Mithat Gonen

Gracie Square Hospital, New York, NY, New York, New York, United States

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Publications (381)

  • J. Smith · O. Chow · A. Eaton · [...] · P. B. Paty
    Conference Paper · Feb 2015
  • Article · Feb 2015 · Journal of Vascular and Interventional Radiology
  • Article · Feb 2015 · Radiology
  • Article · Feb 2015 · Journal of Vascular and Interventional Radiology
  • Article: Response.
    Article · Feb 2015 · Radiology
  • Conference Paper · Jan 2015
  • [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVES:: To evaluate the association of tumor-associated neutrophils (TANs) with malignant progression in intraductal papillary mucinous neoplasms (IPMNs) and to study the cyst fluid from these lesions for biomarkers of the inflammation-carcinogenesis association. BACKGROUND:: There is a strong link between TANs and malignant progression. Inflammatory mediators released by these cells may be a measurable surrogate marker of this progression. METHODS:: We evaluated 78 resected IPMNs (2004-2013). Lesions were divided into the low-risk (low- and intermediate-grade dysplasia: n = 48) and high-risk (high-grade dysplasia and invasive carcinoma: n = 30) groups. TANs were assessed and categorized (negative, low, and high). A multiplexed assay was performed to evaluate 87 different cyst fluid proteins, including cyst fluid inflammatory markers (CFIMs), as possible surrogate markers for parenchymal inflammation. RESULTS:: Significant positive correlation between grade of dysplasia and TANs was found. High levels of TANs were identified in 2%, 33%, and 89% of the lesions when stratified by grade of dysplasia into low/intermediate-grade dysplasia, high-grade dysplasia, and invasive carcinoma, respectively (P < 0.001). Higher grades of dysplasia were also found to have positive correlation with 29 of the measured proteins, of which 23 (79%) were CFIMs. Higher levels of TANs correlated with higher levels of 18 CFIMs, of which 16 (89%) were also found to be associated with higher grades of dysplasia. CONCLUSIONS:: In this study, TANs were strongly associated with malignant progression in IPMNs. Measurement of CFIMs may be a surrogate marker for IPMN progression and allow for the identification of high-risk disease.
    Article · Jan 2015 · Annals of Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: One quarter of colorectal cancer patients will present with liver metastasis at the time of diagnosis. Recent studies have shown that simultaneous resections are safe and feasible for stage IV colon cancer. Limited data are available for simultaneous surgery in stage IV rectal cancer patients. One hundred ninety-eight patients underwent surgical treatment for stage IV rectal cancer. In 145 (73%) patients, a simultaneous procedure was performed. Fifty-three (27%) patients underwent staged liver resection. A subpopulation of 69 (35%) patients underwent major liver resection (3 segments or more) and 30 (44%) patients with simultaneous surgery. The demographics of the 2 groups were similar. Complication rates were comparable for simultaneous or staged resections, even in the group subjected to major liver resection. Total hospital stay was significantly shorter for the simultaneously resected patients (P < .01). Simultaneous resection of rectal primaries and liver metastases is a safe procedure in carefully selected patients at high-volume institutions, even if major liver resections are required. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Dec 2014 · The American Journal of Surgery
  • Article · Oct 2014 · Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: Objectives This study was conducted to evaluate the prognostic value of, respectively, the 6th and 7th editions of the American Joint Committee on Cancer (AJCC) staging system for patients with resected perihilar cholangiocarcinoma (PHC).Methods Patients who underwent resection of PHC between 1991 and 2012 were identified from prospective databases at two centres. Overall survival was estimated using the Kaplan–Meier method and compared across stage groups with the log-rank test. The concordance index and Brier score were used to compare the prognostic accuracy of the staging systems.ResultsData for a total of 306 patients were analysed. Staging according to the 7th edition upstaged 63% of patients in comparison with staging by the 6th edition. The log-rank P-value for both staging systems was highly statistically significant (P < 0.001). Staging according to the 6th edition categorized 93% of patients as having stage I or II disease, whereas staging according to the 7th edition distributed patients more equally across stages. Prognostic accuracy was similar between the staging systems: the concordance index was 0.59 and the Brier score 0.17 for both the 6th and 7th editions. The same prognostic accuracy was achieved using an alternative tumour–node–metastasis (TNM) stage grouping simplified to four rather than six stage groups.Conclusions The 6th and 7th editions of the AJCC staging system for PHC have similar prognostic accuracy. Other prognostic factors can potentially improve individual patient prognostication.
    Article · Oct 2014 · HPB
  • [Show abstract] [Hide abstract] ABSTRACT: Treatment with the tyrosine kinase inhibitor imatinib represents the standard of care for newly diagnosed patients with chronic myeloid leukemia. In recent years, several second generation inhibitors - such as dasatinib and nilotinib - have become available that promise to overcome some of the mutations associated with acquired resistance in these patients. Despite eliciting similar clinical responses, the molecular effects of these agents on different subpopulations of leukemic cells remain incompletely understood. Furthermore, the consequences of using high-dose imatinib therapy have not been investigated in detail. Here we utilized clinical data from patients treated with dasatinib, nilotinib, or high-dose imatinib, together with a statistical data analysis and mathematical modeling approach, to investigate the molecular treatment response of leukemic cells to these agents. We found that these drugs elicit very similar responses if administered front-line. However, the patient population displays significantly different kinetics when treated second line, both in terms of differences between front-line and second line treatment for the same drug, and among agents when used second-line. We then utilized a mathematical framework describing the behavior of four differentiation levels of leukemic cells during therapy to predict the treatment response kinetics for the different patient cohorts. The dynamics of BCR-ABL1 clearance observed in our study suggest that the use of standard or high-dose imatinib or a second generation TKI such as nilotinib or dasatinib elicit similar responses when administered as frontline therapy for patients with CML in chronic phase.
    Article · Sep 2014 · Haematologica
  • [Show abstract] [Hide abstract] ABSTRACT: Unlabelled: National Comprehensive Cancer Network guidelines consider (18)F-FDG PET/CT for only clinical stage III breast cancer patients. However, there is debate whether TNM staging should be the only factor in considering if PET/CT is warranted. Patient age may be an additional consideration, because young breast cancer patients often have more aggressive tumors with potential for earlier metastases. This study assessed PET/CT for staging of asymptomatic breast cancer patients younger than 40 y. Methods: In this Institutional Review Board-approved retrospective study, our hospital information system was screened for breast cancer patients younger than 40 y who underwent staging PET/CT before any treatment. Patients with symptoms or conventional imaging findings suggestive of distant metastases or with prior malignancy were excluded. Initial stage was based on physical examination, mammography, ultrasound, and breast MR imaging. PET/CT was then evaluated to identify unsuspected extraaxillary regional nodal and distant metastases. Results: One hundred thirty-four patients with initial breast cancer stage I to IIIC met inclusion criteria. PET/CT findings led to upstaging to stage III or IV in 28 patients (21%). Unsuspected extraaxillary regional nodes were found in 15 of 134 patients (11%) and distant metastases in 20 of 134 (15%), with 7 of 134 (5%) demonstrating both. PET/CT revealed stage IV disease in 1 of 20 (5%) patients with initial clinical stage I, 2 of 44 (5%) stage IIA, 8 of 47 (17%) stage IIB, 4 of 13 (31%) stage IIIA, 4 of 8 (50%) stage IIIB, and 1 of 2 (50%) stage IIIC. All 20 patients upstaged to stage IV were histologically confirmed. Four synchronous thyroid and 1 rectal malignancies were identified. Conclusion: PET/CT revealed distant metastases in 17% of asymptomatic stage IIB breast cancer patients younger than 40 y. Although guidelines of the National Comprehensive Cancer Network recommend against systemic staging in patients with stage II disease, our data suggest that PET/CT might be valuable in younger patients with stage IIB and III disease. Use of PET/CT in younger patients has the potential to reduce the morbidity and cost of unnecessary therapies in young breast cancer patients.
    Article · Sep 2014 · Journal of Nuclear Medicine
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    Neeta Pandit-Taskar · Joseph A O'Donoghue · Volkan Beylergil · [...] · Steven M Larson
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. (89)Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. Methods: Ten patients with metastatic prostate cancer received 5 mCi of (89)Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by (89)Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of (89)Zr-huJ591 was done. Optimal time for imaging post-injection was determined. Results: The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of (89)Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 ± 4.5 h (range 1.1-14 h) and 62 ± 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 ± 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 ± 1.5 cGy/mCi, renal cortex 3.5 ± 0.4 cGy/mCi, and bone marrow 1.2 ± 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 ± 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on (89)Zr-huJ591, while the remaining 11 lesions were (89)Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on (89)Zr-huJ591 study, while the conventional imaging modality was negative. Conclusion: (89)Zr-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 ± 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer.
    Full-text Article · Aug 2014 · European journal of nuclear medicine and molecular imaging
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: Several recently reported recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) are linked to pathological and clinical outcomes. We determined if any of the recurrent cancer gene mutations or copy number alterations identified in the Cancer Genome Atlas (TCGA) ccRCC dataset could add to the predictive accuracy of the current prognostic models. Materials and Methods: 413 patients who underwent nephrectomy/partial nephrectomy with whole exome, copy number array analyses, and clinical variables were interrogated. Sixty-five recurrent genomic alterations were identified based on prevalence and combined into 35 alterations including 12 cancer gene mutations. The genomic markers were modeled using the elastic-net algorithm with preoperative variables (tumor size + age) and in the postoperative setting using the externally validated Mayo Clinic stage, size, grade, and necrosis (SSIGN) prognostic scoring system. These models were subjected to internal validation using bootstrap. Results: The median follow up for survivors was 45 months. Several markers correlated with adverse cancer-specific survival (CSS) and time to recurrence (TTR) on univariate analysis. However, most lost significance when controlling for tumor size +/- age in the preoperative models or SSIGN score in the postoperative setting. The addition of multiple genomic markers selected by the elastic-net algorithm failed to substantially add to the predictive accuracy of any of the preoperative or postoperative models for CSS or TTR. Conclusions: While recurrent copy number alterations and cancer gene mutations are biologically significant, they do not appear to improve the predictive accuracy of existing clinical CSS or TTR models in ccRCC.
    Article · Jul 2014 · The Journal of urology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Of the 24 million people predicted to have cancer by 2050, 70% will live in low- and middle-income countries (LMIC). As a result, cancer care is becoming a priority for health care systems in West Africa. This study compares the presentation and pattern of spread of colorectal cancer (CRC) observed in a hospital in West Africa with that of a North American referral center. Methods: Data on all adults presenting with CRC at a hospital in Nigerian patients (West Africa; 1990-2011) and all adults with stages III or IV CRC at a specialty hospital in (New York City, New York, North America; 2005-2011) were examined retrospectively. Demographic data, stage of disease, site of metastasis, and survival were compared. Results: There were 160 patients identified in West Africa and 1,947 patients identified in North America. Nigerian patients were younger (52 vs 59 years; P < .01) and presented with a later stage of disease (58% stage IV vs 47%; P < .01). Site of disease presentation was different between West African and North American patients (P < .01); 2.2% of West African patients presented with liver metastases only compared with 48.1% of North American patients. Conversely, 61.3% of patients in West Africa presented with peritoneal metastases only compared with 5.4% in North America. Overall survival stratified by stage at presentation (III/IV) showed worse prognosis for patients in either stage subgroup in Nigeria than North America. Conclusion: We found differences in the presentation, metastatic pattern, and outcomes of CRC in Nigerian (West Africa) when compared with New York City (North America). Late detection and differential tumor biology may drive the differences observed between the sites. Future studies on early CRC detection and on tumor biology in LMIC will be critical for understanding and treating CRC in this region.
    Article · Jun 2014 · Surgery
  • Camilo Correa-Gallego · Yuman Fong · Mithat Gonen · [...] · T Peter Kingham
    [Show abstract] [Hide abstract] ABSTRACT: Background: Microwave (MWA) and radiofrequency ablation (RFA) are the most commonly used techniques for ablating colorectal-liver metastases (CRLM). The technical and oncologic differences between these modalities are unclear. Methods: We conducted a matched-cohort analysis of patients undergoing open MWA or RFA for CRLM at a tertiary-care center between 2008 and 2011; the primary endpoint was ablation-site recurrence. Tumors were matched by size, clinical-risk score, and arterial-intrahepatic or systemic chemotherapy use. Outcomes were compared using conditional logistic regression and stratified log-rank test. Results: We matched 254 tumors (127 per group) from 134 patients. MWA and RFA groups were comparable by age, gender, median number of tumors treated, proximity to major vessels, and postoperative complication rates. Patients in the MWA group had lower ablation-site recurrence rates (6% vs. 20%; P < 0.01). Median follow-up, however, was significantly shorter in the MWA group (18 months [95% confidence interval 17-20] vs. 31 months [95% confidence interval 28-35]; P < 0.001). Kaplan-Meier estimates of ablation-site recurrence at 2 years were significantly lower for the lesions treated with MWA (7% vs. 18%, P: 0.01). Conclusions: Ablation-site recurrences of CRLM were lower with MWA compared with RFA in this matched cohort analysis. Longer follow-up time in the MWA may increase the recurrence rate; however, actuarial local failure estimations demonstrated better local control with MWA.
    Article · Jun 2014 · Annals of Surgical Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: Mechanisms that generate transcript diversity are of fundamental importance in eukaryotes. Although a large fraction of human protein-coding genes and lincRNAs produce more than one mRNA isoform each, the regulation of this phenomenon is still incompletely understood. Much progress has been made in deciphering the role of sequence-specific features as well as DNA-and RNA-binding proteins in alternative splicing. Recently, however, several experimental studies of individual genes have revealed a direct involvement of epigenetic factors in alternative splicing and transcription initiation. While histone modifications are generally correlated with overall gene expression levels, it remains unclear how histone modification enrichment affects relative isoform abundance. Therefore, we sought to investigate the associations between histone modifications and transcript diversity levels measured by the rates of transcription start-site switching and alternative splicing on a genome-wide scale across protein-coding genes and lincRNAs. We found that the relationship between enrichment levels of epigenetic marks and transcription start-site switching is similar for protein-coding genes and lincRNAs. Furthermore, we found associations between splicing rates and enrichment levels of H2az, H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me3, H3K27ac, H3K27me3, H3K36me3, H3K79me2, and H4K20me, marks traditionally associated with enhancers, transcription initiation, transcriptional repression, and others. These patterns were observed in both normal and cancer cell lines. Additionally, we developed a novel computational method that identified 840 epigenetically regulated candidate genes and predicted transcription start-site switching and alternative exon splicing with up to 92% accuracy based on epigenetic patterning alone. Our results suggest that the epigenetic regulation of transcript isoform diversity may be a relatively common genome-wide phenomenon representing an avenue of deregulation in tumor development.
    Full-text Article · Jun 2014 · PLoS Computational Biology
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction The increasing use of molecular imaging probes as biomarkers in oncology emphasizes the need for robust and stable methods for quantifying tracer uptake in PET imaging. The primary motivation for this research was to find an accurate method to quantify the total tumor uptake. Therefore we developed a histogram-based method to calculate the background subtracted lesion (BSL) activity and validated BSL by comparing the quantitative consistency with the total lesion glycolysis (TLG) in phantom and patient studies. Methods A thorax phantom and a PET-ACR quality assurance phantom were scanned with increasing FDG concentrations. Volumes of interest (VOIs) were placed over each chamber. TLG was calculated with a fixed threshold at SUV 2.5 (TLG2.5) and a relative threshold at 42% of SUVmax (TLG42%). The histogram for each VOI was built and BSL was calculated. Comparison with the total injected FDG activity (TIA) was performed using concordance correlation coefficients (CCC) and the slope (a). Fifty consecutive patients with FDG-avid lung tumors were selected under an IRB waiver. TLG42%, TLG2.5 and BSL were compared to the reference standard calculating CCC and the slope. Results In both phantoms, the CCC for lesions with a TIA ≤ 50 ml*SUV between TIA and BSL was higher and the slope closer to 1 (CCC = 0.933, a = 1.189), than for TLG42% (CCC = 0.350, a = 0.731) or TLG2.5 (CCC = 0.761, a = 0.727). In 50 lung lesions BSL had a slope closer to 1 compared to the reference activity than TLG42% (a = 1.084 vs 0.618 - for high activity lesions) and also closer to 1 than TLG2.5 (a = 1.117 vs 0.548 - for low activity lesions). Conclusion The histogram based BSL correlated better with TIA in both phantom studies than TLG2.5 or TLG42%. Also in lung tumors, the BSL activity is overall more accurate in quantifying the lesion activity compared to the two most commonly applied TLG quantification methods.
    Article · May 2014 · Nuclear Medicine and Biology
  • [Show abstract] [Hide abstract] ABSTRACT: This prospective single-institution study examined the impact of positron emission tomography (PET) with the use of 2-[(18)F] fluoro-2-deoxyglucose and computed tomography (CT) scan radiation treatment planning (TP) on target volume definition in lymphoma. 118 patients underwent PET/CT TP during June 2007 to May 2009. Gross tumor volume (GTV) was contoured on CT-only and PET/CT studies by radiation oncologists (ROs) and nuclear medicine physicians (NMPs) for 95 patients with positive PET scans. Treatment plans and dose-volume histograms were generated for CT-only and PET/CT for 95 evaluable sites. Paired t test statistics and Pearson correlation coefficients were used for analysis. 70 (74%) patients had non-Hodgkin lymphoma, 10 (11%) had Hodgkin lymphoma, 12 (10%) had plasma-cell neoplasm, and 3 (3%) had other hematologic malignancies. Forty-three (45%) presented with relapsed/refractory disease. Forty-five (47%) received no prior chemotherapy. The addition of PET increased GTV as defined by ROs in 38 patients (median, 27%; range, 5%-70%) and decreased GTV in 41 (median, 39.5%; range, 5%-80%). The addition of PET increased GTV as defined by NMPs in 27 patients (median, 26.5%; range, 5%-95%) and decreased GTV in 52 (median, 70%; range, 5%-99%). The intraobserver correlation between CT-GTV and PET-GTV was higher for ROs than for NMPs (0.94, P<.01 vs 0.89, P<.01). On the basis of Bland-Altman plots, the PET-GTVs defined by ROs were larger than those defined by NMPs. On evaluation of clinical TPs, only 4 (4%) patients had inadequate target coverage (D95 <95%) of the PET-GTV defined by NMPs. Significant differences between the RO and NMP volumes were identified when PET was coregistered to CT for radiation planning. Despite this, the PET-GTV defined by ROs and NMPs received acceptable prescription dose in nearly all patients. However, given the potential for a marginal miss, consultation with an experienced PET reader is highly encouraged when PET/CT volumes are delineated, particularly for questionable lesions and to assure complete and accurate target volume coverage.
    Article · Apr 2014 · International journal of radiation oncology, biology, physics
  • Article · Apr 2014 · The Journal of Urology