Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study.

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Bevacizumab plus irinotecan in recurrent malignant glioma shows high overall survival in a multicenter retrospective pooled series of the Spanish Neuro-Oncology Research Group (GEINO).

There is no 'standard of care' for recurrent malignant glioma (MG). Our aim is to confirm the efficacy and safety of bevacizumab 10 mg/kg plus irinotecan 125 mg/m² (or 340 mg/m² if enzyme-inducing antiepileptic drugs) every 2 weeks for a maximum of 1 year in a retrospective pooled series of patients with recurrent MG. The inclusion criteria were as follows: age 18 years and above, histology of MG, progression after radiation and temozolomide, Karnofsky performance status (KPS) of at least 60, and signed informed consent for bevacizumab compassionate use. Response was assessed by MRI using the Macdonald criteria and evaluation of the FLAIR sequence every 8 weeks. A total of 130 patients were enrolled; 72% had glioblastoma (GBM). The median age of the patients was 53 years (20-78); the median KPS was 80%; the median number of prior chemotherapy lines was 2 (1-5); the median interval between the diagnosis of MG and inclusion was 14.6 months (2-166); and the median number of bevacizumab infusions was 8 (1-39). The median follow-up duration was 7.2 months (1-47). The median overall survival (OS) was 8.8 months for GBM and 11.2 months for anaplastic glioma (AG). The median progression-free survival was 5.1 months for GBM and 4.6 months for AG. The response rate was 56% for GBM and 68% for AG. Neurological and KPS improvements were observed in 49 and 45% of patients. Only KPS less than 80% was associated with a worse significant response rate (odds ratio, 0.57; 95% confidence interval, 0.22-0.96). The most frequent grades 3-4 toxicities were asthenia (7%), diarrhea (6%), and thromboembolic events (5%). There were five toxic deaths (4%). Bevacizumab plus irinotecan in recurrent MG improves responses, progression-free survival, and OS compared with historical data. KPS of at least 80% was a predictive factor for response and OS.

Characterization of Mesothelin Glycosylation in Pancreatic Cancer: Decreased Core Fucosylated Glycoforms in Pancreatic Cancer Patients' Sera.

Currently, there are no reliable biomarkers for the diagnosis of pancreatic cancer (PaC). Glycoproteomic approaches that analyze the glycan determinants on specific glycoproteins have proven useful to develop more specific cancer biomarkers than the corresponding protein levels. In PaC, mesothelin (MSLN) is a neo-expressed glycoprotein. MSLN glycosylation has not been described and could be altered in PaC. In this work, we aimed to characterize MSLN glycans from PaC cells and serum samples to assess their potential usefulness as PaC biomarkers. First, we analyzed MSLN glycans from PaC cell lines and then we developed an enzyme-linked lectin assay to measure core fucosylated-MSLN (Cf-MSLN) glycoforms. MSLN glycans from PaC cells were analyzed by glycan sequencing and through Western blotting with lectins. All of the cell lines secreted MSLN, with its three N-glycosylation sites occupied by complex-type N-glycans, which were mainly α2,3-sialylated, core fucosylated and highly branched. The Cf-MSLN glycoforms were quantified on PaC serum samples, and compared with MSLN protein levels. The Cf-MSLN was significantly decreased in PaC patients compared to control sera, while no differences were detected by using MSLN protein levels. In conclusion, Cf-MSLN glycoforms were differently expressed in PaC, which opens the way to further investigate their usefulness as PaC biomarkers.

Population-based incidence and survival of central nervous system (CNS) malignancies in Girona (Spain) 1994-2005.

The purpose of this study was to describe the incidence and survival of primary Central Nervous System (CNS) malignancies using data from the population-based cancer registry for Girona province (north-east Spain).We included all cases of primary CNS malignancies registered between 1994 and 2005. Pathological diagnoses were reviewed and grouped according to the 2007 WHO Classification. Meningeal, soft tissue tumours, spinal cord tumours and primary CNS lymphoma were not included. Cases notified only by death certificate were excluded from the survival analysis. Kaplan and Meier survival curves were calculated from date of diagnosis to death or end of study (31 December 2005), as was relative survival. A total of 493 new CNS cancer patients were registered during the study period: 49.3% astrocytic, 3.4% oligodendroglial and oligoastrocytic tumours, 2.6% ependimal tumours, 3.7% embryonal tumours, 0.2% choroid plexus and 41% without histological confirmation. The mean age (in years) for embryonal tumours was 18.17 years, these being the younger patients in the sample, and 66.34 years for those without histological confirmation, the older patients. Overall, the age standardised incidence rate was 5.88 cases/100,000 people/year (men = 6.81; women = 4.99) with an increasing trend by age until the 70-74 age group. Five-year observed survival rates were: 14.6% for astrocytic tumours, 35.7% for oligodendroglial and oligoastrocytic tumours, 41.0% for ependymal tumours, 32.4% for embryonal tumours and 7.5% for those without histological confirmation (log rank test: P < 0.001). Five-year observed survival rates for astrocytic tumours were analyzed separately by tumour grading, with 37% for diffuse astrocytoma, 7.1% for anaplastic astrocytoma and 4.7% for glioblastoma (log rank test: P < 0.001).Our results show that astrocytic tumours are most frequently diagnosed and glioblastoma patients have the worst survival figures for the area covered by our population cancer registry.The high observed incidence of histologically unverified tumours is most probably due to easy access to state of the art CNS imaging in our area.

Microfibril associated protein 4 (MFAP4) is a carrier of the tumor associated carbohydrate sialyl-Lewis x (sLex) in pancreatic adenocarcinoma.

Late diagnosis of pancreatic ductal adenocarcinoma (PDA) is one of the reasons of its low 5-year survival rate and it is due to its unspecific symptoms during the first stages of the disease and the lack of reliable serological markers. Since PDA shows an altered glycan expression, here we have focused on finding novel potential biomarkers, namely glycoproteins that express the tumor associated carbohydrate structure sialyl-Lewis x (sLex), which is described in PDA. Through a glycoproteomic approach, we have analyzed target proteins containing sLex from PDA tissues by 2DE and immunodetection techniques, and have identified by mass spectrometry the protein MFAP4 as a carrier of sLex in PDA. MFAP4 showed a higher expression in PDA tissues compared with pancreatic control tissues. In addition, the colocalization of sLex over MFAP4 was found only in PDA and not in control pancreatic tissues. The analysis of MFAP4 expression in PDA cell lines and their secretome, in combination with immunohistochemistry of pancreatic tissues, revealed that MFAP4 was not produced by PDA cells, but it was found in the pancreatic extracellular matrix. The specificity of MFAP4 glycoform containing sLex in PDA tissues shows its relevance as a potential PDA biomarker. SIGNIFICANCE: Despite advances in the field of cancer research, pancreatic ductal adenocarcinoma (PDA) lacks of a specific and sensitive biomarker for its early detection, when curative resection is still possible before metastases arise. Thus, efforts to discover new PDA biomarkers represent the first line in the fight against the increase of its incidence reported in recent years. Glycan alterations on glycoconjugates, such as glycoproteins have emerged as a rich source for the identification of novel cancer markers. In the present work, we aimed to shed light on novel biomarkers based on altered glycosylation in PDA, in particular those glycoproteins of PDA tissues carrying the tumor carbohydrate antigen sialyl-Lewis x (sLex). Through a glycoproteomic approach, we have shown that the glycoprotein MFAP4 carries sLex in PDA tissues and not in control pancreatic tissues. MFAP4 is found in the extracellular matrix in PDA and although its role in cancer progression is unclear, its sLex glycoform could be a potential biomarker in pancreatic ductal adenocarcinoma.

Incidence and Survival Trends of Pancreatic Cancer in Girona: Impact of the Change in Patient Care in the Last 25 Years.

(1) Background: We investigated the incidence and survival trends for pancreatic cancer (PC) over the last 25 years in the Girona region, Catalonia, Spain; (2) Methods: Data were extracted from the population-based Girona Cancer Registry. Incident PC cases during 1994-2015 were classified using the International Classification of Diseases for Oncology Third Edition (ICD-O-3). Incidence rates age-adjusted to the European standard population (ASRE) and world standard population (ASRW) were obtained. Trends were assessed using the estimated annual percentage of change (EAPC) of the ASRE13. Observed and relative survivals (RS) were estimated with the Kaplan-Meier and Pohar Perme methods, respectively; (3) Results: We identified 1602 PC incident cases. According to histology, 44.4% of cases were exocrine PC, 4.1% neuroendocrine, and 51.1% malignant-non-specified. The crude incidence rate (CR) for PC was 11.43 cases-per-100,000 inhabitants/year. A significant increase of incidence with age and over the study period was observed. PC overall 5-year RS was 7.05% (95% confidence interval (CI) 5.63; 8.84). Longer overall survival was observed in patients with neuroendocrine tumours (5-year RS 61.45%; 95% CI 47.47; 79.55). Trends in 5-year RS for the whole cohort rose from 3.27% (95% CI 1.69-6.35) in 1994-1998 to 13.1% (95% CI 9.98; 17.2) in 2010-2015; (4) Conclusions: Incidence rates of PC in Girona have increased in the last two decades. There is a moderate but encouraging increase in survival thorough the study period. These results can be used as baseline for future research.

Trends in net survival from pancreatic cancer in six European Latin countries: results from the SUDCAN population-based study.

Pancreatic cancer represents a real clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from pancreatic cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results were reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modelling strategy. There were little differences between countries in age-standardized net survivals (2000-2004). The 5-year net survival was poor (range: 6-10%). The changes in net survival from 1992 to 2004 were mostly related to early survival and patients aged 60 years. A slight decrease in the excess mortality rate between 1992 and 2004 was observed, limited to the 18 months after diagnosis. This study confirmed that, despite some improvement, survival from pancreatic cancer is still poor throughout European Latin countries. The major improvements in clinical imaging did not result in improvements in prognosis. Development of truly innovative treatments is highly needed to improve prognosis.

Descriptive epidemiology of primary malignant and non-malignant central nervous tumors in Spain: Results from the Girona Cancer Registry (1994-2013).

BACKGROUND: Systematic registration of non-malignant central nervous system (CNS) tumors is a rare practice among European cancer registries. Thus, the real burden of all CNS tumors across Europe is underestimated. The Girona Cancer Registry provides here the first data on CNS tumor incidence and survival trends in Spain for all histological types, including malignant and non-malignant tumors. METHODS: Data on all incident cases of primary CNS tumors notified to the Girona population-based cancer registry from 1994 to 2013 (n=2,131) were reviewed. Incidences rates (IRs) were standardized to the 2013 European population and annual percentage changes (EAPC) were estimated using a piecewise log linear model. 1- and 5-year observed (OS) and relative survival (RS) were also calculated. Results were expressed by sex, age-group, histological subtype and behavior. RESULTS: The overall IR was 16.85 and increased across the period of study (EAPC=+2.2%). The proportion and IRs of malignant (50.2%; IR=9.35) and non-malignant cases (49.8%; IR=9.14) were similar; however, non-malignant tumors were more frequent in women (sex ratio=0.63). The most frequently reported histologies were meningioma (27.6%; IR=5.11) and glioblastoma (22.2%; IR=4.15), which also accounted for the highest and lowest 5-year RS (80.2%; 3.7%, respectively). Globally, 5-year RS was lower in men (42.6% vs. 58.3%, respectively) and in the elderly (64.9% for 0-14years vs. 23.0% for >74years). CONCLUSION: This study presents a comprehensive overview of the epidemiology of malignant and non-malignant CNS primary tumors from the well-established region-wide Girona Cancer Registry (1994-2013). Incidence rates were recovered for all histologies. Survival is still dramatically associated to both age and histological subtype.

Biological markers of cisplatin resistance in advanced testicular germ cell tumours.

INTRODUCTION: Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course. RESULTS: The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival. CONCLUSIONS: Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.

Expression of EGFR, HER-2/neu and KIT in germ cell tumours.

BACKGROUND: Germ cell tumours (GCTs) represent an extraordinarily chemosensitive malignancy. However, 20-30% of patients with advanced disease cannot be cured by currently available treatments. The role of tyrosine kinase receptors has been widely studied in other malignancies. Yet, limited information is available on GCTs. METHODS: One hundred and nine paraffin-embedded GCTs in 84 patients were assessed by immunohistochemistry for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2)/neu and KIT (CD117) expression. Univariate and multivariate analyses were performed to evaluate their role as predictive and/or prognostic factors. RESULTS: EGFR and HER-2/neu staining was detected in 28% and 13% of tumours, respectively, predominantly in nonseminomatous GCTs. KIT protein was almost universally expressed in seminomas (97%), being virtually absent in choriocarcinoma and teratocarcinoma subtypes. EGFR expression showed inverse association with tumour response of borderline significance. With a median follow-up of 10.6 years, no significant association was observed between the expression of any of these markers and relapse-free or overall survival. CONCLUSIONS: EGFR, HER-2/neu and KIT have differential patterns of expression in GCTs according to histological subtypes. The expression of these markers in our series had no prognostic or predictive significance.

Irinotecan (CPT-11)-based chemotherapy as induction treatment for advanced colorectal cancer.

The role of irinotecan-based chemotherapy as induction treatment of non-resectable advanced colorectal cancer (ACRC) is currently being elucidated. The objective of this retrospective study was to determine complete resection (R0), response rate, time to progression (TTP) and overall survival (OS) in patients with non-resectable ACRC after being treated with neoadjuvant irinotecan-based chemotherapy. Thirty-six patients with ACRC were selected, of whom 23 (64%) were treated with irinotecan (250 mg/m2 on day 1), UFT (300 mg/m2/day for 14 days) plus leucovorin (45 mg/day for 14 days) every 3 weeks. Another 13 (36%) received the FOLFIRI schedule of irinotecan plus 5-fluorouracil/leucovorin. A total of 214 cycles of irinotecan/UFT/LV (median 8, range 1-15) and 97 cycles of the FOLFIRI schedule (median 9, range 1-30) were administered. The overall response rate was 58% (95% confidence interval 42-74), with six complete and 15 partial responses, whereas seven patients (19%) showed stable disease. Laparotomy was performed in 12 patients, of whom eight (22%) achieved R0 and two (6%) a pathological complete response. Median TTP was 10.0 months and median OS was 38.0 months for all patients. After a median follow-up of 20 months (range 1-49), median TTP in patients with R0 was not reached (mean TTP, 33.1 months), whereas median TTP in non-resected patients was 7.5 months (p=0.016). Toxicity was manageable and no toxic deaths occurred. This retrospective study showed a high resectability rate, and a prolonged TTP and OS in patients with ACRC after induction treatment with irinotecan-based chemotherapy. Both toxicity profile and postoperative complications were acceptable. Nevertheless, the definitive role of irinotecan as induction treatment should be confirmed in future clinical trials.

Assessment of procalcitonin as a diagnostic and prognostic marker in patients with solid tumors and febrile neutropenia.

BACKGROUND: Cancer patients with fever and neutropenia currently are assessed on clinical grounds only. The current study prospectively evaluated the efficacy of baseline procalcitonin (PCT) in the detection of bacteremia and in the prediction of outcome in patients with solid tumors and febrile neutropenia. METHODS: PCT levels were determined at baseline and every 48 hours in 104 patients undergoing chemotherapy who developed fever (axillary temperature > 38 degrees C on 2 occasions or > 38.3 degrees C in a single record) and neutropenia (absolute neutrophil count < 500 cells/microL). RESULTS: The median baseline PCT values were significantly higher in patients who had microbiologically documented infections (1.24 ng/mL) compared with patients who had clinically documented infections (0.27 ng/mL) or fever of unknown origin (0.21 ng/mL; P < 0.01). Accordingly, a PCT cut-off value of 0.5 ng/mL was reached more frequently in patients who had microbiologically documented infections compared with patients who had clinically documented infections or fever of unknown origin (66.7% vs. 13.4%, respectively; P < 0.001). Furthermore, this threshold also was associated with an increased likelihood of treatment failure (70.0% vs. 14.9%; P < 0.001). All 4 septic patients and all 5 patients who ultimately died presented PCT values 5-fold to 10-fold greater than the median values. Clinical evaluation in combination with baseline PCT assessment appeared to improve clinical risk evaluation alone. CONCLUSIONS: Baseline PCT levels were higher in patients who had febrile neutropenia with bacteremia compared with patients who had clinical infections or fever of unknown origin. PCT helped to identify patients who had microbiologic infections and patients who were at high risk of treatment failure, and PCT may constitute a complementary tool in the initial assessment of such patients.