models of DMFS

Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines.

International audienceAfter therapeutic hormone deprivation, prostate cancer (CaP) cells often develop androgen-independent growth through not-well-defined mechanisms. The presence of neuroendocrine (NE) cells is often greater in prostate carcinoma than in normal prostate, and the frequency of NE cells correlates with tumor malignancy, loss of androgen sensitivity, increase of autocrine-paracrine activity, and poor prognosis. In some CaPs, neuropeptides have been previously implicated as growth factors. Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. In the present work, we demonstrate that androgen-independent PC-3 and DU145 cell lines, derived from human CaP, express PAM in vitro and in xenografts implanted in athymic nude mice, indicating that they are able to produce alpha-amidated peptides. Contrarily, barely detectable levels of PAM were found in the androgen-sensitive LNCaP cell line. We also show that whereas PC-3 and DU145 cells produce and secrete adrenomedullin (AM), a multifunctional amidated peptide, no expression was found in LNCaP cells. We further demonstrate that AM acts as a growth factor for DU145 cells, which suggests the existence of an autocrine loop mechanism that could potentially drive neoplastic growth. PAM mRNA levels were found to be 3-fold higher in prostate adenocarcinomas compared with that of human benign prostate hyperplasia (BPH) as demonstrated by real-time quantitative reverse transcription-PCR. The analysis of AM message expression in BPH and CaP (Gleason's score, 6-9) shows a clear distinction between benign and CaP. The expression was detected only in adenocarcinomas tissues with a marked increase in samples with a high Gleason's score. Immunocytochemically, AM was localized in the carcinomatous epithelial compartment. NE phenotype, assessed after the immunocytochemical localization of neuron-specific enolase (NSE), was found in both the epithelial and the stromal compartments of cancers; in BPH, only some spare basal cells were NSE-labeled. Cancer progression could be accelerated by peptides secreted by a population of cells capable of inducing androgen-independent tumoral growth via autocrine-paracrine mechanisms

MODELING ANTICANCER RELATED LATE EFFECT ON NEUROCOGNITION (MARLEN STUDY)

International audienceLong-term survivors of pediatric medulloblastoma present significantimpairments in specific cognitive functions. Our major objective was to create retrospectively amathematical model evaluating the contribution of key clinical factors as hydrocephalus, age, and sex at diagnosis and cranial irradiation to impaired neurocognitive performances and their dynamic interactions

Coxiella burnetii Lipopolysaccharide: What Do We Know?

International audienceA small gram-negative bacterium, Coxiella burnetii (C. burnetii), is responsible for a zoonosis called Q fever. C. burnetii is an intracellular bacterium that can survive inside microbicidal cells like monocytes and macrophages by hijacking several functions of the immune system. Among several virulence factors, the lipopolysaccharide (LPS) of C. burnetii is one of the major factors involved in this immune hijacking because of its atypical composition and structure. Thus, the aim of this mini-review is to summarize the repressive effects of C. burnetii LPS on the antibacterial immunity of cells

Local Recurrence Risk Score to Predict Relapse after Stereotactic Body Radiation Therapy for Lung Tumors

International audienceBackground: After stereotactic body radiation therapy (SBRT) for lung tumors, follow-up CT scans remain a pitfall. The early detection of local relapse is essential to propose a new treatment. We aim to create a local recurrence predictive score using pre- and post-therapeutic imaging criteria and test it on a validation cohort.Methods: Between February 2011 and July 2016, lung tumors treated by SBRT with available pretreatment fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) and follow-up CT scans were retrospectively analyzed. The risk factors associated with relapse were identified by univariate logistic regression on a train cohort. The score was created using these factors, merging clinical and imaging criteria associated with local relapse, and then tested on an independent validation cohort. Overall and local relapse-free survival at 1 and 3 years were recorded.Results: Twenty-eight patients were included in the train cohort and ten in the derivation cohort (male 74%, median age 70 ± 12 years). Five variables significantly associated with local recurrence (female gender; sequential enlargement; craniocaudal growing; bulging margins; standardized uptake value (SUVmax > 5.5)) were combined to create the score on five points. With the threshold >2.5/5, the sensitivity and specificity of the score on the validation cohort were 100% and 88%, respectively. Overall survival and local relapse-free survival at 1 and 3 years were 89% and 42%, and 89% and 63%, respectively.Conclusion: The local recurrence risk score created has high sensitivity (100%) and specificity (88%), upon independent validation cohort, to detect local relapse. This score is easy to use in daily clinical practice