Comparison of the LiMAx test vs. the APRI+ALBI score for clinical utility in preoperative risk assessment in patients undergoing liver surgery - A European multicenter study.

INTRODUCTION: Posthepatectomy liver failure (PHLF) remains the main reason for short-term mortality after liver surgery. APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), score and the liver function maximum capacity test (LiMAx) are both established preoperative (preop) liver function tests. The aim of this study was to compare both tests for their predictive potential for clinically significant PHLF grade B and C (B+C). MATERIALS AND METHODS: 352 patients were included from 4 European centers. Patients had available preop APRI+ALBI scores and LiMAx results. Predictive potential for PHLF, PHLF B+C and 90-day mortality was compared using receiver operating characteristic (ROC) curve analysis and calculation of the area under the curve (AUC). Published cutoffs of ≥ -2.46 for APRI+ALBI and of <315 for LiMAx were assessed using chi-squared test. RESULTS: APRI+ALBI showed superior predictive potential for PHLF B+C (N = 34; AUC = 0.766), PHLF grade C (N = 20; AUC = 0.782) and 90-day mortality (N = 15; AUC = 0.750). When comparing the established cutoffs of both tests, APRI+ALBI outperformed LiMAx in prediction of PHLF B+C (APRI+ALBI ≥2.46: Positive predictive value (PPV) = 19%, negative predictive value (NPV) = 97%; LiMAx <315: PPV = 3%, NPV = 90%) and 90-day mortality (APRI+ALBI ≥2.46: PPV = 12%, NPV = 99%; LiMAx <315: PPV = 0%, NPV = 94%) CONCLUSION: In our analysis, APRI+ALBI outperformed LiMAx measurement in the preop prediction of PHLF B+C and postoperative mortality, at a fraction of the costs, manual labor and invasiveness.

Isolated Pancreatic Metastases of Renal Cell Carcinoma-Clinical Particularities and Seed and Soil Hypothesis.

A meta-analysis of 1470 isolated pancreatic metastases of renal cell carcinoma revealed, that, in addition to the unusual exclusive occurrence of pancreatic metastases and the favourable treatment results, the isPMRCC is characterised by further peculiarities of the clinical course: The lack of prognostic significance of volume and growth rate dependent risk factors and the independence of treatment results from standard or local resections. As an explanation for all these peculiarities, according to today's knowledge, a strong acting seed and soil mechanism can serve, which allows embolized tumour cells to grow to metastases only in the pancreas, and prevents them definitively or for years in all other organs. The good prognosis affects not only isolated PM, but also multi-organ metastases of the RCC, in which the additional occurrence of PM is also associated with a better prognosis. Genetic studies revealed specific changes in cases of PM of RCC: Lack of loss of 9p21.3 and 14q31.2, which are otherwise specific gene mutations at the onset of generalization, a low weight genome instability index, i.e., high genetic stability, and a low rate of PAB1 and a high rate of BPRM1 alterations, which signal a more favourable course. The cause of pancreatic organotropism in isPMRCC is still unclear, so only those factors that have been identified as promoting organotropism in other, more frequent tumour entities can be presented: Formation of the pre-metastatic niche, chemokine receptor-ligand mechanism, ability to metabolic adaptation, and immune surveillance.

Isolated Pancreatic Metastases of Renal Cell Cancer: Genetics and Epigenetics of an Unusual Tumour Entity.

Isolated pancreatic metastases of renal cell carcinoma (isPMRCC) are a rare manifestation of metastatic renal cell carcinoma (mRCC) characterized by two peculiarities: (1). The definite or at least long-term exclusive occurrence of metastases in the pancreas and (2). an unusual low tumour aggressiveness with slow tumour progression and consecutive, good treatment results. According to current knowledge, the exclusive occurrence of pancreatic metastases is due to a highly specific and highly selective seed and soil mechanism, which does not allow metastases settlement outside the pancreas, and whose detailed genetic/epigenetic causes are not yet elucidated. Recent studies have shed light on some of the pathways involved for the protracted course of the disease and highlighted a special genetic profile (lack of loss of 9p, lower weight genome instability index, low frequency of BAP1 alterations, and a high frequency of PBRM1 loss), which deviates from the conventional mRCC profile. Finally, the question of the reasons for the long-term relative genetic stability of the involved cell clones, which is an essential prerequisite for a favourable prognosis, remains unanswered.

Tumour Evolution and Seed and Soil Mechanism in Pancreatic Metastases of Renal Cell Carcinoma.

In metastatic renal cell carcinoma, pancreatic metastases can appear in two clinical manifestations: (a) very rarely as isolated pancreatic metastases and (b) in the context with multi-organ metastatic disease. Both courses are characterised by rare, unusual clinical features. For isolated pancreatic metastases, the literature shows no effect on survival in all 11 publications that examined the effect of singular versus multiple pancreatic metastases; a lack of effect on survival time was also present in all 8 studies on pancreatic metastases size, in 7 of 8 studies on the influence of disease-free interval (DFI), and in 6 of 7 studies on the influence of synchronous versus metachronous metastases. In multi-organ site metastases observations, on the other hand, all five available references showed significantly better results in patients with concurrent pancreatic metastases compared to those without pancreatic metastases, although the total number of affected organs in the pancreatic metastases cohort was larger. Tumour volume-dependent risk factors thus remain surprisingly ineffective in both groups, which contradicts the usual behaviour of solid tumours. The reasons for this unusual behaviour and possible relations to tumour evolution and the hypothesis of an influence of a seed and soil mechanism in the occurrence of pancreatic metastases in metastatic renal cell carcinoma are discussed.

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms: An International Multicenter Cohort Study.

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein modulating cell-matrix interactions and was found up-regulated in tumor stroma. To explore the effect of high stromal SPARC on colorectal cancer (CRC) cell behavior and clinical outcome, this study determined SPARC expression in patients suffering from stage II and III CRC using a publicly available mRNA data set and immunohistochemistry of tissue microarray sections. Moreover, in vitro co-culture models using CRC cell lines together with colon-associated fibroblasts were established to determine the effect of fibroblast-derived SPARC on cancer cells. In 466 patient samples, high SPARC mRNA was associated with a shorter disease-free survival. In 99 patients of the tissue microarray cohort, high stromal SPARC in the primary tumor was an independent predictor of shorter survival in patients with relapse (27 cases; HR = 4574, p = 0.004). In CRC cell lines, SPARC suppressed phosphorylation of focal adhesion kinase and stimulated cell migration. Colon-associated fibroblasts increased migration velocity by 30% and doubled track-length in SPARC-dependent manner. In a 3D co-culture system, fibroblast-derived SPARC enhanced tumor cell invasion. Taken together, stromal SPARC had a pro-metastatic impact in vitro and was a characteristic of aggressive tumors with poor prognosis in CRC patients.

Exploring the surgical landscape of pancreatic neuroendocrine neoplasia in Austria: Results from the ASSO pNEN study group.

INTRODUCTION: Pancreatic neuroendocrine neoplasia (pNEN) show increasing incidence and management is complex due to biological heterogeneity. Most publications report isolated high-volume single-centre data. This Austrian multi-centre study on surgical management of pNENs provides a comprehensive real-life picture of quality indicators, recurrence-patterns, survival factors and systemic treatments. METHODS: Retrospective, national cohort-study from 7 medium-/high-volume centres in Austria, coordinated under the auspices of the Austrian Society of Surgical Oncology (ASSO). RESULTS: Two-hundred patients underwent resection for pNEN, 177 had non-functioning tumours and 31 showed stage 4 disease. Participating centres were responsible for 2/3 of pNEN resections in Austria within the last years. The mean rate of completeness of variables was 98.6%. Ninety-days mortality was 3.5%, overall rate of complications was 42.5%. Morbidity did not influence long-term survival. The 5-year overall-survival (OS) was 81.3%, 10-year-OS 52.5% and 5-year recurrence-free-survival (RFS) 69.8%. Recurrence was most common in the liver (68.1%). Four out of five patients with recurrence underwent further treatment, most commonly with medical therapy or chemotherapy. Multivariable analysis revealed grading (HR:2.7) and metastasis (HR:2.5) as significant factors for relapse. Tumours-size ≥2 cm (HR:5.9), age ≥60 years (HR:3.1), metastasis (HR:2.3) and grading (HR:2.0) were associated with OS. Tumours <2 cm showed 93.9% 10-year-OS, but 33% had G2/G3 grading, 12.5% positive lymph-nodes and 4.7% metastasis at diagnosis, each associated with significant worse survival. CONCLUSION: Resection of pNENs in Austria is performed with internationally comparable safety. Analysed factors allow for risk-stratification in clinical treatment and future prospective trials. A watch-and-wait strategy purely based on tumour-size cannot be recommended.

Distal gastrectomy in pancreaticoduodenectomy is associated with accelerated gastric emptying, enhanced postprandial release of GLP-1, and improved insulin sensitivity.

OBJECTIVE: This study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity after pancreaticoduodenectomy (PD). BACKGROUND: Abnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after PD, the cause of which is unclear. The procedure is carried out with pylorus preservation (PPPD) or with distal gastrectomy (Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1) conceivably play a role in glucose metabolism after PD. It was the purpose of this study to shed light on the relationship between gastric emptying, GLP-1 and glycemic control after PPPD and the Whipple procedure. METHODS: A 75-g oral glucose tolerance test was carried out in 13 patients having undergone PPPD and in 13 after the Whipple procedure, median age 61 (range, 32-70) years, following an interval of 23 (range, 5-199) months. Gastric emptying was measured by the paracetamol absorption method. Plasma concentrations of glucose, insulin, GLP-1 and paracetamol were measured at baseline, 10, 20, 30 60, 90, 120, 150 and 180 min. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations. RESULTS: Patients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p = 0.01) which correlated with early (0-30 min) integrated GLP-1 (AUC30; r (2) = 0.61; p = 0.02) and insulin sensitivity (r (2) = 0.41; p = 0.026) and inversely with HOMA-IR (r (2) = 0.17; p = 0.033). Two of 13 Whipple patients (15 %) as compared to seven of 13 after PPPD (54 %) had postload glucose concentrations (i.e. 120 min postmeal) ≥200 mg/dl (p < 0.05). None of 13 (0 %) after Whipple procedure but four of 13 patients (31 %) after PPPD had fasting glucose concentrations ≥126 mg/dl (p < 0.05) CONCLUSIONS: Gastric emptying was accelerated after Whipple procedure as compared to patients who have undergone PPPD, resulting in higher postprandial GLP-1 concentrations and insulin sensitivity and improved glycemic control.

TNM stage and grade in predicting the prognosis of operated, non-functioning neuroendocrine carcinoma of the pancreas--a single-institution experience.

OBJECTIVE: To evaluate the prognostic significance of TNM and grading categories in curatively resected non-functioning neuroendocrine pancreatic carcinoma (nfnepC). METHOD: Eighteen nfnepC were retrospectively analyzed for differences in survival. RESULTS: (1) There was a correlation between pT (P = 0.026), respectively pM categories (P = 0.016) and survival. (2) G categories and length of survival were closely correlated (P = 0.0036). (3) Disease stages I-IV had a significant effect on survival (P = 0.051). (4) The WHO classification in well and poorly differentiated carcinomas proved to be the most conclusive predictive factor (P = 0.0009). (5) Subgroups with significantly different prognoses determined by histological grade were present within disease stage II. CONCLUSIONS: The retrospective analysis showed a good correlation between survival and pT, pM, tumor stage, G categories, and WHO classification in well and poorly differentiated carcinomas. Including histological differentiation in the staging system or carrying it out separately in well and poorly differentiated carcinomas, could enhance the predictive potential of TNM-based disease stages.