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

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

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

Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. Methods: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. Results: Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14+ cells. Conclusion: MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment

Diagnosis and treatment of exocrine pancreatic insufficiency in chronic pancreatitis: An international expert survey and case vignette study.

Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence