Independent Validation and Assay Standardization of Improved Metabolic Biomarker Signature to Differentiate Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature. METHODS: We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography-tandem mass spectrometry platform. A machine learning-aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance. RESULTS: The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-9 >2 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-9 <37 U/mL, 39.7%, 94.1%, and 76.3%, respectively. CONCLUSIONS: The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.

Identification and validation of a multivariable prediction model based on blood plasma and serum metabolomics for the distinction of chronic pancreatitis subjects from non-pancreas disease control subjects.

OBJECTIVE: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to organ dysfunction, chronic pain, an increased risk for pancreatic cancer and considerable morbidity. Due to a lack of specific biomarkers, diagnosis is based on symptoms and specific but insensitive imaging features, preventing an early diagnosis and appropriate management. DESIGN: We conducted a type 3 study for multivariable prediction for individual prognosis according to the TRIPOD guidelines. A signature to distinguish CP from controls (n=160) was identified using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry on ethylenediaminetetraacetic acid (EDTA)-plasma and validated in independent cohorts. RESULTS: A Naive Bayes algorithm identified eight metabolites of six ontology classes. After algorithm training and computation of optimal cut-offs, classification according to the metabolic signature detected CP with an area under the curve (AUC) of 0.85 ((95% CI 0.79 to 0.91). External validation in two independent cohorts (total n=502) resulted in similar accuracy for detection of CP compared with non-pancreatic controls in EDTA-plasma (AUC 0.85 (95% CI 0.81 to 0.89)) and serum (AUC 0.87 (95% CI 0.81 to 0.95)). CONCLUSIONS: This is the first study that identifies and independently validates a metabolomic signature in plasma and serum for the diagnosis of CP in large, prospective cohorts. The results could provide the basis for the development of the first routine laboratory test for CP.

Induction Chemotherapy for Primarily Unresectable Locally Advanced Pancreatic Adenocarcinoma-Who Will Benefit from a Secondary Resection?

Background and Objectives: An increasing number of patients (pts) with locally advanced pancreatic cancer (LAPC) are treated with an intensive neoadjuvant therapy to obtain a secondary curative resection. Only a certain number of patients benefit from this intention. The aim of this investigation was to identify prognostic factors which may predict a benefit for secondary resection. Materials and Methods: Survival time and clinicopathological data of pts with pancreatic cancer were prospective and consecutively collected in our Comprehensive Cancer Center Database. For this investigation, we screened for pts with primarily unresectable pancreatic cancer who underwent a secondary resection after receiving induction therapy in the time between March 2017 and May 2019. Results: 40 pts had a sufficient database to carry out a reliable analysis. The carbohydrate-antigen 19-9 (CA 19-9) level of the pts treated with induction therapy decreased by 44.7% from 4358.3 U/mL to 138.5 U/mL (p = 0.001). The local cancer extension was significantly reduced (p < 0.001), and the Eastern Cooperative Oncology Group (ECOG) performance status was lowered (p = 0.03). The median overall survival (mOS) was 20 months (95% CI: 17.2-22.9). Pts who showed a normal CA 19-9 level (<37 U/mL) at diagnosis and after neoadjuvant therapy or had a Body Mass Index (BMI) below 25 kg/m2 after chemotherapy had a significant prolonged overall survival (29 vs. 19 months, p = 0.02; 26 vs. 18 months, p = 0.04; 15 vs. 24 months, p = 0.01). Pts who still presented elevated CA 19-9 levels >400 U/mL after induction therapy did not profit from a secondary resection (24 vs. 7 months, p < 0.001). Nodal negativity as well as the performance of an adjuvant therapy lead to better mOS (25 vs. 15 months, p = 0.003; 10 vs. 25 months, p < 0.001). Conclusion: The pts in our investigation had different benefits from the multimodal treatment. We identified the CA 19-9 level at time of diagnosis and after neoadjuvant therapy as well as the preoperative BMI as predictive factors for overall survival. Furthermore, diagnostics of presurgical nodal status should gain more importance as nodal negativity is associated with better outcome.

Postoperative acute necrotizing pancreatitis of the pancreatic remnant (POANP): a new definition of severe pancreatitis following pancreaticoduodenectomy.

BACKGROUND: Recent studies have suggested acute pancreatitis as a separate pancreatic-specific complication following pancreaticoduodenectomy. However, data on necrotizing pancreatitis of the pancreatic remnant is limited. This study aimed to evaluate parameters of patients undergoing completion pancreatectomy (CP) after initial pancreaticoduodenectomy (PD) and compare those with or without necrosis of the pancreatic remanent. METHODS: Patients who underwent CP following PD between January 2005 and December 2017 were identified from a prospectively collected database. Perioperative parameters were recorded, and patients were divided into those with or without histological evidence of necrosis of the pancreatic remnant. RESULTS: Postoperative acute necrotizing pancreatitis (POANP) was histologically detected in 33 (41%) of 79 patients after CP. Serum CRP levels on POD 2 and the day of revision were significantly higher in the POANP group (p < 0.001 for each). POANP was reflected by higher APACHE II and SOFA scores after PD (P < 0.001 for each). Although patients with POANP had an earlier revision, length of ICU and total hospital stay was prolonged (p < 0.001 for each). POANP was associated with more major complications (Clavien-Dindo ≥ 3) and more often necessitated reoperations within 30 days (p < 0.001 for each). CONCLUSION: Patients requiring CP following PD for POANP have an increased risk of major complications, and longer hospital stay. CRP levels, APACHE II and SOFA score, seem to correlate with the severity and might predict POANP. Universally accepted definitions with a clinically validated grading system of severity for POAP and POANP are needed to facilitate appropriate treatment strategies and enable comparison of future studies.

EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video).

BACKGROUND AND AIMS: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce. METHODS: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis. RESULTS: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10-4). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10-14). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10-9). CONCLUSIONS: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.

Analysis of outcomes and predictors of long-term survival following resection for retroperitoneal sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPS) include a heterogeneous group of rare malignant tumours, and various treatment algorithms are still controversially discussed until today. The present study aimed to examine postoperative and long-term outcomes after resection of primary RPS. PATIENTS AND METHODS: Clinicopathological data of patients who underwent resection of primary RPS between 2005 and 2015 were assessed, and predictors for overall survival (OS) and disease-free survival (DFS) were identified. RESULTS: Sixty-one patients underwent resection for primary RPS. Postoperative morbidity and mortality rates were 31 and 3%, respectively. After a median follow-up time of 74 months, 5-year OS and DFS rates were 58 and 34%, respectively. Histologic high grade (5-year OS: G1: 92% vs. G2: 54% vs. G3: 43%, P = 0.030) was significantly associated with diminished OS in univariate and multivariate analyses. When assessing DFS, histologic high grade (5-year DFS: G1: 63% vs. G2: 24% vs. G3: 22%, P = 0.013), positive surgical resection margins (5-year DFS: R0: 53% vs. R1: 10% vs. R2: 0%, P = 0.014), and vascular involvement (5-year DFS: yes: 33% vs no: 39%, P = 0.001), were significantly associated with inferior DFS in univariate and multivariate analyses. CONCLUSIONS: High-grade tumours indicated poor OS, while vascular involvement, positive surgical resection margins, and histologic grade are the most important predictors of DFS. Although multimodal treatment strategies are progressively established, surgical resection remains the mainstay in the majority of patients with RPS, even in cases with vascular involvement.

Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma.

BACKGROUND: The prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial. METHODS: Haematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm2 field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm2). RESULTS: Tumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well. CONCLUSIONS: Tumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.

Prognostic Accuracy of the Seventh Edition of the TNM Classification Compared with the Fifth and Sixth Edition for Distal Cholangiocarcinoma.

BACKGROUND: The TNM classification for distal cholangiocarcinoma was first introduced in the 7th edition, which was published in 2009; however, prognostic accuracy compared with the 5th and 6th editions has not yet been evaluated and requires validation. METHODS: A prospective histological database of patients with distal bile duct cancer was analyzed, and histological parameters and stage of the distal cholangiocarcinoma were assessed according to the 5th, 6th, and 7th editions of the TNM classification. RESULTS: Between 1994 and 2012, a total of 516 patients underwent pancreatic head resection, of whom 59 patients (11.4 %) experienced histologically confirmed distal cholangiocarcinoma. The median overall survival time was 22.2 months (13.1-31.4). Tumor recurrence occurred in 23 patients after a median disease-free survival time of 14.1 months. The 7th edition showed a monotonicity of all gradients, with a stepwise increase of mortality related to a stepwise increase of tumor stage (log-rank test; p < 0.05) demonstrating best discrimination of all tested editions [area under the receiver operating characteristic curve (AUC) 0.82; 95 % CI 0.70-0.95; p = 0.012]. The discrimination rate was low for the 5th (AUC 0.67; 95 % CI 0.42-0.91; p = 0.18) and 6th editions (AUC 0.70; 95 % CI 0.47-0.93; p = 0.11), while the log-rank test did not reach statistical significance. On multivariate analysis, lymph node involvement and positive resection margins were positive and independent predictors of inferior survival (p < 0.05). CONCLUSIONS: The 7th edition of the TNM classification was favorable in terms of predicting outcome, and generated a monotonicity of all grades. Strikingly, the 7th edition, but not the 5th and 6th editions, was of prognostic significance to predict outcome.

Predictive factors for extrahepatic recurrence of hepatocellular carcinoma following liver transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) in patients treated with liver transplantation (LT) is associated with diminished survival. Particularly, extrahepatic localization of HCC recurrence contributes to poor prognosis. PATIENTS AND METHODS: Clinicopathological data of patients who underwent LT for HCC between 1989 and 2010 in a high-volume transplant center were retrospectively evaluated, and predictors of extrahepatic recurrence were identified. RESULTS: Three hundred and sixty-four patients underwent LT for HCC. After a median follow-up time of 78 months, 93 patients (25%) were diagnosed with a recurrence. Median time to recurrence was 19 months. Recurrence was located exclusively in the liver in 19 cases (20%), and 74 patients (80%) had extrahepatic recurrence. Factors associated with extrahepatic recurrence in multivariate analysis included HCC beyond the Milan criteria (p < 0.0001) and the presence of macrovascular tumor invasion (p = 0.035). In patients with HCC beyond the Milan criteria who developed a recurrence (N = 73), macrovascular invasion was the only positive predictor of extrahepatic recurrence in multivariate analysis (p < 0.0001). In patients with HCC within the Milan criteria who recurred after LT (N = 20), DNA-index >1.5 (p = 0.013) was the only predictive factor for extrahepatic recurrence in multivariate analysis. CONCLUSIONS: Advanced HCC beyond the Milan criteria and the presence of macrovascular invasion are associated with an increased risk for extrahepatic recurrence and are currently considered as relative contraindications to LT. In patients with HCC within the Milan criteria, the DNA-index represents a valuable prognostic marker for the development of extrahepatic recurrence and may support the selection of patients for intensified postoperative tumor surveillance.

Implications of imaging criteria for the management and treatment of intraductal papillary mucinous neoplasms - benign versus malignant findings.

OBJECTIVES: Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. METHODS: Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate-grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). RESULTS: Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size ≥30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). CONCLUSIONS: Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non-invasive subtypes. KEY POINTS: • CT and MRI can differentiate benign from malignant forms of IPMN. • Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. • Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT.

Prognostic significance of DNA cytometry for adjuvant therapy response in pancreatic cancer.

BACKGROUND AND OBJECTIVES: The continuous progress in treatment options for pancreatic adenocarcinoma has lead to a re-evaluation of prognostic markers. In this study the prognostic relevance of DNA Index and classical histopathological parameters with regard to disease-free (DFS) and overall survival (OS) was analyzed within the CONKO-001 patient population. METHODS: One hundred forty three fresh-frozen paraffin-embedded tissue samples of the resected tumor specimen of the CONKO-001 patient population were available for DNA index analysis to evaluate its impact on patient outcome. RESULTS: Median DFS (7.3 vs. 14.3 months; P = 0.004) and median OS (16.6 vs. 29.2 months; P = 0.011) were significantly decreased in patients with a high DNA index (>1.4). Multivariate analysis revealed both DNA index (DFS: P = 0.002; OS: P = 0.019) and tumor grading (DFS: P = 0.004; OS: P = 0.004) as individual prognostic markers for DFS and OS. The following prognostic subgroups were identified: good (low DNA Index + G1/2 tumor grading), intermediate (low DNA Index + G3 tumor grading or high DNA Index + G1/2 tumor grading), poor (high DNA Index + G3 tumor grading). CONCLUSION: The DNA index/tumor grading constellation may serve as a helpful guide for personalized treatment recommendations for adjuvant therapy of patients with pancreatic adenocarcinoma.

Tumor DNA Index and α-Fetoprotein Level Define Outcome following Liver Transplantation for Advanced Hepatocellular Carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are expected to have inferior outcome after liver transplantation (LT) and are therefore currently not considered for LT in many countries. The purpose of this study was to identify predictive factors for overall survival following LT for HCC that may support the Milan criteria in the selection of appropriate transplant candidates. METHODS: Clinicopathological data on 364 patients with HCC who underwent LT between 1989 and 2010 were retrospectively evaluated. Predictors of overall survival in the entire cohort as well as in subsets of patients within (n = 214) and beyond (n = 150) the Milan criteria were analyzed. RESULTS: Multivariate analysis in the entire cohort identified DNA index >1.5 (p < 0.0001), α-fetoprotein level (AFP) >200 ng/ml (p = 0.005), and HCC beyond the Milan criteria (p = 0.002) to be associated with worse overall survival. In patients within the Milan criteria (median survival: 170 months), DNA index >1.5 (p < 0.0001) was the only predictor of worse overall survival in multivariate analysis. In patients beyond the Milan criteria (median survival: 44 months), DNA index >1.5, AFP >200 ng/ml, microvascular invasion, patient age >60 years, and DNA index >1.5 concomitant with AFP >200 ng/ml were associated with worse overall survival in univariate analysis. Multivariate analysis identified DNA index >1.5 concomitant with AFP >200 ng/ml (p < 0.0001) as the only independent predictor of worse overall survival. Consequently, patients beyond the Milan criteria with a combined favorable DNA index ≤1.5 and AFP ≤200 ng/ml had a median survival (147 months) comparable to that of patients within the Milan criteria. CONCLUSIONS: DNA index and AFP level predict overall survival following LT in patients with advanced HCC beyond the Milan criteria. A combined assessment of these markers during the evaluation of transplant candidates can contribute to the selection of patients with HCC who may benefit from LT independently of their tumor burden.

Patient and tumour biology predict survival beyond the Milan criteria in liver transplantation for hepatocellular carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are not considered for liver transplantation (LT) in many centres; however, LT may be the only treatment able to achieve long-term survival in patients with unresectable HCC. The aim of this study was to assess the role of recipient age and tumour biology expressed by the DNA index in the selection of HCC patients for LT. PATIENTS: Clinicopathological data of 364 patients with HCC who underwent LT between 1989 and 2010 were evaluated. Overall survival (OS) was analysed by patient age, tumour burden based on Milan criteria and the DNA index. RESULTS: After a median follow-up time of 78 months, the median survival was 100 months. Factors associated with OS on univariate analysis included Milan criteria, patient age, hepatitis C infection, alpha-fetoprotein (AFP) level, the DNA index, number of HCC, diameter of HCC, bilobar HCC, microvascular tumour invasion and tumour grading. On multivariate analysis, HCC beyond Milan criteria and the DNA index >1.5 independently predicted a worse OS. When stratifying patients by both age and Milan criteria, patients ≤ 60 years with HCC beyond Milan criteria had an OS comparable to that of patients >60 years within Milan criteria (10-year OS: 33% versus 37%, P = 0.08). Patients ≤ 60 years with HCC beyond Milan criteria but a favourable DNA index ≤ 1.5 achieved excellent long-term outcomes, comparable with those of patients within Milan criteria. CONCLUSIONS: Patients ≤ 60 years may undergo LT for HCC with favourable outcomes independently of their tumour burden. Additional assessment of tumour biology, e.g. using the DNA index, especially in this subgroup of patients can support the selection of LT candidates who may derive the most long-term survival benefit, even if Milan criteria are not fulfilled.

Patient age and extent of liver resection influence outcome of liver resection for hepatocellular carcinoma in non-cirrhotic liver.

BACKGROUND/AIMS: Data about the clinical course after liver resection for HCC in non-cirrhotic liver (NCL) is rare in western countries. Although the patients with HCC in NCL tolerate major liver resections, it is less clear if an underlying steatosis or NASH increase the perioperative and postoperative risk. The purpose of this study was to characterize the clinical course after hepatic resection in patients with HCC in the absence of liver cirrhosis and in the absence of viral hepatitis. METHODOLOGY: The data of 148 patients with HCC in non-cirrhotic liver, who underwent curatively intented liver resection, were analyzed. Patients with hepatitis B or C infection were excluded. Patients with fibrolamellar HCC or liver cirrhosis or fibrosis higher than grade 2 according to the Desmet-Scheuer score were also excluded. RESULTS: The overall 1-, 3- and 5-year survival rates were 75.4%, 54.7% and 38.9%. Increased patient age (elder than 70 years) influenced the cumulative survival significantly. Especially the combination of increased patient age and major resection (>2 segments) at once influenced the cumulative survival. The overall postoperative morbidity was 37.8 %. No intraoperative death was observed. Postoperative increased leucocytes, urea and creatinin increased the postoperative complications. In the subgroup with major resection increased GGT correlated with steatosis, and raised AST correlated with elevated patient age. CONCLUSIONS: In Western countries HCC in non-cirrhotic liver is rare. Liver resection is safe and is the only curative therapy option for the time by HCC without liver cirrhosis. Further studies are necessary for identification of more prognostic factors and optionally special treatment

Homogeneous Gynephiles and Heterogeneous Androphiles: A Factor Analysis of Differences and Similarities in Attractions to the Sexes as a Function of Sexual Orientation.

What is it about men and women that make them sexually attractive to those people who find them attractive? Which parts of the body? Which sexual acts? We address this question empirically through a factor analysis of people's ratings of the attractiveness of women's and men's body parts, and of particular sex acts with men and women. Participants of a wide variety of sexual orientations (including a rich sample of bisexuals) rated body parts (by sex) and sex acts (by sex) on 1-to-5 scales. We factor-analyzed answers to these 50 questions to reveal the factor structure of people's attractions as a function of their sexual orientation (itself derived from a previously reported cluster analysis of the Klein Sexual Orientation Grid), then calculated average responses of the male and female clusters on the factors that had emerged. The data showed: (1) The factor structure of men's and women's attractions to women were remarkably similar. (2) The factor structure of men's and women's attractions to men's bodies were remarkably different, identifying an attraction to adult masculinity that differed from attraction to adult boyishness. (3) Lesbian group variability was usually much higher than in any of the other groups. (4) Even though our sample was intentionally diverse, many of our participants only reported attractions to members of one sex. (5) Bisexuals were neither consistently intermediate between homosexuals and heterosexuals nor consistently similar to homosexuals and heterosexuals. (6) Bi-heterosexuals (one of 3 bisexual subgroups) seemed to be more sexually adventurous than might be expected from their position in the progression from pure heterosexual to pure homosexual, especially with regard to anal sex (albeit moderately so). (7) Homosexual men were not intrinsically attracted to anal sex per se. (8) Among men, nonsexual body parts and non-sexual acts were picked out in factor analyses and explained somewhat more variance between men of different sexual orientations than explicitly erotic variables do. (9) Among female respondents, the biggest differences in attractions to men by sexual orientation pertained to specifically erotic differences, not affectionate or bodily stimuli. (10) Although oral-anal contacts generally received low ratings by all the groups of women, ratings of oral-anal contacts were particularly low among lesbians. We believe that this is the first empirical study to report what it is about women and men that forms the basis for attractions to them, and the first to identify significant subgroups among men who are attracted to men.

Cluster Analysis of the Klein Sexual Orientation Grid in Clinical and Nonclinical Samples: When Bisexuality Is Not Bisexuality.

We used a cluster analysis to empirically address whether sexual orientation is a continuum or can usefully be divided into categories such as heterosexual, homosexual, and bisexual using scores on the Klein Sexual Orientation Grid (KSOG) in three samples: groups of men and women recruited through bisexual groups and the Internet (Main Study men; Main Study women), and men recruited for a clinical study of HIV and the nervous system (HIV Study men). A five-cluster classification was chosen for the Main Study men (n = 212), a four-cluster classification for the Main Study women (n = 120), and a five-cluster classification for the HIV Study men (n = 620). We calculated means and standard deviations of these 14 clusters on the 21 variables composing the KSOG. Generally, the KSOG's overtly erotic items (Sexual Fantasies, Sexual Behavior, and Sexual Attraction), as well as the Self Identification items, tended to be more uniform within groups than the more social items were (Emotional Preference, Socialize with, and Lifestyle). The result is a set of objectively identified subgroups of bisexual men and women along with characterizations of the extent to which their KSOG scores describe and differentiate them. The Bisexual group identified by the cluster analysis of the HIV sample was distinctly different from any of the bisexual groups identified by the clustering process in the Main Sample. Simply put, the HIV sample's bisexuality is not like bisexuality in general, and attempts to generalize (even cautiously) from this clinical Bisexual group to a larger population would be doomed to failure. This underscores the importance of recruiting non-clinical samples if one wants insight into the nature of bisexuality in the population at large. Although the importance of non-clinical sampling in studies of sexual orientation has been widely and justly asserted, it has rarely been demonstrated by direct comparisons of the type conducted in the present study.

Matched-pair analysis of postoperative morbidity and mortality for pancreaticogastrostomy and pancreaticojejunostomy using mattress sutures in soft pancreatic tissue remnants.

BACKGROUND: After pancreaticoduodenectomy, the incidence of postoperative pancreatic fistula remains high, especially in patients with "soft" pancreatic tissue remnants. No "gold standard" surgical technique for pancreaticoenteric anastomosis has been established. This study aimed to compare the postoperative morbidity and mortality of pancreaticogastrostomy and pancreaticojejunostomy for "soft" pancreatic tissue remnants using modified mattress sutures. METHODS: Seventy-five patients who had undergone pancreaticogastrostomy and 75 who had undergone pancreaticojejunostomy after pancreaticoduodenectomy between 2002 and 2008 were retrospectively compared using matched-pair analysis. A modified mattress suture technique was used for the pancreaticoenteric anastomosis. Patients with an underlying "hard" pancreatic tissue remnant, as in chronic pancreatitis, were excluded. Both groups were homogeneous for age, gender, and underlying disease. Postoperative morbidity, mortality, and preoperative and operative data were analyzed. RESULTS: There were no significant differences between the groups for the incidence of postoperative pancreatic fistula (10.7% in both). Postoperative morbidity and mortality, median operation time, median length of hospital stay, intraoperative blood loss, and the amount of intraoperatively transfused erythrocyte concentrates also did not significantly differ between the groups. Patient age >65 years (P=0.017), operation time >350 minutes (P=0.001), and intraoperative transfusion of erythrocyte concentrates (P=0.038) were identified as risk factors for postoperative morbidity. CONCLUSIONS: Our results showed no significant differences between the groups in the pancreaticogastrostomy and pancreaticojejunostomy anastomosis techniques using mattress sutures for "soft" pancreatic tissue remnants. In our experience, the mattress sutures are safe and simple to use, and pancreaticogastrostomy in particular is feasible and easy to learn, with good endoscopic accessibility to the anastomosis region. However, the location of the anastomosis and the surgical technique need to be individually evaluated to further reduce the incidence of postoperative pancreatic fistula.

Pancreatoenteral anastomosis or direct closure of the pancreatic remnant after a distal pancreatectomy: a single-centre experience.

BACKGROUND: A major complication of a distal pancreatectomy (DP) is the formation of a post-operative pancreatic fistula (POPF). In spite of the utilization of numerous surgical techniques no consensus on an appropriate technique for closure of the pancreatic remnant after DP has been established yet. The aim of this study was to analyse the impact of pancreatoenteral anastomosis (PE) vs. direct closure (DC) of the pancreatic remnant on POPF. METHODS: A total of 198 consecutive patients who underwent a distal pancreatectomy between 2002 and 2010 at our institution were retrospectively analysed for post-operative morbidity and mortality. RESULTS: One hundred and fifty-one patients (76.3%) received DC whereas PE was performed in 47 patients (23.7%). The incidence of POPF was higher in the DC group (22% vs. 11%), whereas the rate of post-operative haemorrhage was higher in the PE group (11% vs. 7%). However, these differences were not significant. Additionally, there were no significant differences in overall post-operative morbidity and mortality between the groups. CONCLUSIONS: The performance of PE instead of DC may be considered as a safe alternative in individual patients, but it does not significantly lead to a general improvement in post-operative outcome after DP. An interdisciplinary collaboration in the prevention and treatment of POPF therefore remains essential.

Safety of pancreatic surgery in patients with simultaneous liver cirrhosis: a single center experience.

BACKGROUND/AIMS: Pancreatic surgery is associated with an increased risk of postoperative complications. We therefore investigated the impact of an additional liver function disorder on the postoperative outcome using a case-control study of patients with or without liver cirrhosis who underwent pancreatic surgery at our department. METHODS: Between 1998 and 2008, 1,649 pancreatic resections were performed. Of these, 32 operations were performed in patients who also suffered from liver cirrhosis (30× Child A, 2× Child B). For our case-control study, we selected another 32 operated patients without cirrhosis who were matched according to age, sex, diagnosis and tumor classification. The following parameters were compared between both groups: operating time, number of transfusions, duration of ICU and hospital stay, incidence of complications, rate of reoperation, mortality. RESULTS: Patients with cirrhosis experienced complications significantly more often (69 vs. 44%; p = 0.044), especially major complications (47 vs. 22%; p = 0.035) requiring reoperation (34 vs. 12%; p = 0.039). These patients also had a prolonged hospital stay (27.9 vs. 24.3 days) and a significantly longer ICU stay (8.6 vs. 3.7 days; p = 0.033), and required twice as many transfusions. Overall, 3 patients died following surgery, 1 with Child A (3% of all Child A patients) and 2 with Child B cirrhosis. CONCLUSION: Pancreatic surgery is associated with an increased risk of postoperative complications in patients with liver cirrhosis, and is therefore not recommended in patients with Child B cirrhosis. In Child A cirrhotic patients the mortality is, however, comparable to noncirrhotic patients. Due to the demanding medical efforts that these patients require, they should be treated exclusively in high-volume centers. and IAP.

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.