Overlapping Myocarditis and Postural Orthostatic Tachycardia Syndrome After COVID-19 Messenger RNA Vaccination: A Case Report.

The worldwide spread of the coronavirus disease 2019 (COVID-19) pandemic and the significant morbidity and mortality rate associated with it led to the rapid development of several COVID-19 vaccines. While serious side effects related to the vaccines are rare, various adverse events have been reported to occur after COVID-19 messenger RNA (mRNA) vaccination, including myocarditis, Guillain-Barré syndrome, and thrombosis. Postural orthostatic tachycardia syndrome (POTS) is a chronic cardiovascular dysautonomia among young and middle-aged individuals. Although the pathophysiology of POTS is thought to be heterogeneous, vaccine-induced immune-mediated autonomic dysfunction is hypothesized to be one cause of the syndrome. In this report, we present a case of myocarditis and POTS occurring in a 13-year-old male following COVID-19 mRNA vaccination. He presented with persistent severe fatigue and headache. The patient's symptoms improved after intravenous immunoglobulin for myocarditis, non-pharmacologic interventions, and multiple medications for POTS.

Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma is macroscopically classified into three subtypes, mass-forming-type, periductal infiltrating-type, and intraductal growth-type. Each subtype should be preoperatively differentiated to perform the valid surgical resection. Recent researches have revealed the clinical, radiologic, pathobiological characteristics of each subtype. We reviewed recently published studies covering various aspects of intrahepatic cholangiocarcinoma (ICC), focusing especially on the macroscopic subtypes and stem cell features to better understand the pathophysiology of ICC and to establish the valid therapeutic strategy.

A large hepatic cyst with obstructive jaundice successfully treated with single-incision laparoscopic deroofing.

We herein present a case of hepatic cysts causing obstructive jaundice that was treated with single-incision laparoscopic deroofing. A 72-year-old female patient was referred to hospital due to a large hepatic cyst that compressed the intrahepatic bile ducts. The patient was scheduled to undergo single-incision laparoscopic deroofing. The EZ ACCESS(TM) oval type (Hakko Co. Ltd.) was placed at the umbilicus using a 25-mm incision with two 5-mm trocars. An additional 12-mm port was placed at the left epigastric region. We unroofed and excised the cyst wall using a vessel sealing system in liver segment 4. After surgery, the patient was found to be asymptomatic. The unroofed cysts were completely diminished. Notably, the remnant liver had fairly regenerated. The estimated regeneration volume of the normal liver was 153 cm(3). To prevent surgical complications, clinicians should perform adequate management and use of devices. To prevent postoperative recurrence of cysts, performing complete deroofing is essential. Single-incision laparoscopic deroofing contributes to improving the quality of life of patients and should be considered a standard treatment.

Mucinous cystic neoplasm of the pancreas in a male patient.

Mucinous cystic neoplasms (MCNs) make up a morphologic family of similar appearing tumors arising in the ovary and various extraovarian organs such as pancreas, hepatobiliary tract and mesentery. MCNs of the pancreas occur almost exclusively in women. Here, we report a rare case of MCN in a male patient. A 39-year-old man was admitted to our hospital with the chief complaint of back pain. Abdominal computed tomography revealed a multilocular cyctic mass 6.3 cm in diameter in the pancreatic tail. In addition, the outer wall and septae with calcification were demonstrated in the cystic lesion. On magnetic resonance imaging , the cystic fluid had low intensity on T1-weighted imaging and high intensity on T2-weighted imaging. Endoscopic retrograde cholangio-pancreatography (ERCP) showed neither communication between the cystic lesion and the main pancreatic duct nor encasement of the main pancreatic duct. Endoscopic ultrasonography revealed neither solid component nor thickness of the septae in the cystic lesion. Consequently, we performed distal pancreatectomy with splenectomy under the diagnosis of cystic neoplasia of the pancreas. Histopathologically, the cystic lesion showed two distinct component: an inner epithelial layer and an outer densely cellular ovarian-type stromal layer. Based on these findings, the cystic lesion was diagnosed as MCN.

Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer.

OBJECTIVES: Thymidylate synthase (TS) inhibitors activate human equilibrative nucleoside transporter 1. We evaluated the contribution of TS expression to determine a treatment method providing an effect from gemcitabine (GEM). METHODS: The expression of 5-fluorouracil (5-FU) and GEM metabolic factors (5-FU: TS, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase; GEM: human equilibrative nucleoside transporter 1, deoxycytidine kinase, cytidine deaminase, 5'-nucleotidase) were studied in 7 pancreatic cancer cell lines by Western blotting, and drug resistance was evaluated by 3-[4,5-dimethylthiazol]-2,5-dephenyl tetrazolium bromide assay. The expression of 5-FU factors was observed immunohistochemically in resected pancreatic cancer specimens. RESULTS: Gemcitabine concentrations that inhibited colony formation by 50% correlated with TS protein expression (P = 0.0169). With a 5-FU non-growth-inhibiting dose, GEM concentrations that inhibited colony formation by 50% were significantly reduced by one fourth to one tenth. Knockout of TS expression by small interfering RNA decreased resistance to GEM in the cell lines (P = 0.0019). Immunohistochemically, TS expression related to disease-free survival time of patients treated with GEM (P = 0.0224). A high expression of 5-FU factors was detected: orotate phosphoribosyltransferase: differentiated cases (P = 0.0137), lower T factor (P = 0.0411); dihydropyrimidine dehydrogenase: nerve invasion (P = 0.0188), lymph node recurrence (P = 0.0253); TS, positive N factor (P = 0.0061). CONCLUSIONS: The expression of TS provides an alternative source of substrate for DNA synthesis and positively correlates with GEM resistance and shortened patient survival.

Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study.

BACKGROUND AND PURPOSE: The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. A dose-escalation study of docetaxel combined with cisplatin and 5-fluorouracil (5-FU) was performed to determine the optimal dose in patients with advanced esophageal squamous cell carcinoma. PATIENTS AND METHOD: We studied a total of 18 patients who had previously untreated thoracic esophageal squamous cell carcinoma with T4 tumors and/or metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3: 30, 35, 40 mg/m(2), respectively) and an infusion of cisplatin (40 mg/m(2)) on days 1 and 15 plus a continuous infusion of 5-FU (400 mg/m(2)/day) on days 1-5 and 15-19. RESULTS: Dose-limiting toxicities (DLT) included febrile neutropenia and leukopenia. DLT occurred in 2 of 6 patients at level 1, 2 and in 3 of 6 patients at level 3. The response rate was 88.9%, including a complete response rate of 33.3%. CONCLUSIONS: To minimize toxicity and maximize dose intensity, we elected to investigate a biweekly regimen. The maximum tolerated dose was level 3, and the recommended dose was determined to be docetaxel 35 mg/m(2) with cisplatin 40 mg/m(2) plus 5-FU 400 mg/m(2), administered biweekly. This regimen was tolerable and highly active. A phase II study has been started.

Immunohistochemical study of claudin 18 involvement in intestinal differentiation during the progression of intraductal papillary mucinous neoplasm.

BACKGROUND AND AIM: A comparison was made between pancreatic ductal adenocarcinoma (PDAC), pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous carcinoma (IPMC) in order to understand the association between several markers and malignant potential. PATIENTS AND METHODS: Fifteen surgically resected PDACs and four IPMCs were subjected to immunohistochemistry with primary antibodies to Ki-67, p53, MUC2, Gli-1, and Claudin-18 (CLDN18). RESULTS: Ki-67, P53, MUC2, Gli-1 and CLDN18 were positive in 6 (50%), 10 (66.6%), 0 (0%), 4 (26.6%), and 6 (40%) of the 15 PDACs, respectively. Low- to high-grade PanIN complexes were found in 2 out of the 15 PDACs. Gli-1 was continuously expressed in low- and high-grade PanINs. CLDN18 was specifically expressed in high-grade PanINs, whereas the corresponding invasive tubules did not express CLDN18. P53 was positively stained in one of the 4 IPMCs in which minimally invasive tubular type carcinomas were observed. Ki-67 and CLDN18 were positively stained in all 4 IPMCs. CLDN18 was specifically expressed in intestinal-type components of IPMCs. CONCLUSION: CLDN18 is involved in intestinal-type epithelial differentiation in the progression of IPMCs, contradicting the previous knowledge of its specificity in gastric epithelial differentiation.

Liver abscess after common hepatic artery embolization for delayed hemorrhage following pancreaticoduodenectomy: a case report.

A 55-year-old man underwent pancreaticoduodenectomy for bile duct carcinoma in March 2009. The patient developed anastomotic leakage and had a short episode of hemorrhage from the drainage tubes with spontaneous disappearance. CT and upper endoscopy did not reveal the source of bleeding. A massive life-threatening hemorrhage occurred on the 18th postsurgical day. Emergency angiography showed a 2.7-cm pseudoaneurysm of the gastroduodenal artery stump, and hepatic artery embolization was performed. After embolization, an abscess appeared in segments 2/3 of the liver without involving the right lobe. We treated conservatively by drainage and antibiotics. During the course of therapy after embolization, the patient experienced several episodes of high fever but did not develop hepatic failure. On the 68th day after embolization, the abscess had penetrated to the lesser sac, which was immediately treated by percutaneous drainage. Anastomotic leakage was treated by continuous irrigation from the drain, for which complete resolution was achieved by the 34th day after embolization. The patient was discharged 101 days after embolization. Imaging and the clinical course demonstrate a unique mechanism of abscess formation after embolization.

Clinical significance of aggressive hepatectomy for colorectal liver metastasis, evaluated from the HGF/c-Met pathway.

Liver metastasis is one of the most critical factors in deciding the prognosis of patients with colorectal cancer (CRC). Hepatectomy is the most curative treatment for liver metastasis of CRC. The high amount of hepatocyte growth factor (HGF) is produced to promote liver regeneration by hepatectomy. Theoretically, HGF produced after hepatectomy stimulates the progression of CRC cells with c-Met in residual liver. This study was aimed to evaluate the value of hepatectomy towards liver metastasis of CRC in relation to the HGF/c-Met pathway. Ninety-four patients with CRC (including 24 liver metastasis cases) were operated at Gifu University Hospital (2002-2004). For these cases, the expression of c-Met in the primary and liver metastatic sites was evaluated by immunohistochemistry and Western blot. Experiments were also conducted on CT26 murine CRC cell line and a mouse liver metastasis model. In clinical study, the c-Met expression in liver metastatic sites was lower than in the primary sites in 87% of 24 cases. In basic study, the expression of c-Met protein in the liver tumor was significantly lower than in culture cells according to Western blot (p=0.033). The growth of residual liver tumors was not significantly different between 30% hepatectomy group and no operation group. The over-expression of c-Met was closely associated with CRC liver metastases. On the other hand, in liver metastatic lesions, the c-Met expression was reduced in comparison to primary lesions. Therefore, even if serum HGF levels increased due to liver resection during the regeneration period, residual liver metastases of CRC was not promoted in its progression. Aggressive hepatectomy would still be acceptable and favorable as a curative therapy.

Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer.

BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common cancers worldwide, and a strategy to assess and control liver metastasis will be critical to control patient prognosis. To evaluate therapeutic approaches, the biological responses associated with hepatectomy were studied with a focus on hepatocyte growth factor (HGF). METHODOLOGY: In 54 patients with metastatic liver tumors due to CRC, c-Met expression was estimated by western blotting from resected tissue specimens. Serum HGF levels were measured by an ELISA method and compared with other liver function serum factors. RESULTS: The preoperative serum level of HGF was found to be related to ICGR15, ALP, CHE and AST, but after hepatectomy, the change was not correlated with other liver function factors. From an evaluation of pre-operative liver condition using ICGR15, an increasing rate (post/pre) of AST, ALT, ALP and HGF was observed to be higher in cases with positive outcomes. In cases with normal pre-operative levels of serum HGF, the increasing rate (post/pre) of HGF after surgery was higher than in cases with abnormally high pre operative values (3.07 +/- 0.87 and 2.38 +/- 0.74, respectively; p = 0.0102). In cases where tumors recurred within 6 months (early recurrence cases), the c-Met value in tumor tissue was higher than in cases with no recurrence, even in cases where there was no tendency for an increasing rate of HGF. In addition, multiplying data serum HGF increasing rate by c-Met value in tissue was significantly higher in early recurrence cases than in cases with no recurrence, (3.96 +/- 0.62 and 3.00 +/- 1.16 respectively; p = 0.0135). A similar finding was also detected following curative operations involving multiple tumor resection (3.93 +/- 0.64 vs. 2.84 +/- 1.24 for early and no recurrence, respectively; p = 0.0147). CONCLUSION: The present study demonstrated that cancer with high c-Met expression and under high level of its ligand, HGF, led to recurrence soon after hepatectomy, leading to unfavorable patient prognosis. If pathological or biochemical factors from resected specimens could help identify patients with a high risk of relapse, innovative adjuvant chemotherapy protocols could be initiated.

Critical role of c-Met and Ki67 in progress of biliary carcinoma.

The purpose of this study was to evaluate the pattern of expression of c-Met and Ki67 in several components of biliary carcinoma. Fourteen surgically resected samples, including five intrahepatic cholangiocarcinomas, five gallbladder carcinomas, and four extrahepatic bile duct carcinomas, were subjected to immunohistochemistry with primary antibodies. In all 13 cases, intraductal neoplastic components showed diffuse staining for c-Met localized in the cell membrane, whereas 10 of the 14 cases lacked expression of c-Met in the corresponding invasive components. In four cases, invasive components composed of undifferentiated carcinoma (n = 2), signet-ring cell carcinoma (n = 1), and squamous cell carcinoma (n = 1) showed nuclear or perinuclear staining for c-Met. Conversely, 11 of the 13 cases did not express Ki67 in intraductal neoplastic components, whereas corresponding invasive components showed diffuse nuclear staining in all 14 cases. A comparison of the patterns of expression between c-Met and Ki67 at the boundary between intraductal and invasive components clearly demonstrated the complementary expression of c-Met and Ki67. Our results suggested that c-Met is involved in early events of carcinogenesis and Ki67 is involved in the formation of invasive carcinoma. However, exceptional cases were also observed, which might be associated with specificity for histologic subtypes and malignant potential.

A case delayed hemorrhage from the stump of the superior rectal artery after abdominoperineal resection of the rectum.

A 66-year-old man underwent abdominoperineal resection for advanced rectal cancer. On day 3 post surgery, a decompression tube was placed for postoperative ileus. Symptoms associated with ileus immediately disappeared. On day 7 post surgery, the patient vomited large amounts of fresh blood and became hemodynamically unstable. An emergency angiography revealed active bleeding from the stump of the superior rectal artery communicating with the third portion of the duodenum. Complete obliteration of the stump by proximal coil embolization was performed to achieve successful hemostasis. The postclinical course was uneventful and the patient was discharged on day 40 post surgery.

Serial analysis of gene expression of esophageal squamous cell carcinoma: ADAMTS16 is upregulated in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. To identify potential diagnostic markers for ESCC and therapeutic targets for ESCC, we used Serial Analysis of Gene Expression (SAGE) on one ESCC sample. We obtained a total of 14,430 tags, including 5765 that were unique. By comparing SAGE tags from the ESCC sample with those from normal human squamous esophagus, we found several genes that were differentially expressed between ESCC and normal squamous esophagus. Among these, we focused on the ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) gene because quantitative RT-PCR analysis showed a high level of ADAMTS16 expression in eight out of 20 ESCC samples (40%), but not in 15 kinds of normal tissues. Western blot analysis also showed upregulation of ADAMTS16 protein in ESCC tissues. Furthermore, ADAMTS16 protein was detected in culture media from the TE5 esophageal cancer cell line. Knockdown of ADAMTS16 in TE5 cells inhibited both cell growth and invasion ability. Our present SAGE data provide a list of genes potentially associated with ESCC. ADAMTS16 could be a novel diagnostic and therapeutic target for ESCC.

Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells.

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.

A Case Report of Intraductal Papillary-Mucinous Neoplasm of the Pancreas Showing Morphologic Transformation during Followup Periods.

A 64-year-old man underwent MRCP for further examination of gallbladder stones and IPMN of branch-type (IPMN-Br) was pointed out. Yearly MRCP had revealed the gradual increase of the cystic components, marked dilation of the main pancreatic duct (MPD), and filling defects in the MPD. After follow-up for three years, he underwent pancreatoduodenectomy. Histologically, the dilated MPD and connecting dilated branch ducts were filled with nodular growth of tumor cells consisting of gastric-type adenoma with pyloric gland-like structures. In the MPD, a transition from gastric-type adenoma to intestinal-type carcinoma was observed. In addition, in a dilated branch duct, some components of intestinal-type carcinoma with marked arborizing structures were observed. A minimally invasion was observed around branch ducts. Immunohistochemistry revealed diffuse nuclear accumulation of PCNA and Ki67 in the tumor cells of branch dusts. Our observations suggest that the secondary infiltration to the MPD of IPMN-Br and IPMN-Br possesses malignant potential for microinvasion.

Clinical evaluation of modified reconstruction method after pancreatoduodenectomy.

BACKGROUND/AIMS: The new reconstruction procedure after pancreatoduodenectomy (PD) is described to evaluate its usefulness. METHODOLOGY: The jejunum was made for an end-to-side choledochojejunostomy, and the cut proximal jejunum for approximately 20 cm was led to the pancreatic stump for end-to-end anastomosis with telescoping. Approximately 20 cm of jejunum was created with a side-to-end anastomosis with the stomach, and end-to-side jejuno-jejunostomy for Roux-en Y reconstruction. As a postoperative course, separated loop method (SL, n=38) was evaluated by comparing pancreatogastrostomy (PG, n=31) and Imanaga method (IM, n=26). RESULTS: On SL, PG and IM cases, the high amylase level in drainage fluid was noted in 2.6%, 6.5% and 19.2%, respectively. The delayed gastric emptying was seen in PG and IM, but not in SL. Serum albumin levels were similar, but cholinesterase and total cholesterol levels were significant better in SL. CONCLUSIONS: SL method is safe for complications after PD.

Invasive ductal carcinoma of the pancreas showing exophytic growth.

BACKGROUND: Invasive pancreatic carcinoma generally appears as poorly defined mass reflecting the infiltrative growth. We aimed to identify the histological and immunohistochemical features in a rare case of pancreatic carcinoma showing exophytic growth. METHODS: A 67-year-old woman presented with a mass of 5.0 cm in diameter in the pancreatic head. Preoperative computed tomography revealed a well-demarcated, primarily solid mass with a central low-density area. Magnetic resonance cholangiopancreatography revealed neither encasement nor dilation of the main pancreatic duct. An incorrect preoperative diagnosis was made of solid pseudopapillary tumor of the pancreas. Elevated serum carcinoembryonic antigen (CEA) levels and abnormal FDG positron emmission tomography accumulation suggested that the tumor had malignant potential requiring a pancreatoduodenectomy. RESULTS: The head of the pancreas contained a well-circumscribed encapsulated mass of 5.0 cm in diameter, comprising 50% adenocarcinoma, with mucinous carcinoma in the center and anaplastic carcinoma at the periphery. The anaplastic carcinoma comprised pleomorphic cells (PCs) and pleomorphic giant cells (PGCs). The PGCs phagocytozed mononuclear PCs and lymphocytes adjacent to the capsule without infiltrating the capsule itself. Immunohistochemistry revealed that the anaplastic carcinoma cells including PGCs were positive for the tumor antigen Mucin 1 and CEA but negative for vimentin. CONCLUSION: Our observations suggest anaplastic carcinoma components in the present tumor have a ductal origin and that the exophytic tumor growth is associated with the phagocytotic activity of PGCs.

Successful surgical resection for peritoneal implantation of hepatocellular carcinoma at the paracardial portion.

Peritoneal implantation from hepatocellular carcinoma has been rarely reported. It may occur at various sites. Here we present a surgically resected case of peritoneal implantation to the diaphragm from hepatocellular carcinoma. A 50-year-old woman underwent right hemihepatectomy extended to a medial part of Couinaud segment IV for hepatocellular carcinoma in May 2000. In December 2008, the elevation of alpha-phetoprotein and the appearance of a heterogeneously enhanced mass, with dimensions of 9 x 7 cm, and adjacent to the remnant liver and pericardium suggested intrahepatic recurrence with markedly enhanced growth. After transcatheter arterial embolization, surgical resection under laparotomy combined with median sternotomy was selected. Samples of pericardial fluid showed no malignancy after cytological examination. At the superior border of the tumor, the confluence of pericardium and diaphragm was displaced, but the tumor itself showed a generally expanding but not invasive growth. The resected tumor showed moderately differentiated hepatocellular carcinoma whose pathology revealed a peritoneal implantation to the diaphragm. The patient is in good health without any postoperative complications or any further sign of recurrence.

Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy.

Reactivation of hepatitis B virus (HBV) infection is a frequent complication of cytotoxic chemotherapy that includes steroids. International studies have shown that lamivudine reduces the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy to treat malignancies. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations. Here, we studied the role of entecavir in preventing morbidity and mortality associated with HBV reactivation. Three patients with both solid malignancies and hepatitis B surface antigen-positive hepatitis B underwent cytotoxic chemotherapy with steroids. They were followed up for at least 6 months after the completion of chemotherapy. The chemotherapeutic regimens comprised carboplatin and paclitaxel for non-small-cell lung cancer, and docetaxel monotherapy or cyclophosphamide plus epirubicin for breast cancer, respectively. All patients completed chemotherapy with steroids without developing severe hepatitis that could be attributable to HBV reactivation. Entecavir prevented the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Although further studies are required to evaluate whether entecavir can prevent the increased risk of YMDD mutation and decrease the rates of disrupted chemotherapy due to severe hepatitis more effectively than lamivudine, entecavir should be considered before lamivudine for such patients.