Preoperative fine-needle aspiration of pancreatic neuroendocrine tumors: a reliable tool to assess diagnosis and grading - A prospective single-center analysis of 100 cases

Background & Aims:Fine-needle aspiration (FNA) of pancreatic neuroendocrine tumors (Pan-NENs) has been proposed to obtain the grading, using Ki-67 proliferation index calculation. Data on reliability of grading (G) and Ki-67 index calculations from FNA cell blocks are controversial as there are potential limitations. Methods:One hundred patients subjected to FNA for a presumed PanNEN and subsequent resection material were evaluated at a single institution. FNA was obtained with endoultrasonography or with a percutaneous approach. Ki-67 calculation was performed using WHO guidelines. A comparison be-tween cytology (c) and histology (h) was performed for grading, Ki-67 values and diagnostic rate. Results:The overall level of agreement for G (n=63) was moderate (Cohen\u2019s k = 0.455, 95%CI from 0.219 to 0.691, p<0.001; r=0.430, 95%CI from 0.204 to 0.613, p<0.001). The overall sensitivity for G was 76.2%, whereas for G1, G2, and G3 it was 76.6%, 84.6% and 33.3% respectively. Mean in-dex values of cKi-67 and hKi-67 were 4.35 \ub1 9.5% and 5.26 \ub1 12% respectively (p=0.334). Spear-man\u2019s r for Ki-67 was good and very good for the overall population and for PanNENs of tumor size 64 20 mm (respectively r=0.615, 95%CI from 0.434 to 0.749, p<0.001, and r=0.862, 95%CI from 0.718 to 0.935, p<0.001).The Bland-Altman plot showed an agreement between cKi-67 and hKi-67 assessment.The overall concordance rate for diagnosis was 100%. Conclusions:In the presence of a suspected PanNEN, FNA (especially obtained through endoultra-sonography) achieves an excellent diagnostic rate, with satisfactory and reliable results for grading and Ki-67 assessment, particularly for tumors 64 20 mm

Expert Judgment Supporting a Bayesian Network to Model the Survival of Pancreatic Cancer Patients

Purpose: Pancreatic cancer is known for its poor prognosis. The most effective treatment combines surgery with peri-operative chemotherapy. Current prognostic tools are designed to predict patient outcomes and inform treatment decisions based on collected data. Bayesian networks (BNs) can integrate objective data with subjective clinical insights, such as expert opinions, or they can be independently based on either element. This pilot study is one of the first efforts to incorporate expert opinions into a prognostic model using a Bayesian framework. Methods: A clinical hybrid BN was selected to model the long-term overall survival of pancreatic cancer patients. The SHELF expert judgment method was employed to enhance the BN’s effectiveness. This approach involved a two-phase protocol: an initial single-center pilot phase followed by a definitive international phase. Results: Experts generally agreed on the distribution shape among the 12 clinically relevant predictive variables identified for the BN. However, discrepancies were noted in the tumor size, age, and ASA score nodes. With regard to expert concordance for each node, tumor size, and ASA score exhibited absolute concordance, indicating a strong consensus among experts. Ca19.9 values and resectability status showed high concordance, reflecting a solid agreement among the experts. The remaining nodes showed acceptable concordance. Conclusions: This project introduces a novel clinical hybrid Bayesian network (BN) that incorporates expert elicitation and clinical variables present at diagnosis to model the survival of pancreatic cancer patients. This model aims to provide research-based evidence for more reliable prognosis predictions and improved decision-making, addressing the limitations of existing survival prediction models. A validation process will be essential to evaluate the model’s performance and clinical applicabilit

Adjuvant Therapy After Upfront Resection of Resectable Pancreatic Cancer: Patterns of Omission and Use-A Prospective Real-Life Study

Background: Little is known about adjuvant therapy (AT) omission and use outside of randomized trials. We aimed to assess the patterns of AT omission and use in a cohort of upfront resected pancreatic cancer patients in a real-life scenario. Methods: From January 2019 to July 2022, 317 patients with resected pancreatic cancer and operated upfront were prospectively enrolled in this prospective observational trial according to the previously calculated sample size. The association between perioperative variables and the risk of AT omission and AT delay was analyzed using multivariable logistic regression. Results: Eighty patients (25.2%) did not receive AT. The main reasons for AT omission were postoperative complications (38.8%), oncologist's choice (21.2%), baseline comorbidities (20%), patient's choice (10%), and early recurrence (10%). At the multivariable analysis, the odds of not receiving AT increased significantly for older patients (odds ratio [OR] 1.1, p < 0.001), those having an American Society of Anesthesiologists score ≥II (OR 2.03, p = 0.015), or developing postoperative pancreatic fistula (OR 2.5, p = 0.019). The likelihood of not receiving FOLFIRINOX as AT increased for older patients (OR 1.1, p < 0.001), in the presence of early-stage disease (stage I-IIa vs. IIb-III, OR 2.82, p =0.031; N0 vs. N+, OR 3, p = 0.03), and for patients who experienced postoperative major complications (OR 4.7, p = 0.009). A twofold increased likelihood of delay in AT was found in patients experiencing postoperative complications (OR 3.86, p = 0.011). Conclusions: AT is not delivered in about one-quarter of upfront resected pancreatic cancer patients. Age, comorbidities, and postoperative complications are the main drivers of AT omission and mFOLFIRINOX non-use. Clinicaltrials registration: NCT03788382

Prevalence of CDKN2A, CDK4, POT1, BAP1, MITF, ATM, and TERT Pathogenic Variants in a Single-Center Retrospective Series of Patients With Melanoma and Personal or Family History Suggestive of Genetic Predisposition

Introduction: Approximately 20%-45% of familial melanoma (FM) cases are associated with genetic predisposition. Objectives: This single-center retrospective study aimed to assess the frequency of pathogenic variants (PV) in the main melanoma-predisposing genes in patients with cutaneous melanoma and investigate the clinical predictors of genetic predisposition. Methods: Patients included were those diagnosed with cutaneous melanoma at the Dermatology Unit of the University Hospital, Verona, Italy, from 2000 to 2022, presenting at least one of the following: multiple melanomas (≥3); personal/family history of pancreatic cancer (PC) (up to second-degree relatives); ≥2 first-degree relatives with melanoma; ≥1 first-degree relatives with early onset (<45 years) melanoma and tested for CDKN2A, CDK4, POT1, BAP1, MITF, ATM, and TERT. Results: During the study period, 35 out of 1,320 patients (2.7%) underwent genetic testing. Four patients (11.4%) harbored a PV in a melanoma-predisposing gene, 3 in CDKN2A (8.6%), and 1 in MITF (2.9%). Variants currently classified as being of unknown clinical significance (VUS) were detected in CDKN2A (n=1), MITF (n=1), and ATM (n=2). Family history of PC and ≥5 melanomas, personal history of ≥50 nevi, and ≥4 melanomas were significantly associated with PV in tested genes (P<0.05). Conclusions: The prevalence of PV in predisposing genes in FM was lower than previously reported in Italian registries. Possible reasons include deleterious variants in untested intermediate-/low-penetrance genes or yet-to-be-discovered high-penetrance genes and environmental risk factors. A family history of PC, a high number of nevi and melanomas predict a monogenic predisposition to melanoma

The effect of early oral postoperative feeding on the recovery of intestinal motility after gastrointestinal surgery: a systematic review and meta-analysis of randomized clinical trials

Background and aimsPostoperative ileus is a frequent condition, leading to complications and a longer hospital stay. Few studies have demonstrated the benefit of early oral feeding in preventing ileus after gastrointestinal surgery. This study aims to evaluate the efficacy of early versus delayed oral feeding on the recovery of intestinal motility, length of hospital stay, and complications.MethodsWe conducted a systematic review and meta-analysis of randomized control trials, searching PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and the ClincalTrials.gov until 31 December 2022. We evaluated the first passage of the stool, the first flatus, complications, length of postoperative stay, and vomiting. We assessed the risk of bias using the Cochrane risk of bias tool (version 2) for randomized trials and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation methodology.ResultsWe included 34 studies with a median sample size of 102 participants. With a moderate certainty of the evidence, the early oral feeding may reduce the time taken for the first passage of the stool (MD −0.99 days; CI 95% −1.25, −0.72), the first flatus (MD −0.70 days; CI 95% -0.87, −0.53), and the risk of complications (RR 0.69; CI 95% 0.59–0.80), while with a low certainty of evidence, it may reduce the length of stay (MD −1.31 days; CI 95% −1.59, −1.03). However, early feeding likely does not affect the risk of vomiting (RR 0.90; CI 95% 0.68, 1.18).ConclusionThis review suggests that early oral feeding after gastrointestinal surgery may lead to a faster intestinal recovery, shorter postoperative stays, and fewer complications. However, careful interpretation is needed due to high heterogeneity and the moderate-to-low quality of evidence. Future studies should focus on the type and starting time of early oral feeding

Impact of exercise in patients with pancreatic cancer across different treatment phases: a systematic review

Background: With a dismal prognosis of 8-10% 5-year survival since diagnosis, pancreatic cancer remains one of the most aggressive oncological diseases. This work aimed to evaluate the effects of exercise medicine on safety and feasibility, physical fitness, body composition, patient-reported outcomes, and clinical outcomes across different treatment phases in patients with pancreatic cancer. Method: PubMed, Cochrane, and Scopus databases were systematically screened to identify single-arm studies and randomized/non-randomized controlled trials investigating a physical exercise intervention in patients with pancreatic cancer. The RoB 2 and ROBINS-I tools were used to evaluate study quality for randomized and non-randomized studies, respectively. Qualitative and quantitative synthesis approaches were used. Results: Among the 5,550 identified records, 11 randomized controlled trials and 6 non-randomized studies were considered eligible. Five investigations were conducted in the neoadjuvant setting, eight in the rehabilitative and three during palliative phases. Regarding neoadjuvant exercise, there were no significant changes in cardiorespiratory fitness and muscle strength, whilst a gain in muscle mass was detected. Similarly, in the rehabilitative setting, mixed results were observed for cardiorespiratory fitness and body composition; a positive impact was registered in strength, glucose levels, tryptophan metabolism, and quality of life after 3 months of intervention. In the palliative setting, significant improvements were observed for muscle strength and quality of life, but not for clinical outcomes. Conclusion: Although physical exercise may ameliorate sequelae of pancreatic cancer, further investigation is necessary to understand the real impact of exercise medicine interventions in this population and across different treatment phases

ERAS with or without supplemental artificial nutrition in open pancreatoduodenectomy for cancer. A multicenter, randomized, open labeled trial (RASTA study protocol)

PurposeThe role of supplemental artificial nutrition in patients perioperatively treated according to enhanced recovery programs (ERAS) on surgery-related morbidity is not known. Therefore, there is a need of a clinical trials specifically designed to explore whether given a full nutritional requirement by parenteral feeding after surgery coupled with oral food “at will” compared to oral food “at will” alone, within an established ERAS program, could achieve a reduction of the morbidity burden.Materials and analysisRASTA will be a multicenter, randomized, parallel-arm, open labeled, superiority trial. The trial will be conducted in five Italian Institutions with proven experience in pancreatic surgery and already applying an established ERAS program. Adult patients (age ≥ 18 and &lt; 90 years of age) candidate to elective open pancreatoduodenectomy (PD) for any periampullary or pancreatic cancer will be randomized to receive a full ERAS protocol that establishes oral food “at will” plus parenteral nutrition (PN) from postoperative day 1 to day 5 (treatment arm), or to ERAS protocol without PN (control arm). The primary endpoint of the trial is the complication burden within 90 days after the day of surgery. The complication burden will be assessed by the Comprehensive Complication Index, that incorporates all complications and their severity as defined by the Clavien-Dindo classification, and summarizes postoperative morbidity with a numerical scale ranging from 0 to 100. The H0 hypothesis tested is that he administration of a parenteral nutrition added to the ERAS protocol will not affect the CCI as compared to standard of care (ERAS). The H1 hypothesis is that the administration of a parenteral nutrition added to the ERAS protocol will positively affect the CCI as compared to standard of care (ERAS). The trial has been registered at ClinicalTrials.gov (number: NCT04438447; date: 18/05/2020).ConclusionThis upcoming trial will permit to establish if early postoperative artificial nutritional support after PD may improve postoperative outcomes compared to oral nutrition alone within an established ERAS program

Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC

Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients

Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas - A multicentric European study on radically resected patients

Background: Acinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. Methods: This is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. Results: 59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0&nbsp;mm. 61.0% were pT3 (n&nbsp;=&nbsp;36), nodal positivity rate was 37.3% (n&nbsp;=&nbsp;22), and synchronous distant metastases were present in 10.1% of the patients (n&nbsp;=&nbsp;6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n&nbsp;=&nbsp;18 only systemic, n&nbsp;=&nbsp;6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p&nbsp;=&nbsp;0.004, p&nbsp;=&nbsp;0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p&nbsp;=&nbsp;0.542) nor DFS (p&nbsp;=&nbsp;0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. Discussion: Radical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting

Body composition parameters, immunonutritional indexes, and surgical outcome of pancreatic cancer patients resected after neoadjuvant therapy: A retrospective, multicenter analysis

Background and aims: Body composition parameters and immunonutritional indexes provide useful information on the nutritional and inflammatory status of patients. We sought to investigate whether they predict the postoperative outcome in patients with pancreatic cancer (PC) who received neoadjuvant therapy (NAT) and then pancreaticoduodenectomy. Methods: Data from locally advanced PC patients who underwent NAT followed by pancreaticoduodenectomy between January 2012 and December 2019 in four high-volume institutions were collected retrospectively. Only patients with two available CT scans (before and after NAT) and immunonutritional indexes (before surgery) available were included. Body composition was assessed and immunonutritional indexes collected were: VAT, SAT, SMI, SMA, PLR, NLR, LMR, and PNI. The postoperative outcomes evaluated were overall morbidity (any complication occurring), major complications (Clavien-Dindo ≥ 3), and length of stay. Results: One hundred twenty-one patients met the inclusion criteria and constituted the study population. The median age at the diagnosis was 64 years (IQR16), and the median BMI was 24 kg/m2 (IQR 4.1). The median time between the two CT-scan examined was 188 days (IQR 48). Skeletal muscle index (SMI) decreased after NAT, with a median delta of −7.8 cm2/m2 (p &lt; 0.05). Major complications occurred more frequently in patients with a lower pre-NAT SMI (p = 0.035) and in those who gained in subcutaneous adipose tissue (SAT) compartment during NAT (p = 0.043). Patients with a gain in SMI experienced fewer major postoperative complications (p = 0.002). The presence of Low muscle mass after NAT was associated with a longer hospital stay [Beta 5.1, 95%CI (1.5, 8.7), p = 0.006]. An increase in SMI from 35 to 40 cm2/m2 was a protective factor with respect to overall postoperative complications [OR 0.43, 95% (CI 0.21, 0.86), p &lt; 0.001]. None of the immunonutritional indexes investigated predicted the postoperative outcome. Conclusion: Body composition changes during NAT are associated with surgical outcome in PC patients who receive pancreaticoduodenectomy after NAT. An increase in SMI during NAT should be favored to ameliorate the postoperative outcome. Immunonutritional indexes did not show to be capable of predicting the surgical outcome