BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer: A Case Report.

Metastatic colorectal neuroendocrine carcinoma (NEC) is often treated using a chemotherapy protocol for small-cell lung cancer; however, the prognosis is extremely poor. A 55-year-old woman with BRAF V600E-mutated transverse colon NEC and liver metastases underwent colectomy followed by FOLFOXIRI plus bevacizumab. Consequently, the liver metastases markedly shrank. Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

Efficacy of minocycline hydrochloride aspiration sclerotherapy with additional monoethanolamine oleate aspiration sclerotherapy for symptomatic hepatic cysts.

AIM: Minocycline hydrochloride (MINO) aspiration sclerotherapy (AS) has been widely used for treating hepatic cysts (HC). However, cyst recurrence remains problematic. Information on monoethanolamine oleate (EO) AS, another effective HC treatment, is currently limited. We investigated the efficacy of EO on ineffective MINO treatments, and the relationship between MINO AS and cyst fluid pH. METHODS: A total of 22 cases with symptomatic HC underwent AS with 500 mg of MINO from January 2016 to June 2021. Cyst fluid pH was measured before and after MINO injection. Cyst volume ratio (CVR, %) after 2 weeks was calculated as follows:cyst volume 2 weeks after MINO injection / pre-treatment cyst volume × 100. Treatment was completed if CVR after 2 weeks was ≤35% (MINO-group). For patients with CVR >35%, 2 g of EO was added (MINO/EO-group). Cyst volume ratio was measured every 12 months thereafter. RESULTS: There were no recurrence symptoms in any of the patients during follow-up. Of the 22 cases, 21 had CVR ≤20% after 12 months. The MINO/EO-group (n = 8) tended to have smaller CVRs after 12 months than the MINO-group (n = 14). Cyst volume ratio after 2 weeks was correlated to pH change (p = 0.012) and was larger in patients whose pH decreased by <1.5 (p = 0.015). All adverse events were mild, including in elderly patients. CONCLUSION: Adding EO is an effective and safe treatment for symptomatic HC when MINO AS alone is insufficient. Patients with pH decreases of <1.5 should be considered for additional EO treatment.

[A case of gastric cancer showing a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse events].

The Japanese guidelines for the treatment of gastric cancer recommend nivolumab as third-line chemotherapy for metastatic gastric cancer. We report a case of gastric cancer exhibiting a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse event (irAE). A 64-year-old man with advanced HER2-positive gastric cancer and distant lymph node metastasis received nivolumab as fourth-line therapy. After two courses of nivolumab, the lymph nodes showed progression. However, the treatment was discontinued because of interstitial pneumonia as an irAE. Disease regression was sustained for approximately 11 months without the readministration of nivolumab.

A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer.

BACKGROUND: We evaluated the efficacy and safety of 5-weekly S-1 and cisplatin combined with trastuzumab, a monoclonal antibody against human epidermal growth factor receptor type 2 (HER2) for HER2-positive advanced gastric cancer (AGC). METHODS: This phase II study treatment consisted of S-1 (80-120 mg per day) orally on day 1-21, cisplatin (60 mg/m(2)) intravenously on day 8, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival, progression-free survival (PFS), response rate (RR), and safety. RESULTS: A total 22 patients from seven centers were enrolled. In the 20 patients evaluable for analysis, the 1-year survival rate was 70 % (95 % confidence interval (CI) 49.9-90.1 %), and median survival time, PFS, and RR were 15.3, 7.5 months and 41.2 %, respectively. Major grade 3/4 adverse events were neutropenia (30 %), anorexia (30 %), leukopenia (25 %), fatigue (20 %), and anemia (15 %). CONCLUSIONS: Five-weekly S-1 and cisplatin combined with trastuzumab showed effective with favorable safety profile in patients with HER2-positive AGC.

Treatment of renal anaemia with erythropoiesis-stimulating agents in predialysis chronic kidney disease patients: Haemoglobin profile during the 6 months before initiation of dialysis.

AIM: Erythropoiesis-stimulating agents (ESAs) are all effective for renal anaemia in patients with chronic kidney disease (CKD). However, it was reported that the haemoglobin (Hb) concentration decreases to 8.4 g/dL during the initial phase of dialysis despite treatment with recombinant human erythropoietin (rHuEPO). This study compared Hb at the initiation of dialysis among patients treated with three different ESAs (rHuEPO, darbepoetin alfa [DA], and a continuous erythropoietin receptor activator [CERA]). METHODS: The subjects were 82 CKD patients who started dialysis at Kawashima Hospital between 1 January 2009 and 28 February 2015 and who received only one kind of ESA for at least 6 months before initiation of dialysis. Baseline characteristics and laboratory data at initiation of dialysis were compared among the three groups. Then changes of the Hb, ESA dose, and erythropoiesis resistance index were assessed over time during the 6 months before initiation of dialysis. Differences of Hb at the initiation of dialysis were also assessed. RESULTS: Among the 82 patients, 36 received rHuEPO, 13 received DA, and 33 received CERA. Baseline characteristics and laboratory data of the patients showed no significant differences among the three groups. The monthly Hb decreased gradually during the 6-month period before initiation of dialysis in all three groups. Hb was significantly higher in the CERA group than the rHuEPO group at the initiation of dialysis. CONCLUSION: Long-acting ESAs may be more useful for predialysis patients with CKD because they do not attend hospital frequently, unlike haemodialysis patients.

Vascular access for long-term hemodialysis/hemodiafiltration patients.

PURPOSE: We investigated the characteristics of patients who received long-term hemodialysis/hemodiafiltration (HD/HDF) treatment for over 30 years at our group of hospitals and type of vascular access (VA) used. SUBJECTS AND METHODS: As of August 2014, 950 patients were receiving HD/HDF treatment at one of our hospitals. Of those, we investigated 41 (4.3%) undergoing long-term treatment in regard to their characteristics and VA type. The items subjected to analysis were sex, primary illness, age at time of dialysis initiation, present age, duration (years) of HD/HDF, type of arteriovenous fistula (AVF) and arteriovenous graft (AVG), history of surgery and AVF persistence rate. RESULTS: The subjects consisted of 22 men and 19 women, and their mean HD/HDF duration was 33.4 ± 2.8 years. For primary illness, the majority (n = 31) had chronic glomerulonephritis. The age at time of dialysis initiation was 31.7 ± 7.76 years and present age was 64.5 ± 7.65 years. They had received 3.8 VA surgeries. For present VA type, 23 patients (56.0%) had an AVF and 13 (31.7%) an AVG, while 4 AVF patients (9.7%) had a history of AVG use. One patient (2.4%) had a superficialized artery. The mean HD/HDF duration of the 13 AVG patients was 7 years and the longest was 18 years. AVF persistence rate estimated by the Kaplan-Meier method was 75% at 30 years after dialysis initiation. CONCLUSIONS: The present results suggest that the ratio of patients with AVG increased with prolonged HD/HDF treatment. AVG has a higher probability of complications and lower patency as compared to AVF, thus careful management is needed. On the other hand, AVG contributes more to a good long prognosis, as it offers efficient dialysis. In cases of vascular deterioration due to long-term hemodialysis, it is inevitable to change from AVF to AVG, thus the ratio of AVG patients is expected to increase in cases of long-term HD/HDF.

Reduction or discontinuation of antibiotic prophylaxis in vascular access surgery, tendon sheath incision and PD catheter placement.

PURPOSE: Immune response in dialysis patients is suppressed and these patients are susceptible to bacterial infections. Therefore, minimal use of antibiotics in dialysis patients is recommended to avoid generating drug-resistant bacteria. However, minor surgeries including vascular access surgery, tendon sheath incision and peritoneal dialysis (PD) catheter placement are inevitable in dialysis patients and evidence-based recommendations on the judicious use of antibiotics are not currently available for these procedures. In this study, the optimal antibiotic prophylaxis for minor surgeries was evaluated. METHODS: This is a retrospective study. In dialysis patients at Kawashima Hospital, a three-step reduction of antibiotic use was performed in 651 cases of arteriovenous fistula (AVF) and tendon sheath incision surgeries from July 2009 through October 2012. Moreover, general surgical guidelines-recommended dose of preoperative antibiotics only were used in 532 cases of arteriovenous graft (AVG) and PD catheter placement from January 2010 through October 2012. The surgical site was observed for 2 weeks after the surgery. RESULTS: In only one case of AVF surgery, redness of the skin around the stitches was noticed 5 days after the surgery, which was healed with antibiotics taken orally for 3 days. Neither AVG nor PD catheter placement demonstrated any infection at the surgical site during the 2-week observation period. CONCLUSIONS: Even in dialysis patients, neither pre- nor postoperative antibiotics are necessary for AVF and tendon sheath incision surgeries. AVG and PD catheter placement surgeries require only a small amount of antibiotics preoperatively.

Multicenter, prospective trial of white-light imaging alone versus white-light imaging followed by magnifying endoscopy with narrow-band imaging for the real-time imaging and diagnosis of invasion depth in superficial esophageal squamous cell carcinoma.

BACKGROUND: Magnifying endoscopy with narrow-band imaging (ME-NBI) has been used to estimate the invasion depth of superficial esophageal squamous cell carcinoma (SESCC), but the real diagnostic power of ME-NBI remains unclear because of few prospective studies. OBJECTIVES: To evaluate whether ME-NBI adds additional information to white-light imaging (WLI) for the diagnosis of invasion depth of SESCC. DESIGN: Multicenter, prospective trial using real-time imaging and diagnosis. SETTING: Seven Japanese institutions. PATIENTS: Fifty-five patients with SESCC were enrolled from June 2011 to October 2013, and the results for 49 lesions were analyzed. INTERVENTIONS: Patients underwent primary WLI followed by ME-NBI, and reports of primary WLI (WLI alone) were completed before secondary ME-NBI (WLI followed by ME-NBI). To standardize diagnosis among examiners, this trial was started after achievement of a mean κ value≥.6 among 11 participating endoscopists. MAIN OUTCOME MEASUREMENTS: Diagnosis of invasion depth by each tool was divided into cancer limited to the epithelium and the lamina propria mucosa and cancer invading beyond the muscularis mucosae (≥T1a-MM) and then collated with the final pathologic diagnosis by an independent pathologist blinded to the clinical data. RESULTS: The accuracy of invasion depth in WLI alone and WLI followed by ME-NBI was 71.4% and 65.3% (P=.375), respectively. Sensitivity for ≥T1a-MM was 61.1% for both groups (P=1.000), and specificity for ≥T1a-MM was 77.4% for WLI alone and 67.7% for WLI followed by ME-NBI (P=.375). LIMITATION: Open-label trial. CONCLUSIONS: ME-NBI showed no additional benefit to WLI for diagnosis of invasion depth of SESCC. (University Hospital Network Clinical Trials Registry number: UMIN000005632.).

Coexpression of organic anion-transporting polypeptides 1B3 and multidrug-resistant proteins 2 increases the enhancement effect of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid on hepatocellular carcinoma in magnetic resonance imaging.

AIM: We aimed to elucidate the relationship between the contrast enhancement effect of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) on magnetic resonance imaging (MRI) of hepatocellular carcinomas (HCC) and the expressions of hepatocyte transporters (i.e. organic anion-transporting polypeptide [OATP]1B3, multidrug-resistant protein [MRP]2 and MRP3) and to clarify the characteristics of HCC with an MRI high-contrast enhancement effect. METHODS: We retrospectively examined the relationship between the relative enhancement ratio (RER) of HCC, absolute and relative immunohistochemical staining scores of hepatocyte transporters, and histological differentiation of 22 HCC from 21 patients who had undergone preoperative Gd-EOB-DTPA-enhanced MRI. RESULTS: RER had a significant correlation with OATP1B3 expression according to the absolute and relative scores (P = 0.016 vs 0.0006). The RER of HCC with high OATP1B3 and MRP2 expression levels was higher than that of HCC with low OATP1B3 or MRP2 expression levels (P = 0.0003). The RER of HCC with higher OATP1B3 rates was greater than that of HCC with lower OATP1B3 rates (P = 0.0005). HCC histological differentiation showed a significant correlation with OATP1B3 expression and RER (P = 0.023 vs 0.0095). CONCLUSION: We found that coexpression of OATP1B3 and MRP2 influenced the high contrast enhancement of HCC on MRI.

Survey of the effects of a column for adsorption of ß2-microglobulin in patients with dialysis-related amyloidosis in Japan.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of ß2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of ß2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

The effect of vitamin E-bonded polysulfone membrane dialyzer on a new oxidative lipid marker.

The use of vitamin E-bonded cellulose membrane dialyzers has been reported to cause a decrease in oxidative lipid marker levels (Nakai et al., Ther Apher Dial 14:505-540, 1; Nakai et al., J Jpn Soc Dial Ther 45:1-47, 2; Mashiba et al., Arterioscler Thromb Vasc Biol 21:1801-1808, 3). However, few studies have identified this effect with vitamin E-bonded polysulfone membranes, and no studies report the same effect on alpha (1) antitrypsin-LDL complex, a new oxidative lipid marker. This prompted us to examine the influence of use of VPS-HA vitamin E-bonded polysulfone high-flux membrane dialyzers on this new oxidative lipid marker. The subjects were 17 patients who had been dialyzed with VPS-HA for 12 months. The subjects' baseline characteristics were as follows. Their average age was 65.6 ± 13.1 years, comprising 8 males and 9 females; hemodialysis vintage was 83.8 ± 85.4 months. Eight had chronic glomerular nephropathy and five had diabetic nephropathy. The primary outcome was defined as alpha (1) antitrypsin-LDL complex level after 12 months, as a post-study using VPS-HA. Secondary outcomes included triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol levels. The data were analyzed pre-study and after 3, 6, 9 and 12 months for alpha (1) antitrypsin-LDL complex, and pre-study and post-study for the other indicators. Twelve months after switching to VPS-HA, alpha (1) antitrypsin-LDL complex, total cholesterol and LDL cholesterol had significantly decreased. Triglycerides and HDL cholesterol had not significantly changed. Hemodialysis therapy with VPS-HA was shown to decrease alpha (1) antitrypsin-LDL complex, an index of oxidative stress, and also to decrease some lipid markers.

An overview of regular dialysis treatment in Japan (as of 31 December 2010).

A nationwide statistical survey of 4226 dialysis facilities was conducted at the end of 2010, and 4166 facilities (98.6%) responded. The number of new patients introduced into dialysis was 37,512 in 2010. This number has decreased for two consecutive years since it peaked in 2008. The number of patients who died in 2010 was 28,882, which has been increasing every year. The number of patients undergoing dialysis at the end of 2010 was 298,252, which is an increase of 7591 (2.6%) compared with that at the end of 2009. The number of dialysis patients per million at the end of 2010 was 2329.1. The crude death rate of dialysis patients in 2010 was 9.8%, and has been gradually increasing. The mean age of the new patients introduced into dialysis was 67.8 years and the mean age of the entire dialysis patient population was 66.2 years. Regarding the primary disease of the new patients introduced into dialysis, the percentage of patients with diabetic nephropathy was 43.6%, which is a slight decrease from that in the previous year (44.5%). Patients with diabetic nephropathy as the primary disease accounted for 35.9% of the entire dialysis patient population, which approaches the percentage of patients with chronic glomerulonephritis as the primary disease (36.2%). The percentage of patients who had undergone carpal tunnel release surgery (CTx) was 4.3%, which is a slight decrease from that at the end of 1999 (5.5%). The decrease in the percentage of patients who had undergone CTx was significant among the patients with dialysis durations of 20-24 years (1999, 48.0%; 2010, 23.2%). A total weekly Kt/V attributable to peritoneal dialysis and their residual functional kidney was 1.7 or higher for 59.4% of patients who underwent peritoneal dialysis.

[A case of malignant tumor of the ascending part of duodenum with osteoclast-like giant cells].

Extraskeletal neoplasms with osteoclast-like giant cells are very rare. These tumors are most frequently reported in the breast and pancreas, and but rarely in other sites. We report a case of duodenal malignant tumor with osteoclast-like giant cells. The patient was a 76-year-old man who presented with vomiting. Computed tomography, magnetic resonance imaging, and gastrointestinal endoscopy revealed a giant tumor in the ascending part of duodenum. Biopsy specimens showed an undifferentiated malignant tumor with benign multinucleated giant cells. Immunohistochemical staining indicated that the tumor cells were reactive with vimentin, but not with epithelial markers or the other mesenchymal markers, and the multinucleated giant cells were reactive with CD68. Thus, we diagnosed a malignant tumor of the ascending part of duodenum with osteoclast-like giant cells. To the best of our knowledge, this is the first case of duodenal malignant tumor with osteoclast-like giant cells in Japan.

Effect of large-size dialysis membrane and hemofiltration/hemodiafiltration methods on long-term dialysis patients.

Over 2,000 substances have been reported as uremic substances that are accumulated or produced due to renal failure that causes various clinical symptoms and complications. These substances include many medium to large molecular weight (MW) substances such as ß(2)-microglobulin (ß(2)-MG). In hemofiltration/hemodiafiltration (HD/HDF) therapy using high-performance membrane targeting less albumin loss and removal of ß(2)-MG with a MW of 11,800, many cases showed insufficient improvement in the clinical outcome contrary to the decrease in serum ß(2)-MG concentration. Focusing on these facts, HD/HDF therapy, which associates albumin loss, was implemented targeting the substances in the regions whose MWs are larger than ß(2)-MG. HD/HDF therapy with protein-permeable membrane, compared to the therapy without protein-permeable membrane, achieved higher success in the removal of larger MW substances including ß(2)-MG, cytokine, homocysteine and complement factor D, and higher clinical outcomes were reported, such as prevention of development of amyloidosis, anemia, osteoarthritis and pruritus, and improvement in life prognosis and biocompatibility in Japan. Therefore, in the current circumstances, it is essential to administer a treatment that can get as close to the glomerular basement membrane as possible, use dialysis membrane to effectively remove a wide range of substances, and aim to remove all of the substances accumulated in the body of patients with kidney dysfunction.

Blood purification for critical illness: cytokines adsorption therapy.

Blood purification therapies have been clinically applied to treat cytokine-induced pathological effects. The effects of broad-spectrum adsorption using Lixelle (beta2-microglobulin adsorption column; Kaneka Corporation, Osaka, Japan) for the condition of hypercytokinemia in vitro, in an animal model and in humans with sepsis were investigated. We found that Lixelle could selectively adsorb not only beta2-microglobulin but also cytokines composed of glycoproteins in vitro. In addition, Lixelle beads could adsorb not only endotoxin (ET) but also microbial fragments such as peptidoglycan (PG) which is a component of Gram-positive bacteria. Hypercytokinemic rats were connected to a direct hemoperfusion (DHP) system using a mini Lixelle column and time-course changes in plasma levels of inflammatory cytokines were examined. In addition, a Lixelle column was used in direct hemoperfusion in patients with systemic inflammatory response syndrome (SIRS), and the relationship between a decrease in cytokines and clinical course was examined. The increases in plasma levels of IL-6 and tumor necrosis factor-alpha (TNF-alpha) were significantly inhibited in the group treated with the Lixelle column in an animal model. In humans with sepsis, for IL-1beta, IL-1Ra, IL-6, IL-8, and TNF-alpha, the adsorbing rates in vivo before and after the use of the Lixelle column tended to decrease with time. However, the reduction rates at 5 min after the start were 31.4, 39.3, 36.4, 76.2 and 71.6%, respectively, and at 3 h after the start, the rates were 18.0, 17.7, 12.9, 31.8, and 32.9%, respectively. Clinically, their blood pressure increased and they recovered from shock status. These results suggest that SIRS and sepsis with hypercytokinemia can be treated with the DHP using the Lixelle column.

[Relationship between cyclooxygenase (COX)-2 and malignant tumors].

Recently, epidemiologic studies and animal experiments have demonstrated that nonsteroidal anti-inflammatory drugs(NSAIDs) reduce the incidence of colorectal carcinoma. Cyclooxygenase(COX) is the principal target of NSAIDs. COX is the first oxidase in the process of prostaglandins(PGs) production from arachidonic acid(AA). PGs and COX enzyme may be involved in the initiation and/or the promotion of carcinogenesis because the major action of NSAIDs is the inhibition of COX. In this review, we demonstrated the expression of COX-2 in urological cancer(renal cell carcinoma, bladder tumor, prostate cancer, and testicular tumor) tissues as well as the effects of COX inhibitors.

5-Lipoxygenase inhibitors attenuate growth of human renal cell carcinoma and induce apoptosis through arachidonic acid pathway.

The metabolism of arachidonic acid by either the cyclooxygenase or lipoxygenase (LOX) pathway is believed to play an important role in tumor promotion. We investigated the expression of 5- and 12-LOX in renal cell carcinoma (RCC), as well as the effects of their inhibitors on cell proliferation in 2 RCC cell lines (Caki-1 and A498). Expression of 5- and 12-LOX was detected by immunohistochemistry and RT-PCR. Effects of LOX inhibitors on RCC cell growth were examined by MTT assay, and Hoechst staining was used to determine whether or not the LOX inhibitors induce apoptosis. While 5- and 12-LOX expression levels were slightly detected in NK tissues, marked expressions of 5- and 12-LOX were detected in RCC tissues. 5-LOX inhibitors caused marked reduction of RCC cells in a concentration- and time-dependent manner. The effect of the 5-LOX inhibitor was stronger than the 12-LOX inhibitor. Furthermore, the 5-LOX inhibitor caused a marked reduction of RCC cells through apoptosis. LOX, especially 5-LOX, is induced in RCC, and the results suggest that the 5-LOX inhibitor may mediate potent anti-proliferative effects against RCC cells. Thus, 5-LOX may become a new target in treatment of RCC.

Influence of glucose and inflammatory cytokines on TGF-beta1 and CTGF mRNA expressions in human peritoneal mesothelial cells.

Peritoneal fibrosis is a major complication of long-term continuous ambulatory peritoneal dialysis (CAPD) treatment. Transforming growth factor-beta (TGF-beta) has been reported to play an important role in the fibrosis of various tissues by stimulating connective tissue growth factor (CTGF) expression. In order to elucidate the mechanism of CAPD-related peritoneal fibrosis, we studied the influence of high glucose concentrations and inflammatory cytokines on mRNA expressions of TGF-beta and CTGF in cultured human peritoneal mesothelial cells (HPMC). HPMC were isolated from normal omentum and cultured with 0.5 or 1.0% glucose or mannitol for 7 days. TGF-beta1 and CTGF mRNA were quantified by one step real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). TGF-beta1 and CTGF mRNA expression levels were significantly increased (p<0.05) by glucose in a dose-dependent manner, but not by mannitol. The expression levels were correlated between TGF-beta1 and CTGF. Effects of inflammatory cytokines were also examined by adding tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or interleukin-6 (IL-6) to the medium at 0.1 ng/ml for 2 days. TGF-beta1 expression tended to be increased by TNF-alpha and IL-6. On the other hand, CTGF expression was significantly decreased (p<0.01) by IL-1 but not changed by TNF-alpha or IL-6. These results suggest that high glucose concentration may play a central role in peritoneal fibrosis. Responses of TGF-beta1 and CTGF to inflammatory cytokines were not necessarily identical, suggesting that CTGF may be a better therapeutic target for peritoneal fibrosis than TGF-beta1.

Markers in peritoneal effluent for withdrawal from peritoneal dialysis: multicenter prospective study in Japan.

The most serious problem in peritoneal dialysis (PD) is the risk of final complication by encapsulating peritoneal sclerosis (EPS) because of peritoneal deterioration. Markers useful for the noninvasive evaluation ofperitoneal deterioration are therefore required. In this multicenter prospective study of stable PD patients, we compared the dialysate-to-plasma (D/P) concentration ratios of albumin, immunoglobulin G, and c2-macroglobulin, and effluent levels of interleukin 6 (IL-6) and fibrinogen/fibrin degradation products (FDPs) to clarify the relationship between inflammation, fibrinolysis markers, and permeability to large molecules. At the beginning of the present study, significantly positive correlations were noted between the IL-6 and FDP concentrations and the D/P ratios of albumin and a2-macroglobulin. In addition, a significantly positive correlation was noted between the FDP and IL-6 concentrations. However, the D/P ratio of creatinine obtained by peritoneal equilibration test did not positively correlate with those markers. Moreover, a significantly positive correlation was noted between changes in the effluent concentrations of FDPs and IL-6 and in permeability markers for large molecules. The effluent IL-6 and FDP concentrations reflect a chronic inflammatory state in the peritoneum, which is associated with increased permeability to large molecules. In individual PD patients, careful observation of the clinical course and evaluation of changes in such markers are expected to predict peritoneal deterioration and the development of EPS.