Maximilian Bockhorn

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.

Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: A consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)

BACKGROUND The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy. METHODS During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience. RESULTS The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Lns along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Lns. Consensus was reached on selectively removing suspected Lns outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive. CONCLUSION Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Lns outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies.

When to perform a pancreatoduodenectomy in the absence of positive histology? A consensus statement by the International Study Group of Pancreatic Surgery

BACKGROUND Pancreatoduodenectomy (PD) provides the best chance for cure in the treatment of patients with localized pancreatic head cancer. In patients with a suspected, clinically resectable pancreatic head malignancy, the need for histologic confirmation before proceeding with PD has not historically been required, but remains controversial. METHODS An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature and worked together to establish a consensus on when to perform a PD in the absence of positive histology. RESULTS The incidence of benign disease after PD for a presumed malignancy is 5-13%. Diagnosis by endoscopic cholangiopancreatography brushings and percutaneous fine-needle aspiration are highly specific, but poorly sensitive. Aspiration biopsy guided by endoscopic ultrasonography (EUS) has greater sensitivity, but it is highly operator dependent and increases expense. The incidence of autoimmune pancreatitis (AIP) in the benign resected specimens is 30-43%. EUS-guided Trucut biopsy, serum levels of immunoglobulin G4, and HISORt (Histology, Imaging, Serology, Other organ involvement, and Response to therapy) are used for diagnosis. If AIP is suspected but not confirmed, the response to a short course of steroids is helpful for diagnosis. CONCLUSION In the presence of a solid mass suspicious for malignancy, consensus was reached that biopsy proof is not required before proceeding with resection. Confirmation of malignancy, however, is mandatory for patients with borderline resectable disease to be treated with neoadjuvant therapy before exploration for resection. When a diagnosis of AIP is highly suspected, a biopsy is recommended, and a short course of steroid treatment should be considered if the biopsy does not reveal features suspicious for malignancy.

Is the Whipple procedure harmful for long-term outcome in treatment of chronic pancreatitis? 15-years follow-up comparing the outcome after pylorus-preserving pancreatoduodenectomy and Frey procedure in chronic pancreatitis.

Objective:The aim of this study was to report on 15-year long-term results of a randomized controlled trial comparing extended drainage procedure (Frey) and classical resectional procedure [pylorus-preserving pancreatoduodenectomy (PD)] in patients with chronic pancreatitis. Background:Chronic pancreatitis is a common inflammatory disease with a prevalence of 10 to 30 cases per 100,000 inhabitants. It is characterized by the progressive conversion of pancreatic parenchyma to fibrous tissue. Different surgical procedures are used in treatment of persistent pain. Methods:Sixty-four patients suffering from chronic pancreatitis with inflammatory mass in the pancreatic head were randomly assigned in 2 treatment groups (PD, n = 32) and (Frey, n = 32). The perioperative course of the randomized controlled trial and the 7 years follow-up have been previously published. All participating patients were contacted with a standardized, validated questionnaire (EORTC QLQ C30) to evaluate the long-term survival, quality-of-life pain, and exocrine and endocrine function. Results:In the 15-year long-term follow-up, the pain control was good and comparable between both groups, but the quality of life was better after Frey procedure in regard of the physical status [PD: 100 (0–100) vs PD: 60 (0–100) (P = 0.011)]. No significant differences in terms of the Pain Score were detected between both groups [PD: 7 (0–100) vs Frey 4 (0–100) P = 0.258]. Seven patients after Frey OP and 6 patients after PD were free of pain. Analyzing the postoperative overall survival, a higher long-term mortality was found after PD (53%) than that found after Frey procedure (30%) resulting in a longer mean survival (14.5 ± 0.8 vs 11.3 ± 0.8 years; P = 0.037). No correlation between endocrine or exocrine pancreatic function and pain was found, whereas continuous alcohol consumption was associated with poorer outcome regarding quality of life (P < 0.001) and pain score (P < 0.001). Conclusions:PD and Frey procedure provide good and permanent pain relief and improvement of the quality of life in long-term follow-up. In addition, a longer survival was found after the organ sparing resection. Together with better short-term results, the organ-sparing procedure seems to be favorable in treatment of chronic pancreatitis.

Options and limitations in applying the fistula classification by the International Study Group for Pancreatic Fistula.

Background: Because of its retrospective character, the classification system of the International Study Group of Pancreatic Fistula (ISGPF) lacks prognostic capacity regarding fistula-related complications. This study aimed to evaluate the options and limitations of the ISGPF classification system and to identify risk factors with respect to clinical decision making. Methods: Between 1992 and 2009, 1966 patients underwent surgery of the pancreas. All patient data were entered into a prospective clinical data management system. Results: After surgery, 276 patients (14%) developed postoperative pancreatic fistula (POPF). ISGPF type A fistula was seen in 69 patients (25%), type B in 110 (39.9%), and type C in 97 (34.1%). Solely due to their death, 16 patients had to be classified as type C fistula, even though they suffered only type A or B. Compared to genuine C fistulas, we were not able to detect any significant predictors, which may allow to distinguish the development in their further clinical course. The level of drainage amylase is of no use, whereas univariate analysis identified underlying disease, type of operation, and high levels of serum amylase or bilirubin on the day of onset of POPF to be prognostic parameters for reoperation. Multivariate analysis found elevated serum C-reactive protein to be an independent factor for increased in-hospital mortality. Conclusions: The ISGPF classification system has its limitations in clinical decision making, because it does not adequately describe a large subgroup of patients. To improve clinical decision making about management of patients, it is crucial that the ISGPF classification system is merged with newer clinical data.

Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

BackgroundPancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line.MethodsThe newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-ras, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp-/-/rag2-/- mice. Sensitivity towards chemotherapy was analysed by MTT assay.ResultsPaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp-/-/rag2-/- mice resulted in formation of primary tumors and spontaneous lung metastasis.ConclusionThe established PaCa 5061 cell line and its injection into pfp-/-/rag2-/- mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.

Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma.

Chemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The aim of this study was to evaluate the prognostic impact of the expression of the chemokine receptors CXCR4 and CXCR7 in patients with pancreatic adenocarcinoma (PAC).

CD161+ MAIT cells are severely reduced in peripheral blood and lymph nodes of HIV-infected individuals independently of disease progression

Mucosal-associated invariant T (MAIT) cells are characterized by the combined expression of the semi-invariant T cell receptor (TCR) Vα7.2, the lectin receptor CD161, as well as IL-18R, and play an important role in antibacterial host defense of the gut. The current study characterized CD161+ MAIT and CD161–TCRVα7.2+ T cell subsets within a large cohort of HIV patients with emphasis on patients with slow disease progression and elite controllers. Mononuclear cells from blood and lymph node samples as well as plasma from 63 patients and 26 healthy donors were analyzed by multicolor flow cytometry and ELISA for IL-18, sCD14 and sCD163. Additionally, MAIT cells were analyzed after in vitro stimulation with different cytokines and/or fixed E.coli. Reduced numbers of CD161+ MAIT cells during HIV infection were detectable in the blood and lymph nodes of all patient groups, including elite controllers. CD161+ MAIT cell numbers did not recover even after successful antiretroviral treatment. The loss of CD161+ MAIT cells was correlated with higher levels of MAIT cell activation; an increased frequency of the CD161–TCRVα7.2+T cell subset in HIV infection was observed. In vitro stimulation of MAIT cells with IL-18 and IL-12, IL-7 and fixed E.coli also resulted in a rapid and additive reduction of the MAIT cell frequency defined by CD161, IL-18R and CCR6. In summary, the irreversible reduction of the CD161+ MAIT cell subset seems to be an early event in HIV infection that is independent of later stages of the disease. This loss appears to be at least partially due to the distinctive vulnerability of MAIT cells to the pronounced stimulation by microbial products and cytokines during HIV-infection.

Activated leukocyte cell adhesion molecule (CD166)--its prognostic power for colorectal cancer patients.

BACKGROUND The activated leukocyte cell adhesion molecule (ALCAM, CD166) has been reported to be involved in tumorigenesis of colorectal cancer (CRC) and to function as a cancer stem cell marker. Controversial data exist regarding the prognostic power of ALCAM expression in CRC. Here, we evaluate the expression of ALCAM in a cohort of CRC patients and its usage as a prognostic marker for survival. MATERIALS AND METHODS Tissue specimens from 299 patients with CRC treated between 1993 and 2006 were analyzed via ALCAM immunohistochemistry (clone MOG/07) using a tissue microarray. Results were correlated with clinical, histopathological, and patient survival data (Chi-square test, Kaplan-Meier analysis, and log-rank test, respectively). Multivariate analysis also was performed (Cox regression). RESULTS ALCAM is expressed in most primary (76%) and secondary (62%) CRC lesions (P = 0.014). Immunohistochemistry revealed an inverse association with tumor grading (P = 0.002) but not with any other clinical or histopathological data. Kaplan-Meier survival analysis revealed a significant overall survival benefit in the group of ALCAM-positive patients (P = 0.019). Multivariate analysis showed that ALCAM is an independent positive prognostic marker for overall survival (P = 0.023). CONCLUSIONS ALCAM expression is a positive prognostic marker for overall survival of CRC patients, and its detection might help to optimize the existing prognostic staging system. Elevated expression in higher differentiated tumors might indicate a potential role in the early steps of tumorigenesis, and its loss might be associated with reduced cellular adhesion, resulting in a higher metastatic potential of the tumor. Further studies must be conducted investigating these hypotheses.

ALCAM (CD166) expression and serum levels are markers for poor survival of esophageal cancer patients

The expression of the activated leukocyte cell adhesion molecule (ALCAM and CD166) is increased in various types of cancer. We aimed to evaluate its role as a prognostic marker for esophageal cancer (EC). We retrospectively analyzed ALCAM expression in 299 primary lesions, 147 lymph node and 46 distant metastases from EC patients, on a tissue microarray using immunohistochemistry. Bone marrow samples from representative cancer patients (n = 16), taken before primary surgery, were stained by double‐immunofluorescence for ALCAM and cytokeratins (CK). Blood serum samples from 236 cancer patients and 127 controls were analyzed for serum ALCAM (s‐ALCAM) by ELISA. The immunohistochemical analysis showed increased ALCAM expression in the majority of lesions (primary tumor 71%, lymph node 76% and distant metastases 80%). ALCAM expression was not associated with histopathological parameters except for tumor grading (p = 0.015). ALCAM‐positive patients had significantly worse recurrence‐free and overall survival (OS; p = 0.002). Disseminated tumor cells (DTC) in bone marrow showed two phenotypes, ALCAM+/CK+ (36%) and ALCAM‐/CK+ (64%). Multivariate analysis revealed that ALCAM expression and elevated s‐ALCAM serum values are powerful prognostic variables for OS in patients with EC (hazard ratio [HR] 3.987, 95% confidence interval [95%CI] 1.906–8.340, p < 0.001 and HR 1.915, 95%CI 1.021–3.592, p = 0.043). The results of our study provide preliminary evidence for the potential clinical utility of ALCAM as a prognostic biomarker for EC, which might be a basis for future clinical application. In addition, ALCAM expression in a subset of DTC of the bone marrow indicates a potential function in the metastatic cascade of EC.