5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1).

BACKGROUND: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). METHODS: The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm. RESULTS: RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332). CONCLUSION: The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions.

Identification of a urinary CD276 fragment for detecting resectable pancreatic cancer using a C-terminal proteomics strategy.

This study aimed to confirm urinary protein fragments in relation to the presence of pancreatic ductal adenocarcinoma (PDAC) via a C-terminal proteomics strategy using exploratory and validation cohorts. Urinary fragments were examined by iTRAQ-labelling of tryptic peptides and concentrations of C-terminal fragments were evaluated. Only the urinary CD276 fragment showed a fold change (FC) of > 1.5 with a significant difference of P < 0.01 between healthy (H) and PDAC participants in both the exploratory (H, n = 42; PDAC, n = 39) and validation cohorts (H, n = 36; resectable PDAC, n = 28). The sensitivity and specificity of the CD276 fragment for diagnosing resectable PDAC were 75% and 89%, respectively, in the validation cohort. Postoperative urinary levels of the CD276 fragment were low as compared to those before surgery (n = 18, P < 0.01). Comprehensive C-terminus proteomics identified an increase in the urinary CD276 fragment level as a feature of patients with PDAC. The urinary CD276 fragment is a potential biomarker for detecting resectable PDAC.

Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment. METHODS: In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC. RESULTS: CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival. CONCLUSIONS: This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

Treatment outcomes of gemcitabine plus nab-paclitaxel in pancreatic cancer patients with malignant ascites.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) therapy has been shown to improve the prognosis in patients with metastatic pancreatic cancer (PC); however, the efficacy and safety of GnP in PC patients with malignant ascites (MA) remains unknown. METHODS: We retrospectively investigated PC patients with peritoneal dissemination who had received GnP as first-line chemotherapy at our institution between March 2015 and August 2021. The following patient data were reviewed: patient characteristics, overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and relative dose intensity (RDI). The severity of MA was categorized based on the CT findings as grade 1 (small), grade 2 (moderate), or grade 3 (massive). RESULTS: A total of 189 patients were included; the study endpoints were compared between patients with each ascites grade and 41 patients without MA. The MA was classified as grade 1 in 85 patients, grade 2 in 41 patients, and grade 3 in 22 patients. In the patients with MA, the median OS, PFS and ORR were 11.2 months, 5.7 months and 24.3%, respectively. The OS and PFS decreased with increasing the severity of MA; in particular, patients with grade 2 and 3 showed a poorer prognosis. There were no differences in AEs, except for anorexia, or the RDI according to the severity of MA. CONCLUSION: GnP showed moderate efficacy with manageable safety profile in PC patients with MA. However, PC patients with moderate to massive ascites still have a dismal prognosis, and further development of effective treatments is needed.

Covered self-expandable metallic stent placement for tumor bleeding from duodenal invasion in patients with unresectable pancreatic cancer.

Patients with unresectable pancreatic cancer often present with duodenal bleeding, a potentially life-threatening complication. In our case series of six unresectable pancreatic cancer patients with tumor bleeding, we explored the efficacy and safety of placement of a covered self-expandable metallic stent in the duodenum as a treatment option; we achieved a hemostasis rate of 67% (4/6), with a rebleeding rate of 50% (2/4). No complications occurred with stent placement, except for food impaction in one patient. Covered self-expandable metallic stent placement is a moderately effective treatment option for tumor bleeding in patients with unresectable pancreatic cancer. Although its hemostatic efficacy is limited, covered self-expandable metallic stent placement is safe and beneficial in some cases, warranting consideration in this disease setting with limited treatment options.

Palliative radiotherapy for tumor bleeding in patients with unresectable pancreatic cancer: a single-center retrospective study.

BACKGROUND: Patients with unresectable pancreatic cancer (PC) sometimes experience gastrointestinal bleeding (GIB) due to tumor invasion of the gastrointestinal tract (tumor bleeding); no standard treatment has been established yet for this complication. Palliative radiotherapy (PRT) could be promising, however, there are few reports of PRT for tumor bleeding in patients with unresectable PC. Therefore, we evaluated the outcomes of PRT for tumor bleeding in patients with unresectable PC. METHODS: We reviewed the medical records of patients with unresectable PC diagnosed at our institution between May 2013 and January 2022, and identified patients with endoscopically confirmed tumor bleeding who had received PRT. PRT was administered at a total dose of 30 Grays (Gy) in 10 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction, and the dose selection was left to the discretion of the attending radiation oncologists. RESULTS: During the study period, 2562 patients were diagnosed as having unresectable PC at our hospital, of which 225 (8.8%) developed GIB. Among the 225 patients, 63 (2.5%) were diagnosed as having tumor bleeding and 20 (0.8%) received PRT. Hemostasis was achieved in 14 of the 20 patients (70%) who received PRT, and none of these patients developed grade 3 or more adverse events related to the PRT. The median time to hemostasis was 8.5 days (range 7-14 days). The rebleeding rate was 21.4% (3/14). The median hemoglobin level increased significantly (p < 0.001) from 5.9 to 9.1 g/dL, and the median volume of red blood cell transfusion tended (p = 0.052) to decrease, from 1120 mL (range 280-3360 mL) to 280 mL (range 0-5560 mL) following the PRT. The median overall survival (OS) was 52 days (95% confidence interval [CI] 39-317). Of the 14 patients in whom hemostasis was achieved following PRT, chemotherapy could be started/resumed in seven patients (50%), and the median OS in these patients was 260 days (95% CI 76-not evaluable [NE]). Three patients experienced rebleeding (21.4%), on days 16, 22, and 25, after the start of PRT. CONCLUSION: This study showed that PRT is an effective and safe treatment modality for tumor bleeding in patients with unresectable PC.

Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin-bound paclitaxel (nab-PTX)-refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab-PTX. Patients initially received TCZ 8 mg/kg on Day 1 and nab-PTX 100 mg/m2 + GEM 750 mg/m2 on Days 2, 9, and 16. Before and at the end of Cycle 1, biopsy of liver metastases was performed 3-5 h after levofloxacin (LVFX) administration to measure LVFX infiltration into tumor tissue. No dose-limited toxicities occurred, and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events occurred in 80% of patients, of which decreased neutrophil count was the most common. Tumor reduction during Cycle 1 was observed in four patients, who were defined as responders. In paired-biopsy samples, responder-related biological activities were an increase of cleaved PARP expression of tumor nuclei (p = 0.01), a decrease of proliferative cancer-associated fibroblasts (CAFs) (p = 0.08), and an increase of LVFX infiltration in the tumor (p = 0.04). A decrease of phosphorylated STAT3 expression (p = 0.02) favored an increase in LVFX infiltration. In conclusion, TCZ + GEM/nab-PTX-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and improved intratumoral drug infiltration in MPC.

Case Report: Atezolizumab plus bevacizumab for combined hepatocellular-cholangiocarcinoma.

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare subtype of primary liver cancers. Therapeutic strategies for patients with cHCC-CCA are limited, and no standard systemic treatment has been established for unresectable cHCC-CCA. Here, we present six cases of cHCC-CCA treated with atezolizumab plus bevacizumab. We observed three partial responses and one stable disease as the best responses; two of these patients were still being treated with atezolizumab plus bevacizumab at the time of reporting (at least five months of treatment), whereas the remaining two patients were unable to continue treatment owing to adverse events. Atezolizumab plus bevacizumab may be an effective treatment for unresectable cHCC-CCA.

Complete response to definitive chemoradiotherapy in unresectable locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Although definitive chemoradiotherapy (CRT) is the standard therapy for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), poor survival has been reported. Although the complete response (CR) rate is strongly correlated with good prognosis, the predictive factors for CR have not been elucidated. METHODS: This registry study aimed to identify predictors of CR to definitive CRT in patients with unresectable locally advanced ESCC. "Unresectable" was defined as the primary lesion invading unresectable adjacent structures such as the aorta, vertebral body, and trachea (T4b), or the regional and/or supraclavicular lymph nodes invading unresectable adjacent structures (LNT4b). RESULTS: Overall, 175 patients who started definitive CRT between January 2013 and March 2020 were included. The confirmed CR (cCR) rate was 24% (42/175). The 2-year progression-free survival (PFS) and overall survival (OS) rates of cCR cases vs. non-cCR cases were 59% vs. 2% (log-rank p < 0.001) and 90% vs. 31% (log-rank p < 0.001), with a median follow-up period of 18.5 and 40.5 months, respectively. Multivariate analysis of clinicopathological factors revealed that tumor length ≥ 6 cm [odds ratio (OR) 0.446; 95% CI 0.220-0.905; p = 0.025] was a predictor of cCR. CONCLUSIONS: Favorable PFS and OS rates were observed in patients with cCR. Tumor length was a predictive factor for cCR.

Serum microRNAs as new criteria for referral to early palliative care services in treatment-naïve advanced cancer patients.

A major obstacle to the implementation of early palliative care (EPC) is the lack of objective criteria for referral to EPC. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers. The present study investigated objective definitions for referral to EPC using microRNA. A total of 178 serum samples were obtained from patients with lung, gastrointestinal, colorectal, bile duct, pancreas and bladder cancers who were treatment-naïve and received chemotherapy between January 2011 and December 2013 at National Cancer Center Hospital East. We investigated expression levels of miRNAs using microarrays. The primary outcome was prediction of admission to a palliative care unit ≤6 months after first visit. Diagnostic models using clinical characteristics, miRNAs and combinations of both were constructed. The miRNA models were constructed using 6 miRNA levels. The best areas under the receiver operating characteristic curve (AUCs) of the clinical model was 0.741, while the average AUCs of miRNA-based models and combination models were 0.769 and 0.806, respectively. Combination models showed higher AUCs than the clinical model (p < 0.023). The present combination models might offer new objective definitions for referral to EPC and thus contribute to real-world implementation of EPC.

Incidence of and risk factors for severe neutropenia during treatment with the modified FOLFIRINOX therapy in patients with advanced pancreatic cancer.

Although FOLFIRINOX (L-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27-111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18-7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.

Automated surgical workflow identification by artificial intelligence in laparoscopic hepatectomy: Experimental research.

BACKGROUND: To perform accurate laparoscopic hepatectomy (LH) without injury, novel intraoperative systems of computer-assisted surgery (CAS) for LH are expected. Automated surgical workflow identification is a key component for developing CAS systems. This study aimed to develop a deep-learning model for automated surgical step identification in LH. MATERIALS AND METHODS: We constructed a dataset comprising 40 cases of pure LH videos; 30 and 10 cases were used for the training and testing datasets, respectively. Each video was divided into 30 frames per second as static images. LH was divided into nine surgical steps (Steps 0-8), and each frame was annotated as being within one of these steps in the training set. After extracorporeal actions (Step 0) were excluded from the video, two deep-learning models of automated surgical step identification for 8-step and 6-step models were developed using a convolutional neural network (Models 1 & 2). Each frame in the testing dataset was classified using the constructed model performed in real-time. RESULTS: Above 8 million frames were annotated for surgical step identification from the pure LH videos. The overall accuracy of Model 1 was 0.891, which was increased to 0.947 in Model 2. Median and average accuracy for each case in Model 2 was 0.927 (range, 0.884-0.997) and 0.937 ± 0.04 (standardized difference), respectively. Real-time automated surgical step identification was performed at 21 frames per second. CONCLUSIONS: We developed a highly accurate deep-learning model for surgical step identification in pure LH. Our model could be applied to intraoperative systems of CAS.

[Development of Therapy for Cancer Cachexia in Pancreatic Cancer].

Cancer cachexia is a metabolic disorder syndrome that causes skeletal muscle loss and progressive physical dysfunction, which is observed in more than half of patients with advanced pancreatic cancer. Cancer cachexia is considered to be associated with poor prognosis, worsening adverse events, decreased treatment compliance, and decreased treatment efficacy. The ghrelin receptor agonist leads skeletal muscle gain, weight gain, and the improvement of anorexia in patients with cancer cachexia, and has been approved as an anti-cachexia treatment in Japan. Cancer cachexia patients who present with cachexia symptoms such as appetite loss as well as weight loss are able to receive the treatment of the ghrelin receptor agonist, but the evidence for patients with advanced pancreatic cancer is limited. Further research is needed to evaluate the efficacy of the ghrelin receptor agonist for cancer cachexia in pancreatic cancer patients. Inhibition of inflammatory cytokine such as interleukin-1α and nutrition and exercise therapy are under development for anti-cachexia therapy.

Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer.

BACKGROUND: Nerve invasion (N-inv) is an important prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Elucidation of circulating N-inv stimulators could provide deeper insights and novel perspectives for PDAC therapy. The interleukin (IL)-6/gp130 axis was evaluated in this study as a candidate N-inv stimulator. METHODS: A human pancreatic cancer (PC) cell, Capan-1, was confirmed to have the stimulant activity of IL-6/gp130 axis through the evaluation of mRNA, cell surface protein and intracellular protein levels and chemotaxis and wound healing assay. The upregulation of IL-6/gp130 axis was evaluated using tumor-derived IL-6 level and intratumoral pSTAT3 expression in N-inv of murine sciatic nerves by intraneural injection of Capan-1 cell (N-inv model) and using resected pancreatic cancer tissue and clinical data from 46 PDAC patients. RESULTS: mRNA and protein expressions of IL-6 and IL-6 receptor were found in whole cell lysate and condition medium from PC cell. Cell surface protein expression of gp130 were clearly detected on PC cell. IL-6 promoted migration and chemotaxis of PC cell. Serum IL-6 and tumoral IL-6 mRNA levels in N-inv model mice were significantly higher than those in subcutaneous tumor mice (p = 0.004 and p = 0.002, respectively). Silencing of IL-6 and gp130 on PC cell and administration of an anti-IL-6 receptor antibody, tocilizumab, suppressed N-inv, compared to each control (p = 0.070, p = 0.118 and p = 0.122, respectively). In PDAC patients, the high-N-inv group showed poor prognosis (p =0.059) and elevated serum levels of IL-6 and C-reactive protein, synthesis of which is promoted by IL-6, compared to those in the low-N-inv group (p = 0.006 and p = 0.075, respectively). Tumoral gp130 expression at N-inv was higher than that in the primary pancreatic tumor (p = 0.026). CONCLUSION: Biological activity of IL-6/gp130 axis promoted N-inv in murine model and was upregulated in PDAC patients with severe N-inv. This study is the first evidence that the IL-6/gp130 axis offers a potential therapeutic target in PDAC with N-inv.

Real-time detection of the recurrent laryngeal nerve in thoracoscopic esophagectomy using artificial intelligence.

BACKGROUND: Artificial intelligence (AI) has been largely investigated in the field of surgery, particularly in quality assurance. However, AI-guided navigation during surgery has not yet been put into practice because a sufficient level of performance has not been reached. We aimed to develop deep learning-based AI image processing software to identify the location of the recurrent laryngeal nerve during thoracoscopic esophagectomy and determine whether the incidence of recurrent laryngeal nerve paralysis is reduced using this software. METHODS: More than 3000 images extracted from 20 thoracoscopic esophagectomy videos and 40 images extracted from 8 thoracoscopic esophagectomy videos were annotated for identification of the recurrent laryngeal nerve. The Dice coefficient was used to assess the detection performance of the model and that of surgeons (specialized esophageal surgeons and certified general gastrointestinal surgeons). The performance was compared using a test set. RESULTS: The average Dice coefficient of the AI model was 0.58. This was not significantly different from the Dice coefficient of the group of specialized esophageal surgeons (P = 0.26); however, it was significantly higher than that of the group of certified general gastrointestinal surgeons (P = 0.019). CONCLUSIONS: Our software's performance in identification of the recurrent laryngeal nerve was superior to that of general surgeons and almost reached that of specialized surgeons. Our software provides real-time identification and will be useful for thoracoscopic esophagectomy after further developments.

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer.

BACKGROUND: The previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited. MATERIALS AND METHODS: We retrospectively analyzed data for patients with HER2-positive metastatic breast cancer who received T-DXd at our institution from April 2020 to March 2021. We evaluated the associations between clinicopathological and molecular biomarkers and the efficacy of T-DXd. RESULTS: Twenty-two patients were enrolled in this study. The median progression-free survival (PFS) was 9.7 months (95% confidence interval [CI], 7.0-not reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3+ and 2+/1+ at initial diagnosis (ORR: 50.0% vs. 72.7%, p = 0.39; median PFS, 9.7 months [95%CI, 2.6-NR] vs. 8.3 months [95%CI, 7.1-NR]; hazard ratio, 1.86 [95%CI, 0.53-6.57], p = 0.34). Two patients with heterogenous HER2 expression had a partial response or long stable disease (≥6 months). Three of four patients with re-biopsy samples after anti-HER2 targeted therapy and with latest HER2 immunohistochemistry scores of 1+ experienced partial responses (75.0%) to T-DXd, but none had responded to prior T-DM1. CONCLUSIONS: T-DXd demonstrated favorable activity in clinical practice. Moreover, T-DXd showed meaningful benefit in patients with heterogeneity, reduction, or loss of HER2 expression.

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System.

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer. SIGNIFICANCE: GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic and epigenomic features. This article is highlighted in the In This Issue feature, p. 587.