Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies.

BACKGROUND: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer. METHODS: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case-control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies. RESULTS: The OR/mGy was 1.02 (95% confidence interval, 1.00-1.03). We found significant associations between DTC and rs7164173 in CHD2 (P = 5.79 × 10-5), rs6067822 in NFATc2 (P = 9.26 × 10-5), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses (P = 3.40 × 10-4). CONCLUSIONS: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk. IMPACT: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.

Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma.

BACKGROUND: New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. METHODS: This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). RESULTS: Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67). CONCLUSIONS: Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

The challenge of rapid diagnosis in oncology: Diagnostic accuracy and cost analysis of a large-scale one-stop breast clinic.

PURPOSE: Rapid diagnosis is a key issue in modern oncology, for which one-stop breast clinics are a model. We aimed to assess the diagnosis accuracy and procedure costs of a large-scale one-stop breast clinic. PATIENTS AND METHODS: A total of 10,602 individuals with suspect breast lesions attended the Gustave Roussy's regional one-stop breast clinic between 2004 and 2012. The multidisciplinary clinic uses multimodal imaging together with ultrasonography-guided fine needle aspiration for masses and ultrasonography-guided and stereotactic biopsies as needed. Diagnostic accuracy was assessed by comparing one-stop diagnosis to the consolidated diagnosis obtained after surgery or biopsy or long-term monitoring. The medical cost per patient of the care pathway was assessed from patient-level data collected prospectively. RESULTS: Sixty-nine percent of the patients had masses, while 31% had micro-calcifications or other non-mass lesions. In 75% of the cases (87% of masses), an exact diagnosis could be given on the same day. In the base-case analysis (i.e. considering only benign and malignant lesions at one-stop and at consolidated diagnoses), the sensitivity of the one-stop clinic was 98.4%, specificity 99.8%, positive and negative predictive values 99.7% and 99.0%. In the sensitivity analysis (reclassification of suspect, atypical and undetermined lesions), diagnostic sensitivity varied from 90.3% to 98.5% and specificity varied from 94.3% to 99.8%. The mean medical cost per patient of one-stop diagnostic procedure was €420. CONCLUSIONS: One-stop breast clinic can provide timely and cost-efficient delivery of highly accurate diagnoses and serve as models of care for multiple settings, including rapid screening-linked diagnosis.

Re-irradiation of recurrent pediatric ependymoma: modalities and outcomes: a twenty-year survey.

BACKGROUND: Standard treatment for recurrent ependymomas is not defined. Re- irradiation has been proposed but its modalities and results are still to be explored. PATIENTS AND METHODS: From June 1994 to December 2013, 32 pediatric patients with ependymoma were re-irradiated for local (n = 15) or metastatic (n = 17) relapses. Files were reviewed retrospectively. RESULTS: Local relapses were treated with hypofractionated focal radiotherapy (hypoFFRT) (n = 8) or focal fractionated radiotherapy (FFRT) (n = 7). Metastatic relapses were treated with hypoFFRT (n = 3), FFRT (n = 3), spinal radiotherapy (n = 4) and craniospinal irradiation (CSI) (n = 7). Median PFS and OS after re-irradiation were 1.2 and 3.5 years respectively with a median follow-up of 2.1 years (0.2-11.4). For local relapses, median PFS was 2.5 years for patients treated with hypoFFRT versus 1.2 years for patients treated with FFRT (p = 0.2). For metastatic relapses, median PFS was 0.7 years for patients treated with focal radiotherapy (hypoFFRT, FFRT, spinal radiotherapy) versus 6.8 years for patients treated with CSI (p = 0.073). 15 patients achieved greater PFS after second radiotherapy (RT2) than after first radiotherapy (RT1). 27 patients (84 %) had surgery before re-irradiation. PFS was better for patients with GTR before RT2 (14.7 vs 6.7 months) (p = 0.05). 5 patients developed radionecrosis; only one required corticosteroids. CONCLUSION: Re-irradiation at relapse is a safe, feasible and potentially curative treatment. Metastatic relapse may require CSI even when isolated and re-operated. For local relapses, considering conflicting results in the literature, a randomized trial is warranted to explore fractionated focal radiotherapy versus hypofractionated focal irradiation.

Percutaneous Computed Tomography-Guided Thermal Ablation of Pulmonary Osteosarcoma Metastases in Children.

INTRODUCTION: The role of percutaneous thermal ablation as a minimally-invasive treatment has not been evaluated in children under 18 years of age with pulmonary osteosarcoma metastases. METHODS: This was a retrospective review of children treated with percutaneous thermal ablation for pulmonary osteosarcoma metastasis after prior surgical metastasectomy and chemotherapy. Selection criteria included number of pulmonary nodules <5 and nodule size smaller than 2 cm. Indications were discussed at multidisciplinary meetings. The goal was to achieve complete remission using percutaneous thermal ablation, thereby avoiding additional thoracotomies. RESULTS: A total of 26 pulmonary nodules (mean size 6.7 mm, range 2-16 mm) were successfully treated by percutaneous computed tomography (CT)-guided thermal ablation in 11 children with osteosarcoma between the ages of 7 and 17 years (median 12.5). Patients denied post-procedure pain. Complications were limited to three pneumothoraxes (two minor, one major), and median hospitalization duration was 2.0 days. One patient died of rapidly progressive lumbar metastasis discovered 20 days post-ablation. Of the remaining 10 patients, local control at the ablation site was achieved, with median follow up of 16.7 months (range 4.1-41.8). Five patients remained in complete remission after median follow-up of 37.5 months, and five patients developed new metastases (one osseous, four pulmonary), of which two are in remission after subsequent treatment. CONCLUSION: Percutaneous thermal ablation is a safe and effective minimally-invasive curative local treatment alternative for children with oligometastatic pulmonary osteosarcoma in whom surgical intervention is clinically contraindicated or unappealing.

Diagnostic Performance of MR-guided Vacuum-Assisted Breast Biopsy: 8 Years of Experience.

Breast magnetic resonance imaging (MRI) has demonstrated increased sensitivity over conventional imaging in identifying and characterizing in situ and invasive, multifocal, and multicentric disease. A histologic diagnosis is required for any enhancing lesion displaying suspicious features, especially in the presence of lower and often variable reported specificity values. Breast MRI findings occult on mammography and ultrasound should undergo an MR-guided biopsy. We retrospectively evaluate our 8 years' experience with this procedure. Our study included 259 lesions in 255 consecutive patients referred for MR-guided breast biopsy. MRI screening of women at a high risk for developing breast cancer accounted for 84 lesions, 54 lesions were detected on MRI staging for multifocal and multicentric disease, and 115 were incidental findings or lesions that presented diagnosis related issues on conventional imaging. Six procedures were cancelled due to lack of visualization. MR-guided breast biopsy was performed for 100 mass and 153 nonmass enhancements. Pathology results were classified into benign (113 lesions), high risk (47 lesions), and malignant (40 ductal carcinoma in situ, 38 invasive ductal carcinoma, 15 invasive lobular carcinoma). Subsequent surgery for high risk and malignant findings revealed an underestimation rate of 34% (16/47) for high risk lesions and of 7.5% for ductal carcinoma in situ (3/40). The overall positive predictive value (PPV) was calculated at 43.1% (33.3% for high-risk women, 70.3% for cancer staging, and 37.4% for incidental/undetermined lesions). The PPV was higher for mass (57%) versus nonmass enhancements (34%). MR-guided breast biopsy proved to be a reliable procedure for the diagnosis and management of occult breast MRI findings, or lesions that preclude biopsy under conventional guidance. The PPV displayed significant variation between patient subgroups, correlating higher values with a higher associated breast cancer prevalence.

Image-defined risk factor assessment of neurogenic tumors after neoadjuvant chemotherapy is useful for predicting intra-operative risk factors and the completeness of resection.

BACKGROUND: Patients with neuroblastoma are now stratified at diagnosis according to the presence and number of image-defined risk factors (IDRFs). We examined the added value of IDRF assessment after neoadjuvant chemotherapy for predicting surgical resection. MATERIAL AND METHODS: From 2009-2012, 39 out of 91 patients operated on in our institution for neuroblastic tumors received neoadjuvant chemotherapy based on ongoing SIOPEN protocols or treatment guidelines. IDRFs were assessed both at diagnosis and preoperatively on CT and/or MRI. RESULTS: Median age at diagnosis was 30 months [range 2-191]. The tumor locations were adrenal (n = 20), paravertebral (n = 13) and perivascular (n = 6). INRGSS stages were L2 (n = 13), M (n = 25) and Ms (n = 1). Eleven tumors (28%) were MYCN-amplified. Chemotherapy reduced the number of IDRFs in 54% of patients overall (21/39): 61.5% (16/26) of M and Ms patients, and 38.5% (5/13) of non metastatic patients (P < 0.001). The number of IDRFs lost after chemotherapy was proportional to the degree of tumor shrinkage (P = 0.002), independent of the primary tumor location (P = 0.73), although the number was higher in patients with left versus right adrenal locations (P = 0.004). Patients with neuroblastoma on post-surgical histology lost more IDRFs (median: 1[0-9]) than patients with ganglioneuroblastoma (median: 0[0-4]) (P < 0.001). The completeness of resection was related only to the number of preoperative IDRFs (P = 0.028). CONCLUSION: IDRF assessment after neoadjuvant chemotherapy is useful for predicting completeness of resection of neurogenic tumors. A larger international study is needed to confirm these results and to explore a possible correlation between preoperative IDRF status and survival.

Minimally invasive surgery of neuroblastic tumors in children: Indications depend on anatomical location and image-defined risk factors.

BACKGROUND: Minimally invasive surgery (MIS) is still not a well-accepted surgical approach to remove neuroblastic tumors. We aimed to assess the indications and limits of MIS in this childhood tumor according to tumor location and image-defined risk factors (IDRFs). PROCEDURE: Between 2006 and 2012, 39 patients underwent MIS for neuroblastic tumors, using thoracoscopic (n = 20), retroperitoneoscopic (n = 1) or laparoscopic approaches (n = 18). The tumor locations were paravertebral (n = 18; thoracic n = 15, lumbar n = 3), perivascular (n = 5; abdominal n = 2; thoracic n = 3), adrenal (n = 13), pleural (n = 2) and pelvic (n = 1). Two patients were treated for relapses. According to the INRG staging system, IDRFs were absent in 20 patients and present in 19 patients. Ten patients received chemotherapy preoperatively. Mean largest diameter was 35 mm for thoracic tumors (range: 7-85 mm) and 34 mm for abdominal tumors (range: 10-75 mm). Mean follow-up was 25 months (range: 5-116 months). RESULTS: Resection was macroscopically incomplete (R2) for six thoracic tumors and one adrenal tumor. Conversion was necessary for three thoracic L2 tumors. Postoperative complications consisted of chylothorax in three patients with L2 paravertebral thoracic tumors, Horner's syndrome in a patient with a cervicothoracic tumor, and renal atrophy in a patient with a L2 abdominal tumor. No perioperative or postoperative complications occurred in patients with adrenal and abdominal paravertebral tumors. The overall survival rate was 98%. CONCLUSION: In carefully selected cases, MIS permits safe and efficient resection of neuroblastic tumors in children. Open surgical approach should be considered if organ or vascular control or quality of resection is jeopardized. Pediatr Blood Cancer 2015;62:257-261. © 2014 Wiley Periodicals, Inc.

Optimization of contrast-enhanced spectral mammography depending on clinical indication.

The objective is to optimize low-energy (LE) and high-energy (HE) exposure parameters of contrast-enhanced spectral mammography (CESM) examinations in four different clinical applications for which different levels of average glandular dose (AGD) and ratios between LE and total doses are required. The optimization was performed on a Senographe DS with a SenoBright® upgrade. Simulations were performed to find the optima by maximizing the contrast-to-noise ratio (CNR) on the recombined CESM image using different targeted doses and LE image quality. The linearity between iodine concentration and CNR as well as the minimal detectable iodine concentration was assessed. The image quality of the LE image was assessed on the CDMAM contrast-detail phantom. Experiments confirmed the optima found on simulation. The CNR was higher for each clinical indication than for SenoBright®, including the screening indication for which the total AGD was 22% lower. Minimal iodine concentrations detectable in the case of a 3-mm-diameter round tumor were 12.5% lower than those obtained for the same dose in the clinical routine. LE image quality satisfied EUREF acceptable limits for threshold contrast. This newly optimized set of acquisition parameters allows increased contrast detectability compared to parameters currently used without a significant loss in LE image quality.

Breast lesion excision sample (BLES biopsy) combining stereotactic biopsy and radiofrequency: is it a safe and accurate procedure in case of BIRADS 4 and 5 breast lesions?

The aim of this study was to evaluate the accuracy and safety of breast lesion excision system (BLES) procedure with an Intact system device, under stereotactic and ultrasound guidance. Retrospective data review of 32 breast lesions BI-RADS 4 or 5 underwent Intact procedures, from March 2010 to January 2012. Underestimation rates of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were evaluated; percentage of complete radiologic and histologic removal of the breast lesion were analyzed, as were the complications due to procedure. Complete radiologic excision of the target lesion was achieved in all masses and 58.6% of calcifications. Lesion size was less than 11 mm (mean size 5.6 mm). Underestimation of ADH and DCIS was 0% and 10%, respectively. Low complication rate was noted: only one hematoma. BLES appears an accurate and safe biopsy system for sampling nonpalpable breast lesions, especially in case of microcalcifications clusters categorized as BI-RADS 4 and 5.

Impact of extensive surgery in multidisciplinary approach of pterygopalatine/infratemporal fossa soft tissue sarcoma.

BACKGROUND: To evaluate a strategy whereby extensive surgery ± external radiotherapy (RT) could improve local control in pterygopalatine/infratemporal fossa (PIF) sarcoma. PROCEDURE: Forty-one patients with a diagnosis of sarcoma involving the PIF and referred to our Institute from 1984 to 2009 were included in the analysis. Patients received multidrug chemotherapy and radiotherapy ± surgery, depending on the period of treatment. RESULTS: The median age at diagnosis was 7.6 years (range: 0.1-22 years). There were 36 RMS, 3 undifferentiated sarcoma and 2 other soft-tissue sarcomas. Sixty-eight percent of patients had meningeal risk factors at diagnosis. Local treatment consisted of RT alone in 19 patients, surgery in combination to RT in 19 patients and surgery alone in 3 patients. The local progression rate (LPR) at 5 years was 45% for the entire population, 59% for the 19 patients treated with RT alone and 34% for the 22 patients who had surgery as part of their treatment. All locoregional failures after extensive surgery occurred at the skull base and/or in leptomeningeal spaces. CONCLUSIONS: Multidisciplinary approach including extensive surgery for PIF sarcoma is feasible and yields good local control with 15/22 patients in local complete remission. Future studies are warranted to confirm these promising results, to evaluate the possibility of avoiding RT or limiting the RT field, and to extend the indication for extensive surgery to other "worse" sites of PM sarcoma such as the paranasal sinuses.

[Breast cancer imaging]. / Imagerie dans le cancer du sein.

Imaging of breast cancer is multimodal. Mammography uses X-rays, the development of digital mammography has improved its quality and enabled implementations of new technologies such astomosynthesis (3D mammography) or contrast-enhanced digital mammography. Ultrasound is added to mammography when there is need to improve detection in high-density breast, to characterize an image, or guide apuncture or biopsy. Breast MRI is the most sensitive imaging modality. It detects a possible tumor angiogenesis by highlighting an early and intense contrast uptake. This method has an excellent negative predictive value, but its lack of specificity (false positives) can be problematic, thus it has to be prescribed according to published standards. An imaging breast screening report must be concluded by the BI-RADS lexicon classification of the ACR and recommendations about monitoring or histological verification.

Variability and errors when applying the BIRADS mammography classification.

To standardize mammographic reporting, the American College of Radiology mammography developed the Breast Imaging Reporting and Data System (BIRADS) lexicon. However, wide variability is observed in practice in the application of the BIRADS terminology and this leads to classification errors. This review analyses the reasons for variations in BIRADS mammography, describes the types of errors made by readers with illustrated examples, and details BIRADS category 3 which is the most difficult category to use in practice.

Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma.

The purpose of this study is to evaluate the efficacy and toxicity of radiation therapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG). Newly diagnosed patients younger than 18 years with histologically proven DIPG were treated with focal radiotherapy to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m(2)/day). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m(2)/day, days 1-5) was given every 28 days up to six cycles. Responses/progressions were assessed by clinical and 2-monthly MRI follow-up studies. Between September 2005 and September 2009, 21 patients with newly diagnosed histologically confirmed DIPG were eligible for this study. Median age at diagnosis was 6.4 years (range 4-16 years). At last update in August 2010, 17 children have died, 1 child was alive with progressive disease and 3 with stable disease. Metastatic relapse was documented in the cerebral site in two patients and in spinal cord in two cases. The median time to progression was 7.5 months (range 28 days-14.5 months) and the median survival was 11.7 months (range 26 days-17.5 months). The 1-year PFS and the 1-year OS were 33 and 50%, respectively. Five patients presented radiological findings compatible with pseudoprogression during the treatment. Haematological toxicity (Grade III/IV thrombocytopenia and leucopenia) was the most commonly found and led to dose reductions of TMZ in 58% of the patients. TMZ with radiation therapy has not yielded any significant improvement in outcome of children with DIPG and is associated with higher toxicity compared with radiotherapy alone. Novel treatment modalities are needed to improve the outcome of these patients.

Infantile fibrosarcoma: magnetic resonance imaging findings in six cases.

PURPOSE: To retrospectively review magnetic resonance (MR) imaging features in a series of six infantile fibrosarcomas to find out if MR can suggest this unusual diagnosis and to highlight the value of MR during and following treatment. MATERIALS AND METHODS: The records of six cases of histologically proven infantile fibrosarcoma were retrieved from the files of our cancer center. All imaging data available were consensually reviewed by two radiologists. RESULTS: There were five females and one male (age range at diagnosis, 0-12 months; mean, 6 months). The most common finding was a well-circumscribed single mass in five patients (83%). All tumors had arisen on limbs; at their proximal or distal extremity or at the root of the limb. The masses were 9 cm large in mean diameter. The initial tumor signal was isointense to muscle on T1-weighted and hyperintense on T2-weighted sequences. All masses were well circumscribed and half of them contained internal fibrous septa. The internal signal was homogeneous in three patients and heterogeneous in the three others. An intense enhancement was seen in all three contrast-enhanced exams available; heterogeneous in two cases and homogeneous in one. Osseous erosion was observed in only one patient who was the only one with distant metastasis. After treatment (chemotherapy and very limited surgery), tumors had totally disappeared, leaving muscle fat infiltration in two patients and subcutaneous fat hypertrophy in one patient. CONCLUSION: Although imaging findings are not specific of infantile fibrosarcoma, this diagnosis could be suggested when MR imaging depicts a large well-circumscribed mass arising in a limb at birth or during the neonatal period. This mass is sometimes heterogeneous and septate and exhibits an isointense T1- and hyperintense T2-weighted signals and strong enhancement. MR is also the technique of choice for follow-up during treatment which consists nowadays almost exclusively in chemotherapy.