Combination immunohistochemistry for CK5/6, p63, GATA6, and HNF4a predicts clinical outcome in treatment-naïve pancreatic ductal adenocarcinoma.

Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p < 0.001) and demonstrated the worst overall survival among our cohort (p = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01-2.38), p = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31-6.08), p = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.

Gastroduodenal Stenting with a Flexible Stent Demonstrates Favorable Clinical Effectiveness despite Gradual Expansion: A Multicenter Prospective Study.

AIMS: This study aimed to evaluate the effectiveness and safety of stenting with a flexible braided self-expandable metal stent (SEMS) for unresectable malignant gastric outlet obstruction (GOO). METHODS: Palliative stenting was prospectively carried out at seven university hospitals between October 2017 and August 2020. All procedures were performed using a flexible branded SEMS of the same brand. The primary endpoint was clinical success rate at 7 days after stenting. Secondary endpoints were procedural success rate, adverse events, recurrent gastric outlet obstruction (RGOO), and patient survival time. RESULTS: Sixty patients were enrolled. The procedural and clinical success rates were 100% and 90%, respectively. RGOO occurred in 15 cases (25%). Adverse events other than RGOO were found in seven cases (12%). The 50% survival time was 75.5 days (range: 52-97 days). Median expansion rates at 1, 3, and 7 days after stenting were 55%, 65%, and 75%, respectively. CONCLUSIONS: A flexible braided stent woven with relatively thin wires was used for malignant GOO. Despite a gradual expansion with slightly lower expansile force, the stent functioned sufficiently well and showed favorable results. Clinical Trials Registry ID: UMIN000029496.

A Prospective Study of Neoadjuvant Gemcitabine Plus Nab-paclitaxel in Patients with Borderline-resectable Pancreatic Cancer.

Objectives Neoadjuvant therapy followed by radical resection improves the borderline-resectable pancreatic cancer (BRPC) prognosis; however, the optimal therapeutic regimen remains unclear. Gemcitabine plus nab-paclitaxel (GnP) showed a high anti-tumor effect in primary lesions in a prospective study for metastatic disease. However, evidence concerning its feasibility is still lacking in patients with BRPC. We therefore evaluated the tolerability of neoadjuvant GnP (NAC-GnP) for BRPC. Methods This single-center prospective study evaluated 10 patients with BRPC who were treated with two cycles of NAC-GnP. The primary endpoint was feasibility for NAC-GnP. Treatment feasibility was defined as a successful outcome in at least eight patients. Results Ten patients who had BRPC in contact with the celiac artery (n=5), superior mesenteric artery (n=3), or hepatic artery (n=2) were enrolled. The median age was 75 (range, 40-82) years old. Grade 3 anorexia and grade 2 pneumonia occurred in one patient each, so treatment was feasible in eight patients. The median primary tumor reduction and response rates were 33% (range, 0-68%) and 60%, respectively. Six of eight patients who had abnormal CA19-9 levels at the time of enrolment showed a decrease in CA19-9 levels, with a median decrease of 72%. Five patients underwent radical resection, including R0 resection in four. Postoperative grade IIIa Clavien-Dindo complications occurred in one patient (upper gastrointestinal bleeding and pancreatic fistula). Conclusion Two-cycle NAC-GnP is a feasible treatment for patients with BRPC. Further studies on NAC-GnP in patients with BRPC are warranted.

Successful treatment of mediastinal pancreatic pseudocyst and pancreatic pleural effusion with endoscopic pancreatic duct drainage: A case report.

An 81-year-old man with chronic pancreatitis was being treated with a protease inhibitor. He developed an acute exacerbation of chronic pancreatitis and dyspnea. Contrast-enhanced computed tomography showed disruption of the main pancreatic duct, a cystic lesion connecting the mediastinum to the main pancreatic duct, and left pleural effusion. We diagnosed a pancreatic pseudocyst, mediastinal pancreatic pseudocyst, and pancreatic pleural effusion. Endoscopic retrograde pancreatography showed leakage of contrast medium from the pancreatic body; furthermore, a cystic cavity extending to the mediastinum through a pancreatic duct fistula was visualized. An endoscopic transpapillary nasopancreatic drainage tube was placed in the cystic cavity. Computed tomography showed that the mediastinal pseudocyst and pleural effusion had disappeared. Endoscopic transpapillary pancreatic duct drainage may be useful when a connection between the main pancreatic duct and a mediastinal pseudocyst is confirmed by imaging.

Management of common bile duct stones in a pregnant woman by percutaneous biliary drainage followed by elective endoscopic stone removal after delivery.

A woman in her 30s who was 12 weeks pregnant with her third child presented with jaundice. Blood tests showed elevated hepatobiliary enzymes and direct bilirubin. Abdominal ultrasonography showed dilatation of the common bile duct and strong echo with a 9 mm acoustic shadow in the distal bile duct. She was diagnosed with common bile duct stone disease and biliary drainage was considered necessary. Percutaneous transhepatic biliary drainage (PTBD) was performed considering the effect on both the fetus and the mother, and the procedure was successful without any complications. The PTBD tube was left in place until delivery at 36 weeks 6 days of gestation and endoscopic stone removal was performed 14 days after delivery. The patient was discharged 18 days after delivery without any complications. In pregnant women with common bile duct stones, palliative PTBD followed by elective endoscopic stone removal after delivery can be considered a treatment strategy.

Utility of endoscopic transpapillary pancreatic cyst drainage for intraductal papillary mucinous neoplasm infection.

A 61-year-old woman with intraductal papillary mucinous neoplasm (IPMN) infection, who was treated with antibiotics, developed IPMN reinfection with febrile epigastric pain and was febrile. CT showed that the diameter of the IPMN had grown and hardened, with thickening of the cyst wall. Endoscopic retrograde pancreatography was then performed and a nasopancreatic cyst drainage tube was placed into the cyst. Symptoms and inflammatory findings improved considerably 17 days after endoscopic drainage. Few reports and evidence have been found regarding IPMN infections, and the frequency of onset, route of infection and optimal drainage method remain unknown. This study indicated that endoscopic transpapillary pancreatic cyst drainage was effective and is highly recommended for IPMN infection.

Effectiveness of introducing a 20-gauge core biopsy needle with a core trap in EUS-FNA/B for diagnosing pancreatic cancer.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/B) is a standard method for pathological diagnosis of pancreatic solid lesions. The EchoTip ProCore 20G® (PC20), a 20-gauge biopsy needle with a forward-bevel core trap, has been available in Japan since 2015. METHODS: We compared the efficacy of the PC20 with that of the EchoTip ProCore 22G® (PC22) and Acquire 22G® (AC22) in EUS-FNA/B for diagnosing pancreatic cancer. This retrospective study included 191 patients with pancreatic cancer who underwent EUS-FNA/B using the PC20, PC22, or AC22 at our facility from April 2013 to October 2019. We investigated the patients' clinical characteristics and the diagnostic accuracy and safety of each needle. RESULTS: A sufficient stroke length of puncture was secured in all patients. The maximum length under EUS was shorter with the AC22 (22.1 ± 2.2 mm) than PC20 (30.6 ± 0.7 mm, p < 0.01) and PC22 (30.3 ± 0.8 mm, p < 0.01). The histological accuracy was 96.4% with the PC20 but only 58.8% with the PC22 (adjusted p (p-adj) < 0.0001) and 75.0% with the AC22 (p-adj = 0.06). The diagnostic accuracy of the combination of histology and cytology was 96.4% with the PC20, while it was 72.1% with the PC22 (p-adj < 0.0001) and 91.7% with the AC22 (p-adj > 0.99). One patient (0.9%) in the PC20 group developed mild pancreatitis, but no adverse events occurred with the other needles. CONCLUSIONS: The PC20 showed better diagnostic capability than the PC22. The diagnostic efficacy was similar between the PC20 and AC22. The high histological accuracy of the PC20 could be advantageous for lesions in which histological assessment is critical.

Gastropathy associated with lanthanum phosphate deposition that was endoscopically tracked for 3 years. A case report.

BACKGROUND: With the recent increased use of lanthanum carbonate, several cases of lanthanum phosphate deposition to gastric mucosa in dialysis patients have been reported. However, the endoscopic appearance of the early-stage lesion and the over-time alterations of endoscopic findings due to the progression of lanthanum phosphate deposition remain unclear. CASE PRESENTATION: An 80-year-old man receiving dialysis and taking lanthanum carbonate as a phosphate binder over a 4-year period underwent upper gastrointestinal endoscopy four times beginning 1 year after initiation of treatment. The first endoscopic examination (after 1 year of exposure to lanthanum carbonate) revealed rough mucosa with a few areas of white granular mucosa. Over the 3 years of endoscopic follow-up, the white granular mucosa spread and multiple erosions appeared. Histopathological findings of biopsy specimens from an erosion showed extensive infiltration by histiocytes containing deposits. Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) revealed that the presence of the deposits containing phosphorus and lanthanum in the gastric mucosa. On the basis of these results, the patient was diagnosed with gastropathy associated with lanthanum phosphate deposition. CONCLUSIONS: Over a 3-year period, endoscopic findings associated with lanthanum deposition gradually changed and expanded from the early stage.

Utilization of a new technology of 3D biliary CT for ERCP-related procedures: a case report.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is still performed using two-dimensional (2D) X-ray images. The success rate and risk of complications are considered operator-dependent. We explored performing an ERCP-related procedure with 3D-computed tomography (CT) biliary imaging for preoperative simulation and intraoperative reference in a patient with malignant biliary obstruction. CASE PRESENTATION: The patient was a 66-year-old man who underwent rectal resection and postoperative chemotherapy for rectal cancer. A liver metastasis caused obstructive jaundice and acute cholangitis, necessitating emergency hospitalization. A 3.5 cm mass in the hilar region of the biliary tree caused type IV biliary obstruction according to the Bismuth-Corlette classification of hilar cholangiocarcinoma. ERCP and biliary drainage were performed repeatedly, but had no effect. Given that selective bile duct drainage had proven extremely difficult with the conventional procedures, three-dimensional (3D) images were created from preoperative CT image data using a 3D image reconstruction system (SYNAPSE VINCENT version 5, FUJIFILM Corporation, Tokyo, Japan). Using the 3D images for preoperative planning and intraoperative reference, biliary drainage and stent placement were successfully performed without complications. Postoperatively, the patient had no further cholangitis or need for stent replacement up to his death. CONCLUSIONS: We report the first case of an ERCP-related procedure with 3D biliary imaging for preoperative simulation and intraoperative reference in a patient with malignant biliary obstruction. The 3D image reconstruction is useful for preoperative planning and could contribute to an increased success rate, decreased complications, a shorter operation time, and reduced radiation exposure to the operator.

Assessment of preoperative pancreatic biopsy, cytological/histological review of cell-block-specimens obtained by endoscopic ultrasound-guided fine-needle aspiration: Laboratory-based study.

BACKGROUND: Pancreatic cancer is among the most lethal cancers worldwide due to the limited availability of techniques for early detection of signs and symptoms. Reportedly, it is the fourth-leading cause of cancer-related mortality among Japanese adults. With the advent of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for diagnosing pancreatic cancer, the rate of the cytological and histological diagnoses of cell-block-specimens has significantly increased in Japan. METHODS: The cytological specimens of 165 patients with pancreatic lesions obtained using EUS-FNA between January 2010 and July 2016 at the Kyorin University Hospital were investigated. The clinical course of 153 patients was assessed from their clinical records, which included information on their imaging diagnosis, laboratory data, final clinical diagnosis and treatment; moreover, the accuracy of the cytological/histological examination and clinical diagnosis at our hospital were analysed. RESULTS: The number of cells in cell-block-specimens was too small to estimate data. However, cytological specimens were sufficient to observe the findings of suspected malignancy such as necrosis. Biopsy was deemed necessary for diagnosis using both histological and cytological specimens. CONCLUSION: EUS-FNA can be used not only to diagnose benign or malignant types of pancreatic cancers but also to assess the sensitivity of molecular target drugs and chemotherapy methods. Therefore, both histological and cytological diagnoses are required to enhance diagnostic precision both in our hospital and at other institutions.

Pharmacokinetic-pharmacodynamic comparison of ceftriaxone regimens in acute cholangitis.

The most important factors determining the prognosis of patients with acute cholangitis (AC) are prompt biliary drainage and appropriate choice of antibiotics. This study was performed to evaluate whether dividing the number of doses based on the PK-PD theory contributes to better clinical outcome in the management of acute cholangitis. We measured ceftriaxone levels in blood and bile in 21 cases diagnosed with moderate-to-severe AC. Eleven cases were administered 2 g of ceftriaxone once-daily (group A) and 10 cases were given 1 g of ceftriaxone twice-daily (group B). The theoretical effect of ceftriaxone was evaluated by pharmacokinetic-pharmacodynamic (PK-PD) parameters. Clinical efficacy was evaluated by body temperature, white blood cell count and serum levels of C-reactive protein. Minimum level of ceftriaxone in serum (in mg/L) in groups A and B at 24 h after the first dose was 9.1 and 9.2, whereas that in bile was 2.9 and 2.5, respectively. The minimum inhibitory concentration (MIC) of ceftriaxone for all isolated bacteria was below the minimum serum and biliary concentration of ceftriaxone 24 h after the first administration (except for Enterococcus species). The MIC for isolated bacterial strains was <16 mg/L, which is the PK-PD breakpoint for ceftriaxone at 2 g/day. Both regimens showed clinical efficacy and did not contradict the effect predicted based on PK-PD.

A Multicenter Phase II Study of Gemcitabine plus S-1 Chemotherapy for Advanced Biliary Tract Cancer.

BACKGROUND: Gemcitabine (GEM) plus cisplatin (CDDP) chemotherapy has been used worldwide as the standard first-line treatment for advanced biliary tract cancer (BTC). A phase II trial has also suggested promising activity of GEM plus S-1 chemotherapy against advanced BTC. The aim of this study was to evaluate the efficacy and safety of GEM plus S-1 chemotherapy in patients with advanced BTC. PATIENTS AND METHODS: The eligibility criteria were as follows: histologically-proven BTC, unresectable or recurrent disease, ECOG performance status (PS) 0-1 regardless of previous treatment. Gemcitabine was administered intravenously at the dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S-1 was administered orally at doses of 60/80/100 mg/day based on the BSA, from day 1 to day 14, every 3 weeks. The primary endpoint was the response rate according to RECIST, ver. 1.1, and the secondary endpoints were the frequency/severity of toxicities, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 38 patients were enrolled between August 2008 and November 2011. There were 19 men and 19 women, with a median age of 66 years (range=44-81 years). Seven patients had a previous history of first-line or adjuvant chemotherapy after surgery. The PS was 0 and 1 in 30 and 7 patients, respectively. The treatment response was classified as partial response in 6 patients (15.8%) and as stable disease in 18 patients (47.4%). The median PFS and OS were 5.8 and 15.9 months, respectively. The toxicity was generally mild, and the most common grade 3/4 toxicities were leukopenia (31.6%), neutropenia (36.8%), nausea/vomiting (2.6%), and diarrhea (2.6%). There was one treatment-related death due to interstitial pneumonia. CONCLUSION: Our study revealed that gemcitabine plus S-1 chemotherapy was well-tolerated and exhibited favorable antitumor activity in patients with advanced BTC.

The usefulness and safety of carbon dioxide insufflation during endoscopic retrograde cholangiopancreatography in elderly patients: a prospective, double-blind, randomized, controlled trial.

BACKGROUND/AIMS: Carbon dioxide (CO2) insufflation has been used in endoscopic retrograde cholangiopancreatography (ERCP). However, its usefulness and safety are controversial in elderly patients. Our aim was to assess the safety and usefulness of CO2 insufflation during ERCP in elderly patients. METHODOLOGY: Between April 2010 and June 2011, a total of 60 patients 75 years old or older, who underwent ERCP, were randomized into the CO2 group (n = 30) and the air group (n = 30). Main outcomes were determined by assessing abdominal symptoms according to the Wong-Baker FACES Pain Rating Scale, calculating the volume of residual gas retention within the intestines on abdominal X-ray quantitatively and observing the cardiopulmonary states. RESULTS: 30 patients in the CO2 group and 30 patients in the air group were analyzed. Abdominal distension (P < 0.01), discomfort (P < 0.01) and nausea (P < 0.01) at 2 hours after ERCP were significantly reduced in the CO2 group. The gas volume scores immediately after ERCP (P < 0.01) and at 2 hours (P < 0.01) were significantly lower in the CO2 group. CONCLUSIONS: CO2 insufflation instead of air insufflation is safe and useful for the prevention of post-ERCP abdominal symptoms in elderly patients.

[Managements for jaundice].

Jaundice is a yellowish pigmentation of skin and mucous membranes caused by hyperbilirubinemia, which itself has various causes. Jaundice related to malignant tumors is classified as obstructive jaundice. This disease proceeds from biliary tract obstruction and liver failure by progression of intrahepatic tumors, including metastases from other malignancies. Biliary tract cancer, pancreatic head cancer, or lymph nodes metastases from other sites of cancer are mainly responsible for the obstruction of the bile duct. In patients with obstructive jaundice, biliary drainage is often required in order to give treatments such as chemotherapy. In patients with biliary drainage, various complications arise, such as cholangitis due to obstruction ofa biliary stent, and bleeding from the ulcer due to a dislodged stent to the duodenum. It is crucial to manage those complications as oncologic emergencies. Jaundice of liver failure due to hepatic metastases is often observed in patients with gastrointestinal malignancies such as gastric cancer or colorectal cancer. Although chemotherapy is the usual application for those patients, useful anti-cancer agents are limited. It is crucial to diagnose and decide the best treatments as soon as possible for patients with very advanced hepatic metastases.

[Endoscopic treatment for hemorrhagic peptic ulcer in patients aged 70 years or more].

In this study on endoscopic hemostasis in patients aged 70 years or older with gastrointestinal ulcer bleeding, presence of shock, volume of transfusion over 6 units, and ulcer size over 3cm and solitary ulcer were significant risk factors for rebleeding. For 30-day mortality, concomitant disease and inpatient status were significant risk factors. Based on these results, we consider elderly patients with the above risk factors as high-risk patients for rebleeding or fatal outcome. The purpose of this study was to evaluate the efficacy of prevention of rebleeding such as by combined hemostatic methods and scheduled second-look endoscopy, and also to evaluate the offers of multidisciplinary approach such as interventional radiology for decreasing of mortality. Our conclusion is that we were able to reduce rebleeding rate and mortality after endoscopic hemostasis in high-risk patients and implement strategy to provide more careful endoscopic management with a multidisciplinary approach.

[NSAID and its effect on prostaglandin].

Recently, the use of non-steroidal anti-inflammatory drug(NSAID) as an anti-inflammatory analgesic and antithrombotic has increased with the general aging of our society. Although it is understood that gastric mucosal injury is most-frequent side-effect of NSAID, there are actually a variety of mechanisms that NSAID has, some which are due to the depressed production of prostaglandin (PG). The main action of PG in the gastric mucosa is the regulation of gastric mucosa protecting mechanism and if PG is insufficient, the gastric mucosa is weakened. As endogenous PG decreases, there is a decrease in mucus production accompanied by a decrease in bicarbonate secretion, problems with, an increase of stomach motility, tissue restoration suppression and so on. As a result, it is considered that the defense mechanisms decrease and gastric mucosal injury occurs.

Resection area of 15 mm as dividing line for choosing strip biopsy or endoscopic submucosal dissection for mucosal gastric neoplasm.

BACKGROUND: Endoscopic mucosal resection (EMR) is effective treatment for mucosal gastric neoplasm. Endoscopic submucosal dissection (ESD), a novel EMR method, has been reported to enable en bloc resection more frequently than conventional EMR methods such as strip biopsy (SB). However, ESD requires more time than SB. A small lesion can be resected en bloc and effectively treated with SB. GOAL: To evaluate using a 15 mm resection area as the dividing line between SB and ESD prospectively. STUDY: SB was applied for resection area less than 15 mm (SB group) and ESD for 15 mm or larger resection (ESD group). We compared characteristics of lesions and outcomes of EMR between the 2 groups. RESULTS: Ninety lesions were prospectively assigned to SB group (36 lesions) and ESD group (54 lesions). The average neoplasm size was 9.0+/-3.9 mm in the SB group and 19.1+/-11.3 mm in the ESD group (P<0.01). The average resection time was 11.7+/-5.8 minutes in the SB group and 128.9+/-102.8 minutes in the ESD group (P<0.01). The complete resection rate was 91.6% in the SB group and 83.3% in the ESD group (P=0.25). The complication rate was not significantly different between SB group and ESD group (11.1% vs. 16.7%, P=0.12). During follow-up (median 23+/-5 mo), 1 patient in each group, who had piecemeal resection at original EMR had recurrent neoplasm. CONCLUSIONS: Gastric mucosal neoplasms which require only small (<15 mm) resection can be treated with SB, as effectively as with ESD.