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Whole-genome characterization of myoepithelial carcinomas of the soft tissue

Cyrta, Joanna; Rosiene, Joel; Bareja, Rohan; Kudman, Sarah; Al Zoughbi, Wael; Motanagh, Samaneh; Wilkes, David C; Eng, Kenneth; Zhang, Tuo; Sticca, Evan; Mathew, Susan; Rubin, Mark A; Sboner, Andrea; Elemento, Olivier; Rubin, Brian P; Imielinski, Marcin; Mosquera, Juan Miguel
Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers.
PMCID:9808553
PMID: 36577525
ISSN: 2373-2873
CID: 5459312

Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs

Hadi, Kevin; Yao, Xiaotong; Behr, Julie M; Deshpande, Aditya; Xanthopoulakis, Charalampos; Tian, Huasong; Kudman, Sarah; Rosiene, Joel; Darmofal, Madison; DeRose, Joseph; Mortensen, Rick; Adney, Emily M; Shaiber, Alon; Gajic, Zoran; Sigouros, Michael; Eng, Kenneth; Wala, Jeremiah A; Wrzeszczyński, Kazimierz O; Arora, Kanika; Shah, Minita; Emde, Anne-Katrin; Felice, Vanessa; Frank, Mayu O; Darnell, Robert B; Ghandi, Mahmoud; Huang, Franklin; Dewhurst, Sally; Maciejowski, John; de Lange, Titia; Setton, Jeremy; Riaz, Nadeem; Reis-Filho, Jorge S; Powell, Simon; Knowles, David A; Reznik, Ed; Mishra, Bud; Beroukhim, Rameen; Zody, Michael C; Robine, Nicolas; Oman, Kenji M; Sanchez, Carissa A; Kuhner, Mary K; Smith, Lucian P; Galipeau, Patricia C; Paulson, Thomas G; Reid, Brian J; Li, Xiaohong; Wilkes, David; Sboner, Andrea; Mosquera, Juan Miguel; Elemento, Olivier; Imielinski, Marcin
Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.
PMID: 33007263
ISSN: 1097-4172
CID: 4632912

Decreasing length of stay after pancreatoduodenectomy

Brooks AD; Marcus SG; Gradek C; Newman E; Shamamian P; Gouge TH; Pachter HL; Eng K
HYPOTHESIS: Decreased length of stay (LOS) after pancreatoduodenectomy is due to multiple factors, including a lower complication rate and more efficient perioperative care for all patients, with and without complications. DESIGN: A retrospective review, validation cohort. SETTING: A single university hospital referral center. PATIENTS: A consecutive sample of patients undergoing pancreatoduodenectomy from January 9, 1986, to December 21, 1992 (group 1 [n = 104]) and from February 16, 1993, to November 9, 1998 (group 2 [n = 111]). INTERVENTION: Mann-Whitney test and linear [correction of logistic] regression analysis applied to clinical variables and LOS. MAIN OUTCOME MEASURES: Difference in median LOS between early and late groups and identification of factors predictive of decreased LOS. RESULTS: Total LOS decreased between the 2 groups (26 days [range, 13-117 days] vs 15 days [range, 5-61 days]; P<.001), with a decrease in preoperative (4 days [range, 0-28 days] vs 2 days [range, 0-36 days]; P<.001) and postoperative (19 days [range, 11-95 days] vs 12 days [range, 4-58 days]; P<.001) LOS (data given for group 1 vs group 2). Major complications decreased from 49% in group 1 to 25% in group 2 (P<.001). Postoperative LOS decreased for patients with (25 days [range, 15-95 days] vs 20 days [range, 8-58 days]; P = .05) and without (15 days [range, 11-47 days] vs 11 days [range, 4-55 days]; P<.001) major complications (data given for group 1 vs group 2). Multivariate analysis identified age (P = .01), pancreatic fistula (P<.001), delayed gastric emptying (P<.001), biliary complications (P<.001), operative time (P<.005), extra-abdominal infection (P<.005), use of a percutaneous stent (P = .04), and year of operation (P<.001) as independent predictors of total LOS. CONCLUSION: A reduction in complications in combination with factors leading to a streamlining of perioperative care has contributed to the decreased LOS after pancreatoduodenectomy
PMID: 10896377
ISSN: 0004-0010
CID: 9076

Expression of Von Willebrand factor, an endothelial cell marker, is up-regulated by angiogenesis factors: a potential method for objective assessment of tumor angiogenesis

Zanetta L; Marcus SG; Vasile J; Dobryansky M; Cohen H; Eng K; Shamamian P; Mignatti P
von Willebrand factor (vWF), a glycoprotein produced uniquely by endothelial cells and megakaryocytes, is routinely used to identify vessels in tissue sections. Vessel density in tumor specimens, as determined by immuno-histochemical staining for vWF or other endothelial cell markers, is a negative prognostic factor for many solid tumors. vWF is heterogeneously distributed throughout the vasculature, transcriptional control in response to the tissue microenvironment being responsible for local variations in endothelial cell levels of vWF. Here, we report that fibroblast growth factor-2 and vascular endothelial growth factor, potent angiogenesis inducers expressed in a variety of tumors, up-regulate expression of vWF mRNA and protein in cultured endothelial cells with a synergistic effect. Our data support the measurement of vWF mRNA in tumors to detect activated endothelium or angiogenesis. For this purpose, we developed a semi-quantitative RT-PCR for vWF mRNA. Preliminary results obtained with specimens from colon carcinoma and the corresponding normal colonic mucosa showed higher vWF mRNA levels in most tumors than in their normal counterparts. The differences in vWF mRNA levels were much larger than the differences in vessel counts between a tumor and the corresponding normal mucosa, indicating that high vWF mRNA levels in tumors may indeed be an early sign of activation of the endothelium. The rapidity, objectivity, sensitivity and specificity of this technique make it suitable for routine clinical application to identify aggressive, highly angiogenic tumors.
PMID: 10629090
ISSN: 0020-7136
CID: 9014

Predicting comorbidity in patients with pancreatic fistulae following pancreaticoduodenectomy [Meeting Abstract]

Karpoff, HM; Sivamurthy, N; Oh, C; Gouge, TH; Pachter, HL; Eng, K; Shamamian, P; Marcus, SG
ISI:000073089605684
ISSN: 0016-5085
CID: 53477

Matrix metalloproteinase (MMP) 2 and 9 activity in experimental acute pancreatitis [Meeting Abstract]

Patel, S; Schwartz, J; Chaung, N; Marcus, SG; Pachter, HL; Deutsch, E; Galloway, AC; Eng, K; Mignatti, P; Shamamian, P
ISI:000073089605758
ISSN: 0016-5085
CID: 53478

Carboxypeptidase A activity in pancreatic cancer and acute pancreatitis [Meeting Abstract]

Shamamian, P; Marcus, S; Deutsch, E; Maldonado, T; Liu, A; Stewart, J; Eng, K; Gilvarg, C
ISI:000073089605802
ISSN: 0016-5085
CID: 53479

Soluble factor(s) released from neutrophils activates endothelial cell matrix metalloproteinase-2

Schwartz JD; Monea S; Marcus SG; Patel S; Eng K; Galloway AC; Mignatti P; Shamamian P
OBJECTIVE: Polymorphonuclear leukocyte (PMN) infiltration and microvascular injury are hallmarks of the tissue remodeling associated with multiple organ failure. These processes require the concerted action of various proteolytic enzymes, including serine and matrix metalloproteinases (MMPs). Matrix metalloproteinase-2 (MMP-2) plays an important role in the turnover of various ECM components, including type IV collagen, fibronectin, and gelatins. Like all MMPs, MMP-2 is secreted as an inactive zymogen (proMMP-2) and activated extracellularly by limited proteolytic cleavage. The physiologic mechanism(s) of proMMP-2 activation remains unclear. This study was designed to characterize the effect of PMNs on the activation of proMMP-2 produced by endothelial cells. METHODS: PMNs and human umbilical vein endothelial cells (HUVECs) were grown either separately or together for 2-16 h. To evaluate the role of cell-cell contact, cocultures were also established in which the two cell types were separated by a semipermeable polycarbonate membrane. Alternatively, PMN-conditioned medium was added to HUVEC cultures with or without various proteinase inhibitors (aprotinin, 1,10-phenanthroline, Batimastat, E-64, eglin c peptide, or pepstatin A). After incubation, the culture supernatants were analyzed by gelatin zymography to characterize the gelatinases. RESULTS: HUVECs produce MMP-2 in its inactive (72 kDa) form. PMNs produce high levels of MMP-9 (gelatinase B, 92 kDa) but no MMP-2. Coculture of PMNs with or addition of PMN-conditioned medium to HUVECs results in the production of active (62 kDa) MMP-2. ProMMP-2 activation by PMN-conditioned medium is not blocked by inhibitors of plasmin, cysteine-, acid-, or metalloproteinases. CONCLUSION: PMNs release a soluble factor that activates endothelial cell MMP-2 through a novel mechanism independent of cell-cell contact and not attributable to the activities of plasmin, cysteine-, acid-, or metalloproteinases. These findings may provide insight into the tissue remodeling that accompanies PMN-mediated microvascular injury
PMID: 9695744
ISSN: 0022-4804
CID: 9018

Endoscopic biliary drainage before pancreaticoduodenectomy for periampullary malignancies

Marcus SG; Dobryansky M; Shamamian P; Cohen H; Gouge TH; Pachter HL; Eng K
Despite decreased operative mortality, pancreaticoduodenectomy (PD) remains a formidable operation with substantial morbidity. We have evaluated the influence of preoperative endoscopic biliary drainage (EBD) on morbidity after PD for malignant biliary obstruction by retrospectively reviewing the medical records of 182 patients undergoing PD between April 1985 and August 1996. Of 52 study patients with malignant obstructive jaundice, 22 underwent preoperative EBD, and 30 were not drained. Eighty-three patients were excluded for bilirubin levels less than 5 mg/dl, 43 had other biliary drainage, and 4 had jaundice with benign pathology. Preoperative, intraoperative, and postoperative factors were compared. The two groups were well matched for clinical presentation and operative characteristics except for lower preoperative values of liver chemistries in patients undergoing EBD. Length of postoperative hospitalization for patients undergoing EBD was 13.5 days, compared with 19 days for patients who were not drained (p = 0.02). Patients who were not drained tended to have more overall complications (p = 0.054). Multivariate analysis revealed time to regular diet (p < 0.0001) and no preoperative drainage (p = 0.04) to be independent factors significantly increasing the length of hospitalization. Endoscopic biliary drainage before PD significantly reduced the length of postoperative hospitalization and was associated with less postoperative morbidity. Further studies, including cost analysis, are warranted
PMID: 9563924
ISSN: 0192-0790
CID: 7673

Lexipafant inhibits platelet activating factor enhanced neutrophil functions

Schwartz JD; Shamamian P; Grossi EA; Schwartz DS; Marcus SG; Steiner F; Jacobs CE; Tayyarah M; Eng K; Colvin SB; Galloway AC
Platelet activating factor (PAF) enhances polymorphonuclear leukocyte (PMN) superoxide (.O2-) production, CD11b expression, and elastase release, all essential components in the pathophysiology of multiple-organ failure. This study was designed to determine the effects of Lexipafant, a PAF receptor antagonist, on PAF-mediated PMN functions. PMNs from 10 healthy volunteers were isolated and pretreated with various concentrations of Lexipafant (0-100 microM). PMNs were then incubated for 5 min with 200 nM PAF for .O2- detection or 2000 nM PAF for elastase measurement and activated with 1 microM N-formylmethionylleucylphenylalanine. The mean rate of .O2- production was determined by a cytochrome c reduction assay (nmole .O2-/min/1.33 x 10(5) PMN +/- SEM). Elastase release was measured by the cleavage of the synthetic elastase substrate Meo-Suc-Ala-Ala-Pro-Val-pNA (mean elastolytic activity +/- SEM). In parallel experiments, PMNs were incubated with 200 nM PAF for 30 min following pre-treatment with Lexipafant and CD11b expression was determined by flow cytometry (mean fluorescence intensity +/- SEM). Statistical analysis was performed using repeated-measures ANOVA (P < 0.05). Lexipafant inhibited PAF-enhanced PMN .O2- generation, CD11b expression and elastase release in a dose dependent fashion. The IC50 of Lexipafant for .O2- production, CD11b expression, and elastase release was 0.046, 0.285, and 0.05 microM, respectively. Lexipafant attenuated the PAF-mediated upregulation of PMN .O2- production, CD11b expression, and elastase release in a dose dependent fashion. These data support the hypothesis that Lexipafant may reduce the severity of the inflammatory response to injury produced by PAF-enhanced activation of PMNs
PMID: 9224389
ISSN: 0022-4804
CID: 9020