Regorafenib in patients with relapsed advanced or metastatic chordoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study.

BACKGROUND: REGOBONE multicohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the cohort of patients with relapsed advanced or metastatic chordoma. METHODS: Patients with relapsed chordoma progressing despite 0-2 prior lines of systemic therapy, were randomised (2 : 1) to receive regorafenib (160 mg/day, 21/28 days) or placebo. Patients on placebo could cross over to receive regorafenib after centrally-confirmed progression. The primary endpoint was the progression-free rate at 6 months (PFR-6) (by RECIST 1.1). With one-sided α of 0.05, and 80% power, at least 10/24 progression-free patients at 6 months (PFR-6) were needed for success. RESULTS: From March 2016 to February 2020, 27 patients were enrolled. A total of 23 patients were assessable for efficacy: 7 on placebo, 16 on regorafenib, 16 were men, median age was 66 (32-85) years. At 6 months, in the regorafenib arm, 1 patient was not assessable, 6/14 were non-progressive (PFR-6: 42.9%; one-sided 95% CI = 20.6) 3/14 discontinued regorafenib due to toxicity; and in the placebo arm, 2/5 patients were non-progressive (PFR-6: 40.0%; one-sided 95% CI = 7.6), 2 were non-assessable. Median progression-free survival was 8.2 months (95% CI 4.5-12.9 months) on regorafenib and 10.1 months (95% CI 0.8 months-non evaluable [NE]) on placebo. Median overall survival rates were 28.3 months (95% CI 14.8 months-NE) on regorafenib but not reached in placebo arm. Four placebo patients crossed over to receive regorafenib after centrally-confirmed progression. The most common grade ≥3 regorafenib-related adverse events were hand-foot skin reaction (22%), hypertension (22%), pain (22%), and diarrhoea (17%), with no toxic death. CONCLUSION: This study failed to show any signal of benefit for regorafenib in patients with advanced/metastatic recurrent chordoma.

Protuberant fibro-osseous lesion of the temporal bone: report of four cases and review of the literature.

'Bullough lesions', also referred to as protuberant fibro-osseous lesions (PFOL), are rare temporal bone lesions initially described in 1999. Since only 12 cases have been reported, several key issues, such as their origin and recommended management strategies, remain unresolved. This article reports the largest cohort included in the literature to date, comprising four patients with PFOL. PFOL appears to be characterized by female and right-side predominance. These lesions were consistently located regarding the mastoid, generally diagnosed in early adulthood, without functional symptoms, and were always fibro-osseous. Invasive/malignant features were not found on imaging or histology. The main differential diagnosis was malignant low-grade parosteal osteosarcoma. Clinical examination and computed tomography images provided strong elements supporting the diagnosis of PFOL. Biopsy allowed molecular biology investigations (MDM2 and CDK4 amplification), in order to rule out low-grade parosteal osteosarcoma.

Percutaneous cryoablation of osteoblastoma in the proximal femur.

A 37-year-old man presented with a 2-year history of left hip pain. Pretherapeutic imaging demonstrated a 4 cm osteoblastoma located in the intertrochanteric region of the proximal femur, surrounded by extensive bone marrow edema. After multidisciplinary meeting, percutaneous cryoablation was decided and performed under computed tomography guidance using three cryoprobes to match the exact size and shape of the tumor, resulting in complete resolution of symptoms. Magnetic resonance imaging follow-up demonstrated resolution of the bone marrow edema pattern and ingrowth of fat at the periphery of the ablation zone consistent with long-term healing of the tumor.

Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

BACKGROUND: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. PATIENTS AND METHODS: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. RESULTS: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. CONCLUSION: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells.

Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1high states, characterized by highly active cell proliferation, and EWSR1-FLI1low states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.

"Giant cell reparative tumor: An exceptional differential diagnosis for a lytic lesion of the temporal bone".

BACKGROUND AND IMPORTANCE: Giant cell reparative granuloma is a very rare benign osteolytic lesion. It typically arises in the mandible and rarely involves the skull. CLINICAL PRESENTATION: A 25-year-old male was admitted in August 2002 for a painless left preauricular mass of several months duration. CT scan revealed an osteolytic extradural lesion located in the temporal bone, with extension to infratemporal fossa. We performed a surgical partial resection of the tumour via a frontotemporal approach. At 36 months after surgery, the lesion continued growth and subsequently we decided to perform a preauricular infratemporal approach. After a ten year-follow-up, the patient remained asymptomatic and a small tumour remnant was visible and stable. CONCLUSION: Giant cell reparative granulomas that originate from the temporal bone are exceptional. There are no typical radiological features of this disease. Diagnosis is confirmed by analysis of the surgical specimen. Tumor growth requires surgical resection.

Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution.

BACKGROUND: Pilocytic astrocytomas (PAs) are characterized by an excellent prognosis although several factors of adverse outcome have been reported. The mitogen-activated protein kinase pathway plays a major role in their tumorigenesis. AIM: To report a series of 148 PAs in children to define clinicopathological and biological prognostic factors. METHODS: Clinical data were collected from patient files and mail inquiry. Pathological specimens were centrally reviewed. The three major KIAA1549:BRAF fusion subtypes were analysed by reverse transcription - polymerase chain reaction (RT-PCR) in a subset of 47 frozen cases and by fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue in 23 cases. Tumour location, age at surgery, extent of surgical removal, histological subtype and KIAA1549:BRAF fusion by RT-PCR were searched for prognostic significance. RESULTS: Pilomyxoid astrocytoma (PMA) and the hypothalamo-chiasmatic (H/C) location were associated with a worse prognosis [P < 0.001 for overall survival (OS) and P = 0.001 for progression-free survival (PFS)]. Patients who underwent complete surgical excision had a better OS (P = 0.004) and a longer PFS (P < 0.001) than the others. Age was also a strong prognostic factor for OS but not for PFS. Infants (<1 year) and young children (<3 years) had a much worse outcome than the others (P < 0.001 and P = 0.004 respectively). KIAA1549:BRAF fusion status was not predictive of outcome. CONCLUSION: This study highlights the good prognostic factors of PAs but H/C PA remains a subgroup with dismal prognosis associated with young age, PMA variant and incomplete surgery. Search for KIAA1549:BRAF fusion in tumours with PA pattern is recommended even though the prognostic impact is still unclear.

Value of diffusion-weighted images in differentiating mid-course responders to chemotherapy for osteosarcoma compared to the histological response: preliminary results.

BACKGROUND: Preoperative diffusion-weighted MRI (DW-MRI) has been described as an efficient method to differentiate good and poor responders to chemotherapy in osteosarcoma patients. A DW-MRI performed earlier during treatment could be helpful in monitoring chemotherapy. OBJECTIVE: To assess the accuracy of DW-MRI in evaluating response to chemotherapy in the treatment of osteosarcoma, more specifically at mid-course of treatment. MATERIALS AND METHODS: This study was carried out on a prospective series of adolescents treated for long-bone osteosarcoma. MR examinations were performed at diagnosis (MRI-1), at mid-course of chemotherapy (MRI-2), and immediately before surgery (MRI-3). A DW sequence was performed using diffusion gradients of b0 and b900. The apparent diffusion coefficients (ADC1, ADC2, ADC3, respectively), their differentials (ADC2 - ADC1 and ADC3 - ADC1), and their variation (ADC2 - ADC1/ADC1 and ADC3 - ADC1/ADC1) were calculated for each of these three time points. RESULTS: Fifteen patients were included. Patients with no increase in ADC showed a poor response to chemotherapy on their histology results. At mid-course, the three calculated values were significantly different between good and poor responders. ADC2 - ADC1 enabled us to detect, with 100% specificity, four out of seven of the poor responders. There was no significant difference in the values at MRI-3 between the two groups. CONCLUSION: DW-MRI performed both at baseline and mid-course of neoadjuvant chemotherapy is an efficient method to predict further histological response of osteosarcoma. This method could be used as an early prognostic factor to monitor preoperative chemotherapy.

Histomolecular classification of adult diffuse gliomas: the diagnostic value of immunohistochemical markers.

Adult gliomas are most often infiltrative. The World Health Organization (WHO) has classed them into three major groups according to the presomptive cell of origin: astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Depending on the presence or absence of a small number of signs of anaplasia (mitosis, nuclear atypia, cell density, microvascular proliferation and necrosis) the WHO distinguishes grade II (LGG), III (anaplastic), and IV (glioblastomas, GBM). Mutation in the isocitrate deshydrogenase I and II (IDH1 and 2) genes distinguishes grade II, III and secondary GBM from primary GBM. Moreover two additional genetic alterations are recorded in grade II and III gliomas: TP53 mutations that characterize astrocytomas and 1p19q codeletion (as the result of t(1;19)(q10;p10) translocation) recorded in oligodendrogliomas. Mixed gliomas, the most non-reproducible category, share with astrocytomas and oligodendrogliomas the same genetic alterations. Interestingly TP53 mutation (p53+) and 1p19q codeletion (1p19q+) are mutually exclusive and involve IDH mutated (IDH+) glial precursor cells. According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Interestingly, p53 expression and internexin alpha (INA) expression can replace to some extent TP53 mutation and 1p19 codeletion, respectively. Moreover the antibody directed against the IDH1R132H isoform is highly specific. Because this mutation is the most frequent it is sufficient to assess IDH status in more than 80% of grade II and III gliomas. Taken together these three immunohistochemical markers are contribute greatly to the classification of gliomas and should be tested routinely as diagnostic markers. Finally, although GBM are genetically heterogeneous, the vast majority display EGFR amplification, often associated with EGFR expression, which can be helpful for diagnosis in certain cases.

A study of 28 flat bone osteosarcomas: prognostic factors and early and long-term outcome.

Limited information is available on clinical management of Flat Bone Osteosarcomas (FBOS). We retrospectively analysed prognostic factors and outcome. Twenty-eight patients were treated in our institution. Survival curves were obtained by the Kaplan-Meier method and compared with the log-rank test. The overall survival (OS) rates at 5 and 10 years were 52.4% and 45.8% respectively. The event-free survival (EFS) rates at 5 and 10 years were 41.5%. The factors influencing EFS in univariate analysis were location, metastatic disease at diagnosis, effect of neoadjuvant chemotherapy, histological response and adequate local tumour control. Location, metastatic disease at diagnosis, effect of neoadjuvant chemotherapy, histological response and local recurrence were statistically correlated with OS. Multivariate analysis retained metastatic disease at diagnosis as prognostic factors of EFS and OS. Our results suggest a more favourable outcome of FBOS as the use of a treatment scheme based on the protocols for long bone osteosarcomas. However, an adequate local treatment is essential to ensure a better outcome.

[Glioblastomas: gliomagenesis, genetics, angiogenesis, and microenvironment]. / Glioblastomes : oncogenèse et bases biologiques.

BACKGROUND AND PURPOSE: Glioblastomas are the most malignant gliomas of the central nervous system. Currently, numerous studies are attempting to decipher their genetic and epigenetic modifications, to identify the cells at the origin of gliomagenesis, and to better understand the molecular bases responsible for invasion and angiogenesis processes. METHODS: This article reviews recent data on the cellular and molecular biology of gliomas delineated by several teams including ours. We and others have underlined the role played by cancer stem cells in gliomagenesis; the Cancer Genome Atlas Network has described most glioblastoma genetic alterations. RESULTS: According to many studies, glioblastomas derive from malignant transformation of stem cells and/or glial precursor cells. Moreover, the topographic microenvironment is important regarding invasion and angiogenesis processes. Finally, it is now well established, thanks to IDH1 mutation identification, that primary and secondary glioblastomas are two different clinical and genetic entities. Interestingly, IDH1 mutation seems to be a very early genomic modification in astrocytoma, oligodendroglioma, and secondary glioblastoma tumorigenic processes. CONCLUSIONS: Regarding all these data, we suggest a hypothetical model of glioma initiation, growth, and progression. Moreover, the histomolecular glioma classification has been substantially revised and new therapeutic targets have been identified.

[Morphological classification of glioblastomas]. / Classification morphologique des glioblastomes.

BACKGROUND AND PURPOSE: In the 2007 WHO classification, glioblastomas are classified among the group of astrocytic tumors. They are highly malignant (grade IV). This group of tumors is morphologically heterogeneous. The WHO distinguishes between clinico-pathological entities, variants of entities and histological pattern. Variants are defined as being reliably indentified histologically and having some relevance for clinical outcome but as still being part of a previously defined overarching entity. Patterns of differentiation are identifiable by histological appearances but without clinical or pathological significance. METHODS: The description of the histological and immunohistochemical features is based on the 2007 WHO classification. RESULTS: In addition to the classic form of glioblastoma, two variants exist: the giant cell GBM and the gliosarcoma. The first but not the second would have a better outcome than the classic glioblastoma. The WHO classification also distinguishes several patterns of differentiation: small cells glioblastoma; glioblastoma with lipidized cells; glioblastoma with oligodendroglioma component; glioblastoma with heterologous differentiation. These patterns have to be recognized because they represent sometimes a diagnostic challenge. GFAP, Olig2 and Mib1/Ki67 are the most relevant immunohistochemical markers. Diagnostic value of neuronal markers is still controversial. EGFR or p53 expression can be detected and their prognosis value is discussed in this chapter. A systematic analysis of some markers in routine, for example IDH1 or internexin-a, could help to define more homogeneous groups of patients.

Advanced hip osteoarthritis: magnetic resonance imaging aspects and histopathology correlations.

OBJECTIVES: To correlate magnetic resonance imaging (MRI) aspects of the femoral head with histological findings in advanced hip osteoarthritis (OA), with special emphasis on bone marrow edema (BME). METHODS: MRI was performed in patients with advanced hip OA scheduled for hip arthroplasty. Coronal T1-, fat-suppressed T2-, T1 with gadolinium intravenous injection sequences were obtained on a 1.5 T MR-scanner within 1 month before surgery. Coronal MR images corresponding to the ligamentum teres plane were analyzed by two independent readers blinded to histological data. Normal bone marrow, subchondral cyst, subchondral fracture, edema-like, necrosis-like, and necrosis MR patterns were reported on a synthesis scheme. After surgery, the femoral heads specimens were cut through the ligamentum teres plane and histologically analyzed for correlations. RESULTS: Twenty-three femoral heads were analyzed (female 56.5%, mean age 64.5 years). Edema-like MR pattern was correlated with histological (H) edema (Kappa (K): 0.77). Necrosis-like MR pattern was correlated with H fibrosis (K: 0.49) and with H necrosis (K: 0.24). Cyst MR pattern was correlated with H bone cysts (K: 0.58). Necrosis MR pattern corresponded to a mixture of histological lesions. Sensitivity and specificity of MRI varied from 26% to 80% and from 86% to 95% respectively. CONCLUSION: In advanced hip OA, the so-called "BME" MR lesion corresponds to a combination of edema, fibrosis, and necrosis at histopathology. When the classical "BME" is more specifically separated into edema-like and necrosis-like MR patterns, MR Imaging and histological findings show substantial agreement, with edema-like MR pattern mainly corresponding to histological edema.

Fatal lung metastasis secondary to index finger giant cell tumor in an 8-year-old child.

We report the case of a 7-year-old girl presenting with giant cell tumor (GCT) of the index finger, complicated by lung metastases. Index disarticulation, pulmonary metastasectomy and chemotherapy failed to produce a cure, and the child died at the age of 8 years after 1 year's evolution. The pulmonary metastases were discovered following hypoxia during initial biopsy. A review of the literature shows this observation to be original, in terms of the patient's age and of the location, onset and fatal outcome of metastasis. The hypoxic episode complicating biopsy raises the issue of early screening for lung metastases in GCT. Pulmonary dissemination of GCT is of severe prognosis.

[Pulmonary epithelioid haemangioendothelioma: two different clinical courses]. / Hémangioendothéliome épithélioïde pulmonaire: à propos de deux observations.

The first case report concerns a 59-year-old man presenting a chronic cough and the second a 23-year-old woman farmer presenting with worsening dyspnoea associated with cough, expectoration and haemoptysis. In the second case, the woman died 7 months after the onset of the respiratory symptoms. In both cases, chest radiography and thoracic CT scans showed multiple, bilateral pulmonary nodules, bronchial endoscopy was normal and surgical biopsy revealed epithelioid haemangioendothelioma. It is a rare primary pulmonary tumour which is usually found in soft tissue, bone or liver. Epithelioid haemangioendothelioma is a vascular tumour usually affecting women less than 40 years of age. The histological appearance is characteristic and may be confirmed by immunohistochemistry. Chemotherapy and radiotherapy are generally ineffective and surgery is sometimes impossible because of the multifocal lesions. Epithelioid haemangioendothelioma is considered a sarcoma without precise histological prognostic criteria. In its pulmonary location it is responsible for death due to respiratory failure in 50% of cases.

[Degenerating neurocysticercosis cysts: differential diagnosis with cerebral metastasis]. / Neurocysticercose cérébrale au stade de dégénérescence : diagnostic différentiel des métastases cérébrales.

INTRODUCTION: Neurocysticercosis is the most common parasitic disease of the central nervous system. It has a worldwide distribution. CASE REPORT: We report the case of a 70-year-old woman from Guadeloupe presenting gait abnormalities, impaired ideation, right hemiparesis in a context of weight loss, and fatigue. Blood analyses were normal with neither inflammatory syndrome nor blood hypereosinophilia. Brain computed tomography and magnetic resonance imaging showed hydrocephaly in relation with Sylvius' aqueduc stenosis, and diffuse contrast-enhancing lesions suggesting metastases. Because of clinical symptoms, the patient underwent ventriculostomy; the cerebral spinal fluid examination was normal. Then a frontal biopsy was performed. Histological examination was compatible with neurocysticercosis and confirmed by serology. The patient was successfully treated with albendazole and steroids. CONCLUSION: Neurocysticercosis must be considered as a differential diagnosis of cerebral metastasis, especially in patients from endemic countries.

[Desmoplastic small round-cell tumor: two cases of diffuse abdominopelvic infiltration]. / Tumeur desmoplastique à petites cellules rondes: deux cas d'atteinte abdominopelvienne diffuse.

Desmoplastic small round-cell tumors are a rare malignant tumor that affects male children and young adults. It frequently presents as a large abdominal mass with widespread peritoneal involvement at diagnosis. We report two cases of desmoplastic small round-cell tumors, with diffuse infiltration in the abdomen and pelvis in two adult caucasian males. The first case-report is a middle-aged man and the second a young adult man with early recurrence and diffuse metastatic lymph nodes. Both tumors have a distinct morphology, a polyphenotypic differentiation and a t(11;22) (p13;q12) translocation. The prognosis remains poor and leads to death in most cases, despite surgical resection, radiotherapy and high-dose chemotherapy.