Adult Pancreatoblastoma: Clinical Insights and Outcomes Compared to Pancreatic Ductal Adenocarcinoma (PDAC).

Pancreatoblastoma is perceived to be aggressive in adults; however, data are limited due to the rarity of the disease. We benchmarked clinico-pathologic characteristics, outcomes, and survival of adult patients with pancreatoblastoma to a comparable PDAC cohort using the National Cancer Database (NCDB). This study included 301,204 patients: 35 with pancreatoblastoma and 301,169 PDAC patients. Pancreatoblastoma patients were younger than PDAC patients (56 vs. 69 years, p < 0.001). More pancreatoblastoma patients were managed at academic institutions (63.0% vs. 40.7%, p = 0.047). The most frequent primary site was the head and the neck of the pancreas. There were no differences in tumor size (4.2 cm vs. 3.7 cm, p = 0.828), lymph node positivity (14.3% vs. 26.4%, p = 0.103), or metastasis at time of diagnosis (31.4% vs. 46.1%, p = 0.081). The majority of pancreatoblastoma patients underwent resection compared to a minority of PDAC patients (69.7% vs. 15.5%, p < 0.001). Time from diagnosis to surgery was longer for pancreatoblastoma patients (33 vs. 14 days, p = 0.030). Pancreaticoduodenectomy was the most common type of resection in the pancreatoblastoma and PDAC groups (47.8% vs. 67.7%, p = 0.124). Among resected patients, pancreatoblastoma patients were less likely to receive radiation (4.8% vs. 37.0%, p = 0.002), but the use of chemotherapy was similar to PDAC patients (60.9% vs. 70.7%). After matching, median overall survival was longer for pancreatoblastoma than PDAC (59.8 months vs. 15.2 months, p = 0.014).

Distinct Indications for Adjuvant Therapy in Resected Invasive Mucinous Cystic Neoplasms of the Pancreas Compared with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN. PATIENTS AND METHODS: The National Cancer Database (2004-2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed. RESULTS: For 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47-11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02-6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47-5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28-12.27; p < 0.001), and stage III disease (HR 12.46, 95% CI 1.40-111.05; p = 0.024) were associated with worse OS. Receipt of adjuvant systemic therapy was independently associated with decreased risk of mortality in node positive patients (HR 0.23, 95% CI 0.10-0.69; p = 0.002). Survival was not associated with adjuvant therapy in patients with negative lymph nodes or margin negative status. CONCLUSION: In contrast to pancreatic ductal adenocarcinoma (PDAC), where adjuvant therapy improves OS for every tumor stage, surgery alone for invasive MCN is not associated with improved OS compared with surgery plus adjuvant therapy in node-negative patients. Surgery alone is likely sufficient for a subset of invasive MCN.

Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.

BACKGROUND: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

A Novel Machine Learning Approach to Predict Textbook Outcome in Colectomy.

BACKGROUND: Several calculators exist to predict risk of postoperative complications. However, in low-risk procedures such as colectomy, a tool to determine the probability of achieving the ideal outcome could better aid clinical decision-making, especially for high-risk patients. A textbook outcome is a composite measure that serves as a surrogate for the ideal surgical outcome. OBJECTIVE: To identify the most important factors for predicting textbook outcomes in patients with nonmetastatic colon cancer undergoing colectomy and to create a textbook outcome decision support tool using machine learning algorithms. DESIGN: This was a retrospective analysis study. SETTINGS: Data were collected from the American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS: Adult patients undergoing elective colectomy for nonmetastatic colon cancer (2014-2020) were included. MAIN OUTCOME MEASURES: Textbook outcome was the main outcome, defined as no mortality, no 30-day readmission, no postoperative complications, no 30-day reinterventions, and a hospital length of stay of ≤5 days. Four models (logistic regression, decision tree, random forest, and eXtreme Gradient Boosting) were trained and validated. Ultimately, a web-based calculator was developed as proof of concept for clinical application. RESULTS: A total of 20,498 patients who underwent colectomy for nonmetastatic colon cancer were included. Overall, textbook outcome was achieved in 66% of patients. Textbook outcome was more frequently achieved after robotic colectomy (77%), followed by laparoscopic colectomy (68%) and open colectomy (39%, p < 0.001). eXtreme Gradient Boosting was the best performing model (area under the curve = 0.72). The top 5 preoperative variables to predict textbook outcome were surgical approach, patient age, preoperative hematocrit, preoperative oral antibiotic bowel preparation, and patient sex. LIMITATIONS: This study was limited by its retrospective nature of the analysis. CONCLUSIONS: Using textbook outcome as the preferred outcome may be a useful tool in relatively low-risk procedures such as colectomy, and the proposed web-based calculator may aid surgeons in preoperative evaluation and counseling, especially for high-risk patients. See Video Abstract . UN NUEVO ENFOQUE DE APRENDIZAJE AUTOMTICO PARA PREDECIR EL RESULTADO DE LOS LIBROS DE TEXTO EN COLECTOMA: ANTECEDENTES:Existen varias calculadoras para predecir el riesgo de complicaciones posoperatorias. Sin embargo, en procedimientos de bajo riesgo como la colectomía, una herramienta para determinar la probabilidad de lograr el resultado ideal podría ayudar mejor a la toma de decisiones clínicas, especialmente para pacientes de alto riesgo. Un resultado de libro de texto es una medida compuesta que sirve como sustituto del resultado quirúrgico ideal.OBJETIVO:Identificar los factores más importantes para predecir el resultado de los libros de texto en pacientes con cáncer de colon no metastásico sometidos a colectomía y crear una herramienta de apoyo a la toma de decisiones sobre los resultados de los libros de texto utilizando algoritmos de aprendizaje automático.DISEÑO:Este fue un estudio de análisis retrospectivo.AJUSTES:Los datos se obtuvieron de la base de datos del Programa Nacional de Mejora de la Calidad del Colegio Americano de Cirujanos.PACIENTES:Se incluyeron pacientes adultos sometidos a colectomía electiva por cáncer de colon no metastásico (2014-2020).MEDIDAS PRINCIPALES DE RESULTADO:El resultado de los libros de texto fue el resultado principal, definido como ausencia de mortalidad, reingreso a los 30 días, complicaciones posoperatorias, reintervenciones a los 30 días y una estancia hospitalaria ≤5 días. Se entrenaron y validaron cuatro modelos (regresión logística, árbol de decisión, bosque aleatorio y XGBoost). Finalmente, se desarrolló una calculadora basada en la web como prueba de concepto para su aplicación clínica.RESULTADOS:Se incluyeron un total de 20.498 pacientes sometidos a colectomía por cáncer de colon no metastásico. En general, el resultado de los libros de texto se logró en el 66% de los pacientes. Los resultados de los libros de texto se lograron con mayor frecuencia después de la colectomía robótica (77%), seguida de la colectomía laparoscópica (68%) y la colectomía abierta (39%) (p<0,001). XGBoost fue el modelo con mejor rendimiento (AUC=0,72). Los cinco principales variables preoperatorias para predecir el resultado en los libros de texto fueron el abordaje quirúrgico, la edad del paciente, el hematocrito preoperatorio, la preparación intestinal con antibióticos orales preoperatorios y el sexo femenino.LIMITACIONES:Este estudio estuvo limitado por la naturaleza retrospectiva del análisis.CONCLUSIONES:El uso de los resultados de los libros de texto como resultado preferido puede ser una herramienta útil en procedimientos de riesgo relativamente bajo, como la colectomía, y la calculadora basada en la web propuesta puede ayudar a los cirujanos en la evaluación y el asesoramiento preoperatorios, especialmente para pacientes de alto riesgo. (Traducción-Yesenia Rojas-Khalil ).

A Machine Learning Approach to Predict Postoperative Pancreatic Fistula After Pancreaticoduodenectomy Using Only Preoperatively Known Data.

BACKGROUND: Clinically-relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) is a major postoperative complication and the primary determinant of surgical outcomes. However, the majority of current risk calculators utilize intraoperative and postoperative variables, limiting their utility in the preoperative setting. Therefore, we aimed to develop a user-friendly risk calculator to predict CR-POPF following PD using state-of-the-art machine learning (ML) algorithms and only preoperatively known variables. METHODS: Adult patients undergoing elective PD for non-metastatic pancreatic cancer were identified from the ACS-NSQIP targeted pancreatectomy dataset (2014-2019). The primary endpoint was development of CR-POPF (grade B or C). Secondary endpoints included discharge to facility, 30-day mortality, and a composite of overall and significant complications. Four models (logistic regression, neural network, random forest, and XGBoost) were trained, validated and a user-friendly risk calculator was then developed. RESULTS: Of the 8666 patients who underwent elective PD, 13% (n = 1160) developed CR-POPF. XGBoost was the best performing model (AUC = 0.72), and the top five preoperative variables associated with CR-POPF were non-adenocarcinoma histology, lack of neoadjuvant chemotherapy, pancreatic duct size less than 3 mm, higher BMI, and higher preoperative serum creatinine. Model performance for 30-day mortality, discharge to a facility, and overall and significant complications ranged from AUC 0.62-0.78. CONCLUSIONS: In this study, we developed and validated an ML model using only preoperatively known variables to predict CR-POPF following PD. The risk calculator can be used in the preoperative setting to inform clinical decision-making and patient counseling.

Robotic-assisted approach for complex cholecystectomies.

Robotic approaches have facilitated the minimally invasive completion of increasingly complex surgical procedures. In the management of the difficult gallbladder, we have found that the wristed instruments, three-dimensional camera, the ability to use indocyanine green (ICG) with integrated fluorescent imaging, and ease of intracorporeal suturing to be useful in tackling the challenges associated with complex benign gallbladder disease. We describe the rationale and technical lessons learned during four cases of complex cholecystectomies that highlight the management principles and technical advantages afforded by the use of the robotic-assisted laparoscopic (RAL) approach. The cases include a subtotal fundus-first reconstituting cholecystectomy, subtotal fenestrating cholecystectomy, a cholecystocolonic fistula managed by a RAL subtotal fenestrating cholecystectomy, and an iatrogenic cholecystoduodenal fistula managed by RAL cholecystectomy. In each case, the operation was performed safely without intraoperative injury or conversion to open, and three of the four patients were discharged from the recovery room. In our view, these favorable outcomes were greatly facilitated by the robotic platform. It is our intent to share adaptations and innovations that we found helpful to encourage other surgeons with sufficient robotic experience to tackle complex gallbladder cases minimally invasively.

Minimally Invasive Distal Pancreatectomy Techniques: A Contemporary Analysis Exploring Trends, Similarities, and Differences to Open Surgery.

Limited contemporary data has compared similarities and differences between total laparoscopic (LDP), hand-assisted (HALDP), and open distal pancreatectomy (ODP). This study aimed to examine similarities and differences in outcomes between these three approaches in a contemporary cohort. Methods: Patients undergoing elective LDP, HALDP, and ODP in the NSQIP dataset (2014−2019) were included. Descriptive statistics and multivariate regression analyses were employed to compare postoperative outcomes. Results: Among 5636 patients, 33.9% underwent LDP, 13.1% HALDP, and 52.9% ODP. Compared with the LDP approach, surgical site infections were more frequent in HALDP and ODP approaches (1.2% vs. 2.6% vs. 2.8%, respectively, p < 0.01). After adjustment, the LDP approach was associated with a significantly lower likelihood of surgical site infection (OR 0.25, p = 0.03) when compared to ODP. There was no difference in the likelihood of surgical site infection when HALDP was compared to ODP (OR 0.59, p = 0.40). Unadjusted operative times were similar between approaches (LDP = 192 min, HALDP = 193 min, ODP = 191 min, p = 0.59). After adjustment, the LDP approach had a longer operative time (+10.3 min, p = 0.04) compared to ODP. There was no difference in the adjusted operative time between HALDP and ODP approaches (+5.4 min, p = 0.80). Conclusions: Compared to ODP, LDP was associated with improved surgical site infection rates and slightly longer operative times. There was no difference in surgical site infection rates between ODP and HALDP. Surgeon comfort and experience should decide the operative approach, but it is important to discuss the differences between these approaches with patients.

Assessing the role of robotic proctectomy in obese patients: a contemporary NSQIP analysis.

Robotic proctectomy has become increasingly popular for both benign and malignant indications. The purpose of this study was to determine if the robotic approach has a distinct advantage over laparoscopy in obese patients, which has been suggested by previous subgroup analyses. We performed a retrospective review of 2016-2018 National Surgery Quality Improvement Program (NSQIP) data to compare outcomes between patients who underwent robotic versus laparoscopic proctectomy, stratified by Body Mass Index (BMI) subgroups. We also compared outcomes of converted minimally invasive proctectomy to planned open operations. Four thousand four hundred eighteen (69.3%) patients underwent laparoscopic proctectomy, and 1956 (30.7%) patients underwent robotic proctectomy. Robotic proctectomy was associated with a significantly lower conversion rate compared to laparoscopic proctectomy (5.1% vs 12.3%; p = 0.002), and this relationship was maintained on an adjusted model. Obese (BMI > 30) patients were more likely to require conversion in both laparoscopic and robotic groups with the greatest difference in the conversion rate in the obese subgroup. Patients who underwent conversion had higher composite morbidity compared to patients who underwent planned open operations (50.8% vs 41.3%; p < 0.001). And among patients with rectal cancer, robotic proctectomy was associated with a greater incidence of positive radial tumor margins compared to laparoscopic proctectomy (8.0% vs 6.4%; p = 0.039), driven primarily by the obese subgroup. Our study demonstrates that robotic proctectomy is associated with a 7% lower conversion rate compared to laparoscopy and that obese patients are more likely to require conversion than non-obese patients. Among obese patients with rectal cancer, we identified an increased risk of positive radial margins with robotic compared to laparoscopic proctectomy.

Determining Hospital Volume Threshold for Safety of Minimally Invasive Pancreaticoduodenectomy: A Contemporary Cutpoint Analysis.

BACKGROUND: Guidelines recommend limiting minimally invasive pancreaticoduodenectomy (MIPD) to high-volume centers. However, the definition of high-volume care remains unclear. We aimed to objectively define a minimum number of MIPD performed annually per hospital associated with improved outcomes in a contemporary patient cohort. PATIENTS AND METHODS: Resectable pancreatic adenocarcinoma patients undergoing MIPD were included from the National Cancer Database (2010-2017). Multivariable modeling with restricted cubic splines was employed to identify an MIPD annual hospital volume threshold associated with lower 90-day mortality. Outcomes were compared between patients treated at low-volume (≤ model-identified cutoff) and high-volume (> cutoff) centers. RESULTS: Among 3079 patients, 141 (5%) died within 90 days. Median hospital volume was 6 (range 1-73) cases/year. After adjustment, increasing hospital volume was associated with decreasing 90-day mortality for up to 19 (95% CI 16-25) cases/year, indicating a threshold of 20 cases/year. Most cases (82%) were done at low-volume (< 20 cases/year) centers. With adjustment, MIPD at low-volume centers was associated with increased 90-day mortality (OR 2.7; p = 0.002). Length of stay, positive surgical margins, 30-day readmission, and overall survival were similar. On analysis of the most recent two years (n = 1031), patients at low-volume centers (78.2%) were younger and had less advanced tumors but had longer length of stay (8 versus 7 days; p < 0.001) and increased 90-day mortality (7% versus 2%; p = 0.009). CONCLUSIONS: The cutpoint analysis identified a threshold of at least 20 MIPD cases/year associated with lower postoperative mortality. This threshold should inform national guidelines and institution-level protocols aimed at facilitating the safe implementation of this complex procedure.

The surgical resident experience in serious illness communication: A qualitative needs assessment with proposed solutions.

BACKGROUND: Serious illness communication skills are important tools for surgeons, but training in residency is limited. METHODS: Thirteen senior surgical residents at an academic center were interviewed about their experiences with serious illness communication. Conventional content analysis was performed using established communication frameworks and inductive development of themes. RESULTS: Residents had frequent conversations and employed known communication strategies. Three themes highlighted challenges they face. Illness severity included factors attributed to the illness that made serious illness communication more challenging: symptoms, poor prognosis, and urgency. Knowledge and feelings included the factual understanding and emotional experience of residents, patients, and families. Academic structure included hierarchy and the residents' dual role as learners and teachers. On reflection, residents identified needing greater experiential practice, analogous to learning procedural skills. CONCLUSIONS: Surgical residents regularly face serious illness conversations with little training beyond observation of role models. Dedicated training may help meet this need.

Plasma miRNA Biomarkers in Limited Volume Samples for Detection of Early-stage Pancreatic Cancer.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 µL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66-0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63-0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58-0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81-0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86-0.97), 0.94 (95% CI, 0.89-0.98), and 0.92 (95% CI, 0.87-0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings. PREVENTION RELEVANCE: Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention.

Cost-effectiveness of consensus guideline based management of pancreatic cysts: The sensitivity and specificity required for guidelines to be cost-effective.

BACKGROUND: Detection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment. METHODS: We developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended. RESULTS: "Surveillance" using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment ("do nothing"). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and "do nothing." Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than "do nothing" for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided. CONCLUSION: Current management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.

Ampullary stenosis and choledocholithiasis post Roux-En-Y gastric bypass: challenges of biliary access and intervention.

BACKGROUND: Ampullary stenosis following Roux-en-Y gastric bypass (RYGB) is increasingly encountered. We describe cases of biliary obstruction from ampullary stenosis and choledocholithiasis to illustrate the associated diagnostic and interventional challenges with this condition. METHODS: We reviewed medical records of patients with prior RYGB who underwent a biliary access procedure or surgery for non-malignant disease from January 2012-December 2018. RESULTS: We identified 15 patients (4 male, 11 female; mean age 53.7 years) who had RYGB on average 11.7 years (range 1-32) years before diagnosis of biliary obstruction. Fourteen patients reported abdominal pain, 5 had nausea/emesis, 12 had elevated liver function tests, and 6 had ascending cholangitis. Mean common bile duct (CBD) diameter at presentation was 16.9 mm (range 4.0-25.0 mm). Operations included 3 transduodenal ampullectomies (2 with biliary bypass), 2 CBD explorations with stone extraction, 1 laparoscopic cholecystectomy alone, 1 Whipple procedure, 1 balloon enteroscopy with sphincterotomy, and 7 transgastric endoscopic retrograde cholangiopancreatography. All ampulla pathology was benign in patients who underwent resection. At follow-up (mean 15.4 months; range 0.23-44.5 months), 12/15 (80%) reported symptom resolution or improvement. DISCUSSION: Ampullary stenosis after RYGB presents challenges for diagnostic evaluation and intervention, often requiring multi-disciplinary expertise. The underlying pathology remains to be elucidated.

Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer.

PURPOSE: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics. EXPERIMENTAL DESIGN: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant. RESULTS: 89Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of 177Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of 225Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by 225Ac-4A06 (HR = 2.56; P < 0.05). CONCLUSIONS: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.

Abdominal Imaging of Pancreatic Cysts and Cyst-Associated Pancreatic Cancer in BRCA1/2 Mutation Carriers: A Retrospective Cross-Sectional Study.

BACKGROUND: Direct-to-consumer BRCA testing will increase BRCA diagnoses and subsequent abdominal imaging. It is unclear whether BRCA carriers are at higher risk of developing pancreatic cysts (PCs) or cyst-associated pancreatic ductal adenocarcinoma (PDAC). We investigated the prevalence of PCs in BRCA-tested patients, and whether BRCA-carriers have higher rates of PDAC when PCs are found. STUDY DESIGN: This is a retrospective cross-sectional study of patients with BRCA testing and abdominal imaging between 1996 and 2018. Pancreatic cysts were identified on original imaging reports. Prevalence and risk characteristics of PCs, as well as incidence of PDAC, were compared between BRCA+, BRCA-, and BRCA-untested patients. RESULTS: Pancreatic cysts were identified in 4,045 patients among 128,164 unique patients with abdominal imaging, including 33 patients with PCs in 1,113 BRCA-tested patients. There was no difference in PC prevalence between BRCA+, BRCA-, and untested patients (3.6%, 2.6%, 3.2%, respectively; p = 0.64). Pancreatic cysts were diagnosed in BRCA+ patients at a younger age (57.1 vs 65.3 years, p < 0.001); however, there was no difference in risk stratification compared with BRCA- or untested patients by consensus criteria. Across the population of imaged patients, patients with PCs had significantly higher rates of PDAC compared with those without PCs (18.2% vs 2.4%, p < 0.001). Incidence of cyst-associated PDAC was similar in BRCA+ and BRCA- patients (13.3% vs 22.2%, p = 0.84). CONCLUSIONS: BRCA+ patients have similar rates of PCs, high-risk features in their cysts, and PDAC as BRCA- and untested patients. BRCA+ patients likely do not require dedicated abdominal imaging to evaluate for PCs and should follow management guidelines similar to those as the untested general population if an incidental PC is identified.

The lysosomal aminopeptidase tripeptidyl peptidase 1 displays increased activity in malignant pancreatic cysts.

Incidental detection of pancreatic cysts has increased dramatically over the last decade, but risk stratification and clinical management remain a challenge. Mucinous cysts are precursor lesions to pancreatic cancer, however, the majority are indolent. Current diagnostics cannot identify mucinous cysts that harbor cancer or reliably differentiate these lesions from nonmucinous cysts, which present minimal risk of malignant progression. We previously determined that activity of two aspartyl proteases was increased in mucinous cysts. Using a global protease activity profiling technology, termed multiplex substrate profiling by mass spectrometry (MSP-MS), we now show that aminopeptidase activity is also elevated in mucinous cysts. The serine aminopeptidase, tripeptidyl peptidase 1 (TPP1), was detected by proteomic analysis of cyst fluid samples and quantitation using targeted MS demonstrated that this protease was significantly more abundant in mucinous cysts. In a cohort of 110 cyst fluid samples, TPP1 activity was increased more than 3-fold in mucinous cysts relative to nonmucinous cysts. Moreover, TPP1 activity is primarily associated with mucinous cysts that harbor high-grade dysplasia or invasive carcinoma. Although only 59% accurate for differentiating these lesions, measurement of TPP1 activity may improve early detection and treatment of high-risk pancreatic cysts when used in conjunction with other promising biomarkers.

Comparison of Tumor Regression Grading of Residual Pancreatic Ductal Adenocarcinoma Following Neoadjuvant Chemotherapy Without Radiation: Would Fewer Tier-Stratification Be Favorable Toward Standardization?

To assess whether the College of American Pathologists (CAP) and the Evans grading systems for neoadjuvant chemotherapy without radiation-treated pancreatectomy specimens are prognostic, and if a 3-tier stratification scheme preserves data granularity. Conducted retrospective review of 32 patients with ordinary pancreatic ductal adenocarcinoma treated with neoadjuvant therapy without radiation followed by surgical resection. Final pathologic tumor category (AJCC eighth edition) was 46.9% ypT1, 34.4% ypT2, and 18.7% ypT3. Median follow-up time was 29.8 months, median disease-free survival (DFS) was 19.6 months, and median overall survival (OS) was 34.2 months. CAP score 1, 2, 3 were present in 5 (15.6%), 18 (56.3%), and 9 (28.1%) patients, respectively. Evans grade III, IIb, IIa, and I were present in 10 (31.2%), 8 (25.0%), 7 (21.9%), and 7 (21.9%) patients, respectively. OS (CAP: P=0.005; Evans: P=0.001) and DFS (CAP: P=0.003; Evans: P=0.04) were statistically significant for both CAP and Evans. Stratified CAP scores 1 and 2 versus CAP score 3 was statistically significant for both OS (P=0.002) and DFS (P=0.002). Stratified Evans grades I, IIa, and IIb versus Evans grade III was statistically significant for both OS (P=0.04) and DFS (P=0.02). CAP, Evans, and 3-tier stratification are prognostic of OS and DFS.

Surgical overtreatment of pancreatic intraductal papillary mucinous neoplasms: Do the 2017 International Consensus Guidelines improve clinical decision making?

BACKGROUND: Significant overtreatment of intraductal papillary mucinous neoplasms can be attributed to low specificity of the current International Consensus Guidelines as well as nonconformity with the guidelines. We compare the ability of the 2012 and revised 2017 intraductal papillary mucinous neoplasms International Consensus Guidelines to predict high-grade dysplasia/invasive cancer and to determine the preoperative variables that predict resection of benign or low-grade dysplasia in tertiary care centers. METHODS: Clinical, radiographic, and pathologic data for resected intraductal papillary mucinous neoplasms at 3 high-volume National Cancer Institute Cancer Centers were reviewed and the 2012 and 2017 consensus criteria were retrospectively applied. When International Consensus Guidelines were not met, clinical decision analysis was used to determine the primary indication for resection. Logistic regression identified variables associated with pathologic grade. RESULTS: Records for a total of 251 patients were reviewed, 129 of whom (52%) had low-grade dysplasia. The revised 2017 International Consensus Guidelines had high sensitivity (98.4%) and negative predicted value (96.1%), and all high-risk stigmata predicted high-grade dysplasia/invasive cancer; however, specificity remained low (14.8%). Nonconformity with International Consensus Guidelines was the most powerful predictor of low-grade dysplasia on final pathologic examination (9.5; 2.12-40.78). Independent predictors of low-grade dysplasia included age younger than 50 (2.46; 1.08-5.62), fine-needle aspiration without epithelial cells (2.6; 1.43-4.72), and normal duct diameter (3.07; 1.99-4.75). Diabetes developed in 30% of patients after resection. CONCLUSION: Management of intraductal papillary mucinous neoplasms remains clinically challenging. Low specificity of the International Consensus Guidelines and nonconformity with the guidelines continue to contribute to unnecessary pancreatic resections. Improved tools for disease classification as well as a better understanding of the natural history, biology, and rates of progression of intraductal papillary mucinous neoplasms are needed to avoid surgical overtreatment of low-grade intraductal papillary mucinous neoplasms.