Perioperative risk of pancreatic head resection-nomogram-based prediction of severe postoperative complications as a decisional aid for clinical practice.

PURPOSE: To develop nomograms for pre- and early-postoperative risk assessment of patients undergoing pancreatic head resection. METHODS: Clinical data from 956 patients were collected in a prospectively maintained database. A test (n = 772) and a validation cohort (n = 184) were randomly generated. Uni- and multi-variate analysis and nomogram construction were performed to predict severe postoperative complications (Clavien-Dindo Grades III-V) in the test cohort. External validation was performed with the validation cohort. RESULTS: We identified ASA score, indication for surgery, body mass index (BMI), preoperative white blood cell (WBC) count, and preoperative alkaline phosphatase as preoperative factors associated with an increased perioperative risk for complications. Additionally to ASA score, BMI, indication for surgery, and the preoperative alkaline phosphatase, the following postoperative parameters were identified as risk factors in the early postoperative setting: the need for intraoperative blood transfusion, operation time, maximum WBC on postoperative day (POD) 1-3, and maximum serum amylase on POD 1-3. Two nomograms were developed on the basis of these risk factors and showed accurate risk estimation for severe postoperative complications (ROC-AUC-values for Grades III-V-preoperative nomogram: 0.673 (95%, CI: 0.626-0.721); postoperative nomogram: 0.734 (95%, CI: 0.691-0.778); each p ≤ 0.001). Validation yielded ROC-AUC-values for Grades III-V-preoperative nomogram of 0.676 (95%, CI: 0.586-0.766) and postoperative nomogram of 0.677 (95%, CI: 0.591-0.762); each p = 0.001. CONCLUSION: Easy-to-use nomograms for risk estimation in the pre- and early-postoperative setting were developed. Accurate risk estimation can support the decisional process, especially for IPMN-patients with an increased perioperative risk.

R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial.

PURPOSE: Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. METHODS: One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. RESULTS: Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p < 0.001). CONCLUSION: Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.

Clinical course and pancreas parenchyma sparing surgical treatment of severe pancreatic trauma.

INTRODUCTION: Pancreatic trauma (PT) involving the main pancreatic duct is rare, but represents a challenging clinical problem with relevant morbidity and mortality. It is generally classified according to the American Association for the Surgery of Trauma (AAST) and often presents as concomitant injury in blunt or penetrating abdominal trauma. Diagnosis may be delayed because of a lack of clinical or radiological manifestation. Treatment options for main pancreatic duct injuries comprise highly complex surgical procedures. PATIENTS AND METHODS: We retrospectively analyzed clinical data from 12 patients who underwent surgery in two tertiary centers in Germany during 2003-2016 for grade III-V PT with affection of the main pancreatic duct, according to the AAST classification. RESULTS: The median age was 23 (range: 7-44) years. In nine patients blunt abdominal trauma was the reason for PT, whereas penetrating trauma only occurred in three patients. MRI outperformed classical trauma CT imaging with regard to detection of duct involvement. Complex procedures as i.e. an emergency pancreatic head resection, distal pancreatectomy or parenchyma sparing pancreatogastrostomy were performed. Compared to elective pancreatic surgery the complication rate in the emergency setting was higher. Yet, parenchyma-sparing procedures demonstrated safety. CONCLUSIONS: Often extension of diagnostics including MRI and/or ERP at an early stage is necessary to guide clinical decision-making. If, due to main duct injuries, surgical therapy for PT is required, we suggest consideration of an organ preservative pancreatogastrostomy in grade III/IV trauma of the pancreatic body or tail.

The rate of postoperative pancreatic fistula after distal pancreatectomy is independent of the pancreatic stump closure technique - A retrospective analysis of 284 cases.

BACKGROUND: Many techniques have been developed to prevent postoperative pancreatic fistula (POPF) after distal pancreatectomy, but POPF rates remain high. The aim of our study was to analyze POPF occurrence after closure of the pancreatic remnant by different operative techniques. METHODS: Between 2006 and 2017, 284 patients underwent distal pancreatectomy in our institution. For subgroup analysis the patients were divided into hand-sewn (n = 201) and stapler closure (n = 52) groups. The hand-sewn closure was performed in three different ways (fishmouth-technique, n = 27; interrupted transpancreatic U-suture technique, n = 77; common interrupted suture, n = 97). All other techniques were summarized in a separate group (n = 31). Results were gained by analysis of our prospective pancreatic database. RESULTS: The median age was 63 (range 23-88) years. 74 of 284 patients (26%) were operated with spleen preservation (similar rates in subgroups). ASA-classes, median BMI as well as frequencies of malignant diseases, chronic pancreatitis, alcohol and nicotine abuse were also comparable in the subgroups. Neither the rates of overall POPF (fishmouth-technique 30%, common interrupted suture 40%, stapler closure 33% and interrupted U-suture 38%) nor the rates of POPF grades B and C showed significant differences in the subgroups. However is shown to be associated with pancreatic function and parenchymal texture. CONCLUSION: In our experience the technique of pancreatic stump closure after distal resection did not influence postoperative pancreatic fistula rate. As a consequence patient specific reasons rather than surgical techniques may be responsible for POPF formation after distal pancreatectomy.

Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial.

BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).

Management and outcomes of intraductal papillary mucinous neoplasms.

Background: This study evaluated the outcome and survival of patients with radiologically suspected intraductal papillary mucinous neoplasms (IPMNs). Methods: IPMN management was reviewed according to Fukuoka risk factors and IPMN localization, differentiating main-duct (MD), mixed-type (MT) and branch-duct (BD) IPMNs. Perioperative results were compared with those of patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) over the same interval (2010-2014). Overall (OS) and disease-specific (DSS) survival rates were calculated and subgroups compared. Results: Of 142 patients with IPMNs, 26 had MD-IPMN, eight had MT-IPMN and 108 had BD-IPMN. Some 74 per cent of patients with MD- and MT-IPMN were managed by primary resection, whereas this was used in only 27·8 per cent of those with BD-IPMN. The risk of secondary resection and malignant transformation for BD-IPMNs smaller than 20 mm was 8 and 2 per cent respectively during follow-up. Pancreatic head resection of IPMNs was associated with an increased risk of postoperative pancreatic fistula grade B/C compared with resection of PDAC (12 of 33 (36 per cent) versus 41 of 221 (18·6 per cent) respectively; P = 0·010), and greater morbidity and mortality (Clavien-Dindo grade III: 15 of 33 (45 per cent) versus 56 of 221 (25·3 per cent) respectively; grade IV: 1 (3 per cent) versus 7 (3·2 per cent); grade V: 2 (6 per cent) versus 2 (0·9 per cent); P = 0·008). Five-year OS and DSS rates in patients with MD-IPMN were worse than those for MT- and BD-IPMN (OS: 44, 86 and 97·4 per cent respectively, P < 0·001; DSS: 60, 100 and 98·6 per cent; P < 0·001). Patients with invasive IPMN had worse OS and DSS rates than those with non-invasive dysplasia (OS: IPMN-carcinoma (10 patients) 33 per cent, high-grade dysplasia 100 per cent, intermediate-grade dysplasia 63 per cent, low grade-dysplasia 100 per cent, P < 0·001; DSS: IPMN-carcinoma 43 per cent, all grades of dysplasia 100 per cent, P < 0·001). Patients with high-risk stigmata had poorer survival than those without risk factors (OS: high-risk stigmata (35 patients) 55 per cent, worrisome features (31) 95 per cent, no risk factors (76) 100 per cent, P < 0·001; DSS: 71, 100 and 100 per cent respectively, P < 0·001). Conclusion: The risk of malignant transformation was very low for BD-IPMNs, but the development of high-risk stigmata was associated with disease-specific mortality. Patients with IPMN had greater morbidity after resection than those having resection of PDAC.

Levels of activated platelet-derived microvesicles in patients with soft tissue sarcoma correlate with an increased risk of venous thromboembolism.

BACKGROUND: Microvesicles are small vesicles expressing specific antigens from their cells of origin. Elevated levels of microvesicles have been shown to be associated with coagulation disorders as well as with different types of malignancies. This study aims to evaluate a possible correlation of different microvesicle subpopulations with a positive history of venous thromboembolism (VTE) in patients with soft tissue sarcoma. METHODS: Annexin V - positive microvesicles, leukocyte (CD45-positive), platelet (CD61-positive), activated platelet (CD62P-, CD63-positive), endothelium-derived (CD62E-positive) and tissue-factor (CD142-positive) microvesicles were identified in the peripheral blood of patients with soft tissue sarcoma (n = 39) and healthy controls (n = 17) using fluorescence-activated cell sorting (FACS). RESULTS: Both the total amount of Annexin V-positive microvesicles and levels of endothelium-derived (CD62E-positive) microvesicles were shown to decrease significantly after tumor resection (n = 18, p = 0.0395 and p = 0.0109, respectively). Furthermore, the total amount of Annexin V - positive microvesicles as well as leukocyte (CD45-positive) and endothelium-derived (CD62E-positive) microvesicles were significantly higher in patients with grade 3 (G3) soft tissue sarcoma (n = 9) compared to healthy controls (n = 17) (p = 0.0304, p = 0.0254 and p = 0.0357, respectively). Moreover, patients with G3 soft tissue sarcoma (n = 9) presented higher levels of Annexin V-positive and endothelium-derived (CD62E-positive) microvesicles compared to patients with grade 2 (G2) soft tissue sarcoma (n = 8) (p = 0.0483 and p = 0.0045). Patients with grade 1 (G1) soft tissue sarcoma (n = 3) presented with significantly lower levels of platelet (CD61-positive) microvesicles than patients with G3 soft tissue sarcoma (n = 9) (p = 0.0150). In patients with a positive history of VTE (n = 11), significantly higher levels of activated platelet (CD62P- and CD63-positive) microvesicles (p = 0.0078 and p = 0.0450, respectively) were found compared to patients without a history of VTE (n = 28). CONCLUSION: We found significantly higher levels of Annexin V-positive and endothelium-derived (CD62E-positive) microvesicles to be circulating in the peripheral blood of patients with G3 soft tissue sarcoma compared to patients with G2 soft tissue sarcoma. Furthermore, we showed that high counts of activated platelet-derived microvesicles correlate with the occurrence of VTE. Thus, the detection of these microvesicles might be an interesting new tool for early diagnosis of soft tissue sarcoma patients with increased risk for VTE, possibly facilitating VTE prevention by earlier use of thromboprophylaxis.

Pancreatitis After Pancreatoduodenectomy Predicts Clinically Relevant Postoperative Pancreatic Fistula.

BACKGROUND: Morbidity after pancreas resection is still high with postoperative pancreatic fistulas (POPF) being the most frequent complication. However, exocrine insufficiency seems to protect from POPF. In clinical practice, patients showing increased postoperative systemic amylase concentrations appear to frequently develop POPF. We therefore retrospectively examined the occurrence of systemic amylase increase after pancreas resections and its association with the clinical course. PATIENTS AND METHODS: Perioperative data from 739 consecutive pancreas resections were assessed in a prospectively maintained SPSS database. Serum and drain amylase concentrations were determined by routine clinical chemistry. POPFs were graded into A-C according to ISGPF definitions. RESULTS: In patients with reduced serum amylase (n = 89) on day 1 after pancreatoduodenectomy, clinically relevant POPFs were not observed. In patients with normal serum amylase concentrations, clinically relevant POPFs occurred in 9 %, while in 39 % of the patients with more than three times elevated amylase concentrations, a clinically relevant postoperative fistula was observed (p < 0.001). Systemic hyperamylasemia detected on postoperative day 1 after pancreatoduodenectomy was further a good predictor for clinically relevant POPFs (AUROC = 0.797, p < 0.001). CONCLUSION: Patients with a high risk for developing clinically relevant POPFs can be identified on the first postoperative day by determining serum amylase.

[Complications of minimally invasive pancreas resection for pancreatic neuroendocrine tumors]. / Komplikationen der minimal-invasiven Pankreasresektion bei neuroendokrinen Pankreastumoren.

BACKGROUND: Laparoscopic pancreas resections are performed with increasing frequency for pancreatic neuroendocrine tumors and other benign and malignant diseases. OBJECTIVES: This article describes the complications arising from laparoscopic resection of pancreatic neuroendocrine tumors and compares them to complications arising from similar open procedures. METHODS: Case series, reports, trials and meta-analyses were analyzed and the results are described and discussed. RESULTS: The types and the frequencies of complications are comparable for laparoscopic and open resection of pancreatic neuroendocrine tumors. The lack of the ability to perform an intraoperative examination of the pancreas to detect the tumors can be alleviated by laparoscopic ultrasound examination or in the case of tumors expressing somatostatin receptors by preoperative DOTATATE positron emission tomography (PET) computed tomography (CT) scanning. CONCLUSION: The complications arising from the resection of pancreatic neuroendocrine tumors do not justify a recommendation for a laparoscopic or open approach.

Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-TAG-72 single-chain Fvs.

One major constraint in the clinical application of murine monoclonal antibodies (MAbs) is the development of a human antimurine antibody response. The immunogenicity of MAbs can be minimized by replacing nonhuman regions with corresponding human sequences. The studies reported in our article were undertaken to analyze the immunoreactivity and the immunogenicity of the CC49 single-chain antibody fragments (scFvs): (i) an scFv construct comprised of mouse CC49 VL and VH (m/m scFv), (ii) a light chain shuffled scFv with human VL (Hum4 VL) and mouse CC49 VH (h/m scFv), and (iii) a humanized scFv assembled from Hum4 VL and CC49 VH complementary determining regions (CDRs) grafted onto a VH framework of MAb 21/28' CL (h/CDR scFv). The CC49 scFvs competed for an antigen binding site with CC49 IgG in a similar fashion in a competition radioimmunoassay and were able to inhibit the binding of CC49 IgG to the antigen completely. The immunogenicity of CC49 scFvs was tested using sera with antiidiotypic antibodies to MAb CC49 obtained from patients treated by CC49 IgG in clinical trials. All tested sera exhibited the highest reactivity to the m/m scFv. However, the sera demonstrated differential reactivities to h/CDR scFv and h/m scFv. Replacement of the mouse chain in h/m scFv and h/CDR scFv decreased or completely averted serum reactivity. Our studies compared for the first time the antigen binding and immunogenicity of different scFv constructs containing the mouse, CDR grafted or human variable chains. These results indicate that the humanized CC49 scFv is potentially an important agent for imaging and therapeutic applications with TAG-72-positive tumors.

Decreased androgen-responsive growth of human prostate cancer is associated with increased genetic alterations.

Genetic mechanisms involved in prostate tumor progression from the androgen-responsive to androgen-unresponsive stage are not well understood because of the tremendous heterogeneity in the tumor as well as the lack of suitable models. Using 165 repeat microsatellite DNA markers distributed equally over all of the chromosomes, we determined an association between genetic alterations and androgen-unresponsive growth in three stages of LNCaP cell model (C33: early, androgen-responsive; C51: mid, decreased androgen-responsive; and C81: late, androgen-unresponsive and increased tumorigenicity). Furthermore, the genetic alterations were confirmed in laser microdissected normal and cancerous tissues from 15 clinical samples of human prostatic adenocarcinomas using selected markers. A stem-line karyotype analysis exhibited an identical chromosomal pattern in both C33 and C81 stage cells except for the structural rearrangements of chromosome 3 and a gain of one copy of the Y chromosome in the androgen-unresponsive C81 stage cells. Nine microsatellite DNA markers on seven different chromosomes (1, 4, 5, 11, 17, 18, and 19) showed microsatellite instability (MSI) in both C51 and C81 stage cells. Additionally, 23 markers on 15 different chromosomes revealed MSI in C81 cells. Chromosomal regions demonstrating allelic loss (AL) include 1q, 3p, 5p, 8q, 9q, and 13q in C51 and C81 cells. In clinical human specimens, MSI was observed on chromosomes 1 (20%), 5 (23%), 17 (40%), and 19 (36%), whereas ALs were found 40% on chromosomal region 1q, 20% on 3p, 26% on 5p and 8q, and 33% on 13q. In conclusion, the LNCaP cell model showed the increasing number of genetic changes including MSI and AL. These increased genetic alterations may be associated with the development of the androgen-unresponsive phenotype.

Identification and sequencing of the Syrian Golden hamster (Mesocricetus auratus) p16(INK4a) and p15(INK4b) cDNAs and their homozygous gene deletion in cheek pouch and pancreatic tumor cells.

Previous studies have shown that the p16(INK4a) tumor suppressor gene is inactivated in up to 98% of human pancreatic cancer specimens and 83% of oral squamous cell carcinomas. Inactivation of the related p15(INK4b) gene has also been identified in a number of tumors and cell lines, however, its role as an independent tumor suppressor remains to be elucidated. Chemically-induced tumors in the Syrian Golden hamster (Mesocricetus auratus) have been shown to be excellent representative models for the comparative development and progression of a number of human malignancies. The purpose of this study was to determine the importance of the p16(INK4a) and p15(INK4b) genes in two experimental hamster models for human pancreatic and oral carcinogenesis. First, hamster p16(INK4a) and p15(INK4b) cDNAs were cloned and sequenced. The hamster p16(INK4a) cDNA open reading frame (ORF) shares 78%, 80%, and 81% identity with the human, mouse, and rat p16(INK4a) sequences, respectively. Similarly, the hamster p15(INK4b) cDNA ORF shares 82% and 89% sequence identity with human and mouse p15(INK4b), respectively. Second, a deletion analysis of hamster p16(INK4a) and p15(INK4b) genes was performed for several tumorigenic and non-tumorigenic hamster cell lines and revealed that both p16(INK4a) and p15(INK4b) were homozygously deleted in a cheek pouch carcinoma cell line (HCPC) and two pancreatic adenocarcinoma cell lines (KL5B, H2T), but not in tissue matched, non-tumorigenic cheek pouch (POT2) or pancreatic (KL5N) cell lines. These data strongly suggest that homozygous deletion of the p16(INK4a) and p15(INK4b) genes plays a prominent role in hamster pancreatic and oral tumorigenesis, as has been well established in correlative studies in comparable human tumors. Furthermore, this study supports the comparative importance of the hamster pancreatic and cheek pouch models of carcinogenesis in subsequent mechanistic-, therapeutic-, and preventive-based studies aimed at providing important translational data applicable to pancreatic adenocarcinoma and oral squamous cell carcinoma in humans.

Mucin antibodies - new tools in diagnosis and therapy of cancer.

Many cancer and diseased cells are distinguished from their normal counterparts by an altered expression of cell-surface epitopes. One family of molecules that show altered expression on tumor cells is mucins (MUC). Unlike normal tissue where MUC exists as heavily glycosylated form, the disease- or tumor-associated MUC molecules are underglycosylated. Such underglycosylation of the core protein in cancer tissues exposes new epitopes on the cell surface that are unique to cancer tissues. Several monoclonal antibodies (Mabs) have been generated against these normal and tumor-associated mucins. Enzymatic fragments of Mabs like F(ab')2 and Fab have shown improved clinical utility for diagnosis, imaging, and therapy of cancer. Genetic-engineering methods have been used to design antibody fragments exhibiting high functional affinity, good tumor localization, and rapid clearance from the blood stream thus minimizing radiation exposure to the normal tissues. Such recombinant fragments have shown encouraging results in preclinical studies using xenografted tumor bearing mice and present a whole new avenue for radioimmunotherapy and diagnosis of cancer.

Leukocytes, the Janus cells in inflammatory disease.

BACKGROUND: Leukocytes, also called white blood cells, can be categorized into three main groups, granulocytes, monocytes, and lymphocytes, which can be further classified into various subgroups. Lymphocytes are known to intervene in immune responses such as secreting cytokines, killing cells, or the production of antibodies. Monocytes/macrophages participate in chronic inflammation by synthesizing numerous mediators and eliminating various pathogens. DISCUSSION: The main type of granulocytes is the neutrophil, also called the polymorphmononuclear (PMN) leukocyte; these are usually not found in normal "healthy" tissue and are referred to as 'the first line of defense' against invading pathogens. However, besides the beneficial microbicidal activity of neutrophils, this cell type is also involved in the pathophysiology of organ damage in ischemia/reperfusion, trauma, sepsis, or organ transplantation. The exact role or function of leukocytes during inflammatory processes is far from being elucidated and can only be estimated from the enormous amount of literature on these cell types. The present review will focus mainly on PMN leukocytes and their ambiguous role in normal and inflamed tissue.