Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Pancreatic Cancer Multidisciplinary Clinic is Associated with Improved Treatment and Elimination of Socioeconomic Disparities.

OBJECTIVE: To identify the association between multidisciplinary clinic (MDC) management and disparities in treatment for patients with pancreatic cancer. BACKGROUND: Socioeconomic status (SES) predicts treatment and survival for pancreatic cancer. Multidisciplinary clinics (MDCs) may improve surgical management for these patients. METHODS: This is a retrospective cohort study (2010-2018) of all pancreatic cancer patients within a large, regional hospital system with a high-volume pancreatic cancer MDC. The primary outcome was receipt of treatment (surgery, chemotherapy, radiation, clinical trial participation, and palliative care); the secondary outcomes were overall survival and MDC management. Multiple logistic regressions were used for binary outcomes. Survival was analyzed using Kaplan-Meier survival analysis, Cox proportional hazards, and inverse probability of treatment weighting (IPTW). RESULTS: Of the 4141 patients studied, 1420 (34.3%) were managed by the MDC. MDC management was more likely for patients who were younger age, married, and privately insured, while less likely for low SES patients (all p < 0.05). MDC patients were more likely to receive all treatments, including neoadjuvant chemotherapy (OR 3.33, 95% CI 2.82-3.93), surgery (OR 1.39, 95% CI 1.15-1.68), palliative care (OR 1.21, 95% CI 1.05-1.38), and clinical trial participation (OR 3.76, 95% CI 2.86-4.93). Low SES patients were less likely to undergo surgery outside of the MDC (OR 0.47, 95% CI 0.31-0.73) but there was no difference within the MDC (OR 1.10, 95% CI 0.68-1.77). Across multiple survival analyses, low SES predicted inferior survival outside of the MDC, but there was no association among MDC patients. CONCLUSION: Multidisciplinary team-based care increases rates of treatment and eliminates socioeconomic disparities for pancreatic cancer patients.

Postoperative infectious complications worsen oncologic outcomes following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreaticoduodenectomy (PD) remains the only curative option for patients with pancreatic adenocarcinoma (PDAC). Infectious complications (IC) can negatively impact patient outcomes and delay adjuvant therapy in most patients. This study aims to determine IC effect on overall survival (OS) following PD for PDAC. STUDY DESIGN: Patients who underwent PD for PDAC between 2010 and 2020 were identified from a single institutional database. Patients were categorized into two groups based on whether they experienced IC or not. The relationship between postoperative IC and OS was investigated using Kaplan-Meier and Cox-regression multivariate analysis. RESULTS: Among 655 patients who underwent PD for PDAC, 197 (30%) experienced a postoperative IC. Superficial wound infection was the most common type of infectious complication (n = 125, 63.4%). Patients with IC had significantly more minor complications (Clavien-Dindo [CD] < 3; [59.4% vs. 40.2%, p < 0.001]), major complications (CD ≥ 3; [37.6% vs. 18.8%, p < 0.001]), prolonged LOS (47.2% vs 20.3%, p < 0.001), biochemical leak (6.1% vs. 2.8%, p = 0.046), postoperative bleeding (4.1% vs. 1.3%, p = 0.026) and reoperation (9.6% vs. 2.2%, p < 0.001). Time to adjuvant chemotherapy was delayed in patients with IC versus those without (10 vs. 8 weeks, p < 0.001). Median OS for patients who experienced no complication, noninfectious complication, and infectious complication was 33.3 months, 29.06 months, and 27.58 months respectively (p = 0.023). On multivariate analysis, postoperative IC were an independent predictor of worse OS (HR 1.32, p = 0.049). CONCLUSIONS: IC following PD for PDAC independently predict worse oncologic outcomes. Thus, efforts to prevent and manage IC should be a priority in the care of patients undergoing PD for PDAC.

Cross-Sectional Imaging Characteristics of Pancreatic Intraductal Oncocytic Papillary Neoplasms.

PURPOSE: Pancreatic intraductal oncocytic papillary neoplasms (IOPN) are rare precursors to pancreatic ductal adenocarcinoma. We report cross-sectional computed tomography and magnetic resonance imaging (where available) findings of pancreatic IOPNs. MATERIALS AND METHODS: Consecutive cases of pancreatic IOPNs identified on pathology between 2008 and 2020 at University of Pittsburgh and Johns Hopkins University were included in the study. Cross-sectional imaging of all patients was reviewed by two subspecialty trained abdominal radiologists. Patient demographics, cross-sectional imaging appearances and growth characteristics were evaluated. RESULTS: In this dual-center study, 14 patients with IOPNs were included. Median age was 64 years, and 64% were male. The median size of the lesions was 5.4 cm (range, 1.4-12.3 cm). All patients had either an enhancing mural nodule (93% of patients) and/or thick internal septations (29%). Thin/imperceptible outer wall was seen in 93%. Main duct was involved in 64% of the cases. Only 14% of the cases did not demonstrate abutment of the main duct. Histologic evaluation of surgical specimen showed high-grade dysplasia without invasive carcinoma in 57% and invasive carcinoma in 43% of cases. Lesions with invasive carcinoma were larger (7.1 cm vs 4.3 cm, P = 0.05) and tended to have larger mural nodule (3.7 cm vs 1.8 cm) compared with those without invasive carcinoma. CONCLUSION: Pancreatic IOPNs are rare cystic premalignant lesions, which among resected cases, are predominantly seen in middle aged men, are often large, have enhancing mural nodules and frequently harbor invasive carcinoma.

Robotic Pancreaticoduodenectomy: Increased Adoption and Improved Outcomes: Is Laparoscopy Still Justified?

OBJECTIVE: To compare the rate of postoperative 30-day complications between laparoscopic pancreaticoduodenectomy (LPD) and robotic pancreaticoduodenectomy (RPD). BACKGROUND: Previous studies suggest that minimally invasive pancreaticoduodenectomy (MI-PD)-either LPD or RPD-is noninferior to open pancreaticoduodenectomy in terms of operative outcomes. However, a direct comparison of the two minimally invasive approaches has not been rigorously performed. METHODS: Patients who underwent MI-PD were abstracted from the 2014 to 2019 pancreas-targeted American College of Surgeons National Sample Quality Improvement Program (ACS NSQIP) dataset. Optimal outcome was defined as absence of postoperative mortality, serious complication, percutaneous drainage, reoperation, and prolonged length of stay (75th percentile, 11 days) with no readmission. Multivariable logistic regression models were used to compare optimal outcome of RPD and LPD. RESULTS: A total of 1540 MI-PDs were identified between 2014 and 2019, of which 885 (57%) were RPD and 655 (43%) were LPD. The rate of RPD cases/year significantly increased from 2.4% to 8.4% ( P =0.008) from 2014 to 2019, while LPD remained unchanged. Similarly, the rate of optimal outcome for RPD increased during the study period from 48.2% to 57.8% ( P <0.001) but significantly decreased for LPD (53.5% to 44.9%, P <0.001). During 2018-2019, RPD outcomes surpassed LPD for any complication [odds ratio (OR)=0.58, P =0.004], serious complications (OR=0.61, P =0.011), and optimal outcome (OR=1.78, P =0.001). CONCLUSIONS: RPD adoption increased compared with LPD and was associated with decreased overall complications, serious complications, and increased optimal outcome compared with LPD in 2018-2019.

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Neoadjuvant Therapy Versus Upfront Resection for Nonpancreatic Periampullary Adenocarcinoma.

BACKGROUND: In contrast to pancreatic ductal adenocarcinoma (PDAC), neoadjuvant therapy (NAT) for periampullary adenocarcinomas is not well studied, with data limited to single-institution retrospective reviews with small cohorts. We sought to compare outcomes of NAT versus upfront resection (UR) for non-PDAC periampullary adenocarcinomas. PATIENTS AND METHODS: Using the National Cancer Database (NCDB), we identified patients who underwent surgery for extrahepatic cholangiocarcinoma, ampullary adenocarcinoma, or duodenal adenocarcinoma from 2006 to 2016. We compared outcomes between NAT versus UR groups for each tumor subtype with 1:3 propensity score matching. Cox regression was used to identify predictors of survival. RESULTS: Among 7656 patients who underwent resection for non-PDAC periampullary adenocarcinoma, the proportion of patients who received NAT increased from 6 to 11% for cholangiocarcinoma (p < 0.01), 1 to 4% for ampullary adenocarcinoma (p = 0.01), and 5 to 8% for duodenal adenocarcinoma (p = 0.08). Length of stay, readmission, and 30-day mortality were comparable between NAT and UR. All tumor subtypes were downstaged following NAT (p < 0.01). The R0 resection rate was significantly higher in patients with extrahepatic cholangiocarcinoma who received NAT, and these patients had improved median overall survival (38 vs 26 months, p < 0.001). After adjustment for clinicopathologic factors and adjuvant chemotherapy, use of NAT was associated with improved survival in patients with cholangiocarcinoma [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.54-0.89, p = 0.004] but not duodenal or ampullary adenocarcinoma. The survival advantage for cholangiocarcinoma persisted after propensity matching. CONCLUSION: This national cohort analysis suggests, for the first time, that neoadjuvant therapy is associated with improved survival in patients with extrahepatic cholangiocarcinoma.

Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms (Pseudomyxoma Peritonei).

BACKGROUND: Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients. METHODS: Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). RESULTS: Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and GNAS due to their ubiquitous nature, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (p < 0.040). Patients harboring TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). CONCLUSIONS: Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.

Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. PATIENTS AND METHODS: This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. RESULTS: Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. CONCLUSIONS: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

Appendectomy Is Oncologically Equivalent to Right Hemicolectomy for Well-Differentiated T1 Appendiceal Adenocarcinoma.

BACKGROUND: Right hemicolectomy is recommended for appendiceal adenocarcinoma but may not be needed for early stage disease. OBJECTIVE: This study aimed to determine whether appendectomy offers adequate oncologic outcomes for T1 appendiceal adenocarcinoma from a national cohort of patients. DESIGN: Patients with T1 appendiceal adenocarcinoma (mucinous and nonmucinous histology) treated with either a right hemicolectomy or appendectomy between 2004 and 2016 were retrieved. Multivariate Cox regression analysis was used to identify predictors of overall survival. SETTING: The study was conducted using a national cancer database. PATIENTS: A total of 320 patients (median age, 62 y; 47% women) were identified: 69 (22%) underwent an appendectomy and 251 (78%) underwent a right hemicolectomy. MAIN OUTCOME MEASURE: Overall survival was measured. RESULTS: Nonmucinous adenocarcinoma was identified in 194 (61%), whereas 126 (39%) had mucinous adenocarcinoma. Of the overall cohort, 43% had well-differentiated histology, 39% had moderately differentiated disease, and 4% had poorly differentiated tumors. The rate of lymph node metastasis was lower in well-differentiated tumors (3%) compared with moderately (10%) or poorly differentiated tumors (25%). On univariate survival analysis, right hemicolectomy was associated with improved 1-, 3-, and 5-year overall survival in patients with moderately/poorly differentiated disease ( p < 0.001) but not for well-differentiated disease ( p = 1.000). After adjustment, right hemicolectomy was associated with overall survival improvement for moderately/poorly differentiated T1 adenocarcinoma (HR = 0.26 [95% CI, 0.08-0.82]; p = 0.02) but not for well-differentiated disease. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: The current analysis from the National Cancer Database demonstrates that appendectomy is associated with equivalent survival to right hemicolectomy for well-differentiated T1 adenocarcinoma, whereas for moderately and poorly differentiated disease, right hemicolectomy is oncologically superior to appendectomy. See Video Abstract at http://links.lww.com/DCR/B689 . LA APENDICECTOMA ES ONCOLGICAMENTE EQUIVALENTE A LA HEMICOLECTOMA DERECHA PARA EL ADENOCARCINOMA APENDICULAR T BIEN DIFERENCIADO: ANTECEDENTES:La hemicolectomía derecha se recomienda para el adenocarcinoma apendicular, pero puede no ser necesaria para la enfermedad en estadio temprano.OBJETIVO:Este estudio tuvo como objetivo determinar si la apendicectomía ofrece resultados oncológicos adecuados para el adenocarcinoma apendicular T1 de una cohorte nacional de pacientes.DISEÑO:Se recuperaron pacientes con adenocarcinoma apendicular T1 (histología mucinoso y no mucinoso) tratados con hemicolectomía derecha o apendicectomía entre 2004-2016. Se utilizó un análisis de regresión de Cox multivariante para identificar los predictores de la supervivencia global.ENTORNO CLÍNICO:Base de datos nacional sobre cáncer.PACIENTES:Se identificaron un total de 320 pacientes (mediana de edad 62 años, 47% mujeres): 69 (22%) se sometieron a una apendicectomía y 251 (78%) se sometieron a una hemicolectomía derecha.PRINCIPAL MEDIDA DE RESULTADO:Sobrevida global.RESULTADOS:Se identificó adenocarcinoma no mucinoso en 194 (61%) mientras que 126 (39%) tenían adenocarcinoma mucinoso. De la cohorte general, el 43% tenía una histología bien diferenciada, el 39% tenía una enfermedad moderadamente diferenciada y el 4% tenía tumores poco diferenciados. La tasa de metástasis en los ganglios linfáticos fue menor en los tumores bien diferenciados (3%) en comparación con los tumores moderadamente (10%) o pobremente diferenciados (25%). En el análisis de sobrevida univariante, la hemicolectomía derecha se asoció con una mejor sobrevida general a 1, 3, y 5 años en pacientes con enfermedad moderada / pobremente diferenciada ( p < 0,001) pero no para la enfermedad bien diferenciada ( p = 1,000). Después del ajuste, la hemicolectomía derecha se asoció con una mejora de la sobrevida general para el adenocarcinoma T1 moderadamente / poco diferenciado (HR = 0,26, IC del 95%: 0,08-0,82, p = 0,02) pero no para la enfermedad bien diferenciada.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva.CONCLUSIONES:El análisis actual de la base de datos nacional de cáncer demuestra que la apendicectomía se asocia con una sobrevida similar a la hemicolectomía derecha para el adenocarcinoma T1 bien diferenciado, mientras que para la enfermedad moderada y pobremente diferenciada, la hemicolectomía derecha es oncológicamente superior a la apendicectomía. Consulte Video Resumen en http://links.lww.com/DCR/B689 . (Traducción-Dr. Yazmin Berrones-Medina ).

Obesity Is Associated With Increased Risk for Adverse Postoperative Outcomes After Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Conflicting reports exist about the effect obesity has on adverse postoperative surgical outcomes after distal pancreatectomy (DP). The aim of this study is to explore the role of obesity in terms of morbidity and pancreas-specific complications following DP for pancreatic ductal adenocarcinoma (PDAC). METHODS: All patients who underwent DP at a single institution over 10 y were analyzed (2009-2020). Patients were categorized as nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI ≥ 30 kg/m2). Independent predictors of adverse postoperative outcomes were calculated using multivariate logistic regression models. Overall survival was assessed using Kaplan-Meier survival analysis. RESULTS: Of the 178 patients included, 58 (32.5%) were obese. Clinically relevant postoperative pancreatic fistula (CR-POPF) formation rate was significantly higher in the obese group (20.6% versus 7.5%, P value = 0.011). We did not identify any significant difference between obese and nonobese patients in median overall survival (30.2 mon versus 28.9 mon, P value = 0.811). On multivariate binary logistic regression analysis, BMI ≥ 30 was an independent predictor of morbidity (any complication) and CR-POPF formation after DP for PDAC. CONCLUSIONS: Obesity is associated with a significantly increased risk for CR-POPF in patients undergoing DP for PDAC. Obesity should be considered as a variable in fistula risk calculators for DP.

Robotic approach mitigates the effect of major complications on survival after pancreaticoduodenectomy for periampullary cancer.

BACKGROUND: Major complications (MCs) after pancreaticoduodenectomy (PD) are a known independent predictor of worse oncologic outcomes. There are limited data on the effect of major complications on long-term outcomes after robotic PD (RPD). The aim of this study is to compare the effect of MC on overall (OS) and disease-free survival (DFS) after RPD and open PD (OPD). METHODS: This is a single-center, retrospective review of a prospectively maintained database of all patients undergoing PD for periampullary cancer including ampullary adenocarcinoma, distal cholangiocarcinoma, and duodenal carcinoma. Univariate analysis was performed on all clinical, pathologic, and treatment factors. MCs were defined as Clavien-Dindo ≥ grade 3. Kaplan-Maier survival analysis was performed with log-rank test for group comparison. Multivariable Cox regression analysis was used to identify factors associated with overall survival (OS) in both the OPD and RPD groups. RESULTS: A total of 190 patients with ampullary carcinoma (n = 98), cholangiocarcinoma (n = 55), and duodenal adenocarcinoma (n = 37) were examined over the study period with 61.1% (n = 116) undergoing RPD and 38.9% (n = 74) undergoing OPD. There was no significant difference in patient demographics between the RPD and OPD cohorts. Furthermore, R0 resection rates, tumor size, and lymph node involvement were similar between the RPD and OPD cohorts. OPD had higher rate of MC (40.5% vs 28.3% in RPD, p = 0.011) including clinically relevant pancreatic fistula (25.7% vs 8.6%, p = 0.001) and wound infection (34.5% vs 13.8%, p < 0.001). MCs were associated with a lower OS in the OPD cohort (HR = 2.18, 95%CI 1.0-4.55, p = 0.038). MCs were not associated with OS in the RPD cohort (HR = 1.55, 95%CI 0.87-2.76, p = 0.14). CONCLUSION: MCs are associated with worse patient outcomes after OPD but not after RPD. Robotic approach mitigates and possibly abrogates the negative effects of MCs on patient outcomes after PD for malignancy and is associated with improved adjuvant chemotherapy completion rates.

Pancreaticoduodenectomy for benign and premalignant pancreatic and ampullary disease: is robotic surgery the better approach?

BACKGROUND: The robotic platform is increasingly being utilized in pancreatic surgery, yet its overall merits and putative advantages remain to be adjudicated. We hypothesize that the benefits of minimally invasive pancreatic surgery are maximized in pancreatic benign and premalignant disease, in the setting of friable pancreatic tissue and small pancreatic duct. METHODS: Retrospective analysis of our prospectively maintained pancreatic database of all consecutive patients who underwent pancreaticoduodenectomy (PD) for benign or premalignant conditions between 2010 and 2020. Peri-operative outcomes and long-term complications were compared between robotic pancreaticoduodenectomy (RPD) and open pancreaticoduodenectomy (OPD). RESULTS: One hundred and eighty eight (n = 188) patients met our inclusion criteria, of which 68 were OPD and 120 RPD. Malignant histologies were excluded. There were only minor differences in baseline characteristics between the two groups. Post-operative merits of the RPD included lower clinically relevant post-operative pancreatic fistula 10 (8.3%) vs 24 (35.3%), p < 0.001, fewer surgical site infections; 9 (7.5%) vs 11 (16.2%), p = 0.024, shorter operative time, greater lymph node yield; 29 (IQR 21, 38) vs 21 (IQR 13, 34), p = 0.001, and lower 90 days mortality; 1 (0.8%) vs 4 (5.9%), p = 0.039. Rates of long-term complications were similar, exception made for a higher occurrence of small bowel obstruction (SBO) 2 (1.7%) vs 4 (5.9%), p = 0.031 and need for surgical intervention for SBO 0 (0.0%) vs 2 (2.9%), p = 0.019 in the OPD group. CONCLUSION: Our study suggests that RPD benefits include lower 90-day mortality, shorter LOS, and lower rates of selected complications compared to open pancreaticoduodenectomy.

National adoption of neoadjuvant chemotherapy: paradigm shift in the treatment of pancreatic cancer.

BACKGROUND: The historical standard of care in treating operable pancreatic cancer via upfront surgery has been challenged recently using a neoadjuvant approach. The aim of the study is to examine the national practice patterns in the management of pancreatic cancer with an emphasis on the trends of neoadjuvant systemic therapy use. METHODS: This is a cross-sectional time-series study using the National Cancer Database from 2006 to 2019. Patients who underwent resection for stage I-II pancreatic adenocarcinoma were selected. RESULTS: Overall, 25% of patients had neoadjuvant chemotherapy, 49% had surgery followed by adjuvant chemotherapy and 26% had surgery alone. The rate of neoadjuvant chemotherapy has increased from 11% in 2006 to 43% in 2019. There was a decrease in the rate of surgery followed by chemotherapy from 48% to 38%, and a decrease in the rate of surgery alone from 41% to 19%. The rate of radiation therapy use has decreased over time, as has the resection rate, while median overall survival has steadily improved over the years. CONCLUSIONS: In 2019, the rate of using neoadjuvant systemic therapy overtook the rate of surgery first followed by adjuvant systemic therapy, marking a pragmatic national shift in the clinical management of pancreatic cancer.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients.

BACKGROUND: Activities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients METHOD: A single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. RESULTS: 742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56-0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53-0.86],p = 0.002) for overall survival. CONCLUSION: In this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

No survival benefit with suboptimal CA19-9 response: defining effective neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer.

BACKGROUND/PURPOSE: Neoadjuvant chemotherapy (NAC) is gaining popularity over a surgery-first (SF) approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, what constitutes effective neoadjuvant chemotherapy is unknown. METHODS: We retrospectively analyzed resectable and borderline resectable PDAC patients who underwent pancreaticoduodenectomy (2010-2019) at a single institution. Optimal CA19-9 response was defined as normalization AND >50% reduction. We utilized Kaplan-Meier and multivariable-adjusted Cox models and competing risk subdistribution methods for statistical analysis. RESULTS: 586 patients were included in this study. The multivariable-adjusted analysis demonstrated OS benefit in the NAC group only when OS was calculated from diagnosis (HR = 0.72, p = 0.02), but not from surgery (HR = 0.81, p = 0.1). However, in 59 patients who achieved optimal CA19-9 response, OS is significantly longer than the 134 patients with suboptimal CA19-9 response (39.3 m vs. 21.5 m, p = 0.005) or the 117 SF patients (39.3 m vs. 19.5 m, p < 0.001). Notably, a suboptimal CA19-9 response conferred no OS advantage compared to SF patients. The accumulative incidence of liver metastases (but not other metastases) was significantly reduced only in patients with optimal CA19-9 response to NAC (multivariable-adjusted subdistribution HR = 0.26, p = 0.03). CONCLUSION: CA19-9 response to NAC may serve as the marker for effective NAC. These findings warrant validation in a multi-institutional study.

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

Significance of Uncinate Duct Dilatation in IPMNs: A New High-risk Criterion?

OBJECTIVE: To evaluate the significance of UDD in IPMNs. BACKGROUND: The uncinate process of the pancreas has an independent ductal drainage system. International consensus guidelines of IPMNs still consider it as a branch-duct, even though it is the main drainage system for the uncinate process. METHODS: A retrospective review of all surgically treated IPMNs at our institution after 2008 was performed. Preoperative radiological studies were reviewed by an abdominal radiologist who was blinded to the pathological results. In addition to the Fukuoka criteria, presence of UDD was recorded. Using multivariate analysis, the pathological significance of UDD in predicting advanced neoplasia [high grade dysplasia or invasive carcinoma (HGD/ IC)] was determined. RESULTS: Two hundred sixty patients were identified (mean age at diagnosis was 68 years and 49% were females): 122 (47%) had HGD/IC. UDD was noted in 59 (23%), of which 36 (61%) had HGD/IC (P < 0.003). On multivariate analysis, UDD was an independent predictor of HGD/IC (odds ratio = 2.99, P < 0.04). Subgroup analysis on patients with IPMNs confined to the dorsal portion of the gland (n = 161), also demonstrated UDD to be a significant predictor of HGD/IC in those remote lesions (odds ratio: 4.41, P = 0.039). CONCLUSIONS: This is the largest study to evaluate the significance of UDD in IPMNs and shows it to be a high-risk feature. This association persisted for remote IPMNs limited to the dorsal pancreas, suggesting UDD may be associated with an aggressive phenotype even in remote IPMN lesions.

Tumor Size Differences Between Preoperative Endoscopic Ultrasound and Postoperative Pathology for Neoadjuvant-Treated Pancreatic Ductal Adenocarcinoma Predict Patient Outcome.

BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.

Long-Term Outcomes for Patients with Multiple Endocrine Neoplasia Type 1 and Duodenopancreatic Neuroendocrine Neoplasms.

BACKGROUND: Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. METHODS: This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990-2021) for liver metastasis-free survival (LMFS) and overall survival (OS). RESULTS: Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6-17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21-2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08-3.06; p = 0.46). CONCLUSIONS: Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior.