Olaparib not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer.

OBJECTIVE: To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model. METHODS: Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact. RESULTS: Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait. CONCLUSIONS: Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

Predicting the Risk of Morbidity by GLIM-Based Nutritional Assessment and Body Composition Analysis in Oncologic Abdominal Surgery in the Context of Enhanced Recovery Programs : The PHase Angle Value in Abdominal Surgery (PHAVAS) Study.

BACKGROUND: Preoperative nutritional status and body structure affect short-term prognosis in patients undergoing major oncologic surgery. Bioimpedance vectorial analysis (BIVA) is a reliable tool to assess body composition. Low BIVA-derived phase angle (PA) indicates a decline of cell membrane integrity and function. The aim was to study the association between perioperative PA variations and postoperative morbidity following major oncologic upper-GI surgery. PATIENTS AND METHODS: Between 2019 and 2022 we prospectively performed BIVA in patients undergoing surgical resection for pancreatic, hepatic, and gastric malignancies on the day before surgery and on postoperative day (POD) 1. Malnutrition was defined as per the Global Leadership Initiative on Malnutrition criteria. The PA variation (ΔPA) between POD1 and preoperatively was considered as a marker for morbidity. Uni and multivariable logistic regression models were applied. RESULTS: Overall, 542 patients with a mean age of 64.6 years were analyzed, 279 (51.5%) underwent pancreatic, 201 (37.1%) underwent hepatobiliary, and 62 (11.4%) underwent gastric resections. The prevalence of preoperative malnutrition was 16.6%. The overall morbidity rate was 53.3%, 59% in those with ΔPA < -0.5 versus 46% when ΔPA ≥ -0.5. Age [odds ratio (OR) 1.11; 95% confidence interval (CI) (1.00; 1.22)], pancreatic resections [OR 2.27; 95% CI (1.24; 4.18)], estimated blood loss (OR 1.20; 95% CI (1.03; 1.39)], malnutrition [OR 1.77; 95% CI (1.27; 2.45)], and ΔPA [OR 1.59; 95% CI (1.54; 1.65)] were independently associated with postoperative complications in the multivariate analysis. CONCLUSIONS: Patients with preoperative malnutrition were significantly more likely to develop postoperative morbidity. Moreover, a decrease in PA on POD1 was independently associated with a 13% increase in the absolute risk of complications. Whether proactive interventions may reduce the downward shift of PA and the complication rate need further investigation.

Efficient Assessment of Tumor Vascular Shutdown by Photodynamic Therapy on Orthotopic Pancreatic Cancer Using High-Speed Wide-Field Waterproof Galvanometer Scanner Photoacoustic Microscopy.

To identify the vascular alteration by photodynamic therapy (PDT), the utilization of high-resolution, high-speed, and wide-field photoacoustic microscopy (PAM) has gained enormous interest. The rapid changes in vasculature during PDT treatment and monitoring of tumor tissue activation in the orthotopic pancreatic cancer model have received limited attention in previous studies. Here, a fully two-axes waterproof galvanometer scanner-based photoacoustic microscopy (WGS-PAM) system was developed for in vivo monitoring of dynamic variations in micro blood vessels due to PDT in an orthotopic pancreatic cancer mouse model. The photosensitizer (PS), Chlorin e6 (Ce6), was utilized to activate antitumor reactions in response to the irradiation of a 660 nm light source. Microvasculatures of angiogenesis tissue were visualized on a 40 mm2 area using the WGS-PAM system at 30 min intervals for 3 h after the PDT treatment. The decline in vascular intensity was observed at 24.5% along with a 32.4% reduction of the vascular density at 3 h post-PDT by the analysis of PAM images. The anti-vascularization effect was also identified with fluorescent imaging. Moreover, Ce6-PDT increased apoptotic and necrotic markers while decreasing vascular endothelial growth factor (VEGF) expression in MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. The approach of the WGS-PAM system shows the potential to investigate PDT effects on the mechanism of angiographic dynamics with high-resolution wide-field imaging modalities.

Epidemiology and economic burden of Von Hippel-Lindau Disease-associated central nervous system hemangioblastomas and pancreatic neuroendocrine tumors in the United States.

BACKGROUND: To date, real-world evidence around the clinical and economic burden related to von Hippel-Lindau (VHL) disease is limited. Therefore, this study characterized the prevalence, healthcare resource utilization (HRU), and economic burden of von Hippel-Lindau-associated central nervous system hemangioblastoma (VHL-CNS-Hb) and pancreatic neuroendocrine tumors (VHL-pNET) in the United States (US). METHODS: Patients with VHL-CNS-Hb or VHL-pNET were identified from Optum's de-identified Clinformatics® Data Mart Database (2007-2020) and matched 1:5 to control patients without VHL disease or CNS-Hb/pNET. Prevalence rates of VHL-CNS-Hb and VHL-pNET (standardized by age and sex) in 2019 were estimated. HRU and healthcare costs (2020 US dollars) were compared between the VHL-CNS-Hb/VHL-pNET and control cohorts. RESULTS: In 2019, US prevalence rates of VHL-CNS-Hb and VHL-pNET were estimated to be 1.12 cases per 100,000 (3,678 patients) and 0.12 cases per 100,000 (389 patients), respectively. Patients with VHL-CNS-Hb (N = 220) had more inpatient, outpatient, and emergency department visits and $49,645 higher annual healthcare costs than controls (N = 1,100). Patients with VHL-pNET (N = 20) had more inpatient and outpatient visits and $56,580 higher annual healthcare costs than controls (N = 100). Costs associated with surgical removal of CNS-Hb and pNET were particularly high. CONCLUSIONS: In this retrospective, claims-based study, both VHL-CNS-Hb and VHL-pNET were associated with substantial HRU and healthcare costs, particularly tumor reduction surgery-related costs. These findings provide important insight for healthcare payers regarding the expected real-world costs that enrollees with VHL-CNS-Hb and VHL-pNET may incur over the course of their disease.

Artificial intelligence for assessment of vascular involvement and tumor resectability on CT in patients with pancreatic cancer.

OBJECTIVE: This study aimed to develop and evaluate an automatic model using artificial intelligence (AI) for quantifying vascular involvement and classifying tumor resectability stage in patients with pancreatic ductal adenocarcinoma (PDAC), primarily to support radiologists in referral centers. Resectability of PDAC is determined by the degree of vascular involvement on computed tomography scans (CTs), which is associated with considerable inter-observer variability. METHODS: We developed a semisupervised machine learning segmentation model to segment the PDAC and surrounding vasculature using 613 CTs of 467 patients with pancreatic tumors and 50 control patients. After segmenting the relevant structures, our model quantifies vascular involvement by measuring the degree of the vessel wall that is in contact with the tumor using AI-segmented CTs. Based on these measurements, the model classifies the resectability stage using the Dutch Pancreatic Cancer Group criteria as either resectable, borderline resectable, or locally advanced (LA). RESULTS: We evaluated the performance of the model using a test set containing 60 CTs from 60 patients, consisting of 20 resectable, 20 borderline resectable, and 20 locally advanced cases, by comparing the automated analysis obtained from the model to expert visual vascular involvement assessments. The model concurred with the radiologists on 227/300 (76%) vessels for determining vascular involvement. The model's resectability classification agreed with the radiologists on 17/20 (85%) resectable, 16/20 (80%) for borderline resectable, and 15/20 (75%) for locally advanced cases. CONCLUSIONS: This study demonstrates that an AI model may allow automatic quantification of vascular involvement and classification of resectability for PDAC. RELEVANCE STATEMENT: This AI model enables automated vascular involvement quantification and resectability classification for pancreatic cancer, aiding radiologists in treatment decisions, and potentially improving patient outcomes. KEY POINTS: • High inter-observer variability exists in determining vascular involvement and resectability for PDAC. • Artificial intelligence accurately quantifies vascular involvement and classifies resectability for PDAC. • Artificial intelligence can aid radiologists by automating vascular involvement and resectability assessments.

Short-term serial circulating tumor DNA assessment predicts therapeutic efficacy for patients with advanced pancreatic cancer.

PURPOSE: We investigated the potential clinical utility of short-term serial KRAS-mutated circulating cell-free tumor DNA (ctDNA) assessment for predicting therapeutic response in patients undergoing first-line chemotherapy for advanced pancreatic cancer. METHODS: We collected 144 blood samples from 18 patients with locally advanced or metastatic cancer that were undergoing initial first-line chemotherapy of gemcitabine plus nab-paclitaxel (GEM plus nab-PTX). Analysis of KRAS-mutated ctDNA was quantified by digital droplet polymerase chain reaction (ddPCR) as mutant allele frequency (MAF). This study investigated pretreatment KRAS-mutated ctDNA status and ctDNA kinetics every few days (days 1, 3, 5 and 7) after initiation of chemotherapy and their potential as predictive indicators. RESULTS: Of the 18 enrolled patients, an increase in KRAS-mutated ctDNA MAF values from day 0-7 after initiation of chemotherapy was significantly associated with disease progression (P < 0.001). Meanwhile, positive pretreatment ctDNA status (MAF ≥ 0.02%) (P = 0.585) and carbohydrate antigen 19-9 (CA19-9) values above the median (P = 0.266) were not associated with disease progression. In univariate analysis, this short-term increase in ctDNA MAF values (day 0-7) was found to be associated with significantly shorter progression free survival (PFS) (hazard ration [HR], 24.234; range, (2.761-212.686); P = 0.0002). CONCLUSION: This short-term ctDNA kinetics assessment may provide predictive information to reflect real-time therapeutic response and lead to effective refinement of regimen in patients with advanced pancreatic cancer undergoing systemic chemotherapy.

Magnetic Resonance Imaging-Based Assessment of Pancreatic Fat Strongly Correlates With Histology-Based Assessment of Pancreas Composition.

OBJECTIVE: The aim of the study is to assess the relationship between magnetic resonance imaging (MRI)-based estimation of pancreatic fat and histology-based measurement of pancreatic composition. MATERIALS AND METHODS: In this retrospective study, MRI was used to noninvasively estimate pancreatic fat content in preoperative images from high-risk individuals and disease controls having normal pancreata. A deep learning algorithm was used to label 11 tissue components at micron resolution in subsequent pancreatectomy histology. A linear model was used to determine correlation between histologic tissue composition and MRI fat estimation. RESULTS: Twenty-seven patients (mean age 64.0 ± 12.0 years [standard deviation], 15 women) were evaluated. The fat content measured by MRI ranged from 0% to 36.9%. Intrapancreatic histologic tissue fat content ranged from 0.8% to 38.3%. MRI pancreatic fat estimation positively correlated with microanatomical composition of fat (r = 0.90, 0.83 to 0.95], P < 0.001); as well as with pancreatic cancer precursor ( r = 0.65, P < 0.001); and collagen ( r = 0.46, P < 0.001) content, and negatively correlated with pancreatic acinar ( r = -0.85, P < 0.001) content. CONCLUSIONS: Pancreatic fat content, measurable by MRI, correlates to acinar content, stromal content (fibrosis), and presence of neoplastic precursors of cancer.

Label-free assessment of pathological changes in pancreatic intraepithelial neoplasia by biomedical multiphoton microscopy.

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion that has the potential to progress to invasive pancreatic cancer, and early and rapid detection may offer patients a chance for treatment before the development of invasive carcinoma. Therefore, the identification of PanIN holds significant clinical importance. In this study, we first used multiphoton microscopy (MPM) combining two-photon excitation fluorescence and second-harmonic generation imaging to label-free detect PanIN and attempted to differentiate between normal pancreatic ducts and different grades of PanIN. Then, we also developed an automatic image processing strategy to extract eight morphological features of collagen fibers from MPM images to quantify the changes in collagen fibers surrounding the ducts. Experimental results demonstrate that the combination of MPM and quantitative information can accurately identify normal pancreatic ducts and different grades of PanIN. This study may contribute to the rapid diagnosis of pancreatic diseases and may lay the foundation for further clinical application of MPM.

Trends and disparities in access to minimally invasive distal pancreatectomy (midp): an eight-year analysis from the national cancer database.

Laparoscopic and robotic approaches to distal pancreatectomy are becoming the standard of care. The aim of our study was to evaluate the trends of utilization and disparities in access to minimally invasive approaches in distal pancreatectomy. We queried the National Cancer Database (NCDB) and analyzed all the patients who underwent distal pancreatectomy from 2010 to 2017. Patients were divided into groups of those with open distal pancreatectomy (ODP) and those with laparoscopic or robotic distal pancreatectomy (MIDP = minimally invasive distal pancreatectomy). Our outcome measures were trends of MIDP and disparities in access to MIDP. Cochran Armitage trend analysis and multivariate regression analysis were used to evaluate outcomes. A total of 13,537 patients with distal pancreatectomy were identified in the NCDB from 2010 to 2017. 7548 (55.8%) underwent ODP, while 5989 (44.2%) underwent MIDP. The MIDP rates increased from 25% in 2010 to 52% in 2017 (p < 0.01). On regression analysis, when controlled for age, gender, diagnosis, tumor size, grade, staging, and chemoradiotherapy, African American patients were 30% less likely to undergo MIDP than White (OR 0.7, 95% CI [0.5-0.8], p < 0.01). Similarly, Hispanic patients were 25% less likely to undergo MIDP than non-Hispanic patients OR 0.75, 95% CI [0.6-0.9], p = 0.02). Compared to Medicare/private insured patients, uninsured patients were 50% less likely to undergo MIDP (OR 0.5, 95% CI [0.4-0.7], p < 0.01). Based on the medium household income, compared to patients in the fourth quartile, patients in the third quartile OR 0.9, 95% CI [0.3-0.9], p = 0.03). Second OR 0.8, 95%CI [0.5-0.9], p < 0.01), first quartile OR 0.7, 95% CI [0.5-0.8], p < 0.01) were less likely to undergo MIPD as well. Utilization of MIDP has increased from one in every four patients in 2010 to every other patient in 2017. However, African Americans, Hispanics, the uninsured, and those from low-income quartiles are less likely to undergo MIDP. Efforts should be made to ensure access to minimally invasive approches are available to minorities.

Trends in access to minimally invasive pancreaticoduodenectomy for pancreatic cancers.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD), including robotic (RPD) and laparoscopy (LPD), is becoming more frequently employed in the management of pancreatic ductal adenocarcinoma (PDAC), though the majority of operations are still performed via open approach (OPD). Access to technologic advances often neglect the underserved. Whether disparities in access to MIPD exist, remain unclear. METHODS: The National Cancer Database (NCDB) was queried (2010-2020) for patients who underwent pancreatoduodenectomy for PDAC. Cochran-Armitage tests assessed for trends over time. Social determinants of health (SDH) were compared between approaches. Multinomial logistic models identified predictors of MIPD. RESULTS: Of 16,468 patients, 80.03 % underwent OPD and 19.97 % underwent MIPD (22.60 % robotic; 77.40 % laparoscopic). Black race negatively predicted LPD (vs white (OR 0.822; 95 % CI 0.701-0.964)). Predictors of RPD included Medicare/other government insurance (vs uninsured or Medicaid (OR 1.660; 95 % CI 1.123-2.454)) and private insurance (vs uninsured or Medicaid (OR 1.597; 95 % CI 1.090-2.340)). Early (2010-2014) vs late (2015-2020) diagnosis, stratified by race, demonstrated an increase in Non-White patients undergoing OPD (13.15 % vs 14.63 %; p = 0.016), but not LPD (11.41 % vs 13.57 %;p = 0.125) or RPD (14.15 % vs 15.23 %; p = 0.774). CONCLUSION: SDH predict surgical approach more than clinical stage, facility type, or comorbidity status. Disparities in race and insurance coverage are different between surgical approaches.

Characteristics Associated With Survival in Surgically Nonresected Pancreatic Adenocarcinoma in the Military Health System.

OBJECTIVES: Pancreatic cancer is often diagnosed at advanced stages with high-case fatality. Many tumors are not surgically resectable. We aimed to identify features associated with survival in patients with surgically nonresected pancreatic cancer in the Military Health System. METHODS: We used the Military Cancer Epidemiology database to identify the Department of Defense beneficiaries aged 18 and older diagnosed with a primary pancreatic adenocarcinoma between January 1998 and December 2014 who did not receive oncologic surgery as treatment. We used Cox Proportional Hazard regression with stepwise procedures to select the sociodemographic and clinical characteristics related to 2-year overall survival, expressed as adjusted hazard ratios (aHR) and 95% CIs. RESULTS: Among 1148 patients with surgically nonresected pancreatic cancer, sex, race-ethnicity, marital status, and socioeconomic indicators were not selected in association with survival. A higher comorbidity count (aHR 1.30, 95% CI: 1.06-1.59 for 5 vs. 0), jaundice at diagnosis (aHR 1.57, 95% CI: 1.33-1.85 vs. no), tumor grade G3 or G4 (aHR 1.32, 95% CI: 1.05-1.67 vs. G1/G2), tumor location in pancreas tail (aHR 1.49, 95% CI: 1.22-1.83 vs. head) or body (aHR 1.30, 95% CI: 1.04-1.62 vs. head), and metastases were associated with survival. Patients receiving chemotherapy (aHR 0.66, 95% CI: 0.57-0.76) had better survival compared with no treatment. CONCLUSIONS: In a comprehensive health system, sociodemographic characteristics were not related to survival in surgically nonresected pancreatic cancer. This implicates access to care in reducing survival disparities in advanced pancreatic cancer and emphasizes the importance of treating patients based on clinical features.

Deep learning-based assessment of CT markers of sarcopenia and myosteatosis for outcome assessment in patients with advanced pancreatic cancer after high-intensity focused ultrasound treatment.

OBJECTIVES: To evaluate the prognostic value of CT-based markers of sarcopenia and myosteatosis in comparison to the Eastern Cooperative Oncology Group (ECOG) score for survival of patients with advanced pancreatic cancer treated with high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: For 142 retrospective patients, the skeletal muscle index (SMI), skeletal muscle radiodensity (SMRD), fatty muscle fraction (FMF), and intermuscular fat fraction (IMFF) were determined on superior mesenteric artery level in pre-interventional CT. Each marker was tested for associations with sex, age, body mass index (BMI), and ECOG. The prognostic value of the markers was examined in Kaplan-Meier analyses with the log-rank test and in uni- and multivariable Cox proportional hazards (CPH) models. RESULTS: The following significant associations were observed: Male patients had higher BMI and SMI. Patients with lower ECOG had lower BMI and SMI. Patients with BMI lower than 21.8 kg/m2 (median) also showed lower SMI and IMFF. Patients younger than 63.3 years (median) were found to have higher SMRD, lower FMF, and lower IMFF. In the Kaplan-Meier analysis, significantly lower survival times were observed in patients with higher ECOG or lower SMI. Increased patient risk was observed for higher ECOG, lower BMI, and lower SMI in univariable CPH analyses for 1-, 2-, and 3-year survival. Multivariable CPH analysis for 1-year survival revealed increased patient risk for higher ECOG, lower SMI, lower IMFF, and higher FMF. In multivariable analysis for 2- and 3-year survival, only ECOG and FMF remained significant. CONCLUSION: CT-based markers of sarcopenia and myosteatosis show a prognostic value for assessment of survival in advanced pancreatic cancer patients undergoing HIFU therapy. CLINICAL RELEVANCE STATEMENT: The results indicate a greater role of myosteatosis for additional risk assessment beyond clinical scores, as only FMF was associated with long-term survival in multivariable CPH analyses along ECOG and also showed independence to ECOG in group analysis. KEY POINTS: • This study investigates the prognostic value of CT-based markers of sarcopenia and myosteatosis for patients with pancreatic cancer treated with high-intensity focused ultrasound. • Markers for sarcopenia and myosteatosis showed a prognostic value besides clinical assessment of the physical status by the Eastern Cooperative Oncology Group score. In contrast to muscle size measurements, the myosteatosis marker fatty muscle fraction demonstrated independence to the clinical score. • The results indicate that myosteatosis might play a greater role for additional patient risk assessments beyond clinical assessments of physical status.

Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection.

BACKGROUND: Repurposing existing drugs for use in oncology is more efficient, cost-effective and safe than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance. This study assessed the impact of calcium channel blockers (CCB) in pancreatic cancer. METHODS: Retrospective population study of patients undergoing resection (curative intent) of pancreatic ductal adenocarcinoma (SEER-Medicare, 2007-2017). Cox models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, the impact of CCB was assessed separately in patients receiving neoadjuvant chemotherapy. RESULTS: 6,223 patients were included, of whom 660 were prescribed CCB. In total, 591 received neoadjuvant chemotherapy; in this cohort CCB prescription was associated with improved overall survival when adjusting for multiple prognostic factors (aHR = 0.715, 0.514-0.996, P = 0.047). This effect was not observed in patients not receiving neoadjuvant chemotherapy (aHR = 1.082, 0.982-1.191, P = 0.112). CONCLUSION: CCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy, mirroring the chemosensitising effect in laboratory studies. This defines patients receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.

Pancreas CT assessment for pancreatic ductal adenocarcinoma resectability: effect of tube voltage and slice thickness on image quality and diagnostic performance.

OBJECTIVES: To assess the resectability of pancreatic ductal adenocarcinoma (PDAC), the evaluation of tumor vascular contact holds paramount significance. This study aimed to compare the image quality and diagnostic performance of high-resolution (HR) pancreas computed tomography (CT) using an 80 kVp tube voltage and a thin slice (1 mm) for assessing PDAC resectability, in comparison with the standard protocol CT using 120 kVp. METHODS: This research constitutes a secondary analysis originating from a multicenter prospective study. All participants underwent both the standard protocol pancreas CT using 120 kVp with 3 mm slice thickness (ST) and HR-CT utilizing an 80 kVp tube voltage and 1 mm ST. The contrast-to-noise ratio (CNR) between parenchyma and tumor, along with the degree of enhancement of the abdominal aorta and main portal vein (MPV), were measured and subsequently compared. Additionally, the likelihood of margin-negative resection (R0) was evaluated using a five-point scale. The diagnostic performance of both CT protocols in predicting R0 resection was assessed through the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 69 patients (37 males and 32 females; median age, 66.5 years) were included in the study. The median CNR of PDAC was 10.4 in HR-CT, which was significantly higher than the 7.1 in the standard CT (P=0.006). Furthermore, HR-CT demonstrated notably higher median attenuation values for both the abdominal aorta (579.5 HU vs. 327.2 HU; P=0.002) and the MPV (263.0 HU vs. 175.6 HU; P=0.004) in comparison with standard CT. Following surgery, R0 resection was achieved in 51 patients. The pooled AUC for HR-CT in predicting R0 resection was 0.727, slightly exceeding the 0.699 of standard CT, albeit lacking a significant statistical distinction (P=0.128). CONCLUSION: While HR pancreas CT using 80 kVp offered a notably greater degree of contrast enhancement in vessels and a higher CNR for PDAC compared to standard CT, its diagnostic performance in predicting R0 resection remained statistically comparable.

Preoperative assessment of peripheral vascular invasion of pancreatic ductal adenocarcinoma based on high-resolution MRI.

OBJECTIVES: Preoperative imaging of vascular invasion is important for surgical resection of pancreatic ductal adenocarcinoma (PDAC). However, whether MRI and CT share the same evaluation criteria remains unclear. This study aimed to compare the diagnostic accuracy of high-resolution MRI (HR-MRI), conventional MRI (non-HR-MRI) and CT for PDAC vascular invasion. METHODS: Pathologically proven PDAC with preoperative HR-MRI (79 cases, 58 with CT) and non-HR-MRI (77 cases, 59 with CT) were retrospectively collected. Vascular invasion was confirmed surgically or pathologically. The degree of tumour-vascular contact, vessel narrowing and contour irregularity were reviewed respectively. Diagnostic criteria 1 (C1) was the presence of all three characteristics, and criteria 2 (C2) was the presence of any one of them. The diagnostic efficacies of different examination methods and criteria were evaluated and compared. RESULTS: HR-MRI showed satisfactory performance in assessing vascular invasion (AUC: 0.87-0.92), especially better sensitivity (0.79-0.86 vs. 0.40-0.79) than that with non-HR-MRI and CT. HR-MRI was superior to non-HR-MRI. C2 was superior to C1 on CT evaluation (0.85 vs. 0.79, P = 0.03). C1 was superior to C2 in the venous assessment using HR-MRI (0.90 vs. 0.87, P = 0.04) and in the arterial assessment using non-HR-MRI (0.69 vs. 0.68, P = 0.04). The combination of C1-assessed HR-MRI and C2-assessed CT was significantly better than that of CT alone (0.96 vs. 0.86, P = 0.04). CONCLUSIONS: HR-MRI more accurately assessed PDAC vascular invasion than conventional MRI and may contribute to operative decision-making. C1 was more applicable to MRI scans, and C2 to CT scans. The combination of C1-assessed HR-MRI and C2-assessed CT outperformed CT alone and showed the best efficacy in preoperative examination of PDAC.

Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and KrasG12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log2 OR = 1.65, P = 3.08 × 10-3). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67+ cells increased significantly in pancreatic organoids derived from Galc knockout KrasG12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.

Trends in and Prognostic Significance of Time to Treatment in Pancreatic Cancer: A Population-Based Study.

INTRODUCTION: The association of time to treatment (TTT) with survival remains unclear in pancreatic adenocarcinoma (PDAC). In this study, we evaluate the recent trends in TTT, causes for delay, and its effect on survival. METHODS: We included patients with PDAC of all stages from the National Cancer Database (2004-2020) who underwent either surgery or chemotherapy/radiotherapy (CT/RT). TTT was defined as the duration between tissue diagnosis and first treatment. Linear regression (ß) was used to study the temporal trends in time delay. RESULTS: A total of 239,638 patients were included. The median TTT was 25 days. Using multivariable analysis, we found that increasing age (OR 1.48), female gender (OR 1.04), Black race (OR 1.3), lower educational status (OR 1.2), Medicaid, Medicare insurance, and uninsured (OR 1.2, 1.5, and 1.2, respectively), treatment at academic centers (OR 1.3), higher Charlson-Deyo comorbidity index (OR 1.2), and CT/RT (OR 1.5) were associated with increased TTT. There was a steady rise in median TTT from 21 to 28 days between 2004 and 2020 (ß = 0.3), suggestive of a worsening trend. Concurrently, there was an increasing trend in utilization of neoadjuvant CT/RT between 2004 and 2020 in early-stage PDAC. On Cox regression, TTT delay was associated with poor overall survival in stage I-IV patients (HR 1.1, 1.1, 1.09, and 1.53, respectively). CONCLUSIONS: Delayed treatment approaching 2 months was observed in 10% of the population. The rising temporal trend in TTT may be attributed to the increasing shift toward neoadjuvant CT/RT in early-stage PDAC and/or the increasing use of tissue biopsy prior to surgery.

Determination of "borderline resectable" pancreatic cancer - A global assessment of 30 shades of grey.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Accurate preoperative assessment using computed tomography (CT) to determine resectability is crucial in ensuring patients are offered the most appropriate therapeutic strategy. Despite the use of classification guidelines, any interobserver variability between reviewing surgeons and radiologists may confound decisions influencing patient treatment pathways. METHODS: In this multicentre observational study, an international group of 96 clinicians (42 hepatopancreatobiliary surgeons and 54 radiologists) were surveyed and asked to report 30 pancreatic CT scans of pancreatic cancer deemed borderline at respective multidisciplinary meetings (MDM). The degree of interobserver agreement in resectability among radiologists and surgeons was assessed and subgroup regression analysis was performed. RESULTS: Interobserver variability between reviewers was high with no unanimous agreement. Overall interobserver agreement was fair with a kappa value of 0.32 with a higher rate of agreement among radiologists over surgeons. CONCLUSION: Interobserver variability among radiologists and surgeons globally is high, calling into question the consistency of clinical decision making for patients with PDAC and suggesting that central review may be required for studies of neoadjuvant or adjuvant approaches in future as well as ongoing quality control initiatives, even amongst experts in the field.