Effects and risk factors of TAS-102 in real-world patients with metastatic colorectal cancer, EROTAS-R study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an anticancer drug for metastatic colorectal cancer (CRC). This study aimed to analyze the effects and risk factors about effects of TAS-102 in real-world patients with metastatic CRC (the EROTAS-R study). METHODS: This study retrospectively analyzed 271 patients aged ≥ 20 years who underwent TAS-102 for metastatic CRC at nine related institutions from 2014 to 2021. Therapeutic results of TAS-102 + bevacizumab (Bev) and TAS-102, effect predictors, adverse events (AE), and AE predictors were examined. RESULTS: The backgrounds of all cases were as follows: average age, 66.7 ± 10.9 years; male ratio, 59.5%; performance status (PS) 0/1/2, 43.5%/50.6%/5.9%; and tumor site right/left, 25.5%/74.5%. The therapeutic results of 109 cases receiving TAS-102 + Bev and 162 cases receiving TAS-102 were as follows: disease control rate, 53.2% vs. 28.0% (p < 0.01); progressive free survival (PFS), 6.2 vs. 4.2 months (p < 0.01); and overall survival (S), 11.8 vs. 9.3 months (p = 0.03). Multivariate analysis for effect-related factors (odds ratio (OR), 95%confidence interval (CI)) showed the following: PS1 + 2 (0.257, 0.134-0.494, p < 0.01) and a combination of Bev (3.052, 1.598-5.827, p < 0.01). The rates of grade 3 AE for TAS-102 + Bev and TAS-102 were 53.2% and 48.8%, respectively (p = 0.47). Various AE predictors were as follows: male sex (p = 0.69), age ≥ 75 years (p = 0.59), PS1 + 2 (p = 0.20), body surface area < 1.53 m2 (p = 0.26), eGFR < 50 ml/min (p = 0.02), and AST ≥ 50 IU/L (p = 0.64). CONCLUSION: A better OS and PFS comparing TAS-102 + Bev to TAS-102 for CRC was achieved in a large number of real-world patients.

Estimation of the vitamin D (VD) status of pregnant Japanese women based on food intake and VD synthesis by solar UV-B radiation using a questionnaire and UV-B observations.

Although vitamin D (VD; serum 25 hydroxyvitamin D) deficiency (< 20 ng/mL) is widespread among Japanese women, the VD status among pregnant women is unknown. This study aimed to determine the VD status of pregnant Japanese women during different meteorological seasons and to determine the factors controlling VD status. A total of 309 pregnant Japanese women were recruited at 28 weeks of gestation at the gynecology department of a university hospital in Tokyo between August 2018 and October 2019. Blood samples were collected to measure serum 25(OH)D levels. Two questionnaires were completed: a brief self-administered dietary history questionnaire (BDHQ) and an outdoor exposure history questionnaire to determine skin sunlight exposure and the use of sunscreen. Among the recruited subjects, 268 were included in the statistical analysis. The average VD intake from food was 9.0 µg/day, the average VD synthesis from UV-B was 15.2 µg/day, and the average sum of VD intake and nominal VD synthesis was 24.1 µg/day; this exceeded the recommended 2011 Dietary Reference Intake for the USA and Canada (15.0 µg/day). However, the average serum 25(OH)D level (11.4 ng/mL) was very low, indicating widespread VD deficiency. Serum 25(OH)D and VD synthesis by solar UV-B were significantly correlated only during the high UV-B season. The 25(OH)D level was weakly correlated with the VD intake from food in all seasons. We obtained a statistically significant correlation between serum 25(OH)D level and VD intake from food using the BDHQ. We also obtained a statistically significant correlation between the serum 25(OH)D level and VD synthesis from solar UV-B exposure, especially during the high UV-B season. Our logistic regression analysis model predicted VD deficiency in 88.0% of subjects. Our method might be possible to be used to predict the VD status of pregnant Japanese women, although another validation cohort is needed to verify the ability of the estimation equation.

A Case of Streptozocin Monotherapy for Unresectable Duodenal Neuroendocrine Tumor G2.

BACKGROUND: Duodenal neuroendocrine tumors (NET) are rare, and few reports have demonstrated the effectiveness of chemotherapy for duodenal NET, with not many other treatment options available. Here, we present a case of unresectable duodenal NET G2 that was effectively treated with streptozocin (STZ) monotherapy. We also perform a literature review. CASE SUMMARY: A 57-year-old man presented with multiple lymph node metastasis, liver metastasis, and bone metastasis that occurred after the primary resection of the duodenal NET G2. His long-term survival was obtained; the duration of stable disease exceeded 1 year and 6 months following STZ monotherapy. In addition, his CA 19-9 levels, which previously were increasing, normalized following treatment. CONCLUSION: To our knowledge, no study has reported the effectiveness of STZ monotherapy for duodenal NET. Our findings demonstrate that for unresectable duodenal NETs, STZ should be first administered as a high volume/single dose to stabilize the disease. However, if the disease progresses, a combination therapy may be effective in obtaining a long-term prognosis of the patient. Furthermore, CA19-9 levels may be an effective factor for determining the therapeutic effect of STZ in NET with other metastases.

[A case of mature intestinal malrotation with cecal volvulus].

We report an uncommon case of an elderly patient with cecal volvulus caused by intestinal malrotation. We performed lower gastrointestinal endoscopy on an 84-year-old man with a chief complaint of abdominal distention and fever. However, emergency surgery had to be performed because intestinal perforation had occurred. The patient had cecal volvulus associated with incomplete rotation of the intestine. Subsequently, the patient developed multiple organ failure and died 2 days after the surgery. Despite its low incidence, we believe that the possibility of intestinal malrotation should be considered in elderly patients who present with abdominal distention for which the definitive diagnosis cannot be easily obtained.

[A Case of Laparoscopic Whole Layer Cholecystectomy for Elevated Lesion Suspected Biliary Cancer].

A case of attempted laparoscopic cholecystectomy for elevated lesion which was clearly early biliary cancer. Laparoscopic cholecystectomy has become popular as a minimally invasive surgical method, and is the primary choice for benign diseases. However for cases of suspected biliary cancer, open cholecystectomy, rather than laparoscopic, is recommended according to medical guidelines. The reason for this is that in cases of damage to the gallbladder, bile spillage to the abdominal cavity may occur, leading to port site recurrence and peritoneal recurrence. In addition, for invasion depth exceeding ss, or in cases of RAS cancer, the cancer may become exposed on the resected surface and remain. Hypothetically though, if the gallbladder is resected by total layer resection, RAS cancer can be removed. At this time, we performed a laparoscopic whole layer cholecystectomy for elevated lesion. We would like to report this case along with some bibliographic considerations.

[A Two-Stage Right Hemicolectomy Case in Which the First Surgery Was Laparoscopic Ileocecal Resection Based on Preoperative Diagnosis of Acute Appendicitis].

We report a case oftwo -stage right hemicolectomy in which the first surgery performed was laparoscopic ileocecal resection based on the preoperative diagnosis ofacute appendicitis. The second surgery was performed based on pathological diagnosis ofadvanced cecal cancer accompanied by appendicitis. A 49-year-old woman came to our hospital with a chief complaint of abdominal pain in the lower quadrant for 1 week. Blood test results indicated an inflammatory response, with white blood cells at 10,000/mL and C-reactive protein of1 7.5mg/dL. Abdominal computed tomography showed a swollen appendix and increased uptake in adipose tissue around the appendix. The patient was diagnosed with acute appendicitis, and emergency laparoscopic surgery was performed. Because the cecum wall was thickened and formed an inflammatory mass, ileocecal resection was performed. The pathological diagnosis was advanced cecal cancer accompanied by appendicitis, with metastasis to lymph node No. 201; thus, right hemicolectomy and D3 dissection were performed 14 days after the first surgery. No tumor was found in additional resected tissues. The final diagnosis was cecal cancer: adenocarcinoma tub1, SE, N1, M0, Stage III a. The patient received adjuvant chemotherapy with XELOX and remains relapse free. Acute appendicitis is induced by certain mechanisms that cause appendiceal obstruction. Unlike young patients, middle-aged and elderly patients rarely develop acute appendicitis because ofa tumor causing appendiceal obstruction, which often makes preoperative or perioperative diagnosis difficult. The presence of cancer, such as cecal cancer, should be considered when appendicitis is accompanied by severe inflammation in elderly patients.

Regeneration of peritoneum using amniotic membrane to prevent postoperative adhesions.

BACKGROUND/AIMS: Adhesions following intraperitoneal surgery are frequent causes of small bowel obstruction. Attempts to prevent postoperative adhesions have mostly proven disappointing clinically. Currently used by ophthalmologists in ocular surface disorders, amniotic membrane transplantation can reduce inflammation and promote re-epithelization. We used amniotic membrane for facilitating peritoneal regeneration and prevention of adhesions with surgical trauma. METHODOLOGY: 20 rats were randomized in equal number into treatment or control groups. Seven days after operation, the incidence and severity of adhesions were evaluated. Histologic and immunohistochemical analyses were examined at 1, 4, 10 weeks after operation. RESULTS: While severe adhesions were observed after 1 week between the cecum and surrounding organs in the control group, adhesion formation was significantly reduced in the amniotic membrane group. Histologic examination demonstrated that free-floating myofibroblasts in the peritoneal cavity attached to surfaces of amniotic membrane grafts to form a layered structure. Free-floating mesothelial cells were incorporated into the regenerating mesothelium on the myofibroblast layer in 4 weeks, while implanted amniotic membrane grafts were absorbed by 10 weeks. In the amniotic membrane group the cecum appeared nearly normal. CONCLUSIONS: Amniotic membrane grafts reduced intraperitoneal adhesions after surgical trauma, were well absorbed, and served as a substrate for regenerating mesothelium.

Quantitative analysis of tumor-derived methylated RUNX3 sequences in the serum of gastric cancer patients.

PURPOSE AND EXPERIMENTAL DESIGN: Using real-time quantitative methylation-specific PCR (RTQ-MSP), methylated RUNX3 sequences were quantified and the fractional concentrations of circulating tumor DNA in serum were determined, along with peripheral blood cells collected preoperatively, intraoperatively and postoperatively from 65 patients with gastric cancer. RESULTS: RTQ-MSP was sufficiently sensitive to detect RUNX3 methylation. Quantitative MSP data were expressed in terms of the methylation index, which was defined as the relative amount of methylated RUNX3 sequences divided by the concentration of methylated actin. High levels of methylated RUNX3 sequences were detected in the peripheral circulation of 29% (19 of 65) of the gastric cancer patients. The RUNX3 methylation index was concordant with cancer stage, histology, lymphatic and vascular invasion, and was more sensitive than carcinoembryonic antigen (CEA) as a biomarker. Twenty-nine percent (19 out of 65) of preoperative serum samples had methylated RUNX3 sequences, ranging from 5.2 to 1625955 (median quantity=43 m-index, sensitivity 95.5%, specificity 62.5%, AUC 0.8651). After surgical resection, the median RUNX3 methylation index in serum significantly decreased. These results demonstrate the clinical usefulness and effectiveness of peripheral blood RTQ-MSP for detecting and monitoring gastric cancer after treatment. Furthermore, 5 out of the 30 preoperative control samples of benign disease (cases of panperitonitis due to acute appendicitis or cholecystitis) showed transient RUNX3 methylation which decreased after the operation in accordance with recovery. CONCLUSION: Quantification of epigenetic changes in serum RUNX3 methylation using RTQ-MSP is useful for the detection and monitoring of gastric cancer.

Laparoscope-assisted superlow anterior resection combined with inter sphincteric rectal dissection for very low advanced rectal cancers combined with preoperative chemotherapy.

Transanal intersphincteric resection (ISR) has been increasingly used as a surgical treatment for extremely low rectal cancer. We hypothesized that high quality less invasive surgery could be achieved if ISR and laparoscopic surgery were combined. The patient was a 46-year-old male with advanced rectal cancer on the lower rectum adjacent to the dentate line. The patient refused abdomino-perineal resection (APR), so we performed laparoscope-assisted ISR after preoperative chemotherapy. Previous dissection of this patient facilitated the muscle layer-oriented curative dissection, and more importantly, made the subsequent laparoscopic rectal excision effortless. This patient showed favorable recovery including postoperative anal function with no complications or recurrent disease. This procedure is feasible and has favorable short-term results for the radical treatment of very low rectal disease, while preserving anal function. This operative procedure may be appropriate for locally advanced rectal cancers to avoid a permanent colostomy.

Long-term survival of a case with multiple liver metastases from duodenal gastrointestinal stromal tumor drastically reduced by the treatment with imatinib and hepatectomy.

Constitutive activation of KIT receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors (GISTs). But there is little information on whether combination of imatinib mesylate (IM) and surgical treatment can prolong survival in the cases with unresectable multiple liver metastases. We report a case of postoperative recurrence of GIST treated by the tyrosine kinase inhibitor IM and surgical treatment. The initial complete response (CR) to treatment continued for 18 mo, but single liver metastasis showed regrowth in the left hepatic lobe during IM treatment. After partial resection of the recurrent tumor, postoperative course was uneventful and the patient has survived without recurrence for 24 mo. Currently, imatinib is the first-line therapy for non-resectable GISTs, but a single agent therapy often leads to tumor resistance. Even if tolerance to imatinib occurs, a combination of imatinib and surgical treatment can prolong survival in some cases as reported here. However, further studies on a large number of cases of recurrent GIST are necessary to evaluate the effectiveness of IM treatment combined with surgery.

[A long-term survival case with multiple liver metastases from duodenal gastrointestinal stromal tumor that was drastically reduced by the treatment with imatinib].

Constitutive activation of c-kit receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, has been shown in clinical studies to work against such tumors. But there is little information on whether a combination of IM and surgical treatment can prolong survival in a case of unresectable multiple liver metastases. We report a case of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor IM and surgical treatment. Therefore, we discuss some important implications. This 37-year-old Japanese man underwent a pancreaticoduodenectomy for GIST of the duodenum in January 2003. The postoperative course was good at first, but 3 months after the initial operation, MRI showed multiple liver metastases. The patient was treated with 400 mg of IM once daily with only weak liver dysfunction as a side effect. The initial response to treatment of CR continued for 18 months. Currently, IM is the first-line therapy for non-resectable GISTs. As the mechanisms of recurrence and resistance to imatinib in GIST remain unclear, they should be intensively performed in the sight of both clinical and molecular biological viewpoints. Further examination in more cases of recurrent GIST is also necessary to estimate the effectiveness of treatment with IM.

Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells.

OBJECTIVE: Tumor necrosis factor (TNF)-alpha-induced endothelial injury, which is associated with atherosclerosis, is mediated by intracellular reactive oxygen species. Iron is essential for the amplification of oxidative stress. We tested whether TNF-alpha accelerated iron accumulation in vascular endothelium, favoring synthesis of hydroxyl radical. METHODS AND RESULTS: Diverse iron transporters, including iron import proteins (transferrin receptor [TfR] and divalent metal transporter 1 [DMT1]) and an iron export protein (ferroportin 1 [FP1]) coexist in human umbilical endothelial cells (HUVECs). TNF-alpha caused upregulation of TfR and DMT1 and downregulation of FP1, which were demonstrated in mRNA as well as protein levels. These changes in iron transporters were accompanied by accumulation of iron that was both transferrin-dependent and transferrin-independent. Modifications of these mRNAs were regulated post-transcriptionally, and were coordinated with activation of binding activity of iron regulatory protein 1 to the iron responsive element on transporter mRNAs. Using a salicylate trap method, we observed that only simultaneous exposure of endothelial cells to iron and TNF-alpha accelerated hydroxyl radical production. CONCLUSIONS: TNF-alpha could cause intracellular iron sequestration, which may participate importantly in the pathophysiology of atherosclerosis and cardiovascular disease.

Possible involvement of RUNX3 silencing in the peritoneal metastases of gastric cancers.

PURPOSE: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear. We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray. EXPERIMENTAL DESIGN AND RESULTS: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-beta (TGF-beta)-induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of approximately 21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified approximately 28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in the TGF-beta signaling pathway. CONCLUSION: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.

Comparison of cytotoxicity of cysteine and homocysteine for renal epithelial cells.

BACKGROUND: Although the cytotoxic effects of cysteine (Cys) on renal cells have been established, the effects of homocysteine (Hcy), which causes endothelial cell dysfunction, have not been well tested. We compared the direct toxicity of Hcy on renal tubular cells to that of Cys and examined the mechanism of cell toxicity. METHODS: LLC-PK1 cells were incubated with test media containing 500 microM Cys or Hcy in the presence or absence of 100 microM copper. Lactate dehydrogenase release and thiobarbituric acid reactive substance were measured for estimating cytolysis and lipid peroxidation, respectively. The generation of hydrogen peroxide and hydroxyl radical, and the cell redox state were analyzed using the scopoletin method, salicylate-trap method, and glutathione (GSH) content, respectively. Superoxide dismutase, catalase, and vitamin E also were used for clarifying the mechanism of toxicity. RESULTS: In the presence of copper (+ Cu), cytolysis at 16 h was more prominent in cells exposed to Cys than Hcy. In accordance with cytotoxicity, lipid peroxidation at 4 h of incubation, as well as hydrogen peroxide and hydroxyl radical formation in a shorter incubation, were remarkably greater in Cys + Cu than Hcy + Cu. The addition of Hcy, but not Cys, decreased GSH content significantly. CONCLUSION: In the presence of copper, Cys was extraordinarily more cytotoxic to renal cells than Hcy. Cytotoxicity from Hcy may be dependent upon depletion of cellular GSH, while Cys cytotoxicity is primarily dependent upon the generation of reactive oxygen species and lipid peroxidation.

Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer.

Our previous studies suggest that lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer, but potential roles of other members of the RUNX family genes have not yet been reported. We examined the expression of 3 Runt-related (RUNX) genes, RUNX1, RUNX2 and CBFB, in gastric cancer cell lines and primary gastric cancer specimens and compared them to those of RUNX3 reported earlier in conjunction with clinicopathologic factors. Expression of RUNX family genes in 9 gastric cancer cell lines, 56 primary gastric cancer specimens and surrounding normal gastric mucosa were estimated by Northern blot analysis, quantitative RT-PCR and in situ hybridization. Northern blot analysis in gastric cancer cell lines showed downregulation of RUNX1 and RUNX3 in 67% and 78% of the cell lines tested, respectively. The ratio of the average RUNX mRNA/beta-actin mRNA ratio (x10(3)) for RUNX1 was 48.0 +/- 21.1 vs. 21.4 +/- 8.1; RUNX2, 1.1 +/- 0.3 vs. 1.0 +/- 0.2; RUNX3, 9.2 +/- 6.3 vs. 3.1 +/- 1.3 and CBFB, 42.0 +/- 19.4 vs. 21.0 +/- 8.4 (normal vs. tumor, respectively, average +/-SD). The basal RUNX2 expression was very weak, and there was no significant change in gastric cancers. Both RUNX1 and RUNX3 showed remarkable downregulation in 62% and 69%, respectively, of surgically resected specimens compared to surrounding mucosa analyzed by quantitative RT-PCR (p < 0.01). Furthermore, CBFB, the gene encoding the cofactor of RUNX1, -2, -3, was also downregulated in significant fraction (32%, p < 0.05). The percentage of downregulation of RUNX1, RUNX3 and CBFB increased as the cancer stage progressed. Tricostatin A and 5'-azacitidin reactivate RUNX3 expression, but they could not reactivate expression of RUNX1 and CBFBeta in gastric cancer cells, suggesting that the downregulation was due to mechanisms other than methylation of the promoter region. These findings suggest that RUNX1 and CBFBeta in addition to RUNX3 play some roles in gastric cancers and that roles of RUNX gene family in gastric cancer are more widespread and complex than previously realized.

Accumulation of cyanide and thiocyanate in haemodialysis patients.

BACKGROUND: Cyanide is a toxic agent, and its detoxification product, thiocyanate, may be a major pathogenetic substance in uraemia. Recent studies examining the myeloperoxidase(MPO)/thiocyanate system have suggested a link between thiocyanate and atherosclerosis. However, inaccuracies in conventional assays for cyanide and thiocyanate have limited the understanding of their metabolism in haemodialysis (HD) patients. METHODS: We used high-performance liquid chromatography to measure cyanide in erythrocytes and thiocyanate in plasma in 43 HD patients and in a group of 46 healthy controls that included 15 current smokers. To clarify the metabolic conversion of cyanide to thiocyanate in uraemic patients, we also measured cysteine and sulfate. We then used stepwise regression analysis to analyse factors that determine erythrocyte cyanide and plasma thiocyanate. RESULTS: Mean cyanide and thiocyanate were significantly greater in HD patients than in non-smoking controls. However, cyanide was far below lethal concentrations in dialysis patients. Thiocyanate was six to seven times greater in HD patients than in non-smoking controls, and decreases in thiocyanate following dialysis were only 19.3+/-3.5%. Multiple regression analysis showed a positive correlation between cyanide and thiocyanate in controls, but a negative correlation in HD patients. In patients, an inverse relationship between thiocyanate and BUN was also observed. CONCLUSIONS: The elevation of thiocyanate in patients undergoing dialysis probably is secondary to both limited efficiency of HD and deranged metabolism of cyanide and thiocyanate. Because thiocyanate is a preferred substrate for MPO, it may play a role in uraemic complications including cardiovascular events.

[Possible involvement of inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers].

Our previous study using a cDNA microarray demonstrated that positive identification of differently expressed genes among gastric cancer cells involved in peritoneal dissemination could be accomplished. One of these genes with overexpression is inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3). IP3R3 is an intracellular Ca2+ release channel responsible for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned, and their genes have been classified into a family. But the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancers is still unclear. In this study, IP3R3 is overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in gastric cancer cell lines established from primary tumor as well as in normal gastric epithelial cells. IP3R1 and 2 are expressed only weakly or not at all in these cells. The antagonist of IP3R, 2-APB, inhibited cell proliferation and induced apoptosis of gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose dependent manner. Conversely, 2-APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia cell HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells that express IP3R3 mRNA (i.e., pancreatic aciner cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2-APB, may thus be useful for the treatment of gastric cancer, especially for peritoneal dissemination.

[A case of sarcoidosis overlapping with rheumatoid arthritis].

We report the case of a 54-year-old woman who presented on May 28, 2001 with sarcoidosis overlapping with rheumatoid arthritis. She had experienced morning stiffness 2 years previously and was diagnosed as having rheumatoid arthritis. She had been treated with bucillamine and loxoprofen for 3 months. In October 2000, she developed proteinurea. The patient discontinued treatment with bucillamine and loxoprofen. Proteinurea persisted, and the patient's renal function declined. On admission, subcutaneous nodules were palpable in the patient's legs. The patient's serum creatinine and calcium levels were 2.49 mg/dl and 11.6 mg/dl, respectively. Intact-PTH was suppressed, and PTHrP was not elevated. Despite the presence of hypercalcemia, the patient's serum 1 alpha 25(OH)2D3 was not suppressed. Serum ACE and lysozyme levels were elevated beyond the normal ranges. A renal biopsy was performed, and non-caseous epithelioid granuloma was found in the renal interstitium. Based on the histological findings, the patient was diagnosed as having sarcoidosis. Following treatment with prednisolone, the patient's serum calcium levels returned to normal and her renal function improved.

A nitric oxide-generating beta-blocking agent prevents renal injury in the rat remnant kidney model. Comparative study of two beta-blocking drugs, nipradilol and propranolol.

BACKGROUND: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether beta-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis. METHODS: Nipradilol, a beta-blocker with an ONO(2) group (5, 10 or 15 mg/kg/day) and propranolol, a beta-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro-L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U(NOx)) and cyclic GMP (U(cGMP)). RESULTS: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U(NOx) in comparison with the sham-operated rats. Nipradilol increased U(NOx) and U(cGMP) significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U(NOx). The addition of nipradilol increased U(NOx) and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect. CONCLUSION: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The beta-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.