Efficacy of RAD001 (everolimus) against advanced gastric cancer with peritoneal dissemination

Peritoneal dissemination occurs frequently in patients with unresectable advanced-stage gastric cancer. In this study, we tested the efficacy of the mTOR inhibitor RAD001 (everolimus) against advanced gastric cancer with peritoneal dissemination. Using the two cell lines, 58As1, a cell line exhibiting a high propensity for peritoneal metastasis, and its parental cell line, HSC-58, a human scirrhous gastric cancer cell line, we first examined the growth-inhibitory activity of everolimus in vitro. Methylene blue assay demonstrated a moderate inhibitory effect of the drug on both cell lines under normal culture conditions (maximal inhibitory effect: 50.5% at 1 μM, HSC-58, 65.3%, 58As1). However, under the hypoxic condition (1% O₂), while the growth-inhibitory activity of everolimus was greatly reduced in the HSC-58 cell line, the degree of reduction of the inhibitory activity was much smaller in the 58As1 cell line. Western blotting revealed that the degree of phosphorylation of mTOR and its downstream signaling molecules, p70S6K and 4E-BP1, was decreased under hypoxic conditions in HSC-58. On the other hand, phospho-p70S6K and phospho-4E-BP1 remained active under hypoxic conditions in 58As1, the molecular activity was suppressed by everolimus. Cell-cycle analysis showed that hypoxia-induced G1 arrest was not manifested in the 58As1 cells, unlike in the HSC-58 cells. Separately, an in vivo orthotopic mouse model of 58As1 revealed that everolimus significantly reduced peritoneal dissemination as evaluated by the quantitative photon counting method. Taken together, our results suggest that everolimus may have favorable activity against gastric cancer, particularly in cases with peritoneal dissemination.     

Intra-Islet PACAP Protects Pancreatic β-Cells Against Glucotoxicity and Lipotoxicity

Pituitary adenylate cyclase-activating polypeptide (PACAP), a potent insulinotropin, is localized in pancreatic islets. Hyperglycemia and hyperlipidemia impair islet β-cell functions, being recognized as glucotoxicity and lipotoxicity. In this study, we examined whether endogenous PACAP protects islet β-cells against the toxicities. Pancreatic islets were prepared from wild-type and PACAP-null mice, and cultured for 2 days in control conditions containing 5.6 mM glucose, those with elevated 25 mM glucose and those supplemented with 0.4 mM palmitate. After culture in control conditions, a rise in the superfusate glucose concentration from 2.8 mM to a physiologic 8.3 mM increased cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in both wild-type and PACAP-null mouse islets. In contrast, after culture with high glucose or palmitate, the glucose-induced first phase [Ca²⁺]_i increases were severely impaired in islets of PACAP-null mice while they were preserved in islets of wild-type mice. Treatment with high glucose or palmitate also impaired glucose-induced insulin secretion in islets and increased mRNA expression of uncoupling protein 2 (UCP2) in islets of PACAP-null, but not wild-type, mice. These data indicate that islet-produced PACAP protects β-cells from deteriorating action of high glucose and palmitate at least partly by blocking the elevation of UCP2, suggesting an anti-diabetic role for PACAP.     

Clinical course of pain in a patient with neuropathic pain induced by ligation of an intercostal nerve

A patient with severe right chest pain and mechanical allodynia induced by an intercostal drainage tube to his chest is presented. It was not relieved by treatment with diclofenac sodium and was worsened by movement and touch to the right chest wall. Mechanical allodynia was also present. The patient's wrenching pain disappeared immediately after stitch removal, but the dull pain and mechanical allodynia persisted, gradually decreasing to zero in 7 days.     

A comparative study of IgA nephropathy between two institutions in Japan and Korea

As an approach to the geopathological evaluation of kidney disease, we conducted a comparative study on IgA nephropathy (IgANP) between Saga Medical School (SMS) in Japan and Kosin Medical College (KMC) in Korea for the period 1983-1987. The relative incidence of IgANP among primary glomerular diseases was significantly higher (P less than 0.05) at SMS (103 cases of IgANP among 250 cases of primary glomerular diseases, 41.2%) than at KMC (63 cases among 201 cases, 31.3%). Clinical and histological comparisons of the IgANP between the institutions revealed that the SMS series was generally milder than the KMC series. When the renal manifestations at the time of biopsy for all cases with primary glomerular diseases were compared, asymptomatic urinary abnormalities were more commonly found at SMS than at KMC. This suggests that certain differences in medical practice may exist between the two institutions, as follows: 1) the medical checkup system may be more efficient, 2) the accessibility to medical service may be easier, and 3) the biopsy criteria may be more liberal in Japan/SMS than in Korea/KMC. Thus, the real differences in incidence and severity of IgANP between the two institutions could be smaller than those reported here.     

DNA index as a significant indicator of lymph node metastasis and local recurrence of rectal cancer

To confirm the prognostic significance of the DNA index (DI) in cases of rectal cancer, the nuclear DNA content of tumor cells was examined in 184 cases of rectal cancer treated with curative surgery, and the incidence of lymph node metastasis and recurrence of the cancer was analyzed. The incidence of lymph node metastasis was 43.9 percent in cases with aneuploidy (DI above 1.5), being statistically different from the 18.0 percent incidence in cases with diploidy (P <0.001). Although the extent of lymph node metastasis was limited to adjacent lymph nodes in cases with diploidy, distant lymph node metastases were frequent in cases with aneuploidy, especially in those with a DI above 1.5. Furthermore, the incidence of recurrence of cancer, and especially of local recurrence, was significantly higher (P <0.001) in cases with aneuploidy (DI above 1.5) than in cases with diploidy and aneuploidy (DI below 1.4). These findings indicate the significant value of the DNA index for the prediction of lymph node metastasis and local recurrence in patients with rectal cancer.     

Characteristics of Ceftibuten Uptake into Caco-2 Cells

The characteristics of ceftibuten uptake into Caco-2 cells grown in a collagen-coated dish were examined. Ceftibuten showed stereoselective and pH-dependent uptake. The pH-dependency of ceftibuten was more marked than that of cefaclor or cephalexin, but all three antibiotics showed maximal uptake at pH 5.5. Ceftibuten uptake was linear for the initial 1 hr and then reached a plateau. The initial uptake (15 min) was markedly reduced by the addition of 2,4-dinitrophenol or FCCP (a protonophore), or by lowering the incubation temperature. The uptake of ceftibuten into the brush-border membrane vesicles prepared from cultured Caco-2 cells showed an overshoot in the presence of an H⁺-gradient. These findings indicated that the uptake of ceftibuten was energy-dependent, especially H⁺-gradient-dependent. Uptake inhibition by various compounds was compared using Caco-2 cells. Amino acids and a tetrapeptide did not inhibit uptake, whereas di- or tri-peptides were effective inhibitors. These observations suggest that ceftibuten is taken up by a carrier-mediated transport system(s) for dipeptides. Various antibiotics differed in their ability to inhibit uptake, with cyclacillin showing maximum inhibition. Differences in the inhibitory effect may be accounted for by the heterogeneity (multiplicity) of the transport systems.     

Total callosotomy for a case of lissencephaly presenting with West syndrome and generalized seizures

Case report An 11-month-old girl had an onset of oculogyric crisis at 2 months and she presented with epileptic spasms and generalized tonic seizures with series formation at 3 months. Her seizures were medically intractable and her development had gradually regressed after that. MRI showed severe lissencephaly in bilateral hemispheres. Interictal EEG showed hypsarrhythmia periodically and sporadic spike waves in the right hemisphere. The generalized tonic seizures began with bi-frontal polyspikes on EEG. Our diagnosis was lissencephaly presenting with West syndrome and generalized tonic seizures. A total callosotomy was performed at 11 months.Outcome Postoperative frequency of seizures decreased prominently and developmental progression was resumed.Conclusions This case showed that the corpus callosum may play an important role in some types of symptomatic West syndrome. Corpus callosotomy for treating symptomatic West syndrome should be considered as an option after careful selection and consideration of the timing of surgery.     

Morphological changes of the ligamentum flavum as a cause of nerve root compression

The ligamentum flavum is considered to be one of the important causes of radiculopathy in lumbar degenerative disease. Although there have been several reports anatomically examining the positional relationship between the ligamentum flavum and nerve root, there are few reports on ventral observation. The purpose of this study is to clarify the shape of the ligamentum flavum seen ventrally, and to obtain anatomic findings related to nerve root compression. The subjects were 18 adult embalmed cadavers, with an average age of 78 years at the time of death. The ventral shapes of the ligamentum flavum were observed. The relationships between the morphological change of the ligamentum flavum and nerve root compression or radiographic findings were statistically evaluated. Among the shapes of the ligamentum flavum, bulging of the ligament was most frequently observed. Proximal bulging indicates the type with the cranial portion bulging from the subarticular zone to the foraminal zone of the ligamentum flavum. In this type associated with a decrease in disc height, nerve root compression was frequently observed. Thus, we could more realistically grasp the relationship between bulging morphology of the ligamentum flavum and nerve root compression.