Mithat Gonen

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (328)2108.9 Total impact

  • Journal of Vascular and Interventional Radiology 03/2014; 25(3):S40-S41. DOI:10.1016/j.jvir.2013.12.098 · 2.41 Impact Factor
  • Journal of Vascular and Interventional Radiology 03/2014; 25(3):S32. DOI:10.1016/j.jvir.2013.12.078 · 2.41 Impact Factor
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    ABSTRACT: We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.
    Science translational medicine 02/2014; 6(224):224ra25. DOI:10.1126/scitranslmed.3008226 · 15.84 Impact Factor
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    ABSTRACT: Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial (1) H MRS measurements of hepatic lipids in patients over the time course of a 24-week chemotherapeutic regimen to determine whether (1) H MRS could be used to monitor the progression of chemotherapy-induced steatosis. Thirty-four patients with stage III or IV colorectal cancer receiving 5-fluorouracil, folinic acid and oxaliplatin (n = 21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n = 13) were studied prospectively. (1) H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A (1) H MR spectrum was acquired from the liver during a breath hold and the ratio of fat to fat + water (FFW) was calculated to give a measure of hepatic triglycerides (HTGCs). The methodology was histologically validated in 18 patients and the reproducibility was assessed in 16 normal volunteers. Twenty-seven patients completed baseline, 6-week and 24-week (1) H MRS examinations and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to nonsteatotic liver. Patients whose 6-week hepatic lipid levels had increased significantly relative to baseline also had a high probability of lipid elevation relative to baseline at the completion of treatment. Serial (1) H MRS is effective for the monitoring of HTGC changes during chemotherapy and for the detection of chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks. Copyright © 2012 John Wiley & Sons, Ltd.
    NMR in Biomedicine 02/2014; 26(2). DOI:10.1002/nbm.2837 · 3.04 Impact Factor
  • Journal of Surgical Research 02/2014; 186(2):554. DOI:10.1016/j.jss.2013.11.460 · 1.94 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):C47-C47. DOI:10.1158/1535-7163.TARG-13-C47 · 5.68 Impact Factor
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    ABSTRACT: Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. Weanalyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. Wecalculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naive primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2_ tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease. (C) 2014 AACR.
    Cancer Research 01/2014; 74(5). DOI:10.1158/0008-5472.CAN-13-2357-T · 9.33 Impact Factor
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    ABSTRACT: Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy. Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate. Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%). For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.
    Journal of Clinical Oncology 01/2014; 32(6). DOI:10.1200/JCO.2013.51.7904 · 18.43 Impact Factor
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    ABSTRACT: The prognosis of signet ring cell (SRC) gastric adenocarcinoma is regarded as poor, although studies addressing outcomes in relation to non-SRC tumors are conflicting. Our objective was to compare the survival of SRC tumors with stage-matched intestinal-type tumors in a cohort of Western patients. Review of a prospectively maintained database identified 569 patients undergoing curative resection (R0) from 1990 to 2009. Patients were divided into three histologic groups on the basis of the Lauren classification: SRC (n = 210), intestinal well- or moderately differentiated (WMD, n = 242) disease, and intestinal poorly differentiated (PD, n = 117) disease. Patient demographics, clinicopathologic features, and postoperative outcomes were determined. Stage-stratified disease-specific mortality was calculated and multivariate analysis performed. When compared with WMD and PD tumors, SRC tumors were associated with younger age (63 years SRC vs. 71 years WMD and 72 years PD, p < 0.0001) and with female sex (58 % SRC vs. 40 % WMD and 40 % PD, p = 0.0003). Median follow-up was 115 months. Patients with stage Ia SRC lesions had a better 5-year disease-specific mortality compared with stage-matched intestinal-type tumors (0 % SRC vs. 8 % WMD and 24 % PD, p = 0.001). In contrast, SRC patients with stage III disease fared significantly worse (78 % SRC vs. 54 % WMD and 72 % PD, p = 0.001). On multivariate analysis, the risk of death from gastric cancer comparing all three groups was lowest for SRC in stage I and highest for SRC in stage III disease (stage III hazard ratio: SRC 1 vs. 0.47 WMD and 0.85 PD). When compared with intestinal-type tumors, SRC tumors at early stages are not necessarily associated with poor outcomes.
    Annals of Surgical Oncology 01/2014; 21(5). DOI:10.1245/s10434-013-3466-8 · 3.93 Impact Factor
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    ABSTRACT: To identify factors affecting periprocedural morbidity and mortality and long-term survival following hepatic artery embolization (HAE) of hepatic neuroendocrine tumor (NET) metastases. This single-center, institutional review board-approved retrospective review included 320 consecutive HAEs for NET metastases performed in 137 patients between September 1996 and September 2007. Forty-seven HAEs (15%) were performed urgently to manage refractory symptoms in inpatients (urgent group), and 273 HAEs (85%) were elective (elective group). Overall survival (OS) was estimated by Kaplan-Meier methodology. Complications were categorized per Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to determine independent predictors for OS, complications, and 30-day mortality. The independent factors were combined to develop clinical risk score groups. Urgent HAE (P = .007), greater than 50% liver replacement by tumor (P < .0001), and extrahepatic metastasis (P = .007) were independent predictors for shorter OS. Patients with all three risk factors had decreased OS versus those with none (median, 8.5 vs 86 mo; P < .001). Thirty-day mortality was significantly lower in the elective (1%) versus the urgent group (8.5%; P = .0009). There were eight complications (3%) in the elective group and five (10.6%) in the urgent group (P = .03). Male sex and urgent group were independent factors for higher 30-day mortality rate (P = .023 and P =.016, respectively) and complications (P = .012 and P =.001, respectively). Urgent HAE, replacement of more than 50% of liver by tumor, and extrahepatic metastasis are strong independent predictors of shorter OS. Male sex and urgent HAE carry higher 30-day mortality and periprocedural morbidity risks.
    Journal of vascular and interventional radiology: JVIR 01/2014; 25(1):22-30. DOI:10.1016/j.jvir.2013.09.013 · 2.41 Impact Factor
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    ABSTRACT: Solid and cystic splenic masses discovered on imaging studies often pose diagnostic and management dilemmas. This study analyses a large series of splenectomies to identify preoperative factors associated with malignant splenic masses. Pathology records at a single institution were reviewed for all splenectomies. Those performed as a component of a larger resection, such as staging or debulking were excluded. Demographic and clinicopathologic factors were obtained. Univariate and multivariate analyses identified factors associated with an increased risk of malignancy. Between 1986 and 2012, 2,743 patients underwent a splenectomy, 148 of which were performed for lesions identified on imaging. The indications were suspicion of malignancy (120, 81%), growth over time (28, 19%), or symptoms (39, 26%). Resected splenic lesions were malignant in 93 patients (63%); the most common pathologies included ovarian cancer (n = 39), melanoma (n = 14), and colorectal cancer (n = 9). On multivariate analysis of clinicopathologic factors, a previous history of cancer was the only independent predictor of malignancy in the splenic lesion (odds ratio 6.3; 95% CI, 2.32-16.97; P = 0.001). While the spleen is an uncommon site of metastatic disease, in patients with a history of cancer, splenic masses selected for resection are frequently malignant. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 12/2013; 108(8). DOI:10.1002/jso.23433 · 3.24 Impact Factor
  • Radiology 12/2013; 269(3):949-950. DOI:10.1148/radiol.13134035 · 6.87 Impact Factor
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    ABSTRACT: Purpose: To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16β-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer. Materials and methods: This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression. Results: In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = -0.3007; P < .001; reader 2: r = -0.3147; P < .001) and FDHT (reader 1: r = -0.2680; P = .001; reader 2: r = -0.3656; P < .001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051-1.109; P < .001) and reader 2 (HR, 1.026-1.082; P ≤ .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38). Conclusion: In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival.
    Radiology 11/2013; 271(1):130625. DOI:10.1148/radiol.13130625 · 6.87 Impact Factor
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    ABSTRACT: To determine mechanisms by which SCCRO5 (aka DCUN1D5) promotes oncogenesis. SCCRO5 mRNA and protein expression were assessed in 203 randomly selected primary cancer tissue samples, matched histologically normal tissues, and cell lines by use of real-time PCR and Western blot analysis. SCCRO5 overexpression was correlated with survival. The effect of SCCRO5 knockdown on viability was assessed in selected cancer cell lines. Structure-function studies were performed to determine the SCCRO5 residues required for binding to the neddylation components, for neddylation-promoting activity, and for transformation. In oral and lung squamous cell carcinomas, SCCRO5 mRNA levels corresponded with protein levels and overexpression correlated with decreased disease-specific survival. Knockdown of SCCRO5 by RNAi resulted in a selective decrease in the viability of cancer cells with high endogenous levels, suggesting the presence of oncogene addiction. SCCRO5 promoted cullin neddylation while maintaining conserved reaction processivity paradigms involved in ubiquitin and ubiquitin-like protein conjugation, establishing it as a component of the neddylation E3. Neddylation activities in vitro required the potentiating of neddylation (PONY) domain but not the nuclear localization sequence (NLS) domain. In contrast, both the NLS domain and the PONY domain were required for transformation of NIH-3T3 cells. Our data suggest that SCCRO5 has oncogenic potential and that it imparts its oncogenicity as a component of the neddylation E3. Neddylation activity and nuclear localization of SCCRO5 are important for its in vivo function.
    Clinical Cancer Research 11/2013; 20(2). DOI:10.1158/1078-0432.CCR-13-1252 · 8.72 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 10/2013; 87(2):S413. DOI:10.1016/j.ijrobp.2013.06.1085 · 4.26 Impact Factor
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    ABSTRACT: Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC. Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP. We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders. Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function.
    BMC Medical Genetics 09/2013; 14(1):97. DOI:10.1186/1471-2350-14-97 · 2.08 Impact Factor
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    ABSTRACT: Clinical decision making for patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas is challenging. Even with strict criteria for resection, most resected lesions lack high-grade dysplasia (HGD) or invasive carcinoma. We evaluated patients who underwent resection of histologically confirmed IPMN and had preoperative imaging available for review. A hepatobiliary radiologist blinded to histopathologic subtype reviewed preoperative imaging and recorded cyst characteristics. Patients with mixed-type IPMN were grouped with main-duct lesions for this analysis. Based on an ordinal logistic regression model, we devised two independent nomograms to predict the findings of adenoma, high-grade dysplasia (HGD-CIS), and invasive carcinoma, separately in both main and branch-duct IPMN. Bootstrap validation was used to evaluate the performance of these models, and a concordance index was derived from this internal validation. There were 219 patients who met criteria for this study. Branch-duct IPMN (bdIPMN) comprised 56 % of the resected lesions. The proportion of HGD-CIS was 15 % for bdIPMN and 33 % for main-duct lesions (mdIPMN); P = 0.003. Invasive carcinoma was identified in 15 % of bdIPMN and 41 % of main-duct lesions (P < 0.001). On multivariate regression, patient gender, history of prior malignancy, presence of solid component, and weight loss were found to be significantly associated with the ordinal outcome for patients with mdIPMN and built into the nomogram (concordance index 0.74). For patients with bdIPMN weight loss, solid component, and lesion diameter were associated with the outcome; (concordance index 0.74). Based on the analysis of patients selected for resection, two nomograms were created that predict a patient's individual likelihood of harboring HGD or invasive malignancy in radiologically diagnosed IPMN. External validation is ongoing.
    Annals of Surgical Oncology 09/2013; 20(13). DOI:10.1245/s10434-013-3207-z · 3.93 Impact Factor
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    ABSTRACT: To explore whether pre-reoperative dynamic contrast-enhanced (DCE)-MRI findings correlate with clinical outcome in patients who undergo surgical treatment for recurrent rectal carcinoma. A retrospective study of DCE-MRI in patients with recurrent rectal cancer was performed after obtaining an IRB waiver. We queried our PACS from 1998 to 2012 for examinations performed for recurrent disease. Two radiologists in consensus outlined tumour regions of interest on perfusion images. We explored the correlation between K(trans), Kep, Ve, AUC90 and AUC180 with time to re-recurrence of tumour, overall survival and resection margin status. Univariate Cox PH models were used for survival, while univariate logistic regression was used for margin status. Among 58 patients with pre-treatment DCE-MRI who underwent resection, 36 went directly to surgery and 18 had positive margins. K(trans) (0.55, P = 0.012) and Kep (0.93, P = 0.04) were inversely correlated with positive margins. No significant correlations were noted between K(trans), Kep, Ve, AUC90 and AUC180 and overall survival or time to re-recurrence of tumour. K(trans) and Kep were significantly associated with clear resection margins; however overall survival and time to re-recurrence were not predicted. Such information might be helpful for treatment individualisation and deserves further investigation. • Morphological MRI features are not sufficiently predictive of complete rectal tumour resection. • Survival and time to re-recurrence of tumour were not predicted by DCE-MRI. • But perfusion data from dynamic enhanced MRI may provide more helpful information. • Ktrans/Kep were shown to be significantly associated with clear resection margins. • Functional information from DCE-MRI might be helpful for treatment individualisation.
    European Radiology 08/2013; 23(12). DOI:10.1007/s00330-013-2984-x · 4.01 Impact Factor
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    ABSTRACT: Progress in adoptive T-cell therapy for cancer and infectious diseases is hampered by the lack of readily available, antigen-specific, human T lymphocytes. Pluripotent stem cells could provide an unlimited source of T lymphocytes, but the therapeutic potential of human pluripotent stem cell-derived lymphoid cells generated to date remains uncertain. Here we combine induced pluripotent stem cell (iPSC) and chimeric antigen receptor (CAR) technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture. These iPSC-derived, CAR-expressing T cells display a phenotype resembling that of innate γδ T cells. Similar to CAR-transduced, peripheral blood γδ T cells, the iPSC-derived T cells potently inhibit tumor growth in a xenograft model. This approach of generating therapeutic human T cells 'in the dish' may be useful for cancer immunotherapy and other medical applications.
    Nature Biotechnology 08/2013; 31(10). DOI:10.1038/nbt.2678 · 41.51 Impact Factor
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    ABSTRACT: Additional chemotherapy in patients with resectable colorectal liver metastases (CRLM) likely improves outcomes. Whether to administer chemotherapy as perioperative or adjuvant therapy remains controversial. We analyzed outcomes between these two treatment strategies. Patients were identified from a prospective CRLM database and studied retrospectively. Patients with extrahepatic disease or initially unresectable CRLM were excluded. Only patients receiving oxaliplatin- and/or irinotecan-containing chemotherapy regimens were included. Univariate and Cox regression models were developed for recurrence and death. Between 1998 and 2007, 236 patients (57.4 %) in the adjuvant group and 175 patients (42.6 %) in the perioperative group were compared. The perioperative group was younger and had more tumors, shorter disease-free intervals, and higher clinical risk scores (CRS), but had smaller tumors. The overall survival was similar between the groups (perioperative 72.9 months vs. adjuvant 71.5 months; p = 0.48). When the comparison was adjusted for other clinicopathologic factors and CRS, the differences remained insignificant. On univariate analysis, there was a significant difference in recurrence-free survival between the groups (perioperative 17.2 months vs. adjuvant 27.4 months, p = 0.036). However, when the recurrence-free survival was adjusted for other clinicopathologic factors and the CRS, differences were not significant. The timing of additional chemotherapy for resectable CRLM is not associated with outcomes. Trials comparing adjuvant and perioperative chemotherapy would have to be powered for small differences in outcome.
    Annals of Surgical Oncology 07/2013; 20(13). DOI:10.1245/s10434-013-3162-8 · 3.93 Impact Factor

Publication Stats

15k Citations
2,108.90 Total Impact Points


  • 2001–2015
    • Memorial Sloan-Kettering Cancer Center
      • • New York Branch at Memorial Sloan-Kettering Cancer Center
      • • Epidemiology & Biostatistics Group
      • • Department of Surgery
      New York, New York, United States
  • 2013
    • Gracie Square Hospital, New York, NY
      New York, New York, United States
    • Lenox Hill Hospital
      New York, New York, United States
  • 2005
    • Texas Tech University
      Lubbock, Texas, United States
  • 2004
    • Cornell University
      Ithaca, New York, United States
    • Canadian Society for Epidemiology and Biostatistics