Valérie Dumaine

The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis

Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies. Experimental Design: The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial–mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines. Results: The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active β-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann–mesenchymal transition. Conclusion: We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis. Clin Cancer Res; 20(2); 358–71. ©2013 AACR.

Acute pancreatitis related to tigecycline: case report and review of the literature.

Tigecycline is a new broad-spectrum antibiotic. Nausea and vomiting are its most common side-effects. We describe here a case of severe acute pancreatitis related to tigecycline in order to highlight the possible occurrence of this adverse event and to remind clinicians to measure the lipase rate if in any doubt.

MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis

BackgroundNeurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals. The hallmarks of NF1 are the development of peripheral nerve sheath tumors either benign (dermal and plexiform neurofibromas) or malignant (MPNSTs).ResultsTo comprehensively characterize the role of microRNAs in NF1 tumorigenesis, we analyzed 377 miRNAs expression in a large panel of dermal and plexiform neurofibromas, and MPNSTs. The most significantly upregulated miRNA in plexiform neurofibromas was miR-486-3p that targets the major tumor suppressor gene, PTEN. We confirmed PTEN downregulation at mRNA level. In plexiform neurofibromas, we also report aberrant expression of four miRNAs involved in the RAS-MAPK pathway (miR-370, miR-143, miR-181a, and miR-145). In MPNSTs, significant deregulated miRNAs were involved in PTEN repression (miR-301a, miR-19a, and miR-106b), RAS-MAPK pathway regulation (Let-7b, miR-195, and miR-10b), mesenchymal transition (miR-200c, let-7b, miR-135a, miR-135b, and miR-9), HOX genes expression (miR-210, miR-196b, miR-10a, miR-10b, and miR-9), and cell cycle progression (miR-195, let-7b, miR-20a, miR-210, miR-129-3p, miR-449a, and miR-106b).ConclusionWe confirmed the implication of PTEN in genesis of plexiform neurofibromas and MPNSTs in NF1. Markedly deregulated miRNAs might have potential diagnostic or prognostic value and could represent novel strategies for effective pharmacological therapies of NF1 tumors.

Surgical management of pelvic primary bone tumors involving the sacroiliac joint

INTRODUCTION Pelvic primary malignant bone tumours, especially when involving the sacroiliac joint are difficult to treat. Abdominoperineal amputations are today used, only in life-threatening situations. HYPOTHESIS A precisely planed surgical technique can save the affected extremity without compromising the resection quality and subsequent patient survival. OBJECTIVE To assess the procedures used for resection and reconstruction of bone tumours invading the sacroiliac joint as well as their effects on cancer outcome and functional results. MATERIALS AND METHODS This is a continuous and retrospective analysis of 24 patients treated between 1986 and 2003. Six tumours affected the sacral body and 18 tumours involved the wing of the ilium. The joint articular surface was invaded in only six cases. Seventeen patients received neoadjuvant chemotherapy. The procedure was performed through an enlarged iliac crest incision, giving access to two sections of the pelvic ring. Six cases required neurological sacrifice. Initial tumour grading was based on the Enneking classification, and the functional results, on the Musculoskeletal Tumour Society (MSTS) scoring system. RESULTS The average operation lasted 5.27 hours. Reconstruction was performed with bone autograft and instrumentation. Resection was large with adequate margins 11 times, marginal 12 times, and contaminated once. Average follow-up was 4.77 years. The 5-year survival rate was 50%. Twelve patients either died from their disease or were in the metastatic stage at final follow-up. Survival was linked to the quality of resection and initial tumour staging. Hemisacrectomy did not affect patient survival. Local recurrences had a poor prognosis with eight cases of secondary metastases out of 11. Bone healing occurred in 13 patients, 10 of whom survived. Of the 12 patients who survived and were in complete remission at final follow-up, the average MSTS score was 61%. The score was at 38.6% in cases involving neurological sacrifice, and at 77.1% for the rest of the group. It was at 64% in healed cases and 13% in nonunion cases. DISCUSSION The survival of patients presenting with a sacroiliac joint tumour is substantially related to both tumour histology and resection quality. Local recurrences carry a poor prognosis with a high rate of secondary metastatic dissemination. In situations where disease control can be achieved, the proposed method of reconstruction allows, satisfactory bone healing and fair functional recovery, provided no major neurological sacrifice has taken place. LEVEL OF EVIDENCE level IV: Retrospective Therapeutic Study.

Pelvic chondrosarcomas: Surgical treatment options

INTRODUCTION Chondrosarcoma (CS) is a primary malignant bone tumor with cartilaginous differentiation. The only available treatment is carcinological surgical resection since the usual adjuvant treatments are ineffective. The pelvic location creates specific technical difficulties both for exeresis and reconstruction. Our objective was to evaluate the carcinological and functional outcomes of inter-ilioabdominal amputation and conservative surgery. MATERIALS AND METHODS We retrospectively studied 59 cases of pelvis chondrosarcoma managed in our department between 1968 and 2003. Demographic, anatomopathological, surgical and survival data were analyzed. Survival was estimated by the Kaplan-Meier curves and the cumulative incidence method. Multivariate analysis was used to identify all possible independent prognostic variables. RESULTS There were 33 men and 26 women, with an average age of 48 years. The average follow-up duration was 94 months. Eleven patients had a grade 1 chondrosarcoma, 36 a grade 2 chondrosarcoma, five were grade 3, and seven were dedifferentiated chondrosarcoma. Eleven patients underwent an inter-ilioabdominal disarticulation, and 48 had a more conservative surgery. Resection margins proved healthy in 46 patients (78%). Eighteen patients (31%) had a local recurrence, and 12 (20%) had metastases. At last follow-up, 30 patients (51%) were still alive without any sign of recurrence. Twenty-three patients (39%) died from the disease. Multivariate analysis showed that margin invasion was associated with a definitely increased local recurrence rate. A high tumoral grade was correlated with a greater risk of metastases occurrence. These two last factors (margin status and tumor grade) as well as acetabulum involvement were correlated with a reduced survival rate. Function was better among patients treated by conservative surgery, and among them, even better when the peri-acetabular area remained intact. Our study confirmed that resection margins quality is a major prognostic factor both for local control and for survival. On the other hand, local recurrence is an adverse survival prognosis factor and is itself correlated with resection margins quality. Peri-acetabular chondrosarcoma location (in zone 2) appears to be a poor oncological prognosis factor since, in this location, obtaining healthy margins appears particularly difficult. Compared to resection, inter-ilioabdominal amputation did not prove its superiority concerning resection margins quality or survival. However, resection guaranteed a better functional outcome. CONCLUSION Chondrosarcoma of the pelvic girdle remains of worse prognosis than peripheral bones chondrosarcoma since the critical prognosis factor is the resection margins quality. This location, and especially the peri-acetabular zone, poses difficult specific technical problems when conservative surgery is selected. Various imaging techniques should help better envision tumor resection extent. Inter-ilioabdominal amputation should only be resorted to in non-metastatic patients, when the tumor does not seem to be removable with sufficient healthy margins guarantee, or when local conditions make it impossible to hope for a good quality reconstruction. LEVEL OF EVIDENCE Level IV; therapeutic retrospective study.

Intercalary defects reconstruction of the femur and tibia after primary malignant bone tumour resection. A series of 13 cases

INTRODUCTION Performing intercalary segment reconstruction after malignant bone tumour resection results in both mechanical and biological challenges. Fixation must be solid enough to avoid short-term or mid-term mechanical failure. The use of an allograft or autograft must ensure long-term survival of the reconstruction. The goal of this study was to analyse the clinical and radiological outcomes of these reconstructions. PATIENTS AND METHODS Thirteen patients were operated on eight femurs and five tibias. The median age was 20 years old (range 14-50). The most common diagnosis was osteosarcoma. The median resection length was 15cm (Q1-Q3: 6-26). A plate was used for fixation in nine cases and an intramedullary locked nail in four cases. An isolated bone autograft was used in two cases, an isolated bone allograft in one case, a dual autograft-allograft composite in six cases, and vascularised fibula and allograft combination in four cases. RESULTS The cumulative probability of union was 46% (95% CI: 0-99%) at 1 year; at the final follow-up, union was achieved in 12 patients (92%). Because of non-unions, 13 iterative procedures were needed to obtain these results. A non-displaced fracture of a cuboid-shaped tibial graft occurred in one patient, which was treated conservatively. Three infections occurred. DISCUSSION The results of intercalary segmental defects reconstruction after bone tumour resection were good, both from an oncologic and radiological point-of-view. One or more iterative procedures are sometimes needed to finally obtain bone union. We prefer to use a free rectangular cuboidal tibial graft since reconstruction with a vascularised autograft is technically more difficult. The choice of fixation methods is still controversial and no approach was found to be superior. LEVEL OF EVIDENCE Level IV. Retrospective study.

Our experience of solitary plasmacytoma of the bone: improved PFS with a short-course treatment by IMiDs or proteasome inhibitors combined with intensity-modulated radiotherapy

Emmanuelle Le Ray, Lisa Belin, Corine Plancher, Philippe Anract, Antoine Babinet, Val erie Dumaine, J erôme Tamburini, B en edicte Deau Fischer, Lise Willems, Leonardo Magro, Thierry Facon, Xavier Leleu, Didier Bouscary and Youlia M. Kirova Service d’H ematologie, Hôpital Cochin, AP-HP, Paris, France; Facult e de M edecine Sorbonne Paris Cit e, Universit e Paris Descartes, Paris, France; Department of Biostatistics, Institut Curie, Paris, France; Service de chirurgie orthop edique, Hôpital Cochin, AP-HP, Paris, France; Institut Cochin, D epartement D eveloppement Reproduction Cancer, CNRS UMR8104, INSERM U1016, Paris, France; Service d’H ematologie, CHRU Lille, Lille, France; Service d’h ematologie, CHU de Poitiers, Poitiers, France; Department of Radiation Therapy, Institut Curie, Paris, France

Principios terapéuticos quirúrgicos de los tumores óseos de los miembros (incluyendo la cintura escapular y el hueso coxal)

Los tumores oseos malignos primarios son tumores infrecuentes. Su baja incidencia y la necesidad de un tratamiento multidisciplinario, a cargo de medicos con experiencia en esta afeccion, imponen el traslado de estos pacientes a los centros de referencia o, como minimo, el analisis de los casos en reuniones de concertacion multidisciplinaria especializada. La reseccion quirurgica de los tumores malignos oseos debe ser amplia, es decir, habra que dejar en contacto con el tumor una capa de tejido sano (margen). En mas del 80% de los casos es posible reconstruir el segmento oseo o la articulacion y, por tanto, conservar el miembro. Las diafisis se reconstruyen con preferencia mediante una combinacion de auto y aloinjerto con osteosintesis. En la mayoria de los casos, las articulaciones se reconstruyen con una protesis masiva o se efectua una reconstruccion compuesta (protesis rodeada por un aloinjerto). Cuando, ademas de la articulacion, la reseccion incluye los musculos periarticulares, se prefiere la artrodesis. Las resecciones de la pelvis, si se limitan al ala iliaca o al marco isquiopubico, no necesitan reconstruccion. En cambio, las resecciones de la region acetabular y del ala iliaca, que interrumpen la continuidad del anillo pelvico, imponen la reconstruccion a efectos de lograr un resultado funcional aceptable. La reconstruccion de la cadera tras la reseccion del acetabulo es mucho mas dificil. En caso de reseccion de la region acetabular, sola o asociada a la del marco isquiopubico, los autores de este articulo prefieren la reconstruccion con un autoinjerto de femur proximal y una protesis. Tambien es posible usar las protesis en silla de montar, las de tipo Mac Minn con auto o aloinjerto, las protesis modulares y a medida, los aloinjertos masivos con o sin protesis y las artrodesis femoroiliacas. En caso de reseccion del ala iliaca y de la region acetabular, las reconstrucciones posibles son: la artrodesis isquiofemoral y femorosacra, la reconstruccion mediante autoinjerto de femur proximal y protesis, la medializacion de la cabeza femoral, los aloinjertos y las protesis masivas. Las amputaciones se tratan en otro articulo de la EMC.