Tadayuki Takagi

Characterization of Small Solid Tumors in the Pancreas: The Value of Contrast-Enhanced Harmonic Endoscopic Ultrasonography

OBJECTIVES:Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS), a novel technology, visualizes parenchymal perfusion in the pancreas. This study prospectively evaluated how accurately CH-EUS characterizes pancreatic lesions and compared its diagnostic ability with that of contrast-enhanced multidetector-row computed tomography (MDCT) and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA).METHODS:A total of 277 consecutive patients with pancreatic solid lesions that were detected by conventional EUS underwent CH-EUS for evaluation of vascularity. After infusing an ultrasound contrast, CH-EUS was performed by using an echoendoscope and a specific mode for contrast harmonic imaging. On the basis of the intensity of enhancement, the lesions were categorized into four patterns: nonenhancement, hypoenhancement, isoenhancement, and hyperenhancement. For comparison, all patients underwent MDCT. The ability of CH-EUS to differentiate ductal carcinomas from the other solid tumors, particularly small lesions (≤2 cm in diameter) was assessed, and compared with the differentiating abilities of MDCT and EUS-FNA.RESULTS:In terms of reading the CH-EUS images, the κ-coefficient of the interobserver agreement test was 0.94 (P<0.001). CH-EUS-depicted hypoenhancement diagnosed ductal carcinomas with a sensitivity and specificity of 95.1% (95% confidence interval (CI) 92.7–96.7%) and 89.0% (95% CI 83.0–93.1%), respectively. For diagnosing small carcinomas by CH-EUS, the sensitivity and specificity were 91.2 % (95% CI 82.5–95.1%) and 94.4% (95% CI 86.2–98.1%), respectively. CH-EUS-depicted hypervascular enhancement diagnosed neuroendocrine tumors with a sensitivity and specificity of 78.9% (95% CI 61.4–89.7%) and 98.7% (95% CI 96.7–98.8%), respectively. Although CH-EUS and MDCT did not differ significantly in diagnostic ability with regard to all lesions, CH-EUS was superior to MDCT in diagnosing small (≤2 cm) carcinomas (P<0.05). In 12 neoplasms that MDCT failed to detect, 7 ductal carcinomas and 2 neuroendocrine tumors had hypoenhancement and hyperenhancement on CH-EUS, respectively. When CH-EUS was combined with EUS-FNA, the sensitivity of EUS-FNA increased from 92.2 to 100%.CONCLUSIONS:CH-EUS is useful for characterizing conventional EUS-detected solid pancreatic lesions. EUS equipped with contrast harmonic imaging may play an important role in the characterization of small tumors that other imaging methods fail to depict and may improve the diagnostic yield of EUS-FNA.

Diagnostic approach to pancreatic tumors with the specimens of endoscopic ultrasound-guided fine needle aspiration

Endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) has enabled clinicians to histologically diagnose pancreatic tumors. However, EUS‐FNA specimens often result in tiny fragmented tissues, so auxiliary utilities are necessary. Using immunostaining of CK7, CDX2, neuroendocrine markers and KRAS mutation analysis, we examined 57 FNA cell block sections and 61 surgically‐resected specimens (25 invasive ductal carcinomas, 25 endocrine tumors, and 11 acinar cell tumors). In the majority of the matched pairs, the diagnoses between EUS‐FNA and surgical specimens were concordant using the following criteria: neuroendocrine markers negative, CK7 positive, and mutated KRAS gene for invasive ductal carcinomas; neuroendocrine markers diffusely positive, CK7 and CDX2 negative, and wild‐type KRAS gene for well‐differentiated endocrine tumors; and neuroendocrine markers no more than focal positive, CK7 and CDX2 with various staining patterns, and wild‐type KRAS gene for acinar cell carcinomas. Expression of CK7 and/or CDX2 in addition to KRAS mutations were occasionally seen in endocrine carcinomas, but not in well‐differentiated endocrine tumors, suggesting that ductal differentiation in an endocrine tumor may be a predictor of aggressive disease. The usefulness of these markers was confirmed using 13 additional pancreatic tumors, prospectively. Although minimal in selection, these markers are helpful in making diagnosis from EUS‐FNA specimens of the major pancreatic tumors.

Role of para‐esophageal collateral veins in patients with portal hypertension based on the results of endoscopic ultrasonography and liver scintigraphy analysis

Background and Aims: Para‐esophageal collateral veins (para‐ECV) are observed by endoscopic ultrasonography (EUS) in patients with portal hypertension. However, the role of para‐ECV in the portal venous system is not clear. To verify the role of para‐ECV in the portal venous system, we investigated the relationship between the development of para‐ECV as determined by EUS, and the portal blood flow ratio (PBFR) as determined by liver scintigraphy using 99mTc‐phytate.

Prospective evaluation of the optimal number of 25-gauge needle passes for endoscopic ultrasound-guided fine-needle aspiration biopsy of solid pancreatic lesions in the absence of an onsite cytopathologist

Introduction:  A prior study with 22‐gauge needles recommended more than seven needle passes for endoscopic ultrasound‐guided fine‐needle aspiration biopsy (EUS‐FNA) of solid pancreatic lesions (SPL) without onsite cytopathology for optimal acquisition of cytopathological diagnosis. The feasibility of this recommendation should be re‐evaluated considering the later development and popularity of 25‐gauge EUS‐FNA needles. We aimed to determine the optimal number of needle passes for cytopathological specimen acquisition with 25‐gauge needles for EUS‐FNA of SPL.

Phase I trial of preoperative intratumoral injection of immature dendritic cells and OK-432 for resectable pancreatic cancer patients

PurposeTo determine the feasibility, safety and histological change of preoperative endoscopic ultrasound-guided fine-needle injection (PEU-FNI) of immature DCs (iDCs) with OK-432 in pancreatic cancer patients.MethodsNine patients enrolled in the trial (DC group) and were compared with 15 patients operated on without iDC injection (non-DC group). Adverse events of PEU-FNI and postoperative complications were evaluated according to CTC-AE ver.3.0 and the Clavien–Dindo classification/ISGPF definition, respectively. Histological changes within the tumor and lymph nodes were evaluated by immunohistochemical examination of infiltrating inflammatory cells (CD4+, CD8+, Foxp3+ and CD83+).ResultsThere were no severe toxicities following PEU-FNI, except for one transient grade 3 fever, and there were no significant differences in the incidence of postoperative complications between the two groups. Colliquative necrosis and diffusely scattered TUNEL-positive cells were observed at the injection sites. CD83+ cells significantly accumulated in the regional lymph nodes of the DC group as well as Foxp3+ cells in the regional and distant lymph nodes. The two DC group patients, one of which was stage IV with distant lymph node metastasis, survived more than 5 years without requiring adjuvant theraphy.ConclusionPEU-FNI was feasible and safe, and further study needs to confirm and enhance antitumor responses.

Efficacy of endoscopic ultrasonography-guided fine needle aspiration for pancreatic neuroendocrine tumor grading

AIM To evaluate the efficacy of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) for grading pancreatic neuroendocrine tumors (PNETs). METHODS A total of 22 patients were diagnosed with PNET by EUS-FNA between October 2001 and December 2013 at Fukushima Medical University Hospital. Among these cases, we targeted 10 PNET patients who were evaluated according to the World Health Organization (WHO) 2010 classification. Surgery was performed in eight patients, and chemotherapy was performed in two patients due to multiple liver metastases. Specimens obtained by EUS-FNA were first stained with hematoxylin and eosin and then stained with chromogranin, synaptophysin, CD56, and Ki-67. The specimens were graded by the Ki-67 index according to the WHO 2010 classification. Specimens obtained by surgery were graded by the Ki-67 index and mitotic count (WHO 2010 classification). For the eight specimens obtained by EUS-FNA, the Ki-67 index results were compared with those obtained by surgery. In the two cases treated with chemotherapy, the effects and prognoses were evaluated. RESULTS The sampling rate for histological diagnosis by EUS-FNA was 100%. No adverse effects were observed. The concordance rate between specimens obtained by EUS-FNA and surgery was 87.5% (7/8). For the two cases treated with chemotherapy, case 1 received somatostatin analog therapy and transcatheter arterial infusion (TAI) targeting multiple liver metastases. Subsequent treatment consisted of everolimus. During chemotherapy, the primary tumor remained unconfirmed, although the multiple liver metastases diminished dramatically. Case 2 was classified as neuroendocrine carcinoma (NEC) according to the Ki-67 index of a specimen obtained by EUS-FNA; therefore, cisplatin and irinotecan therapy was started. However, severe adverse effects, including renal failure and diarrhea, were observed, and the therapy regimen was changed to cisplatin and etoposide. TAI targeting multiple liver metastases was performed. Although the liver metastases diminished, the primary tumor remained unconfirmed. These chemotherapy regimens had immediate effects for both unresectable neuroendocrine tumor (NET) and NEC cases. These two subjects are still alive. CONCLUSION EUS-FNA was effective for PNET diagnosis and Ki-67 index grading for WHO 2010 classification, enabling informed decisions on unresectable PNET treatment by identifying NET or NEC.

Collateral vessels around the esophageal wall in patients with portal hypertension: comparison of EUS imaging and microscopic findings at autopsy.

BACKGROUND In patients with portal hypertension, EUS reveals the presence of collateral vessels within and outside the esophageal wall such as esophageal varices, periesophageal collateral veins (peri-ECVs), paraesophageal collateral veins (para-ECVs), and perforating veins. This study retrospectively compared radial EUS images of these collateral vessels with histopathologic findings. METHODS Four patients with esophageal varices treated by endoscopic injection sclerotherapy were studied. EUS was performed to evaluate the effects of endoscopic injection sclerotherapy. After endoscopic injection sclerotherapy, the segment of the esophagus from the esophagogastric junction to a point 5 cm proximal to junction was imaged with a 20-MHz radial scanning catheter US probe. Esophageal collateral veins outside the esophageal wall were identified as peri-ECVs (veins lateral to muscularis propria or within adventitia) and para-ECVs (veins lateral and separate from muscularis propria) along with perforating veins (veins connecting extramural collateral veins to submucosal varices). At autopsy, the esophagus with surrounding tissue was removed and cross-sectioned at 1-cm intervals from the esophagogastric junction to a point 5 cm proximal to the junction. Radial EUS images were correlated with histopathologic findings. RESULTS Radial EUS after endoscopic injection sclerotherapy demonstrated peri-ECVs and perforating veins in all cases and para-ECVs in 3 cases. Based on histopathologic findings, veins associated with the esophageal wall were divided into 3 groups: those adjacent to the muscularis propria, veins separated from the wall without contact with the muscularis propria, and veins perforating the muscularis propria. All 3 groups of veins were observed in all cases. These 3 types of veins identified by histopathologic examination corresponded, respectively, to the peri-ECVs, para-ECVs, and perforating veins observed by EUS. CONCLUSION Collateral esophageal veins demonstrated by radial EUS in patients with portal hypertension correspond to collateral veins identified histopathologically. In patients with portal hypertension, EUS is useful for assessment of vascular anatomy around the esophageal wall.

Pancreatobiliary drainage using the EUS-FNA technique: EUS-BD and EUS-PD

The recent progression of endoscopic ultrasonography (EUS) enables EUS-guided transmural drainage based on the EUS-guided fine-needle aspiration biopsy technique. Prior to the development of EUS-guided drainage procedures, the options for treating obstruction of the pancreatobiliary system included surgical drainage, percutaneous drainage using ultrasound and radiological guidance, and endoscopic (non EUS-guidance) transmural drainage. Today, using EUS guidance and dedicated accessories, it is possible to create bilio- or pancreato-digestive anastomosis, EUS-guided biliary drainage (EUS-BD), and EUS-guided pancreatic drainage (EUS-PD). The recent literature describes that EUS-BD and EUS-PD have acceptable success and complication rates. These procedures are anticipated for use as alternatives to surgery or percutaneous drainage when endoscopic transpapillary procedures fail.

Endoscopic ultrasound-guided choledochoduodenostomy.

Endoscopic biliary drainage (EBD) may be unsuccessful in some patients, because of failed biliary cannulation or tumor infiltration, limiting endoscopic access to major papilla. The alternative method of percutaneous transhepatic biliary drainage carries a risk of complications, such as bleeding, portal vein thrombus, portal vein occlusion and intra‐ or extra‐abdominal bile leakage. Recently, endoscopic ultrasonography (EUS)‐guided biliary stent placement has been described in patients with malignant biliary obstruction. Technically, EUS‐guided biliary drainage is possible via transgastric or transduodenal routes or through the small intestine using a direct access or rendezvous technique. We describe herein a technique for direct stent insertion from the duodenal bulb for the management of patients with jaundice caused by malignant obstruction of the lower extrahepatic bile duct. We think transduodenal direct access is the best treatment in patients with jaundice caused by inoperable malignant obstruction of the lower extrahepatic bile duct when EBD fails.

An automated spring-loaded needle for endoscopic ultrasound-guided abdominal paracentesis in cancer patients.

AIM To evaluate the feasibility of using an automated spring-loaded needle device for endoscopic ultrasound (EUS)-guided abdominal paracentesis (EUS-P) to see if this would make it easier to puncture the mobile and lax gastric wall for EUS-P. METHODS The EUS database and electronic medical records at Fukushima Medical University Hospital were searched from January 2001 to April 2011. Patients with a history of cancer and who underwent EUS-P using an automated spring-loaded needle device with a 22-gauge puncture needle were included. The needle was passed through the instrument channel and advanced through the gastrointestinal wall under EUS guidance into the echo-free space in the abdominal cavity and ascitic fluid was collected. The confirmed diagnosis of malignant ascites included positive cytology and results from careful clinical observation for at least 6 mo in patients with negative cytology. The technical success rate, cytology results and complications were evaluated. RESULTS We found 11 patients who underwent EUS-P with an automated spring-loaded needle device. In 4 cases, ascites was revealed only with EUS but not in other imaging modalities. EUS-P was done in 7 other cases because there was minimal ascitic fluid and no safe window for percutaneous abdominal aspiration. Ascitic fluid was obtained in all cases by EUS-P. The average amount aspirated was 14.1 mL (range 0.5-38 mL) and that was sent for cytological exam. The etiology of ascitic fluid was benign in 5 patients and malignant in 6. In all cases, ascitic fluid was obtained with the first needle pass. No procedure-related adverse effects occurred. CONCLUSION EUS-P with an automated spring-loaded needle device is a feasible and safe method for ascites evaluation.