Prognostic value of major pathological response following neoadjuvant therapy for non resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The aim of this study is to evaluate the impact of major pathological response on overall survival (OS) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma following neoadjuvant treatment, and to identify predictors of major pathological response. METHODS: Patients surgically resected following neoadjuvant treatment between 2010 and 2020 at the Pederzoli Hospital were retrospectively analyzed. Pathologic response was assessed using the College of American Pathologists (CAP) score, and major pathological response was defined as CAP 0-1. OS was estimated and compared using the Kaplan-Meier method and log-rank test. A logistic and Cox regression model were performed to identify predictors of major pathologic response and OS. RESULTS: Overall, 200 patients were included in the study. A major and complete pathological response were observed in 52(26.0%) and 15(7.3%) patients respectively. The 1-, 3-, 5-year OS was 92.7, 67.2, and 41.7%, and 71.0, 37.4, and 20.8% in patients with or without major pathologic response respectively (log-rank test p < 0.001). Major pathologic response was confirmed as independent predictor of OS (OR 0.50 95%CI 0.29-0.88, p = 0.01). Post-treatment CA19-9 normalization (OR 4.20 95%CI 1.14-10.35, p = 0.02) and radiological post-treatment tumor residual size<25 mm (OR 2.71 95%CI 1.27-5.79, p = 0.01) were found to be independent predictors of major pathologic response. CONCLUSION: Patients experienced a major pathological response after neoadjuvant treatment have an increased survival, and major pathologic response is an independent predictor of OS. A normal CA19-9 value and radiological tumor size at restaging are confirmed to be independent predictors of major pathologic response.

Hepatic Artery Anomalies in Pancreaticoduodenectomy: Outcomes from a High-Volume Center.

INTRODUCTION: Hepatic artery anomalies (HAA) may have an impact on surgical and oncological outcomes of patients undergoing pancreaticoduodenectomy (PD). METHODS: Patients who underwent PD at our institution between July 2015 and January 2020 were retrospectively reviewed and classified into two groups: group 1, with presence of HAA, and group 2, with no HAA. A weighted logistic regression model was employed to assess the association between HAA and postoperative complications, and to assess the association between HAA and R status in patients with pancreatic cancer. RESULTS: 502 patients were considered for analysis, with 75 (15%) of them in group 1. They had either an accessory (n = 28, 40.8%) or replaced (n = 26, 36.6%) right hepatic artery. Most patients underwent surgery for a malignancy (n = 451; 90%); among them, vascular resection was performed in 69 cases (15%). The presence of a HAA was reported at preoperative imaging only in 4 cases (5%) and the aberrant vessel was preserved in 72% of patients. At weighted multivariable logistic regression analysis, HAA were not associated to higher odds of morbidity (odds ratio [OR]: 0.753, 95% confidence interval [CI]: 0.543-1.043) nor to R1 status in case of pancreatic cancer (OR: 1.583, 95% CI: 0.979-2.561). CONCLUSION: At our institution, the presence of HAA does not have an impact on postoperative outcomes or affects oncological clearance after PD. Hospitals', surgeons', volume and systematic review of preoperative imaging are all factors that help reduce possible adverse events.

Telemedicine and Pancreatic Cancer: A Systematic Review.

Introduction: Pancreatic cancer requires a multidisciplinary approach in a high-volume center for all the steps of the diagnostic-therapeutic course. However, the most experienced centers are not evenly distributed throughout the country causing a real "health migration" that involves patients and families with relevant economic, time, and energy costs to bear. The COVID-19 pandemic had a deep impact on surgical and oncological care and the travel limits due to COVID-related restrictions, have delayed the care of cancer patient living far from the referral centers. In this scenario, several telemedicine approaches have been proposed to reduce the distance between clinicians and patients and to allow a fast and effective access to care even for patients distant from referral centers. The aim of the study is to analyze the evidence and describe the current utility of telemedicine tool for patients with pancreatic cancer. Methods: We systematically searched the literature in the following databases: Web of Science, PubMed, Scopus, and MEDLINE. The inclusion criteria were article describing a telemedicine intervention (virtual visits, telephone follow-up/counseling, mobile or online apps, telemonitoring) and focusing on adult patients with pancreatic cancer at any stage of the disease. Results: In total, 846 titles/abstracts were identified. Following quality assessment, the review included 40 studies. Telemedicine has been proposed in multiple clinical settings, demonstrating high levels of patient and health professional satisfaction. Conclusion: Successful telemedicine applications in patients with pancreatic cancer are telerehabilitation and nutritional assessment, remote symptom control, teledischarge after pancreatic surgery, tele-education and medical mentoring regarding pancreatic disease as well as telepathology.

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 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 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.

Prognostic Factors After Pancreatectomy for Pancreatic Cancer Initially Metastatic to the Liver.

BACKGROUND: Resection of initially oligometastatic pancreatic ductal adenocarcinoma (PDAC) following response to first-line chemotherapy is controversial. We herein updated a previous case series to investigate the oncologic outcomes and preoperative factors that could drive the decision-making process. METHODS: This retrospective analysis was limited to patients with liver-only synchronous metastases who experienced complete regression of the metastatic component and underwent pancreatectomy between October 2008 and July 2020 at two high-volume institutions. Clinical-pathologic variables were captured, and inflammation-based prognostic scores were calculated. Recurrence and survival analyses were performed using standard statistical methods. RESULTS: Overall, 52 patients were included. FOLFIRINOX was the most employed chemotherapy regimen (63.5%). Post-treatment tumor size, serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) were significantly decreased relative to baseline evaluation. The median time from diagnosis to pancreatectomy was 10.2 months, while the median time from chemotherapy completion to pancreatectomy was 2 months. Major postoperative complications occurred in 26.9% of patients, while postoperative mortality was nil. The median disease-free survival (DFS) and overall survival (OS) from pancreatectomy were 16.5 and 23.0 months, respectively, and the median OS from diagnosis was 37.2 months. At multivariable analysis, vascular resection, operative time, prognostic nutrition index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were associated with OS. Operative time, platelet × neutrophil/lymphocyte count (SII), and PNI were associated with DFS. CONCLUSIONS: We confirm promising outcomes of selected patients who underwent pancreatectomy following downstaging of liver metastases. The absence of vascular involvement of the primary tumor, good nutritional status, and low inflammatory index scores could be useful to select candidates for resection.

401 consecutive minimally invasive distal pancreatectomies: lessons learned from 20 years of experience.

BACKGROUND: This study aimed to discuss and report the trend, outcomes, and learning curve effect after minimally invasive distal pancreatectomy (MIDP) at two high-volume centres. METHODS: Patients undergoing MIDP between January 1999 and December 2018 were retrospectively identified from prospectively maintained electronic databases. The entire cohort was divided into two groups constituting the "early" and "recent" phases. The learning curve effect was analyzed for laparoscopic (LDP) and robotic distal pancreatectomy (RDP). The follow-up was at least 2 years. RESULTS: The study population included 401 consecutive patients (LDP n = 300, RDP n = 101). Twelve surgeons performed MIDP during the study period. Although patients were more carefully selected in the early phase, in terms of median age (49 vs. 55 years, p = 0.026), ASA class higher than 2 (3% vs. 9%, p = 0.018), previous abdominal surgery (10% vs. 34%, p < 0.001), and pancreatic adenocarcinoma (PDAC) (7% vs. 15%, p = 0.017), the recent phase had similar perioperative outcomes. The increase of experience in LDP was inversely associated with the operative time (240 vs 210 min, p < 0.001), morbidity rate (56.5% vs. 40.1%, p = 0.005), intra-abdominal collection (28.3% vs. 17.3%, p = 0.023), and length of stay (8 vs. 7 days, p = 0.009). Median survival in the PDAC subgroup was 53 months. CONCLUSION: In the setting of high-volume centres, the surgical training of MIDP is associated with acceptable rates of morbidity. The learning curve can be largely achieved by several team members, improving outcomes over time. Whenever possible resection of PDAC guarantees adequate oncological results and survival.

A randomized controlled trial of stapled versus ultrasonic transection in distal pancreatectomy.

BACKGROUND: The pancreatic transection method during distal pancreatectomy is thought to influence postoperative fistula rates. Yet, the optimal technique for minimizing fistula occurrence is still unclear. The present randomized controlled trial compared stapled versus ultrasonic transection in elective distal pancreatectomy. METHODS: Patients undergoing distal pancreatectomy from July 2018 to July 2020 at two high-volume institutions were considered for inclusion. Exclusion criteria were contiguous organ resection and a parenchymal thickness > 17 mm on intraoperative ultrasound. Eligible patients were randomized in a 1:1 ratio to stapled transection (Endo GIA Reinforced Reload with Tri-Staple Technology®) or ultrasonic transection (Harmonic Focus® + or Harmonic Ace® + shears). The primary endpoint was postoperative pancreatic fistula. Secondary endpoints included overall complications, abdominal collections, and length of hospital stay. RESULTS: Overall, 72 patients were randomized in the stapled transection arm and 73 patients in the ultrasonic transection arm. Postoperative pancreatic fistula occurred in 23 patients (16%), with a comparable incidence between groups (12% in stapled transection versus 19% in ultrasonic dissection arm, p = 0.191). Overall complications did not differ substantially (35% in stapled transection versus 44% in ultrasonic transection arm, p = 0.170). There was an increased incidence of abdominal collections in the ultrasonic dissection group (32% versus 14%, p = 0.009), yet the need for percutaneous drain did not differ between randomization arms (p = 0.169). The median length of stay was 8 days in both groups (p = 0.880). Intraoperative blood transfusion was the only factor independently associated with postoperative pancreatic fistula on logistic regression analysis (OR 4.8, 95% CI 1.2-20.0, p = 0.032). CONCLUSION: The present randomized controlled trial of stapled versus ultrasonic transection in elective distal pancreatectomy demonstrated no significant difference in postoperative pancreatic fistula rates and no substantial clinical impact on other secondary endpoints.

Open radiofrequency ablation as upfront treatment for locally advanced pancreatic cancer: Requiem from a randomized controlled trial.

BACKGROUND: Local ablation of pancreatic cancer has been suggested as an option to manage locally advanced pancreatic cancer (LAPC) although no robust evidence has been published to date to support its application. The aim of this study is to compare overall survival (OS) and progression-free survival (PFS) in patients receiving both radiofrequency ablation (RFA) and conventional chemoradiotherapy (CHRT) with patients receiving CHRT only. METHODS: This is a multicentre prospective randomized controlled trial (RCT). Patients with LAPC diagnosed by the Pancreas-Ablation-Team-Verona were randomly assigned to open RFA (Group A) or CHRT (Group B). Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at p < 0.05. RESULTS: One hundred LAPC patients were enrolled from January 2014 to August 2016. 33% of patients in Group A did not receive the designated procedure because of intraoperative findings of liver (18.7%) or peritoneal metastases (43.8%), or technical contraindications (37.5%). We did not observe any statistically significant survival benefit from RFA compared to CHRT, neither in terms of OS (medians of 14.2 months and 18.1 months, respectively, p = 0.639) nor PFS (medians of 8 months and 6 months respectively, p = 0.570). Mortality was nil and RFA-related morbidity was 15.6%. In 13% of subjects, conversion to surgery occurred (2 after RFA and 11 after CHRT). CONCLUSIONS: This is the first RCT evaluating the impact of upfront RFA in the multimodal treatment of LAPC. Compared to CHRT, RFA alone did not provide any advantage in terms of OS or PFS. It could be considered as a therapeutic option for LAPC within a multimodal context and after neoadjuvant therapies.

Role of next-generation genomic sequencing in targeted agents repositioning for pancreaticoduodenal cancer patients.

BACKGROUND: Pancreaticoduodenal cancer (PDC) is a group of malignant tumors arising in the ampullary region, which lack approved targeted therapies for their treatment. METHODS: This retrospective, observational study is based on Secondary Data Use (SDU) previously collected during a multicenter collaboration, which were subsequently entered into a predefined database and analyzed. FoundationOne CDx or Liquid, a next-generation DNA sequencing (NGS) service, was used to identify genomic alterations of patients who failed standard treatments. Detected alterations were described according to ESMO Scale of Clinical Actionability for molecular Targets (ESCAT). RESULTS: NGS analysis was performed in 68 patients affected by PDC. At least one alteration ranking tier I, II, III, or IV according to ESCAT classification was detected in 8, 1, 9, and 12 patients respectively (44.1%). Ten of them (33.3%) received a matched therapy. Patients with ESCAT tier I to IV were generally younger than the overall population (median = 54, range = 26-71 years), had an EGOG performance status score = 0 (83.3%), and an uncommon histological or clinical presentation. The most common mutations with clinical evidence of actionability (ESCAT tier I-III) involved genes of the RAF (10.3%), BRCA (5.9%) or FGFR pathways (5.9%). We present the activity of the RAF kinases inhibitor sorafenib in patients with RAF-mutated advanced PDC. CONCLUSIONS: In advanced PDC, NGS is a feasible and valuable method for enabling precision oncology. This genomic profiling method might be considered after standard treatments failure, especially in young patients maintaining a good performance status, in order to detect potentially actionable mutations and offer molecularly targeted therapeutic approaches.

Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA): A Pan-European Propensity Score Matched Study.

OBJECTIVE: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. METHODS: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. RESULTS: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60-400) vs 300 mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929). CONCLUSIONS: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

Results of First-Round of Surveillance in Individuals at High-Risk of Pancreatic Cancer from the AISP (Italian Association for the Study of the Pancreas) Registry.

INTRODUCTION: Surveillance programs on high-risk individuals (HRIs) can detect pre-malignant lesions or early pancreatic cancer (PC). We report the results of the first screening round of the Italian multicenter program supported by the Italian Association for the study of the Pancreas (AISP). METHODS: The multicenter surveillance program included asymptomatic HRIs with familial (FPC) or genetic frailty (GS: BRCA1/2, p16/CDKN2A, STK11/LKB1or PRSS1, mutated genes) predisposition to PC. The surveillance program included at least an annual magnetic resonance cholangio pancreatography (MRCP). Endoscopic ultrasound (EUS) was proposed to patients who refused or could not be submitted to MRCP. RESULTS: One-hundreds eighty-seven HRIs underwent a first-round screening examination with MRCP (174; 93.1%) or EUS (13; 6.9%) from September 2015 to March 2018.The mean age was 51 years (range 21-80).One-hundreds sixty-five (88.2%) FPC and 22 (11.8%) GF HRIs were included. MRCP detected 28 (14.9%) presumed branch-duct intraductal papillary mucinous neoplasms (IPMN), 1 invasive carcinoma/IPMN and one low-grade mixed-type IPMN, respectively. EUS detected 4 PC (2.1%): 1 was resected, 1 was found locally advanced intraoperatively, and 2 were metastatic. Age > 50 (OR 3.3, 95%CI 1.4-8), smoking habit (OR 2.8, 95%CI 1.1-7.5), and having > 2 relatives with PC (OR 2.7, 95%CI 1.1-6.4) were independently associated with detection of pre-malignant and malignant lesions. The diagnostic yield for MRCP/EUS was 24% for cystic lesions. The overall rate of surgery was 2.6% with nil mortality. DISCUSSION: The rate of malignancies found in this cohort was high (2.6%). According to the International Cancer of the Pancreas Screening Consortium the screening goal achievement was high (1%).

Technique, safety, and feasibility of EUS-guided radiofrequency ablation in unresectable pancreatic cancer.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is a well-recognized local ablative technique applied in the treatment of different solid tumors. Intraoperative RFA has been used for non-metastatic unresectable pancreatic ductal adenocarcinoma (PDAC), showing increased overall survival in retrospective studies. A novel RFA probe has recently been developed, allowing RFA under endoscopic ultrasound (EUS) guidance. Aim of the present study was to assess the feasibility and safety of EUS-guided RFA for unresectable PDACs. METHODS: Patients with unresectable non-metastatic PDAC were included in the study following neoadjuvant chemotherapy. EUS-guided RFA was performed using a novel monopolar 18-gauge electrode with a sharp conical 1 cm tip for energy delivery. Pre- and post-procedural clinical and radiological data were prospectively collected. RESULTS: Ten consecutive patients with unresectable PDAC were enrolled. The procedure was successful in all cases and no major adverse events were observed. A delineated hypodense ablated area within the tumor was observed at the 30-day CT scan in all cases. CONCLUSIONS: EUS-guided RFA is a feasible and safe minimally invasive procedure for patients with unresectable PDAC. Further studies are warranted to demonstrate the impact of EUS-guided RFA on disease progression and overall survival.

Radiofrequency ablation for locally advanced pancreatic cancer: SMAD4 analysis segregates a responsive subgroup of patients.

PURPOSE: SMAD4 mutational status correlates with pancreatic ductal adenocarcinoma (PDAC) failure pattern. We investigated in a subset of locally advanced patients submitted to radiofrequency ablation (RFA) whether the assessment of SMAD4 status is a useful way to select the patients. METHODS: Clinical, radiological, and follow-up details of patients submitted to RFA for locally advanced pancreatic cancer (LAPC), in whom cytohistological material was available at our institution, were retrospectively retrieved. SMAD4 expression was evaluated by immunohistochemistry (IHC) and considered "negative" or "positive." The survival analysis was conducted using Kaplan-Meier and Cox proportional hazards models. RESULTS: The study population consisted of 30 patients. Thirteen patients (43.3%) received RFA upfront, whereas 17 (56.7%) after induction treatments. SMAD4 was mutant in 18 out of 30 patients (60%). The overall estimated post-RFA disease-specific survival (DSS) was 15 months (95% CI 11.64-18.35). The estimated post-RFA DSS of patients with wild-type and mutant SMAD4 was 22 and 12 months, respectively (log-rank p < 0.05). At the multivariate analysis, SMAD4 was the only independent predictor of survival (p = 0.05). The pattern of failure was not associated with SMAD4 status (p = 0.4). CONCLUSIONS: Within patients undergoing RFA for LAPC, SMAD4 analysis could segregate a subgroup of subjects with improved survival, who likely benefited from tumor ablation.

Polyester sutures for pancreaticojejunostomy protect against postoperative pancreatic fistula: a case-control, risk-adjusted analysis.

BACKGROUND: There is wide variability in the use of suture material for pancreatic anastomosis after pancreaticoduodenectomy (PD). This study evaluates the role of suture material on clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticojejunostomy (PJ) in a risk-adjusted setting. METHODS: A retrospective study comparing (polyester) PE with polydioxanone (PDO) in 520 PDs. Patients were matched for risk for CR-POPF according to the fistula risk score (FRS) with the propensity score. RESULTS: The matched PE and PDO groups consisted of 232 patients. The incidence of CR-POPF was lower for PE group (11.6 vs. 22%, p<0.01), with a lower rate of grade B (10.3 vs. 15.5%, p<0.01) and C (1.3 vs. 6.5%, p<0.01). After stratifying by fistula risk zone, PE suture remained associated with a reduced incidence of CR-POPF (9.4 vs. 15.6% low-, p = 0.04; 15.6 vs. 28.1% intermediate-, p = 0.02; 16.7 vs. 83.3% high-risk zone, p<0.01, respectively). Multivariable analysis demonstrated that pancreatic texture, preoperative diagnosis, FRS and the use of PE sutures were independent predictors of CR-POPF. CONCLUSIONS: In the setting of a case-control matched for risk analysis, the use of PE suture for PJ is associated with a significant reduction of CR-POPF.

Downstaging in Stage IV Pancreatic Cancer: A New Population Eligible for Surgery?

BACKGROUND: Recent papers consider surgery as an option for synchronous liver oligometastatic patients [metastatic pancreatic ductal adenocarcinoma (mPDAC)]. In this study, we present our series of resected mPDACs after neoadjuvant chemotherapy (nCT). PATIENTS AND METHODS: All patients resected after downstaging of mPDAC were included in this study. Downstaging criteria were disappearance of liver metastasis and a decrease in cancer antigen (CA) 19-9. The type and duration of nCT, last nCT surgery interval, histology, morbidity, and mortality were recorded, and overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: Overall, 24 of 535 patients (4.5%) observed with mPDAC were included. These patients received gemcitabine alone (5/24), gemcitabine + nanoparticle albumin-bound (nab)-paclitaxel (3/24), and FOLFIRINOX (16/24). Primary tumor size decreased from 31 to 19 mm (p < 0.001), and serum CA19-9 decreased from 596 to 18 U/mL (p < 0.001). In 14/24 patients, the tumor was located in the head. Median interval nCT surgery was 2 months, there were no mortalities, and the postoperative course was uneventful in 34% of cases. Grade B/C pancreatic fistula, postoperative bleeding, and sepsis occurred in 17/4, 4, and 12% of cases, respectively, and reoperation rate was 4%. R0 resection was achieved in 88% of cases, with 17% complete pathological response. Positive nodes were found in 9/24 patients with a median node ratio of 0.37, and OS and DFS was 56 and 27 months, respectively. CONCLUSIONS: Patients with mPDAC who were fully responsive to nCT may be cautiously considered for surgery, with potential benefit in survival compared with palliative chemotherapy alone. This is supported by results of our retrospective study, which is the largest ever reported.

Immunomodulation after radiofrequency ablation of locally advanced pancreatic cancer by monitoring the immune response in 10 patients.

OBJECTIVE/BACKGROUND: RFA of pancreatic cancer has been demonstrated to be feasible and safe with a positive impact on survival. The aim was to investigate whether an immune reaction is activated after locally advanced pancreatic cancer (LAPC) ablation. METHODS: Peripheral Blood samples were obtained preoperatively and on post-operative days 3-30. Evaluated parameters were: cells [CD4+, CD8+ and activated subsets, T-Reg, Monocytes, myeloid and plasmocytoid Dendritic cells (mDC and pDC)] and cytokines [Interleukin (IL)-6, Stromal-cells derived factor (SDF)-1, IL-1ß, Tumour-Necrosis Factor (TNF)-α, Interferon (IFN)-γ, Vascular Endothelial Growth Factor (VEGF), chemokine (C-C motif) ligand 5 (CCL-5), Transforming-Growth Factor (TGF)-ß]. RESULTS: Ten patients were enrolled. CD4+, CD8+ and TEM increased from day 3 suggesting the activation of the adaptive response. Immunosuppressive T-Reg cells were stable despite the possibility that laparotomy and heating might favour their expansion. Myeloid DCs, that present tumour-associated antigens, increased at day 30. RFA dramatically increased circulating IL-6 at day 3 but this decreased to baseline by day 30, consistent with the supposed anti-tumour effect. RFA did not significantly modulate essential chemokines, such as CCL-5 and SDF1, VEGF, TGF-ß and TNF-α, that favour tumour-growth by sustaining cancer angiogenesis and fuelling tumour-associated inflammation. CONCLUSIONS: This study provides the first evidence of RFA-based immunomodulation in LAPC. We observed a general activation of adaptive response along with a decrease of immunosuppression. Furthermore, most cells showed prolonged activation some weeks after the procedure, suggesting true immunomodulation rather than a normal inflammatory response.

Results of 100 pancreatic radiofrequency ablations in the context of a multimodal strategy for stage III ductal adenocarcinoma.

BACKGROUND: Stage III pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with the results of chemoradiation being disappointing. Radiofrequency is an ablation technique employed in many unresectable solid tumours, but its application to pancreatic cancer is limited. We report our experience of radiofrequency ablation (RFA) with cytoreductive intent in stage III PDAC. PATIENTS AND METHODS: One hundred consecutive patients affected by stage III PDAC received RFA combined with chemoradiotherapy. Follow-up was planned on a 3-month basis including clinical evaluation, serum markers and computed tomography scan or MRI. Short-term outcomes and survival data were evaluated. RESULTS: Forty-eight patients received upfront RFA, and 52 had associated palliative surgery. Abdominal complications occurred in 24 patients, and in 15 cases, they were related to RFA. The mortality rate was 3 %. At a median follow-up of 12 months, 55 patients had died of disease and four patients due to unknown causes. Nineteen patients are alive with disease progression, and 22 are alive and progression free. CONCLUSIONS: We presented the broadest experience of RFA in stage III PDAC, focusing on the rationale of its application and considering the advanced stage of disease and the cytoreductive purpose of the procedure. The critical aspects of the technique, along with the unexpected results in efficacy, were discussed.

Triple approach strategy for patients with locally advanced pancreatic carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is a relatively new technique, applied to metastatic solid tumours which, in recent studies, has been shown to be feasible and safe on locally advanced pancreatic carcinoma (LAPC). RFA can be combined with radio-chemotherapy (RCT) and intra-arterial plus systemic chemotherapy (IASC). The aim of this study was to investigate the impact on the prognosis of a multimodal approach to LAPC and define the best timing of RFA. METHODS: This is a retrospective observational study of patients who have consecutively undergone RFA associated with multiple adjuvant approaches. RESULTS: Between February 2007 and December 2011, 168 consecutive patients were treated by RFA, of which 107 were eligible for at least 18 months of follow-up. Forty-seven patients (group 1) underwent RFA as an up-front treatment and 60 patients as second treatment (group 2) depending on clinician choice. The median overall survival (OS) of the whole series was 25.6 months: 14.7 months in the group 1 and 25.6 months in the group 2 (P = 0.004). Those patients who received the multimodal treatment (RFA, RCT and IASC-triple approach strategy) had an OS of 34.0 months. CONCLUSIONS: The multimodal approach seems to be feasible and associated with an improved longer survival rate.

Learning Curves of Minimally Invasive Distal Pancreatectomy in Experienced Pancreatic Centers.

Importance: Understanding the learning curve of a new complex surgical technique helps to reduce potential patient harm. Current series on the learning curve of minimally invasive distal pancreatectomy (MIDP) are mostly small, single-center series, thus providing limited data. Objective: To evaluate the length of pooled learning curves of MIDP in experienced centers. Design, Setting, and Participants: This international, multicenter, retrospective cohort study included MIDP procedures performed from January 1, 2006, through June 30, 2019, in 26 European centers from 8 countries that each performed more than 15 distal pancreatectomies annually, with an overall experience exceeding 50 MIDP procedures. Consecutive patients who underwent elective laparoscopic or robotic distal pancreatectomy for all indications were included. Data were analyzed between September 1, 2021, and May 1, 2022. Exposures: The learning curve for MIDP was estimated by pooling data from all centers. Main Outcomes and Measures: The learning curve was assessed for the primary textbook outcome (TBO), which is a composite measure that reflects optimal outcome, and for surgical mastery. Generalized additive models and a 2-piece linear model with a break point were used to estimate the learning curve length of MIDP. Case mix-expected probabilities were plotted and compared with observed outcomes to assess the association of changing case mix with outcomes. The learning curve also was assessed for the secondary outcomes of operation time, intraoperative blood loss, conversion to open rate, and postoperative pancreatic fistula grade B/C. Results: From a total of 2610 MIDP procedures, the learning curve analysis was conducted on 2041 procedures (mean [SD] patient age, 58 [15.3] years; among 2040 with reported sex, 1249 were female [61.2%] and 791 male [38.8%]). The 2-piece model showed an increase and eventually a break point for TBO at 85 procedures (95% CI, 13-157 procedures), with a plateau TBO rate at 70%. The learning-associated loss of TBO rate was estimated at 3.3%. For conversion, a break point was estimated at 40 procedures (95% CI, 11-68 procedures); for operation time, at 56 procedures (95% CI, 35-77 procedures); and for intraoperative blood loss, at 71 procedures (95% CI, 28-114 procedures). For postoperative pancreatic fistula, no break point could be estimated. Conclusion and Relevance: In experienced international centers, the learning curve length of MIDP for TBO was considerable with 85 procedures. These findings suggest that although learning curves for conversion, operation time, and intraoperative blood loss are completed earlier, extensive experience may be needed to master the learning curve of MIDP.