Hybrid Repair with Reversed Sequence Supra-aortic Debranching in Ruptured Arch Aneurysm.

Aortic arch pathology in a high-risk patient in whom the resternotomy approach is unfeasible due to treated mediastinitis after ascending aortic replacement presents a unique challenge for hybrid arch repair (HAR) because of the need for supra-aortic debranching from unusual inflow sites other than the ascending aorta. This report describes a "reversed sequence" extra-anatomical supra-aortic debranching procedure as a salvage technique performed to enable HAR. An 83-year-old woman with a history of ascending aortic replacement for type A aortic dissection, mediastinitis complicated by sternal osteomyelitis, and a chest wall reconstructed with a rectus abdominis myocutaneous flap presented with chest pain because of a contained dissecting arch aneurysm rupture. The patient underwent supra-aortic debranching from the bilateral common femoral arteries and thoracic endovascular aortic repair to the ascending aorta under cerebral near-infrared spectroscopy (NIRS) monitoring. Completion imaging by angiography demonstrated successful exclusion of the ruptured aneurysm. The regional cerebral oxygen saturation level, monitored by NIRS, did not change markedly during surgery. The patient was neurologically intact with adequate cerebral blood flow assessed postoperatively by 123 I-IMP single photon emission computed tomography. Total debranching of the supra-aortic vessels from the common femoral artery for inflow is feasible and provides adequate cerebral perfusion. This procedure may offer an alternative treatment option in patients with complex conditions involving aortic arch pathology.

[A Case of Advanced Gastric Cancer with Distant Lymph Nodes Metastasis Showing a Complete Response to Six-Courses Chemotherapy].

This study reports a 66-year-old female presenting abdominal pain. Gastrointestinal endoscopy showed the presence of a type 3 tumor in the lesser curvature of the stomach, and biopsy revealed poorly differentiated adenocarcinoma. CT images displayed thickening of the stomach wall and enlarged paraaortic lymph nodes, left supraclavicular lymph nodes, and left iliac lymph nodes. FDG-PET/CT scan showed abnormal accumulation at the same site. The patient was diagnosed with unresectable highly advanced gastric cancer(cT4aN2H0P0M1[LYM], Stage Ⅳ). She was treated with combination chemotherapy of S-1 and CDDP(SP). Tumor markers normalized(CA19-9 11,158→20 U/mL)after 3 courses with a marked reduction of lesions. After 5 courses of chemotherapy, the tissue biopsy did not reveal any cancer and a complete response(CR) was achieved. Adverse events of diarrhea and loss of appetite were observed. Subsequently, chemotherapy was discontinued after 6 courses, and CR remained for the next 5 years. Thus, we experienced a rare case of unresectable advanced gastric cancer with distant lymph nodes metastasis, showing long-term recurrence-free survival after receiving 6 courses of SP chemotherapy.

[A Case of Internal Hernia Incarceration of a Mesenteric Defect following Laparoscopic Ileocecal Resection].

A 75-year-old man underwent laparoscopic ileocecal and partial small bowel resections for the management of appendiceal cancer. The pathological diagnosis was cecal cancer(T4b[ileum, abdominal wall],N0[0/13], M0, pStage Ⅱc). After 4 months of surgery, he suddenly experienced abdominal pain and vomiting and was presented to our emergency room. He was diagnosed with bowel obstruction following which, conservative treatment was initiated through a nasogastric ileus tube implantation; however, he did not show any improvement. Subsequently, he underwent experimental laparotomy on the 18th day of the disease. Intraabdominal examination revealed herniated small intestine through a mesenteric defect, which was closed following repositioning of the herniated small intestine. The postoperative course was good, and the patient was discharged on the 10th day after surgery. No recurrence of intestinal obstruction has been observed after 1 year and 6 months. Closure of the mesenteric defect, although not commonly performed in laparoscopic colorectal surgery, is worth considering because of the risk of developing an internal hernia requiring surgical treatment, as in our case.

[Surgical Technique for Prevention of Incisional Hernia in Laparoscopic Small Bowel Resection in the Obese Patient].

A 67-year-old woman reporting lower abdominal pain and anemia was examined. Small intestinal tumor was diagnosed by small intestinal radiographic contrast study and small intestinal endoscopy, and we decided to perform a laparoscopic partial resection of the small bowel. Since she was obese patients(BMI 36.3, abdominal wall 6 cm)at high risk of postoperative incisional hernia, we devised a way to make the wound smaller. We judged thick abdominal wall make umbilical wound larger in single port surgery. We performed multi-port surgery by using one 15 mm trocar, and removed small intestinal tumor from 15 mm port incision. In addition, to prevent incisional hernia, we used a trocar with a wound closure assist function for securely closing the port wound in all layers. Histopathological diagnosis was neuroendocrine tumor. The patient is being followed up without recurrence and without incisional hernia. In partial small bowel resection of obese patient, the use of a 15 mm port to minimize wound site and the use of trocar with a wound closure assist function may lead to prevent incisional hernia.

[Laparoscopic Tumor Resection for Retroperitoneal Leiomyosarcoma-A Case Report].

A 59-year-old man visited our department because of cholecystectomy. Preoperative CT revealed a tumor shadow measuring 50 mm in front of the right iliopsoas muscle. MRI showed a low signal intensity on T1-weighted images and a slightly high signal intensity on the T2-weighted image. PET-CT showed accumulation of FDG(SUVmax 5.39)in the tumor but no other abnormal accumulations. We performed tumor resection for diagnostic purposes because malignancy could not be ruled out owing to the large size of the mass. Intraoperative findings showed a well-circumscribed margin of the tumor without invasion to other tissues. The retroperitoneum was incised circumferentially along the tumor under laparoscopic guidance, and the tumor was resected. Histopathological and immunostaining findings were consistent with leiomyosarcoma. In laparoscopic surgery, the surgical margin is observed in detail through the magnifying effect. Therefore, laparoscopic surgery can be a surgical option for tumors that may be completely excised based on preoperative findings.

[A Long-Term Survival Case of Neuroendocrine Carcinoma of Gallbladder-Report of a Case].

The patient is 77-year-old man. He received open cholecystectomy and choledocholithotomy when he was 74 years old. Because postoperative diagnosis was small cell neuroendocrine carcinoma(NEC), the resection of gallbladder bed and hilus lymph nodes were performed. During the follow up period, the liver metastases and portal vein tumor thrombosis appeared. Therefore, chemotherapy was performed according to small cell lung cancer. In addition to chemotherapy, radiation therapy was performed for the purpose of local control. He is still alive about 3 years after the first operation. This case suggested the efficacy of multidisciplinary treatment including operation, chemotherapy, and radiation therapy in NEC of gallbladder patient with liver metastasis.

[Pathological Complete Response in a Case of Advanced Gastric Cancer with Para-Aortic Lymph Nodes Metastasis Treated by Preoperative Chemotherapy with S-1 and Oxaliplatin(SOX Therapy)].

The patient was a 73-year-old man, diagnosed as advanced gastric cancer with para-aortic lymph nodes(PAN)metastasis. He was treated by 3 courses of neoadjuvant chemotherapy(NAC)with S-1 and oxaliplatin(SOX therapy). CT showed significant reduction of both primary tumor and metastatic lymph nodes. We performed distal gastrectomy with D2 plus PAN dissection. The histopathological findings showed no residual viable tumor cell. The pathological effect of chemotherapy was judged Grade 3(pCR)in both primary tumor and dissected lymph nodes. He is alive without recurrence 21 months after surgery.

Prediction Characteristics of Oral Absorption Simulation Software Evaluated Using Structurally Diverse Low-Solubility Drugs.

The purpose of the present study was to characterize current biopharmaceutics modeling and simulation software regarding the prediction of the fraction of a dose absorbed (Fa) in humans. As commercial software products, GastroPlus™ and Simcyp® were used. In addition, the gastrointestinal unified theoretical framework, a simple and publicly accessible model, was used as a benchmark. The Fa prediction characteristics for a total of 96 clinical Fa data of 27 model drugs were systematically evaluated using the default settings of each software product. The molecular weight, dissociation constant, octanol-water partition coefficient, solubility in biorelevant media, dose, and particle size of model drugs were used as input data. Although the same input parameters were used, GastroPlus™, Simcyp®, and the gastrointestinal unified theoretical framework showed different Fa prediction characteristics depending on the rate-limiting steps of oral drug absorption. The results of the present study would be of great help for the overall progression of physiologically based absorption models.

[A Case of Resected Metachronous Pancreatic Metastasis from Rectal Carcinoma].

A 69-year-old man underwent a Miles operation with D3 lymph node dissection for rectal cancer. The pathological diagnosis was adenocarcinoma(Rb, A, ly2, v3, N2M0P0H0, Stage Ⅲb). Adjuvant chemotherapy was added for 6 months after the rectal resection. Metastasis in the left lung was detected 1 year and 10 months after rectal resection for which large segmental resection was performed. Without the onset of any new lesions, the patient underwent subsequent follow-up examinations. Abdominal CT performed for increased tumor marker levels observed at 6 years and 8 months after rectal resection revealed a mass suggestive of pancreatic ductal adenocarcinoma for which distal pancreatectomy was performed. The pathological diagnosis was metastasis to the pancreas from the rectal cancer as the tumor cells were immunohistochemically negative for cytokeratin 7 and positive for cytokeratin 20. There has been no indication of recurrence for 13 months after the pancreatic surgery. Resectable pancreatic metastasis from colorectal cancer is rarely reported. However, pancreatic resection may result in long-term survival in some cases. Patients that tolerate pancreatectomy and have no metastasis in the other organs should be considered good candidates for pancreatic resection. We present this case with a review of the literature.

[A Case of Cystic Biliary Hamartoma with a Difficult Preoperative Diagnosis].

Intrahepatic bile duct dilatation was detected in a 63-year-old man based on abdominal ultrasonography. The computed tomography and magnetic resonance imaging scans showed an intrahepatic cystic lesion in the hilar bile duct that led to intrahepatic bile duct dilatation. As a result, intraductal papillary neoplasm of the bile duct(IPNB)was suspected. Moreover, the intrahepatic bile duct dilatation was confirmed by endoscopic retrograde cholangiopancreatography(ERCP). Biliary and brushing cytology indicated that the cystic lesion was class Ⅱ and class Ⅲ, respectively. Radiological imaging test did not rule out the possibility of a malignant lesion. Hence, a radical left hepatectomy was performed. Histopathological examination of the resected specimen indicated that it was a non-malignant cystic biliary hamartoma. Cystic biliary hamartoma or the von Meyenburg complex is a relatively rare disease. Although this disease is categorized as benign, differential diagnosis between benign and malignant forms is difficult, and this is an important clinical issue.

[A Case of Superior Mesenteric Vein Thrombosis during Administration of Bevacizumab for Rectal Cancer].

A colonoscopy to investigate fecal incontinence revealed a type 3 tumor in the rectum of a 67-year-old man. Histological findings demonstrated rectal adenocarcinoma. CT revealed multiple metastases in the liver, and the patient was diagnosed as having rectal cancer(Rb, Ant, type 3, T3, N3, M1a[H2], cStage Ⅳa). No intestinal stenosis due to the tumor was found, and chemotherapy(FOLFIRI plus bevacizumab)was initiated. After 5 courses of the chemotherapy, a thrombus was found in the superior mesenteric vein on enhanced CT. The patient had no subjective symptoms, and anticoagulation therapy was started after admission. After confirming the shrinkage of the thrombus, laparoscopic abdominoperineal resection(prxD3)was performed to remove the primary tumor. The thrombus did not grow during the perioperative time and disappeared after 6 months. For the next 2 years, no new thrombus was detected. Mesenteric vein thrombosis is a notable complication of chemotherapy with bevacizumab.

Inhibition of catechol-O-methyltransferase in the cynomolgus monkey by opicapone after acute and repeated administration.

INTRODUCTION: The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose. METHODS: Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics. RESULTS: Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15-25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration. CONCLUSION: Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.

Glycocalyx Shedding is Enhanced by Age and Correlates with Increased Fluid Requirement in Patients with Major Burns.

BACKGROUND: Massive fluid shift after severe burn injury leads to edema and intravascular fluid loss that may result in burn-induced compartment syndrome (BICS) when corrected by aggressive fluid resuscitation. Factors causing this fluid shift remain unclear. Because glycocalyx regulates endothelial permeability, we hypothesized that glycocalyx shedding would increase fluid requirements in burn patients. This prospective cohort study aimed to identify relationships between shedding of the glycocalyx and fluid requirements after burn injury. METHODS: Patients aged more than 18 years with burn injury over more than 20% total body surface area (TBSA) were enrolled. Patient background factors including age, sex, burn size, and inhalation injury were recorded at patient enrollment. Serum syndecan-1, known as a biomarker of glycocalyx shedding, was serially measured on admission, day 1, days 3 to 5, around 1 and 2 weeks, and 1 month after the injury to observe postburn injury kinetics of syndecan-1. As biomarkers of endothelial damage, soluble thrombomodulin, antithrombin III, and plasminogen activator inhibitor-1 were also measured. We determined the relationship between syndecan-1 and initial 24-h fluid requirements and between syndecan-1 and morbidity/mortality. RESULTS: We enrolled 39 patients (median age, 55 years; median burn size, 35%TBSA): 16 developed BICS, and 10 patients died. Syndecan-1 level on admission was significantly higher than that in healthy volunteers and remained so. Syndecan-1 level on admission was associated with patient age (ρ = 0.50, P = 0.001) but not burn size (ρ = 0.08, P = 0.63), and antithrombin III level on admission was negatively associated with burn size (ρ = -0.48, P = 0.002). The syndecan-1 level on admission was significantly associated with fluid requirement (mL/kg) (ρ = 0.38, P = 0.017). After adjustment for age, sex, %TBSA, and inhalation injury, syndecan-1 was an independent parameter for the increase in fluid requirement (P = 0.04) and development of BICS (P = 0.03) by multivariable regression analysis. These findings suggested that glycocalyx shedding increased in an age-dependent manner, whereas antithrombin III decreased according to burn size. CONCLUSIONS: Glycocalyx shedding occurs soon after burn injury in an age-dependent manner. To reduce fluid-related complications such as BICS, new strategies to protect glycocalyx in burn patients are needed.

Acute pancreatitis and necrotizing colitis following extensive burn injury.

Case: We describe a patient with severe pancreatitis and ischemic colitis after extensive burn injury. An 81-year-old man presented with a 55% total body surface area burn with inhalation injury. A low-density area was detected in the pancreas on the abdominal computed tomography scan on admission. The clinical course of the patient was good until 28 days after injury when he complained of abdominal pain and distension. Abdominal computed tomography revealed acute pancreatitis and ischemic colitis. Outcome: The patient died 59 days after burn injury. Conclusions: Extensive burn injury can cause acute pancreatitis. Further work-up is necessary to identify pancreatic complications after severe burn injury.

In vitro metabolism and inhibitory effects of pranlukast in human liver microsomes.

We investigated the metabolism of pranlukast, a selective leukotriene agonist, and the potential for drug-drug interactions. Although cytochrome P450 (CYP) 3A4 appeared to be the major cytochrome P450 isoform involved in the metabolism of pranlukast, the results suggested that pranlukast metabolism was inhibited less than 50% by ketoconazole, a reversible CYP3A4 inhibitor, or by anti-CYP3A4 antibodies. Irreversible macrolide CYP3A4 inhibitors, clarithromycin, erythromycin and roxithromycin, exhibited little effect on pranlukast metabolism. On the other hand, pranlukast reversibly inhibited CYP2C8 and/or 2C9, and CYP3A4, with K(i) values of 3.9 and 4.1 micromol/l, respectively. The [I](in,max,u)/K(i) ratios were 0.004 and 0.003, respectively. The K(i) values were about 300-fold greater than the [I](in,max,u), therefore it is suggested that, at clinical doses, pranlukast will not affect the pharmacokinetics of concomitantly administered drugs that are primarily metabolized by CYP2C8 and/or 2C9 or CYP3A4.

Exclusion of NEU1 and PPGB from candidate genes for a lysosomal storage disease in Japanese Black cattle.

A case of lysosomal storage disease has been reported in a calf of Japanese Black cattle. Lysosomal storage diseases are hereditary diseases caused by deficiency of lysosomal hydrolases. The clinical and pathological features and accumulated substrates of the affected animal indicated a possibility of sialidosis or galactosialidosis caused by deficiency of neuraminidase (NEU1) or protective protein for beta-galactosidase (PPGB). In the present study, we investigated nucleotide sequences of the genes encoding these two proteins to evaluate whether mutation of these genes is involved in this disease. We determined cattle genomic sequences of these two genes by using bovine EST sequences and the nucleotide sequences of all exons of these genes were compared between affected and normal animals. The results showed several nucleotide substitutions, but none of them was a functional mutation or specific to the affected animal. Furthermore, genotyping of the microsatellite markers in the vicinity of these two genes revealed no homozygosity of the chromosomal regions including these genes in the affected animal. These findings indicated that neither NEU1 nor PPGB gene is responsible for the lysosomal storage disease of Japanese Black cattle and therefore the disease is neither sialidosis nor galactosialidosis.

Effect of clarithromycin on the pharmacokinetics of pranlukast in healthy volunteers.

Pranlukast is a cysteinyl leukotriene receptor antagonist that has been used to treat bronchial asthma and allergic rhinitis. In vitro data suggest that pranlukast is a substrate of CYP3A4. Thus, the effect of clarithromycin, a potent CYP3A4 inhibitor, on the pharmacokinetics of pranlukast was examined in an open-label, randomized, two-way crossover study in 16 healthy male volunteers. In treatment A, volunteers received a single, 225 mg dose of pranlukast. In treatment B, 200 mg of clarithromycin was administered twice daily for 7 days and a single, 225 mg dose of pranlukast was coadministered on day 7. Blood samples were collected up to 24 hours after treatment, and pranlukast concentrations in the plasma were measured. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for pranlukast AUC(0-infinity) and C(max) (with/without clarithromycin) were 1.06 (0.91, 1.24) and 1.17 (0.95, 1.45), respectively. In conclusion, clarithromycin and pranlukast could be coadministered without dose adjustment because clarithromycin minimally affected the pharmacokinetics of pranlukast.

Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism.

Chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive disorder characterized by short limbs. Previously, we mapped the locus responsible for the disease on the distal end of bovine chromosome 6. Here, we narrowed the critical region to approximately 2 cM by using linkage analysis, constructed a BAC and YAC contig covering this region, and identified a gene, LIMBIN (LBN), that possessed disease-specific mutations in the affected calves. One mutation was a single nucleotide substitution leading to an activation of a cryptic splicing donor site and the other was a one-base deletion resulting in a frameshift mutation. Strong expression of the Lbn gene was observed in limb buds of developing mouse embryos and in proliferating chondrocytes and bone-forming osteoblasts in long bones. These findings indicate that LBN is responsible for bovine chondrodysplastic dwarfism and has a critical role in a skeletal development.