Identification of DNA Repair-related Genes as Biomarkers Reflecting MSI, TMB, and TIL in Colorectal Cancer.

BACKGROUND/AIM: There are no established biomarkers for immune checkpoint inhibitors (ICI) in colorectal cancer (CRC) with microsatellite stability (MSS) or proficient mismatch repair (pMMR). Therefore, this study aimed to identify biomarkers for ICI benefit in patients with pMMR by analyzing the down-regulated DNA repair-related genes involved in highly immunogenic and immune responses, and comparing their expression levels and clinical features. MATERIALS AND METHODS: Mismatch repair (MMR), tumor-infiltrating lymphocytes (TIL), and tumor mutation burden (TMB) were evaluated in 13 CRC cases and mRNA expression levels of 95 DNA repair-related genes were measured. DNA repair-related genes with reduced mRNA expression in the high immunogenicity and high immune response groups were identified. Then, the mRNA expression levels of the identified DNA repair-related genes were measured in 135 patients with CRC. Hierarchical cluster analysis was performed using the mRNA expression levels to compare the clinicopathological characteristics of each cluster. RESULTS: ATR, LIG4, and RAD52 mRNA levels were significantly down-regulated in the high immunogenicity group. GADD45B, SMUG1, and XRCC6 mRNA levels were significantly down-regulated in the high immune response group. Cases in the cluster with reduced mRNA expression of the six genes were pMMR cases. CD8 mRNA expression level was higher in this cluster than in the other clusters. CONCLUSION: Decreased mRNA expression levels of ATR, LIG4, RAD52, GADD45B, SMUG1, and XRCC6 genes were associated with high cytotoxic T cell and TMB levels, suggesting that these genes could serve as biomarkers for ICI efficacy in pMMR cases.

Pancreatic juice cytology for diagnosing invasive pancreatic carcinoma/high-grade pancreatic intraepithelial neoplasia without visible tumors on endoscopic ultrasound.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) with a diameter ≤10 mm and high-grade pancreatic intraepithelial neoplasia (HG-PanIN) require pre-operative diagnosis. Most cases present only indirect imaging findings without visible tumors on endoscopic ultrasound (EUS). Therefore, EUS-guided fine-needle aspiration/biopsy is not applicable. An alternative diagnostic method is pancreatic juice cytology (PJC) via endoscopic naso-pancreatic drainage (ENPD-PJC), which is not the standard practice. This study aimed to investigate ENPD-PJC for diagnosing suspected PDAC/HG-PanIN cases without visible tumors on EUS. METHODS: Data of patients with suspected PDAC/HG-PanIN without visible tumors who underwent PJC were retrospectively evaluated. One PJC sample was collected during endoscopic retrograde pancreatography (ERP-PJC), and 12 samples were collected during ENPD-PJC, 3-hourly for cytological analysis. ERP-PJC, ERP/ENPD-PJC, and ENPD-PJC positivity indicated cytologically positive samples. Patients with positive/negative PJC with follow-up for <4-years were excluded as undiagnosed cases. A non-malignant diagnosis was based on histopathological absence/stable imaging findings for ≥4-years. The primary endpoint was to demonstrate that ERP/ENPD-PJC has a higher diagnostic ability than ERP-PJC. RESULTS: Twenty-two patients with histopathologically diagnosed PDAC/HG-PanIN and 31 with a non-malignant diagnosis were enrolled. ERP-PJC, ERP/ENPD-PJC, and ENPD-PJC showed sensitivities of 36.4 %, 86.4 %, and 77.3 %, specificities of 93.5 %, 87.1 %, and 93.5 %, and accuracies of 69.8 %, 86.7 %, and 86.7 %, respectively. ERP/ENPD-PJC and ENPD-PJC demonstrated superior sensitivity and accuracy compared to ERP-PJC. A greater occurrence of positive outcomes markedly distinguished true positives from false positives. CONCLUSIONS: ERP/ENPD-PJC and ENPD-PJC had higher diagnostic accuracies for PDAC/HG-PanIN without visible tumors on EUS. ENPD-PJC is recommended for the diagnosis of these lesions.

Multivalent dendritic DNA aptamer molecules for the enhancement of therapeutic effects.

Dendritic DNA molecules, referred to as DNA dendrons, consist of multiple covalently linked strands and are expected to improve the cellular uptake and potency of therapeutic oligonucleotides because of their multivalency. In this study, we developed an efficient synthetic method for producing DNA dendrons using strain-promoted azide-alkyne cycloaddition. Integration of the antitumor aptamer AS1411 into DNA dendrons enhanced cellular uptake and antiproliferative activity in cancer cells. These findings demonstrate that the incorporation of multivalent aptamers into DNA dendrons can effectively boost their therapeutic effects.

Development of a Cytosolic DNA Sensor Agonist Using GALA Peptide-Conjugated DNA and Long Single-Stranded DNA.

Cytosolic DNA sensors (CDSs) recognize DNA molecules that are abnormally located in the cytosol, thus leading to the activation of the stimulator of interferon genes (STING) and the induction of type 1 interferon. In turn, type 1 interferon evokes defensive reactions against viral infections and activates the immune system; therefore, the use of agonists of CDSs as cancer therapeutics and vaccine adjuvants is expected. Double-stranded DNA molecules with dozens to thousands of bases derived from bacteria and viruses are agonists of CDSs. However, DNA is a water-soluble molecule with a high molecular weight, resulting in poor cellular uptake and endosomal escape. In contrast, long single-stranded DNA (lssDNA) obtained by rolling circle amplification is efficiently taken up and localized to endosomes. Here we constructed a CDS-targeting lssDNA via the facilitation of its intracellular transport from endosomes to the cytosol. An endosome-disrupting GALA peptide was used to deliver the lssDNA to the cytosol. A peptide-oligonucleotide conjugate (POC) was successfully obtained via the conjugation of the GALA peptide with an oligonucleotide complementary to the lssDNA. By hybridization of the POC to the complementary lssDNA (POC/lssDNA), the CDS-STING pathway in dendritic cells was efficiently stimulated. GALA peptide-conjugated DNA seems to be a helpful tool for the delivery of DNA to the cytosol.

Pancreatic duct epithelial malignancy suggested by large focal pancreatic parenchymal atrophy in cystic diseases of the pancreas.

BACKGROUND: /Objectives: A cystic lesion is common in the pancreas. Focal pancreatic parenchymal atrophy (FPPA) has been reported as a sign of high-grade pancreatic intraepithelial neoplasia/carcinoma in situ (HGP/CIS). Some cystic lesions accompany FPPA. However, the relationship between a cystic lesion, FPPA, and the histopathological background of the pancreatic duct is unknown. METHODS: We retrospectively evaluated the data of 98 patients with a cystic lesion who underwent serial pancreatic juice aspiration cytologic examination (SPACE) because of accompanying FPPA, increased size of the cystic lesion, and pancreatic duct stricture at the base. RESULTS: The clinical diagnosis of a cystic lesion was intraductal papillary mucinous neoplasia (IPMN) and cysts in 72 (73.5%) and 26 (26.5%) patients, respectively. Ninety of the 98 patients (91.8%) had FPPA. Positive results (adenocarcinoma and suspicion) on SPACE were observed in 56 of all cases (57.1%), 48 of IPMN (66.7%), 8 of cysts (30.8%), and 54 of FPPA (59.3%), and were significantly associated with IPMN (p = 0.002) and the large FPPA (>269.79 mm2,p = 0.0001); moreover, these disorders are considerably related (p = 0.0003). Fifty patients (51.0%) with positive results on SPACE underwent surgery, with the histopathological diagnosis of epithelial malignancy in 42 patients (42.9%, 42/50, 84%). Many cystic lesions clinically diagnosed as IPMN were dilated branches covered by pancreatic intraepithelial neoplasia. CONCLUSIONS: Positive results on SPACE were significantly associated with the clinical diagnosis of IPMN and the large FPPA. Moreover, these disorders are significantly related. Surgery owing to positive results could lead to the histopathological diagnosis of HGP/CIS.

Laparoscopic left hepatectomy in a goat as a training model for laparoscopic anatomic liver resection: results of training courses with a total of 70 goats.

BACKGROUND: To create a suitable animal model for the training of laparoscopic anatomic liver resection, we performed left hepatectomy using a goat and found its suitability. We have since started using goats for wet-lab training and have gradually standardized the relevant procedures. Herein, we report our standardized training procedures using a goat and discuss its feasibility as a novel training model. METHODS: The standardized wet-lab training courses of laparoscopic liver resection conducted on 62 tables with a total of 70 goats were reviewed. The training course began by encircling the hepatoduodenal ligament for the Pringle maneuver, which was repeated during the parenchymal dissection. Following partial liver resection of the left lateral section, left hepatectomy was performed by a standardized procedure for humans in which the liver was split, exposing the entire length of the middle hepatic vein trunk from the dorsal side after extrahepatic transection of the left Glissonean pedicle. If a goat deceased before initiating left hepatectomy, the training was restarted with a new goat. The surgical procedures were performed by surgeons of varying skill levels. RESULTS: A total of 184 surgeons including 10 surgical residents participated in the training. Partial liver resection was initiated in 62 tables, with 8 (13%) dying during or after the procedure of partial liver resection. Subsequently, left hepatectomy was initiated in 61 and completed in 59 tables (98%), regardless of whether the goat survived or deceased, and was not completed in 2 tables (3%) due to time limitation. In 14 tables (23%), the goats deceased during the procedure, however, the procedure was completed. The causes of death were multifactorial, including massive bleeding, reperfusion injury after the Pringle maneuver, and carbon dioxide gas embolism. CONCLUSIONS: Left hepatectomy in a goat is useful as a training model for laparoscopic anatomic liver resection.

[Retrospective Analysis of Treatment Strategies for Local Recurrence following Radical Resection of Rectal Cancer].

We report the findings from a retrospective study to determine the optimum treatment strategy for local recurrence following radical resection of rectal cancer. In our department, among all 430 patients that underwent radical resection of rectal cancer from 2012 to 2018, there were 28 patients that developed local recurrence. Of those patients, 12 underwent surgical treatment(Op group)and 16 did not(N-Op group). In the Op group, 8 patients underwent radical resection, of which 2 patients remained recurrence-free, and the other 6 patients developed recurrence. In the N-Op group, 6 patients were treated with systemic chemotherapy alone, a further 6 patients had palliative irradiation in addition to systemic chemotherapy, and the other 4 selected best supportive care(2 patients were treated with palliative irradiation). In the 8 patients who had palliative irradiation, 7 showed a decrease in numerical rating scale(NRS)after irradiation. The adverse events of palliative irradiation were scrotal dermatitis in 1 patient and perianal inflammation in another 3 patients. Our surgical results for local recurrence of rectal cancer in our department were worse in terms of recurrence rate, so these findings suggest that the preoperative surgical strategy could be reviewed, as well as the actual surgical methods such as the optimal circumferential resection margin. Palliative irradiation was found to be useful for pain control. However, the occurrence of adverse events remains a concern.

A Near-Infrared Fluorogenic Pyrrole-Imidazole Polyamide Probe for Live-Cell Imaging of Telomeres.

Telomeres are closely associated with cellular senescence and cancer. Although some techniques have been developed to label telomeres in living cells for study of telomere dynamics, few biocompatible near-infrared probes based on synthetic molecules have been reported. In this study, we developed a near-infrared fluorogenic pyrrole-imidazole polyamide probe (SiR-TTet59B) to visualize telomeres by conjugating a silicon-rhodamine (SiR) fluorophore with a tandem tetramer pyrrole-imidazole polyamide targeting 24 bp in the telomeric double-stranded (ds) DNA. SiR-TTet59B was almost nonfluorescent in water but increased its fluorescence dramatically on binding to telomeric dsDNA. Using a peptide-based delivery reagent, we demonstrated the specific and effective visualization of telomeres in living U2OS cells. Moreover, SiR-TTet59B could be used to observe the dynamic movements of telomeres during interphase and mitosis. This simple imaging method using a synthetic near-infrared probe could be a powerful tool for studies of telomeres and for diagnosis.

How to dissect the liver parenchyma: Excavation with cavitron ultrasonic surgical aspirator.

BACKGROUND: A large amount of blood flows in and out of the liver through the inflow system consisting of the portal vein and hepatic artery within the Glissonean cord and the outflow system constituted by the hepatic veins. METHODS: During liver parenchymal dissection, useful methods to maintain a dry operative field are to control the inflow system with the Pringle maneuver and the outflow system by managing the central venous pressure. Additionally, mature techniques of dissecting the liver parenchyma, which can prevent injury to the blood vessels and appropriately and promptly stop bleeding, are fundamental. Similar to archaeological excavation, in which buried remains are unearthed and exposed in intact form, the Glissonean cords and hepatic veins buried in the liver parenchyma should be exposed or isolated without causing injury to these structures during liver parenchymal dissection. RESULTS: The cavitron ultrasonic surgical aspirator (CUSA) is useful as a surgical device for excavation because it has multiple functions in one device. However, there have been no systematic guidelines on how to use it effectively during hepatectomy. CONCLUSION: We herein describe how to use the CUSA, based on our knowledge and experiences.

Basic knowledge of and a small trick for atraumatic needle driving in laparoscopic suturing.

Highlight Although recent advances in robotic surgery have enabled more precise movements of the needle driver, a sophisticated laparoscopic suturing technique is still desired. Honda and colleagues describe the basic knowledge of and a small but useful trick for atraumatic needle driving in laparoscopic suturing, based on mechanistic considerations.

Laparoscopic Liver Resection of Segments 7 and 8: from the Initial Restrictions to the Current Indications.

Since the beginning of laparoscopic liver surgery, resection of the posterosuperior segments has been considered one of the most challenging procedure due to its difficult access. The main drawbacks of the laparoscopic approach to dome lesions are poor visualization, the difficulty of instrumentation and the greater complexity in the control of bleeding. In the evolution of minimally invasive techniques from hybrid techniques to the current purely laparoscopic approaches, the different authors have established gradually the currents indications and surgical techniques to operate these segments with a similar feasibility and safety than open approach. The standardization in the patient position, the use of intercostal trocars, the learning curve in laparoscopic liver surgery, the management of the hepatic blood flow and the refinement of the technique in the extrahepatic and intrahepatic Glissonean pedicle approaches, has allowed to leave behind the initial contraindications about the laparoscopic approach in these segments. In the present review of the literature, the accumulated experience of the different groups in minimally invasive liver surgery together with the technological advances in the different laparoscopic devices have facilitated the resection of tumors in segments 7 and 8 with similar and even better results than open surgery.

Effect of antithrombic therapy on bleeding complications in patients receiving emergency cholecystectomy for acute cholecystitis.

BACKGROUND: The risk of developing hemorrhagic complications during or after emergency cholecystectomy in patients with antithrombic therapy (ATT) remains uncertain. In this study, we evaluate outcomes in patients with ATT undergoing emergency cholecystectomy and assess the relevance between ATT and perioperative complications including bleeding complications. METHODS: We retrospectively evaluated 296 patients who were diagnosed as acute cholecystitis and underwent emergency cholecystectomy between 2005 and 2017. One hundred and thirty-three of them (45%) were on ATT. The primary outcome measures were intraoperative blood loss over 500 ml and postoperative complications including bleeding complications. This study was approved by our institutional review board (#13072904). RESULTS: There were 23 patients (8%) who experienced intraoperative blood loss over 500 ml and nine postoperative bleeding complications (3%). Multivariable analyses showed that male sex (P = 0.027), Performance Status 2-4 (P = 0.031) and grade II or III acute cholecystitis (P = 0.033) were independent risk factors for intraoperative bleeding over 500 ml, whereas not single antiplatelet therapy (APT) use but multiple APT (P = 0.034) and anticoagulation therapy (ACT) (P = 0.032) were independently associated with postoperative bleeding complications. Additionally, laparoscopic surgery, but not ATT, was a significant prognostic factor for severe postoperative complications. CONCLUSIONS: Single APT was not remained as an independently associated factor of intraoperative excessive bleeding or severe postoperative complications including bleeding complications. However, patients treated with multiple APT or ACT still represent a challenging group and must be carefully managed to avoid postoperative bleeding complications.

TAMRA-polypyrrole for A/T sequence visualization on DNA molecules.

Fluorophore-linked, sequence-specific DNA binding reagents can visualize sequence information on a large DNA molecule. In this paper, we synthesized newly designed TAMRA-linked polypyrrole to visualize adenine and thymine base pairs. A fluorescent image of the stained DNA molecule generates an intensity profile based on A/T frequency, revealing a characteristic sequence composition pattern. Computer-aided comparison of this intensity pattern with the genome sequence allowed us to determine the DNA sequence on a visualized DNA molecule from possible intensity profile pattern candidates for a given genome. Moreover, TAMRA-polypyrrole offers robust advantages for single DNA molecule detection: no fluorophore-mediated photocleavage and no structural deformation, since it exhibits a sequence-specific pattern alone without the use of intercalating dyes such as YOYO-1. Accordingly, we were able to identify genomic DNA fragments from Escherichia coli cells by aligning them to the genomic A/T frequency map based on TAMRA-polypyrrole-generated intensity profiles. Furthermore, we showed band and interband patterns of polytene chromosomal DNA stained with TAMRA-polypyrrole because it prefers to bind AT base pairs.

Partial Hepatectomy with Middle Hepatic Vein Reconstruction Using a Left Inferior Vena Cava Graft.

Duplicated inferior vena cava (IVC) is a rare congenital anomaly. We describe the utility of a new graft from the left IVC in a patient with duplicated IVC for reconstructing the middle hepatic vein (MHV) after partial hepatectomy with MHV resection. A 67-year-old woman with hepatitis C was found to have a liver tumor. Magnetic resonance imaging confirmed that the tumor, which was attached to the MHV, was hepatocellular carcinoma. Central bisectionectomy (S4, S5, and S8 resection) could not be tolerated because of poor liver function and a low future liver remnant volume. Therefore, partial hepatectomy with MHV resection was performed. The left IVC was harvested as a venous graft and was substituted for the resected MHV. She recovered uneventfully and was discharged on postoperative day 12. To the best of our knowledge, this is the first report of using the left IVC as a venous graft. The left IVC is a good candidate graft for the MHV or for portal vein reconstruction because of its length, diameter, and easy harvesting (it did not require an extra incision) in a patient with duplicated IVC.

Pancreaticoduodenectomy following gastrectomy reconstructed with Billroth II or Roux-en-Y method: Case series and literature review.

INTRODUCTION: The ideal reconstruction method for pancreaticoduodenectomy following a gastrectomy with Billroth II or Roux-en-Y reconstruction is unclear. METHODS: We reviewed a series of seven pancreaticoduodenectomies performed after gastrectomy with the Billroth II or Roux-en-Y method. RESULTS: While preserving the existing gastrojejunostomy or esophagojejunostomy, pancreaticojejunostomy and hepaticojejunostomy were performed by the Roux-en-Y method using a new Roux limb in all cases. Four patients experienced postoperative complications, although the specific complications varied. DISCUSSION: A review of the literature revealed 13 cases of pancreaticoduodenectomy following gastrectomy with Billroth II or Roux-en-Y reconstruction. Three patients out of six (50%) in whom the past afferent limb was used for the reconstruction of the pancreaticojejunostomy and hepaticojejunostomy experienced afferent loop syndrome, while 14 previous and current patients in whom a new jejeunal limb was used did not experience this complication. CONCLUSION: The Roux-en-Y method, using the distal intestine of previous gastrojejunostomy or jejunojejunostomy as a new jejunal limb for pancreaticojejunostomy and hepaticojejunostomy, may be a better reconstruction method to avoid the complication of afferent loop syndrome after previous gastrectomy with Billroth II or Roux-en-Y reconstruction if the afferent limb is less than 40cm.

Feasibility of a new approach for creating a preperitoneal space in transabdominal preperitoneal repair inguinal hernia repair: using a sandwich approach.

PURPOSE: In Japan, transabdominal preperitoneal (TAPP) inguinal hernia repair is performed by firmly pulling the peritoneum inwards to lift it from the underlying deep layer of subperitoneal fascia. It decreases the postoperative pain and discomfort in the inguinal area. The aim of this study was to evaluate the feasibility of the sandwich approach, which is a new technique for creating a preperitoneal space. METHODS: The operation was performed via the sandwich approach. We made sure to protect the preperitoneal fascia areolar layer when making the preperitoneal space. RESULTS: We performed TAPP in 745 patients (876 hernias) treated between October 2006 and April 2015 at Himeji Medical Center and Kurashiki Central Hospital. Before October 2010, we did not use the sandwich approach, and recurrence was observed in three patients. From October 2010, we always used the sandwich approach and never experienced any cases of recurrence. Clavien-Dindo classification Grade 3 or higher postoperative complications occurred in 6 patients (0.8%) between October 2006 and April 2015. Mesh-related ileus was the most frequently observed morbidity. There were no cases of vas differentia or spermatic vessel injury, postoperative chronic pain, or urinary retention. CONCLUSION: The sandwich approach is feasible as another standard dissective procedure for TAPP.

Targeting 24 bp within Telomere Repeat Sequences with Tandem Tetramer Pyrrole-Imidazole Polyamide Probes.

Synthetic molecules that bind sequence-specifically to DNA have been developed for varied biological applications, including anticancer activity, regulation of gene expression, and visualization of specific genomic regions. Increasing the number of base pairs targeted by synthetic molecules strengthens their sequence specificity. Our group has been working on the development of pyrrole-imidazole polyamides that bind to the minor groove of DNA in a sequence-specific manner without causing denaturation. Recently, we reported a simple synthetic method of fluorescent tandem dimer polyamide probes composed of two hairpin moieties with a linking hinge, which bound to 12 bp in human telomeric repeats (5'-(TTAGGG)n-3') and could be used to specifically visualize telomeres in chemically fixed cells under mild conditions. We also performed structural optimization and extension of the target base pairs to allow more specific staining of telomeres. In the present study, we synthesized tandem tetramer polyamides composed of four hairpin moieties, targeting 24 bp in telomeric repeats, the longest reported binding site for synthetic, non-nucleic-acid-based, sequence-specific DNA-binding molecules. The novel tandem tetramers bound with a nanomolar dissociation constant to 24 bp sequences made up of four telomeric repeats. Fluorescently labeled tandem tetramer polyamide probes could visualize human telomeres in chemically fixed cells with lower background signals than polyamide probes reported previously, suggesting that they had higher specificity for telomeres. Furthermore, high-throughput sequencing of human genomic DNA pulled down by the biotin-labeled tandem tetramer polyamide probe confirmed its effective binding to telomeric repeats in the complex chromatinized genome.

Telomere Visualization in Tissue Sections using Pyrrole-Imidazole Polyamide Probes.

Pyrrole-Imidazole (PI) polyamides bind to specific DNA sequences in the minor groove with high affinity. Specific DNA labeling by PI polyamides does not require DNA denaturation with harsh treatments of heat and formamide and has the advantages of rapid and less disruptive processing. Previously, we developed tandem hairpin PI polyamide probes (TH59 series), which label telomeres in cultured cell lines more efficiently than conventional methods, such as fluorescence in situ hybridization (FISH). Here, we demonstrate that a TH59 derivative, HPTH59-b, along with immunostaining for specifying cell types in the tissues, visualizes telomeres in mouse and human tissue sections. Quantitative measurements of telomere length with single-cell resolution suggested shorter telomeres in the proliferating cell fractions of tumor than in non-tumor tissues. Thus, PI polyamides are a promising alternative for telomere labeling in clinical research, as well as in cell biology.

Undifferentiated carcinoma with osteoclast-like giant cells of the ampullary region: Short term survival after pancreaticoduodenectomy.

INTRODUCTION: Undifferentiated carcinomas with osteoclast-like giant cells (UC-OGCs) of the ampullary region are very rare, with only a few cases reported to date. The clinicopathological features, treatment options, and prognosis of UC-OGCs are unclear. This report describes a patient with UC-OGCs of the ampullary region. PRESENTATION OF CASE: A 78-year-old male patient was admitted for epigastric pain and fever. Contrast-enhanced computed tomography revealed a 2.6-cm mass at the duodenal papilla. Duodenoscopy revealed a smooth red protruding mass compressing the orifice of the papilla of Vater. Biopsy of the mass showed proliferation of osteoclast-like giant cells. A subtotal stomach-preserving pancreaticoduodenectomy was performed, and the tumor was histologically diagnosed as an UC-OGCs of the ampullary region. Carcinoma in situ was also observed, spreading from the tumor at the terminal segment of the common bile duct to the common hepatic duct, with carcinoma cells at the surgical margin of the common hepatic duct. One year after surgery, the patient is alive and without tumor recurrence. DISCUSSION: UC-OGCs of the ampullary region is very rare neoplasm containing osteoclast-like giant cells and mononuclear cells. Osteoclast-like giant cells may originate from reactive mesenchymal cells and carcinoma in situ may spread to the common hepatic duct. Surgery including pancreaticoduodenectomy may be a treatment option for resectable tumors, whereas gemcitabine may be a treatment option for unresectable tumors. CONCLUSION: Carcinoma in situ may spread quite far (5cm) to the common hepatic duct, making it desirable to intraoperatively confirm negative bile duct margins by rapid pathologic diagnosis.