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author:("Gonen, mithal")
1.  Pancreatic Cyst Fluid and Serum Mucin Levels Predict Dysplasia in Intraductal Papillary Mucinous Neoplasms of the Pancreas 
Annals of surgical oncology  2010;18(1):199-206.
There are no reliable markers of dysplasia in patients with incidentally discovered intraductal papillary mucinous neoplasms of the pancreas (IPMN). IPMN dysplasia may be associated with mucin protein (MUC) expression and histopathologic subtype. We hypothesize that MUC expression in cyst fluid and serum can identify lesions with high risk of malignancy.
Cyst fluid and serum were collected from 40 patients during pancreatectomy for IPMN between 2005 and 2009. Samples were grouped into low-risk (low-grade or moderate dysplasia, n = 21) and high-risk groups (high-grade dysplasia or carcinoma, n = 19). Mucin expression (MUC1, MUC2, MUC4, and MUC5AC) was assessed utilizing enzyme-linked immunosorbent assays.
MUC2 and MUC4 cyst fluid concentrations were elevated in high-risk versus low-risk groups (10 ± 3.0 ng/ml vs. 4.4 ± 1.2 ng/ml, p = 0.03; 20.6 ± 10.6 ng/ml vs. 4.5 ± 1.4 ng/ml, p = 0.03, respectively). Corresponding serum samples revealed higher levels of MUC5AC in high-risk compared with low-risk patients (19.9 ± 9.3 ng/ml vs. 2.2 ± 1.1 ng/ml, p = 0.04). Histopathologic subtype was significantly associated with grade of dysplasia, and the intestinal subtype displayed increased MUC2 cyst fluid concentrations (13.8 ± 6.5 ng/ml vs. 4.1 ± 0.9 ng/ml, p = 0.02).
In this study, high-risk IPMN showed elevated cyst fluid concentrations of MUC2 and MUC4, and increased serum levels of MUC5AC. High-risk IPMN also displayed a distinct mucin expression profile in specific histologic subtypes. These data, if validated, may allow surgeons to more appropriately select patients for operative resection.
PMCID: PMC4241376  PMID: 20717734
2.  Comparison of Disease-Specific Survival in the United States and Korea After Resection for Early-Stage Node-Negative Gastric Carcinoma 
Journal of surgical oncology  2012;107(6):634-640.
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).
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.
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).
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.
PMCID: PMC4180518  PMID: 23192297
gastric carcinoma; early gastric cancer; Eastern and Western
3.  Image guided thermal ablation of tumors increases the plasma level of IL-6 and IL-10 
To identify changes in plasma cytokine levels following image-guided thermal ablation of human tumors and to identify the factors that independently predict changes in plasma cytokine levels.
Whole blood samples were collected from 36 patients at 3 time points: pre-ablation, post-ablation (within 48 hours), and in follow-up (1–5 weeks after ablation). Plasma levels of IL-1a, IL-2, IL-6, IL-10 and TNFa 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.
There was a significant increase in the plasma level of IL-6 post-ablation when compared to pre-ablation (9.6+/−31 fold, p<0.002). IL-10 also showed a significant increase postablation (1.9 +/−2.8 fold, p<0.02). Plasma levels of IL-1a, IL-2, and TNFa were not significantly changed after ablation. Cryoablation resulted in the largest change in IL-6 level (>54 fold), while radiofrequency and microwave ablation showed 3.6 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<0.0003), and primary diagnosis (p<0.03) were independent predictors of changes to IL-6 following ablation. Age was the only independent predictor of IL-10 levels following ablation (p<0.019).
Image guided thermal ablation of tumors increases the plasma level of IL-6 and IL-10, without increasing the plasma level of IL-1a, IL-2, or TNFa.
PMCID: PMC4167629  PMID: 23582441
thermal ablation; radiofrequency; microwave; cryoablation; cytokine; inflammation; growth factor
4.  Biliary self-expandable metal stents do not adversely affect pancreaticoduodenectomy 
Controversy exists regarding whether to place a plastic or metal endobiliary stent in patients with resectable pancreatic cancer who require biliary drainage. Although self-expandable metal stents (SEMS) provide better drainage compared to 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 versus plastic endoscopic stents (PES) and no stents (NS).
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 regards to perioperative complications, margin status, and the rate of intraoperative determination of unresectability.
593 patients underwent attempted PD. 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 to other groups, with 16 (19.3%) in SEMS, compared to 29 (17.7%) in PES (p = 0.862), and 31 (17.5%) in NS (p = 0.732).
Placement of SEMS is not contraindicated in patients with resectable pancreatic cancer who require preoperative biliary drainage.
PMCID: PMC4159071  PMID: 23545711
5.  18F-FDG PET of Locally Invasive Breast Cancer and Association of Estrogen Receptor Status with Standardized Uptake Value: Microarray and Immunohistochemical Analysis 
PET imaging is useful for evaluating locally advanced primary breast cancer. Expression of specific molecular markers in these cancers, such as estrogen receptor (ER), progesterone receptor (PR), and HER2 status, has direct prognostic and therapeutic implications in patient management. This study aimed to determine whether a relationship exists between tumor glucose use and important molecular markers in invasive breast cancer. For our purposes, tumor glucose use is quantified by the PET-derived parameter maximum standardized uptake value (SUV).
Breast tumors from 36 patients were excised and examined histologically after PET. ER, PR, and HER2 status were determined for all lesions histopathologically. In addition, genomewide expression for a subset of 20 tumors was analyzed using the human genome U133A oligonucleotide microarray.
A significant association was found between estrogen ER status and lesion SUV. ER-negative tumors (n = 17; median SUV, 8.5) demonstrated a significantly higher maximum SUV than did ER-positive tumors (n = 19; median SUV, 4.0) (P < 0.001). No significant association existed between SUV and PR status, HER2/neu status, lymph node involvement, or tumor size. Unsupervised hierarchic clustering of the 20 genetically profiled cancers segregated tumor samples into 2 primary groups of 10 patients each, largely corresponding to ER status.
In locally invasive primary breast cancer, ER-negative tumors display higher 18F-FDG uptake than ER-positive tumors. Microarray analysis confirms these data and identifies genes associated with increased glucose use as measured by PET. These genes significantly overlap those of a previously validated ER-status molecular phenotype. These preliminary data support a growing body of evidence that ER-positive and ER-negative breast cancers have distinct disease-specific patterns. Further validation prospectively and with larger numbers will be required to establish a robust molecular signature for metabolic uptake and patterns of aggressive behavior in advanced breast cancer.
PMCID: PMC4141648  PMID: 20237034
18F-FDG PET; breast cancer, microarray; estrogen; SUV; gene expression
6.  Ki-67 is a Prognostic Biomarker of Survival after Radiofrequency Ablation of Liver Malignancies 
Annals of surgical oncology  2012;19(13):4262-4269.
To assess the predictive value of examinations of tissue adherent to multitined electrodes on local tumor progression-free survival (LPFS) and overall survival (OS) after liver tumor radiofrequency ablation (RFA).
An institutional review board–approved, Health Insurance Portability and Accountability Act–compliant review identified 68 liver tumors treated with RFA in 63 patients with at least 3 years’ follow-up. Tissue adherent to the electrode after liver tumor RFA was evaluated with proliferation (Ki-67) and apoptotic (caspase-3) markers. LPFS and OS were evaluated by Kaplan–Meier methodology and the log-rank test. Multivariate analysis assessed the effect of tumor size, pathology, and post-RFA tissue characteristics on LPFS and OS.
Post-RFA tissue examination classified 55 of the 68 tumors as completely ablated with coagulation necrosis, with cells positive for caspase-3 and negative for Ki-67 (CN). Thirteen had viable Ki-67-positive tumor cells. Mean liver tumor size was larger in the viable (V) group versus the CN group (3.4 vs. 2.5 cm, respectively; P = .017). For the V and CN groups, respectively, local tumor progression occurred in 12 (92 %) of 13 and 23 (42 %) of 55 specimens. One, 3-, and 5-year LPFS was 8 %, 8 %, and 8 %, and 79 %, 47 %, and 47 % (P <.001) for the V and CN groups, respectively. During a 63-month median follow-up, 92 % of patients in the V group and 58 % in the CN group died, resulting in 1-, 3-, and 5-year OS of 92 %, 25 %, and 8 % vs. 92 %, 59 %, and 33 % (P = .032), respectively.
Ki-67-positive tumor cells on the electrode after liver tumor RFA is an independent predictor of LPFS and OS. Size, initially thought to be an independent risk factor for local tumor progression in tumors 3–5 cm, does not hold its significance at long follow-up.
PMCID: PMC4122119  PMID: 22752375
7.  Margin Size is an Independent Predictor of Local Tumor Progression After Ablation of Colon Cancer Liver Metastases 
This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM).
An institutional review board-approved, HIP-PA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4–8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1–5, 6–10, and 11–15 mm. Follow-up included CT every 2–4 months. Kaplan–Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP.
Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1–5 mm, 6–10 mm, 11–15 mm were 26, 46, 74, and 80 % (p < 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5-mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %.
An ablation zone with a minimal margin uniformly larger than 5 mm 4–8 weeks postablation CT is associated with the best local tumor control.
PMCID: PMC4122121  PMID: 22535243
Ablation; Radiofrequency ablation; Minimal margin; Local tumor progression; Colon cancer liver metastasis; Image guided; CT guided; Ablation margin evaluation method
8.  Intraoperative Fluid Management and Complications Following Pancreatectomy 
Journal of surgical oncology  2012;107(5):529-535.
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.
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.
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.
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.
PMCID: PMC4105692  PMID: 23136127
pancreatic resection; intraoperative fluid; complications
9.  The value of 18F-FDG PET/CT in recurrent gynecologic malignancies prior to pelvic exenteration 
Gynecologic oncology  2013;129(3):586-592.
In patients undergoing pelvic exenteration for recurrent gynecological malignancies, we assessed the performance of [18F]-FDG PET/CT for delineating disease extent and evaluated the association between quantitative FDG uptake metrics (SUVmax, total lesion glycolysis [TLG] and metabolic tumor volume [MTV]) and progression-free survival (PFS) and overall survival (OS).
Retrospective study of patients undergoing pelvic exenteration for gynecologic malignancies between January 2002 and November 2011 who had FDG PET/CT within 90 days before surgery. Two readers (R1, R2) independently determined the presence of bladder, rectum, vagina, cervix and pelvic side wall invasion and measured SUVmax, 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.
33 patients (mean age 56 years, 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 to 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 SUVmax 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).
In patients undergoing pelvic exenteration for recurrent gynecological malignancies, 18F-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.
PMCID: PMC4104687  PMID: 23369941
Cervical cancer; Endometrial cancer; PET; Pelvic exenteration; Cancer recurrence; Total lesion glycolysis
10.  A prognostic nomogram for prediction of recurrence in desmoid fibromatosis 
Annals of surgery  2013;258(2):347-353.
To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors.
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.
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 dataset.
Desmoids were treated surgically in 495 patients (median follow-up 60 months). Of 439 patients undergoing complete gross resection, 100 (23%) had recurrence. Five-year local recurrence–free survival (LRFS) was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved LRFS. 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 LRFS 91%). Age, site, and size were used to construct a nomogram with concordance index 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, gender, depth, and primary vs. recurrent presentation) did not importantly improve concordance (internal concordance index 0.707).
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.
PMCID: PMC4096320  PMID: 23532110
11.  Conditional Probability of Survival Nomogram for 1-, 2-, and 3-Year Survivors After an R0 Resection for Gastric Cancer 
Annals of surgical oncology  2012;20(5):1623-1630.
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.
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.
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.
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.
PMCID: PMC4091759  PMID: 23143591
12.  Clinical and Pathologic Factors That Predict Lymph Node Yield From Surgical Specimens in Colorectal Cancer 
Cancer  2010;116(11):2560-2570.
The National Quality Forum endorses the recommendation of examining at least 12 lymph nodes (LNs) from colorectal cancer (CRC) specimens. However, heterogeneity in LN harvest exists. The objective of this study was to investigate the clinicopathologic factors that influence LN yield.
The authors used the Surveillance, Epidemiology, and End Results database to identify patients who were diagnosed with stage I, II, and III CRC between 1994 and 2005. Poisson regression was used to model the number of LNs examined as a function of individual clinicopathologic factors, including age, sex, race, year of diagnosis, geographic region, anatomic site, pre-operative radiation, tumor size, tumor classification, tumor differentiation, and LN positivity.
In total, 153,483 patients with CRC were identified. The mean number of LNs examined (±standard deviation) was 12 (±9.3). Separate multivariate analyses revealed that age, year of diagnosis, tumor size, and tumor classification were significant predictors of LN yield for colon and extraperitoneal rectal cancers (P < .01 for all covariates). Tumor location and radiotherapy were significant predictors of LN yield in patients with colon cancer and rectal cancer, respectively. Overall LN yields increased between 2% and 3% annually.
Despite the increasing yields observed over time, patients with rectal cancer and older patients who had distally located, early colon cancer were less likely to meet the benchmark yield of 12 LNs. Further investigation into how LN yield is influenced by alterable factors, such as the extent of mesenteric resection and the pathologic technique, as well as nonalterable factors, such as patient age and tumor location, may reveal innovative ways to improve current staging methods.
PMCID: PMC4067456  PMID: 20499400
colorectal cancer; lymph node yield; staging; Surveillance; Epidemiology, and End Results; clinicopathologic factors
13.  What is the Significance of the Circumferential Margin in Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy? 
Annals of surgical oncology  2013;20(4):1179-1184.
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.
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.
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).
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.
PMCID: PMC4067458  PMID: 23328971
14.  Adverse Outcomes in Clear Cell Renal Cell Carcinoma with Mutations of 3p21 Epigenetic Regulators BAP1 and SETD2: a Report by MSKCC and the KIRC TCGA Research Network 
To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer specific survival (CSS) of 609 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts.
Patients and Methods
Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was performed to interrogate the genotype-phenotype associations. These findings were compared to analyses of the genomic and clinical dataset from our non-overlapping The Cancer Genome Atlas (TCGA) cohort of 421 primary ccRCC patients.
3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts (MSKCC, p=0.002, HR 7.71 (2.08–28.6); TCGA, p=0.002, HR 2.21 (1.35–3.63)). SETD2 are associated with worse CSS in the TCGA cohort (p=0.036, HR 1.68 (1.04–2.73)). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS.
The chromosome 3p21 locus harbors three frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6–12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30–34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.
PMCID: PMC3708609  PMID: 23620406
15.  A Phase 2 Study of Flavopiridol (Alvocidib) in Combination with Docetaxel in Refractory, Metastatic Pancreatic Cancer (NCI#6366) 
Pancreatic adenocarcinoma (PC) harbors frequent alterations of p16, resulting in cell cycle dysregulation. A phase I study of docetaxel and flavopiridol, a pan-cyclin dependent kinase inhibitor, demonstrated encouraging clinical activity in PC. This phase II study was designed to further define the efficacy and toxicity of this regimen in patients with previously treated PC.
Patients with gemcitabine-refractory, metastatic PC were treated with docetaxel 35 mg/m2 followed by flavopiridol 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Tumor measurements were performed every two cycles. A Simon two-stage design was used to evaluate the primary endpoint of response.
Ten patients were enrolled; nine were evaluable for response. No objective responses were observed; however, three patients (33%) achieved transient stable disease, with one of these patients achieving a 20% reduction in tumor size. Median survival was 4.2 months, with no patients alive at the time of analysis. Adverse events were significant, with seven patients (78%) requiring ≥1 dose reduction for transaminitis (11%), grade 4 neutropenia (33%), grade 3 fatigue (44%), and grade 3 diarrhea (22%)
The combination of flavopiridol and docetaxel has minimal activity and significant toxicity in this patient population. These results reflect the challenges of treating patients with PC in a second-line setting where the risk/benefit equation is tightly balanced.
PMCID: PMC4053191  PMID: 19451750
Docetaxel; Flavopiridol; Pancreatic adenocarcinoma
16.  Histone Modifications Are Associated with Transcript Isoform Diversity in Normal and Cancer Cells 
PLoS Computational Biology  2014;10(6):e1003611.
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.
Author Summary
Traditionally, the regulation of gene expression was thought to be largely based on DNA and RNA sequence motifs. However, this dogma has recently been challenged as other factors, such as epigenetic patterning of the genome, have become better understood. Sparse but convincing experimental evidence suggests that the epigenetic background, in the form of histone modifications, acts as an additional layer of regulation determining how transcripts are processed. Here we developed a computational approach to investigate the genome-wide prevalence and the level of association between the enrichment of epigenetic marks and transcript diversity generated via alternative transcription start sites and splicing. We found that the role of epigenetic patterning in alternative transcription start-site switching is likely to be the same for all genes whereas the role of epigenetic patterns in splicing is likely gene-specific. Furthermore, we show that epigenetic data alone can be used to predict the inclusion pattern of an exon. These findings have significant implications for a better understanding of the regulation of transcript diversity in humans as well as the modifications arising during tumor development.
PMCID: PMC4046914  PMID: 24901363
17.  Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel 
Cancer research  2008;68(2):589-596.
Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients. We find that the EGFR mutations found most commonly in patients with lung adenocarcinoma who respond to EGFR TKIs are potently degraded by 17-AAG. Although the expression of wild-type EGFR was also down-regulated by 17-AAG, its degradation required higher concentrations of drug and a longer duration of drug exposure. In animal models, a single dose of 17-AAG was sufficient to induce degradation of mutant EGFR and inhibit downstream signaling. 17-AAG treatment, at its maximal tolerated dose, caused a significant delay in H3255 (L858R EGFR) xenograft growth but was less effective than the EGFR TKI gefitinib. 17-AAG alone delayed, but did not completely inhibit, the growth of H1650 and H1975 xenografts, two EGFR mutant models which show intermediate and high levels of gefitinib resistance. 17-AAG could be safely coadministered with paclitaxel, and the combination was significantly more effective than either drug alone. These data suggest that Hsp90 inhibition in combination with chemotherapy may represent an effective treatment strategy for patients whose tumors express EGFR kinase domain mutations, including those with de novo and acquired resistance to EGFR TKIs.
PMCID: PMC4011195  PMID: 18199556
18.  Comparing primary tumors and metastatic nodes in head and neck cancer using intravoxel incoherent motion imaging: a preliminary experience 
Journal of computer assisted tomography  2013;37(3):10.1097/RCT.0b013e318282d935.
To use intravoxel incoherent motion (IVIM) imaging for investigating differences between primary head and neck tumors and nodal metastases and evaluating IVIM efficacy in predicting outcome.
Sixteen patients with HN cancer underwent IVIM DWI on a 1.5T MRI scanner. The significance of parametric difference between primary tumors and metastatic nodes were tested. Probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
In comparison to 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 standard deviation for D had prolonged PFS and OS (p<0.05).
Pretreatment IVIM measures were feasible in investigating the physiological differences between the two tumor tissues. After appropriate validation, these findings might be useful in optimizing treatment planning and improving patient care.
PMCID: PMC3655331  PMID: 23674004
Intravoxel incoherent motion imaging (IVIM); head and neck (HN) cancer; primary tumor; metastatic neck node
19.  The impact of systemic chemotherapy on testicular FDG activity in young men with Hodgkin’s lymphoma 
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.
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 (SUVmax), SUVmean, functional volume (FV) and total testicular glycolysis (TTG), and blood pool activity determined (SUVmean).
Testicular FDG uptake (SUVmax) 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 SUVmax, SUVmean, 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.
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.
PMCID: PMC4004336  PMID: 23389428
Fertility; Chemotherapy; Lymphoma; BEACOPP; ABVD; FDG; PET/CT
20.  A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-allylamino-17-demethoxygeldanamycin (17AAG) in Patients with Solid Tumors 
Both Hsp90 and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors.
Experimental Design
During the dose-escalation phase, patients received intravenous irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.
Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity (DLT) at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by coadministration of irinotecan, and vice versa. There was no partial response although tumor shrinkage was observed in 6 patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P=0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2/M cell cycle checkpoint, and cell death could be demonstrated in tumor biopsy samples obtained at the MTD.
The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m2 17AAG.
PMCID: PMC3996559  PMID: 18927314
21.  Testing the Incremental Predictive Accuracy of New Markers 
Clinical trials (London, England)  2013;10(5):10.1177/1740774513496490.
It has become commonplace to use receiver operating curve (ROC) methodology to evaluate the incremental predictive accuracy of new markers in the presence of existing predictors. However, concerns have been raised about the validity of this practice. We have evaluated this issue in detail.
Simulations have been used that show clearly that use of risk predictors from nested models as data in subsequent tests comparing areas under the ROC curves of the models leads to grossly invalid inferences. Careful examination of the issue reveals two major problems: (1) the data elements are strongly correlated from case to case; and (2) the model that includes the additional marker has a tendency to interpret predictive contributions as positive information regardless of whether observed effect of the marker is negative or positive. Both of these phenomena lead to profound bias in the test.
We recommend strongly against the use of ROC methods derived from risk predictors from nested regression models to test the incremental information of a new marker.
PMCID: PMC3800241  PMID: 23881367
22.  Regulatory T Cell Infiltration Predicts Outcome Following Resection of Colorectal Cancer Liver Metastases 
Annals of surgical oncology  2012;20(3):946-955.
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.
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.
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 recurrencefree 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.
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.
PMCID: PMC3740360  PMID: 23010736
23.  Serial measurement of hepatic lipids during chemotherapy in colorectal cancer patients: A 1H magnetic resonance spectroscopy study 
NMR in biomedicine  2012;26(2):204-212.
Background and Rationale
Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial 1H magnetic resonance spectroscopy (MRS) measurements of hepatic lipids in patients over the time course of a 24-week chemotherapy regimen to determine whether 1H MRS can be used to monitor the progression of chemotherapy-induced steatosis.
Experimental Procedures
Thirty-four patients with stage III or IV colorectal cancer receiving FOLFOX (n = 21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. 1H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A 1H 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 (HTGC). The methodology was histologically validated in 18 patients and reproducibility was assessed in 16 normal volunteers.
Twenty-seven patients completed baseline, 6-week and 24-week 1H-MRS exams 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 non-steatotic liver. Patients whose six-week hepatic lipid levels had increased significantly compared to baseline had a high probability of lipid elevation relative to baseline at the completion of treatment as well.
Serial 1H-MRS is effective for monitoring HTGC changes during chemotherapy and detecting chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks.
PMCID: PMC3519948  PMID: 22961714
fat; liver; FOLFOX; steatosis; imaging
24.  Cystic Lesions of the Pancreas: Changes in the Presentation and Management of 1,424 Patients at a Single Institution over a 15-year Time Period 
Journal of the American College of Surgeons  2011;212(4):10.1016/j.jamcollsurg.2011.01.016.
Cystic lesions of the pancreas are increasingly identified, and a selective approach to resection is now recommended. The aim of this study was to assess the change in presentation and management of pancreatic cystic lesions evaluated at a single institution over a 15 year time period.
Study design
A prospectively maintained registry of patients evaluated between 1995 and 2010 for the ICD-9 diagnosis of pancreatic cyst was reviewed. The 539 patients managed from 1995 to 2005 were compared with the 885 patients managed from 2005 to 2010.
1424 patients were evaluated, including 1141 with follow-up > 6 months. Initial management (within 6 months of first assessment), was operative in 422 patients (37%), and non-operative in 719 patients (63%). Operative mortality in patients initially submitted to resection was 0.7% (n=3). Median radiographic follow-up in patients initially managed non-operatively was 28 months (range: 6–175). Patients followed radiographically were more likely to have cysts that were asymptomatic (72% vs 49%, p<0.001), smaller (1.5 cm vs 3cm, p <0.001), without solid component (94% vs. 68%, p<0.001), and without main pancreatic duct dilation (88% vs 61%, p<0.001). Changes prompting subsequent operative treatment occurred in 47 patients (6.5%), with adenocarcinoma identified in 8 (17%) and pancreatic endocrine neoplasm in 4 (8.5%). Thus of the 719 patients initially managed non-operatively, invasive malignancy was identified in 12 (1.7%), with adenocarcinoma seen in 1.1 %.
Cystic lesions of the pancreas are being increasingly identified, yet are less likely to present with concerning features of malignancy. Carefully selected patients managed non-operatively had a risk of malignancy that was equivalent to the risk of operative mortality in those patients who initially underwent resection.
PMCID: PMC3817568  PMID: 21463795
pancreatic cyst lesion; follow-up; resection; selective approach; management
25.  Image-Guided PO2 Probe Measurements Correlated with Parametric Images Derived from 18F-Fluoromisonidazole Small-Animal PET Data in Rats 
18F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic 18F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio.
Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with 18F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (PO2). The dynamic 18F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K1 equal to k2 and the other unconstrained. Parametric images of the rate constants were generated. The PO2 measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios.
The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k3, of the constrained model provided a better discrimination of low PO2 than the tissue-to-plasma ratio or the k3 of the unconstrained model.
The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k3, without introducing significant bias, is to constrain K1 equal to k2 during the fitting process.
PMCID: PMC3784982  PMID: 22933821
hypoxia; [18F]-FMISO; [18F]-fluoromisonidazole; kinetic modeling; parametric images; OxyLite probe

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