Outcomes of Visceral Arterial Interposition Graft Reconstruction for Locally Advanced Pancreatic Cancer.

OBJECTIVE: The aim of this study is to determine perioperative outcomes and the patency of interposition conduits for visceral arterial reconstruction in this setting. SUMMARY BACKGROUND DATA: Visceral arterial encasement in locally advanced pancreatic cancer was historically a contraindication for surgery. With modern effective neoadjuvant strategies, our recent experience has made advanced vascular resection and reconstruction feasible in selected patients. METHODS: A retrospective review was performed of patients undergoing pancreatic tumor resection with en bloc arterial resection and interposition revascularization between 6/2002-10/2022. Endpoints included graft patency, vascular-related complications, reinterventions, morbidity, and mortality. RESULTS: Visceral arterial reconstruction with interposition grafting was performed in 111 patients undergoing en bloc arterial resections for pancreatic cancer. Graft types included autologous arterial conduits (n=66, 58 superficial femoral artery (SFA) and 8 splenic artery), cryopreserved arterial allografts (n=24), autologous saphenous veins (n=12), synthetic conduits (n=8), and composite autologous artery and synthetic (n=1). Perioperative 90-day mortality decreased significantly over time to 5% in the last six years. Vascular complications related to arterial reconstruction occurred in 11% (n=12) and included pseudoaneurysm (n=6), graft thrombus (n=2), stenosis requiring reintervention (n=2), hepatic failure (n=1), and hepatic and intestinal ischemia (n=1). Nine (8%) patients underwent vascular-related reinterventions. After median follow-up of 17-months, primary patency was 81% for the entire cohort and was highest in the SFA group (95%). The donor limb/harvest site complication rate was 8% with 100% primary patency. CONCLUSION: Visceral arterial resection with interposition reconstruction for locally advanced pancreatic cancer can be performed with acceptable vascular morbidity and durable patency. Autologous SFA was the most suitable conduit for reconstructions in our experience, with highest primary patency.

Automated Artificial Intelligence Model Trained on a Large Data Set Can Detect Pancreas Cancer on Diagnostic Computed Tomography Scans As Well As Visually Occult Preinvasive Cancer on Prediagnostic Computed Tomography Scans.

BACKGROUND & AIMS: The aims of our case-control study were (1) to develop an automated 3-dimensional (3D) Convolutional Neural Network (CNN) for detection of pancreatic ductal adenocarcinoma (PDA) on diagnostic computed tomography scans (CTs), (2) evaluate its generalizability on multi-institutional public data sets, (3) its utility as a potential screening tool using a simulated cohort with high pretest probability, and (4) its ability to detect visually occult preinvasive cancer on prediagnostic CTs. METHODS: A 3D-CNN classification system was trained using algorithmically generated bounding boxes and pancreatic masks on a curated data set of 696 portal phase diagnostic CTs with PDA and 1080 control images with a nonneoplastic pancreas. The model was evaluated on (1) an intramural hold-out test subset (409 CTs with PDA, 829 controls); (2) a simulated cohort with a case-control distribution that matched the risk of PDA in glycemically defined new-onset diabetes, and Enriching New-Onset Diabetes for Pancreatic Cancer score ≥3; (3) multi-institutional public data sets (194 CTs with PDA, 80 controls), and (4) a cohort of 100 prediagnostic CTs (i.e., CTs incidentally acquired 3-36 months before clinical diagnosis of PDA) without a focal mass, and 134 controls. RESULTS: Of the CTs in the intramural test subset, 798 (64%) were from other hospitals. The model correctly classified 360 CTs (88%) with PDA and 783 control CTs (94%), with a mean accuracy 0.92 (95% CI, 0.91-0.94), area under the receiver operating characteristic (AUROC) curve of 0.97 (95% CI, 0.96-0.98), sensitivity of 0.88 (95% CI, 0.85-0.91), and specificity of 0.95 (95% CI, 0.93-0.96). Activation areas on heat maps overlapped with the tumor in 350 of 360 CTs (97%). Performance was high across tumor stages (sensitivity of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively), comparable for hypodense vs isodense tumors (sensitivity: 0.90 vs 0.82), different age, sex, CT slice thicknesses, and vendors (all P > .05), and generalizable on both the simulated cohort (accuracy, 0.95 [95% 0.94-0.95]; AUROC curve, 0.97 [95% CI, 0.94-0.99]) and public data sets (accuracy, 0.86 [95% CI, 0.82-0.90]; AUROC curve, 0.90 [95% CI, 0.86-0.95]). Despite being exclusively trained on diagnostic CTs with larger tumors, the model could detect occult PDA on prediagnostic CTs (accuracy, 0.84 [95% CI, 0.79-0.88]; AUROC curve, 0.91 [95% CI, 0.86-0.94]; sensitivity, 0.75 [95% CI, 0.67-0.84]; and specificity, 0.90 [95% CI, 0.85-0.95]) at a median 475 days (range, 93-1082 days) before clinical diagnosis. CONCLUSIONS: This automated artificial intelligence model trained on a large and diverse data set shows high accuracy and generalizable performance for detection of PDA on diagnostic CTs as well as for visually occult PDA on prediagnostic CTs. Prospective validation with blood-based biomarkers is warranted to assess the potential for early detection of sporadic PDA in high-risk individuals.

Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with de Novo Pancreatic Adenocarcinoma.

BACKGROUND: The management of invasive intraductal papillary mucinous cystic neoplasm (I-IPMN) does not differ from de novo pancreatic ductal adenocarcinoma (PDAC); however, I-IPMNs are debated to have better prognosis. Despite being managed similarly to PDAC, no data are available on the response of I-IPMN to neoadjuvant chemotherapy. METHODS: All patients undergoing pancreatic resection for a pancreatic adenocarcinoma from 2011 to 2022 were included. The PDAC and I-IPMN cohorts were compared to evaluate response to neoadjuvant therapy (NAT) and overall survival (OS). RESULTS: This study included 1052 PDAC patients and 105 I-IPMN patients. NAT was performed in 25% of I-IPMN patients and 65% of PDAC patients. I-IPMN showed a similar pattern of pathological response to NAT compared with PDAC (p = 0.231). Furthermore, positron emission tomography (PET) response (71% vs. 61%; p = 0.447), CA19.9 normalization (85% vs. 76%, p = 0.290), and radiological response (32% vs. 37%, p = 0.628) were comparable between I-IPMN and PDAC. A significantly higher OS and disease-free survival (DFS) of I-IPMN was denoted by Kaplan-Meier analysis, with a p-value of < 0.001 in both plots. In a multivariate analysis, I-IPMN histology was independently associated with lower risk of recurrence and death. CONCLUSIONS: I-IPMN patients have a longer OS and DFS after surgical treatment when compared with PDAC patients. The more favorable oncologic outcome of I-IPMNs does not seem to be related to early detection, as I-IPMN histological subclass is independently associated with a lower risk of disease recurrence. Moreover, neoadjuvant effect on I-IPMN was non-inferior to PDAC in terms of pathological, CA19.9, PET, and radiological response and thus can be considered in selected patients.

Value of Surgical Cytoreduction in Patients with Small Intestinal Neuroendocrine Tumors Metastatic to the Liver and Peritoneum.

BACKGROUND: Cytoreductive hepatectomy can improve survival and symptoms of hormonal excess in patients with small intestinal neuroendocrine tumor (siNET) liver metastases, but whether to proceed when peritoneal metastases are encountered at the time of planned cytoreductive hepatectomy is controversial. METHODS: This was a retrospective review of patients who underwent surgical management of metastatic siNETs at Mayo Clinic between 2000 and 2020. Patients who underwent cytoreductive operation for isolated liver metastases or both liver and peritoneal metastases were compared. RESULTS: Of 261 patients who underwent cytoreductive operation for siNETs, 211 had isolated liver metastases and 50 had liver and peritoneal metastases. Complete cytoreduction was achieved in 78% of patients with isolated liver metastases and 56% of those with liver and peritoneal metastases (p = 0.002). After complete cytoreduction, median overall survival (OS) was 11.5 years for isolated liver metastases and 11.2 years for liver and peritoneal metastases (p = 0.10), and relief of carcinoid syndrome was ≥ 97% in both groups. After incomplete cytoreduction with debulking of > 90% of hepatic disease and/or closing Lyon score of 1-2, median OS was 6.4 years for isolated liver metastases and 7.1 years for liver and peritoneal metastases (p = 0.12). CONCLUSIONS: Patients with siNETs metastatic to both the liver and peritoneum have favorable outcomes after aggressive surgical cytoreduction, with the best outcomes observed after complete cytoreduction. Therefore, the presence of peritoneal metastases should not by itself preclude surgical cytoreduction in this population.

Neuroendocrine Tumors of Unknown Primary in the Setting of Cytoreductive Hepatectomy.

BACKGROUND: Surgical cytoreduction for neuroendocrine tumor liver metastasis (NETLM) consistently shows positive long-term outcomes. Despite reservations in guidelines for surgery when the primary tumor is unidentified (UP-NET), this study compared the surgical and oncologic long-term outcomes between patients with these rare cases undergoing cytoreductive surgery and patients who had liver resection for known primaries. METHODS: The study identified 32 unknown primary liver metastases (UP-NETLM) in 522 retrospectively evaluated patients who underwent resection of well-differentiated NETLM between January 2000 and December 2020. Tumor and patient characteristics were compared with those in 490 cases of liver metastasis from small intestinal (SI-NETLM) or pancreatic (pNETLM) primaries. Survival analysis was performed to highlight long-term outcome differences. Surgical outcomes were compared between liver resections alone and simultaneous primary resections to assess surgical risk distinctions. RESULTS: The UP-NET patients had fewer NETLMs (p = 0.004), which on the average were larger than SI-NETLMs or pNETLMs (p = 0.002). Expression of Ki-67 was balanced among the groups. Major hepatectomy was performed more often in the UP-NETLM group (p = 0.017). The 10-year survival rate of 53% for UP-NETLM was comparable with that for SI-NETML (58%; p = 0.463) and pNETLMs (47%; p = 0.497). The median hepatic progression-free survival was 26 months for the UP-NETLM patients and 25 months for the SI-NETLM patients compared to 12 months for the pNETLM patients (p < 0.001). Perioperative mortality was lower than 2%, and severe postoperative morbidity occurred in 21%, similarly distributed among all the groups. CONCLUSION: The surgical risk and long-term outcomes for the UP-NETLM patients were comparable with those for other NETLM cases, affirming the validity of equally aggressive surgical cytoreduction as a therapeutic option in carefully selected cases.

Implications of pregnancy on MCN of the pancreas: A multicentric case-control study.

BACKGROUND: Mucinous cystic neoplasms (MCN) of the pancreas express estrogen and progesterone receptors. Several case reports describe MCN increasing in size during gestation. The aim of this study is to assess if pregnancy is a risk factor for malignant degeneration of MCN. METHODS: All female patients who underwent pancreatic resection of a MCN between 2011 and 2021 were included. MCN resected or diagnosed within 12 months of gestation were defined perigestational. MCN with high grade dysplasia or an invasive component were classified in the high grade (HG) group. The primary outcome was defined as the correlation between exposure to gestation and peri-gestational MCN to development of HG-MCN. RESULTS: The study includes 176 patients, 25 (14 %) forming the HG group, and 151 (86 %) forming the low grade (LG) group. LG and HG groups had a similar distribution of systemic contraceptives use (26 % vs. 16 %, p = 0.262), and perigestational MCN (7 % vs 16 %, p = 0.108). At univariate analysis cyst size ≥10 cm (OR 5.3, p < 0.001) was associated to HG degeneration. Peri gestational MCN positively correlated with cyst size (R = 0.18, p = 0.020). In the subgroup of 14 perigestational MCN patients 29 % had HG-MCN and 71 % experienced cyst growth during gestation with an average growth of 55.1 ± 18 mm. CONCLUSIONS: Perigestational MCN are associated to increased cyst diameter, and in the subset of patients affected by MCN during gestation a high rate of growth was observed. Patients with a MCN and pregnancy desire should undergo multidisciplinary counselling.

Early vs conventional onset pancreatic ductal adenocarcinoma: analysis of surgical and oncologic outcomes in patients undergoing curative intent resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) impacts patients in their 60s, but its incidence in younger patients is increasing. We hypothesize that younger patients may have worse oncologic outcomes. METHODS: Patients who underwent curative pancreatic resection for PDAC between January 2011 and December 2021 at a single institution were analyzed. Early-onset pancreatic cancer (EOPC) was defined as pancreatic cancer diagnosed in patients ≤50 years. Clinical and survival outcomes were compared between EOPC and Conventional Onset Pancreas Cancer (COPC). RESULTS: A total of 1133 patients were identified, 65 (5.7%) were EOPC. Preoperative patient characteristics including sex, smoking status, alcohol habitus, diabetes mellitus, CA 19-9, and neoadjuvant therapy were similar between EOPC and COPC (p > 0.05). EOPC patients were more likely non-white (p = 0.03), had lower ASA scores (p = 0.02) and larger median tumor size (33 vs 28 mm, p = 0.04), but had similar pathological stages and rate of R0 resections (p > 0.05). Postoperative outcomes were similar (p > 0.05). There was no statistically significant difference in overall (HR 0.93, CI 0.64, 1.33; p = 0.68) or recurrence free (HR 1.05, CI 0.75, 1.48; p = 0.77) survival between the EOPC and COPC after adjusting for significant factors. CONCLUSION: Patients with EOPC who underwent surgical resection had similar oncological outcomes compared to patients with COPC.

Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC. DESIGN: We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. RESULTS: iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients. CONCLUSION: Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma.

BACKGROUND & AIMS: There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. METHODS: A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. RESULTS: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. CONCLUSIONS: A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. IMPACT AND IMPLICATIONS: Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials.

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

Oncologic Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Highly Selected Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PM) from pancreatic ductal adenocarcinoma (PDAC) are currently treated with palliative systemic chemotherapy alone, with unsatisfactory results. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may provide an oncologic benefit for highly selected patients. PATIENTS AND METHODS: Patients with PDAC and isolated PM who completed ≥ 6 months of systemic chemotherapy with objective response between 2017 and 2022 were retrospectively reviewed. All patients met the inclusion/exclusion criteria as per our previously published PDAC CRS/HIPEC protocol. Patients who underwent CRS/HIPEC were compared with matched patients who underwent systemic therapy alone. Overall survival (OS) from diagnosis of PM and progression-free survival (PFS) from CRS/HIPEC was evaluated. RESULTS: In total, 61 patients met the inclusion criteria: 38 underwent systemic therapy alone and 23 CRS/HIPEC. There were no differences in baseline prognostic factors, including age, sex, tumor size, tumor location, anatomic resectability, or serum cancer antigen (CA) 19-9 (p > 0.05). Median OS from PM diagnosis in patients who underwent systemic therapy alone was 19 months with 1, 2, and 3 year OS of 81%, 31%, and 8%, respectively. In contrast, median OS from PM diagnosis in patients who underwent CRS/HIPEC was 41 months with improved 1, 2, and 3 year OS of 91%, 66%, and 59%, respectively (p = 0.002). In the 21 patients who achieved complete cytoreduction (CC-0), no adjuvant therapy was administered and the median PFS was 17 months. CONCLUSIONS: CRS/HIPEC in highly selected patients with PDAC and PM results in promising oncologic outcomes that are unlikely to be achieved with systemic chemotherapy alone. Further investigation is warranted and ongoing (NCT04858009).

Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion for Pancreatic Cancer with Low-Volume Peritoneal Metastasis: Results from a Prospective Pilot Study.

INTRODUCTION: Resection of oligometastatic pancreatic ductal adenocarcinoma (PDAC) has historically been ineffective, however modern systemic chemotherapy has improved survival. Thus, re-evaluating safety and outcomes of surgical resection in selected patients with limited peritoneal metastasis (PM) warrants consideration. METHODS: From 2018 to 2021, patients with PDAC and positive cytology or limited PM without extraperitoneal metastasis and who had an objective response to ≥ 6 months of systemic chemotherapy were enrolled. Patients underwent laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin/mitomycin C. If amenable to a complete cytoreduction, patients went on to cytoreduction and HIPEC. RESULTS: Overall, 18 patients were enrolled and received a median of 14 (interquartile range [IQR] 12-17) cycles of chemotherapy; 16 (89%) patients received chemoradiation. Laparoscopic HIPEC was completed in 17 patients, with a median length of stay of 1 day, and no grade III complications or hematological toxicities were observed. All 18 patients subsequently underwent a complete cytoreduction (CC-0) along with definitive treatment of the primary tumor, with formal resection (7/18), irreversible electroporation (IRE; 10/18), or intraoperative radiation therapy (IORT; 1/18). Median PCI was 2 (IQR 0-4), median LOS was 7 days (IQR 6-8), and 7 (39%) patients were readmitted. Eight (44%) patients experienced grade 3 or higher complications, including one 30-day mortality. At a median follow-up of 16 months, the median progression-free survival was 20 months and the median overall survival was 26 months. CONCLUSION: Cytoreduction and HIPEC for selected patients with low-volume PM from PDAC is safe and feasible with favorable short-term outcomes. A phase II trial (NCT04858009) is now enrolling to further assess this multimodality approach in select patients.

Survival and Symptomatic Relief After Cytoreductive Hepatectomy for Neuroendocrine Tumor Liver Metastases: Long-Term Follow-up Evaluation of More Than 500 Patients.

BACKGROUND: Distant metastases are the strongest predictor of poor prognosis for patients with neuroendocrine tumors (NETs). Cytoreductive hepatectomy (CRH) can relieve symptoms of hormonal excess and prolong survival for patients with liver metastases (NETLMs), but long-term outcomes are poorly characterized. METHODS: This retrospective single-institution analysis analyzed patients who underwent CRH for well-differentiated NETLMs from 2000 to 2020. Kaplan-Meier analysis estimated symptom-free interval and overall and progression-free survival. Multivariable Cox regression analysis evaluated factors associated with survival. RESULTS: The inclusion criteria were met by 546 patients. The most common primary sites were the small intestine (n = 279) and the pancreas (n = 194). Simultaneous primary tumor resection was performed for 60 % of the cases. Major hepatectomy comprised 27% of the cases, but this rate decreased during the study period (p < 0.001). Major complications occurred in 20%, and the 90-day mortality rate was 1.6%. Functional disease was present in 37 %, and symptomatic relief was achieved in 96%. The median symptom-free interval was 41 months (62 months after complete cytoreduction and 21 months with gross residual disease) (p = 0.021). The median overall survival was 122 months, and progression-free survival was 17 months. In the multivariable analysis, worse overall survival was associated with age, pancreatic primary tumor, Ki-67, number and size of lesions, and extrahepatic metastases, with Ki-67 as the strongest predictor (odds ratio [OR], 1.90 for Ki-67 [3-20%; p = 0.018] and OR, 4.25 for Ki-67 [>20%; p < 0.001]). CONCLUSION: The study showed that CRH for NETLMs is associated with low perioperative morbidity and mortality and excellent overall survival, although the majority will experience recurrence/progression. For patients with functional tumors, CRH can provide durable symptomatic relief.

Bounding box-based 3D AI model for user-guided volumetric segmentation of pancreatic ductal adenocarcinoma on standard-of-care CTs.

OBJECTIVES: To develop a bounding-box-based 3D convolutional neural network (CNN) for user-guided volumetric pancreas ductal adenocarcinoma (PDA) segmentation. METHODS: Reference segmentations were obtained on CTs (2006-2020) of treatment-naïve PDA. Images were algorithmically cropped using a tumor-centered bounding box for training a 3D nnUNet-based-CNN. Three radiologists independently segmented tumors on test subset, which were combined with reference segmentations using STAPLE to derive composite segmentations. Generalizability was evaluated on Cancer Imaging Archive (TCIA) (n = 41) and Medical Segmentation Decathlon (MSD) (n = 152) datasets. RESULTS: Total 1151 patients [667 males; age:65.3 ± 10.2 years; T1:34, T2:477, T3:237, T4:403; mean (range) tumor diameter:4.34 (1.1-12.6)-cm] were randomly divided between training/validation (n = 921) and test subsets (n = 230; 75% from other institutions). Model had a high DSC (mean ± SD) against reference segmentations (0.84 ± 0.06), which was comparable to its DSC against composite segmentations (0.84 ± 0.11, p = 0.52). Model-predicted versus reference tumor volumes were comparable (mean ± SD) (29.1 ± 42.2-cc versus 27.1 ± 32.9-cc, p = 0.69, CCC = 0.93). Inter-reader variability was high (mean DSC 0.69 ± 0.16), especially for smaller and isodense tumors. Conversely, model's high performance was comparable between tumor stages, volumes and densities (p > 0.05). Model was resilient to different tumor locations, status of pancreatic/biliary ducts, pancreatic atrophy, CT vendors and slice thicknesses, as well as to the epicenter and dimensions of the bounding-box (p > 0.05). Performance was generalizable on MSD (DSC:0.82 ± 0.06) and TCIA datasets (DSC:0.84 ± 0.08). CONCLUSION: A computationally efficient bounding box-based AI model developed on a large and diverse dataset shows high accuracy, generalizability, and robustness to clinically encountered variations for user-guided volumetric PDA segmentation including for small and isodense tumors. CLINICAL RELEVANCE: AI-driven bounding box-based user-guided PDA segmentation offers a discovery tool for image-based multi-omics models for applications such as risk-stratification, treatment response assessment, and prognostication, which are urgently needed to customize treatment strategies to the unique biological profile of each patient's tumor.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Endoscopic ultrasound-guided versus percutaneous drainage for the management of post-operative fluid collections after distal pancreatectomy.

BACKGROUND: Post-operative pancreatic fluid collections (POPFCs) can be drained using percutaneous or endoscopic approaches. The primary aim of this study was to compare rates of clinical success between endoscopic ultrasound-guided drainage (EUSD) with percutaneous drainage (PTD) in the management of symptomatic POPFCs after distal pancreatectomy. Secondary outcomes included technical success, total number of interventions, time to resolution, rates of adverse events (AEs), and POPFC recurrence. METHODS: Adults who underwent distal pancreatectomy from January 2012 to August 2021 and developed symptomatic POPFC in the resection bed were retrospectively identified from a single academic center database. Demographic data, procedural data, and clinical outcomes were abstracted. Clinical success was defined as symptomatic improvement and radiographic resolution without requiring an alternate drainage modality. Quantitative variables were compared using a two-tailed t-test and categorical data were compared using Chi-squared or Fisher's exact tests. RESULTS: Of 1046 patients that underwent distal pancreatectomy, 217 met study inclusion criteria (median age 60 years, 51.2% female), of whom 106 underwent EUSD and 111 PTD. There were no significant differences in baseline pathology and POPFC size. PTD was generally performed earlier after surgery (10 vs. 27 days; p < 0.001) and more commonly in the inpatient setting (82.9% vs. 49.1%; p < 0.001). EUSD was associated with a significantly higher rate of clinical success (92.5% vs. 76.6%; p = 0.001), fewer median number of interventions (2 vs. 4; p < 0.001), and lower rate of POPFC recurrence (7.6% vs. 20.7%; p = 0.007). AEs were similar between EUSD (10.4%) and PTD (6.3%, p = 0.28), with approximately one-third of EUSD AEs due to stent migration. CONCLUSION: In patients with POPFCs after distal pancreatectomy, delayed drainage with EUSD was associated with higher rates of clinical success, fewer interventions, and lower rates of recurrence than earlier drainage with PTD.

A Novel ypTLM Staging System Based on LODDS for Gastric Cancer After Neoadjuvant Therapy: Multicenter and Large-Sample Retrospective Study.

BACKGROUND: The accuracy of the eighth AJCC ypTNM staging system on the prognosis of gastric cancer (GC) patients after neoadjuvant therapy (NAT) is controversial. This study aimed to develop and validate a novel staging system using the log odds of positive lymph nodes scheme (LODDS). METHODS: A retrospective analysis of 606 GC patients who underwent radical gastrectomy after neoadjuvant therapy was conducted as the development cohort. (Fujian Medical University Affiliated Union Hospital (n = 183), Qinghai University Affiliated Hospital (n = 169), Mayo Clinic (n = 236), Lanzhou University First Hospital (n = 18)). The validation cohort came from the SEER database (n = 1701). A novel ypTLoddsS (ypTLM) staging system was established using the 3-year overall survival. The predictive performance of two systems was compared. RESULTS: Two-step multivariate Cox regression analysis in both cohorts showed that ypTLM was an independent predictor of overall survival of GC patients after neoadjuvant therapy (HR: 1.57, 95% CI: 1.30-1.88, p < 0.001). In the development cohort, ypTLM had better discrimination ability than ypTNM (C-index: 0.663 vs 0.633, p < 0.001), better prediction homogeneity (LR: 97.7 vs. 70.9), and better prediction accuracy (BIC: 3067.01 vs 3093.82; NRI: 0.36). In the validation cohort, ypTLM had a better prognostic predictive ability (C-index: 0.614 vs 0.588, p < 0.001; LR: 11,909.05 vs. 11,975.75; BIC: 13,263.71 vs 13,328.24; NRI: 0.22). The time-dependent ROC curve shows that the predictive performance of ypTLM is better than ypTNM, and the analysis of the decision curve shows that ypTLM achieved better net benefits. CONCLUSION: A LODDS-based ypTLM staging system based on multicenter data was established and validated. The predictive performance was superior to the eighth AJCC ypTNM staging system.

Surgical and Patient-Reported Outcomes of Open Perforator-Preserving Anterior Component Separation for Ventral Hernia Repair.

BACKGROUND: Abdominal wall reconstruction is challenging for surgeons and may be life altering for patients. There are scant high-quality studies on patient-reported outcomes following abdominal wall reconstruction. We assess long-term surgical and patient-reported outcomes of perforator-preserving open anterior component separation (OPP-ACS) following large ventral hernia repair. METHODS: A retrospective review of patients with large ventral hernia defects who underwent OPP-ACS performed by the authors (B.A.S., M.J.T.) was conducted between 2015 and 2019. Demographics, surgical history, operative details, outcomes, and complications were extracted. A validated questionnaire, Carolinas Comfort Scale (CCS), was used to assess postoperative quality of life. RESULTS: Twenty-two patients (12 males and 10 females) with a mean age and BMI of 60.9 ± 10 years and 28.9 ± 4.8 kg/m2, respectively, were included. Mean follow-up was 28.5 ± 16.3 months. All had prior abdominal surgery; 15 (68%) for abdominopelvic malignancy, 3 (14%) for previous failed hernia repair, and 8 (36%) had history of abdominopelvic radiation. Overall, 16 (73%) hernias were in the midline, 4 (18%) in the right lower quadrant, 1 (4.5%) in the right upper quadrant, and 1 (4.5%) in the left lower quadrant. Mean hernia defect surface area was 145 ± 112 cm2. A total of 9 patients (40.9%) underwent bilateral component separation, whereas 13 (59.1%) had unilateral. Bioprosthetic mesh was used in all patients as underlay. Mean mesh size and thickness were 545.6 ± 207.7 cm2 and 3.4 ± 0.5 mm, respectively. One patient presented with a minor wound dehiscence, and two presented with seromas not requiring aspiration/evacuation. One patient had hernia recurrence 22 months after surgery. One patient was readmitted for partial small bowel obstruction and one required wound revision. A total of 14 (65%) patients responded to the CCS questionnaire. At 12 months, mean score for all 23 items was 0.29 ± 0.21 (0.08-0.62), which corresponds to absence or minimal symptoms. CONCLUSION: The OPP-ACS is a safe surgical option for large, complex ventral hernias. Our cases showed minimal complication rate and hernia recurrence, and our patients reported significant improvement in life quality.

Laparoscopic versus open liver resections for intrahepatic cholangiocarcinoma and gallbladder cancer: the Mayo clinic experience.

BACKGROUND: Data regarding laparoscopic liver resections(LLRs) for Gallbladder cancer(GBC) and Intrahepatic Cholangiocarcinoma(iCCA) are sparse. This study compared LLRs with open liver resections(OLRs) in a high-volume center. METHODS: Data of patients who underwent LLR or OLR for GBC or iCCA at Mayo-Clinic between 01/2016 and 04/2021 were retrospectively compared. Proportional hazards models were used to compare the approach on survival. RESULTS: 32 and 52 patients underwent LLR and OLR during the study period, respectively. 64 and 20 patients had iCCA and GBC, respectively. LLR had lower median blood loss (250 mL vs. 475 mL, p = 0.001) and shorter median length of stay compared to OLR (3.0 days vs. 6.0 days, p = 0.001). LLR and OLR did not differ in post-operative major complication (25% vs. 32.7%, p = 0.62), negative margin (100% vs. 90.4%, p = 0.15) and completeness of lymphadenectomy rates (36.8% vs. 45.5%, p = 0.59). The median number of harvested lymph node was 4.0 and 5.0 for LLR and OLR, respectively (p = 0.347). There were no associations between approach and 3-year overall and disease-free survival between LLR and OLR (49.8% vs. 63.2% and 39.6% vs. 21.5%, p = 0.66 and p = 0.69). DISCUSSION: With appropriate patient selection and when compared to OLRs, LLRs for GBC and iCCA are feasible, safe and offer potential short-term benefits without compromising on oncological resection principals and long-term outcomes.