Abstract Background In metastatic disease (M1), chemotherapy (expected survival: 6–10 months) is considered the only treatment option. The aim of this study was to evaluate the outcome of curative M1 ...PDAC resections. Methods Prospective data of all patients undergoing primary tumour and metastasis resection for stage IV PDAC during a 12-year period was analysed regarding localisation (liver or distant interaortocaval lymph nodes; ILN), morbidity and survival. Patients were stratified with regard to syn- or metachronous metastases resection. Results Patients (n = 128) undergoing PDAC and metastases resection (intention-to-treat, oligometastatic stage; liver n = 85; ILN n = 43) were included. Surgical morbidity and 30-day mortality after synchronous resection of M1 tumours were 45% and 2.9%, respectively. Overall median survival after M1 resection was 12.3 months in both groups. Long-term outcome showed a 5-year survival of 8.1% after surgery for both liver metastases and 10.1% following ILN resection. Conclusions The present collective is the largest series of resected metastatic PDAC and shows that resection of liver or ILN metastases can be done safely and should be considered as it may be superior to palliative treatment, and it is associated with long-term survival of 10% in selected patients. Further studies to stratify patients for these procedures are warranted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary
Hfq, a bacterial member of the Sm family of RNA‐binding proteins, is required for the action of many small regulatory RNAs that act by basepairing with target mRNAs. Hfq binds this family of ...small RNAs efficiently. We have used co‐immunoprecipitation with Hfq and direct detection of the bound RNAs on genomic microarrays to identify members of this small RNA family. This approach was extremely sensitive; even Hfq‐binding small RNAs expressed at low levels were readily detected. At least 15 of 46 known small RNAs in E. coli interact with Hfq. In addition, high signals in other intergenic regions suggested up to 20 previously unidentified small RNAs bind Hfq; five were confirmed by Northern analysis. Strong signals within genes and operons also were detected, some of which correspond to known Hfq targets. Within the argX‐hisR‐leuT‐proM operon, Hfq appears to compete with RNase E and modulate RNA processing and degradation. Thus Hfq immunoprecipitation followed by microarray analysis is a highly effective method for detecting a major class of small RNAs as well as identifying new Hfq functions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
What's new?
Mutations in BRCA2 and CHEK2 are associated with susceptibility to many cancers, including pancreatic. The survival rate for pancreatic cancer remains abysmal, and early diagnostic markers are urgently needed. Here, the authors investigated the effect of a truncating BRCA2 variant (rs11571833) and a missense CHEK2 variant (rs17879961) on sporadic pancreatic ductal adenocarcinoma risk. Using data from the PANDoRA consortium, they tested a large number of samples, making this the first high‐power study to investigate these variants. Both variants, they found, increased the risk of non‐familial PDAC, and these variants may contribute to polygenic risk scores that help identify at‐risk individuals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The RNA chaperone protein Hfq is required for the function of all small RNAs (sRNAs) that regulate mRNA stability or translation by limited base pairing in Escherichia coli. While there have been ...numerous in vitro studies to characterize Hfq activity and the importance of specific residues, there has been only limited characterization of Hfq mutants in vivo. Here, we use a set of reporters as well as co-immunoprecipitation to examine 14 Hfq mutants expressed from the E. coli chromosome. The majority of the proximal face residues, as expected, were important for the function of sRNAs. The failure of sRNAs to regulate target mRNAs in these mutants can be explained by reduced sRNA accumulation. Two of the proximal mutants, D9A and F39A, acted differently from the others in that they had mixed effects on different sRNA/mRNA pairs and, in the case of F39A, showed differential sRNA accumulation. Mutations of charged residues at the rim of Hfq interfered with positive regulation and gave mixed effects for negative regulation. Some, but not all, sRNAs accumulated to lower levels in rim mutants, suggesting qualitative differences in how individual sRNAs are affected by Hfq. The distal face mutants were expected to disrupt binding of ARN motifs found in mRNAs. They were more defective for positive regulation than negative regulation at low mRNA expression, but the defects could be suppressed by higher levels of mRNA expression. We discuss the implications of these observations for Hfq binding to RNA and mechanisms of action.
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► In vivo analysis of 14 chromosomally expressed hfq mutants reveals differential consequences of specific amino acid substitutions. ► Phenotypes confirm a critical role for the proximal face of Hfq in sRNA binding. ► The rim of the Hfq hexamer is important for positive regulation by sRNAs. ► Individual sRNA:mRNA pairs show different sensitivities to hfq mutants. ► The results suggest unexpected complexity in how Hfq promotes sRNA-based regulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Pancreatic surgery has undergone significant progress during recent years. Specialised centres with interdisciplinary expertise have led to improved patient care with decreased morbidity and ...mortality. Regarding evidence-based medicine, consensus definitions on morbidity as well as high-quality studies, systematic reviews and meta-analyses on different topics of pancreatic surgery have been published. In acute pancreatitis paradigms have shifted towards conservative management, in chronic pancreatitis parenchyma-sparing resection techniques have widely become accepted. Management of cystic lesions - especially intraductal papillary mucinous neoplasms (IPMN) - has attracted great interest in surgical practice. In pancreatic cancer treatment not only surgical resection techniques have improved but also the central impact of adjuvant treatment has been demonstrated in large multicentre trials.
Estimation of the risk of malignancy in intraductal papillary mucinous neoplasia (IPMN) of the pancreas is a clinical challenge. Several routinely used clinical factors form the basis of the current ...consensus guidelines. This study aimed to determine the predictive values of the most commonly assessed risk factors.
A meta-analysis of individual risk factors of malignancy in IPMN was performed. Contingency tables were derived from these data, and sensitivity, specificity, negative and positive predictive values, and diagnostic odds ratios (DOR) were determined. Hierarchical summary receiver operating characteristic (HSROC) curves for each factor were calculated and the respective area under the curve (AUC) was assessed.
A total of 3443 studies were screened initially. Analysis of recent literature revealed 60 studies with 13 relevant risk factors including clinical, serological and radiological parameters. The largest area under the HSROC curve was found for weight loss (0·84) and jaundice/raised bilirubin level (0·80), followed by increased carcinoembryonic antigen (CEA) (0·79) or carbohydrate antigen (CA) 19-9 (0·78) levels. The most sensitive factors were patient age (71 per cent) and mural nodules (65 per cent), and jaundice/raised bilirubin level (97 per cent) and increased CEA level (95 per cent) were most specific. None of the analysed factors reached a positive or negative level of prediction beyond 90 per cent.
None of the established criteria safely distinguishes malignant from non-malignant lesions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In a double blind placebo controlled trial by Hanauer and colleagues, 2 nine of 47 (19%) patients receiving a relatively low dose of 6-mercaptopurine (6-MP 50 mg/day), six of 44 (14%) patients ...receiving 5-ASA (3 g/day), and four of 40 (10%) patients on placebo were withdrawn from the study because of adverse events, respectively; reasons for withdrawal were diarrhoea (6-MP, 2, 5-ASA, 2), leucopenia (6-MP, 2; 5-ASA, 0), alopecia (6-MP, 2; 5-ASA, 0), elevated liver enzymes (6-MP, 0; 5-ASA, 1), flatus, gastrointestinal bleeding, phlebitis (6-MP, 1 each), and allergic reaction, bowel obstruction, and arthralgia (5-ASA, 1 each).
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