Frank Makowiec

The Lymph Node Ratio is the Strongest Prognostic Factor after Resection of Pancreatic Cancer

IntroductionSurvival after surgery of pancreatic cancer is still poor, even after curative resection. Some prognostic factors like the status of the resection margin, lymph node (LN) status, or tumor grading have been identified. However, only few data have been published regarding the prognostic influence of the LN ratio (number of LN involved to number of examined LN). We, therefore, evaluated potential prognostic factors in 182 patients after resection of pancreatic cancer including assessment of LN ratio.MethodsSince 1994, 204 patients underwent pancreatic resection for ductal pancreatic adenocarcinoma. Survival was evaluated in 182 patients with complete follow-up evaluations. Of those 182 patients, 88% had cancer of the pancreatic head, 5% of the body, and 7% of the pancreatic tail. Patients underwent pancreatoduodenectomy (85%), distal resection (12%), or total pancreatectomy (3%). Survival was analyzed by the Kaplan–Meier and Cox methods.ResultsIn all 204 resected patients, operative mortality was 3.9% (n = 8). In the 182 patients with follow-up, 70% had free resection margins, 62% had G1- or G2-classified tumors, and 70% positive LN. Median tumor size was 30 (7–80) mm. The median number of examined LN was 16 and median number of involved LN 1 (range 0–22). Median LN ratio was 0.1 (0–0.79). Cumulative 5-year survival (5-year SV) in all patients was 15%. In univariate analysis, a LN ratio ≥ 0.2 (5-year SV 6% vs. 19% with LN ratio < 0.2; p = 0.003), LN ratio ≥ 0.3 (5-year SV 0% vs. 18% with LN ratio < 0.3; p < 0.001), a positive resection margin (p < 0.01) and poor differentiation (G3/G4; p < 0.03) were associated with poorer survival. In multivariate analysis, a LN ratio ≥ 0.2 (p < 0.02; relative risk RR 1.6), LN ratio ≥ 0.3 (p < 0.001; RR 2.2), positive margins (p < 0.02; RR 1.7), and poor differentiation (p < 0.03; RR 1.5) were independent factors predicting a poorer outcome. The conventional nodal status or the number of examined nodes (in all patients and in the subgroups of node positive or negative patients) had no significant influence on survival. Patients with one metastatic LN had the same outcome as patients with negative nodes, but prognosis decreased significantly in patients with two or more LN involved.ConclusionsNot the lymph node involvement per se but especially the LN ratio is an independent prognostic factor after resection of pancreatic cancers. In our series, the LN ratio was even the strongest predictor of survival. The routine estimation of the LN ratio may be helpful not only for the individual prediction of prognosis but also for the indication of adjuvant therapy and herein related outcome and therapy studies.

Postoperative morbidity and long-term survival after pancreaticoduodenectomy with superior mesenterico-portal vein resection

The role of superior mesenteric-portal vein resection (SM-PVR) for vein invasion or tumor adherence during pancreatoduodenectomy (PD) is still under debate. We investigated morbidity, mortality, and long-term survival in patients who underwent PD with or without SM-PVR. Between July 1994 and December 2004, 222 PD (78% pylorus preserving, 19% Whipple, and 3% total pancreatectomy) were performed for malignant disease. Fifty-three patients (24%) had PD with SM-PVR. Sixty-eight percent of the venous resections were performed as wedge excisions and 32% as segmental resections. Long-term survival was analyzed in 165 patients with pancreatic (n=110), ampullary (n=33), or distal bile (n=22) duct cancer using univariate (log-rank) and multivariate (Cox regression) methods. In patients undergoing PD with SM-PVR and conclusive histologic examination of the resected vein specimen (n=42), 60% had true tumor involvement of the venous wall, whereas 40% had no proven tumor infiltration. In the complete study group, negative resection margins were obtained in 69% of patients with SM-PVR and in 79% of patients without SM-PVR (P=0.09). Median duration of surgery was 500 minutes (SM-PVR) versus 440 minutes (no SM-PVR; P<0.001). Volume of intraoperatively transfused blood was 600 ml (median) in both groups. Postoperative surgical complications/mortality occurred in 23%/3.8% (SM-PVR) versus 35%/4.1% (no SM-PVR); P=0.09/0.9. Analysis of long-term survival in all 165 patients included 41 with SM-PVR. Five-year survival rates were 15% in cancer of the pancreatic head, 22% in ampullary cancer, and 24% in distal bile duct cancer (P=0.02). Long-term survival was not influenced by the need for SM-PVR in any of the different tumor entities. In multivariate analysis, a positive resection margin (P<0.01, relative risk [RR]: 1.8, 95% confidence interval [CI]: 1.2–2.7), a histologically undifferentiated tumor (P=0.01, RR: 1.7, 95% CI: 1.1–2.5), and the tumor entity (P<0.01) were significant predictors of survival. Univariate survival analysis of the 110 patients with cancer of the pancreatic head revealed that a histologically undifferentiated tumor (P=0.05) and positive resection margins (P=0.02) were associated with a poorer survival. In multivariate analysis, the resection margin (P=0.02, RR: 5.1, 95% CI: 1.1–2.8) and a histologically undifferentiated tumor (P=0.05, RR: 3.8, 95% CI: 1.0–2.5) significantly influenced survival. After PD, perioperative morbidity and long-term survival in patients with SM-PVR were similar to those of patients without vein resection. In case of tumor adherence or infiltration, combined resection of the pancreatic head and the vein should always be considered in the absence of other contraindications for resection.

Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas

DNA copy number changes represent molecular fingerprints of solid tumors and are as such relevant for better understanding of tumor development and progression. In this study, we applied genome-wide array comparative genomic hybridization (aCGH) to identify gene-specific DNA copy number changes in chromosomal (CIN)- and microsatellite (MIN)-unstable sporadic colorectal cancers (sCRC). Genomic DNA was extracted from microdissected, matching normal colorectal epithelium and invasive tumor cells of formalin-fixed and paraffin-embedded tissues of 22 cases with colorectal cancer (CIN = 11, MIN = 11). DNA copy number changes were determined by aCGH for 287 target sequences in tumor cell DNAs, using pooled normal DNAs as reference. aCGH data of tumor cell DNAs was confirmed by fluorescence in situ hybridization (FISH) for three genes on serial tissues as those used for aCGH. aCGH revealed DNA copy number changes previously described by metaphase CGH (gains 7, 8q, 13q, and 20q; losses 8p, 15q, 18q, and 17p). However, chromosomal regions 20q, 13q, 7, and 17p were preferentially altered in CIN-type tumors and included DNA amplifications of eight genes on chromosome 20q (TOP1, AIB1, MYBL2, CAS, PTPN1, STK15, ZNF217, and CYP24), two genes on chromosome 13q (BRCA2 and D13S25), and three genes on chromosome 7 (IL6, CYLN2, and MET) as well as DNA deletions of two genes on chromosome 17p (HIC1 and LLGL1). Finally, additional CIN-tumor-associated DNA amplifications were identified for EXT1 (8q24.11) and MYC (8q24.12) as well as DNA deletions for MAP2K5 (15q23) and LAMA3 (18q11.2). In contrast, distinct MIN-tumor-associated DNA amplifications were detected for E2F5 (8p22–q21.3), GARP (11q13.5–q14), ATM (11q22.3), KAL (Xp22.3), and XIST (Xq13.2) as well as DNA deletions for RAF1 (3p25), DCC (18q21.3), and KEN (21q tel). aCGH revealed distinct DNA copy number changes of oncogenes and tumor suppressor genes in CIN- and MIN-type sporadic colorectal carcinomas. The identified candidate genes are likely to have distinct functional roles in the carcinogenesis and progression of CIN- and MIN-type sporadic CRCs and may be involved in the differential response of CIN- and MIN-type tumor cells to (adjuvant) therapy, such as 5-fluorouracil.

Delayed gastric emptying after pylorus-preserving pancreatoduodenectomy is strongly related to other postoperative complications

Patients undergoing pylorus-preserving pancreatoduodenenectomy (PPPD) have a risk of up to 50% for developing delayed gastric emptying (DGE) in the early postoperative course. From 1994 to August 2002, a total of 204 patients underwent PPPD for pancreatic or periampullary cancer (50%), chronic pancreatitis (42%), and other indications (8%). Retrocolic end-to-side duodenojejunostomy was performed below the mesocolon. DGE was defined by the inability to tolerate a regular diet after day 10 (DGE10) or day 14 (DGE14) postoperatively, as well as the need for a nasogastric tube at or beyond day 10 (DGE10GT). Postoperative morbidity was 38%, 30-day mortality was 2.9%, and median postoperative length of stay was 15 days. DGE occurred in 14.7% (DGE10), 5.9% (DGE14), and 6.4% (DGE10GT), respectively. After further exclusion of 21 patients (10.3%) with major complications and no possible oral intake (because of death, reoperation, or mechanical ventilation), the frequencies of DGE10, DGE14, and DGE10GT in the remaining group of 183 patients were 9%, 2%, and 2%, respectively. Multivariate analysis revealed postoperative complications (P < 0.001), the presence of portalvenous hypertension (P < 0.01), and tumors as indications for surgery (P < 0.01) as independent risk factors for DGE10. The overall incidence of DGE was low after PPPD. In those patients experiencing DGE, however, other postoperative complications were the most important factor associated with its occurrence.

A simple scoring system based on clinical factors related to pancreatic texture predicts postoperative pancreatic fistula preoperatively.

BACKGROUND Postoperative pancreatic fistula (POPF) is regarded as the most serious complication of pancreatic surgery. The preoperative risk stratification of patients by simple means is of interest in perioperative clinical management. METHODS Based on prospective data, we performed a risk factor analysis for POPF after pancreatoduodenectomy in 62 patients operated between 2006 and 2008 with special focus on clinical parameters that might serve to predict POPF. A predictive score was developed and validated in an independent second dataset of 279 patients operated between 2001 and 2010. RESULTS Several pre- and intraoperative factors, as well as underlying pathology, showed significant univariate correlation with rate of POPF. Multivariate analysis (binary logistic regression) disclosed soft pancreatic texture (odds ratio [OR] 10.80, 95% confidence interval [CI] 1.80-62.20) and history of weight loss (OR 0.15, 95% CI 0.04-0.66) to be the only independent preoperative clinical factors influencing POPF rate. The subjective assessment of pancreatic hardness by the surgeon correlated highly with objective assessment of pancreatic fibrosis by the pathologist (r = -0.68, P < 0.001, two-tailed Spearmans rank correlation). A simple risk score based on preoperatively available clinical parameters was able to stratify patients correctly into three risk groups and was independently validated. CONCLUSIONS Preoperative stratification of patients regarding risk for POPF by simple clinical parameters is feasible. Pancreatic texture, as evaluated intraoperatively by the surgeon, is the strongest single predictive factor of POPF. The findings of the study may have important implications for perioperative risk assessment and patient care, as well as for the choice of anastomotic techniques.

STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation

Aims: To evaluate mRNA and protein expression of signal transducers and activators of transcription (STAT)3 in colorectal carcinomas (CRCs) and to define the association of STAT3 activity with the STAT3-inducible targets cyclin D1, survivin, Bcl-xl and Mcl-1. Materials and methods: Matching serial sections of normal colonic epithelium and invasive CRCs (n = 32) were subjected to quantitative reverse transcriptase polymerase chain reaction specific to STAT3, cyclin D1, survivin, Bcl-xl and Mcl-1, as well as immunohistochemistry. For STAT3 immunohistochemistry, two antibodies, recognising unphosphorylated (UP-) and phosphorylated (tyr705, P-) STAT3 were used. Ki-67 (MIB-1) staining was included as a proliferation marker. Results: Compared with normal colonic epithelium, UP-STAT3 and P-STAT3 (p = 0.023 and 0.006) protein expression and expression of its associated targets cyclin D1, survivin and Bcl-xl were significantly (all p<0.001) increased in carcinoma. In carcinomas, STAT3 (p = 0.019) and Bcl-xl (p = 0.001) mRNAs were correlated with lymph node status. Moreover, nuclear P-STAT3 protein expression (active state) was associated with the expression of its target genes Bcl-xl (p = 0.038) and survivin (p = 0.01) as well as with Ki-67 (p = 0.017). By contrast, cytoplasmic UP-STAT was significantly linked to Bcl-xl mRNA (p = 0.024) and protein (p = 0.001) as well as to cytoplasmic survivin protein expression (p = 0.019). Conclusion: Both inactive (UP-STAT3) and active (P-STAT3) STAT3 proteins are markedly increased in invasive CRCs. This is associated with Bcl-xl and survivin induction, increased proliferation and lymph node metastasis. This study therefore provides the basis for further examination of the prognostic or predictive value of these molecular markers in CRC.

Comprehensive analysis of the α‐fetoprotein‐specific CD8+ T cell responses in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with a poor prognosis and limited therapeutic options. Therefore, the development of novel therapeutic strategies is of high priority. α‐Fetoprotein (AFP) is overexpressed in the majority of HCCs. Priming of immune responses against AFP results in significant protective antitumoral T cell responses in the mouse model. Little information is available about the hierarchy, breadth, frequency, and peripheral versus intrahepatic distribution of AFP‐specific CD8+ T cell responses in patients with HCC. To address these important issues we comprehensively analyzed CD8+ T cell responses against full‐length AFP in peripheral blood, tumor liver tissue, and nontumor liver tissue from patients with HCC using overlapping AFP peptides. The AFP‐specific CD8+ T cell response was also tested in peripheral blood and liver from patients chronically infected with hepatitis C virus (HCV) and compared to the HCV‐specific CD8+ T cell response. The majority of patients with HCC showed AFP‐specific responses, with many responses directed against previously unreported epitopes. These responses were primarily detectable in the HCC tissue and mainly targeted the C‐terminus of AFP. Interestingly, AFP‐specific T cells were not only found in patients with HCC but also in patients with chronic HCV infection, other liver diseases, and less frequently in healthy subjects. Conclusion: In patients with HCC, a high frequency of AFP‐specific CD8+ T cells directed against different epitopes suggest that AFP has a strong and broad immunogenicity. Further, CD8+ T cells specific for the self‐antigen AFP are present in the normal T cell repertoire and are not centrally or peripherally deleted. Our results provide support for strategies to boost AFP‐specific CD8+ T cell responses in patients with HCC but also demonstrate a diversity of immune responses that may be needed for protection. (HEPATOLOGY 2008;48:1821‐1833.)

Management of delayed visceral arterial bleeding after pancreatic head resection.

Despite low mortality, postoperative complications are still relatively frequent after pancreatic head resection. The occurrence of delayed visceral arterial bleeding from erosions or pseudoaneurysms of branches of the celiac trunk or from the stump of the gastroduodenal artery is a rare but life-threatening complication and is probably underreported in the literature. During a 10-year period, we diagnosed and treated 12 patients (three referred from other hospitals) with severe visceral arterial bleeding, presenting 7 to 85 days after pancreatic head resection. Clinical presentation was gastrointestinal bleeding (seven patients) or abdominal bleeding (five patients). The bleeding source was identified by angiography in 10 of the 12 cases. Definitive bleeding control was achieved by angiography in six of the 12 patients (stent 2, coiling 4), or by surgery in five patients. None of the six patients with successful angiographic intervention required further surgery for bleeding control. One patient died due to hemorrhage before bleeding was controlled. Median transfusion requirement was 12.5 (range 3–37) units. Of five patients with interventional or surgical occlusion of the common hepatic artery, three developed hepatic abscesses and two had complications of the hepaticojejunostomy. One of those five patients died four months after definitive bleeding control because of recurrent hepatic abscesses. All other patients eventually recovered completely. We conclude that delayed arterial bleeding from visceral arteries is a rare but life-threatening complication after pancreatic head resection. Angiographic stenting with preservation of hepatic blood flow, if technically possible, represents the best treatment option.

The Inflammatory Pancreatic Head Mass Significant Differences in the Anatomic Pathology of German and American Patients With Chronic Pancreatitis Determine Very Different Surgical Strategies

Background:The indications for surgery and the surgical strategy selected for chronic pancreatitis (CP) vary widely, perhaps because of unaccounted characteristics of different patient populations such as the “inflammatory mass” in the head of the pancreas, commonly described in Europe but not in America. Methods:We compared the pancreatic morphology, anatomic complications, indications leading to intervention, and the operation performed in 93 consecutive patients with CP operated upon either at a German (n = 48) or an American (n = 45) center specializing in pancreatic surgery. Pretreatment computed tomography/magnetic resonance imaging scans were reevaluated by 2 independent radiologists, especially to measure the anterior-posterior diameter of the pancreatic head (the inflammatory mass). Results:The prevalence of endocrine and exocrine insufficiency was not significantly different. The median diameter of the pancreatic head mass was significantly larger in the German group (4.5 vs. 2.6 cm, P < 0.001). Inflammatory mass-dependent symptoms [gastric outlet obstruction (9/48 vs. 1/45; P = 0.02) and hemorrhage (7/48 vs. 0/45; P = 0.013)] were more frequent in the German group. Bile duct stenosis (19/48 vs. 11/43; P = 0.18) and suspicion of malignancy (5/48 vs. 11/43; P = 0.10) were comparable, whereas chronic pain (15/48 vs. 28/43; P = 0.001) was a more frequent indication for surgery in the US group. Splenic or portal vein thrombosis was found only in the German group. The duration of nonoperative therapy was significantly longer in the German group (median 56 vs. 26 months; P = 0.02). In the US group, a pancreatoduodenectomy with antrectomy was performed in most (89%) cases, whereas in the German group a duodenum-preserving head resection was preferred in more than half (25/47) of the cases (P < 0.001). Conclusions:Symptoms, duration of conservative therapy, and selection of surgical treatment all differed significantly between German and American patients with CP. These differences seem to be dependent upon surprising but unexplained disparities in the pathologic pancreatic anatomy between the 2 populations.

Short- and long-term results of duodenum preservation versus resection for the management of chronic pancreatitis: a prospective, randomized study.

BACKGROUND Individualization of operations for chronic pancreatitis (CP) offers tailored operative approaches for the management of complications of CP. For the management of the inflammatory head mass and its complications, duodenum-preserving procedures (Frey and Beger operations) compete in efficacy and quality of life with pancreatoduodenectomy procedures (PPPD and Whipple operations). Our aim was to compare the short- and long-term results of duodenum-preserving and duodenum-resecting techniques in a prospective, randomized trial. METHODS Eighty-five patients with CP were randomized to undergo either pylorus-preserving (PPPD) or duodenum-preserving pancreatic head resection (DPPHR). Perioperative and long term results were evaluated. RESULTS Although the duodenum-preserving operations had a lesser median operating time (360 vs 435 minutes; P = .002), there were no differences in the need for intraoperative blood transfusion (76% vs 79%) or the duration of hospital stay (13 vs 14 days). Postoperative complications in general (33% vs 30%), surgical complications (21% vs 23%), and severe complications such as pancreatic leakage (10% vs 5%) or the need for reoperation (2% vs 2%) did not differ between the DPPHR and the PPPD groups, and there was no mortality (0%). The long-term outcome after a median of >5 years showed no differences between the DPPHR and PPPD regarding quality of life, pain control (67% vs 67%), endocrine status (45% vs 44%), and exocrine insufficiency (76% vs 61%). CONCLUSION Both types of pancreatic head resections are equally effective in pain relief and eventual quality of life after long-term follow-up (>5 years) without differences in endocrine or exocrine function.