[Show abstract][Hide abstract] ABSTRACT: Conventional skeletal chondrosarcoma is a bone neoplasm, which is poorly sensitive to anthracyclines-based chemotherapy. We report on an 18-month-long tumour response to gemcitabine as single agent in a young patient with an advanced secondary peripheral conventional chondrosarcoma, previously treated unsuccessfully with anthracyclines, ifosfamide, platinum, etoposide.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present work was to improve the understanding of the impact of malignancy grade and myogenic/rhabdomyoblastic differentiation on the natural course of retroperitoneal liposarcoma. All consecutive patients affected by primary well-differentiated (WD)/dedifferentiated (DD) retroperitoneal liposarcoma, surgically treated at our institution between January 2002 and December 2011, were retrospectively evaluated. Tumors were stained for mdm2 and 5 myogenic markers (smooth muscle actin-α, h-caldesmon, calponin, desmin, myogenin). The French National Federation of the Centers for the Fight Against Cancer (FNCLCC) grading system was applied. Overall survival, crude cumulative incidence of local recurrence, and distant metastases were calculated. Multivariable analyses were carried out. A total of 144 patients were identified. Median follow-up was 68 months (interquartile range: 46 to 104 mo). Fifty-two patients were affected by WD/G1 and 92 by DD liposarcoma. Among the latter, 60 were grade G2 and 32 G3. Myogenic differentiation was present in 54 cases (8/52 WD/G1, 27/60 DD/G2, 18/32 DD/G3). Seven cases had a rhabdomyoblastic DD component (1/60 DD/G2 and 6/32 DD/G3). Five-year overall survival rates were 93%, 57%, and 21% for WD/G1 liposarcoma, G2 DD, and G3 DD liposarcoma, respectively, and 75%, 42%, and 29% for liposarcoma without myogenic differentiation, with myogenic differentiation, with rhabdomyoblastic differentiation, respectively (P<0.001). Of note, 5/6 patients affected by G3 DD liposarcoma with a rhabdomyoblastic component died within 8 months. FNCLCC grade and myogenic differentiation significantly predicted the outcome of retroperitoneal liposarcoma. These should be factored into treatment decision-making and possibly used to stratify patients in clinical trials.
American Journal of Surgical Pathology 01/2015; 39(3). DOI:10.1097/PAS.0000000000000366 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Papillary thyroid carcinoma (PTC), tall cell (TC) variant, is exceptional in children. In adults it represents about 20% of PTCs, featuring a high-risk neoplasm, with a 4-fold risk of relapse and a 20-fold relapse-related risk of death. Out of 42 cases of pediatric PTCs, we found 3 cases of PTC-TC (7%) with clinical data at onset and follow-up up to June 2014. They were 3 females aged 13, 15, and 15 years. Local extrathyroid extension was present in 2 cases. Neither nodal nor distant metastases were found. Two patients underwent hemithyroidectomy and 1 patient a total thyroidectomy, followed in all cases by life-long suppressive hormonal therapy. On follow-up, the patients were alive and well after 29, 24, and 29 years, respectively. The rarity of PTC-TC in children was confirmed. The behavior was indolent after a median follow-up of about 29 years, following treatment with hemithyroidectomy in 2 cases and controlled by suppressive hormonal therapy. The results of this series, albeit small, suggest that TC morphology in PTC does not carry the same negative prognostic significance in children as it does in adults. A conservative approach should therefore be considered for these 'pediatric type' cases of this tumor type.
International Journal of Surgical Pathology 09/2014; 22(6):499-504. DOI:10.1177/1066896914545399 · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With improvements in the survival rates after childhood cancer, many clinicians have turned their attention to reporting on late effects, and how they might be prevented or treated. In childhood the thyroid gland is especially vulnerable to the carcinogenic action of ionizing radiation. This retrospective study focused on secondary thyroid cancers seen at our institution over more than 30 years (between 1980 and 2012) in patients treated for other malignancies in pediatric age. 36 patients were identified. In most cases, the primary cancer had been Hodgkin disease, and all the patients had been administered radiotherapy for their first malignancy. The secondary thyroid cancers were treated with total thyroidectomy in 27 cases (six with lymphadenectomy), and hemithyroidectomy in nine (one with lymphadenectomy). 12 Patients were also given radiometabolic therapy. All but two had TSH suppression therapy. The histological diagnoses were: 31 papillary and five follicular carcinomas. At 5 and 10 years, the OS was 100 and 95 %, respectively, and the PFS was 96 and 83 %. None of the patients died of their thyroid disease. Nodal involvement at onset was the only factor correlating with recurrence. Surgical sequelae only occurred in patients who underwent total thyroidectomy. Survival in these patients did not depend on the extent of surgery on the thyroid parenchyma. Our data confirm a good prognosis for secondary thyroid cancer, prompting us to encourage a minimalist approach to the treatment of these particular patients wherever possible.
Medical Oncology 08/2014; 31(8):121. DOI:10.1007/s12032-014-0121-6 · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real
impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse
of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic
complexity and response to chemotherapy.
Annals of Oncology 07/2014; 25(11). DOI:10.1093/annonc/mdu362 · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Association of melanoma, neural system tumors and germ line mutations at the 9p21 region in the CDKN2A, CDKN2B and CDKN2BAS genes has been reported in a small number of families worldwide and described as a discrete syndrome in melanoma families registered as a rare disease, the melanoma–astrocytoma syndrome.
We here studied two young patients developing melanoma after radiotherapy for astrocytoma, both reporting lack of family history for melanoma or neural system tumors at genetic counselling. Patient A is a girl treated for anaplastic astrocytoma at 10 years and for multiple melanomas on the scalp associated to dysplastic nevi two years later. Her monozygotic twin sister carried dysplastic nevi and a slow growing, untreated cerebral lesion. Direct sequencing analysis showed no alterations in melanoma susceptibility genes including CDKN2A, CDK4, MC1R and MITF or in TP53. By microsatellite analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization a deletion including the CDKN2A, CDKN2B and CDKN2BAS gene cluster was detected in both twin sisters, encompassing a large region at 9p21.3 and occurring de novo after the loss of one paternal allele.
Patient B is a boy of 7 years when treated for astrocytoma then developing melanoma associated to congenital nevi on the head 10 years later: sequencing and multiplex ligation-dependent probe amplification revealed a normal profile of the CDKN2A/CDKN2B/CDKN2BAS region. Array comparative genomic hybridization confirmed the absence of deletions at 9p21.3 and failed to reveal known pathogenic copy number variations.
By comparison with the other germ line deletions at the CDKN2A, CDKN2B and CDKN2BAS gene cluster reported in melanoma susceptible families, the deletion detected in the two sisters is peculiar for its de novo origin and for its extension, as it represents the largest constitutive deletion at 9p21.3 region identified so far.
In addition, the two studied cases add to other evidence indicating association of melanoma with exposure to ionizing radiation and with second neoplasm after childhood cancer. Melanoma should be considered in the monitoring of pigmented lesions in young cancer patients.
BMC Medical Genetics 05/2014; 15(1):59. DOI:10.1186/1471-2350-15-59 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells.
PLoS ONE 05/2014; 9(5):e96238. DOI:10.1371/journal.pone.0096238 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The survival of patients with axial skeletal or pelvic osteosarcoma (OS) remains poor, and the management of these patients is challenging. The object of this study is a cohort of unselected patients aged < 19 years with primary high-grade pelvic/axial OS. Patients were treated with high-dose methotrexate, doxorubicin, cisplatin, ifosfamide followed or preceded by local treatment (surgery and/or radiotherapy). Twenty patients aged 3-19 years were treated. Eight patients had pelvic OS, 8 axial OS and 4 mandible/maxilla OS. All patients received chemotherapy, after which necrosis was evaluable in 9 patients (≥90 % in 3). Sixteen patients underwent surgery. Radiotherapy was administered to 8 patients (total dose 34-60 Gy). The median follow-up was 35 months (8-276), and the 5-year disease-free survival and overall survival rates were 37 and 40 %, respectively. Six patients were alive at the time of this report: 2 with pelvic OS (both responded well to chemotherapy, one underwent hemipelvectomy and the other had non-radical surgery plus radiotherapy); 1 with axial and multicentric OS (with a good histological response and radical surgery); 3 with mandible/maxilla OS. Two patients died of secondary tumors (one bone and one breast cancer). It is worth noting that 4 patients had a p53 mutation: 1 is alive, 2 died of their OS, 1 of breast cancer. Adequacy of local treatment and pathological response influenced the prognosis for axial OS, which remained dismal. A high incidence of p53 mutation emerged in our series of patients.
Medical Oncology 04/2014; 31(4):875. DOI:10.1007/s12032-014-0875-x · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Large intrathoracic tumors may occasionally present with massive infiltration of the lung and chest wall that would require pneumonectomy and total removal of the rib cage to obtain radical surgical excision, but this operation carries a prohibitive risk of death for cardiopulmonary failure in the absence of adequate chest wall reconstruction.
We report here four consecutive cases of thoracopleuropneumonectomy (TPP) with en-bloc resection of the entire lung, chest wall, and diaphragm and immediate riblike reconstruction for recurrent thoracic sarcomas. Patients had undergone the initial thoracic surgical resection with curative intent 2-14 years before TPP. There was no postoperative mortality, and all patients were alive and free of disease 8-21 months after TPP.
To our knowledge, this is the first report in the medical literature of such an extensive operation, demonstrating technical feasibility, tolerability, and efficacy of one-stage resection and reconstruction by a semirigid three-dimensional riblike prosthesis modeled on a human-derived aluminum cast.
Selected patients with advanced low-intermediate thoracic sarcomas are the ideal candidates for this extreme procedure, to maximize the chance of long-term tumor control and possibly cure.
[Show abstract][Hide abstract] ABSTRACT: AimsEwing sarcoma primary to the ileum (IES) has rarely been documented. Little is known about the pathogenesis and clinical implications of IES, which may be critical to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in ES, as FEV expression is restricted to prostate, brain, and serotonin neuroendocrine cells (NE) and related tumors. Methods and resultsParaffin sections or snap-frozen material was used in this investigation. Tumors were investigated by means of immunohistochemistry, RT-PCR (EWSR1-FLI1, EWSR1-ERG and EWSR1-FEV transcripts), FISH analysis (EWSR1 break-apart and specific EWSR1-FEV translocation) and spectral karyotyping (SKY). Ten ileum neuroendocrine tumors (INET) made up the control group for EWSR1-FEV translocation.Among 445 ES cases spanning a period of 20 years, seven (1.6%) were IES. All tumors were immunoreactive for synaptophysin, CD99, FLI 1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumor showing the uncommon EWSR1-FEV rearrangement upon SKY, RT-PCR and FISH confirmation. The mean survival of EWSR1-FLI1 patients was 14 months, whereas the EWSR1-FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation. Conclusions
Most IES share the common EWSR1-FLI1 translocation, but EWSR1-FEV could be specific of tumors arising in the ileum and showing better prognosis.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.471.
[Show abstract][Hide abstract] ABSTRACT: Patients with localized high risk STS of limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by MDR mechanisms. The aim of the current study was to ascertain whether mRNA and protein expression of ABCB1 (P-gp), ABCC1 (MRP1) and GSTA1 (GST-π) was prognostic in localized high risk STS. Immunohistochemistry and RT-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial which compared 3 vs. 5 cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with RFS were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, p=0.029), histology (5-year RFS rate of 74% in UPS and 43% in synovial sarcoma, p=0.028) and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, p=0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR 2.704, p=0.005) and OS (HR 2.208, p=0.029). ABCC1/MRP1 expression shows robust prognostic relevance in localized high risk STS patients treated with anthracycline based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS.
Molecular Cancer Therapeutics 10/2013; 13(1). DOI:10.1158/1535-7163.MCT-13-0406 · 6.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The role of FDG-PET in Wilms' tumor has not been well established. The aim of this report is to describe the role of FDG-PET to assess chemotherapy efficacy and to show potential correlations between different Standardized Uptake Values (SUVs) and histopatological features in a patient with persisting metastatic disease. CASE description: A 3-year-old boy was diagnosed with Wilms' tumor without anaplasia. The patient underwent treatment as according to the AIEOP-TW-2003 protocol, for stage III tumors. Therapy was discontinued with no evidence of disease, yet 9 months later thorax metastases were found. Although second and third line treatments were administered, conventional imaging demonstrated stable disease. Metronomic chemotherapy as well was employed for 44 months and FDG-PET was annually performed basing on responsible local physician choice trying to better describe the disease status. Four months after fourth line treatment was stopped, the patient manifested clinical symptoms; lesions began to increase their metabolic activity inhomogeneously. Therapy was hence restarted and SUVs decreased. Metastasectomies were then performed and histology revealed a correlation between viable disease shown by higher FDG-PET uptake and viable tumor areas. Conclusions: Our case discussion demonstrates that FDG-PET is potentially valuable in Wilms' tumor correlating SUV values and histological features of the tumor after chemotherapy. This case suggests that FDG-PET is a valid tool to assess chemotherapy response in relapsed Wilms' tumor even in case of no evidence of significant dimensional changes under conventional imaging.