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Frontiers in Oncology 2022Among sarcomas, which are rare cancers with an incidence of <6 per 100.000/year cases, ultra-rare sarcomas have an incidence of approximately ≤1/1,000,000/year cases...
BACKGROUND
Among sarcomas, which are rare cancers with an incidence of <6 per 100.000/year cases, ultra-rare sarcomas have an incidence of approximately ≤1/1,000,000/year cases and altogether account for ~20% of all soft tissue sarcomas (STS) and bone sarcomas. The Italian Sarcoma Group has recently performed a non-interventional, retrospective TrObs study with data from 512 anthracycline-pretreated patients with advanced multiple STS histologies and treated with trabectedin (Palmerini, 2021; ClinicalTrials.gov Identifier: NCT02793050).
METHODS
A analysis of case series to evaluate the efficacy and safety of trabectedin on patients with ultra-rare and other rare translocation-related sarcomas included in TrObs study was performed. Main outcomes comprised investigator-assessed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety.
RESULTS
Thirty-six patients (18 women) with ultra-rare and other rare sarcoma and a median age of 53.0 years (range: 22-81) were included. Most patients had solitary fibrous tumor (SFT; n=11) followed by epithelioid sarcoma (n=5), malignant peripheral nerve sheath tumor (MPNST; n=4), extraskeletal myxoid chondrosarcoma (EMC; n=3), desmoplastic small round cell tumor (DSRCT; n=3), and alveolar soft part sarcoma (ASPS), rhabdomyosarcoma and clear cell sarcoma (n=2 each). Thirty-five patients had metastatic disease and 23 patients received trabectedin as a second-line treatment. Among 35 patients evaluable for response, two patients with SFT and ASPS had a partial response and one patient with DSRCT obtained a complete response, reaching an ORR of 8.6% (95% CI: 2.8-23.4%). Among patients with an ORR, 6-months PFS was 100% in patients with ASPS, 45.7% in patients with SFT and 33.3% in those with DSRCT. Two patients with epithelioid sarcoma and myoepithelioma had disease stabilization lasting >24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6).
CONCLUSIONS
Trabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile.
PubMed: 36568164
DOI: 10.3389/fonc.2022.1042479 -
JPMA. the Journal of the Pakistan... Sep 2022Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, making 50% of all diagnosed cases. It is a complex disease that has the potential to arise from...
Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, making 50% of all diagnosed cases. It is a complex disease that has the potential to arise from any tissue of the body except the bones. There are four types of rhabdomyosarcoma; embryonal, botryoidal, alveolar and pleomorphic. [18F]-FDG PET-CT plays a vital role in staging, response evaluation and follow-up of the disease. Due to significant morbidity and mortality with high-risk disease, proper staging is of paramount importance. Staging of rhabdomyosarcoma depends on tumour localization, infiltration of local structures by the primary tumour, nodal involvement, and presence of visceral metastases. Without timely intervention, rhabdomyosarcoma progresses at an exponential speed.
Topics: Child; Humans; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Tomography, X-Ray Computed; Neoplasm Staging; Positron-Emission Tomography; Rhabdomyosarcoma; Radiopharmaceuticals
PubMed: 36281001
DOI: 10.47391/JPMA.22-96 -
Sarcoma 2022Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma for which subsets of patients have longstanding unmet clinical needs. For example, children with...
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma for which subsets of patients have longstanding unmet clinical needs. For example, children with alveolar rhabdomyosarcoma and metastases at diagnosis will experience only 8% disease-free 5-year survival for nonlocalized unresectable recurrent disease. Hence, development of novel therapeutic strategies is urgently needed to improve outcomes. The Plexin-Semaphorin pathway is largely unexplored for sarcoma research. However, emerging interest in the Plexin-Semaphorin signaling axis in pediatric sarcomas has led to phase I cooperative group dose-finding clinical trials, now completed (NCT03320330). In this study, we specifically investigated the protein expression of transmembrane receptor Plexin-B2 and its cognate SEMA4C ligands in clinical RMS tumors and cell models. By RNA interferences, we assessed the role of Plexin-B2 in cell growth and cell migration ability in selected alveolar and embryonal RMS cell model systems. Our results affirmed expression of Plexin-B2 across human samples, while also dissecting expression of the different protein subunits of Plexin-B2 along with the assessment of preferred Semaphorin ligands of Plexin-B2. Plexin-B2 knockdown had positive or negative effects on cell growth, which varied by cell model system. Migration assayed after Plexin-B2 knockdown revealed selective cell line specific migration inhibition, which was independent of Plexin-B2 expression level. Overall, these findings are suggestive of context-specific and possibly patient-specific (stochastic) role of Plexin-B2 and SEMA4 ligands in RMS.
PubMed: 35570846
DOI: 10.1155/2022/9646909 -
BMJ Case Reports Jul 2021This is the case of a parameningeal alveolar rhabdomyosarcoma (ARMS) in a 13-year-old boy who presented with painless loss of vision in the right eye, but very few other...
This is the case of a parameningeal alveolar rhabdomyosarcoma (ARMS) in a 13-year-old boy who presented with painless loss of vision in the right eye, but very few other physical signs. The ARMS diagnosis was confirmed with imaging and molecular characterisation of the tumour. Despite tolerating the initial chemotherapy and radiotherapy regimens, there was leptomeningeal recurrence and the patient unfortunately passed away. Parameningeal ARMS occurs in an area of the body, which leads to a wide variety of possible presenting symptoms, creating a long list of differentials that can delay treatment. This tumour subtype has a poor prognosis, and due to the location of the tumour around vital structures in the head, treatment toxicities must be taken into account. This highlights the necessity for having a strong index of suspicion for this tumour in atypical presentations in children, and the necessity for prompt treatment to prevent leptomeningeal disease from occurring.
Topics: Adolescent; Child; Family; Head and Neck Neoplasms; Humans; Male; Meningeal Neoplasms; Neoplasm Recurrence, Local; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal
PubMed: 34266827
DOI: 10.1136/bcr-2021-243267 -
Pediatric Blood & Cancer Sep 2021Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell...
BACKGROUND/OBJECTIVES
Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell sclerosing RMS (SRMS). SRMS harbors MYOD1 mutations in a subset of adult cases in association with poor prognosis.
DESIGN/METHODS
To study the level of MYOD1 protein expression and its clinical significance, we have analyzed variable numbers of pediatric (<18 years of age) and adult (age range ≥18 to 35 years) ERMS and SRMS cases for presence or absence of MYOD1 immunoreactivity in correlation with clinical outcome and MYOD1 L122R mutations.
RESULTS
Lack of MYOD1 immunoreactivity, identified in 23.8% of nonalveolar RMS (non-ARMS) cases, was more prevalent in SRMS (44%) than ERMS (17.2%) and was significantly associated with low overall survival and unfavorable tumor sites (p < .05). Lack of MYOD1 immunoreactivity was not associated with MYOD1 L122R mutations, which were identified in 3/37 (8%) cases including only two of 31 (6.5%) pediatric cases, one of 11 or 9% pediatric SRMS, and one case of infant ERMS.
CONCLUSION
These studies highlight the prognostic role of MYOD1 in non-ARMS. Lack of MYOD1 immunoreactivity is associated with poor prognosis in ERMS and SRMS. MYOD1 gene mutations are generally infrequent in pediatric RMS. Although mutations are predominant in SRMS, they may exceptionally occur in infantile ERMS.
Topics: Adolescent; Adult; Child; Humans; Infant; Mutation; MyoD Protein; Prognosis; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Young Adult
PubMed: 33913590
DOI: 10.1002/pbc.29085 -
Clinical Cancer Research : An Official... Sep 2022Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation,...
PURPOSE
Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma models.
PATIENTS AND METHODS
We conducted a phase I, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved four dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3 + 3 dose-escalation scheme. Subjects received two doses of TB-403 (days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics, and detection of pharmacodynamic biomarkers.
RESULTS
Fifteen subjects were treated in four dose levels. All subjects received two doses of TB-403 in cycle 1. Five serious treatment-emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed subjects with medulloblastoma experienced stable disease, which persisted for more than 100 days in 4 of 7 subjects.
CONCLUSIONS
TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with medulloblastoma.
Topics: Antibodies, Monoclonal, Humanized; Brain Neoplasms; Cerebellar Neoplasms; Child; Female; Humans; Maximum Tolerated Dose; Medulloblastoma; Neuroblastoma; Placenta Growth Factor; Rhabdomyosarcoma, Alveolar; Sarcoma, Ewing
PubMed: 35833850
DOI: 10.1158/1078-0432.CCR-22-1169 -
Indian Journal of Pathology &... 2022Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Anaplasia is a rare phenomenon seen in childhood RMS. The most common histologic subtype was...
BACKGROUND
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Anaplasia is a rare phenomenon seen in childhood RMS. The most common histologic subtype was Embryonal followed by Alveolar and spindle subtype.
DESIGN
A total of 11 cases of pediatric RMS were selected from January 2017 to June 2019 presenting at various sites. Out of 11 cases, 2 were further diagnosed as Embryonal, 2 as Alveolar, 2 as Pleomorphic, 1 as Spindle subtype and rest 4 as RMS-NOS based on morphology. All cases were positive for Desmin. The presence of cells with lobated, hyperchromatic nuclei at least three times larger than the tumor cell (anaplastic cells) was selected as the main criterion to diagnose Anaplasia.
RESULTS
Out of the total 11 cases, anaplasia was seen in 7 cases. Out of these seven, five cases showed Focal Anaplasia (FA) (71.4%) and 2 cases showed Diffuse Anaplasia (DA) (28.6%). Out of 2 cases of Embryonal RMS one exhibited focal anaplasia (50%). One case of Spindle RMS showed diffuse anaplasia, 2 cases of pleomorphic RMS showed focal anaplasia. Out of 3 cases of RMS- NOS, 2 exhibited focal anaplaisa and one displayed Diffuse anaplasia. Both Alveolar RMS had no features of anaplasia.
CONCLUSION
Presence of Anaplasia is a frequent observation in pediatric RMS. Anaplasia is often under reported in pediatric RMS. Pathologist should be more aware of this rare phenomenon.
Topics: Child; Humans; Anaplasia; Rhabdomyosarcoma; Sarcoma; Soft Tissue Neoplasms; Rhabdomyosarcoma, Alveolar
PubMed: 36308195
DOI: 10.4103/ijpm.ijpm_178_21 -
International Journal of Molecular... Jan 2023Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and...
Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed. Surface proteins are ideal targets for antibody-based therapies, like bispecific antibodies, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Specific surface targets for RMS are scarce. Here, we performed a surfaceome profiling based on differential centrifugation enrichment of surface/membrane proteins and detection by LC-MS on six fusion-positive (FP) RMS cell lines, five fusion-negative (FN) RMS cell lines, and three RMS patient-derived xenografts (PDXs). A total of 699 proteins were detected in the three RMS groups. Ranking based on expression levels and comparison to expression in normal MRC-5 fibroblasts and myoblasts, followed by statistical analysis, highlighted known RMS targets such as FGFR4, NCAM1, and CD276/B7-H3, and revealed AGRL2, JAM3, MEGF10, GPC4, CADM2, as potential targets for immunotherapies of RMS. L1CAM expression was investigated in RMS tissues, and strong L1CAM expression was observed in more than 80% of alveolar RMS tumors, making it a practicable target for antibody-based therapies of alveolar RMS.
Topics: Child; Animals; Humans; Neural Cell Adhesion Molecule L1; Heterografts; Rhabdomyosarcoma; Cell Line; Transcription Factors; Disease Models, Animal; Neural Cell Adhesion Molecules; Cell Line, Tumor; B7 Antigens; Cell Adhesion Molecules; Receptor, Fibroblast Growth Factor, Type 4
PubMed: 36768928
DOI: 10.3390/ijms24032601 -
Cureus Feb 2022Rhabdomyosarcoma is a highly aggressive cancer that is generally considered a disease of childhood. A vast majority of cases occur in those below the age of 20....
Rhabdomyosarcoma is a highly aggressive cancer that is generally considered a disease of childhood. A vast majority of cases occur in those below the age of 20. Rhabdomyosarcoma can occur in any soft tissue in the body but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities. Prognosis is closely tied to the location of the primary tumor and the extent of metastatic spread. As with most sarcomas, rhabdomyosarcoma has a pattern of hematogenous spread which favors metastasis to the lungs. Other common areas include bone marrows, liver, breasts, and brain. One unusual pattern is the presence of diffuse bone marrow metastases in absence of significant soft tissue disease other than primary (no distant nodal disease, absence of visceral disease in chest and abdomen). Frequently in such cases, patients may have initial presentation similar to hematologic malignancy especially when the primary tumor is not evident. This pattern has been rarely described in the radiology literature. This pattern appears to be well documented in pathology literature. Even more rarely, in some cases, the primary tumor site may not be found after imaging and may remain undetermined even postmortem - only diagnosed by bone marrow aspiration. Awareness of this unique pattern is clearly important for radiologists, especially pediatric radiologists, as misdiagnosis can lead to delay in appropriate treatment that ultimately results in increased mortality. We present a case of rhabdomyosarcoma with this unique pattern of bone marrow metastases in which initial differential diagnosis favored a leukemic picture. This paper will go over the diagnostic techniques utilized throughout our patient's disease course as well as treatment.
PubMed: 35265406
DOI: 10.7759/cureus.21863 -
Clinical Cancer Research : An Official... Jan 2023Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in...
PURPOSE
Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS.
EXPERIMENTAL DESIGN
Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998-2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data.
RESULTS
The trained CNN could accurately classify alveolar RMS, a high-risk subtype associated with PAX3/7-FOXO1 fusion genes, with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67, and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63, respectively. Remarkably, CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification.
CONCLUSIONS
This study demonstrates that high-risk features, including those associated with certain mutations, can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma, which will be tested in prospective COG clinical trials.
Topics: Child; Humans; Young Adult; Deep Learning; Eosine Yellowish-(YS); Hematoxylin; Paired Box Transcription Factors; Prospective Studies; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 36346688
DOI: 10.1158/1078-0432.CCR-22-1663