Background
The incidence of asymptomatic, sporadic, small non‐functioning pancreatic neuroendocrine neoplasms (NF‐PNENs) has increased in recent decades. Conservative treatment has been advocated for ...these tumours. The aim of this study was systematically to evaluate the literature on active surveillance and to compare this with surgical management for asymptomatic sporadic small NF‐PNENs.
Methods
PubMed, Embase and the Cochrane Library were searched systematically for studies that compared the active surveillance of asymptomatic, sporadic, small NF‐PNENs with surgical management. PRISMA guidelines for systematic reviews were followed.
Results
After screening 3915 records, five retrospective studies with a total of 540 patients were included. Of these, 327 patients (60·6 per cent) underwent active surveillance and 213 (39·4 per cent) had surgery. There was wide variation in the tumour diameter threshold considered as inclusion criterion (2 cm to any size). The median length of follow‐up ranged from 28 to 45 months. Measurable tumour growth was observed in 0–51·0 per cent of patients. Overall, 46 patients (14·1 per cent) underwent pancreatic resection after initial conservative treatment. In most patients the reason was an increase in tumour size (19 of 46). There were no disease‐related deaths in the active surveillance group in any of the studies.
Conclusion
This systematic review suggests that active surveillance of patients affected by sporadic, small, asymptomatic NF‐PNENs may be a good alternative to surgical treatment.
Watch and wait is safe
Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, Neoptolemos JP, Greenhalf W, Bartsch DK. PALB2 mutations in European pancreatic cancer families.
Recently, PALB2 was reported to be a ...new pancreatic cancer susceptibility gene as determined by exomic sequencing, as truncating PALB2 mutations were identified in 3 of 96 American patients with familial pancreatic cancer (FPC). Representing the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) and the German National Case Collection for Familial Pancreatic Cancer (FaPaCa), we evaluated whether truncating mutations could also be detected in European FPC families. We have directly sequenced the 13 exons of the PALB2 gene in affected index patients of 81 FPC families. An index patient was defined as the first medically identified patient, stimulating investigation of other members of the family to discover a possible genetic factor. None of these patients carried a BRCA2 mutation. We identified three (3.7%) truncating PALB2 mutations, each producing different stop codons: R414X, 508‐9delAG and 3116delA. Interestingly, each of these three families also had a history of breast cancer. Therefore, PALB2 mutations might be causative for FPC in a small subset of European families, especially in those with an additional occurrence of breast cancer.
Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in ...rPDAC (National Comprehensive Cancer Network criteria).
NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle.
The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B). The pre-defined DFS rate of 55% at 18 months was not reached in both arms A: 33.3% (95% confidence interval CI 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%). Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms.
The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A 25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months). There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined.
The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013–005559-34).
Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer:•Did not meet its primary endpoint in either arm of the study (DFS rate at 18 months of 55% in the mITT population).•Showed that pre-operative chemotherapy can be completed by the majority of patients (90%).•Showed an mOS as a secondary endpoint of 25.5 months in arm A (perioperative) and 16.7 months in arm B (upfront surgery).•Gemcitabine and nab-paclitaxel were safe and well tolerated both in the perioperative as well as the adjuvant setting.
Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme.
To ...evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years.
HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography.
Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1).
In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.
Loss of control over drinking is a key deficit in alcoholism causally associated with malfunction of the medial prefrontal cortex (mPFC), but underlying molecular and cellular mechanisms remain ...unclear. Cue-induced reinstatement of alcohol seeking activates a subset of mPFC neurons in rats, identified by their common expression of the activity marker cFos and comprised of both principal and interneurons. Here, we used cFos-lacZ and pCAG-lacZ transgenic rats for activity-dependent or nonselective inactivation of neurons, respectively, which by their lacZ encoded β-galactosidase activity convert the inactive prodrug Daun02 into the neurotoxin daunorubicin. We report that activity-dependent ablation of a neuronal ensemble in the infralimbic but not the prelimbic subregion induced excessive alcohol seeking. The targeted neuronal ensemble was specific for the cue-induced response because stress-induced reinstatement was not affected in these animals. Importantly, nonselective inactivation of infralimbic neurons, using pCAG-lacZ rats, was without functional consequence on the cue-induced reinstatement task. Thus, inhibitory control over alcohol seeking is exerted by distinct functional ensembles within the infralimbic cortex rather than by a general inhibitory tone of this region on the behavioral output. This indicates a high level of functional compartmentation within the rat mPFC whereat many functional ensembles could coexist and interact within the same subregion.
Hebb's (1949) idea of memories as being represented in local neuronal networks is supported by identification of transiently stable activity patterns within subgroups of neurons. However, it is difficult to link individual networks to specific memory tasks, for example a learned behavior. By a novel approach of activity-dependent ablation, here we identify a specific neuronal ensemble located in the infralimbic subregion of the medial prefrontal cortex that controls a seeking response for alcohol in rats. Our data demonstrate that functional output depends on specific neuronal ensembles within a given brain region rather than on the global activity of that region, which raises important questions about the interpretation of numerous earlier experiments using site-directed silencing or stimulation for elucidating brain function.
Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age ...to begin screening and the optimal screening protocol remain to be determined.
IAR from non-CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed.
253 IAR with a median age of 48 (25-81) years underwent screening with a median of 3 (1-11) screening visits during a median follow-up of 28 (1-152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30).
It appears safe to start screening for PDAC in IAR of non-CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.
Background: Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown ...that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer. Methods: We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2. Results: Three (12%, exact 95% confidence interval CI = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer. Conclusions: Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.
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