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1.
JAMA Oncol ; 8(12): 1802-1808, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36301572

ABSTRACT

Importance: Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear. Objective: To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy. Design, Setting, and Participants: This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions. Interventions: Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease. Main Outcomes and Measures: Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS). Results: Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS. Conclusions and Relevance: The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03109080.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Female , Middle Aged , Male , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/radiotherapy , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mastectomy
2.
Cancers (Basel) ; 13(23)2021 Dec 02.
Article in English | MEDLINE | ID: mdl-34885186

ABSTRACT

BACKGROUND: SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma. METHODS: Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH-MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial. RESULTS: SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible. CONCLUSION: SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.

3.
Int J Cancer ; 149(10): 1828-1832, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34270809

ABSTRACT

Triple-negative breast cancer (TNBC) cells are sensitive to PARP1 inhibitors in vitro. The combination of Olaparib and radiotherapy for TNBC is currently evaluated in the Phase I RADIOPARP trial. RADIOPARP is a monocentric prospective open-label Phase I dose-escalation trial evaluating the combination of breast radiotherapy and Olaparib in TNBC patients with inflammatory, locoregionally advanced or metastatic disease, or with residual disease after neoadjuvant chemotherapy. Olaparib was orally given at increasing dose levels (50, 100, 150 or 200 mg twice a day [BID]); radiotherapy consisted of 50 Gy to the breast or chest wall with or without lymph node irradiation. Twenty-four TNBC patients were enrolled between September 2017 and November 2019. Olaparib was escalated to 200 mg BID without dose-limiting toxicities. At 1-year follow-up, no treatment-related grade ≥3 toxicity was observed. One patient (4.2%) had persistent grade 2 adverse events (breast pain, fibrosis and deformity). There was no cardiac, pulmonary or digestive toxicity related to treatment. The 1-year follow-up report of the RADIOPARP Phase I trial, evaluating Olaparib associated with breast radiotherapy in TNBC patients, consequently demonstrated an excellent toxicity profile of this combination with few low-grade adverse events.


Subject(s)
Phthalazines/therapeutic use , Piperazines/therapeutic use , Radiotherapy/methods , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/radiotherapy , Adult , Aged , Combined Modality Therapy , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Hyperpigmentation/chemically induced , Middle Aged , Pain/chemically induced , Phthalazines/administration & dosage , Phthalazines/adverse effects , Piperazines/administration & dosage , Piperazines/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Prospective Studies , Radiotherapy Dosage , Treatment Outcome
4.
Eur J Radiol ; 141: 109826, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34174485

ABSTRACT

BACKGROUND: Atypical lesions found on percutaneous breast biopsy raise specific management issues. The aim of this study was to validate the previous performance of a decision tree defined by Forgeard et al to select a subset of patients at low-risk of surgical diagnostic upgrade that would be eligible for surveillance. METHODS: A consecutive series of 211 patients diagnosed with ADH on vacuum-assisted biopsy (VAB) of clustered microcalcifications alone, then operated in our institution, was reviewed. Histological findings on percutaneous cores were compared with definitive diagnoses on surgical specimens. The rate of cancer underestimation on VAB was analyzed in the four arms and two management attitudes defined in the scheme, using size and quality of microcalcification removal and the number of ADH foci. RESULTS: Ninety-eight women with ADH met the inclusion criteria. Overall, 20 cancers were diagnosed at surgery, showing a malignancy rate of 44% (17/39 patients) in the surgery group and of 5% (3/59 patients) in the surveillance group, which was not significantly different from the 2% rate in the monitored reference group (p > 0.64). The malignancy rate increased significantly with the size of clustered microcalcifications (0% when < 6mm, 17% when between 6mm and 21 mm, 48% when > 21 mm, p < 0001) and the number of ADH foci on VAB (14% when ≤ 2, 45% when > 2, p < 0.005). CONCLUSION: Our results corroborate - within the limits of large confidence intervals - those obtained with the reference decision tree. Due to statistical uncertainty, however, they need to be prospectively validated in a broader series.


Subject(s)
Breast Neoplasms , Calcinosis , Carcinoma, Intraductal, Noninfiltrating , Breast/diagnostic imaging , Breast/pathology , Breast/surgery , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Calcinosis/diagnostic imaging , Calcinosis/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Decision Trees , Female , Humans , Hyperplasia/pathology , Mammography , Patient Selection , Retrospective Studies
5.
Int J Radiat Oncol Biol Phys ; 109(2): 436-440, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32971187

ABSTRACT

PURPOSE: Preclinical studies have evidenced that triple-negative breast cancer (TNBC) cell lines are more sensitive to poly (ADP-ribose) polymerase inhibitors. This provides a strong rationale for developing a new therapeutic approach for TNBC management based on poly (ADP-ribose) polymerase inhibition. The primary goal of the RADIOPARP phase 1 trial was to evaluate the dose-limiting toxicities (DLT) and the maximum tolerated dose of olaparib combined with locoregional radiation therapy. METHODS AND MATERIALS: RADIOPARP was a single institutional phase 1 trial which evaluated olaparib-radiation therapy combination in patients with inflammatory, locoregionally advanced or metastatic TNBC who received neoadjuvant chemotherapy. Radiation therapy delivered 50 Gy to the breast or to the chest wall. Lymph nodes could be included in target volumes according to local guidelines. The dose-finding toxicity-based study was conducted in sequential and adaptive Bayesian scheme using the time-to-event continual reassessment method, with 4 olaparib dose levels (50 mg, 100 mg, 150 mg, and 200 mg twice per day). RESULTS: Twenty-four patients with Eastern Cooperative Oncology Group Performance Status of 0 or 1 were enrolled from September 2017 to November 2019. Twenty-one patients (87.5%) received the olaparib-radiation therapy combination after breast surgery owing to residual disease after neoadjuvant chemotherapy, and the 3 other patients (12.5%) had unresectable tumors which were refractory to neoadjuvant chemotherapy. All patients received full course combination treatment as follows: 4 patients (pts) at 50 mg twice a day, 8 pts at 100 mg twice a day, 7 pts at 150 mg twice a day, and 5 pts at 200 mg twice a day. No DLT was observed. CONCLUSIONS: Olaparib was escalated to the maximum target dose of 200 mg twice a day without DLT. Further follow-up is needed to evaluate the late toxicities. Pending the long-term results of the RADIOPARP trial, we suggest using 200 mg of olaparib twice per day for future trials.


Subject(s)
Phthalazines/therapeutic use , Piperazines/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/radiotherapy , Adult , Aged , Combined Modality Therapy , Dose-Response Relationship, Radiation , Female , Humans , Middle Aged , Neoplasm, Residual/radiotherapy , Triple Negative Breast Neoplasms/pathology
6.
J Clin Oncol ; 38(31): 3685-3697, 2020 11 01.
Article in English | MEDLINE | ID: mdl-32903140

ABSTRACT

PURPOSE: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome. PATIENTS AND METHODS: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group. RESULTS: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038). CONCLUSION: Genomic aberrations of resectable non-MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 1 , N-Myc Proto-Oncogene Protein/genetics , Neuroblastoma/genetics , Age Factors , Clinical Trials as Topic , Diploidy , Gene Amplification , Genomics , Humans , Infant , Neoplasm Staging , Neuroblastoma/pathology , Neuroblastoma/surgery , Prognosis , Progression-Free Survival , Survival Rate
7.
Cancer Med ; 7(4): 1384-1393, 2018 04.
Article in English | MEDLINE | ID: mdl-29533008

ABSTRACT

A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has emerged as independent prognostic factor associated with the risk of metastatic relapse in synovial sarcoma (SS). The aim was to assess GI in pediatric patients with SS, to determine its value as a prognostic factor. All pediatric/adolescent/young adults' (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Definition of GI was A2 /C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI1 group corresponds to cases with no copy number alterations (flat profile, GI = 0) and GI2 group cases with at least one or more copy number alterations (rearranged profile; GI ≥ 1). Samples were available from 61 patients. The median age of the cohort was 13 years (range: 4-24). Overall, 55.7% were GI1 group, and 44.3% GI2 . After a median follow-up of 62 months (range: 0.1-112), 10 tumor events occurred and five patients died. Respectively, for GI1 versus GI2 groups, five-year event-free survival (EFS) was 93.8 ± 4.2% versus 64.9 ± 10.1% (P < 0.006) and five-year Metastatic-Free Survival (MFS) 93.8 ± 4.2% versus 72.9 ± 9.5% (P < 0.04). In multivariate analysis, GI status as adjusted for IRS group, patient age, site, and tumor size remain independent prognostic for EFS with a relative risk (RR) of 6.4 [1.3-31.9] (P < 0.01) and RR for MFS is 4.8 [0.9-25.7] (P < 0.05). Genomic complexity evaluated through GI may explain the metastatic behavior of pediatric SS.


Subject(s)
Genetic Variation , Genomics , Sarcoma, Synovial/genetics , Adolescent , Adult , Age Factors , Child , Child, Preschool , Comparative Genomic Hybridization , Europe , Female , Genomics/methods , Humans , Male , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Sarcoma, Synovial/pathology , Young Adult
8.
PLoS One ; 12(9): e0185190, 2017.
Article in English | MEDLINE | ID: mdl-28945781

ABSTRACT

PURPOSE: This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome. PATIENTS AND METHODS: This IRB-approved retrospective observational study included 133 NB patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses. RESULTS: A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001). CONCLUSION: Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome.


Subject(s)
Neuroblastoma/diagnostic imaging , Neuroblastoma/genetics , Child , Child, Preschool , Chromosome Aberrations , Comparative Genomic Hybridization , Female , France/epidemiology , Genomics , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Neuroblastoma/mortality , Phenotype , Prognosis , Retrospective Studies , Tomography, X-Ray Computed , Transcriptome
9.
Bull Cancer ; 104(7-8): 625-635, 2017.
Article in French | MEDLINE | ID: mdl-28687117

ABSTRACT

SUBJECT: Prognostic values of an early detection of a relapse after treatment of a localized rhabdomyosarcoma and the interest of performing systematic radiologic assessment after treatment have not yet been evaluated in Europe. MATERIAL AND METHODS: Modalities of relapse of 99 patients under 20 years of age, after an initially localized rhabdomyosarcoma, treated in 9 French centers ("Société française des cancers de l'enfant" consortium) have been analyzed. Prognostic value of the protocol compliance during the observation period after therapy has been evaluated. RESULTS: Relapses have been diagnosed in 59 cases by a "symptom" the child was complaining of, in 12 cases because of "physical signs" detected during the clinical examination of a systematic consultation and in 27 cases thanks to "systematic follow-up imaging" (missing data: 1 case). Survival after relapse at 3 years was 47.5 % (IC95 %: 37.1 %-57.1 %). Diagnosis of the relapse is established earlier in the group "systematic imaging" rather than with other methods of detection ("symptom", "physical signs"), (P= 0.025), with detection of smaller tumors (≤ 5 cm ; 100.0 % vs. 60.9 % vs. 77.8 %, P= 0.007) but without possibility of reaching a second remission (70.4 % vs. 50.8 % vs. 50.0 % P= 0.37), nor significant impact on 5-year overall survival (47.1 % vs. 47.1 % vs. 48.6 % P= 0.94). CONCLUSION: Current methods of systematic surveillance after a first-line treatment of an initially localized rhabdomyosarcoma seem to improve the earliness of the diagnosis, but not the prognosis of the relapse.


Subject(s)
Early Detection of Cancer/methods , Neoplasm Recurrence, Local/diagnosis , Rhabdomyosarcoma/diagnosis , Adolescent , Child , Child, Preschool , Diagnostic Imaging/methods , Early Detection of Cancer/mortality , Female , Follow-Up Studies , Humans , Infant , Male , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Prognosis , Quality of Life , Retrospective Studies , Rhabdomyosarcoma/mortality , Rhabdomyosarcoma/pathology , Rhabdomyosarcoma/therapy , Symptom Assessment/methods , Tumor Burden , Young Adult
10.
Bull Cancer ; 104(2): 128-138, 2017 Feb.
Article in French | MEDLINE | ID: mdl-27939009

ABSTRACT

OBJECTIVE: to describe medical care pathways between first symptoms and first oncologic consultation in children and adolescents with solid cancers in order to analyze a possible relationship between delayed diagnosis and its potential consequences. METHODS: Retrospective study on patients aged less than 25 years at first consultation in the oncology department of pediatric, adolescent and young adult in Institut Curie during one year. Were collected data on cancer characteristics, components of care pathways, and sociodemographic parents' characteristics. RESULTS: Hundred and six patients were selected, with median age of 6 years. Most represented tumor was low-grade cerebral tumor (17.0%). Pain was the most frequent type of disorder observed as first sign (34.3% of patients). First signs were unspecific in only 27.6% of cases. Most patients were first seen by a general practitioner (29.3%). Median total time to diagnosis was one month [ranges: 0-64]. Median number of consultations before referral to oncology expert was 2 [0-7]. Retrospective analysis found a possible delayed diagnosis in 44.3% of patients, with potential vital and functional risks estimated respectively at 14.1 and 20.7% of overall population. Time to diagnosis was shorter if father was of foreign nationality vs. French (34 days vs. 72 days, P<0.05), and longer if parents were separated (74.5 days vs. 42.5 days, P<0.03). CONCLUSIONS: Overall time to diagnosis is quite fast, even if first signs of pediatric cancers are very polymorphic. Some medical and sociodemographic factors could influence characteristics of care pathways.


Subject(s)
Delayed Diagnosis/adverse effects , Neoplasms/diagnosis , Adolescent , Bone Neoplasms/complications , Bone Neoplasms/diagnosis , Bone Neoplasms/epidemiology , Brain Neoplasms/complications , Brain Neoplasms/diagnosis , Brain Neoplasms/epidemiology , Cancer Care Facilities , Cancer Pain/etiology , Child , Child, Preschool , Delayed Diagnosis/statistics & numerical data , Emigrants and Immigrants/statistics & numerical data , Family Characteristics , Female , France , General Practice/statistics & numerical data , Humans , Infant , Infant, Newborn , Male , Mesenchymoma/complications , Mesenchymoma/diagnosis , Mesenchymoma/epidemiology , Neoplasms/complications , Neoplasms/epidemiology , Retrospective Studies , Sarcoma/diagnosis , Sarcoma/epidemiology , Socioeconomic Factors , Symptom Assessment , Young Adult
11.
Head Neck ; 39(1): 24-31, 2017 01.
Article in English | MEDLINE | ID: mdl-27459057

ABSTRACT

BACKGROUND: This article reports risk factors and long-term outcome in localized nonparameningeal head and neck rhabdomyosarcomas in children and adolescents from a combined dataset from 3 consecutive international trials. METHODS: Data from 140 children (9.3% of total) prospectively enrolled in the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT)-84/89/95 studies were analyzed. RESULTS: Primary site was: superficial face in 46%; oral cavity (21%); neck (19%); and salivary glands (14%). Local control was achieved in 96%, but 49% relapsed (locoregionally 91%). At median follow-up of 10 years, 5-year overall survival (OS) was 74.7% (67.4% to 81.9%) and event-free survival 48.9% (40.6% to 57.2%), although this improved with successive studies. Radiotherapy (RT) as first-line treatment was independently prognostic for event-free survival (relative risk [RR] = 0.4 [range, 0.2-0.7]; p < .01) even if it did not impact OS (RR = 1 [range, 0.5-2]). CONCLUSION: High rates of locoregional relapse were seen in head and neck rhabdomyosarcoma that should be prevented by more frequent use of RT in this primary. © 2016 Wiley Periodicals, Inc. Head Neck 39: 24-31, 2017.


Subject(s)
Head and Neck Neoplasms/therapy , Mesenchymoma/therapy , Neoplasm Recurrence, Local/epidemiology , Rhabdomyosarcoma/therapy , Adolescent , Child , Child, Preschool , Combined Modality Therapy , Disease-Free Survival , Female , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Infant , Infant, Newborn , Male , Mesenchymoma/mortality , Mesenchymoma/pathology , Retrospective Studies , Rhabdomyosarcoma/mortality , Rhabdomyosarcoma/pathology , Risk Factors , Survival Rate , Treatment Outcome
12.
Oncoimmunology ; 5(7): e1179414, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27622034

ABSTRACT

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine expressed by epithelial cells during allergic inflammation, and activating dendritic cells (DC). Its expression and functional role in cancer remain controversial. We conducted retrospective (n = 89), and prospective studies including patients with untreated primary head and neck squamous cell carcinoma (HNSCC). We found that TSLP was overexpressed by HNSCC tumor cells, and associated with a highly differentiated status. However, no significant difference in overall and recurrence-free survival was found between patients bearing a tumor with high and low TSLP levels, respectively. Surprisingly, there was no significant association between the levels of TSLP expression, and the number of tumor-infiltrating mature DCLAMP(+) DC. In order to explain the apparent lack of TSLP-induced DC activation, we performed phenotypic and functional experiments on freshly resected tumors. Tumor-infiltrating immune cells, including DC, did not express the TSLP receptor heterodimer (TSLPR chain, IL-7Ralpha chain). Furthermore, freshly sorted blood CD11c(+) DC from healthy donors cultured with tumor-conditioned supernatant exhibited an activated profile, but this was not affected by an anti-TSLP blocking antibody, suggesting a DC activation pathway independent of tumor-derived TSLP. Overall, our results demonstrate that TSLP is overexpressed in HNSCC but its function is hampered by the lack of TSLPR-expressing cells in the tumor microenvironment. Such a dissociated ligand-receptor expression may impact intercellular communication in other immune activation pathways, and tumor types.

13.
Soins ; (800): 17-20, 2015 Nov.
Article in French | MEDLINE | ID: mdl-26567064

ABSTRACT

It is important to support patients with cancer during their care pathway and even beyond. They undergo long and difficult treatments, all anxiety-causing situations and sources of stress. Sophrological techniques help patients to find calm, lessen their fears and offer them the opportunity to work on themselves through simple easily reproducible exercises. This observation has been verified by a study carried out at the Institut Curie with patients undergoing chemotherapy.


Subject(s)
Anxiety/therapy , Mind-Body Relations, Metaphysical , Neoplasms/psychology , Pain Management/methods , Adult , Aged , Anxiety/psychology , Humans , Middle Aged
14.
Pediatr Blood Cancer ; 62(11): 1935-41, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26150380

ABSTRACT

PURPOSE: About one-third of patients with rhabdomyosarcoma relapse despite appropriate treatment and experience a poor outcome. Little meaningful improvement in the outcome of this disease has been observed over the last 30 years. There is no clear international recommendation concerning the use of salvage chemotherapy at relapse. A retrospective multicenter analysis was therefore conducted to analyze the efficacy of various second-line chemotherapy regimens in this setting. METHODS: Forty-nine patients under the age of 18, with initially localized rhabdomyosarcoma, who relapsed after first complete remission, treated in three SFCE centers (Société Française des Cancers de l'Enfant) between 1995 and 2013, were analyzed. RESULTS: First relapse occurred after a median interval of 22 months and remained localized in 71.4% of cases. All patients received second-line chemotherapy with an overall response to this salvage therapy of 39.1%. Best specific response rates were 73.3 and 42.9% for carboplatin/epirubicin/vincristine-ifosfamide/vincristine/etoposide (CEV/IVE) (15 patients) and vincristine/irinotecan ± temozolomide (VI[T]) (seven patients), respectively. Overall, 40 patients (81.6%) were then eligible for delayed local treatment (surgery and/or radiotherapy) and 30 of them (61.2%) achieved second complete remission. After a median follow-up of 5.4 years since the diagnosis of first relapse, 5-year overall survival is 49.4% (95% CI: 34.2-64.6). CONCLUSION: Salvage chemotherapy plays a central role in the management of patients with relapsed rhabdomyosarcoma. CEV/IVE and VI(T) regimens can be recommended as neoadjuvant chemotherapy before local treatment for patients with relapsed rhabdomyosarcoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/mortality , Adolescent , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Disease-Free Survival , Epirubicin/administration & dosage , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Ifosfamide/administration & dosage , Infant , Male , Neoplasm Recurrence, Local/pathology , Retrospective Studies , Rhabdomyosarcoma/pathology , Survival Rate , Vincristine/administration & dosage
15.
Breast ; 24(4): 370-5, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25913288

ABSTRACT

PURPOSE: The purpose of this study was to evaluate the outcome of breast conserving surgery comparing oncoplastic surgery (OS) and standard lumpectomy (SL) after preoperative bracketing wire localization of large neoplastic lesions. METHODS: We retrospectively reviewed the medical records and the mammograms of patients operated on at the Institut Curie between May 2005 and September 2011 after bracketing wire localization under mammographic and/or sonographic guidance. RESULTS: 113 patients underwent surgery for a pre-operative diagnosis of DCIS (n = 80), micro-invasive carcinoma (n = 9) or invasive carcinoma (n = 24), by OS (n = 73) or SL (n = 40). In the OS group, radiological size (52 mm vs 39 mm, p < 0.001) and resection volumes (246 cc vs 88 cc, p < 0.00001) were significantly higher than in the SL group. Rates of clear histologic margins (60 vs 62%, NS), complete excision of microcalcifications (78% vs 72%, NS) and re-intervention rate (40% vs 42%, NS) were equivalent. The rate of local recurrence at 24 months was 3% [0-7.1] in patients with conservative treatment (n = 3). With a median follow-up of 40 months, 5 local relapses (two with axillary metastatic involvement), two distant metastatic evolution, one contralateral breast cancer and one death unrelated to cancer occurred. CONCLUSION: Following bracketing wire localization, OS allowed the conserving management of significantly larger lesions with wider resection volumes, without significant increase in margin involvement or re-intervention rate, and equivalent rate of microcalcifications clearance compared to SL.


Subject(s)
Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/surgery , Fiducial Markers , Mastectomy, Segmental/statistics & numerical data , Neoplasm Recurrence, Local/epidemiology , Adult , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Calcinosis/diagnostic imaging , Carcinoma, Ductal, Breast/pathology , Female , Humans , Mastectomy, Segmental/methods , Middle Aged , Radiography , Retrospective Studies , Surgery, Computer-Assisted , Treatment Outcome , Tumor Burden , Ultrasonography, Interventional
16.
Pediatr Blood Cancer ; 62(9): 1536-42, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25663103

ABSTRACT

BACKGROUND: The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image-defined risk factors (IDRF) on operative complications and survival (EFS and OS). PROCEDURE: 534 patients with localised, non-MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo-adjuvant chemotherapy. RESULTS: In L1 patients (Group 1) 5-year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients. CONCLUSIONS: In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning.


Subject(s)
Diagnostic Imaging , Multicenter Studies as Topic/statistics & numerical data , Neuroblastoma/epidemiology , Abdominal Neoplasms/diagnosis , Abdominal Neoplasms/drug therapy , Abdominal Neoplasms/epidemiology , Abdominal Neoplasms/pathology , Abdominal Neoplasms/surgery , Adolescent , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Diagnostic Imaging/methods , Europe/epidemiology , Female , Genes, myc , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/epidemiology , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/surgery , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Multimodal Imaging , Neoadjuvant Therapy , Neoplasm Invasiveness , Neoplasm Staging , Neuroblastoma/diagnosis , Neuroblastoma/drug therapy , Neuroblastoma/pathology , Neuroblastoma/surgery , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Retrospective Studies , Risk Assessment , Risk Factors , Thoracic Neoplasms/diagnosis , Thoracic Neoplasms/drug therapy , Thoracic Neoplasms/epidemiology , Thoracic Neoplasms/pathology , Thoracic Neoplasms/surgery , Treatment Outcome
17.
Clin Exp Ophthalmol ; 43(1): 12-9, 2015.
Article in English | MEDLINE | ID: mdl-24923774

ABSTRACT

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) is associated with an excellent survival rate greater than 85%, and is considered to be a favourable site for this tumour. Treatment is based on combination chemotherapy together with best local therapy, sometimes surgery but more often radiation therapy. Local therapy is associated with frequent and potentially severe late sequelae. DESIGN: Retrospective hospital single-centre analysis. PARTICIPANTS: Eighty-two patients treated in Institut Curie, Paris. METHODS: To define long-term status of survivors after localized ORMS, patients treated between 1975 and 2010 were analysed. MAIN OUTCOME MEASURES: Clinical structural and functional orbital, and general sequelae. RESULTS: Median age at diagnosis was 6 years (range: 8 months-19 years), and median follow up was 8.5 years (range: 7 months-24 years). The 5-year globe conservation rate was 90.4%. Ophthalmic dysfunction was present in 79% of patients. Impaired visual acuity (VA), was present in 62% of patients; 38% of them had severe visual disability with VA < 6/60. Late effects on orbitofacial structure were present in 39.8% of patients. Ocular or palpebral sequelae were present in 79% of survivors, mainly cataract (42%), ocular surface lesions such as keratoconjunctivitis (40%) and eyelid abnormalities (29%). General late effects were rare. CONCLUSIONS: These data suggest that ocular and orbital late effects are frequent after treatment of ORMS, indicating the need for systematic long-term ophthalmologic follow up of these patients. Radiation therapy is an important part of the total burden of therapy.


Subject(s)
Orbital Neoplasms/pathology , Rhabdomyosarcoma/pathology , Adolescent , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Orbital Neoplasms/mortality , Orbital Neoplasms/therapy , Postoperative Complications , Radiotherapy , Retrospective Studies , Rhabdomyosarcoma/mortality , Rhabdomyosarcoma/therapy , Survival Rate , Young Adult
18.
Pediatr Blood Cancer ; 61(12): 2191-8, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25176412

ABSTRACT

BACKGROUND: This retrospective multicenter study assessed the clinical, radiological and pathological presentation, treatment and outcome of 26 patients with Ewing-like sarcoma harboring BCOR-CCNB3 gene fusion transcript. Tumor samples had been collected between 1994 and April 2012. PROCEDURE: Eligibility criteria included assessment of a BCOR-CCNB3 transcript-positive tumor after molecular analysis and availability of minimal clinical and pathological data. Radiological data were also retrieved when possible. Data were analyzed by descriptive statistics and methods for survival analysis. RESULTS: Median age at diagnosis was 13.1 years (5.9 to 25.6 years). Most patients (24/26) had localized tumors. All tumors but five were localized to bone. CCNB3 immunochemistry showed strong nuclear staining on all samples. No specific radiological features were found. Most patients received chemotherapy (15 according to protocols designed for Ewing tumors), before and/or after local treatment (surgery and/or radiotherapy, with 46.2% receiving both). Local and metastatic relapses were of poor prognosis. Induction chemotherapy and treatment according to an Ewing protocol might influence survival for patients with localized tumors. Sixteen patients are alive in complete remission with a median follow-up of 86 months. Five year overall survival and disease-free survival were respectively 76.5% (95% CI, 58%-95%) and 67.9% (95% CI, 48%-88%). CONCLUSIONS: BCOR-CCNB3 transcript-positive Ewing-like sarcoma diagnosis should be discussed for a transcript-negative small round cell sarcoma in a child, adolescent or young adult patient. Diagnosis needs to be stated through CCNB3 immunochemistry or transcript identification. The exquisite chemosensitivity of these tumors should encourage the use of polychemotherapy for appropriate care, associated with best local tumor control.


Subject(s)
Bone Neoplasms/pathology , Cyclin B/genetics , Gene Fusion , Lung Neoplasms/secondary , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Sarcoma, Ewing/secondary , Adolescent , Adult , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/genetics , Child , Combined Modality Therapy , Female , Follow-Up Studies , France , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/genetics , Male , Neoplasm Staging , Prognosis , Radiography , Retrospective Studies , Sarcoma, Ewing/diagnostic imaging , Sarcoma, Ewing/genetics , Survival Rate , Young Adult
19.
J Pediatr Hematol Oncol ; 36(8): 605-12, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25171453

ABSTRACT

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) treatment is based on combination chemotherapy associated with best local therapy, sometimes surgery but more often radiation therapy. A retrospective single-center analysis was conducted to more clearly define the long-term outcome of patients with ORMS, to identify patients in whom aggressive first-line local therapy can be avoided. POPULATION: A total of 95 patients with localized parameningeal (PM) or nonparameningeal (NPM) ORMS, treated at the Institut Curie between 1975 and 2010, were analyzed. RESULTS: Median age at diagnosis was 6 years (range, 8 mo to 19.5 y), and median follow-up was 8.5 years (range, 7 mo to 24 y). A total of 25 patients presented PM extension. Radiation therapy was part of primary therapy for 78 patients. Five-year event-free survival and overall survival rates were 65.4%±5.2% and 85.6%±3.9%, respectively. On multivariate analysis, initial tumor size was identified as a significant prognostic factor. Event-free survival was similar for PM and NPM tumors (60.3%±10.4% vs. 62.7%±5.9%, P=0.57), whereas there was a trend for overall survival to be better for NPM tumors (90%±3.9% vs. 72.7%±9.6%, P=0.07). CONCLUSIONS: Localized ORMS has a favorable outcome despite the current trend toward less aggressive and more limited indications of local therapy. Patients with a favorable pattern of strictly ORMS can be treated without first-line radiation therapy.


Subject(s)
Chemoradiotherapy/methods , Orbital Neoplasms/therapy , Rhabdomyosarcoma/therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Cyclophosphamide/therapeutic use , Dactinomycin/therapeutic use , Disease-Free Survival , Epirubicin/therapeutic use , Follow-Up Studies , Humans , Ifosfamide/therapeutic use , Infant , Neoplasm Staging , Orbital Neoplasms/diagnostic imaging , Orbital Neoplasms/pathology , Prognosis , Radionuclide Imaging , Retrospective Studies , Rhabdomyosarcoma/diagnostic imaging , Rhabdomyosarcoma/pathology , Treatment Outcome , Vincristine/therapeutic use , Young Adult
20.
PLoS One ; 9(7): e101990, 2014.
Article in English | MEDLINE | ID: mdl-25013904

ABSTRACT

BACKGROUND: Somatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN. METHODS: Genomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected. RESULTS: In total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%±11% vs 34.9%±7%, log-rank p<0.05). CONCLUSION: NBs harbouring regional amplification(s) without MNA are rare and seem to show atypical features in clinical presentation and genomic profile. Further high resolution genetic explorations are justified in this heterogeneous group, especially when considering these alterations as predictive markers for targeted therapy.


Subject(s)
Gene Amplification/genetics , Neuroblastoma/genetics , Nuclear Proteins/genetics , Oncogene Proteins/genetics , Child, Preschool , Comparative Genomic Hybridization , Female , Humans , Infant , Male , N-Myc Proto-Oncogene Protein , Retrospective Studies
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