Faik G. Uzunoglu

Borderline resectable pancreatic cancer: A consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)

BACKGROUND This position statement was developed to expedite a consensus on definition and treatment for borderline resectable pancreatic ductal adenocarcinoma (BRPC) that would have worldwide acceptability. METHODS An international panel of pancreatic surgeons from well-established, high-volume centers collaborated on a literature review and development of consensus on issues related to borderline resectable pancreatic cancer. RESULTS The International Study Group of Pancreatic Surgery (ISGPS) supports the National Comprehensive Cancer Network criteria for the definition of BRPC. Current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis; in addition, a new classification of extrahepatic mesentericoportal venous resections is proposed by the ISGPS. Suspicion of arterial involvement should lead to exploration to confirm the imaging-based findings. Formal arterial resections are not recommended; however, in exceptional circumstances, individual therapeutic approaches may be evaluated under experimental protocols. The ISGPS endorses the recommendations for specimen examination and the definition of an R1 resection (tumor within 1 mm from the margin) used by the British Royal College of Pathologists. Standard preoperative diagnostics for BRPC may include: (1) serum levels of CA19-9, because CA19-9 levels predict survival in large retrospective series; and also (2) the modified Glasgow Prognostic Score and the neutrophil/lymphocyte ratio because of the prognostic relevance of the systemic inflammatory response. Various regimens of neoadjuvant therapy are recommended only in the setting of prospective trials at high-volume centers. CONCLUSION Current evidence justifies portomesenteric venous resection in patients with BRPC. Basic definitions were identified, that are currently lacking but that are needed to obtain further evidence and improvement for this important patient subgroup. A consensus for each topic is given.

Characterization of different CTC subpopulations in non-small cell lung cancer.

Circulating tumour cells (CTCs) serve as valuable biomarkers. However, EpCAM positive CTCs are less frequently detected in NSCLC patients compared to other epithelial tumours. First, EpCAM protein expression was analysed in primary and metastatic lung cancer tissue. In both groups 21% of the samples were EpCAM negative. Second, the CellSearch system identified 15% of patients (n = 48) as CTC positive whereas a multiplex RT-PCR for PIK3CA, AKT2, TWIST, and ALDH1 following EGFR, HER2 and EpCAM based enrichment detected CTCs in 29% of the patients. Interestingly, 86% of CTC positive patients were found to express ALDH1. Only 11% of the patients were CTC-positive by both techniques. CTC positivity was associated with patient disease state when assessed by the multiplex RT-PCR assay (p = 0.015). Patients harbouring tumours with an altered EGFR genotype were more frequently CTC-positive compared to patients with EGFR wildtype tumours. In subsets of patients, CTCs were found to express genes involved in resistance to therapy such as HER3 and MET. In conclusion, using multiple targets for CTC capture and identification increases the sensitivity of CTC detection in NSCLC patients, which can be explained by the presence of different CTC subtypes with distinct molecular features.

Preoperative Pancreatic Resection (PREPARE) score: a prospective multicenter-based morbidity risk score.

Objectives:Development of a simple preoperative risk score to predict morbidity related to pancreatic surgery. Background:Pancreatic surgery is standardized with little technical diversity among institutions and unchanging morbidity and mortality rates in recent years. Preoperative identification of high-risk patients is potentially one of the rare avenues for improving the clinical course of patients undergoing pancreatic surgery. Methods:Using a prospectively collected multicenter database of patients undergoing pancreatic surgery (n = 703), surgical complications were classified according to the Clavien-Dindo classification. A new scoring system for preoperative identification of high-risk patients that included only objective preoperatively assessable variables was developed using a multivariate regression model. Subsequently, this scoring system was prospectively validated from 2011 to 2013 (n = 429) in a multicenter setting. Results:Eight independent preoperatively assessable variables were identified and included in the scoring system: systolic blood pressure, heart rate, hemoglobin level, albumin level, ASA (American Society of Anesthesiologists) score, surgical procedure, elective surgery or not, and disease of pancreatic origin or not. On the basis of 3 subgroups (low risk, intermediate risk, high risk), the proposed scoring system reached an accuracy of 75% for correctly predicting occurrence or nonoccurrence of major surgical complications in 80% of all analyzed patients within the validation cohort (c-statistic index = 0.709, P < 0.001, 95% confidence interval = 0.657–0.760). Conclusions:We present an easily applied scoring system with convincing accuracy for identifying low-risk and high-risk patients. In contrast to other systems, the score is exclusively based on objective preoperatively assessable characteristics and can be rapidly and easily calculated.

The Multifunctional Growth Factor Midkine Promotes Proliferation and Migration in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has a devastating prognosis among solid tumors and despite increased knowledge of the molecular mechanisms contributing to progression and metastasis, minimal progress has been done in establishing new targeted therapies for this deadly disease. The expression of the multifunctional growth/differentiation factor midkine (MK) promotes a variety of cellular functions leading to increased angiogenesis, proliferation, migration, and survival. Moreover, MK is intensively discussed as a potential new-therapy target and as biomarker for cancer progression and chemotherapeutic resistance in multiple cancers. Therefore, the present study investigated the molecular role of MK in pancreatic cancer. It was found that MK is elevated in PDAC and differentially expressed in other histologic subtypes of pancreatic cancer, whereas normal pancreatic cells did not express MK, thus making it an attractive candidate for targeted therapies. As a secreted growth/differentiation factor, MK was investigated as a biomarker in clinical serum specimens using ELISA. In addition, knockdown studies of MK revealed a link to proliferation and migration status in vitro. Finally, upstream signaling pathways were analyzed, with TNF-α and EGF being the main inductors of MK expression in PDAC. Implications: This study presents novel MK functions and new upstream signaling effectors that induce its expression to promote PDAC and therefore defines an attractive new therapeutic target in pancreatic cancer. Mol Cancer Res; 12(5); 670–80. ©2014 AACR.

Opposite roles of FOXA1 and NKX2-1 in lung cancer progression.

Gene copy number profiles of primary lung tumors were screened for high‐level amplifications. We detected 22 high‐level amplifications in various loci, including 14q13. This locus is known to harbor the adenocarcinoma (AC) lineage‐specific target gene NKX2‐1, which is not expressed in squamous cell carcinoma (SCC). As the 14q amplification was also found in SCC, we investigated whether or not FOXA1 might be the corresponding target gene for SCC. Focusing on these two target genes, we assessed gene amplifications and protein expression of NKX2‐1 and FOXA1 in primary lung tumors (n = 554) and brain metastases (n = 68). Primary AC (n = 194) showed positive protein expression of NKX2‐1 in 58.2% of the samples compared with 4.2% of primary SCC samples (n = 212). Positive staining for FOXA1 was seen in 34.7% of the SCC samples, which was comparable with 39.6% in the AC samples. For brain metastases, FOXA1 expression was slightly higher in the SCC samples (55.6%) compared with the non‐matched primary SCC tumor samples (43.4%), whereas NKX2‐1 expression was comparable in both primary tumors and brain metastases. Positive FOXA1 and NKX2‐1 expression was associated with a gain or amplification in 34.6% and 28.6% of cases, respectively. The expression of NKX2‐1 was associated with early stage and grade among the AC cases. In contrast, FOXA1 expression in SCC was associated with distant metastases as well as an unfavorable survival rate (P = 0.039). These results suggest that both FOXA1 and NKX2‐1 may act as lineage‐specific target genes within the 14q amplicon with opposite functions in lung cancer.

An Attempt at Validation of the Seventh Edition of the Classification by the International Union Against Cancer for Esophageal Carcinoma

BACKGROUND The aim of our study was to investigate the ability of the Seventh edition of the classification by the International Union Against Cancer (UICC) to identify patients at higher risk and to predict the overall survival in patients with esophageal carcinoma. METHODS Demographic and clinical data of 605 patients, who underwent esophagectomy for esophageal carcinoma between 1992 and 2009, were analyzed. Tumor stage and grade were classified according to the sixth and seventh editions of the UICC classification. RESULTS Tumor depth (T), lymph node affection (N), and metastasis (M) status according to the seventh edition of the UICC classification showed significant differences in survival of each single status. Kaplan-Meier analysis of overall survival by the seventh edition of the UICC classification showed poor discrimination between stages Ib and IIa (p=0.098), stages IIIa and IIIb (p=0.672), and stages IIIc and IV (p=0.799). Further, the estimated median survival time between stages IIa and IIb was discordant. CONCLUSIONS The seventh edition of the UICC TNM classification cannot satisfactorily distinguish among different risk groups of patients with resected esophageal carcinoma. The new subgroups do not unify the different TNM stages with similar survival. We strongly propose that the next revision of the UICC classification should reduce the stages to groups with similar survival, without defining complex subgroups.

Ultrasonic dissection versus conventional dissection techniques in pancreatic surgery: a randomized multicentre study

Objective:This prospective randomized multicenter trial was performed to assess the potential benefits of ultrasonic energy dissection compared with conventional dissection techniques in pancreatic surgery. Background:Surgical procedures for tumors of the pancreatic head involve time-consuming manual dissection. The primary hypothesis was that use of ultrasonic tissue and vessel dissection would lead to substantial saving in operative time during pancreatic resection. Methods:Patients eligible for pancreaticoduodenectomy (PD) or pylorus-preserving PD (PPPD) were randomized to group A (dissection with ultrasonic device) or group B (conventional dissection) from March 2009 to May 2011. The primary endpoint was overall duration of operation time. Secondary endpoints were time to end of resection phase, intraoperative blood loss, number of transfused units of blood, and postoperative morbidity. Results:Analysis of primary and secondary endpoints included 101 patients, who received either PD or PPPD. Demographical characteristics and clinical parameters were similar in both groups. The use of an ultrasonic dissection device did not significantly reduce overall operation time (median 316 minutes in group A and 319 minutes in group B, P = 0.95) and did not significantly increase the costs of surgery. Analysis of secondary endpoints revealed no difference in postoperative course. Conclusions:Tissue dissection and vessel closure using an ultrasonic device is equivalent to dissection with conventional techniques in pancreatic surgery.

Loss of 4q21.23-22.1 Is a Prognostic Marker for Disease Free and Overall Survival in Non-Small Cell Lung Cancer

This study was performed to assess the prognostic relevance of genomic aberrations at chromosome 4q in NSCLC patients. We have previously identified copy number changes at 4q12-q32 to be significantly associated with the early hematogenous dissemination of non-small cell lung cancer (NSCLC), and now aim to narrow down potential hot-spots within this 107 Mb spanning region. Using eight microsatellite markers at position 4q12-35, allelic imbalance (AI) analyses were performed on a preliminary study cohort (n = 86). Positions indicating clinicopathological and prognostic associations in AI analyses were further validated in a larger study cohort using fluorescence in situ hybridization (FISH) in 209 NSCLC patients. Losses at positions 4q21.23 and 4q22.1 were shown to be associated with advanced clinicopathological characteristics as well as with shortened disease free (DFS) and overall survival (OS) (DFS: P = 0.019; OS: P = 0.002). Multivariate analyses identified the losses of 4q21.23-22.1 to be an independent prognostic marker for both DFS and OS in NSCLC (HR 1.64–2.20, all P<0.04), and especially in squamous cell lung cancer (P<0.05). A case report study of a lung cancer patient further revealed a loss of 4q21.23 in disseminated tumor cells (DTCs). Neither gains at the latter positions, nor genomic aberrations at 4q12, 4q31.2 and 4q35.1, indicated a prognostic relevance. In conclusion, our data indicate that loss at 4q21.23-22.1 in NSCLC is of prognostic relevance in NSCLC patients and thus, includes potential new tumor suppressor genes with clinical relevance.

LigaSure™ vs. conventional dissection techniques in pancreatic surgery--a prospective randomised single-centre trial.

BackgroundSurgical procedures in pancreatic surgery are well established, but still involve time-consuming manual dissection. We compared the use of LigaSure with conventional dissection techniques in pancreatic surgery in a prospective randomised single-centre trial (registration number: NCT00850291).MethodsPatients with tumours of the pancreatic head that were assumed to be technically resectable were randomised to LigaSure or conventional surgery. The primary endpoint of this study was overall operation time. Secondary endpoints were preparation time until tumour resection, intraoperative blood loss, number of given units of packed red blood cells, costs of surgery, postoperative morbidity, length of hospital stay and mortality.ResultsThere was no difference in overall operation time between the two groups (P = 0.227). Median costs for pancreatic surgery were significantly less in the conventional group with €3,047 (range 2,004–5,543) vs. €3,527 (range 2,516–5,056, P = 0.009). Preparation time, intraoperative blood loss, number of units of packed red blood cells, postoperative morbidity, length of hospital stay and mortality did not differ between the two groups.ConclusionOur data indicate that the LigaSure device is equivalent to conventional dissection modalities in pancreatic surgery.

Evaluation of the germline single nucleotide polymorphism rs583522 in the TNFAIP3 gene as a prognostic marker in esophageal cancer

Most esophageal cancer patients die because of disease relapse, hence an accurate prognosis of disease relapse and survival is essential. Genetic variations in cancer patients may serve as important indicators. Three genotypes (GG, AG, and AA) are displayed by the single nucleotide polymorphism (SNP) rs583522, which maps to the TNFAIP3 gene on chromosome 6. Evaluation of the potential prognostic value of the TNFAIP3-SNP in esophageal cancer (EC) was the aim of this study. A total of 158 patients underwent complete surgical resection of the esophagus for EC. None of them received any neoadjuvant or adjuvant treatment. Peripheral blood was sampled, and genomic DNA was extracted from leukocytes before each operation. Clinicopathologic parameters, tumor cell dissemination in bone marrow, and clinical outcome were correlated with the TNFAIP3-SNP. A-allele carriers showed advanced tumor stages compared with those of homozygous G-allele carriers (P<0.001). Patients with an A-allele genotype (AA or AG) were significantly more likely to experience a relapse (P=0.003). Survival analysis (log-rank test) revealed a significant difference in overall survival between the three groups (P=0.039); however, none of the genotypes was identified as a disease stage-independent prognostic marker. In conclusion, TNFAIP3-SNP stratifies patients into different risk groups; however, it could not be identified as an independent prognostic marker.