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Raut, Chandrajit

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Raut

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Chandrajit

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Raut, Chandrajit
Author's Publications: search.filters.isAuthorOfPublication.13883cef-719f-47d1-8554-fd82c7b9e328

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    MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation
    (Nature Publishing Group, 2017) Schaefer, Inga-Marie; Wang, Yuexiang; Liang, Cher-wei; Bahri, Nacef; Quattrone, Anna; Doyle, Leona; Mariño-Enríquez, Adrian; Lauria, Alexandra; Zhu, Meijun; Debiec-Rychter, Maria; Grunewald, Susanne; Hechtman, Jaclyn F.; Dufresne, Armelle; Antonescu, Cristina R.; Beadling, Carol; Sicinska, Ewa; van de Rijn, Matt; Demetri, George; Ladanyi, Marc; Corless, Christopher L.; Heinrich, Michael C.; Raut, Chandrajit; Bauer, Sebastian; Fletcher, Jonathan
    KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.
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    Comparison of a Lymph Node Ratio–Based Staging System With the 7th AJCC System for Gastric Cancer
    (Ovid Technologies (Wolters Kluwer Health), 2012) Wang, Jiping; Dang, Ping; Raut, Chandrajit; Pandalai, Prakash K.; Maduekwe, Ugwuji N.; Rattner, David; Lauwers, Gregory Y.; Yoon, Sam
    OBJECTIVES: The American Joint Committee on Cancer (AJCC) staging system for gastric cancer bases N status on absolute number of metastatic nodes, regardless of the number of examined nodes. We examined a modified staging system utilizing node ratio (Nr), the ratio of metastatic to examined nodes. METHODS: A total of 18,043 gastric cancer patients who underwent gastrectomy were identified from the US Surveillance, Epidemiology, and End Results (SEER) database. A training set was divided into 5 Nr groups, and a TNrM staging system was constructed. Median survival and overall survival, based on 7th edition AJCC and TNrM staging systems, were compared, and the analysis was repeated in a validation set. RESULTS: Median examined nodes were 10 to 11. For the training set, overall survival for all 5 AJCC N categories was significantly different when subgrouped into 15 or fewer versus more than 15 examined nodes, but overall survival was similar regardless of the number of examined nodes in 4 of 5 Nr categories. Seven AJCC stages had statistically different overall survival between subgroups, whereas only 1 TNrM stage had statistically different overall survival between subgroups. When misclassification was defined as any subgroup in which median survival fell outside the 95% confidence interval of the group's overall median survival, AJCC staging misclassified 57% of patients and TNrM staging misclassified only 12%. Similar results were found in the validation set. CONCLUSIONS: The AJCC system classifies SEER gastric cancer patients into stages in which subgroups often have wide variations in survival. For patients undergoing limited lymph node analysis, the proposed TNrM system may predict survival more accurately.
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    Dystrophin Is a Tumor Suppressor in Human Cancers with Myogenic Programs
    (2014) Wang, Yuexiang; Marino-Enriquez, Adrian; Bennett, Richard R.; Zhu, Meijun; Shen, Yiping; Eilers, Grant; Lee, Jen-Chieh; Henze, Joern; Fletcher, Benjamin S.; Gu, Zhizhan; Fox, Edward A.; Antonescu, Cristina R.; Fletcher, Christopher; Guo, Xiangqian; Raut, Chandrajit; Demetri, George; van de Rijn, Matt; Ordog, Tamas; Kunkel, Louis M.; Fletcher, Jonathan
    Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS), feature myogenic differentiation1–3. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions inactivate larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence, and invadopodia formation, and dystrophin inactivation was found in 96%, 100%, and 62% of metastatic GIST, embryonal RMS, and LMS, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer.
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    High-dose-rate Interstitial Brachytherapy Boost with a Pedicled Latissimus Dorsi Myocutaneous Flap for Myxofibrosarcoma of the Arm
    (Wolters Kluwer Health, 2014) Lane, Jordan D.; Pomahac, Bohdan; Raut, Chandrajit; Baldini, Elizabeth; Devlin, Phillip
    Summary: A 71-year-old man was found to have a 7.4 × 2.9 × 7.0 cm myxofibrosarcoma of the right medial arm close to neurovascular structures. He received 50 Gray (Gy) of preoperative external beam radiation. Radical resection resulted in a 15 × 10 cm defect. Nine brachytherapy catheters were placed, and a pedicled latissimus dorsi myocutaneous flap was used in reconstruction. Final pathology confirmed myxofibrosarcoma, high grade. The tumor was <1 mm from 2 margins. A total of 17.5 Gy of brachytherapy was delivered to the surgical bed from postoperative days 7 to 9. The flap developed fat necrosis distally which eventually required surgical debridement on postoperative day 58. It subsequently healed well and maintained good function of the limb. The patient remains under surveillance without evidence of recurrence.
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    Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948)
    (Public Library of Science, 2012) Raut, Chandrajit; Boucher, Yves; Duda, Dan; Morgan, Jeffrey; Quek, Richard; Ancukiewicz, Marek; Lahdenranta, Johanna; Eder, Joseph Paul; Demetri, George; Jain, Rakesh
    Purpose: Jain Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density. Patients and Methods: Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP). Results: In 15 patients accrued, the median TTP was 45 days (range 14–228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1\(\alpha\) and decreased sVEGFR-2 levels. Increased plasma SDF1\(\alpha\) and decreased sVEGFR-2 levels on day 28 correlated with disease progression. Conclusions: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.