Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors.

BACKGROUND AND STUDY AIM: Malignancy in pancreatic neuroendocrine tumors (PNETs) is graded by assessing the resected specimens according to the World Health Organization (WHO) 2010 criteria. The feasibility of such grading using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens remains unclear. The aim of this study was to ascertain the optimal method of measuring the Ki-67 index in EUS-FNA specimens, using resected specimens as the criterion standard. PATIENTS AND METHODS: A total of 58 consecutive patients diagnosed with PNETs between March 1998 and May 2011 were included. The study measured intratumoral Ki-67 index heterogeneity, concordance rates of PNET grading by EUS-FNA with grade of the resected tumor, optimal method of measuring the Ki-67 index in EUS-FNA specimens, and survival analysis based on EUS-FNA specimen grading. RESULTS: Intratumoral dispersion of Ki-67 index in resected specimens was 0.033 for Grade 1 and 0.782 for Grade 2 tumors (P<0.001). Concordance rates for WHO classification between EUS-FNA and resected specimens were 74.0% using the mean Ki-67 index in EUS-FNA specimens and 77.8% using the highest Ki-67 index. The concordance rate rose to 90% when EUS-FNA samples with less than 2000 tumor cells were excluded (26% of EUS-FNA cases). The Kaplan-Meier survival curves were significantly stratified by the EUS-FNA grading of PNETs with 5-year survival rates of 100%, 58.3%, and 0%, for Grade 1, Grade 2, and neuroendocrine carcinoma (NEC) tumors, respectively. CONCLUSIONS: Grading of PNETs by the highest Ki-67 index in EUS-FNA specimens with adequate cellularity has a high concordance with grading of resected specimens, and can predict long term patient survival with high accuracy.

Successful conversion surgery after FOLFIRINOX therapy in a patient with advanced pancreatic acinar cell carcinoma with a solitary peritoneal dissemination: A case report.

BACKGROUND: Pancreatic acinar cell carcinoma is rare; it accounts for 1% of all malignant pancreatic exocrine tumors. Although surgical resection is an option for curative treatment, the safety and efficacy of conversion surgery in patients with pancreatic acinar cell carcinoma with metastasis remain unknown. CASE: A 67-year-old man with epigastric pain and a pancreatic tumor was referred to our hospital. Computed tomography revealed a large tumor with a maximum diameter of 67 mm at the pancreatic head and a 23-mm mass in the left upper abdominal cavity. Because a definitive diagnosis could not be made based on endoscopic ultrasonography-guided fine needle aspiration biopsy findings, a diagnostic laparoscopy was performed. The tumor in the greater omentum at the left upper abdomen, resected under laparoscopy, was histopathologically diagnosed as pancreatic acinar cell carcinoma. Therefore, the pancreatic tumor was diagnosed as an unresectable pancreatic acinar cell carcinoma with a solitary peritoneal dissemination. The size of the main pancreatic tumor decreased to 15 mm after 18 courses of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). Subsequently, the patient underwent conversion surgery, and the initial diagnosis of pancreatic acinar cell carcinoma was confirmed on pathological examination. The patient was discharged 31 days postoperatively, following which he received adjuvant chemotherapy with S-1. No sign of recurrence has been observed for 32 months after surgical resection. CONCLUSION: FOLFIRINOX may be effective in patients with pancreatic acinar cell carcinoma, and conversion surgery after FOLFIRINOX may be applicable to selective patients.

Pancreatic FDG uptake on follow-up PET/CT in patients with cancer.

To evaluate the breakdown of unexpected pancreatic 18F-fluorodeoxyglucose (FDG) uptake and the proportion of secondary primary pancreatic cancer on follow-up, patients with cancer underwent positron emission tomography/computed tomography (PET/CT). The participants consisted of 4,473 consecutive patients with cancer who underwent follow-up PET/CT between January 2015 and March 2019 at Kochi Medical School. Among the participants, 225 with a history of pancreatic cancer were excluded from the present study. Retrospective and blinded PET/CT evaluations of 4,248 patients were performed. In patients with pancreatic FDG uptake, the distribution of FDG uptake in the pancreas was evaluated. The final diagnosis was determined pathologically. A total of 14 (0.3%) of the 4,248 patients exhibited FDG uptake in the pancreatic area. Pancreatic abnormalities were detected in 14 patients, and included five cases of pancreatic metastases (36%), four cases of secondary primary pancreatic cancer (29%), two cases of lymph node metastases (14%), one case of malignant lymphoma (7%), one case of autoimmune pancreatitis (7%) and one case of pseudolesion (7%). One patient with early-stage secondary primary pancreatic cancer had a maximum standardized uptake value (SUVmax) <3.0. The remaining 13 patients had a SUVmax >3.0 in the pancreas. Of the 14 patients, two had multiple foci of FDG uptake in the pancreas. Patients with multiple foci of FDG uptake exhibited pancreatic metastasis from renal cell carcinoma and malignant lymphoma. In conclusion, the majority of patients with unexpected pancreatic FDG uptake on follow-up PET/CT exhibited malignancies; furthermore, ~30% of the malignancies detected in patients with pancreatic FDG uptake were secondary primary pancreatic cancers. In patients with unexpected pancreatic FDG uptake on follow-up PET/CT, primary cancer should be considered as well as metastatic tumors.

Circulating pancreatic cancer exosomal RNAs for detection of pancreatic cancer.

Diagnostic biomarkers for the early diagnosis of pancreatic cancer are needed to improve prognosis for this disease. The aim of this study was to investigate differences in the expression of four messenger RNAs (mRNAs: CCDC88A, ARF6, Vav3, and WASF2) and five small nucleolar RNAs (snoRNAs: SNORA14B, SNORA18, SNORA25, SNORA74A, and SNORD22) in serum of patients with pancreatic cancer and control participants for use in the diagnosis of pancreatic cancer. Results were compared with the expression of sialylated Lewis (a) blood group antigen CA19-9, the standard clinical tumor biomarker. Reverse transcription quantitative real-time PCR showed that all of the mRNAs and snoRNAs, except CCDC88A, were encapsulated in exosomes and secreted from cultured pancreatic cancer cells, and present in cell culture medium. In a discovery-stage clinical study involving 27 pancreatic cancer patients and 13 controls, the area under the receiver operating characteristic curve (AUC) of two mRNAs (WASF2 and ARF6) and two snoRNAs (SNORA74A and SNORA25) was > 0.9 for distinguishing pancreatic cancer patients from controls; the AUC of CA19-9 was 0.897. Comparing serum levels of WASF2, ARF6, SNORA74A, SNORA25, and CA19-9 revealed that levels of WASF2 were the most highly correlated with the risk of pancreatic cancer. The AUCs of WASF2, ARF6, SNORA74A, and SNORA25 in serum from patients in the early stages of pancreatic cancer (stages 0, I, and IIA) were > 0.9, compared with an AUC of 0.93 for the level of CA19-9. The results of this study suggest that WASF2, ARF6, SNORA74A, and SNORA25 may be useful tools for the early detection of pancreatic cancer. Monitoring serum levels of WASF2 mRNA may be particularly useful, as it was the most highly correlated with pancreatic cancer risk.

Long-term effects of multimodal treatment for patients with resectable carcinoma of the pancreas.

The treatment of pancreatic carcinoma remains one of the most formidable challenges in oncology. Curative resection, currently the only available treatment option, provides no significant impact on long-term survival. The recent development of multimodal treatment options for pancreatic cancer has provided clinical benefits and improved patient survival. In this study, we retrospectively evaluated our experiences with multimodal therapy, including radiotherapy and chemotherapy with gemcitabine, for the treatment of resectable pancreatic cancer. Fifty-eight patients with ordinary pancreatic carcinoma who underwent surgical resection at Kochi Medical School were studied. The clinical and pathological factors and multimodal treatment for pancreatic carcinoma that influenced patient survival were analyzed. Cumulative 1-, 3- and 5-year survival rates after surgery for ordinary pancreatic carcinoma were 62.2, 20.3 and 20.3%, respectively. The overall 4-year survival rate of patients subjected to adjuvant chemotherapy with gemcitabine after curative resection for ordinary pancreatic carcinoma is 39.1%. Adjuvant chemotherapy with gemcitabine provided a significantly better prognosis for patients following curative surgical resection than curative surgical resection alone (P=0.035). Although the rate of survival was greater for patients who underwent radiotherapy than those who did not, the difference was not statistically significant (P=0.054). Postoperative local recurrence around the nerve plexus of celiac and superior mesenteric arteries was better controlled in patients who underwent radiotherapy than those who did not. Adjuvant chemotherapy with gemcitabine after curative resection provides a significant survival benefit for patients with pancreatic carcinoma. Our results suggest that the postoperative recurrence of ordinary pancreatic carcinoma will be reduced by multimodal treatment using radiotherapy and adjuvant chemotherapy with gemcitabine.

A long-survived case with solitary splenic metastasis from ovarian carcinoma.

A61-year-old postmenopausal woman with ovarian carcinoma was treated with two surgical operations and a series of platinum-based chemotherapy. A solitary metastasis into the splenic parenchyma was identified 33 months after the second surgery by abdominal computed tomography with an increased serum level of CA-125. She underwent a pancreaticosplenectomy and received platinum-based adjuvant chemotherapy continuously for 2 years. Her serum CA-125 level decreased to a normal range and she has lived without any recurrence for more than 10 years after the splenectomy. Solitary metastases from ovarian cancer into the splenic parenchyma are extremely rare. Among 18 cases previously reported, this present case shows the longest disease-free survival. Because these cases show favorable prognosis after splenectomy, surgical treatment should be considered along with adjuvant chemotherapy.

Duodenum-preserving pancreatic head resection for pancreatic metastasis from renal cell carcinoma: a case report.

INTRODUCTION: We report a case of duodenum-preserving pancreatic head resection (DPPHR) for the treatment of pancreatic head metastasis from renal cell carcinoma (RCC). CASE REPORT: The patient was a 59-year-old male with a medical history of RCC 18 years ago. Abdominal imaging studies revealed a hypervascular mass localized in the pancreatic head without distant metastasis or tumor invasion into the adjacent organs including the common bile duct and duodenum. Under the preoperative diagnosis of pancreatic metastasis from RCC, the tumor was completely resected by DPPHR. The pathological examination of the resected specimen confirmed the preoperative diagnosis. CONCLUSION: As lymph node metastasis has been rarely reported in previous cases of pancreatic metastasis from RCC, DPPHR should be considered as a less invasive surgical option to provide a favorable postoperative quality of life (QOL).

Xanthogranulomatous pancreatic abscess secondary to acute pancreatitis: two case reports.

Xanthogranuloma is a rare type of inflammation and very few cases have been reported in the pancreas. We report two cases with xanthogranulomatous pancreatic abscess that followed acute pancreatitis. In both cases, multiple pseudocysts in the pancreatic tail were infected with several species of bacteria and Candida albicans. In one case, abdominal angiography revealed a hypoperfused pancreatic tail due to prior atherosclerotic obliteration of the celiac and superior mesenteric arteries. In the other case, the splenic artery was completely occluded by a transarterial embolization performed to treat an aneurysm that appeared in the course of pancreatitis. In both cases, distal pancreatectomy was performed as inflammation of the pancreatic tail was resistant to conventional antibiotic therapy, and pathologic examination revealed xanthogranulomatous inflammation around the pancreatic tail and spleen. Although the underlying pathogenesis is unclear, the prolonged infection and/or relative hypoxia induced by hypoperfusion are likely causative factors for the xanthogranulomatous changes in these pancreatic abscesses.

Juxtapapillary Duodenal Diverticulum Impacted with Enterolith.

A 64-year-old man underwent abdominal computed tomography (CT) as periodic follow-up following a distal gastrectomy with lymphadenectomy for gastric cancer and mucosal-associated lymphoid tissue (MALT) lymphoma conducted 31 months earlier. Contrast-enhanced CT demonstrated a well-circumscribed mass lesion with heterogeneous density measuring 2.2 cm in diameter located between the second segment of the duodenum and uncinate process of the pancreas. Esophagogastroduodenoscopy revealed no remarkable findings in the remnant stomach; however, the scope could not reach the duodenum due to altered anatomy by Roux-en-Y reconstruction after the distal gastrectomy. The patient underwent surgical resection of the mass lesion under the clinical diagnosis of MALT lymphoma relapse. An orange calculus was apparent in the thinly extended duodenal wall on stretching, and the hall was closed by meticulous primary suture after the duodenal resection. Macroscopically, the extracted calculus was solid and quite hard, measured 2.2 × 2.1 × 2.1 cm, and the cut surface revealed a layered structure in the outer areas with granulated contents in the center. Although duodenal diverticula are relatively common, an enterolith developing within a juxtapapillary duodenal diverticulum is rare, and to the best of our knowledge, this is the first such case due to altered anatomy after gastrectomy reported in the English literature.

Rapid growth of mucinous cystic adenoma of the pancreas following pregnancy.

A 25-yr-old woman delivered a healthy child by cesarean section. At 8 mo postpartum, she became aware of an upper abdominal tumor. Abdominal computed tomography and upper abdominal ultrasonography revealed a large cystic mass in the body of the pancreas. Endoscopic retrograde pancreatography showed no connection between the main pancreatic duct and the cystic lesion. The patient underwent tumor resection at 11 mo postpartum. Pathological examination of the tumor revealed mucin-producing columnar epithelial cells lining the cystic wall with ovarian-type stromal tissue and no findings indicative of malignancy, giving a diagnosis of mucinous cystic adenoma of the pancreas. Immunohistochemical studies revealed positive staining for progesterone receptor but not for estrogen receptor in the stromal cell nuclei. Postpartum rapid growth of a benign mucinous cystic neoplasm might be linked to the production of female sex hormones during lactation.

Mucinous cystadenocarcinoma of the pancreas with anaplastic carcinoma: A case report and review of the literature.

Few reports of mucinous cystic neoplasm (MCN) in association with anaplastic carcinoma exist. The present study reported an unusual case of a 25-year-old female exhibiting large pancreatic MCN with anaplastic carcinoma. Notably, the patient was a Jehovah's Witness and therefore refused any blood transfusions. Preoperative diagnosis was invasive pancreatic MCN measuring 12.5 cm with ascites. Distal pancreatectomy was performed in combination with splenectomy and partial resection of the transverse colon. Intraoperative estimated blood loss was 400 ml, therefore a blood transfusion was not required. The patient had an uneventful postoperative course. The pathological diagnosis was mucinous cystadenocarcinoma of the pancreas with anaplastic carcinoma. Although the patient underwent postoperative adjuvant chemotherapy with gemcitabine and oral fluoropyrimidine (S-1), recurrence with peritoneal dissemination was detected 20 months following surgery and the patient succumbed to the recurrence 32 months following surgery. To the best of our knowledge, this is the first case report of MCN with anaplastic carcinoma of the pancreas in a Jehovah's Witness patient undergoing pancreatic surgery.

CCDC88A, a prognostic factor for human pancreatic cancers, promotes the motility and invasiveness of pancreatic cancer cells.

BACKGROUND: Coiled-Coil Domain Containing 88A (CCDC88A) was identified as a substrate of the serine/threonine kinase Akt that is capable of binding to the actin cytoskeleton. The aim of this study was to investigate the potential role of CCDC88A in the migration and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: Immunohistochemistry was performed to determine whether high CCDC88A expression in human PDAC tissues is correlated with poor prognosis. Immunoprecipitation, immunoblotting and immunocytochemistry were performed to determine the intracellular distribution of CCDC88A, and its association with the serine/threonine kinase Akt and actin-filaments in PDAC cells. Phosphoprotein array analysis was performed to determine CCDC88A-associated intracellular signaling pathways. Finally, immunofluorescence analyses and Matrigel invasion assays were performed to examine the effects of CCDC88A on the formation of cell protrusions and PDAC cell invasion. RESULTS: Expression of CCDC88A in PDAC tissue was significantly correlated with overall survival. CCDC88A was co-localized with peripheral actin structures in cell protrusions of migrating PDAC cells. Knockdown of CCDC88A inhibited the migration and invasiveness of PDAC cells through a decrease in cell protrusions. Although CCDC88A has been previously reported to be a binding partner and substrate of Akt, the level of active Akt was not associated with the translocation of CCDC88A towards cell protrusions. CCDC88A-dependent promotion of cell migration and invasiveness was not modulated by Akt signaling. Knockdown of CCDC88A decreased phosphorylated Src and ERK1/2 and increased phosphorylated AMPK1 in PDAC cells. Knockdown of AMPK1 inhibited the migration and invasiveness of PDAC cells. The combined data suggest that CCDC88A may be a useful marker for predicting the outcome of patients with PDAC and that CCDC88A can promote PDAC cell migration and invasion through a signaling pathway that involves phosphorylation of Src and ERK1/2 and/or dephosphorylation of AMPK1. CONCLUSIONS: CCDC88A was accumulated in cell protrusions, contributed to the formation of membrane protrusions, and increased the migration and invasiveness of PDAC cells.

Overexpression of carbonic anhydrase-related protein XI promotes proliferation and invasion of gastrointestinal stromal tumors.

Three isoforms of carbonic anhydrase-related protein (CA-RP) are evolutionally well conserved among the CA gene family but lack classical CA activity. Although the biological function of CA-RPs is unknown, overexpression of CA-RP VIII has been reported in certain tumor types. Based on the finding that CA-RPs are commonly expressed in the neuronal cells, we investigated expression of all three CA-RPs in gastrointestinal stromal tumor (GIST). In contrast to no detectable signal of any of the three CA-RPs in intestinal cells of Cajal, immunohistochemical analysis showed distinct cytoplasmic expressions of CA-RPs VIII and XI in 13 (59%) and 20 (91%) of 22 GIST tissue specimens, respectively. The positive signals for both CA-RPs VIII and XI were more intense in the periphery than in the central part of GISTs, whereas no significant signal for CA-RP X expression was observed in any of the GISTs. These expression patterns of CA-RPs were consistently observed by reverse transcription-polymerase chain reaction-Southern blot and immunocytochemistry in the cultured GIST cell line GIST-T1. Ectopic expression of CA-RP XI in GIST-T1 cells induced cell proliferation and invasion in vitro. These findings indicate that CA-RP XI plays a role in the development of GIST.

Effect of carbonic anhydrase-related protein VIII expression on lung adenocarcinoma cell growth.

Carbonic anhydrase-related protein VIII (CA-RP VIII) is expressed in most non-small cell lung cancer, and especially strongly at the front of tumor progression. Screening analysis of CA-RP VIII expression in a panel of cultured lung cancer cell lines showed that a well differentiated adenocarcinoma cell line, PC-9, appeared to lack CA-RP VIII. Subsequently, CA8 cDNA was transfected with an expression vector into PC-9. Ectopic overexpression of CA-RP VIII reduced the growth of PC-9 cells on uncoated culture dishes, especially when the cultures were started at low cell density, but increased cell growth on laminin-coated dishes. Interestingly, ectopic CA-RP VIII expression markedly reduced caspase-3 activity induced by serum starvation and anti-cancer agents in PC-9 cells. The present findings suggest that CA-RP VIII expression promotes progression of lung cancer by multifarious mechanisms.

Serum antibody to carbonic anhydrase II in patients with chronic viral hepatitis: a review of its prevalence in liver diseases.

Serum antibody to carbonic anhydrase II (CA II) has been reported in patients with autoimmune pancreatitis and its related autoimmune liver diseases. To evaluate its diagnostic significance, we studied serum antibodies to CA II and also CA I in patients with chronic viral hepatitis by enzyme-linked immunosorbent assay and reviewed its prevalence previously reported in patients with liver diseases. Anti-CA II antibody was detected in 5 of 20 patients with chronic hepatitis type C (25%, p<0.05 versus normal controls), 2 of 10 patients with chronic hepatitis type B (20%, not significant versus normal controls), and 1 of 30 normal controls (3%). Anti-CA I antibody was detected in 3 of 20 patients with chronic hepatitis type C (15%, not significant versus normal controls). Anti-CA II antibody has previously been reported as being associated with a variety of liver diseases, including primary biliary cirrhosis with or without anti-mitochondrial antibody, autoimmune hepatitis and chronic hepatitis type C. These findings suggest less significance of anti-CA II antibody for the diagnosis of autoimmune pancreatitis and its hepatic involvements than as having been reported. However, the pathogenetic role of the antibody remains uncertain.

Inflammatory pseudotumor of the liver: report of a case diagnosed by needle biopsy.

We report a case of a 76-year-old man with inflammatory pseudotumor, xanthogranuloma type of the liver. The patient showed clinical manifestations of a liver abscess. Abdominal sonography and computed tomography revealed an additional tumor-like lesion adjoining the liver abscess. Following treatment with antibiotics for 20 days, the liver abscess disappeared, but there was no change in the size and shape of the tumor-like lesion. Histological analysis of a specimen obtained from the tumor-like lesion by needle biopsy revealed an infiltration of abundant foamy histiocytes with massive fibrosis. Without any treatment, the tumor-like lesion gradually diminished in 5 months. In previous literatures, most cases with xanthogranuloma of the liver underwent hepatectomy or diagnostic laparotomy. The findings presented herein suggest that in cases of an atypical solid mass in the liver accompanied by a clinical inflammatory process, inflammatory pseudotumor should be considered, and, if the disease is suspected, liver needle biopsy is recommended to prevent an unnecessary surgical operation.

Biliopancreatic fistula caused by an intraductal papillary-mucinous tumor of the pancreas confirmed by biochemical analysis of mucin.

Intraductal papillary-mucinous tumor of the pancreas is occasionally accompanied by biliopancreatic fistula. However, it is difficult to show the inflow of mucin produced by the tumor into the common bile duct. To confirm the biliopancreatic fistula, the mucin-rich fraction was purified from the bile and stained with antimucin antibodies. Western blot analysis showed characteristic smear staining patterns for mucin molecules with three types of antimucin antibodies. Immunohistochemical analysis with the antibody showed significant signals of the cancer cells and the luminal content of the dilated pancreatic duct. These results showed that the bile contained an abundance of mucin, which was produced by the primary pancreatic tumor. In cases with intraductal papillary-mucinous tumor of the pancreas, biochemical analysis of mucin molecules in the bile can be of clinical use in consideration of pathological process of tumor progression.

Diminished cellular immune response to carbonic anhydrase II in patients with Sjögren's syndrome and idiopathic chronic pancreatitis.

CONTEXT: A serum antibody to carbonic anhydrase II has been reported in patients with Sjögren's syndrome and idiopathic chronic pancreatitis. OBJECTIVE: To evaluate cellular immune response to carbonic anhydrase II in patients with Sjögren's syndrome and idiopathic chronic pancreatitis. PATIENTS: Idiopathic chronic pancreatitis (n=23), Sjögren's syndrome (n=12), alcoholic chronic pancreatitis (n=3) and normal controls (n=13). MAIN OUTCOME MEASURES: Proliferation assay of peripheral blood mononuclear cells. RESULTS: Notable increased proliferation of the mononuclear cells upon stimulation with carbonic anhydrase II was observed in 2 patients with idiopathic chronic pancreatitis (9%) and 2 patients with Sjögren's syndrome (17%) but not in patients with alcoholic chronic pancreatitis nor in normal controls. Among the four study groups, there was no significant difference in the prevalence rate of the positive proliferative responses (P=0.444). CONCLUSION: Carbonic anhydrase II may not be a major target antigen for the immunological process in the pathogenesis of Sjögren's syndrome and idiopathic chronic pancreatitis. Serum antibody to carbonic anhydrase II may be detected in these patients as a consequence of the immune reaction against other antigens which mimic carbonic anhydrase II.

[Treatment of acute pancreatitis with protease inhibitor, H2 receptor antagonist and somatostatin analogue].

Acute pancreatitis sometimes develops to severe condition with a variety of clinical manifestations and high mortality. Autodigestion of the pancreas, secondary to the activation of digestive enzymes, plays a major role in the pathogenetic mechanism of acute pancreatitis. To improve the mortality and complication rates, appropriate treatments based on the precise prediction of disease severity are required. To this end, the early administration of protease inhibitors has commonly been employed for the therapy of acute pancreatitis in Japan. However, a number of clinical trials have failed to show the clinical effects of protease inhibitors, H2 receptor antagonist and somatostatin analogue on the treatment of acute pancreatitis. To evidence the therapeutic value of these agents for acute pancreatitis, well-organized clinical studies will be required.