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.
Background
The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; ...INT) and within the Italian Rare Cancer Network (“Rete Tumori Rari”; RTR).
Methods
We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for
WWTR1
rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15–20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
Results
Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic;
WWTR1
rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1–45), with four patients progression-free at 24 months. The clinical benefit (complete response CR + PR + SD
>
6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1–8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients.
Conclusions
A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.
This work describes the set-up of a shared platform among the laboratories of the Alleanza Contro il Cancro (ACC) Italian Research Network for the identification of fusion transcripts in sarcomas by ...using Next Generation Sequencing (NGS). Different NGS approaches, including anchored multiplex PCR and hybrid capture-based panels, were employed to profile a large set of sarcomas of different histotypes. The analysis confirmed the reliability of NGS RNA-based approaches in detecting sarcoma-specific rearrangements. Overall, the anchored multiplex PCR assay proved to be a fast and easy-to-analyze approach for routine diagnostics laboratories.
The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental ...in developing more specific treatment approaches.
Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status.
At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16INK4a and p15INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors.
Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.
Background
NUT carcinoma (NUTc) is a rare and aggressive malignant epithelial tumor characterized by rearrangement of the NUT gene on chromosome 15q14.
Methods
In this article, we present the fifth ...case worldwide of a young woman affected by a NUTc arising from a submandibular gland, presenting as a rapidly evolving mass. She underwent a right scialoadenectomy and received the initial diagnosis of high‐grade mucoepidermoid carcinoma. Due to evidence of local recurrence at magnetic resonance imaging 1 month later, a subsequent right radical neck dissection was performed. The patient then sought a second opinion at our cancer center and finally received the correct diagnosis of NUT carcinoma. Given the well‐known aggressive behavior of this neoplasm, as well as clinical and radiological features, she underwent adjuvant chemo‐radiation (intensity‐modulated radiotherapy + concurrent chemotherapy with cisplatin).
Results
After a disease‐free interval of 2.6 months, a widespread metastatic disease led to rapid deterioration of performance status and patient death in a few weeks after metastatic onset.
Conclusions
We presented a case of NUTc arising from salivary gland aiming to improve the knowledge of this rare malignancy. First, we pointed out that in the setting of rare tumors like salivary gland cancers, the diagnosis should be obtained by expert pathologists, and patients should be referred to tertiary cancer centers for their clinical management. Second, molecular profiling may help to identify possible druggable targets that may be exploited to treat patients suffering from this aggressive malignancy. Sharing the molecular data provided in this case will be useful for further research.
A large series of plasma cell dyscrasias (n=2207) was examined for translocations which deregulate the MAF genes, t(14;20)(q32;q12) and t(14;16)(q32;q23), and their disease behavior was compared to a ...group characterized by the t(4;14)(p16;q32) where CCND2 is also up-regulated. The t(14;20) showed low prevalence in myeloma (27/1830, 1.5%) and smoldering myeloma (1/148, <1%) with a higher incidence in MGUS (9/193, 5% P=0.005). Strong associations with del(13) (76%), non-hyperdiploidy (83%) and gain of 1q (58%) were seen but no association with an IgA M-protein or absence of bone disease was noted. All three translocations were associated with poor outcome in myeloma, but strikingly all t(14;20) MGUS/smoldering myeloma cases (n=10) had stable, low level disease. In contrast, the 10 t(14;16) and 25 t(4;14) MGUS/smoldering myeloma cases were associated with both evolving and non-evolving disease. None of the associated genetic abnormalities helped to predict for progression from MGUS or smoldering myeloma.
Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential ...target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.
We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.
By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.
Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
Background
Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA ...binding protein 1 (EWSR1)‐Wilm's tumor suppressor (WT1) translocation. We used whole‐exome sequencing to interrogate six consecutive pre‐treated DSRCTs whose gene expression was previously investigated.
Methods
DNA libraries were prepared from formalin‐fixed, paraffin‐embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500. Raw sequence data were aligned to the reference genome with Burrows–Wheeler Aligner algorithm. Somatic mutations and copy number alterations (CNAs) were identified using MuTect2 and EXCAVATOR2, respectively. Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis (IPA) software.
Results
A total of 137 unique somatic mutations were identified: 133 mutated genes were case‐specific, and 2 were mutated in two cases but in different positions. Among the 135 mutated genes, 27% were related to two biological categories: DNA damage‐response (DDR) network that was also identified through IPA and mesenchymal–epithelial reverse transition (MErT)/epithelial–mesenchymal transition (EMT) already demonstrated to be relevant in DSRCT. The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre‐mRNA. Half of these genes encoded RNA‐binding proteins or DNA/RNA‐binding proteins, which were recently recognized as a new class of DDR players. CNAs in genes/gene families, involved in MErT/EMT and DDR, were recurrent across patients and mostly segregated in the MErT/EMT category. In addition, recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune‐regulatory genes were recorded.
Conclusions
The emerging picture is an extreme inter‐tumor heterogeneity, characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.
to investigate the events involved in the progression of myxoid liposarcoma (MLS). Gene expression profiling and immunohistochemical/biochemical analyses were applied to specimens representative of ...the opposite ends of the MLS spectrum: pure myxoid (ML) and pure round cell (RC) liposarcomas. The analyses revealed the involvement of both coding and non coding RNAs (SNORDs located in DLK1-DIO3 region) and support a model of stepwise progression mainly driven by epigenetic changes involving tumour vascular supply and tumoral cellular component. In this model, a switch in the vascular landscape from a normal to a pro-angiogenic signature and the silencing of DLK1-DIO3 region mark the progression from ML to RC in concert with the acquisition by the latter of the over-expression of YYI/C-MYC/HDAC2, together with over-expression of genes involved in cell proliferation and stemness: MKNK2, MSX1 and TRIM71. Taken together, these findings strongly suggest that to progress from ML to RC liposarcoma the cells have to overcome the epigenetic silencing restriction point in order to reset their new stem-like differentiation signature. Our findings provide a first attempt at identifying the missing links between ML and RC liposarcomas, that may also have broader applications in other clinico-pathological settings characterised by a spectrum of progression.
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