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Browsing by Subject "Sarcoma"

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    Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis
    (BMC, 2019-03-14) Lawlor, Rita T.; Veronese, Nicola; Pea, Antonio; Nottegar, Alessia; Smith, Lee; Pilati, Camilla; Demurtas, Jacopo; Fassan, Matteo; Cheng, Liang; Luchini, Claudio; Pathology and Laboratory Medicine, School of Medicine
    Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic. METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference. RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p < 0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR = 1.50; 95% CI: 1.15-1.96; p = 0.003; HR = 2.02; 95% CI: 1.22-3.38; p = 0.007). CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.
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    Approach to wild-type gastrointestinal stromal tumors
    (AME Publishing Company, 2018-11-15) Kays, Joshua K.; Sohn, Jeffrey D.; Kim, Bradford J.; Goze, Katherine; Koniaris, Leonidas G.; Surgery, School of Medicine
    Gastrointestinal stromal tumors (GISTs) arise from the intestinal pacemaker cells of Cajal. Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or platelet derived growth factor receptor alpha (PDGFRA) receptors. The lack of these growth-stimulating mutations renders tyrosine kinase receptor inhibitors, such as imatinib mesylate, relatively ineffective against these tumors. WT-GIST arises most commonly due to underlying alternate proliferative signals associated with germ-line, genetic mutations. WT-GIST frequently arises in patients with BRAF mutations, Carney’s Triad or neurofibromatosis type-1 (NF-1). All patients with WT-GIST require a careful examination for germ-line mutations and very close observation for recurrent tumors. Surgery remains a mainstay therapy for these patients. This review aims to discuss the most recent data available on the diagnosis and treatment of WT-GIST.
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    Bilateral Renal Auto-Transplantation for Retroperitoneal Sarcomas: Is It Underutilized?
    (MDPI, 2023-08-14) Robinson, Tyler P.; Milgrom, Daniel P.; Nagaraju, Santosh; Goggins, William C.; Samy, Kannan P.; Koniaris, Leonidas G.; Surgery, School of Medicine
    Sarcomas are a rare tumor of mesenchymal origin. The liposarcoma is the most common sarcoma of the retroperitoneum. Liposarcomas are typically low grade, and present at an advanced stage and a large size. We report a case of a large retroperitoneal liposarcoma, approximately 50 kg, encasing both kidneys, which was managed via a two-stage resection and staged renal auto-transplantation into the intra-peritoneal pelvis. The patient maintained normal renal function throughout, and remains disease free two years post-resection. Renal auto-transplantation with pelvic placement may facilitate improved margin-free resection. Renal relocation may allow the use of curative-intent ablative therapies such as radiofrequency ablation and radiation in cases of retroperitoneal recurrence.
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    Correction: Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
    (Springer Nature, 2022) Gampala, Silpa; Shah, Fenil; Zhang, Chi; Rhodes, Steven D.; Babb, Olivia; Grimard, Michelle; Wireman, Randall S.; Rad, Ellie; Calver, Brian; Bai, Ren-Yuan; Staedtke, Verena; Hulsey, Emily L.; Saadatzadeh, M. Reza; Pollok, Karen E.; Tong, Yan; Smith, Abbi E.; Clapp, D. Wade; Tee, Andrew R.; Kelley, Mark R.; Fishel, Melissa L.; Pediatrics, School of Medicine
    Correction to: British Journal of Cancer 10.1038/s41416-021-01270-8, published online 03 March 2021 The original version of this article unfortunately contained an error in Figure 4, specifically: Figure 4f: the middle cell image was originally a duplicate of the middle cell image from Fig. 4d; the correct image is now used. The corrected figure is displayed below. The correction does not have any effect on the final conclusions of the paper. The original article has been corrected.
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    Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes
    (Springer Nature, 2025-05-06) Soupir, Alex; Ospina, Oscar E.; Hampton, Oliver; Churchman, Michelle; Radmacher, Michael; Hedges, Dale; McKean, David; Agius, Phaedra; Zeeshan, Saman; Seligson, Nathan D.; Pollock, Raphael; Liebner, David; Chen, James L.; Tinoco, Gabriel; Salhia, Bodour; McCarter, Martin; Wilky, Breelyn A.; Miller, Benjamin J.; Cavnar, Michael J.; Groundland, John S.; Schneider, Bryan P.; Riedlinger, Gregory; Edge, Stephen B.; Moskaluk, Christopher A.; Cardona, Kenneth; Naqash, Abdul Rafeh; Gonzalez, Ricardo J.; Mullinax, John E.; Joyce, David M.; Binitie, Odion; Letson, G. Douglas; Naghavi, Arash O.; Druta, Mihaela; Reed, Damon R.; Siegel, Erin M.; Teer, Jamie K.; Fridley, Brooke L.; Brohl, Andrew S.; Medicine, School of Medicine
    Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p < 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p < 0.01). Interestingly, GIST predominantly form a distinct "immune intermediate" cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).
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    Histiocytic sarcoma arising from a lymph node: a diagnostic conundrum
    (Springer, 2021-05-21) Afzal, Anoshia; Asadbeigi, Sepideh N.; Farooque, Umar; Mather, Christy; Khan, Shahbaz; Pathology and Laboratory Medicine, School of Medicine
    Histiocytic Sarcoma (HS) is extremely rare, with only a few hundred cases reported in the literature. The majority of patients present with symptoms due to unifocal or multifocal extra-nodal disease. Less than 20% of these cases show solitary involvement of a lymph node. We report a case of a solitary HS in a 53-year-old woman presenting with a 2.7-cm right groin mass arising from an inguinal lymph node. The initial cytologic examination of the tissue showed a high-grade spindle-shaped morphology with high-grade mitotic activity. A high-grade sarcoma was initially considered considering the absence of normal lymphoid aggregate and the presence of high-grade cytologic features in the cells. To evaluate the tumor in its entirety, the mass was surgically excised. A histological examination of the tumor showed focal rimming of the lymphoid tissue at the periphery and a centrally located stellate necrotic focus. The tumor cells had an epithelioid to spindle cell morphology along with large uniform nuclei and prominent nucleoli. A high mitotic index was present. Immunohistochemistry (IHC) stains showed strong positivity for CD68, CD163, and Vimentin, and were weakly positive for SMA and CD45. Based on the histologic and clinical examination, a diagnosis of HS was made. Multiple malignancies can mimic HS histopathology and the rarity of this tumor makes the diagnosis more challenging. No fine-needle aspiration (FNA) criteria for its diagnosis have been recognized. Herein, we report a rare case of an isolated HS involving a lymph node which resembled high-grade sarcoma on the FNA biopsy to raise awareness among our surgical pathologist colleagues.
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    Incisions and reconstruction approaches for large sarcomas
    (AME Publishing Company, 2018-10-31) Spera, Leigh J.; Danforth, Rachel M.; Hadad, Ivan; Surgery, School of Medicine
    Large intraabdominal, retroperitoneal, and abdominal wall sarcomas provide unique challenges in treatment due to their variable histology, potential considerable size at the time of diagnosis, and the ability to invade into critical structures. Historically, some of these tumors were considered inoperable if surgical access was limited or the consequential defect was unable to be closed primarily as reconstructive options were limited. Over time, there has been a greater understanding of the abdominal wall anatomy and mechanics, which has resulted in the development of new techniques to allow for sound oncologic resections and viable, durable options for abdominal wall reconstruction. Currently, intra-operative positioning and employment of a variety of abdominal and posterior trunk incisions have made more intraabdominal and retroperitoneal tumors accessible. Primary involvement or direct invasion of tumor into the abdominal wall is no longer prohibitive as utilization of advanced hernia repair techniques along with the application of vascularized tissue transfer have been shown to have the ability to repair large area defects involving multiple quadrants of the abdominal wall. Both local and distant free tissue transfer may be incorporated, depending on the size and location of the area needing reconstruction and what residual structures are remaining surrounding the resection bed. There is an emphasis on selecting the techniques that will be associated with the least amount of morbidity yet will restore and provide the appropriate structure and function necessary for the trunk. This review article summarizes both initial surgical incisional planning for the oncologic resection and a variety of repair options for the abdominal wall spanning the reconstructive ladder.
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    Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21Cip1 expression and hampers tumour cell growth in vitro and in vivo
    (Springer Nature, 2012) Raimondi, L.; Ciarapica, R.; De Salvo, M.; Verginelli, F.; Gueguen, M.; Martini, C.; De Sio, L.; Cortese, G.; Locatell, M.; Dang, T. P.; Carlesso, N.; Miele, L.; Stifani, S.; Limon, I.; Locatelli, F.; Rota, R.; Pediatrics, School of Medicine
    Rhabdomyosarcoma (RMS) is a paediatric soft-tissue sarcoma arising from skeletal muscle precursors coexpressing markers of proliferation and differentiation. Inducers of myogenic differentiation suppress RMS tumourigenic phenotype. The Notch target gene HES1 is upregulated in RMS and prevents tumour cell differentiation in a Notch-dependent manner. However, Notch receptors regulating this phenomenon are unknown. In agreement with data in RMS primary tumours, we show here that the Notch3 receptor is overexpressed in RMS cell lines versus normal myoblasts. Notch3-targeted downregulation in RMS cells induces hyper-phosphorylation of p38 and Akt essential for myogenesis, resulting in the differentiation of tumour cells into multinucleated myotubes expressing Myosin Heavy Chain. These phenomena are associated to a marked decrease in HES1 expression, an increase in p21(Cip1) level and the accumulation of RMS cells in the G1 phase. HES1-forced overexpression in RMS cells reverses, at least in part, the pro-differentiative effects of Notch3 downregulation. Notch3 depletion also reduces the tumourigenic potential of RMS cells both in vitro and in vivo. These results indicate that downregulation of Notch3 is sufficient to force RMS cells into completing a correct full myogenic program providing evidence that it contributes, partially through HES1 sustained expression, to their malignant phenotype. Moreover, they suggest Notch3 as a novel potential target in human RMS.
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    Integrating therapies for surgical adult soft tissue sarcoma patients
    (AME Publishing Company, 2018-11-02) Milgrom, Daniel P.; Sehdev, Amikar; Kays, Joshua K.; Koniaris, Leonidas G.; Surgery, School of Medicine
    Sarcomas are an uncommon group of over 50 different individual histological malignancies arising from mesenchymal (non-epithelial or connective) tissues. Overall, they constitute 1% of human malignancies with an annual incidence rate of fewer than 5 patients per million. Sarcoma may arise from any mesenchymal cell lineages including fat, muscle, or other connective tissues. Due to the rarity of these groups of malignancies, many subtypes were, and still today, are managed as a single entity. This review focused on soft tissue sarcomas with an emphasis on how to integrate therapies for patients with this rare disorder. The role for surgical resection in cure and palliation as well as the relative benefits of adjuvant therapies such as chemotherapy and radiation therapy are discussed.
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    Paradoxical Response to Neoadjuvant Therapy in Undifferentiated Pleomorphic Sarcoma: Increased Tumor Size on MRI Associated with Favorable Pathology
    (MDPI, 2025-02-27) Goreish, Mariam H.; Gennaro, Nicolò; Perronne, Laetitia; Durak, Gorkem; Borhani, Amir A.; Savas, Hatice; Kelahan, Linda; Avery, Ryan; Subedi, Kamal; Trabzonlu, Tugce Agirlar; Bagci, Ulas; Turkbey, Baris; Bakas, Spyridon; Sachdev, Sean; Sumagin, Ronen; Alexiev, Borislav A.; de Viveiros, Pedro Hermida; Pollack, Seth M.; Velichko, Yuri S.; Pathology and Laboratory Medicine, School of Medicine
    Background/Objectives: To correlate size changes in undifferentiated pleomorphic sarcoma (UPS) on magnetic resonance imaging (MRI) after neoadjuvant chemoradiation therapy (nCRT) with pathological response, risk of local recurrence, and therapeutic regimens. Methods: This retrospective study analyzed clinical, pathological, and imaging data from 39 biopsy-proven UPS subjects. Four readers measured the tumor dimensions before and after nCRT, including two perpendicular axial diameters and the longest coronal/sagittal diameter. Three cross-sectional areas and bounding volume were also calculated. Responders (pR) were defined as having ≤10% viable cells and non-responders (pNR) as having more. Inter-reader agreement was evaluated using Kendall's concordance coefficient. Changes in tumor size were compared between pR and pNR using one-way ANOVA and Tukey's HSD test for multiple comparisons of means. Results: pR showed a greater increase in size across all measurements compared to pNR. For the longest axial diameter, the mean increase was 30% ± 35% for pR and 14% ± 31% for pNR, with a mean difference (pR-pNR) of 16% (95% CI: 6-27%, p = 0.003). In tumors treated with radiotherapy alone, pR exhibited larger size increases in all dimensions compared to pNR. In contrast, in the chemoradiation group, pR showed a slight increase, while pNR generally shrank, although these differences did not reach statistical significance. Notably, pNR with local recurrence exhibited a reduction in all tumor dimensions compared to pNR without local recurrence. Conclusions: This exploratory study suggests that tumor size changes may predict pathological response and local recurrence after nCRT in UPS; however, the small sample size limits the generalizability of these findings.
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