Anti-Donor T-Cell Responses Are Not Necessarily Attenuated During Cytomegalovirus Infection in Kidney Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV), the most common opportunistic infection of kidney transplantation (KT), is preventable by prophylactic and preemptive antiviral drugs in CMV-immunoglobulin (Ig)G-positive donors. Our preemptive therapy optimized immunosuppressive doses based on mixed lymphocyte response (MLR) results, regardless of preoperative CMV-IgG serostatus pairing. This study used the MLR to compare the anti-donor T-cell responses between CMV antigenemia-positive and -negative cases. METHODS: One hundred patients underwent KT using a cyclosporine (CsA)-based immunosuppressive regimen at Hiroshima University Hospital. CMV antigenemia-positive cells were defined as 4/50,000 CMVpp65-positive cells. T-cell responses to allo-antigens were measured using MLR assays to evaluate patients' anti-donor immune reactivity. After analyzing the proliferation of CD4+ and CD8+ T-cell subsets, the stimulation indices of CD4+ or CD8+ T cells were quantified. The study used no prisoners, and the participants were neither coerced nor paid. The manuscript was created in compliance with the Helsinki Congress and the Declaration of Istanbul. RESULTS: Forty-three patients tested positive for CMV antigenemia within 3 months after KT. No significant differences were found between the CMV antigenemia-positive and -negative groups in the stimulation indices for CD4+ and CD8+ T-cell responses to anti-donor stimulation. However, T-cell responses to third-party stimuli during the postoperative month 1 were significantly less in the CMV antigenemia-positive than -negative group. CONCLUSION: Anti-donor T-cell responses are not necessarily attenuated during CMV infection in KT recipients. In CMV-infected KT recipients, caution should be exercised against inadvertent dose reduction of immunosuppressants.

C-Reactive Protein/Albumin Ratio Is an Independent Risk Factor for Recurrence and Survival Following Curative Resection of Stage I-III Colorectal Cancer in Older Patients.

BACKGROUND: The number of older patients with cancer has increased, and colorectal cancer is expected to be affected by this trend. This study aimed to compare prognostic factors, including nutritional and inflammation-based indices, between patients aged ≥ 70 and < 70 years following curative resection of stage I-III colorectal cancer. PATIENTS AND METHODS: This study included 560 patients with stage I-III colorectal cancer who underwent curative resection between May 2010 and June 2018. A retrospective analysis was performed to identify prognosis-associated variables in patients aged ≥ 70 and < 70 years. RESULTS: Preoperative low body mass index, high C-reactive protein/albumin ratio, and comorbidities were mainly associated with poor prognosis in patients aged ≥ 70 years. Tumor factors were associated with a poor prognosis in patients aged < 70 years. The C-reactive protein/albumin ratio was independently associated with poor overall survival and recurrence-free survival in those aged ≥ 70 years. The time-dependent area under the curve for the C-reactive protein/albumin ratio was superior to those of other nutritional and inflammation-based indices in most postoperative observation periods in patients aged ≥ 70 years. CONCLUSIONS: Tumor factors were associated with a poor prognosis in patients aged < 70 years. In addition to lymph node metastasis, preoperative statuses were associated with poor prognosis in patients aged ≥ 70 years. Specifically, the preoperative C-reactive protein/albumin ratio was independently associated with long-term prognosis in patients aged ≥ 70 years with stage I-III colorectal cancer after curative resection.

Survival outcomes of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: the HiSCO-04 prospective cohort study.

BACKGROUND: The efficacy of adjuvant chemotherapy in elderly patients aged ≥ 80 years with stage III colorectal cancer remains unclear. In parallel with a multicenter prospective phase II trial evaluating the efficacy of uracil-tegafur and leucovorin as adjuvant chemotherapy (HiSCO-03), we conducted a prospective observational study of these patients to assess survival outcomes, including those ineligible for chemotherapy. METHODS: This multi-institutional prospective cohort study included 17 institutions in Hiroshima, Japan. Patients aged ≥ 80 years with stage III colorectal cancer who underwent curative resection were enrolled. The primary endpoint was 3-year disease-free survival, and the secondary endpoints were 3-year overall and relapse-free survival. Propensity score matching was used to assess the effects of adjuvant chemotherapy on survival outcomes. RESULTS: A total of 214 patients were analyzed between 2013 and 2018, including 99 males and 115 females with a median age of 84 years (range 80-101 years). Recurrence occurred in 58 patients and secondary cancers were observed in 17. The 3-year disease-free, overall, and relapse-free survival rates were 63.3%, 76.9%, and 62.9%, respectively. Adjuvant chemotherapy was administered to 65 patients with a completion rate of 52%. In a study of 80 patients that adjusted for background factors using propensity score matching, patients who completed the planned treatment showed improved disease-free survival (3-year disease-free survival: completed, 80.0%; not received, 65.5%; and discontinued, 56.3%; p = 0.029). CONCLUSIONS: Completion of adjuvant chemotherapy may improve the prognosis of patients with colorectal cancer aged ≥ 80 years, although the number of patients who would benefit from it is limited.

Effectiveness of Thermal Barrier Bag for Prolonged Vascular Anastomosis in Kidney Transplantation.

BACKGROUND: In kidney transplantation (KT), efforts to minimize rewarming and optimize anastomosis time during vascular anastomosis improve graft outcomes. We recently reported the safety and efficacy of a pouch-type thermal barrier bag (TBB) made of elastomer gel to reduce second-warm ischemic injury during vascular anastomosis. We aimed to examine the usefulness of the TBB in prolonged vascular anastomosis in KT performed by young transplant fellows. METHODS: Young transplant fellows performed KT under the supervision of certified transplant surgeons. The kidney graft was placed inside the TBB with an outlet for vessels and preserved during vascular anastomosis. A non-contact infrared thermometer measured the graft surface temperature before and after vascular anastomosis. After completion of the anastomosis, the TBB was manually slid out of the transplanted kidney and removed before graft reperfusion. Clinical data, including patient characteristics and perioperative variables, were collected. The primary endpoint was the median graft surface temperature at the end of the anastomosis. RESULTS: Ten living-donor kidney transplant recipients with a median age of 56.5 years (range, 40-69 years) underwent KT procedures performed by young transplant fellows. The median anastomosis time was 53 (43-67) min. At the end of anastomosis, the median graft surface temperature was 17.7°C (16.3-18.3°C); no serious adverse events or delayed graft function were observed. CONCLUSION: The TBB can keep transplanted kidneys at a low temperature even with prolonged vascular anastomosis time, thus contributing to the functional preservation of transplanted kidneys and stable transplant outcomes.

Effect of abdominal aortic calcification on the prognosis and recurrence of colorectal cancer stages II-III: A retrospective cohort study.

PURPOSE: Abdominal aortic calcification (AAC) is a well-known risk marker for cardiovascular disease. However, its clinical effect on patients who underwent radical surgery for colorectal cancer (CRC) stages II-III is unclear. This study aimed to analyze the associations between AAC and prognosis of patients with stage II-III CRC. METHODS: To evaluate the effect of AAC on clinical outcomes, prognosis, and metastatic patterns of CRC, we analyzed 362 patients who underwent radical surgery for stage II-III CRC between 2010 and 2018. RESULTS: The high AAC group had significantly worse overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) after propensity score matching to adjust for differences in baseline characteristics of patients and tumors. In the multivariate Cox regression analyses, a high AAC was an independent risk factor for poor OS (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.23-4.59; p = 0.01), poor CSS (HR, 5.22; 95% CI, 1.74-15.6; p < 0.01), and poor RFS (HR, 1.83; 95% CI, 1.19-2.83; p < 0.01). A high AAC was not associated with a risk of lung metastasis or local or peritoneal recurrence, but a risk for liver metastasis of CRC. CONCLUSION: A high AAC showed a strong relationship with poor OS, CSS, and RFS after curative resection for stage II-III CRC. A high AAC was also associated with a risk for liver metastasis, which may worsen the prognosis in stage II-III CRC. AAC could be a new clinical tool for predicting the prognosis for patients in stage II-III CRC.

Drug-Induced Interstitial Pneumonia due to Application of FOLFOX as Adjuvant Chemotherapy after Rectal Cancer Surgery: A Case Report and Literature Review.

The regimen of oxaliplatin with 5-fluorouracil plus l-leucovorin (FOLFOX) has become one of the most commonly used first-line chemotherapy for patients with advanced colorectal cancer and it provides an increase in disease-free survival as well as an overall survival benefit. Although FOLFOX chemotherapy has helped to improve the clinical outcomes in these patients, the regimen is associated with some therapeutic issues or uncontrolled side effects. Gastrointestinal, neurosensory, and hematological toxicities have frequently been observed in patients treated with FOLFOX, and consequently, some palliative treatment has been established to combat such complications. However, pulmonary toxicities including drug-induced interstitial pneumonia (DI-IP) is rarely observed in these patients and a curative treatment is yet to be established. DI-IP due to chemotherapy is most commonly observed in patients treated with mitomycin, paclitaxel, docetaxel, or gemcitabine. Steroid therapy is mostly used to treat DI-IP, although the efficacy of such treatments is not supported with adequate evidence. FOLFOX-induced interstitial pneumonia (FIIP) is rarely observed, and several case reports of FIIP treated with steroids have been published previously that showed the mortality is extremely high. Here, we present a 74-year-old woman who received modified FOLFOX6 as adjuvant chemotherapy after rectal cancer surgery. The patient experienced FIIP, which improved after application of steroid pulse (high-dose methylprednisolone at 1,000 mg/day for 3 days) and tapering (starting with prednisolone at 40 mg/day) therapy. Our data suggest that such a steroid therapy could represent an effective treatment option for FIIP.

Adenocarcinoma of the duodenum arising from Brunner's gland resected by partial duodenectomy: a case report.

BACKGROUND: Duodenal carcinoma originating in Brunner's gland is rare. Herein, we report a case of duodenal carcinoma arising from Brunner's gland in a 63-year-old man. CASE PRESENTATION: On diagnostic imaging, the lesion presented as a non-invasive carcinoma; the patient also had uncontrolled diabetes and liver cirrhosis. Hence, we decided to perform partial duodenectomy to reduce operative stress. Pathological examination revealed that the tumor consisted of tissue from Brunner's gland. Additionally, the carcinoma cells were strongly positive for Mucin-6 protein, which is an epithelial marker of Brunner's gland. The patient's post-operative course was uneventful, and he has been well for 2 years after the surgery. CONCLUSIONS: This a rare case of an adenocarcinoma arising from Brunner's gland of the duodenum that was resected by duodenectomy.

Perioperative management of a bleeding jejunal tumor in a patient with erythropoietic protoporphyria: A case report and literature review.

INTRODUCTION: Erythropoietic protoporphyria (EPP) is a rare disorder caused by reduced ferrochelatase activity and shows incomplete autosomal dominant inheritance. Meticulous perioperative management can avoid characteristic complications. This report describes a case of a bleeding jejunal tumor in a patient with EPP. PRESENTATION OF CASE: A 49-year-old man with a history of EPP was admitted to our department with abdominal distention and severe anemia. Contrast-enhanced computed tomography revealed an abdominal tumor measuring 5 cm, originating from the small bowel wall or mesentery. Tumor resection was planned after correction of anemia. Red blood cell transfusion restored his hemoglobin to acceptable levels; however, his liver function worsened. Institution of liver support therapy achieved gradual reduction in his elevated liver enzymes; however, hyperbilirubinemia persisted. He underwent tumor resection on the 12th day of hospitalization. Yellow filters were used to avoid operating room light-induced tissue injury. The tumor was located in the jejunum 30 cm from the Treitz ligament toward the anal aspect. The histopathological diagnosis was desmoid-type fibromatosis of the jejunum. Postoperatively, his hemoglobin levels were stabilized; however, his serum bilirubin level remained high. His serum bilirubin level gradually decreased following hemin injections (150 mg/day). DISCUSSION: Reducing heme synthesis and minimizing protoporphyrin generation are important perioperatively. Additionally, preventing operating room light-induced tissue burns and selecting appropriate anesthestic agents are important during surgery. CONCLUSION: The institution of appropriate treatment and adequate intra- and perioperative measures can ensure safe surgery in patients with EPP even under emergency conditions.

Utility of Doppler Ultrasonography in Liver Transplantation With Celiac Axis Compression Syndrome: A Case Report.

BACKGROUND: Celiac axis compression syndrome (CACS) blocks adequate hepatic arterial flow and is a risk factor for hepatic artery thrombosis after liver transplantation. We report a case of living donor liver transplantation in a 65-year-old Brazilian male with liver cirrhosis of Child-Pugh class C and hepatocellular carcinoma caused by hepatitis C virus infection. RESULTS: The patient underwent living donor liver transplantation using the graft of his 34-year-old daughter. Stenosis of the celiac artery was detected on preoperative computed tomography (CT), and CACS was suspected. Maintaining blood supply through the hepatic artery to prevent potential graft loss is essential in liver transplantation. A decrease in common hepatic artery (CHA) flow due to CACS could disturb graft blood supply or lead to hepatic artery thrombosis. In this case, we confirmed CACS through dynamic CT and used intraoperative Doppler ultrasonography (US) to plan the surgical procedure. Three types of hepatic artery reconstruction have been described in liver transplantation for CACS, namely the release of the median arcuate ligament (MAL), aorto-hepatic graft reconstructions, and reconstruction preserving the gastroduodenal artery (GDA) without MAL release. We found that clamping the GDA completely abolished hepatic inflow, but clamping the CHA did not change the hepatic inflow. Therefore, we performed arterial reconstruction without division of the GDA. The patient's postoperative course was good, with excellent hepatic artery flow, as assessed by Doppler US. CONCLUSIONS: Preoperative dynamic CT evaluation, adequate preparation of surgical procedures, and intraoperative evaluation by Doppler US is recommended in liver transplantation patients with CACS.

Perioperative management of polycythemia vera with advanced gastric cancer: A case report.

INTRODUCTION: Polycythemia vera (PV) is a chronic myeloproliferative disorder with generally good prognosis. However, thrombotic and cardiovascular complications are among the leading causes of death in patients with PV and sufficiently effective management strategies are yet to be established. We report a case involving operation for gastric cancer in a patient being treated for PV. PRESENTATION OF CASE: A 73-year-old man was diagnosed as PV on the basis of abnormal laboratory data eight years previously. Three months ago, he was referred to our department for anorexia and melena. The preoperative diagnosis was advanced gastric cancer, Stage IIB. To avoid perioperative thrombotic and hemorrhagic events, low-dose aspirin administration was continued with an additional dose of hydroxyurea. Emergent control was necessary because of the severity of gastric cancer symptoms, including pyloric stenosis and anemia. Distal gastrectomy with D2 lymph node resection was performed. The postoperative course was satisfactory, and the patient is currently doing well without any signs of recurrence or hematological complications. DISCUSSION: We described the successful management of a patient being treated for PV who underwent gastrectomy. As mentioned earlier, thrombotic complications and hemorrhage during the perioperative period are the major risk factors in patients with PV. In this case, control of white blood cell and platelet counts during the perioperative period led to good results. CONCLUSIONS: Perioperative management for PV is important for complication-free surgery. Careful follow up should be performed for gastric cancer and PV recurrence.

Characteristics of the portal vein thrombosis recurrence pattern without liver parenchymal invasion from colorectal cancer: a case report.

BACKGROUND: Portal vein tumor thrombosis from colorectal cancer is rare, and this recurrence pattern was mainly reported in patients with renal cell carcinoma and hepatocellular carcinoma. Furthermore, the recurrence pattern of portal vein tumor thrombosis without liver parenchymal invasion from colorectal carcinoma has not been previously reported. Herein, we present a patient with progressive portal vein tumor thrombosis without liver parenchymal invasion following curative resection. CASE PRESENTATION: A 61-year-old man with a chief complaint of constipation with abdominal pain associated with rectal carcinoma was admitted to our hospital. Computed tomography (CT) showed that the rectosigmoid colon wall was thickened, regional lymph nodes were swollen, and the light space-occupying lesion (SOL) was detected at segment 8 (S8). Neoadjuvant chemotherapy was performed, which was followed by laparoscopic anterior resection. The final diagnosis was stage IIIb (SS, N2, M0). After operation, systemic adjuvant chemotherapy was introduced. At first, tumor marker levels were within the normal range and there were no accumulations on positron emission tomography (PET). Tumor marker levels were elevated, and contrast-enhanced CT demonstrated that the portal vein SOL slowly extended from S8 to S5. Additionally, PET showed that the standardized uptake value was abnormally high at 5.8. Based on the diagnosis of portal vein tumor thrombosis, right hepatectomy was performed. On pathological analysis, tumor thrombosis was associated with rectal carcinoma, and there was no invasion toward the liver parenchyma. Additionally, the surgical cut end was tumor free. Six months after the hepatectomy, the paraaortic lymph nodes showed swelling. The patient is currently undergoing systemic chemotherapy. CONCLUSION: Aggressive surgical resection should be considered in cases of portal vein tumor thrombosis. A good long-term prognosis could be obtained by a combination of curative resection and systemic chemotherapy.

Efficacy of the Gallbladder Cancer Predictive Risk Score Based on Pathological Findings: A Propensity Score-Matched Analysis.

BACKGROUND: The optimal prognostic predictive system for gallbladder carcinoma (GBC) has not been established. The gallbladder cancer predictive risk score (GBRS) based on pathological findings identifies incidental GBC patients at risk of recurrence. OBJECTIVE: We aimed to validate the prognostic ability of the GBRS in all GBC patients following curative surgery. METHODS: Fifty-six patients with GBC who underwent curative surgery between 1996 and 2016 were included in this study. Univariate and multivariate analyses were performed to determine prognostic factors associated with overall and recurrence-free survival, and propensity score-matched analysis was performed. RESULTS: The median patient age was 71.9 years, and 39.3% of patients were males. All patients underwent curative surgery (33.9%, simple cholecystectomy; 66.1%, more advanced procedures, such as hepatectomy; and 32.1%, bile duct reconstruction). On univariate analysis, preoperative carbohydrate antigen 19-9 (CA19-9) ≥ 37 U/mL (p = 0.042), postoperative complications (p = 0.043), and a high GBRS (p < 0.001) were prognostic factors for worse overall survival. On multivariate analysis, CA19-9 ≥ 37 U/mL (p = 0.039 and p = 0.043, respectively) and a high GBRS (p = 0.001 and p = 0.010, respectively) were independent risk factors for poor overall and recurrence-free survival. After propensity score-matched analysis, the GBRS precisely predicted prognosis of patients with GBC. CONCLUSIONS: The GBRS is an easy and novel prognostic predicting score. Our validation revealed good discrimination, suggesting its clinical utility to improve individualized prediction of survival for patients undergoing resection of GBC.

A colovesical fistula with a persistent descending mesocolon due to partial situs inversus: A case report.

INTRODUCTION: Situs inversus viscerum, a congenital condition in which the visceral organs are a mirror image of their normal physiological positions, could be total or partial. Persistent descending mesocolon (PDM) is a congenital anomaly that is asymptomatic because of its short length. PDM causing intestinal obstruction is a known clinical complication. PRESENTATION OF CASE: A 74-year-old woman presented with pneumaturia and enteruria for two months, and recurrent cystitis for a month. An enhanced computed tomography (CT) showed air in the bladder along with sigmoid colonic diverticula adherent to it, suspecting a fistula. The CT also showed partial situs inversus with the common hepatic artery, and left colic artery arising abnormally from the superior mesenteric artery (SMA). Minimally invasive endoscopic closure using the over-the-scope clipping system was difficult because of thickening and scar tissue due to chronic inflammation from diverticulitis. Thus, a sigmoidectomy was performed to close the fistula. Intraoperatively, we noted an abnormally fixed descending mesocolon. An emergency reoperation was performed on the sixth postoperative day owing to an anastomotic leak. Suture failure was attributed to these congenital abnormalities due to insufficient blood flow from an absent marginal vessel and a high endocolonic pressure by adhesions. Sigmoid colon re-resection and maturation of an ileostomy was performed. The patient had no specific postoperative complications, and the ileostomy was closed after three months. CONCLUSION: We report an extremely rare case of colovesical fistula due to a PDM in a patient having partial situs inversus with abnormal branches originating from the SMA.

A case of pancreatic schwannoma showing increased FDG uptake on PET/CT.

INTRODUCTION: Schwannomas are neoplasms originating from Schwann cells in nerve sheath, but pancreatic schwannomas are rare. PRESENTATION OF CASE: A 59-year-old female incidentally pointed out a 2-cm-sized solid mass in the pancreas head by computed tomography (CT) which was performed for other reasons. Magnetic resonance imaging (MRI) showed a mass with hypointensity on T1-weighted images and a heterogenous hyperintensity on T2-weighted images. Magnetic resonance cholangiopancreatography (MRCP) showed no abnormal findings in the main pancreatic duct. The mass of the pancreas head showed a significantly increased uptake on fluorin-18 fluorodeoxyglucose positron emission tomography CT (FDG-PET/CT). Based on the radiological findings, a malignant potential tumor was preliminarily considered. Subtotal stomach-preserving pancreatoduodenectomy (SSSPD) was performed to make a definite diagnosis. The resected specimen showed a well-encapsulated circumscribed mass, measuring 2.0cm, in the pancreas head. Histopathological examination revealed proliferation of spindle cells showing interlacing and palisading patterns in the tumor. The proliferating cells showed no atypia and few mitoses. Immunohistochemically, the spindle cells were positive for S-100 protein. The Ki67 labeling index was approximately 2%. Based on these findings, a diagnosis of benign schwannoma of the pancreas was made. CONCLUSION: Although pancreatic schwannoma is a rare neoplasm, it is important to take into account this tumor in the differential diagnosis of pancreatic tumors. In addition, we should be aware that FDG-PET/CT shows abnormal accumulation in a benign pancreatic schwannoma.

Laparoscopic operation after pre-operative reduction of an intussusception-induced inflammatory fibroid polyp.

Intussusception occurs mainly in children but rarely in adults. About 80-90% of adult cases of intussusception are due to benign or malignant neoplasms as a lead point. One of the causes is an inflammatory fibroid polyp (IFP), a rare, benign entity that occurs more frequently in the stomach than the ileum. We describe an uncommon case of a patient who presented with intussusception-induced IFP of the ileum. A 35-year-old woman presented with a 2-day history of abdominal pain. A computed tomography scan demonstrated ileocolic intussusception. During colonoscopy, reduction by pressured air easily released intussusception, and we suspected a submucosal tumour of the ileum. Successful pre-operative colonoscopic reduction was helpful for performing laparoscopic ileocecal resection 2 days later. Results of the histopathological examination confirmed a large IFP. The patient's post-operative course was uneventful. Pre-operative reduction by colonoscopy is effective for the diagnosis and treatment of intussusception-induced IFP.

[Twenty-Five Cases of Locally Advanced Rectal Cancer That Underwent Laparoscopic Surgery after Preoperative Chemotherapy].

Several recent reports have described the administration of preoperative chemotherapy for locally advanced rectal cancer. In our hospital, preoperative chemotherapy based on oxaliplatin was administered for locally advanced rectal cancer with a tumor diameter of 5 cm or more and half semicircularity or more, and curative resection with laparoscopic surgery was performed after tumor shrinkage. We have experienced 25 cases that underwent preoperative chemotherapy for local advanced rectal cancer in our hospital from May 2012 to April 2016. No tumor increased in size during preoperative chemotherapy and there were no cases where R0 resection was impossible. In addition, no distant metastasis during chemotherapy was observed. Postoperative complications were observed in 3 cases(12%), and anastomotic leakage was observed in 1 case (4%), but conservative treatment was possible. Multidisciplinary treatment of preoperative chemotherapy and surgery should be considered as a therapeutic strategy for locally advanced rectal cancer, mainly in medical institutions without radiation treatment facilities.

A mixed adenoneuroendocrine carcinoma of the pancreas: a case report.

A tumor consisting of an adenocarcinoma component and a neuroendocrine carcinoma component, with each component accounting for at least 30% of the tumor, is defined as a mixed adenoneuroendocrine carcinoma (MANEC). We report a case of MANEC of the pancreas. A 63-year-old man presented with hyperglycemia and was referred to our hospital for further examination. Abdominal contrast-enhanced computed tomography (CT) revealed a mass of 2 cm in size in the pancreas head with portal vein narrowing. Fluorin-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) CT revealed increased accumulation in the mass of the pancreas head. Endoscopic retrograde cholangiopancreatography (ERCP) showed severe narrowing of the main pancreatic duct. Cytological analysis by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) suggested a neuroendocrine tumor. Under the diagnosis of neuroendocrine tumor, pancreaticoduodenectomy with portal vein resection and regional lymph node dissection was performed with curative intent. Histological examination revealed that the tumor consisted of two cell populations. One was well- to moderately differentiated tubular adenocarcinoma. This cell component accounted for 45% of the whole tumor. The second component was non-adenocarcinoma cells arranged in a nest, and the cells had round nuclei, abundant cytoplasm, and coarse chromatin. The Ki67 labeling index was 40%. Immunohistochemically, the adenocarcinoma cells were positive for CEA but negative for chromogranin A (CgA) and synaptophysin (Syn), while the non-adenocarcinoma cells were positive for the expression of CgA and Syn but negative for CEA. Based on the findings, a diagnosis of MANEC of the pancreas was made. Postoperatively, lymph node metastasis and peritoneal dissemination developed rapidly and he died the 6 months after the operation. Due to the small number of reported cases of MANEC of the pancreas, its clinical behavior remains unclear and a standardized management protocol has not been established. Further investigation of more cases of this rare entity is necessary.

A fluorescence-based method for evaluating inositol 1,4,5-trisphosphate receptor ligands: determination of subtype selectivity and partial agonist effects.

Inositol 1,4,5-trisphosphate (IP3) receptors consist of three subtypes: IP3R1, IP3R2, and IP3R3. Although numerous IP3 receptor ligands have been synthesized, none of the subtype-selective ligands are known. We have developed a simple fluorescence method to examine the subtype selectivity of IP3 receptor ligands using FRET-based IP3 biosensors LIBRAvI, LIBRAvII, and LIBRAvIII. The addition of IP3 or adenophostin A (ADA) to permeabilized biosensor-expressing cells increased the fluorescence ratios of these biosensors in a concentration-dependent manner, and the potency of ADA relative to that of IP3 in terms of the changes in the fluorescence ratios of LIBRAvI, LIBRAvII, and LIBRAvIII was 43-, 22-, and 28-fold, respectively. This fluorescence-based method further showed that several ADA analogs had significant differences with respect to subtype selectivity and potency. These results highlight the important role played by the O-glycosidic structure of ADA in the selectivity of the ligands for IP3R1, as evidenced by the modified selectivity following replacement of the 5'-hydroxyl with a phenyl or phenethyl group. We also found that one ADA analog 5'-deoxy-5'-phenyladenophostin A possessed a partial agonistic effect on IP3R1. Together, the novel fluorescent methods described herein are useful for the evaluation of properties of IP3R ligands, including potency, efficacy, and subtype selectivity.

Synthesis of adenophostin A analogues conjugating an aromatic group at the 5'-position as potent IP3 receptor ligands.

Previous structure-activity relationship studies of adenophostin A, a potent IP(3) receptor agonist, led us to design the novel adenophostin A analogues 5a-c, conjugating an aromatic group at the 5'-position to develop useful IP(3) receptor ligands. The common key intermediate, a D-ribosyl alpha-D-glucoside 10alpha, was stereoselectively synthesized by a glycosidation with the 1-sulfinylglucoside donor 11, which was conformationally restricted by a 3,4-O-cyclic diketal protecting group. After introduction of an aromatic group at the 5-position of the ribose moiety, an adenine base was stereoselectively introduced at the anomeric beta-position to form 7a-c, where the tetra-O-i-butyryl donors 9a-c were significantly more effective than the corresponding O-acetyl donor. Thus, the target compounds 5a-c were synthesized via phosphorylation of the 2', 3' ', and 4' '-hydroxyls. The potencies of compounds 5a-c for Ca(2+) release were shown to be indistinguishable from that of adenophostin A, indicating that bulky substitutions at the 5'-position of adenophostin A are well-tolerated in the receptor binding. This biological activity of 5a-c can be rationalized by molecular modeling using the ligand binding domain of the IP(3) receptor.