Mithat Gonen

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

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Publications (292)1741.9 Total impact

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    ABSTRACT: PURPOSE: To identify changes in plasma cytokine levels after image-guided thermal ablation of human tumors and to identify the factors that independently predict changes in plasma cytokine levels. MATERIALS AND METHODS: Whole-blood samples were collected from 36 patients at three time points: before ablation, after ablation (within 48 hours), and at follow-up (1-5 weeks after ablation). Plasma levels of interleukin (IL)-1α, IL-2, IL-6, IL-10, and tumor necrosis factor (TNF)-α were measured using a multiplex immunoassay. Univariate and multivariate analyses were performed using cytokine level as the dependent variable and sample collection, time, age, sex, primary diagnosis, metastatic status, ablation site, and ablation type as the independent variables. RESULTS: There was a significant increase in the plasma level of IL-6 after ablation compared with before ablation (9.6-fold±31-fold, P<.002). IL-10 also showed a significant increase after ablation (1.9-fold±2.8-fold, P<.02). Plasma levels of IL-1α, IL-2, and TNF-α were not significantly changed after ablation. Cryoablation resulted in the largest change in IL-6 level (>54-fold), whereas radiofrequency ablation and microwave ablation showed 3.6-fold and 3.4-fold changes, respectively. Ablation of melanomas showed the largest change in IL-6 48 hours after ablation (92×), followed by ablation of kidney (26×), liver (8×), and lung (6×) cancers. Multivariate analysis revealed that ablation type (P<.0003) and primary diagnosis (P<.03) were independent predictors of changes to IL-6 after ablation. Age was the only independent predictor of IL-10 levels after ablation (P< .019). CONCLUSIONS: Image-guided thermal ablation of tumors increases plasma levels of IL-6 and IL-10, without increasing plasma levels of IL-1α, IL-2, or TNF-α.
    Journal of vascular and interventional radiology: JVIR 04/2013; · 1.81 Impact Factor
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    ABSTRACT: OBJECTIVES:Controversy exists regarding whether to place a plastic or a metal endobiliary stent in patients with resectable pancreatic cancer who require biliary drainage. Although self-expandable metal stents (SEMS) provide better drainage compared with plastic stents, concerns remain that SEMS may compromise resection and increase postoperative complications. Our objective was to compare surgical outcomes of patients undergoing pancreaticoduodenectomy (PD) with SEMS in place vs. plastic endoscopic stents (PES) and no stents (NS).METHODS:We performed a retrospective analysis from a prospective database of all patients undergoing either attempted or successful PD with SEMS, PES, or NS in place at the time of operation. Patients were compared with regard to perioperative complications, margin status, and the rate of intraoperative determination of unresectability.RESULTS:A total of 593 patients underwent attempted PD. Of these, 84 patients were locally unresectable intraoperatively and 509 underwent successful PD, of which 71 had SEMS, 149 had PES, and 289 had NS. Among patients who had a preoperative stent, SEMS did not increase overall or serious postoperative complications, 30-day mortality, length of stay, biliary anastomotic leak, or positive margin, but was associated with more wound infections and longer operative times. In those with adenocarcinoma, intraoperative determination of local unresectability was similar in the SEMS group compared with other groups, with 16 (19.3%) in SEMS compared with 29 (17.7%) in PES (P=0.862), and 31 (17.5%) in NS (P=0.732).CONCLUSIONS:Placement of SEMS is not contraindicated in patients with resectable pancreatic cancer who require preoperative biliary drainage.Am J Gastroenterol advance online publication, 2 April 2013; doi:10.1038/ajg.2013.93.
    The American Journal of Gastroenterology 04/2013; · 9.21 Impact Factor
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    ABSTRACT: PURPOSE: To examine the association between positive resection margins and survival and local recurrence in patients with gastric cancer undergoing resection with curative intent. METHODS: Patients who underwent curative intent resection for gastric carcinoma from 1985 to 2010 were identified from a prospectively maintained database. Positive margins were defined as disease present at the line of luminal transection. Clinicopathological features and outcome of patients undergoing gastrectomy with negative and positive margins were compared. RESULTS: Among 2384 patients undergoing curative intent resection, 108 (4.5 %) had positive margins. Positive margins were associated with higher American Joint Committee on Cancer (AJCC) stage, T stage, N stage, median number of positive nodes, diffuse Lauren type, and poorly differentiated tumors. Treatment of positive margins consisted of: observation (39 %), chemoradiotherapy (26 %), chemotherapy (20 %), repeat resection (10 %), radiotherapy (4 %), and unknown (1 %). Multivariate analysis of the entire cohort demonstrated margin status, T stage, N stage, grade, and perineural invasion to be independent predictors of survival. Margin status was an independent predictor of survival in patients with ≤3 positive nodes or T1-2 disease but was not in patients with >3 positive nodes or T3-4 disease. Local recurrence occurred in 16 % of patients with a positive margin. We identified no factors predictive of local recurrence in patients with positive margins. CONCLUSIONS: Positive resection margin is associated with advanced AJCC stage and aggressive tumor biology but remains an independent predictor of worse survival. The significance of a positive margin in gastric cancer is confined to patients with nontransmural disease and/or limited nodal involvement.
    Annals of Surgical Oncology 03/2013; · 3.94 Impact Factor
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    ABSTRACT: OBJECTIVE:: To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors. BACKGROUND:: The standard management of desmoid tumors is resection, but many recur locally. Other options include observation or novel chemotherapeutics, but little guidance exists on selecting treatment. METHODS:: Patients undergoing resection during 1982-2011 for primary or locally recurrent desmoids were identified from a single-institution prospective database. Cox regression analysis was used to assess risk factors and to create a recurrence nomogram, which was validated using an international, multi-institutional data set. RESULTS:: Desmoids were treated surgically in 495 patients (median follow-up of 60 months). Of 439 patients undergoing complete gross resection, 100 (23%) had recurrence. Five-year local recurrence-free survival was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved local recurrence-free survival. In multivariate analysis, factors associated with recurrence were extremity location, young age, and large tumor size, but not margin. Abdominal wall tumors had the best outcome (5-year local recurrence-free survival rate of 91%). Age, site, and size were used to construct a nomogram with concordance index of 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, sex, depth, and primary vs recurrent presentation) did not importantly improve concordance (internal concordance index of 0.707). CONCLUSIONS:: A postoperative nomogram including only size, site, and age predicts local recurrence and can aid in counseling patients. Systemic therapies may be appropriate for young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions.
    Annals of surgery 03/2013; · 7.19 Impact Factor
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    ABSTRACT: Hepatocellular adenoma (HA) is an uncommon benign hepatic tumour with the potential for malignant change or spontaneous haemorrhage. Resection has been the recommended treatment, but outcomes with other approaches are ill defined. Demographic and outcomes data were retrospectively collected on patients diagnosed with HA at a tertiary hepatobiliary centre from 1992-2011 whom underwent resection, bland embolization or observation. In total, 52 patients with 100 adenomas were divided into single HA (n = 27), multiple HA (n = 18), and adenomatosis (n = 7) groups. Eighty-seven per cent were female and 37% had a history of hormone use. Median sizes of resected, embolized and observed adenomas were 3.6 cm, 2.6 cm and 1.2 cm, respectively. Forty-eight adenomas were resected as a result of suspicion of malignancy (39%) or large size (39%); 61% of these were solitary. Thirty-seven were embolized for suspicion of malignancy (56%) or hsemorrhage (20%); 92% of these were multifocal. Two out of three resected adenomas with malignancy were ≥10 cm and recurred locally [4%, confidence interval (CI) 1-14%]. Ninety-two per cent of the embolized adenomas were effectively treated; three persisted (8.1%, CI 2-22%). Most observed lesions did not change over time. While solitary adenomas are often resected, multifocal HAs are frequently embolized. Small adenomas can safely be observed. Given low recurrence rates, select HAs can be considered for embolization.
    HPB 03/2013; 15(3):235-43. · 2.05 Impact Factor
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    ABSTRACT: BACKGROUND: Splenectomy is performed for a variety of indications in haematological disorders. This study was undertaken to analyse outcomes, and morbidity and mortality rates associated with this procedure. METHODS: Patients undergoing splenectomy for the treatment or diagnosis of haematological disease were included. Indications for operation, preoperative risk, intraoperative variables and short-term outcomes were evaluated. RESULTS: From January 1997 to December 2010, 381 patients underwent splenectomy for diagnosis or treatment of haematological disease. Some 288 operations were performed by an open approach, 83 laparoscopically, and there were ten conversions. Overall 136 patients (35·7 per cent) experienced complications. Postoperative morbidity was predicted by age more than 65 years (odds ratio (OR) 1·63, 95 per cent confidence interval 1·05 to 2·55), a Karnofsky performance status (KPS) score lower than 60 (OR 2·74, 1·35 to 5·57) and a haemoglobin level of 9 g/dl or less (OR 1·74, 1·09 to 2·77). Twenty-four patients (6·3 per cent) died within 30 days of surgery. Postoperative mortality was predicted by a KPS score lower than 60 (OR 16·20, 6·10 to 42·92) and a platelet count of 50 000/µl or less (OR 3·34, 1·25 to 8·86). The objective of the operation was achieved in 309 patients (81·1 per cent). The success rate varied for each indication: diagnosis (106 of 110 patients, 96·4 per cent), thrombocytopenia (76 of 115, 66·1 per cent), anaemia (10 of 16, 63 per cent), to allow further treatment (46 of 59, 78 per cent) and primary treatment (16 of 18, 89 per cent). CONCLUSION: Splenectomy is an effective procedure in the diagnosis and treatment of haematological disease in selected patients.
    British Journal of Surgery 02/2013; · 4.84 Impact Factor
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    ABSTRACT: PURPOSE: Based on prior reports suggesting a positive correlation between fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT and total sperm count and concentration, we sought to identify changes in testicular FDG uptake over the course of chemotherapy in young men with Hodgkin's lymphoma. METHODS: Fifty-two patients with a mean age of 24.2 years (range 15.5-44.4) at diagnosis monitored with FDG PET/CT to assess treatment response for Hodgkin's lymphoma were selected for this retrospective analysis under an Institutional Review Board waiver. Of the patients, 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia (BEACOPP-bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) and 26 with a regimen known to have a much milder effect on gonadal function (ABVD-doxorubicin, bleomycin, vincristine, and dacarbazine). Each patient underwent one FDG PET/CT before treatment and at least one FDG PET/CT after start of chemotherapy. In all examinations, FDG activity was measured in the testes with different quantification metrics: maximum standardized uptake value (SUV(max)), SUV(mean), functional volume (FV) and total testicular glycolysis (TTG), and blood pool activity determined (SUV(mean)). RESULTS: Testicular FDG uptake (SUV(max)) was significantly associated with blood pool activity (p < 0.001). Furthermore, testicular FDG uptake metrics incorporating volume (e.g., FV and TTG) were associated with age. There was no significant change in SUV(max), SUV(mean), FV, and TTG from the PET/CT at baseline to the PET/CTs over the course of chemotherapy either for patients treated with BEACOPP or for patients treated with ABVD. CONCLUSION: For patients undergoing chemotherapy for Hodgkin's lymphoma, there is a significant association between testicular FDG uptake and blood pool activity, but no significant changes in FDG uptake over the course of chemotherapy. Therefore, FDG uptake may not be a feasible surrogate marker for fertility monitoring in patients with Hodgkin's lymphoma undergoing chemotherapy.
    European Journal of Nuclear Medicine 02/2013; · 4.53 Impact Factor
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    ABSTRACT: OBJECTIVE: In patients undergoing pelvic exenteration for recurrent gynecological malignancies, we assessed the performance of [(18)F]-FDG PET/CT for delineating disease extent; and evaluated the association between quantitative FDG uptake metrics (SUV(max,) total lesion glycolysis [TLG] and metabolic tumor volume [MTV]) and progression-free survival (PFS) and overall survival (OS). METHODS: Retrospective study of patients undergoing pelvic exenteration for gynecologic malignancies between January 2002-November 2011 who had FDG PET/CT within 90days before surgery. Two readers (R1,R2) independently determined the presence of bladder, rectum, vagina, cervix and pelvic side wall invasion and measured SUV(max), TLG and MTV in each patient. Areas under the curve (AUCs), for detecting organ invasion were calculated. Kaplan-Meier graphs were used to determine associations between FDG uptake and PFS/OS. Inter-reader agreement was assessed. RESULTS: 33 patients(mean age 56years,range:28-81) were included; primary sites of disease were the cervix (n=18), uterus (n=8) and vagina/vulva (n=7). AUCs for organ invasion ranged from 0.74-0.96. There was a significant association between FDG uptake metrics incorporating tumor volume (TLG and MTV) and OS (p≤0.001) as well as between MTV and PFS (p=0.001). No significant association was identified between SUV(max) and OS/PFS (p=0.604/0.652). Inter-reader agreement for organ invasion was fair to substantial (k=0.36-0.74) and almost perfect for FDG quantification (ICC=0.97-0.99). CONCLUSION: In patients undergoing pelvic exenteration for recurrent gynecological malignancies, (18)F-FDG PET/CT is useful for preoperative assessment of disease extent. Furthermore, quantitative metrics of FDG uptake incorporating MTV serve as predictive biomarkers of progression-free and overall survival in this population.
    Gynecologic Oncology 01/2013; · 3.69 Impact Factor
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    ABSTRACT: BACKGROUND: The circumferential resection margin (CRM) is highly prognostic for local recurrence in rectal cancer surgery without neoadjuvant treatment. However, its significance in the setting of long-course neoadjuvant chemoradiotherapy (nCRT) is not well defined. METHODS: Review of a single institution's prospectively maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/T4 and/or N1) receiving nCRT, followed after 6 weeks by total mesorectal excision (TME). Kaplan-Meier, Cox regression, and competing risk analysis were performed. RESULTS: The authors noted that 75 % of all patients had stage III disease as determined by endorectal ultrasound (ERUS) and/or magnetic resonance imaging (MRI). With median follow-up of 39 months after resection, local and distant relapse were noted in 12 (2.1 %) and 98 (17.4 %) patients, respectively. On competing risk analysis, the optimal cutoff point of CRM was 1 mm for local recurrence and 2 mm for distant metastasis. Factors independently associated with local recurrence included CRM ≤1 mm, and high-grade tumor (p = 0.012 and 0.007, respectively). CRM ≤2 mm, as well as pathological, nodal, and overall tumor stage are also significant independent risk factors for distant metastasis (p = 0.025, 0.010, and <0.001, respectively). CONCLUSION: In this dataset of locally advanced rectal cancer treated with nCRT followed by TME, CRM ≤1 mm is an independent risk factor for local recurrence and is considered a positive margin. CRM ≤2 mm was associated with distant recurrence, independent of pathological tumor and nodal stage.
    Annals of Surgical Oncology 01/2013; · 3.94 Impact Factor
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    ABSTRACT: BACKGROUND: Neoadjuvant chemoradiation therapy for locally unresectable and borderline resectable pancreatic cancer may allow some patients to a undergo a resection, but whether or not this increases post-operative morbidity remains unclear. METHODS: The post-operative morbidity of 29 patients with initially locally unresectable/borderline pancreatic cancer who underwent a resection were compared with 29 patients with initially resectable tumours matched for age, gender, the presence of comorbidities (yes/no), American Society of Anesthesiology (ASA) score, tumour location (head/body-tail), procedure (pancreaticoduodenectomy/distal pancreatectomy) and vascular resection (yes /no). Wilcoxon's signed ranks test was used for continuous variables and McNemar's chi-square test for categorical variables. RESULTS: Compared with patients with initially resectable tumours, patients who underwent a resection after pre-operative chemoradiation therapy had similar rates of overall post-operative complications (55% versus 41%, P = 0.42), major complications (21% versus 21%, P = 1), pancreatic leaks and fistulae (7% versus 10%, P = 1) and mortality (0% versus 1.7%, P = 1). CONCLUSION: Although some previous studies have suggested differences in post-operative morbidity after chemoradiation, our case-matched analysis did not find statistical differences in surgical morbidity and mortality associated with pre-operative chemoradiation therapy.
    HPB 01/2013; · 2.05 Impact Factor
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    ABSTRACT: OBJECTIVE: This study aimed to use intravoxel incoherent motion (IVIM) imaging for investigating differences between primary head and neck tumors and nodal metastases and to evaluate IVIM efficacy in predicting outcome. METHODS: Sixteen patients with head and neck cancer underwent IVIM diffusion-weighted imaging on a 1.5-T magnetic resonance imaging scanner. The significance of parametric difference between primary tumors and metastatic nodes were tested. Probabilities of progression-free survival and overall survival were estimated using the Kaplan-Meier method. RESULTS: In comparison with metastatic nodes, the primary tumors had significantly higher vascular volume fraction (f) (P < 0.0009) and lower diffusion coefficient (D) (P < 0.0002). Patients with lower SD for D had prolonged progression-free survival and overall survival (P < 0.05). CONCLUSIONS: Pretreatment IVIM measures were feasible in investigating the physiologic differences between the 2 tumor tissues. After appropriate validation, these findings might be useful in optimizing treatment planning and improving patient care.
    Journal of computer assisted tomography 01/2013; 37(3):346-352. · 1.38 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVES: Disease-specific survival (DSS) for GC patients differs in Eastern and Western countries. The aim is to compare outcomes of US and Korean patients following resection of early-stage, node-negative gastric carcinoma (GC). METHODS: All patients (1995-2005) with T1N0 gastric carcinoma, excluding gastroesophageal tumors, were evaluated. DSS was compared by adjusting for prognostic variables from an internationally validated GC nomogram. RESULTS: The cohort included 598 Korean patients and 159 US patients. Age and BMI were significantly higher in US patients. Distal tumor location was more frequent in Korea (60% vs. 52%) and proximal location in the US (19% vs. 5%, P < 0.0001). Five-year DSS did not differ significantly between Korea and the US. After multivariate analysis, DSS of Korean patients persisted, with no significant differences when compared to US patients (HR = 1.2, 95% CI: 0.3-5.2, P = 0.83). CONCLUSIONS: Despite widespread speculations that GC differs in the East and West, when we compare similarly staged, node-negative GC patients, survival did not differ significantly between Korea and the US. This suggests that GC is a heterogeneous disease and when similar subtypes of gastric cancer are compared, these differences disappear. This study suggests more similarities than previously hypothesized between US and Korean GC patients. J. Surg. Oncol © 2012 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 11/2012; 107(6). · 2.84 Impact Factor
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    ABSTRACT: PURPOSE: To determine if the pattern of retained contrast on immediate postprocedure computed tomography (CT) after particle embolization of hepatic tumors predicts modified Response Evaluation Criteria in Solid Tumors (mRECIST) response. MATERIALS AND METHODS: This study was approved by the Institutional Review Board with a waiver of authorization. One hundred four liver tumors were embolized with spherical embolic agents (Embospheres, Bead Block, LC Bead) and polyvinyl alcohol. Noncontrast CT was performed immediately after embolization to assess contrast retention in the targeted tumors, and treatment response was assessed by mRECIST criteria on follow-up CT (average time 9.0 ± 7.7 weeks after embolization). Tumor contrast retention (TCR) was determined based on change in Hounsfield units (HUs) of the index tumors between the preprocedure and immediate postprocedure scans; vascular contrast retention (VCR) was rated; and defects in contrast retention (DCR) were also documented. The morphology of residual enhancing tumor on follow-up CT was described as partial, circumferential, or total. Association between TCR variables and tumor response were assessed using multivariate logistic regression. RESULTS: Of 104 hepatic tumors, 51 (49 %) tumors had complete response (CR) by mRECIST criteria; 23 (22.1 %) had partial response (PR); 21 (20.2 %) had stable disease (SD); and 9 (8.7 %) had progressive disease (PD). By multivariate analysis, TCR, VCR, and tumor size are independent predictors of CR (p = 0.02, 0.05, and 0.005 respectively). In 75 tumors, DCR was found to be an independent predictor of failure to achieve complete response (p < 0.0001) by imaging criteria. CONCLUSION: TCR, VCR, and DCR on immediate posttreatment CT are independent predictors of CR by mRECIST criteria.
    CardioVascular and Interventional Radiology 11/2012; · 2.09 Impact Factor
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    ABSTRACT: BACKGROUND: Survival estimates after curative surgery for gastric cancer are based on AJCC staging, or on more accurate multivariable nomograms. However, the risk of dying of gastric cancer is not constant over time, with most deaths occurring in the first 2 years after resection. Therefore, the prognosis for a patient who survives this critical period improves. This improvement over time is termed conditional probability of survival (CPS). Objectives of this study were to develop a CPS nomogram predicting 5-year disease-specific survival (DSS) from the day of surgery for patients surviving a specified period of time after a curative gastrectomy and to explore whether variables available with follow-up improve the nomogram in the follow-up setting. METHODS: A CPS nomogram was developed from a combined US-Dutch dataset, containing 1,642 patients who underwent an R0 resection with or without chemotherapy/radiotherapy for gastric cancer. Weight loss, performance status, hemoglobin, and albumin 1 year after resection were added to the baseline variables of this nomogram. RESULTS: The CPS nomogram was highly discriminating (concordance index: 0.772). Surviving 1, 2, or 3 years gives a median improvement of 5-year DSS from surgery of 7.2, 19.1, and 31.6 %, compared with the baseline prediction directly after surgery. Introduction of variables available at 1-year follow-up did not improve the nomogram. CONCLUSIONS: A robust gastric cancer nomogram was developed to predict survival for patients alive at time points after surgery. Introduction of additional variables available after 1 year of follow-up did not further improve this nomogram.
    Annals of Surgical Oncology 11/2012; · 3.94 Impact Factor
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    ABSTRACT: BACKGROUND: Considerable debate exists as to appropriate perioperative fluid management. Data from several studies suggest that the amount of fluid administered perioperatively influences surgical outcome. Pancreatic resection is a major procedure in which complications are common. We examined 1,030 sequential patients who had undergone pancreatic resection at Memorial Sloan-Kettering Cancer Center. We documented the prevalence and nature of their complications, and then correlated complications to intraoperative fluid administration. METHODS: We retrospectively examined 1,030 pancreatic resections performed at Memorial Sloan-Kettering Cancer Center between May 2004 and December 2009 from our pancreatic database. Intraoperative administration of colloid and crystalloid was obtained from anesthesia records, and complication data from our institutional database. RESULTS: The overall in-hospital mortality was 1.7%. Operative mortality was due predominantly to intraabdominal infection. Sixty percent of the mortality resulted from intraabdominal complications related to the procedure. We did not demonstrate a clinically significant relationship between intraoperative fluid administration and complications, although minor statistical significance was suggested. CONCLUSIONS: In this retrospective review of intraoperative fluid administration we were not able to demonstrate a clinically significant association between postoperative complications and intraoperative crystalloid and colloid fluid administration. A randomized controlled trial has been initiated to address this question. J. Surg. Oncol © 2012 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 11/2012; · 2.84 Impact Factor
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    ABSTRACT: Flavopiridol, a Cdk inhibitor, potentiates irinotecan-induced apoptosis. In a phase I trial of sequential irinotecan and flavopiridol, 2 patients with advanced hepatocellular carcinoma (HCC) had stable disease (SD) for ≥14 months. We thus studied the sequential combination of irinotecan and flavopiridol in patients with HCC. Patients with advanced HCC naïve to systemic therapy, Child-Pugh ≤B8, and Karnofsky performance score (KPS) ≥70% received 100 mg/m(2) irinotecan followed 7 hours later by flavopiridol 60 mg/m(2) weekly for 4 of 6 weeks. The primary end point was an improvement in progression-free survival at 4 months (PFS-4) from 33% to 54%, using a Simon's two-stage design. Tumors were stained for p53. Only 16 patients in the first stage were enrolled: median age, 64 years; median KPS, 80%; Child-Pugh A, 87.5%; and stage III/IV, 25%/75%. The primary end point was not met; PFS-4 was 20%, leading to early termination of the study. Ten patients were evaluable for response: 1 had SD >1 year and 9 had disease progression. Grade 3 fatigue, dehydration, diarrhea, neutropenia with or without fever, lymphopenia, anemia, hyperbilirubinemia, and transaminitis occurred in ≥10% of the patients. Of the 9 patients who progressed, 5 had mutant p53 and 4 had wild-type p53. The patient with stable disease had wild-type p53. Sequential irinotecan and flavopiridol are ineffective and poorly tolerated in patients with advanced HCC. Despite our limited assessments, it is possible that the presence of wild-type p53 is necessary but not sufficient to predict response in HCC.
    Gastrointestinal cancer research: GCR 11/2012; 5(6):185-9.
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    ABSTRACT: Pathologic grading for prognostic stratification of neuroendocrine tumors (NETs) is critical but presents a challenging interpretive dilemma. Tumor cell proliferative rate is an important factor in the determination of prognosis, and immunohistochemical analysis with Ki67 is becoming more widely used to quantify the proliferative rate. However, Ki67 assessment has limitations due to lack of uniformity and consistency in quantification. These limitations are accentuated in well-differentiated NETs, as differences in the range of 1% to 5% can alter tumor grade, with potential implications for treatment. We therefore performed a concordance study to assess different Ki67 quantification techniques including: (a) digital image analysis (DIA); (b) manual counting (MC) of >2000 cells; and (c) "eyeballed" estimate (EE) of labeling percentage by pathologists (n=18), including individuals experienced in evaluating Ki67 labeling as well as others who had little prior experience assessing Ki67 percentages. Forty-five Ki67 images were selected and analyzed using the 3 methods. On the basis of the recommendations of the World health Organization (WHO) for grading NETs, MC of 2000 cells was used as the "gold standard" reference against which the other techniques were compared. Three images were presented twice, the second being inverted, to assess intraobserver consistency. Statistical analyses were performed to evaluate: (a) the concordance between methods; (b) intraobserver and interobserver consistency; and (c) correlation of NET grades on the basis of Ki67 scores by EE versus the gold standard. Agreement between scores was assessed by intraclass correlation (ICC). DIA and MC were highly concordant (ICC=0.98). The ICC between DIA and the mean EE of all observers was 0.88. However, there was discordance among individual observers on all cases quantified by EE (ICC=0.13). The ICC for intraobserver consistency was 0.39±0.26. With Ki67 in the ranges of <1%, 2% to 3%, and >20%, the mean of Ki67 by EE was, respectively, 93%±2%, 55%±7%, and 55%±15% correct against the gold standard. The κ statistics for EE exhibited low agreement (κ=0.24; 95% confidence interval, 0.23-0.25) for all WHO NET grades. Incorrect assessment by EE resulted in upgrading of all WHO G1 group tumors (n=14); in the WHO G2 group, downgrading of 41% cases occurred (n=11) when Ki67 was <5% (by DIA or MC), and upgrading of 59% cases occurred (n=16) when Ki67 was >5%. We conclude that DIA and MC are the acceptable standards for Ki67 assessment. Given the inherent discordance in determining the grade, the use of an approximate EE of the Ki67-labeling index requires critical reevaluation, especially for NETs with a labeling index straddling the cut-points between grades. Consequently, determination of therapeutic strategies should be guided by an amalgamation of clinicopathologic characteristics, including but not limited to the Ki67 index.
    The American journal of surgical pathology 09/2012; · 4.59 Impact Factor
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    ABSTRACT: BACKGROUND: Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. OBJECTIVE: To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). RESULTS AND LIMITATIONS: PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p=0.01 and p=0.001, respectively). Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p=0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p=0.052) and are associated with worse CSS (p=0.01). Clinical outcome data are limited by the number of events. CONCLUSIONS: Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
    European Urology 09/2012; · 10.48 Impact Factor
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    ABSTRACT: BACKGROUND: Tumor-infiltrating lymphocyte (TIL) counts in colorectal cancer liver metastases (CRCLM) predict survival following resection. While CD4 and CD8 T cells have been correlated with outcome following CRCLM resection, the role of regulatory T cells (Treg) is not well defined. METHODS: TIL in 188 patients who underwent CRCLM resection between 1998 and 2000 were analyzed by immunohistochemistry using tissue microarrays. Correlation between TIL composition and outcome was determined while controlling for established prognostic factors. Total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), and Treg (FoxP3) were analyzed. RESULTS: Median follow-up time was 40 months for all patients and 95 months for survivors. Overall survival (OS) at 5 and 10 years was 40 and 25 %, respectively. The CD4 T cell count correlated with OS (p = .02) and recurrence-free survival (p = .04). A high number of CD8 T cells relative to total T cells (CD8:CD3 ratio) predicted longer OS times (p = .05). Analysis of Treg revealed that high FoxP3:CD4 (p = .03) and FoxP3:CD8 (p = .05) ratios were independent predictors of shorter OS. Patients with a high clinical risk score (CRS) were more likely to have a high number of intratumoral Treg, and patients ≥65 years old had a less robust CRCLM T cell infiltration. CONCLUSIONS: A high number of Treg relative to CD4 or CD8 T cells predicted poor outcome, suggesting an immunosuppressive role for FoxP3 + TIL. The intratumoral immune response was an independent predictor of outcome in patients with colorectal liver metastases.
    Annals of Surgical Oncology 09/2012; · 3.94 Impact Factor
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    ABSTRACT: Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by increased risk of myeloid malignancies. Exome sequencing of three elderly females with clonal hematopoiesis, demonstrated by X-inactivation analysis, identified somatic TET2 mutations. Recurrence testing identified TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematological malignancies and were associated with alterations in DNA methylation.
    Nature Genetics 09/2012; 44(11):1179-1181. · 29.65 Impact Factor

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12k Citations
1,741.90 Total Impact Points

Institutions

  • 2002–2014
    • Memorial Sloan-Kettering Cancer Center
      • • Epidemiology & Biostatistics Group
      • • Department of Radiology
      • • Department of Surgery
      New York City, New York, United States
  • 2013
    • Lenox Hill Hospital
      New York City, New York, United States
  • 2011–2012
    • Dana-Farber Cancer Institute
      • Department of Biostatistics and Computational Biology
      Boston, MA, United States
    • University of Illinois at Chicago
      • Department of Surgery (Chicago)
      Chicago, IL, United States
  • 2010–2012
    • Weill Cornell Medical College
      • • Department of Urology
      • • Department of Radiology
      New York City, New York, United States
  • 2008
    • Columbia University
      • Herbert Irving Comprehensive Cancer Center
      New York City, NY, United States
    • David Grant USAF Medical Center
      Sacramento, California, United States
  • 2007
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2005
    • State University of New York Downstate Medical Center
      • Department of Urology
      Brooklyn, NY, United States
  • 2004
    • Cornell University
      Ithaca, New York, United States