RESUMEN
The group of notochordal tumors consists of the benign notochordal cell tumor and the conventional, dedifferentiated and poorly differentiated chordomas in the fifth edition of the WHO classification of bone and soft tissue tumors. This update covers recent advances in the knowledge of the histogenesis and biology of these tumors and their implications in terms of diagnosis, prognosis assessment and therapeutic management.
Asunto(s)
Neoplasias Óseas , Cordoma , Neoplasias de Células Germinales y Embrionarias , Neoplasias de los Tejidos Blandos , Neoplasias Óseas/patología , Cordoma/diagnóstico , Cordoma/patología , Humanos , Neoplasias de Células Germinales y Embrionarias/patología , Notocorda/patología , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Bone tissue can be involved by primitive or metastatic tumors and requires a specific processing both at the department of pathology and during multidisciplinary meetings. The development of fine-needle percutaneous biopsies and of molecular techniques in bone tumor pathology requires a specific management. Moreover, decalcification of samples is crucial but can be deleterious if not controlled or not appropriate. The aim of this review is to provide recommendations for management and decalcification of bone tumor samples.
Asunto(s)
Neoplasias Óseas , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Huesos , Técnica de Descalcificación/métodos , Humanos , InmunohistoquímicaRESUMEN
PURPOSE: We evaluated whether biomarkers on baseline [18F]-FDG PET/CT are associated with recurrence after surgery in patients with invasive breast cancer of no special type (NST). METHODS: In this retrospective single-center study, we included consecutive patients with non-metastatic breast cancer of NST who underwent [18F]-FDG PET/CT before treatment, including surgery, between 2011 and 2016. Clinicopathological data were collected. Tumor SUVmax, total metabolic tumor volume (TMTV), and spleen- and bone marrow-to-liver SUVmax ratios (SLR, BLR) were measured from the PET images. Cut-off values were determined using predictiveness curves to predict 5-year recurrence-free survival (5y-RFS). A multivariable prediction model was developed using Cox regression. The association with stromal tumor-infiltrating lymphocytes (TILs) levels (low if <50%) was studied by logistic regression. RESULTS: Three hundred and three women were eligible, including 93 (31%) with triple-negative breast carcinoma. After a median follow-up of 6.2 years, 56 and 35 patients experienced recurrence and death, respectively. The 5y-RFS rate was 86%. In multivariable analyses, high TMTV (>20 cm3) and high SLR (>0.76) were associated with shorter 5y-RFS (HR 2.4, 95%CI 1.3-4.5, and HR 1.9, 95%CI 1.0-3.6). In logistic regression, high SLR was the only independent factor associated with low stromal TILs (OR 2.8, 95%CI 1.4-5.7). CONCLUSION: High total metabolic tumor volume and high spleen glucose metabolism on baseline [18F]-FDG PET/CT were associated with poor 5y-RFS after surgical resection in patients with breast cancer of NST. Spleen metabolism was inversely correlated with stromal TILs and might be a surrogate for an immunosuppressive tumor microenvironment.
Asunto(s)
Neoplasias de la Mama , Fluorodesoxiglucosa F18 , Biomarcadores , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Femenino , Humanos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Estudios Retrospectivos , Bazo/diagnóstico por imagen , Carga Tumoral , Microambiente TumoralRESUMEN
BACKGROUND: Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. METHODS: Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). RESULTS: We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. CONCLUSIONS: This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.
Asunto(s)
Neoplasias de la Mama/patología , Fibroblastos Asociados al Cáncer/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Fibroblastos Asociados al Cáncer/inmunología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/inmunología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Carcinoma Lobular/terapia , Estudios de Casos y Controles , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Microambiente Tumoral/inmunologíaRESUMEN
Acral soft tissue tumors are common neoplasms, a subset of which pose a diagnostic challenge. We report 10 cases of a previously unrecognized acral benign soft tissue tumor. These tumors arose on the fingers and toes and involved bone in half of cases. Histologically, the tumors were lobulated and displayed an abundant stroma made of variable fibrous, chondroid and myxoid material reminiscent of cartilaginous or myoepithelial differentiation. Tumor cells harbored small round to reniform nuclei with clear chromatin and inconspicuous nucleoli along with scant eosinophilic cytoplasm. The cells were mostly arranged haphazardly in the stroma but also in small clusters. No mitotic activity was detected. No specific feature was identified in recurrent cases. By immunohistochemistry, the cells consistently stained for CD34 (10/10), ERG (9/10), and SOX9 (7/10). Whole RNA sequencing identified a previously undescribed recurrent in frame THBS1-ADGRF5 gene fusion in all cases. The transcript was confirmed by RT-PCR and was not found in the control group of mimickers including soft tissue chondromas. We propose the name of Acral FibroChondroMyxoid Tumors for this new entity.
Asunto(s)
Dedos/patología , Neoplasias de Tejido Conjuntivo/genética , Receptores Acoplados a Proteínas G/genética , Neoplasias de los Tejidos Blandos/genética , Trombospondina 1/genética , Dedos del Pie/patología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fusión de Oncogenes/genéticaRESUMEN
Diagnosis of osteocartilaginous pathologies depends on morphological examination and immunohistochemical and molecular biology analyses. Decalcification is required before tissue processing, but available protocols often lead to altered proteins and nucleic acids, and thus compromise the diagnosis. The objective of this study was to compare the effect of different methods of decalcification on histomolecular analyses required for diagnosis and to recommend an optimal protocol for processing these samples in routine practice. We prospectively submitted 35 tissue samples to different decalcification procedures with hydrochloric acid, formic acid, and EDTA, in short, overnight and long cycles for 1 to >10 cycles. Preservation of protein integrity was examined by immunohistochemistry, and quality of nucleic acids was estimated after extraction (DNA and RNA concentrations, 260/280 ratios, PCR cycle thresholds), analysis of DNA mutations (high-resolution melting) or amplifications (PCR, in situ hybridization), and detection of fusion transcripts (RT-PCR, in situ hybridization). Hydrochloric acid- and long-term formic acid-based decalcification induced false-negative results on immunohistochemistry and molecular analysis. EDTA and short-term formic acid-based decalcification (<5 cycles of 6 h each) did not alter antigenicity and allowed for detection of gene mutations, amplifications or even fusion transcripts. EDTA showed superiority for in situ hybridization techniques. According to these results and our institutional experience, we propose recommendations for decalcification of bone samples, from biopsies to surgical specimens.
Asunto(s)
Artefactos , Enfermedades Óseas/diagnóstico , Técnica de Descalcificación/métodos , Ácidos Nucleicos/agonistas , Ácido Edético/farmacología , Formiatos/farmacología , Humanos , Ácido Clorhídrico/farmacología , Inmunohistoquímica , Ácidos Nucleicos/análisis , Ácidos Nucleicos/efectos de los fármacosRESUMEN
Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Neoplasias Óseas/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma de Células Pequeñas/genética , Transcriptoma/genética , Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Fusión Génica/genética , Humanos , Proteínas Musculares/genética , Proteínas Represoras/genética , Factores de Transcripción/genéticaRESUMEN
Clear cells sarcomas (CCS) are exceptionally rare in the tongue, with, to our knowledge, only three previous reports in anglo-saxon literature. Through our case, we will discuss the differential diagnosis of clear cells tumors of the tongue and bring this tumour closer to the newly described entity of the gastrointestinal tract named "clear cells sarcoma-like gastrointestinal (SCCLGI)", recently renamed "gastrointestinal neuroectodermal tumour (GNET)". SCCLGI/GNET share morphological and molecular characteristics with SCC but had until then been observed only in the digestive tract. Our case could be a lingual localization of a SCCLGI/GNET. SCC and SCCLGI/GNET characteristic molecular profil involves EWSR1-ATF1 [t(12; 22) (q13; q12)] and EWSR1-CREB1 [t(2; 22) (q34; q12)] fusion genes, but it is not specific of these tumours.
Asunto(s)
Tumores Neuroectodérmicos/patología , Sarcoma de Células Claras/patología , Neoplasias de la Lengua/patología , Adulto , Diagnóstico Diferencial , Femenino , Neoplasias Gastrointestinales/patología , HumanosRESUMEN
The infiltration by numerous osteoclastic giant cells is a frequent finding in bone tumors and pseudo-tumors. Pathologists must integrate clinical and radiological data to achieve a correct diagnosis in bone pathology. Benign giant-cell rich lesions of bone encompass giant cell tumor of bone, aneurysmal bone cyst, chondroblastoma, brown tumor and fibrous cortical defect/non-ossifying fibroma. Amongst malignant neoplasms, variants of conventional osteosarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma and bone metastasis must be discussed. Recently, new diagnostic markers, antibodies for immuno-histochemistry and genetic markers, have been developed and are helpful to diagnose such lesions.
Asunto(s)
Enfermedades Óseas/patología , Neoplasias Óseas/patología , Células Gigantes/patología , Biomarcadores de Tumor/análisis , Quistes Óseos Aneurismáticos/química , Quistes Óseos Aneurismáticos/diagnóstico , Quistes Óseos Aneurismáticos/patología , Enfermedades Óseas/diagnóstico , Enfermedades Óseas/metabolismo , Neoplasias Óseas/química , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Condroblastoma/química , Condroblastoma/diagnóstico , Condroblastoma/patología , Diagnóstico Diferencial , Fibroma Osificante/química , Fibroma Osificante/diagnóstico , Fibroma Osificante/patología , Marcadores Genéticos , Tumor Óseo de Células Gigantes/química , Tumor Óseo de Células Gigantes/diagnóstico , Tumor Óseo de Células Gigantes/patología , Humanos , Inmunohistoquímica/métodos , Técnicas de Diagnóstico Molecular , Sarcoma/química , Sarcoma/diagnóstico , Sarcoma/patologíaRESUMEN
BACKGROUND: Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma. METHODS: In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223. FINDINGS: Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion). INTERPRETATION: From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data. FUNDING: French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/cirugía , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/cirugía , Adolescente , Adulto , Neoplasias Óseas/patología , Estudios de Casos y Controles , Niño , Preescolar , Cisplatino/administración & dosificación , Terapia Combinada , Difosfonatos/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Ifosfamida/administración & dosificación , Imidazoles/administración & dosificación , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Osteosarcoma/secundario , Pronóstico , Tasa de Supervivencia , Adulto Joven , Ácido ZoledrónicoRESUMEN
OBJECTIVE: Uterine sarcomas are rare tumors with a poor prognosis. Their diagnosis is often incidental, following surgery. Our goal was to examine the early management strategies for uterine sarcomas, and to assess the impact of guideline adherence and expert center referral on both the management approaches and the clinical outcomes in patients with uterine sarcomas. METHODS: We retrospectively analyzed medical records from patients with uterine sarcoma referred to the Institut Curie and registered in the database of the French NETSARC network. RESULTS: In total, 100 patients, with a median age of 54 years, were included in the analyses. On MRI scans (n = 36), all patients had at least two signs suggestive of malignancy, and 77.8 % had four or more signs. No preoperative biopsy was performed in 65.6 % of cases. Only 14.1 % of patients underwent initial surgery at an expert center. Surgery performed outside the network was significantly associated with morcellation (32.9 % vs. 0 %; p = 0.036), fewer negative margins (R0 margins 52.4 % vs. 100 %; p = 0.006), and poor adherence to surgical guidelines (28.3 vs. 72.7 %; p = 0.013). Multivariate analysis showed that non-adherence to surgical recommendations was not significantly associated with relapse-free survival (HR = 0.54; 95 % CI [0.21-1.38]), but was an independent predictor of poor overall survival (HR = 0.12; 95 % CI [0.03-0.52]; p = 0.005). CONCLUSION: Despite a high frequency of suspicious clinical and radiological signs, a large proportion of women undergoing sarcoma surgery are treated outside of expert networks. We provide guidelines, integrating the clinical context and radiological signs to encourage early referral to reference centers for sarcoma.
Asunto(s)
Neoplasias Pélvicas , Sarcoma , Neoplasias de los Tejidos Blandos , Neoplasias Uterinas , Humanos , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adhesión a Directriz , Sarcoma/diagnóstico por imagen , Sarcoma/cirugía , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/cirugía , Neoplasias de los Tejidos Blandos/cirugía , Derivación y ConsultaRESUMEN
BACKGROUND: Until now, FISH has been the gold standard technique to identify HER2 amplification status in ambiguous cases of breast cancer. Alternative techniques have been developed to increase the capacities of investigating HER2 amplification status. The aims of this multicenter study in a large series of breast cancer patients were to prospectively compare the level of performance of CISH, SISH, and qPCR alternative techniques on paraffin-embedded core biopsies with "gold standard FISH" for evaluation of HER2 amplification status. METHODS: This study was performed on 840 cases scored by immunohistochemistry (IHC): 0=317 (38%), 1+=183 (22%), 2+=109 (13%), 3+=231 (27%). Each of the 15 French centers participating in the study analyzed 56 breast carcinoma cases diagnosed on fixed paraffin-embedded core biopsies. HER2 amplification status was determined by commercially available FISH used as the reference technique with determination of the HER2/CEN17 ratio or HER2 copy number status. The alternative techniques performed on the same cases were commercially available SISH or CISH and a common qPCR method especially designed for the study including a set of 10 primer pairs: 2 for HER2 (exons 8 and 26), 5 to evaluate chromosome 17 polysomy TAOK1, UTP6, MRM1, MKS1, SSTR2 and 3 for diploidy control TSN, LAP3 and ADAMTS16. RESULTS: The concordance between IHC and FISH was 96% to 95% based on the HER2/CEN17 ratio (n=766) or HER2 copy number (n=840), respectively. The concordance of the alternative techniques with FISH was excellent: 97% and 98% for SISH (498 and 587 cases), 98% and 75% for CISH (108 and 204 cases) and 95% and 93% (699 and 773 cases) for qPCR based on the HER2/CEN17 ratio or HER2 copy number, respectively. Similarly, sensitivity ranged from 99% to 95% for SISH, 100% to 99% for CISH and 89% to 80% for qPCR. The concordance with FISH (ratio) in the 2+ cases was 89% for SISH, 100% for CISH and 93% for qPCR. CONCLUSION: These alternative techniques showed an excellent concordance with FISH in core biopsies allowing their use in routine clinical practice. This newly designed qPCR on paraffin-embedded core biopsies deserves special attention, as it is reliable, easy to perform and less expensive than ISH tests.
Asunto(s)
Neoplasias de la Mama/genética , Genes erbB-2/genética , Hibridación in Situ/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Biopsia con Aguja Gruesa , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
OBJECTIVE: Chordomas are rare bone neoplasms characterized by a high recurrence rate and no benefit from any approved medical treatment to date. However, the investigation of molecular alterations in chordomas could be essential to prognosticate, guide clinical decision-making, and identify theranostic biomarkers. The aim of this study was to provide a detailed genomic landscape of a homogeneous series of 64 chordoma samples, revealing driver events, theranostic markers, and outcome-related genomic features. METHODS: The authors conducted whole-exome sequencing (WES), targeted next-generation sequencing, and RNA sequencing of 64 skull base and spinal chordoma samples collected between December 2006 and September 2020. Clinical, histological, and radiological data were retrospectively analyzed and correlated to genetic findings. RESULTS: The authors identified homozygous deletions of CDKN2A/2B, PIK3CA mutations, and alterations affecting genes of SWI/SNF chromatin remodeling complexes (PBRM1 and ARID1A) as potential theranostic biomarkers. Using matched germline WES, they observed a higher frequency of a common genetic variant (rs2305089; p.(Gly177Asp)) in TBXT (97.8%, p < 0.001) compared to its distribution in the general population. PIK3CA mutation was identified as an independent biomarker of short progression-free survival (HR 10.68, p = 0.0008). Loss of CDKN2A/2B was more frequently observed in spinal tumors and recurrent tumors. CONCLUSIONS: In the current study, the authors identified driver events such as PBRM1 and PIK3CA mutations, TBXT alterations, or homozygous deletions of CDKN2A/2B, which could, for some, be considered potential theranostic markers and could allow for identifying novel therapeutic approaches. With the aim of a future biomolecular prognostication classification, alterations affecting PIK3CA and CDKN2A/2B could be considered as poor prognostic biomarkers.
Asunto(s)
Cordoma , Neoplasias de la Base del Cráneo , Neoplasias de la Columna Vertebral , Humanos , Pronóstico , Cordoma/patología , Neoplasias de la Columna Vertebral/genética , Medicina de Precisión , Estudios Retrospectivos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Biomarcadores , Neoplasias de la Base del Cráneo/patología , Base del Cráneo/patología , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
Flat epithelial atypia (FEA) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. We retrospectively reviewed the data for 271 FEA cases among 5,555 breast core biopsies obtained over a 7-year period (January 2003-2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. The 271 FEA comprised 128 cases of pure FEA, 135 cases of FEA + atypical ductal hyperplasia, and 8 cases of FEA + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. The presence of FEA at biopsy warrants surgery.
Asunto(s)
Neoplasias de la Mama/patología , Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Mama/cirugía , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/cirugía , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Osteosarcoma is the most common primary bone malignancy in childhood and adolescence. However, it is very rare in children under 5 years of age. Although studies in young children are limited in number, they all underline the high rate of amputation in this population, with conflicting results being recently reported regarding their prognosis. METHODS: To enhance knowledge on the clinical characteristics and prognosis of osteosarcoma in young children, we reviewed the medical records and histology of all children diagnosed with osteosarcoma before the age of five years and treated in SFCE (Société Française des Cancers et leucémies de l'Enfant) centers between 1980 and 2007. RESULTS: Fifteen patients from 7 centers were studied. Long bones were involved in 14 cases. Metastases were present at diagnosis in 40% of cases. The histologic type was osteoblastic in 74% of cases. Two patients had a relevant history. One child developed a second malignancy 13 years after osteosarcoma diagnosis.Thirteen children received preoperative chemotherapy including high-dose methotrexate, but only 36% had a good histologic response. Chemotherapy was well tolerated, apart from a case of severe late convulsive encephalopathy in a one-year-old infant. Limb salvage surgery was performed in six cases, with frequent mechanical and infectious complications and variable functional outcomes.Complete remission was obtained in 12 children, six of whom relapsed. With a median follow-up of 5 years, six patients were alive in remission, seven died of their disease (45%), in a broad range of 2 months to 8 years after diagnosis, two were lost to follow-up. CONCLUSIONS: Osteosarcoma seems to be more aggressive in children under five years of age, and surgical management remains a challange.
Asunto(s)
Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Osteosarcoma/diagnóstico , Osteosarcoma/terapia , Amputación Quirúrgica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Preescolar , Terapia Combinada , Humanos , Lactante , Estimación de Kaplan-Meier , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Identification of predictive markers of response to treatment is a major objective in breast cancer. A major problem in clinical sampling is the variability of RNA templates, requiring accurate management of tumour material and subsequent analyses for future translation in clinical practice. Our aim was to establish the feasibility and reliability of high throughput RNA analysis in a prospective trial. METHODS: This study was conducted on RNA from initial biopsies, in a prospective trial of neoadjuvant chemotherapy in 327 patients with inoperable breast cancer. Four independent centres included patients and samples. Human U133 GeneChips plus 2.0 arrays for transcriptome analysis and quantitative RT-qPCR of 45 target genes and 6 reference genes were analysed on total RNA. RESULTS: Thirty seven samples were excluded because i) they contained less than 30% malignant cells, or ii) they provided RNA Integrity Number (RIN) of poor quality. Among the 290 remaining cases, taking into account strict quality control criteria initially defined to ensure good quality of sampling, 78% and 82% samples were eligible for transcriptome and RT-qPCR analyses, respectively. For RT-qPCR, efficiency was corrected by using standard curves for each gene and each plate. It was greater than 90% for all genes. Clustering analysis highlighted relevant breast cancer phenotypes for both techniques (ER+, PR+, HER2+, triple negative). Interestingly, clustering on trancriptome data also demonstrated a "centre effect", probably due to the sampling or extraction methods used in on of the centres. Conversely, the calibration of RT-qPCR analysis led to the centre effect withdrawing, allowing multicentre analysis of gene transcripts with high accuracy. CONCLUSIONS: Our data showed that strict quality criteria for RNA integrity assessment and well calibrated and standardized RT-qPCR allows multicentre analysis of genes transcripts with high accuracy in the clinical context. More stringent criteria are needed for transcriptome analysis for clinical applications.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Análisis por Conglomerados , Femenino , Humanos , Terapia Neoadyuvante , Reproducibilidad de los Resultados , Proyectos de InvestigaciónRESUMEN
The survival of osteosarcoma and Ewing family tumours has been improved by the introduction of neoadjuvant chemotherapy. The response to preoperative chemotherapy is evaluated on the microscopic analysis of the surgical resection, by the percentage of tumour necrosis according to the Huvos and Rosen's grading. It remains the only reliable prognostic factor for patients and is used to guide the choice of post-operative chemotherapy. The macroscopic and microscopic management of the surgical resection (cf. supra) is essential and is the subject of a specific protocol. Several studies have been conducted to identify news factors able to predict the response to chemotherapy, the tumour aggressiveness and its ability to develop metastases. Inhibitors of mTOR and/or regulators of the balance RANKL/OPG are promising therapeutics. The study's expression of these new factors could be performed on the biopsy and will offer new therapeutic strategy.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/patología , Quimioterapia Adyuvante , Terapia Neoadyuvante , Osteosarcoma/patología , Patología Clínica , Rol del Médico , Sarcoma de Ewing/patología , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias Óseas/química , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/cirugía , Terapia Combinada , Manejo de la Enfermedad , Humanos , Comunicación Interdisciplinaria , Imagen por Resonancia Magnética , Terapia Molecular Dirigida , Osteosarcoma/química , Osteosarcoma/diagnóstico , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/cirugía , Pronóstico , Sarcoma de Ewing/química , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/cirugía , Manejo de Especímenes/métodos , Resultado del TratamientoRESUMEN
Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical ("OSNew") biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA- patients (padj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy (p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA- patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163-) mostly residing in osteolytic territories and osteoid-matrix-associated CD68-/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets.
RESUMEN
To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial.