[A Case of Advanced Gastric Cancer with Preoperative Liver Metastasis and Postoperative Adrenal Metastasis, That Obtained Long-Term Recurrence-Free Survival after Resection and Chemotherapy].

The case was a 70-year-old man of highly advanced gastric cancer with 2 liver metastases(S3, S8)and pancreatic invasion. Three courses of S-1 plus L-OHP(SOX therapy)were performed, and total gastrectomy and combined resection of the spleen and body and tail of the pancreas and partial resection of the liver S3 and S8 were performed after reduction of primary tumor and liver metastasis. S-1 therapy was continued for 1 year as postoperative adjuvant chemotherapy. Left adrenal metastasis was detected by CT, 1 year and 6 months after the operation. PET-CT revealed no other areas suspected of recurrence, so left adrenalectomy was performed through the retroperitoneal space. Radical resection was not achieved because adhesions and scarring from the previous surgery were severe. Paclitaxel plus Ramucirumab was started and after 10 courses, the disappearance of the tumor shadow was observed on enhanced CT, and PET-CT. Three years and 3 months after the initial surgery and 1 year and 8 months after resection of adrenal metastasis, the patient is alive without recurrence.

[A Case of Repeated Bowel Obstruction Due to Diaphragmatic Hernia after Surgery for Esophagogastric Junction Cancer].

The patient was a 79-year-old man who underwent robot-assisted gastrectomy for esophagogastric junction cancer. pT4aN1M0, pStage ⅢA. Nine months after surgery, he had emergency visit to the hospital due to abdominal pain and vomiting, and contrast CT scan showed a small intestine with poor contrast effect above the left diaphragm. He was diagnosed as a diaphragmatic hernia with small intestinal strangulation and underwent emergency surgery. Under laparotomy, 2 fb hernia orifice were observed on the ventral side of the esophageal hiatus, and a 50 cm jejunum was incarcerated and became necrotic. A partial jejunectomy was performed, and the esophageal hiatus was closed by suturing the stomach with 3-0 absorbable suture. He was discharged from the hospital with good postoperative course. But one month after the operation, the patient was seen in the hospital again with abdominal pain. Under laparotomy, it was found that one suture was dropped off the esophageal hiatus at the previous surgery, and a 100 cm jejunum was incarcerated, which was not necrotic. The hiatal hernia was closed by suturing the stomach and the hiatal hernia with 3-0 non-absorbable suture. Diaphragmatic hernia is a rare late complication of esophagogastric junction cancer.

[A Resected Case of Gallbladder Neuroendocrine Cancer Found as a Liver Mass].

Our patient was a 72-year-old man in whom a liver mass was identified on abdominal ultrasonography at the examination for which he was referred to our hospital. Contrast-enhanced CT showed that the liver mass was a hemangioma with a surrounding AP shunt. Gallbladder wall thickening could not be ruled out as gallbladder cancer; however, a high possibility of adenomyomatosis was considered. EOB-MRI determined that the gallbladder wall thickening was adenomyomatosis and liver mass was a metastatic malignant tumor of unknown primary origin. Our policy was to resect gallbladder adenomyomatosis and the liver tumor for diagnostic purposes. Cholecystectomy plus hepatic S4a subsegmental resection and hepatoduodenal mesenteric lymph node dissection were performed. The histopathological diagnosis was neuroendocrine cancer of the gallbladder. A similar histology of the liver mass suggested continuity from the gallbladder tumor and was considered direct infiltration. Fifteen months after the operation, no recurrence was observed.

[A Case of Rapidly Progressing Colon NEC Treated with Laparoscopic Colectomy and Completely Cured].

We experienced a case of rapidly progressing transverse colon NEC that was treated with laparoscopic right hemispherectomy. A 72-year-old man underwent a follow-up lower gastrointestinal endoscopy at another hospital after a polyp resection. The examination showed a surrounding mass with stenosis of the intestinal tract of the transverse colon. A biopsy led to a diagnosis of poorly differentiated adenocarcinoma. A laparoscopic right hemicolectomy was performed of the transverse colon tumor. He was discharged on postoperative day 13 without complications, and NEC was diagnosed. We decided to administer postoperative adjuvant chemotherapy, starting with cisplatin plus etoposide. Four courses of postoperative adjuvant chemotherapy were completed. Approximately 1 year has passed since the operation, and progress has been observed in the outpatient department without recurrence.

Granuphilin molecularly docks insulin granules to the fusion machinery.

The Rab27a effector granuphilin is specifically localized on insulin granules and is involved in their exocytosis. Here we show that the number of insulin granules morphologically docked to the plasma membrane is markedly reduced in granuphilin-deficient beta cells. Surprisingly, despite the docking defect, the exocytosis of insulin granules in response to a physiological glucose stimulus is significantly augmented, which results in increased glucose tolerance in granuphilin-null mice. The enhanced secretion in mutant beta cells is correlated with a decrease in the formation of the fusion-incompetent syntaxin-1a-Munc18-1 complex, with which granuphilin normally interacts. Furthermore, in contrast to wild-type granuphilin, its mutant that is defective in binding to syntaxin-1a fails to restore granule docking or the protein level of syntaxin-1a in granuphilin-null beta cells. Thus, granuphilin not only is essential for the docking of insulin granules but simultaneously imposes a fusion constraint on them through an interaction with the syntaxin-1a fusion machinery. These findings provide a novel paradigm for the docking machinery in regulated exocytosis.

[An autopsied case of giant small cell carcinoma of the pancreas].

A 58-year-old man who complained of an abdominal tumor was admitted to our hospital. Abdominal CT scan showed that a 15-cm tumor occupied the entire right upper abdomen and that there were ascites and liver metastases. A liver biopsy was performed. The liver biopsy showed a small cell carcinoma pattern, but no definitive origin of the tumor was determined. Considering the extensive peritoneal invasion and multiple liver metastases, he received 2 / courses of cisplatin/etoposide chemotherapy, but his tumor became larger with concomitant abdominal pain and nausea. The patient suddenly died due to multiple organ failure caused by tumor necrosis. The autopsy revealed a pathological diagnosis of primary small cell carcinoma of the pancreas.

Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation.

The monomeric small GTPase Rab27a is specifically localized on both secretory granules and lysosome-related organelles. Although natural mutations of the Rab27a gene in human Griscelli syndrome and in ashen mice cause partial albinism and immunodeficiency reflecting the dysfunction of lysosome-related organelles, phenotypes resulting from the defective exocytosis of secretory granules have not been reported. To explore the roles of Rab27a in secretory granules, we analyzed insulin secretion profiles in ashen mice. Ashen mice showed glucose intolerance after a glucose load without signs of insulin resistance in peripheral tissues or insulin deficiency in the pancreas. Insulin secretion from isolated islets was decreased specifically in response to high glucose concentrations but not other nonphysiological secretagogues such as high K+ concentrations, forskolin, or phorbol ester. Neither the intracellular Ca2+ concentration nor the dynamics of fusion pore opening after glucose stimulation were altered. There were, however, marked reductions in the exocytosis from insulin granules predocked on the plasma membrane and in the replenishment of docked granules during glucose stimulation. These results provide the first genetic evidence to our knowledge for the role of Rab27a in the exocytosis of secretory granules and suggest that the Rab27a/effector system mediates glucose-specific signals for the exocytosis of insulin granules in pancreatic beta cells.

Fever of unknown origin following parathyroidectomy prior to onset of typical polymyalgia rheumatica symptoms: a case report.

Polymyalgia rheumatica (PMR) is a disease commonly seen in elderly individuals, however, the etiology has not been reported. Typical clinical features include bilateral shoulder pain and morning stiffness, while serologic autoantibody test findings are negative. Approximately 40%-50% of affected patients present with low-grade fever, fatigue, and appetite loss, which we often experience in the field of general medicine, and thus, the condition should not be given low priority. However, knowledge regarding such constitutional manifestations is also limited. We encountered an elderly woman with a fever of unknown origin that developed following a parathyroidectomy for a single parathyroid adenoma, after which severe shoulder pain and morning stiffness emerged, leading to a diagnosis of PMR. The fever developed several days prior to appearance of severe pain, which is an uncommon presentation in PMR cases. Our patient had low-grade inflammation without pyrexia prior to the surgery, which might have been an important reason for the accelerated immoderate immune activation leading to PMR induced by surgery in this case. Furthermore, she was infected with the influenza A virus 3 weeks before coming to us. Some reports have suggested a relationship between the influenza virus or vaccine and PMR. It is difficult to conclude regarding the definite trigger in our patient, though the details of this case should be helpful for a better understanding of the disease.

A subset of p23 localized on secretory granules in pancreatic beta-cells.

Proteins on the membrane of secretory granules (SGs) involved in their biogenesis and exocytosis are poorly characterized compared with those of synaptic vesicle in neurons. Thus the secretory granule membrane was prepared from a mouse pancreatic beta-cell line MIN6 by subcellular fractionation, and protein constituents were analyzed by microscale two-dimensional liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Using this proteomics approach, one of the p24 family proteins, p23, was unexpectedly found in the granule fraction, although p24 proteins are generally regarded as functioning in the early secretory pathways between the endoplasmic reticulum and the Golgi apparatus. We further showed that p23 is expressed at high levels in endocrine cells. Furthermore, immunocytochemical analyses of pancreatic beta-cells at the light and electron microscopic levels demonstrated that a significant amount of p23 is localized on the insulin granule membrane, although it is most intensely concentrated at the cis-Golgi compartment as previously shown in non-endocrine cells. These findings suggest that a fraction of p23 enters post-Golgi compartments and may function in the biogenesis and/or quality control of SGs.

[A case of advanced gastric cancer with peritoneal dissemination responding to S-1/CDDP neoadjuvant chemotherapy].

The patient was a 72-year-old male diagnosed with type III poorly-differentiated adenocarcinoma in the lesser curvature by gastric fiberscopy. An abdominal computed tomography (CT) scan showed the thickness of the gastric wall and the enlarged lymph node around the stomach and laparoscopic examination revealed peritoneal dissemination. The patient received neoadjuvant combined chemotherapy with S-1 and CDDP. S-1 (100 mg/day) was orally administered for 3 weeks followed by 2 drug-free weeks as a course, and CDDP (100 mg/body) was administered by intravenous drip on day 8. After the third course, significant tumor reduction was obtained. Total gastrectomy, splenectomy and D2 nodal dissection were performed. Peritoneal dissemination disappeared, and the histological diagnosis revealed complete disappearance of cancer cells in the ascites and no metastasis in all lymph nodes. The patient has now been in good health with no recurrence for 22 months after surgery. The combined neoadjuvant chemotherapy with S-1 and CDDP can be an effective treatment of choice for advanced gastric carcinoma with peritoneal dissemination.

[A case of stage IV advanced gastric cancer responding to TS-1/CDDP neoadjuvant chemotherapy which leads to a pathological complete response].

A 72-year-old male with advanced gastric cancer (cT3N2M0H0P0CY1, cStage IV) was treated with TS-1/CDDP as neoadjuvant chemotherapy. TS-1 (60 mg/m(2)/day) was orally administered for 3 weeks followed by 2 drug free weeks as a course, and CDDP (60 mg/m(2)) was administered by intravenous drip on day 8. After the fourth course,a significant tumor reduction was obtained. Total gastrectomy, splenectomy, and D 2 type nodal dissection were performed. The histological diagnosis revealed complete disappearance of cancer cells in the stomach and all of the lymph nodes, which is a so-called pathological complete response. The patient has now been in good health without a recurrence for 24 months after surgery. This case suggests that neoadjuvant chemotherapy with TS-1/CDDP is a potential regimen for advanced gastric cancer.

[Combined chemotherapy with weekly Paclitaxel and doxifluridine for advanced and recurrent gastric cancers].

We conducted combined therapy of weekly paclitaxel and doxifluridine (5'-DFUR) for 23 cases of advanced and recurrent gastric carcinomas to investigate their efficacy and safety. Subjects included 7 unresectable cases, 5 noncurative resection cases, and 11 recurrent cases. Twenty of the 23 subjects had a history of prior treatment with another anticancer drug. The treatment regime consisted of one course comprising 70 mg/m(2)of paclitaxel weekly for three consecutive weeks followed by one week rest, combined with 800 mg/day of 5'-DFUR orally. Results revealed a response rate of 17.6% (3/17), with 2 cases of CR, 1 case of PR, 10 cases of NC, and 4 cases of PD. One of the CR cases was an unresectable case involving a primary tumor, liver metastasis, and abdominal lymph node metastasis, while the other was a recurrent case involving abdominal lymph node metastasis. The median survival period was 387 days. The one-and two-year survival rates were 52% and 24%, respectively. In terms of adverse effects, there were only single cases of grade 3 leukopenia and grade 3 neutropenia, with no cases of grade 4 hemotoxicity. Both patients could be treated as outpatients. Combination therapy of weekly paclitaxel and 5'-DFUR can be an effective and safe therapy for advanced and recurrent gastric carcinomas.

Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells.

Parathyroid hormone-related protein (PTHrP) increases the content and mRNA level of insulin in a mouse beta-cell line, MIN6, and primary-cultured mouse islets. We examined the mechanism of PTHrP-induced insulin expression. The PTHrP effect was markedly augmented by SB203580, a mitogen-activated protein (MAP) kinase inhibitor, and SB203580 itself increased insulin expression extensively, even without PTHrP. Because SB203580 inhibits both p38 and c-jun NH(2)-terminal kinases (JNKs), we investigated the JNK-specific inhibitor SP600125. SP600125 also increased insulin content and its mRNA level. PTHrP induced dephosphorylation of JNK1/2, and PTHrP-induced insulin expression was blocked by a dominant-negative type JNK-APF. We suspected that dual specificity MAP kinase phosphatases (MKPs) may be involved in the PTHrP-induced insulin expression by inactivating JNK1/2. MIN6 cells contained at least five MKPs, among which only MKP-1 was inducible by PTHrP. PTHrP-induced insulin expression was blocked by the MKP-1 expression inhibitor Ro-31-8220, indicating that the PTHrP effect is mediated by MKP-1. Indeed, adenoviral MKP-1 expression increased insulin expression by decreasing a phosphorylation form of JNKs and a resulting phosphorylated form of c-jun in MIN6 cells. The phosphorylated form of c-jun is known to repress cAMP-dependent insulin gene promoter activity. Thus, MKP-1 controls the insulin expression by downregulating a JNK/c-jun pathway.

Deterministic stochastic resonance in a Rössler oscillator.

We discuss the characteristics of stochastic resonancelike behavior observed in a deterministic system. If a periodically forced Rössler oscillator strays from the phase locking state, it exhibits the intermittent behavior known as phase slips. When the periodic force is modulated by a weak signal, the phase slips synchronize with the weak signal statistically. We numerically demonstrate, in terms of interslip intervals and signal to noise ratio, that the maximum synchronization can be achieved with the optimum intensity of chaotic fluctuations. It is shown that the stochastic resonancelike behavior can be observed regardless of the choice of parameters. The frequency dependence of the signal indicates that there is an optimum frequency for the maximum resonance. The phase slip rate is derived based on the fact that the phase slips are caused by a boundary crisis caused by an unstable-unstable pair bifurcation. The interslip distributions obtained from the derived slip rate and the approximation theory of the time-dependent Poisson process agree with those obtained by numerical simulations. In addition, the maximum enhancement of a weak signal is shown to be achieved by adjusting the chaotic fluctuations even if a signal becomes mixed with noise.

Noise-induced enhancement of fluctuation and spurious synchronization in uncoupled type-I intermittent chaotic systems.

We study the dynamics of a pair of two uncoupled identical type-I intermittent chaotic systems driven by common random forcing. We first observe that the degree of the fluctuation of the local expansion rate of orbits to perturbations of a single system as a function of the noise intensity shows a convex curve and takes its maximum value at a certain noise intensity, whereas the Liapunov exponent itself monotonically increases in this range. Furthermore, it is numerically demonstrated that this nontrivial enhancement of fluctuation causes that two orbits with different initial conditions may synchronize each other after a finite interval of time. As pointed out by Pikovsky [Phys. Lett. A 165, 33 (1992)], since the Liapunov exponent of the present system is positive, the synchronization that we observed is a numerical artifact due to the finite precision of calculations. The spurious noise-induced synchronization in an ensemble of uncoupled type-I intermittent chaotic systems are numerically characterized and the relations between these features and the fluctuation properties of the local expansion rate are also discussed.

Dynamical origin of deterministic stochastic resonance.

We numerically demonstrate stochastic-resonance-like behavior in a deterministic chaotic oscillator system, using a modified Rössler system driven by a sinusoidal external force: intermittent 2 pi phase slips between the system and the external force synchronize with a periodic input signal that weakly modulates the external force in an appropriate parameter range. We show that the dynamical mechanism of this stochastic-resonance-like behavior is explained by a boundary crisis that depends on two bifurcation parameters.

Activin receptor-like kinase 7 suppresses lipolysis to accumulate fat in obesity through downregulation of peroxisome proliferator-activated receptor γ and C/EBPα.

We previously identified a quantitative trait locus for adiposity, non-insulin-dependent diabetes 5 (Nidd5), on mouse chromosome 2. In the current study, we identified the actual genetic alteration at Nidd5 as a nonsense mutation of the Acvr1c gene encoding activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-ß receptors, which results in a COOH-terminal deletion of the kinase domain. We further showed that the ALK7 dysfunction causes increased lipolysis in adipocytes and leads to decreased fat accumulation. Conversely, ALK7 activation inhibits lipolysis by suppressing the expression of adipose lipases. ALK7 and activated Smads repress those lipases by downregulating peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBP) α. Although PPARγ and C/EBPα act as adipogenic transcription factors during adipocyte differentiation, they are lipolytic in sum in differentiated adipocytes and are downregulated by ALK7 in obesity to accumulate fat. Under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. These findings have uncovered a net lipolytic function of PPARγ and C/EBPα in differentiated adipocytes and point to the ALK7-signaling pathway that is activated in obesity as a potential target of medical intervention.

A simple and safe technique for esophagojejunostomy using the hemidouble stapling technique in laparoscopy-assisted total gastrectomy.

In laparoscopy-assisted total gastrectomy, esophagojejunostomy is technically difficult. We describe a safe and simple technique for circular-stapled esophagojejunostomy. After mobilization of the stomach and the esophagus, a semicircumferential esophagotomy is made at the anterior esophageal wall. An anvil of a circular stapling device, secured with a Prolene suture (Ethicon, Inc, Somerville, NJ), is introduced via the esophagotomy. The suture is advanced anteriorly so that the center rod penetrates the esophageal wall. The esophagus is staple transected at this point. The circular-stapled esophagojejunostomy is then performed using the hemidouble stapling technique. Laparoscopy-assisted total gastrectomies were performed in 10 patients with gastric cancers. All patients were completed laparoscopically without any complications. The time of anvil placement was 9 minutes in median. Although a wound infection occurred in 1 patient, there were no major complications. There was no mortality in this series. Esophagojejunostomy using this technique is safe and simple. Its practical value is the elimination of the need for pursestring suture placement.

Multiple benign metastasizing leiomyomas in the pelvic lymph nodes and biceps muscle: report of a case.

A 47-year-old woman with an earlier history of uterine leiomyoma suffered from multiple recurrent tumors in the retroperitoneal lymph nodes and biceps muscle of the right upper arm. The woman with a right lower abdominal tumor was referred to our hospital. An abdominal computed tomography scan revealed two round nodules with well-defined margins in the retroperitoneum in the pelvis, and echography revealed a similar nodule in the biceps of the right upper arm. A biopsy of the abdominal retroperitoneal tumor demonstrated benign metastasizing leiomyoma (BML). An extirpation of the abdominal tumors was therefore performed. After the operation, false climacteric medical treatment was performed for 3 years and no recurrence has since been observed. This is the first reported case of multiple BML in the lymph nodes and muscle occurring simultaneously.

Chromosome 2 locus Nidd5 has a potent effect on adiposity in the TSOD mouse.

We previously reported a quantitative trait locus for body weight, non-insulin-dependent diabetes 5 (Nidd5), on Chromosome 2 in the TSOD (Tsumura, Suzuki, Obese Diabetes) mouse, a model of polygenic obese type 2 diabetes. To find the gene responsible for a specific component of the pathogenesis, we used a marker-assisted selection protocol to produce congenic strains. These mice are designed to carry a control BALB/cA-derived genomic interval and a TSOD background to look for loss of phenotype. One of the strains with the widest congenic interval, D2Mit297-D2Mit304, showed reductions in both body weight and adiposity compared with TSOD mice. The phenotypic analyses of other congenic strains further narrowed the locus in a 9.4-Mb interval between D2Mit433 and D2Mit91, around which numerous loci for body weight and adiposity have been mapped previously. Although the locus showed a relatively modest effect on body weight, it had a major influence on fat mass that explains approximately 60% of the difference in the adipose index between parental TSOD and BALB/cA mice. Furthermore, the congenic strain with a minimal BALB/cA-derived region showed significantly smaller cell sizes of white and brown adipocytes compared with the control littermates. However, the locus did not primarily affect food consumption, general activity, or rectal temperature after cold exposure, although there are clear differences in these traits between the parental strains. The present work physically delineates the major locus for adiposity in the TSOD mouse.