Per Hedenström

Diabetes, Smoking, Alcohol Use, and Family History of Cancer as Risk Factors for Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

Background and Aims: Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs. Methods: MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I2 = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I2 = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I2 = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I2 = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I2 = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I2 = 0.0%) for first-degree family history of cancer. Conclusions: Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET.

Risk and protective factors for the occurrence of sporadic pancreatic endocrine neoplasms

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.

EUS-guided reverse bevel fine-needle biopsy sampling and open tip fine-needle aspiration in solid pancreatic lesions – a prospective, comparative study

Abstract Objectives: Different diagnostic entities can present as solid pancreatic lesions (SPL). This study aimed to explore the utility of endoscopic ultrasound-guided reverse bevel fine-needle biopsy sampling (EUS-FNB) in SPLs. Material and methods: In 2012–2015, consecutive patients with SPLs were prospectively included in a tertiary center setting and subjected to dual needle sampling with a 22 gauge reverse bevel biopsy needle and a conventional 25 gauge open tip aspiration needle (EUS-FNA). The outcome measures were the diagnostic accuracy of sampling, calculated for each modality separately and for the modalities combined (EUS-FNA + FNB), and the adverse event rate related to sampling. Results: In 68 unique study subjects, the most common diagnostic entities were pancreatic neuroendocrine tumor, PNET, (34%), pancreatic ductal adenocarcinoma, PDAC, (32%), pancreatitis (15%) and metastasis (6%). The overall diagnostic accuracy of EUS-FNB was not significantly different from that of EUS-FNA, (69% vs. 78%, p = .31). EUS-FNA + FNB, compared with EUS-FNA alone, had a higher sensitivity for tumors other than PDAC (89% vs. 69%, p = .02) but not for PDACs (95% vs. 85%, p = .5). No adverse event was recorded after the study dual-needle sampling procedures. Conclusions: Endoscopic ultrasound-guided tissue acquisition performed with a 22 gauge reverse bevel biopsy needle is safe but not superior to conventional fine-needle aspiration performed with a 25 gauge open tip needle in diagnosing solid pancreatic lesions. However, the performance of both these modalities may facilitate the diagnostic work-up in selected patients, such as cases suspicious for pancreatic neuroendocrine tumors and metastases. NCT02360839.

Characterizing gastrointestinal stromal tumors and evaluating neoadjuvant imatinib by sequencing of endoscopic ultrasound-biopsies

AIM To evaluate endoscopic ultrasound (EUS)-guided biopsies for the pretreatment characterization of gastrointestinal stromal tumors (GIST) to personalize the management of patients. METHODS All patients with lesions suspected to be GIST who were referred for EUS-sampling at a tertiary Swedish center were eligible for inclusion 2006-2015. During the observational study phase (2006-2011), routine fine-needle-aspiration (EUS-FNA) was performed. In 2012-2015, we converted to an interventional, randomized protocol with dual sampling EUS-FNA and fine-needle-biopsy-sampling (EUS-FNB) for all lesions. c-KIT- and DOG-1-immunostaining was attempted in all samples and a manual count of the Ki-67-index was performed. FNB-sampled tissue and the resected specimens were subjected to Sanger sequencing of the KIT and platelet-derived growth factor alpha (PDGFRA) genes. RESULTS In all, 64 unique patients with GIST were included, and of these, 38 were subjected to pretreatment dual sampling. EUS-FNB had a higher diagnostic sensitivity when compared head-to-head with EUS-FNA (98% vs 58%, P < 0.001) and was more adequate for Ki-67-indexing (Ki-67EUS) (92% vs 40%, P < 0.001). Sequencing of EUS-biopsies was successful in 43/44 (98%) patients, and the mutation profiles (KIT-mutation 73%, PDGFRA-mutation 18%, wild-type 7%) were fully congruent with those detected in the corresponding resected specimens. In imatinib-naïve patients, the Ki-67EUS was comparable with the Ki-67-index in the corresponding surgical specimens (Ki-67SURG) (2.7% vs 2.9%, P = 0.68). In patients treated with neoadjuvant imatinib who also carried mutations indicating sensitivity, the Ki-67EUS was higher than the Ki-67SURG (2.5% vs 0.2%, P = 0.005), with a significant reduction in the Ki-67-index of -91.5% (95%CI: -82.4 to -96.0, P = 0.005). CONCLUSION EUS-guided biopsy sampling is accurate for the pretreatment diagnosis and characterization of GISTs and allows the prediction and evaluation of tumor response to neoadjuvant imatinib therapy.

Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis

Abstract Objectives: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors for SI-NET and to further assess these by meta-analysis. Material and methods: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement. Results: Seven studies evaluating six individual populations were included (study accrual period 1980–2012) in the meta-analysis, involving 765 (range 17–325) cases and 502,282 (range 52–498,376) controls. All studies were case–control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use and ever smoking. The pooled OR was 1.34 (95% CI: 1.12–1.60; p < .01; I2 = 0.0%) for family history of any cancer, 1.43 (95% CI: 1.15–1.79; p < .01; I2 = 0.0%) for family history of colorectal cancer, 1.04 (95% CI: 0.63–1.72; p = .87; I2 = 65.0%) for ever alcohol use and 1.40 (95% CI: 1.06–1.86; p < .05; I2 = 49.3%) for ever smoking. Conclusions: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.

The accuracy and clinical impact of endoscopic ultrasound-guided dual needle sampling in solid pancreatic lesions

Background and Objectives: Different tissue entities can present as solid pancreatic lesions (SPLs). This study aimed to explore the diagnostic accuracy of endoscopic ultrasound-guided dual needle sampling (endoscopic ultrasound-guided fine needle aspiration/biopsy [EUS-FNA/B]) in SPLs. Methods: In 2012-2016, consecutive patients with SPLs were prospectively included in a single-center setting aiming at dual sampling with EUS-FNA (22/25-gauge) and reverse bevel EUS-FNB (22-gauge) in each lesion. Randomization decided if the first pass should be EUS-FNA or EUS-FNB. The primary outcome was the diagnostic accuracy including mandatory immunostaining of all tumors but pancreatic ductal adenocarcinoma (PDAC). The secondary outcome was the clinical impact of dual needle sampling EUS-FNA/B in comparison with single needle EUS-FNA of SPLs performed in the same center 2006-2011 (the comparison cohort). Results: In 108 study subjects, 68 dual needle sampling procedures were performed. The four most common entities were PDAC (32%), neuroendocrine tumor (34%), pancreatitis (15%), and metastasis (6%). EUS-FNA and EUS-FNB had comparable diagnostic accuracy. EUS-FNA/B, compared with EUS-FNA, had a higher sensitivity for malignancy (91% vs. 75%, P = 0.004), higher sensitivity for non-PDAC malignancy (89% vs. 69%, P=0.02), and higher overall accuracy (91% vs. 78%, P=0.004). The performance of an additional diagnostic procedure was less frequent after EUS-FNA/B compared with EUS-FNA of the comparison cohort (4% vs. 21%, P=0.007). Conclusions: Reverse bevel EUS-FNB is not superior to EUS-FNA in the sampling of solid pancreatic lesions. However, dual needle sampling with both modalities (EUS-FNA/B) seems to improve the diagnostic accuracy and facilitate the clinical management, especially in malignant entities other than ductal adenocarcinomas.