Riccardo Casadei

Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis

Despite the genomic characterization of pancreatic cancerxa0(PC), marked advances in the development of prognosis classification and novel therapeutic strategies have yet to come. The present study aimed to better understand the genomic alterations associated with the invasive phenotype of PC, in order to improve patient selection for treatment options. A total of 30xa0PC samples were analysed by either whole transcriptome (9xa0samples) or exome sequencing (21xa0samples) on an Illumina platform (75X2 or 100X2xa0bp), and the results were matched with normal DNA to identify somatic events. Single nucleotide variants and insertions and deletions were annotated using public databases, and the pathogenicity of the identified variants was defined according to prior knowledge and mutation-prediction tools. A total of 43xa0recurrently altered genes were identified, which were involved in numerous pathways, including chromatin remodelling and DNA damage repair. In addition, an analysis limited to a subgroup of early stage patients (50% of samples) demonstrated that poor prognosis was significantly associated with a higher number of known PC mutations (P=0.047). Samples from patients with a better overall survival (>25xa0months) harboured an average of 24xa0events, whereas samples from patients with an overall survival of <25xa0months presented an average of 40xa0mutations. These findings indicated that a complex genetic profile in the early stage of disease may be associated with increased aggressiveness, thus suggesting an urgent requirement for an innovative approach to classify this disease.

Prospective validation of a preoperative risk score model based on pancreatic texture to predict postoperative pancreatic fistula after pancreaticoduodenectomy

BACKGROUNDnIn 2015, basing on objective preoperative factors related to pancreas remnant texture (body mass index, Wirsung duct size and preoperative diagnosis), we proposed a score model to predict the risk of postoperative pancreatic fistula after partial pancreatectomies. The aim of the present study was to prospectively validate this preoperative predictive risk score for postoperative pancreatic fistula after pancreaticoduodenectomy.nnnMETHODSnProspective study of consecutive patients who underwent pancreaticoduodenectomy in which a preoperative risk score, based on factors related to the pancreatic texture, was calculated. The risk score model was tested by comparison with subjective intraoperative assessment of the pancreas remnant texture and drain amylase value on postoperative day 1. Sensitivity, specificity, positive and negative likelihood ratio and area under the curve were calculated.nnnRESULTSnEighty-four patients who underwent pancreaticoduodnectomy were analyzed. Clinically relevant pancreatic fistulas rate was 40.6%. The risk score model with a cut-off of 6 increased the odds of pancreatic fistula approximately 3 fold but it was not independently related to it. On the contrary, considering a cut-off of 5, the risk score model increased the odds of pancreatic fistula 11-16 fold and it was independently related to it. The new risk score model and pancreatic texture had high sensitivity (97% and 88%, respectively) and low specificity (34% and 60%, respectively) while the amylase drain value had low sensitivity (44%) and high specificity (92%).nnnCONCLUSIONSnThe preoperative risk score model with a cut-off of 5 was a useful predictor of clinically relevant pancreatic fistula after pancreaticoduodenectomy. The drain amylase value represents a complementary factor to the risk score in predicting a pancreatic fistula.

Copy number gain of chromosome 3q is a recurrent event in patients with intraductal papillary mucinous neoplasm (IPMN) associated with disease progression

Background Intraductal papillary mucinous neoplasm (IPMN) is the most common cystic preneoplastic lesion of pancreatic cancer. We used an approach coupling high resolution cytogenetic analysis (Affymetrix Oncoscan FFPE Array) with clinically-oriented bioinformatic interpretation of data to understand the most relevant alterations of precursor lesions at different stages to identify new diagnostic markers. Results We identified multiple copy number alterations, particularly in lesions with severe dysplasia, with 7 IPMN with low-intermediate dysplasia carrying a nearly normal karyotype and 13 IPMN with complex Karyotype (> 4 alterations), showing high grade dysplasia. A specific gain of chromosome arm 3q was found in IPMN with complex Karyotype (92%). This gain of 3q is particularly interesting for the presence of oncogenes such as PIK3CA, GATA2 and TERC that are part of pathways that deregulate cell growth and promote disease progression. Quantitative PCR and FISH analysis confirmed the data. Further demonstration of the overexpression of the PIK3CA gene supports the identification of this alteration as a possible biomarker in the early identification of patients with IPMN at higher risk for disease progression. Materials and methods High resolution cytogenetic analysis was performed in 20 formalin fixed paraffin embedded samples of IPMN by Oncoscan FFPE assay. Results were validated by qPCR and FISH analysis. Conclusions The identification of these markers at an early stage of disease onset could help to identify patients at risk for cancer progression and new candidates for a more specific targeted therapy.

Multicolour versus monocolour inking specimens after pancreaticoduodenectomy for periampullary cancer: A single centre prospective randomised clinical trial

BACKGROUNDnR status represents an important prognostic factors in periampullary cancers. Thus, it is useful to verify if it can be influenced by different techniques of margination.nnnMETHODSnSingle-centre, randomised clinical trial of patients affected by periampullary cancer who underwent pancreaticoduodenectomies which included two different types of margination: arm A (multicolour inking) and arm B (monocolour inking). The primary endpoint was the overall R1 resection rate and its difference between the two arms. The secondary endpoints were the R1 resection rate in each margin and its difference between the two arms, and the impact of margin status on survival.nnnRESULTSnFifty patients were randomised, 41 analysed: 22 in arm A, 19 arm B. The overall R1 status was 61%, without significant differences between the two arms. The margin most commonly involved was the superior mesenteric artery (SMA) (36.6%). A trend in favour of arm B was shown for the superior mesenteric artery margin (arm Au202f=u202f22.7% versus arm Bu202f=u202f52.6%; Pu202f=u202f0.060). The anterior surface (Pu202f=u202f0.015), SMA (Pu202f=u202f0.047) and pancreatic remnant (Pu202f=u202f0.018) margins significantly influenced disease-free survival.nnnCONCLUSIONSnThe R status was not influenced by different techniques of margination using a standardised pathological protocol. The SMA margin seemed to be the most important margin for evaluating both R status and disease-free survival.

Organizing pneumonia after pancreatic cancer treatment with nab-paclitaxel and gemcitabine: a case report

The incidence of pancreatic cancer is increasing. Most patients have advanced disease at diagnosis, and therapeutics is limited in this setting. Gemcitabine and nab-paclitaxel combination is indicated as first-line treatment in patients with metastatic cancer of pancreas. The most common adverse events of Grade 3 or higher gemcitabine and nab-paclitaxel combination are neutropenia, fatigue and neuropathy. In this report, we describe a rare case of organizing pneumonia associated with the use of nab-paclitaxel and gemcitabine in metastatic pancreatic cancer. A 68-year-old female underwent total splenopancreatectomy for ductal adenocarcinoma of the neck of the pancreas, followed by adjuvant chemoradiation therapy. Afterwards she relapsed and received first-line chemotherapy with gemcitabine plus nab-paclitaxel combination for 12 cycles. Following the administration of the 12th cycle of gemcitabine plus nab-paclitaxel, the patient experienced low-grade pyrexia, effort dyspnoea, persistent non-productive cough and malaise. High-resolution CT scan of chest revealed new-onset bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas, findings consistent with organizing pneumonia. A thorough microbiological workup was negative. Treatment with steroids resulted in prompt clinical and radiological improvement. Organizing pneumonia closely mimics infection or progressive disease and can be difficult to diagnose in the setting of malignancy. Correct diagnosis is of primary importance since delay in treatment can result in significantly adverse patient outcomes.