[Show abstract][Hide abstract] ABSTRACT: Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels, or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation) and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery dataset and replicated in two validation datasets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single SNP explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), while a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.Journal of Investigative Dermatology accepted article preview online, 07 April 2015. doi:10.1038/jid.2015.138.
[Show abstract][Hide abstract] ABSTRACT: Background
The insulin-like growth factor (IGF) pathway is implicated in the pathogenesis of hepatocellular carcinoma (HCC) and may be important in nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine expression levels of IGFs and receptors in NAFLD-associated HCC.
Tissue microarrays were constructed from patients who underwent hepatectomy for HCC. Immunohistochemistry was performed using antibodies for IGF ligands and receptors. Immunostain results were scored by a pathologist blinded to clinical data.
Among 27 patients with HCC, the most common underlying liver diseases included NAFLD, hepatitis C, and alcoholic hepatitis. Expression levels of IGFs and receptors were not associated with patients’ underlying liver disease. In all patients, IGF-2 expression was upregulated in tumor and adjacent non-neoplastic liver. Expression of IGF-1 was low in adjacent liver in 6 of 10 patients with cirrhosis, compared with 2 of 17 patients without cirrhosis (P = 0.025). Higher IGF-1 expression in liver adjacent to tumor was associated with poorer median survival of 22 months, compared with 72 months with equal or lower IGF-1 expression in adjacent liver relative to tumor (P = 0.006).
Our preliminary results demonstrate significant associations between IGF-1 expression and liver cirrhosis and survival after resection in patients with HCC, independent of their underlying liver disease.
World Journal of Surgical Oncology 07/2014; 12(1):231. DOI:10.1186/1477-7819-12-231 · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In colorectal cancer, the involvement of regional lymph nodes with metastasis is an established prognostic factor. The impact of the number of positive nodes on patient outcome with stage IV disease is not well defined.
A retrospective review was performed of 1,421 patients at two tertiary referral centers with stage IV colorectal cancer who underwent primary tumor resection. Associations between regional nodes, lymph node ratio (LNR), and overall survival (OS) from date of diagnosis were analyzed.
The number of positive regional nodes and LNR correlated with multiple sites of metastases (p < 0.001). Survival was significantly associated with the number of positive nodes and LNR, with a median OS of 43 months with negative nodes, compared to 20 months with ≥7 positive nodes (p < 0.001). The number of regional nodal metastases correlated with OS among 400 patients undergoing resection of liver metastases (p = 0.005) but lost prognostic significance in the subset of 223 patients who underwent hepatectomy with perioperative oxaliplatin- or irinotecan-based chemotherapy (p = 0.48).
In stage IV colorectal cancer, an increasing number of positive regional nodes and LNR correlate with multiple sites of metastases and poorer survival. The number of metastatic regional lymph nodes loses prognostic significance with modern chemotherapy in patients undergoing resection of liver metastases.
Journal of Gastrointestinal Surgery 09/2013; 18(1). DOI:10.1007/s11605-013-2329-8 · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Historically, borderline resectable (BLR) pancreatic cancer has had many definitions, which has made interpretation of treatment data and outcomes difficult. Advances in imaging, surgical technique, and the potential benefit of neoadjuvant therapy have emphasized the need for uniform classification. Despite recent efforts to provide a clearer definition, prospective randomized trials are lacking in the literature. This article reviews current definitions, treatment sequences, outcomes, and prognostic factors associated with BLR pancreatic cancer. Further clarification and consensus on the definition of BLR pancreatic cancer will allow for further data collection and cooperation in future efforts to make progress and standardize treatment.
Surgical Clinics of North America 06/2013; 93(3):663-74. DOI:10.1016/j.suc.2013.02.005 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since the introduction of biologic agents, increasing data have suggested that conventional size-based RECIST criteria are not accurate in the assessment of response to therapy and non-size-based changes in tumor morphology can be a surrogate marker for assessment of chemotherapeutic effect. The morphologic response criteria are recently introduced, non-size-based criteria for patients undergoing chemotherapy for colorectal liver metastases (CLM). These novel criteria predict pathologic response and long-term survival of patients treated with preoperative chemotherapy, with or without bevacizumab, independent of their RECIST response. They have been validated in patients with resectable and unresectable CLM. These criteria are difficult to apply in small metastases and can be used as an adjunct to RECIST in the assessment of response to preoperative chemotherapy.
Current Colorectal Cancer Reports 06/2013; 9(2):198-202. DOI:10.1007/s11888-013-0164-7
[Show abstract][Hide abstract] ABSTRACT: Background:
A theoretical advantage of preoperative therapy in pancreatic adenocarcinoma is that it facilitates the early treatment of micrometastases and reduces postoperative systemic recurrence.
Medical records of 309 consecutive patients undergoing resection of adenocarcinoma in the head of the pancreas were reviewed. Survival was calculated using the Kaplan-Meier method. Associations between preoperative therapy and patterns of recurrence were determined using chi-squared analysis.
Preoperative therapy was administered to 108 patients and upfront surgery was performed in 201 patients. Preoperative therapy was associated with a significantly longer median disease-free survival of 14 months compared with 12 months in patients submitted to upfront surgery (P = 0.035). The rate of local disease as a component of first site of recurrence was significantly lower with preoperative therapy (11.3%) than with upfront surgery (22.9%) (P = 0.016). Preoperative therapy was associated with a lower rate of hepatic metastasis (21.7%) than upfront surgery (34.3%) (P = 0.026). Preoperative therapy did not affect rates of peritoneal or pulmonary metastasis.
Preoperative therapy for pancreatic cancer was associated with longer disease-free survival and lower rates of local and hepatic recurrences. These data support the use of preoperative therapy to reduce systemic and local failures after resection.
[Show abstract][Hide abstract] ABSTRACT: Selection of the optimal surgical and interventional therapies for advanced colorectal cancer liver metastases (CRLM) requires multidisciplinary discussion of treatment strategies early in the trajectory of the individual patient's care. This paper reports on expert consensus on locoregional and interventional therapies for the treatment of advanced CRLM. Resection remains the reference treatment for patients with bilateral CRLM and synchronous presentation of primary and metastatic cancer. Patients with oligonodular bilateral CRLM may be candidates for one-stage multiple segmentectomies; two-stage resection with or without portal vein embolization may allow complete resection in patients with more advanced disease. After downsizing with preoperative systemic and/or regional therapy, curative-intent hepatectomy requires resection of all initial and currently known sites of disease; debulking procedures are not recommended. Many patients with synchronous primary disease and CRLM can safely undergo simultaneous resection of all disease. Staged resections should be considered for patients in whom the volume of the future liver remnant is anticipated to be marginal or inadequate, who have significant medical comorbid condition(s), or in whom extensive resections are required for the primary cancer and/or CRLM. Priority for liver-first or primary-first resection should depend on primary tumour-related symptoms or concern for the progression of marginally resectable CRLM during treatment of the primary disease. Chemotherapy delivered by hepatic arterial infusion represents a valid option in patients with liver-only disease, although it is best delivered in experienced centres. Ablation strategies are not recommended as first-line treatments for resectable CRLM alone or in combination with resection because of high local failure rates and limitations related to tumour size, multiplicity and intrahepatic location.
[Show abstract][Hide abstract] ABSTRACT: The fibrolamellar variant of hepatocellular carcinoma is a rare primary liver cancer occurring in adolescents and young adults without chronic liver disease or known risk factors. Histologically, it is defined by lamellar bands of fibrosis surrounding well-differentiated tumor cells. Radiologic imaging typically demonstrates a large, solitary mass with calcifications and a central scar. Lymph node metastases in the porta hepatis are frequently diagnosed upon presentation. More patients with fibrolamellar carcinoma are candidates for surgical resection than those with conventional hepatocellular carcinoma, owing to their young age and absence of cirrhosis. The most important prognostic factor is surgical resection, which results in 5-year overall survival rates ranging between 50 and 76 %. Despite complete surgical resection, relapse rates are high, and novel therapies are needed to prevent and treat recurrent disease.
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2013; 190:101-10. DOI:10.1007/978-3-642-16037-0_7
[Show abstract][Hide abstract] ABSTRACT: PURPOSEThe purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response. PATIENTS AND METHODS
The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis.ResultsAn optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P < .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P < .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P < .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response. CONCLUSION
Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM.
[Show abstract][Hide abstract] ABSTRACT: Introduction. The purpose of this study is to determine the anatomic course of the first jejunal branch of the superior mesenteric vein (SMV) in relation to the superior mesenteric artery (SMA). Methods. Three hundred consecutive contrast-enhanced computed tomography (CT) scans were reviewed by a surgical oncologist with confirmation of findings by a radiologist. Results. The overall incidence of a first jejunal branch coursing anterior to the SMA was 41%. There was no correlation between patient gender and position of the jejunal branch. In addition, there was no correlation between size of the first jejunal branch and its location in relation to the SMA. The IMV drained into the SMV in 27% of the patients. The IMV drained into the SMV-portal vein confluence in 17% of patients and inserted into the splenic vein in 54%. An anterior coursing first jejunal branch statistically correlated with an IMV that drained into the SMV-portal vein confluence (P = 0.009). Conclusion. The first jejunal branch of the SMV has a highly variable course in relation to the SMA and has a higher incidence of an anterior location in this population than previously reported.
International Journal of Surgical Oncology 02/2012; 2012:538769. DOI:10.1155/2012/538769
[Show abstract][Hide abstract] ABSTRACT: Pathologic response to preoperative therapy is increasingly recognized as an important prognostic factor in solid tumors. The impact of pathologic response on survival in pancreatic adenocarcinoma is not well established.
Data on 135 consecutive patients treated with chemoradiation followed by pancreatectomy for adenocarcinoma of the pancreatic head and/or body between July 1987 and May 2009 were reviewed. Histopathologic examination was performed in 107 patients to determine pathologic response, defined as minor (<50% fibrosis relative to residual neoplastic cells), partial (50-94% fibrosis), or major (95-100% fibrosis).
Minor, partial, and major pathologic response rates were 17% (n = 18), 64% (n = 68), and 19% (n = 21), including a 7% (n = 8) complete pathologic response rate. Pathologic response correlated with R0 resection (P = 0.019), negative lymph nodes (P = 0.006), and smaller tumor size (P = 0.001). Median survival rates by pathologic response were as follows: 17 months [95% confidence interval (CI), 0-36 months] for minor response, 20 months (95% CI, 17-23 months) for partial response, and 66 months (95% CI, 8-124 months) for major response (minor versus partial response, P = not significant; partial versus major response, P < 0.001). On multivariate analysis, major pathologic response was the only factor significantly associated with improved survival (P = 0.025; hazard ratio, 2.26).
Major pathologic response to preoperative therapy occurs in a minority of patients with pancreatic adenocarcinoma and is independently associated with prolonged survival.
[Show abstract][Hide abstract] ABSTRACT: Cytological analysis of body fluids is currently used for detecting cancer. The objective of this study was to determine if the herpes virus carrying an enhanced green fluorescent protein (EGFP) could detect rare cancer cells in body fluids against millions of normal cells. Human cancer cells suspended with normal murine cells were infected with NV1066 at a multiplicity of infection (MOI) of 0.5 and 1.0 for 18 h. Fluorescent microscopy and flow cytometry were used for EGFP detection of cancer cells. EGFP-expressing cells were confirmed as cancer cells with specific markers by immunohistochemistry staining. Limits of detection of cancer cells in body fluid were measured by serial dilutions. Applicability of technique was confirmed with samples from patients with malignant pleural effusions. NV1066 expressed EGFP in 111 human cancer cell lines detected by fluorescent microscopy at an MOI of 0.5. NV1066 selectively infected cancer cells and spared normal cells as confirmed by immunohistochemistry. Sensitivity of detecting fluorescent green cells was 92% (confidence interval [CI] 83% to 97%) at a ratio of 1 cancer cell to 1 million normal cells. EGFP-positive cells were detected by fluorescent microscopy in patients' malignant pleural effusion samples. Our data show proof of the concept that NV1066-induced EGFP expression allows detection of a single cancer cell against a background of 1 million normal cells. This method was demonstrated to be a reliable screening tool for human cancer cells in a suspension of normal murine cells as well as clinical specimens of malignant pleural effusions.
Molecular Medicine 04/2011; 17(7-8):628-34. DOI:10.2119/molmed.2011.00078 · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic adenocarcinoma impinging the portal and/or superior mesenteric vein (PV-SMV) is classified as borderline resectable, and preoperative chemoradiation is recommended to increase the margin-negative resection rate. There is no consensus about what degree of venous impingement constitutes borderline resectability.
All patients undergoing potentially curative pancreatectomy for pancreatic adenocarcinoma were reviewed. Venous involvement was classified by preoperative computed tomography according to Ishikawa types: (I) normal, (II) smooth shift without narrowing, (III) unilateral narrowing, (IV) bilateral narrowing, (V) bilateral narrowing with collateral veins.
From 1990-2009, 109 patients underwent resection of pancreatic adenocarcinoma involving the PV-SMV. Seventy-four patients received preoperative chemoradiation, whereas 35 did not. Patients who received preoperative therapy had a significantly longer median overall survival rate of 23 months compared with 15 months for patients without preoperative therapy (P = 0.001). Preoperative chemoradiation was associated with higher R0 resection rate and negative lymph nodes (both P < 0.0001) but did not affect the need for vein resection. When stratified by Ishikawa types, preoperative therapy was associated with improved overall survival among patients with types II and III but not types IV and V. Similarly, the correlation between preoperative therapy and R0 resection rate was observed only among patients with Ishikawa types II and III.
Preoperative therapy for borderline resectable pancreatic adenocarcinoma is associated with higher margin-negative resection and survival rates in patients with Ishikawa type II and III tumors, defined as a smooth shift or unilateral narrowing of the PV-SMV. Patients with bilateral venous narrowing were less likely to benefit from preoperative treatment.
[Show abstract][Hide abstract] ABSTRACT: Progress in the treatment of hepatic colorectal metastases (HCRM) demands pathologic indicators of therapy response. We observed that a majority of residual tumor cells are seen at the tumor-normal interface (TNI) in resected HCRM specimens and hypothesized that tumor thickness at the TNI correlates with radiologic and pathologic response and recurrence-free survival (RFS).
This study included 103 patients with HCRM resected after preoperative chemotherapy with or without bevacizumab. Imaging response was assessed by response evaluation criteria in solid tumors (RECIST) and recently described CT morphology criteria by Chun et al. The pathologic response was categorized as complete (no tumor cells), major (<50% residual tumor cells), or minor (> or =50% residual tumor cells). The maximum thickness of uninterrupted layers of tumor cells was measured perpendicular to the TNI by 2 pathologists independently, followed by consensus review for discrepant cases. For specimens containing >1 tumor, the average tumor thickness at the TNI was used.
Sixty-five patients received oxaliplatin-based chemotherapy, 38 received irinotecan-based chemotherapy, and 75 received concurrent bevacizumab. A complete pathologic response was seen in 9 patients, a major response in 44, and a minor response in 50. Median tumor thickness at the TNI was 2.8 mm (interquartile range, 0.5 to 6 mm). Tumor thickness correlated better with radiologic response as determined by Chun et al (P<0.0001) than by RECIST criteria (Spearman r=0.35, P<0.001). Tumor thickness correlated with pathologic response (Spearman r=0.80, P<0.0001). Greater thickness predicted shorter recurrence-free survival, and this correlation remained in multivariate analysis (P=0.015). Tumor thickness was smaller in patients treated with bevacizumab than in patients not given bevacizumab (P=0.03).
Tumor thickness measured at the TNI is potentially a new prognostic factor for therapy response and survival outcome in patients with resected HCRM.
The American journal of surgical pathology 09/2010; 34(9):1287-94. DOI:10.1097/PAS.0b013e3181eb2f7b · 5.15 Impact Factor