[Rare pancreatic tumors]. / Seltene Pankreastumoren.

Beyond pancreatic ductal adenocarcinoma, which is by far the most frequent pancreatic neoplasm, a great variety of tumors occur in the pancreas. They include solid and cystic masses and epithelial and nonepithelial neoplasms, and they show a great diversity in their biological behavior, ranging from benign tumors to highly aggressive neoplasms. As examples of rare pancreatic tumors, clinical, morphological, and molecular aspects of acinar cell carcinoma, pancreatoblastoma, solid pseudopapillary neoplasm, and serous cystic neoplasms are presented and discussed.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail.

BACKGROUND: The definition of resection margin (R) status in pancreatic cancer is under debate. Although a margin of at least 1 mm is an independent predictor of survival after resection for pancreatic head cancer, its relevance to pancreatic body and tail cancers remains unclear. This study aimed to validate R status based on a 1-mm tumour-free margin as a prognostic factor for resected adenocarcinoma involving the pancreatic body and tail. METHODS: Patients who underwent distal or total pancreatectomy for adenocarcinomas of the pancreatic body and tail between January 2006 and December 2014 were identified from a prospective database. Resection margins were evaluated using a predefined cut-off of 1 mm. Rates of R0, R1 with invasion within 1 mm of the margin (R1 less than 1 mm), and R1 with direct invasion of the resection margin (R1 direct) were determined, and overall survival in each group assessed by Kaplan-Meier analysis. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival. RESULTS: R0 resection was achieved in 107 (23·5 per cent) and R1 in 348 (76·5 per cent) of 455 patients. Among R1 resections, invasion within 1 mm of the margin was found in 104 (22·9 per cent) and direct invasion in 244 (53·6 per cent). The R0 rate was 28·9 per cent after distal and 18·6 per cent after total pancreatectomy. In the total cohort, median survival times for patients with R0, R1 (less than 1 mm) and R1 (direct) status were 62·4, 24·6 and 17·2 months respectively, with 5-year survival rates of 52·6, 16·8 and 13·0 per cent (P < 0·001). In patients who received adjuvant chemotherapy, respective median survival times were 68·6, 32·8 and 21·4 months, with 5-year survival rates of 56, 22 and 16·0 per cent (P < 0·001). In multivariable analysis, R status was independently associated with survival. CONCLUSION: A cut-off of at least 1 mm for evaluation of resection margins is an independent determinant of survival after resection of adenocarcinomas of the pancreatic body and tail.

Isotensor Dibaryon in the pp→ppπ

Exclusive measurements of the quasifree pp→ppπ^{+}π^{-} reaction have been carried out at WASA@COSY by means of pd collisions at T_{p}=1.2 GeV. Total and differential cross sections have been extracted covering the energy region T_{p}=1.08-1.36 GeV, which is the region of N^{*}(1440) and Δ(1232)Δ(1232) resonance excitations. Calculations describing these excitations by t-channel meson exchange are at variance with the measured differential cross sections and underpredict substantially the experimental total cross section. An isotensor ΔN dibaryon resonance with I(J^{P})=2(1^{+}) produced associatedly with a pion is able to overcome these deficiencies.

Spin Dependence of η Meson Production in Proton-Proton Collisions Close to Threshold.

Taking advantage of the high acceptance and axial symmetry of the WASA-at-COSY detector, and the high polarization degree of the proton beam of COSY, the reaction p[over →]p→ppη has been measured close to threshold to explore the analyzing power A_{y}. The angular distribution of A_{y} is determined with the precision improved by more than 1 order of magnitude with respect to previous results, allowing a first accurate comparison with theoretical predictions. The determined analyzing power is consistent with zero for an excess energy of Q=15 MeV, signaling s-wave production with no evidence for higher partial waves. At Q=72 MeV the data reveal strong interference of Ps and Pp partial waves and cancellation of (Pp)^{2} and Ss^{*}Sd contributions. These results rule out the presently available theoretical predictions for the production mechanism of the η meson.

Image-defined Risk Factors Correlate with Surgical Radicality and Local Recurrence in Patients with Neuroblastoma.

BACKGROUND: Neuroblastoma is the second most common solid pediatric tumor and the most common cancer to be detected in children younger than 12 months of age. To date, 2 different staging systems describe the extent of the disease: the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS). The INRGSS-system is characterized by the presence or absence of so called image-defined risk factors (IDRFs), which are described as surgical risk factors. We hypothesized that IDRFs correlate with surgical complications, surgical radicality, local recurrence and overall survival (OS). PATIENTS AND METHODS: Between 2003 and 2010, 102 patients had neuroblastoma surgery performed in our department. We analyzed medical records for IDRF-status and above named data. RESULTS: 16 patients were IDRF-negative, whereas 86 patients showed one or more IDRF. Intra- or postoperative complications have been reported in 21 patients (21%). 19 of them showed one or more IDRF and 2 patients were IDRF-negative (p=n.s.). Patients who suffered from intra- or postoperative complications demonstrated a decreased OS (p=0.011). Statistical analysis revealed an inverse correlation between the extent of macroscopical removal and IDRF-status (p=0.001). Furthermore, the number of IDRFs were associated with a decreased likelihood of radical tumor resection (p<0.001). 19 patients had local recurrence; all of them were IDRF-positive (p=0.037). CONCLUSIONS: Pediatric surgeons should consider IDRFs as a useful tool for risk assessment and therefore planning for neuroblastoma surgery.

[Pancreatic acinar neoplasms : Comparative molecular characterization]. / Azinäre Pankreasneoplasien : Vergleichende molekulare Charakterisierung.

Pancreatic acinar cell carcinomas are biologically aggressive neoplasms for which treatment options are very limited. The molecular mechanisms of tumor initiation and progression are largely not understood and precursor lesions have not yet been identified. In this study, pancreatic acinar cell carcinomas were cytogenetically characterized as well as by molecular and immunohistochemical analyses. Corresponding investigations were carried out on pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms augmented by functional analyses. We show that pancreatic acinar cell carcinomas display a microsatellite stable, chromosomal unstable genotype, characterized by recurrent chromosomal imbalances that clearly discriminate them from pancreatic ductal adenocarcinomas and neuroendocrine neoplasms. Based on findings obtained from comparative genomic hybridization, candidate genes could be identified, such as deleted in colorectal cancer (DCC) and c-MYC. Furthermore, several therapeutic targets were identified in acinar cell carcinomas and other pancreatic neoplasms, including epidermal growth factor receptor (EGFR), L1 cell adhesion molecule (L1CAM) and heat shock protein 90 (HSP90). Moreover, L1CAM was shown to play a significant role in the tumorigenesis of pancreatic ductal adenocarcinoma. Functional analyses in cell lines derived from pancreatic neuroendocrine neoplasms revealed promising anti-tumorigenic effects using EGFR and HSP90 inhibitors affecting the cell cycle and in the case of HSP90, regulating several other oncogenes. Finally, based on mutational analyses of mitochondrial DNA, molecular evidence is provided that acinar cell cystadenomas (or better cystic acinar transformation) represent non-clonal lesions, suggesting an inflammatory reactive non-neoplastic nature.

Diagnosis and treatment of autoimmune pancreatitis types 1 and 2.

BACKGROUND: Autoimmune pancreatitis (AIP) is characterized by diffuse or focal swelling of the pancreas. AIP has been divided into types 1 and 2. The aim of the study was to evaluate and compare the clinicopathological characteristics, therapy and outcome of patients with AIP. METHODS: The medical records of patients diagnosed with AIP between January 2003 and July 2011 were reviewed. Characteristics of patients with AIP types 1 and 2 were compared with those of patients with pancreatic ductal adenocarcinoma (PDAC). RESULTS: AIP was classified as type 1 in 40 patients and type 2 in 32 according to the HISORt (Histology, Imaging, Serology, Other organ involvement, Response to therapy) criteria. Patients with histologically confirmed AIP type 2 were younger than those with type 1 (P = 0·005). Some 30 of 32 patients with AIP type 2 were found to have a localized tumour-like pancreatic mass and underwent pancreatectomy, compared with only 16 of 40 with type 1 (P < 0·001). Three of 25 patients with AIP type 2 presented with raised serum levels of IgG4 compared with 21 of 38 with type 1 (P < 0·001). There was no difference in symptoms and involvement of other organs between AIP types 1 and 2. Presentation with weight loss was more common among patients with PDAC than those with AIP, but there was no difference in pain or jaundice between the groups. Raised serum carbohydrate antigen 19-9 levels were more prevalent in patients with PDAC. CONCLUSION: Patients with AIP type 2 frequently present with abdominal pain and a tumour-like mass. Differentiating AIP from PDAC is difficult, so making the clinical decision regarding operative versus conservative management is challenging.

Outcome of surgery for pancreatic neuroendocrine neoplasms.

BACKGROUND: The incidence of pancreatic neuroendocrine neoplasms (pNEN) is increasing. This study aimed to evaluate predictors of overall survival and the indication for surgery. METHODS: Data collected between October 2001 and December 2012 were analysed. Histological grading and staging was based on the classifications of the World Health Organization, the International Union Against Cancer and the European Neuroendocrine Tumour Society. RESULTS: Some 310 patients (150 female, 48·4 per cent) underwent surgical resection. The final survival analysis included 291 patients. Five-year overall survival differed according to tumour grade (G): 91·0 per cent among 156 patients with pancreatic neuroendocrine tumours (pNET) G1, 70·8 per cent in 111 patients with pNET G2, and 20 per cent in 24 patients with pancreatic neuroendocrine carcinomas (pNEC) G3 (P < 0·001). Tumours graded G3 (hazard ratio (HR) 6·96, 95 per cent confidence interval 3·67 to 13·21), the presence of distant metastasis (HR 2·41, 1·32 to 4·42) and lymph node metastasis (HR 2·10, 1·07 to 4·16) were independent predictors of worse survival (P < 0·001, P = 0·004 and P = 0·032 respectively). Eight of 61 asymptomatic patients with pNEN smaller than 2 cm had tumours graded G2 or G3, and six of 51 patients had lymph node metastasis. Among patients with pNEC G3, the presence of distant metastasis had a significant impact on the 5-year overall survival rate: 0 per cent versus 43 per cent in those without distant metastasis (P = 0·036). CONCLUSION: Neuroendocrine tumours graded G3, lymph node and distant metastasis are independent predictors of worse overall survival in patients with pNEN.

[Integrated care for depressive disorders]. / Integrierte Versorgung bei depressiven Störungen.

BACKGROUND: According to the special report of the Advisory Council on the Assessment of Developments in the Health Care Sector, the termination of contracts on integrated care (IC) in accordance with §140a-d of the Social Act V (SGB V) was mostly due to high costs and volume expansion by services providers (physicians). However, there is still limited knowledge about the medical and economic impact of projects of integrated care, as such projects were on the one hand not primarily designed with a scientific evaluation in mind and on the other hand health insurance agencies usually do not evaluate data for scientific reasons. AIM: In Aachen the IC project "Integrated Care in Mental Health" ran between 2006 and 2011. During that time a total of 3,408 patients with depressive disorders were treated across institutional and trans-sectoral borders according to the national clinical practice guidelines and S3 guidelines on unipolar depression. This study was initiated in an attempt to describe and evaluate the clinical success of treatment. RESULTS: This study evaluated the outcome of the clinical treatment provided but due to the lack of available data on the economic impact of the project, the study contribution is limited to non-economic aspects. By comparing various clinical parameters it could be shown that scores in certain patient-reported clinical scales, such as the Hamilton rating scale for depression, and the WHO-5 well-being index as well as on the clinician-reported clinical global impression (CGI) improved in a statistically significant manner over time compared to initial assessments. Due to the lack of data on an appropriate comparison cohort of patients any comparative statements concerning the superiority of the treatment of depressive disorders outside an integrated care project remains hypothetical and preliminary. CONCLUSION: This study revealed the limitations of a naturalistic study in an IC setting and showed that without adequate funding a satisfactory evaluation that fulfills scientific criteria seems to be impossible.

Synergistic treatment of infected burn wound utilizing maggot debridement and acellular fish skin grafting - a case report.

Here we report about a patient with a full thickness burn injury of the left lower extremity with approximately 8% of total body surface area affected. Initial therapy consisted of necrosectomy and wound coverage with split thickness graft. The patient developed a wound infection with Pseudomonas aeruginosa, resulting in the failure of the skin graft to achieve complete healing. The case was further complicated by the patient's concurrent presentation of anemia, characterized by a hematocrit level of 19.8% on 11th day after admission. Additionally, the patient refused acceptance of any blood transfusion, adding a significant layer of complexity to the management strategy. In summary, the patient's critical state required an immediate intervention. Due to the contraindication for a further surgical debridement and autograft, we changed the treatment strategy to a conservative approach. First, the wound was debrided employing maggot therapy 17 days after admission. Subsequently, free soft tissue coverage was accomplished using decellularized fish skin dressings on 45th day. This approach yielded satisfactory wound closure. Following an approximately two-month hospitalization period (52nd day after admission), the patient was discharged with a stable wound condition, nearing complete healing.

Intensity modulated radiotherapy as neoadjuvant chemoradiation for the treatment of patients with locally advanced pancreatic cancer. Outcome analysis and comparison with a 3D-treated patient cohort.

BACKGROUND: To evaluate outcome after intensity modulated radiotherapy (IMRT) compared to 3D conformal radiotherapy (3D-RT) as neoadjuvant treatment in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: In total, 57 patients with LAPC were treated with IMRT and chemotherapy. A median total dose of 45 Gy to the PTV_baseplan and 54 Gy to the PTV_boost in single doses of 1.8 Gy for the PTV_baseplan and median single doses of 2.2 Gy in the PTV_boost were applied. Outcomes were evaluated and compared to a large cohort of patients treated with 3D-RT. RESULTS: Overall treatment was well tolerated in all patients and IMRT could be completed without interruptions. Median overall survival was 11 months (range 5-37.5 months). Actuarial overall survival at 12 and 24 months was 36 % and 8 %, respectively. A significant impact on overall survival could only be observed for a decrease in CA 19-9 during treatment, patients with less pre-treatment CA 19-9 than the median, as well as weight loss during treatment. Local progression-free survival was 79 % after 6 months, 39 % after 12 months, and 13 % after 24 months. No factors significantly influencing local progression-free survival could be identified. There was no difference in overall and progression-free survival between 3D-RT and IMRT. Secondary resectability was similar in both groups (26 % vs. 28 %). Toxicity was comparable and consisted mainly of hematological toxicity due to chemotherapy. CONCLUSION: IMRT leads to a comparable outcome compared to 3D-RT in patients with LAPC. In the future, the improved dose distribution, as well as advances in image-guided radiotherapy (IGRT) techniques, may improve the use of IMRT in local dose escalation strategies to potentially improve outcome.

[Gastroenteropancreatic neuroendocrine neoplasms. Role of biopsies]. / Neuroendokrine Neoplasien der Bauchspeicheldrüse und des Gastrointestinaltrakts. Was leistet die Biopsie?

Neuroendocrine neoplasms of the pancreas and the gastrointestinal tract are heterogeneous regarding etiology (e.g. sporadic or hereditary), histomorphology, hormone expression, hormone-related functional activity and especially the malignant potential. In neuroendocrine neoplasms the biopsy-based diagnosis plays an important role for the clinical management of patients. The diagnosis most importantly relies on the differentiation (e.g. organoid versus diffuse growth patterns) and the grading of tumors. The latter is based on the proliferation activity as determined by Ki-67 immunostaining and mitotic count and results in the current tumor classification into neuroendocrine tumors G1, neuroendocrine tumors G2 or neuroendocrine carcinomas G3. Occasionally, tumors may show mixed differentiation containing a non-neuroendocrine cancer component. The neuroendocrine markers synaptophysin and chromogranin A are recommended for the immunohistochemical confirmation of the diagnosis. Furthermore, biopsy material can be used to investigate the expression of therapy-related markers, such as somatostatin receptor-2A. Moreover, if needed, the expression of transcription factors and hormones can be determined to obtain information on the possible site of origin of metastatic neuroendocrine neoplasms or to determine the syndrome-inducing hormone in functionally active neuroendocrine neoplasms. Finally, using the stomach as an example, biopsies may also be successfully used to investigate neuroendocrine precursor lesions which may harbor prognostic significance.

Long-term in vitro culture of hamster pancreatic ß-cells and induction of adenocarcinoma by treatment with N-nitrosobis(2-oxopropyl)amine.

OBJECTIVES: Earlier studies indicated that hamster pancreatic ductal adenocarcinoma not only derives from ductal/ductular structures but also from cells within the islet. So far unidentified cells within the islet are responsive to the carcinogenic effect of N-nitrosobis (2-oxopropyl) amine (BOP) forming poorly differentiated ductal adenocarcinoma. However, studies indicated a major role of ß-cells during carcinogenesis. To find out, if ß-cells are the primary target cells of BOP and if they are capable to form ductal adenocarcinoma after malignant transformation, we established a long-term culture of undifferentiated cells deriving from isolated ß-cells and treated them with BOP. METHODS: Langerhans' islets from pancreata of Syrian golden hamsters were isolated and dispersed into single cells by dispase digestion. Cells were labeled with a highly specific ß-cell surface antibody (K14D10) and these K14D10+ cells were extracted from the suspension by paramagnetic Dynabeads. Cells were cultured in vitro and treated with BOP. Untreated cells served as control. RESULTS: K14D10+ cells formed a monolayer and produced insulin over a period of 28 days in culture. However, with time in culture they became undifferentiated with a higher proliferation rate and after about 60 days in culture BOP treated cells showed anchorage independent growth. These cells autotransplanted s.c. formed a well-differentiated ductal adenocarcinoma. CONCLUSIONS: Pancreatic ß-cells are the primary target of BOP without necessarily being embedded in the compound of the Langerhans' islet. With time in culture, they give rise to undifferentiated cells and after malignant transformation they are able to form ductal adenocarcinoma.

[Frozen section diagnostics in visceral surgery. Liver, bile ducts and pancreas]. / Schnellschnittdiagnostik in der Viszeralchirurgie : Leber, Gallenwege und Pankreas.

Intraoperative examination of specimens from the liver, bile ducts, gallbladder and pancreas are widely used in routine fresh frozen section diagnostics. The main clinical requests focus on diagnosis of masses of unknown dignity as well as evaluation of surgical margins in oncological resections. In addition, assessment of organ quality for transplantation is also often required.

Expression of HOXC8 is inversely related to the progression and metastasis of pancreatic ductal adenocarcinoma.

BACKGROUND: The transcription factor HOXC8 regulates many genes involved in tumour progression. This study was to investigate the role of HOXC8 in pancreatic ductal adenocarcinoma (PDAC) growth and metastasis. METHODS: The Hoxc8 expression was determined in 15 PDAC cell lines and human specimens by RT-polymerase chain reaction and/or immunohistochemistry. The effects of HOXC8 silencing by RNA interference were investigated by functional tests. RESULTS: The Hoxc8 mRNA expression in PDAC cell lines was negatively related to their growth in vivo. Except for Suit2-007 cells, only those with low Hoxc8 mRNA expression grew in nude rats. Successful down-regulation of HOXC8 expression caused increased proliferation, migration (P ≤ 0.05) and colony formation (P ≤ 0.05) in Suit2-007, Panc-1 and MIA PaCa-2 PDAC cells, respectively. The Hoxc8 mRNA levels in diseased human pancreas tissues were significantly increased over normal in PDAC and autoimmune chronic pancreatitis specimens (P<0.01, respectively), but negatively related to tumour stage (P=0.09). In primary and metastatic tumour samples, immunohistochemical staining for HOXC8 was stronger in surrounding than in neoplastic tissues. Furthermore, grading of primary carcinomas was negatively associated with HOXC8 staining (P=0.03). Liver metastases showed the lowest HOXC8 expression of all neoplastic lesions. CONCLUSION: These data indicate that HOXC8 expression is inversely related to PDAC progression and metastasis.

Abashian-Booth-Crowe effect in basic double-pionic fusion: a new resonance?

We report on an exclusive and kinematically complete high-statistics measurement of the basic double-pionic fusion reaction pn→dπ(0)π(0) over the full energy region of the ABC effect, a pronounced low-mass enhancement in the ππ-invariant mass spectrum. The measurements, which cover also the transition region to the conventional t-channel ΔΔ process, were performed with the upgraded WASA detector setup at COSY. The data reveal the Abashian-Booth-Crowe effect to be uniquely correlated with a Lorentzian energy dependence in the integral cross section. The observables are consistent with a narrow resonance with m=2.37 GeV, Γ≈70 MeV and I(J(P))=0(3(+)) in both pn and ΔΔ systems. Necessary further tests of the resonance interpretation are discussed.

Prophylactic glycine administration attenuates pancreatic damage and inflammation in experimental acute pancreatitis.

BACKGROUND/AIMS: Acute pancreatitis (AP) is characterized by premature zymogen activation, systemic inflammatory response resulting in inflammatory infiltrates, sustained intracellular calcium, neurogenic inflammation and pain. The inhibitory neurotransmitter and cytoprotective amino acid glycine exerts a direct inhibitory effect on inflammatory cells, inhibits calcium influx and neuronal activation and therefore represents a putative therapeutic agent in AP. METHODS: To explore the impact of glycine, mild AP was induced in rats by supramaximal cerulein stimulation (10 µg/kg BW/h) and severe AP by retrograde injection of sodium taurocholate solution (3%) into the common biliopancreatic duct. 100/300 mmol glycine was administered intravenously before induction of AP. To elucidate the effect of glycine on AP, we determined pathomorphology, pancreatic cytokines as well as proteases, serum lipase and amylase, pancreatic and lung MPO activity and pain sensation. RESULTS: Glycine administration resulted in a noticeable improvement of pathomorphological alterations in AP, such as a reduction of necrosis, inflammatory infiltrates and cytoplasmic vacuoles in cerulein pancreatitis. In taurocholate pancreatitis, glycine additionally diminished pancreatic cytokines and MPO activity, as well as serum lipase and amylase levels. CONCLUSIONS: Glycine reduced the severity of mild and much more of severe AP by attenuating the intrapancreatic and systemic inflammatory response. Therefore, glycine seems to be a promising tool for prophylactic treatment of AP. and IAP.