Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials.

BACKGROUND: The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. PATIENTS AND METHODS: We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. RESULTS: Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. CONCLUSIONS: Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

BACKGROUND: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance).

BACKGROUND: Observational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown. PATIENTS AND METHODS: We prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards. RESULTS: Patients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status. CONCLUSION: Higher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT00003835.

Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers (CRCs) harbor activating mutations in PIK3CA, making it one of the most frequently mutated genes in CRC. We thus carried out a systematic review and meta-analysis investigating the prognostic significance of PIK3CA mutations in CRC. MATERIALS AND METHODS: Electronic databases were searched from inception through May 2015. We extracted the study characteristics and prognostic data of each eligible study. The hazard ratio (HR) and 95% confidence interval (CI) were derived and pooled using the random-effects Mantel-Haenszel model. RESULTS: Twenty-eight studies enrolling 12 747 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 19 and 10 studies, respectively. Comparing PIK3CA-mutated CRC patients with PIK3CA-wild-type CRC patients, the summary HRs for OS and PFS were 0.96 (95% CI 0.83-1.12) and 1.20 (95% CI 0.98-1.46), respectively. The trim-and-fill, Copas model and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Five studies reported the CRC prognosis for PIK3CA mutations in exons 9 and 20 separately; neither exon 9 mutation nor exon 20 mutation in PIK3CA was significantly associated with patient survival. CONCLUSIONS: Our findings suggest that PIK3CA mutation has the neutral prognostic effects on CRC OS and PFS. Evidence was accumulating for the establishment of CRC survival between PIK3CA mutations and patient-specific clinical or molecular profiles.

A prospective study of plasma inflammatory markers and risk of colorectal cancer in men.

BACKGROUND: Chronic inflammation may mediate risk of colorectal cancer (CRC); however, the association between circulating inflammatory markers and risk of CRC has been inconsistent. METHODS: We prospectively evaluated the association of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and the soluble tumour necrosis factor receptor 2 (sTNFR-2) with incident CRC among 274 cases and 532 matched controls nested in the Health Professionals Follow-up Study. RESULTS: Multivariate relative risk (RR) of CRC comparing the extreme quartiles of plasma IL-6 was 1.54 (95% confidence interval (CI), 0.99-2.40; P(trend)=0.02). However, after excluding cases diagnosed within 2 years of blood draw, this association was not statistically significant (RR=1.26, 95% CI, 0.78-2.05; P(trend)=0.21). In analyses restricted to cases diagnosed at least 2 years after blood draw, the association of IL-6 with CRC appeared to differ by body mass index such that the significantly positive association was only present among lean individuals (P(interaction)=0.03). We did not observe any significant association between CRP or sTNFR-2 and CRC. CONCLUSION: Plasma inflammatory markers are not generally associated with risk of CRC among men. However, the possibility that plasma IL-6 is associated with increased risk of CRC among lean men requires further investigation.

Treatment of giant congenital melanocytic nevi with cultured epithelial autografts: Clinical and histopathological analysis.

INTRODUCTION: Curettage and dermabrasion are effective in the treatment of giant congenital melanocytic nevi (GCMN); however, local infection and hypertrophic scar formation are major issues. Thus, we applied cultured epithelial autografts (CEA) on skin defects after curettage or abrasion of GCMN and assessed the postoperative outcomes. METHODS: Seven nevi lesions of five patients (aged 3 months to 24 years) were treated with CEA after curettage or abrasion with a dermatome or a surgical bar, respectively. We assessed the postoperative outcomes, including CEA take ratio, erosion and/or ulcer formation in the acute phase, hospitalization days, Vancouver scar scale, and color improvement one year after the operation. In addition, a histological evaluation of a skin biopsy was performed over one year after the operation. RESULTS: The CEAs took well on the wound, and the wound surface was mostly epithelized by postoperative day 7 in all cases. While hypertrophic scar formation and slight pigmentation were observed in some lesions, the color was improved in all of the treated lesions. Histopathological examination revealed that the regenerated epidermis had stratified keratinocytes with rete ridges, and the dermal layer without nevus cells regenerated above the remaining dermis layer. CONCLUSIONS: In this study, we found that early epithelialization and regeneration of the dermal layer was achieved after the application of CEA, suggesting that CEA could be an effective option after curettage or abrasion of GCMN.

Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal cancer.

BACKGROUND: AMP-activated protein kinase (AMPK, PRKA) has central roles in cellular metabolic sensing and energy balance homeostasis, and interacts with various pathways (e.g., TP53 (p53), FASN, MTOR and MAPK3/1 (ERK)). AMP-activated protein kinase activation is cytotoxic to cancer cells, supporting AMPK as a tumour suppressor and a potential therapeutic target. However, no study has examined its prognostic role in colorectal cancers. METHODS: Among 718 colon and rectal cancers, phosphorylated AMPK (p-AMPK) and p-MAPK3/1 expression was detected in 409 and 202 tumours, respectively, by immunohistochemistry. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical and tumoral features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. RESULTS: Phosphorylated AMPK expression was not associated with survival among all patients. Notably, prognostic effect of p-AMPK significantly differed by p-MAPK3/1 status (P(interaction)=0.0017). Phosphorylated AMPK expression was associated with superior colorectal cancer-specific survival (adjusted HR 0.42; 95% confidence interval (CI), 0.24-0.74) among p-MAPK3/1-positive cases, but not among p-MAPK3/1-negative cases (adjusted HR 1.22; 95% CI: 0.85-1.75). CONCLUSION: Phosphorylated AMPK expression in colorectal cancer is associated with superior prognosis among p-MAPK3/1-positive cases, but not among p-MAPK3/1-negative cases, suggesting a possible interaction between the AMPK and MAPK pathways influencing tumour behaviour.

Extracorporeal high-pressure therapy (EHPT) for malignant melanoma consisting of simultaneous tumor eradication and autologous dermal substitute preparation.

Surgical resection of skin tumors leads to large defects in surrounding normal tissues, which should be reconstructed thereafter using the patient's own tissues taken from the other site. Our challenge is to solve this problem in dermal malignant melanoma (MM) by a novel process, named extracorporeal high pressure therapy (EHPT), in which the tissue containing tumor is resected and pressurized, and the treated tissue is re-transplant back to the same position as a tumor-free autologous dermal substitute. The key points are complete tumor death and preservation of native extra cellular matrix (ECM) by the hydrostatic pressure. We found that high hydrostatic pressure at 200 MPa for 10 min at room temperature is completely cytocidal against MM cells in suspension form, in monolayer form, and even in the solid tumor form. MM tumor-bearing nude mice were established by injected human MM cells intradermally and treated by EHTP. The denaturation of the dermal extra cellular matrices was so mild that the pressurized skin was well engrafted as tumor free autologous dermal tissues, resulting in the complete eradication of the MM without any unnecessary skin reconstruction surgery. This very simple and short pressing treatment was proved to make the tumor tissue to the transplantable and tumor-free autologous dermal substitute, which can be applicable to the other temporally resectable tissues.

Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.

BACKGROUND: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy. CONCLUSIONS: These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.

Omalizumab is more effective than suplatast tosilate in the treatment of Japanese cedar pollen-induced seasonal allergic rhinitis.

BACKGROUND: Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollens is a major problem in Japan. Omalizumab, a humanized monoclonal anti-IgE antibody, improves symptoms associated with SAR, but a comparative study with an anti-allergy drug has not yet been conducted. OBJECTIVE: To compare the efficacy and safety of omalizumab with suplatast tosilate, a selective T-helper type 2 (Th2) cytokine inhibitor, in patients with Japanese cedar pollen-induced SAR. METHODS: A randomized, double-blind, double-dummy study was conducted in 308 Japanese patients with a history of moderate-to-severe SAR who showed a CAP-RAST value (> or =2+) specifically to Japanese cedar pollens. Patients were treated for 12 weeks with omalizumab plus placebo of suplatast tosilate or suplatast tosilate plus placebo of omalizumab. RESULTS: The mean daily nasal symptom medication scores (sum of the daily nasal symptom severity score and daily nasal rescue medication score) were significantly lower in the omalizumab group than in the suplatast tosilate group during three evaluation periods (P<0.001). The omalizumab group also had significantly lower mean daily nasal severity scores, each of the mean daily nasal and ocular symptom severity scores (sneezing, runny nose, stuffy nose, itchy nose, itchy eyes, watery eyes, and red eyes). Omalizumab reduced rescue medication requirements, and the proportion of days with any rescue medication use in the omalizumab group was significantly lower. Serum-free IgE levels markedly decreased in the omalizumab group and it was associated with clinical efficacy. The adverse reaction profiles were similar between the two groups. The overall incidence of injection site reactions was higher in the omalizumab group than in the suplatast tosilate group, but all these events were of mild degree. No anti-omalizumab antibodies were detected. CONCLUSION: Omalizumab showed significantly greater improvements than suplatast tosilate in the treatment of SAR induced by Japanese cedar pollens.

Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype.

AIMS: Cyclin D1 and cyclin-dependent kinases are commonly activated in colorectal cancer. Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. The aim was to clarify the relationship between cyclin D1, MSI and CIMP. METHODS AND RESULTS: Among 865 colorectal cancers with MSI and CIMP data, 246 tumours (28.4%) showed cyclin D1 overexpression by immunohistochemistry. DNA methylation in p14 and eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) was quantified by real-time polymerase chain reaction (MethyLight). Both MSI-high and CIMP-high were associated with cyclin D1 overexpression (P < 0.0001). After tumours were stratified by MSI and CIMP status, the relationship between MSI-high and cyclin D1 persisted (P < or = 0.02), whereas the relationship between CIMP-high and cyclin D1 did not. Cyclin D1 overexpression was correlated with BRAF mutation (P = 0.0001), p27 loss (P = 0.0007) and p16 loss (P = 0.02), and inversely with p53 expression (P = 0.0002) and p21 loss (P < 0.0001). After stratification by MSI status, the inverse relationship between cyclin D1 and p21 loss still persisted (P < 0.008). CONCLUSIONS: Cyclin D1 activation is associated with MSI and inversely with p21 loss in colorectal cancers. Cyclin D1 may play an important role in the development of MSI-high tumours, independent of CIMP status.

Analysis of disease-dependent sedative profiles of H(1)-antihistamines by large-scale surveillance using the visual analog scale.

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.

Construction of an environmental exposure unit and investigation of the effects of cetirizine hydrochloride on symptoms of cedar pollinosis in Japan.

BACKGROUND: Cedar pollinosis is a widespread seasonal allergy that is unique to Japan. Environmental exposure units (EEU) assist in the development of effective therapeutic and preventive measures because outdoor studies are limited by seasonal variation in pollen exposure. OBJECTIVES: We constructed an EEU to conduct a randomized cross-over double-blind placebo-controlled study of the efficacy of cetirizine (Zyrtec), a second-generation antihistamine. METHODS: The spatial and temporal homogeneity of pollen distribution in the EEU was evaluated by counting the number of pollen grains on petroleum-jelly-smeared glass slides and by real-time pollen monitors. In the clinical study, 20 volunteers with known cedar pollinosis were exposed to pollen for 5 hours, randomly allocated to receive either cetirizine hydrochloride or placebo 30 minutes after exposure. Symptoms and the degree of somnolence were recorded every 30 minutes for 5.5 hours. As a measure of psychomotor performance, the Uchida-Kraepelin test was used to determine work quantity and error rate. RESULTS: The cedar pollen grains were scattered evenly in the exposure room. In the clinical study, symptom scores were elevated in both groups, showing significant symptom induction 30 minutes after exposure. Test drugs were administered 30 minutes after exposure, and 1 hour later patients in the cetirizine hydrochloride group experienced a significant decrease in sneezing, nose-blowing frequency, and nasal congestion compared with the placebo group. There were no significant differences between the 2 groups in terms of subjective somnolence or objective psychomotor performance. CONCLUSION: The first EEU in Japan was used successfully to evaluate cetirizine as a treatment for cedar pollinosis. The results confirmed those from studies in other countries, except for the degree of somnolence, which increased in both groups and may have been related to postprandial sleepiness.

Long-term outcome of renal transplantation in focal glomerulosclerosis.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) has a tendency to recur frequently after kidney transplantation. We evaluated 12 cases to examine the incidence and long-term outcomes of recurrent FSGS. MATERIALS AND METHODS: Twelve patients with renal failure caused by FSGS received kidney allografts from living related donors. Tacrolimus or cyclosporine was used in combination with prednisolone and azathioprine or mycophenolate mofetil. RESULTS: The mean graft survival was 87.4 +/- 46.8 months. The graft survival rates in FSGS recipients were at 1 year, 100%; 5 years, 79.6%; 10 years, 68.2%. Two out of four recipients experienced graft loss due to chronic rejection. The other two out of four recipients with graft loss displayed severe proteinuria diagnosed as recurrence of FSGS. To treat recurrent FSGS, plasma exchange was partially effective to reduce proteinuria. CONCLUSION: Our incidence of recurrent FSGS is 16.7% with graft survivals at 5 and 10 years of 79.6% and 68.2%, respectively. The recurrence of FSGS happened after scheduled reductions in immunosuppressants. Careful observation is required with maintenance of immunosuppression in these patients.

Optimal treatment schedule and antitumor spectrum of 4-carbamoylimidazolium 5-olate (SM-108) in murine tumors.

By designing optimal administration schedules, it was found that 4-carbamoylimidazolium 5-olate (SM-108) showed an excellent antitumor potency against a number of murine tumors. The optimal administration schedule of SM-108 was an intermittent multiple administration, in which the drug was multiply administered to mice at definite intervals of less than 3 hr for about 1 day on Days 1, 5, and 9 following tumor implantation. Although usual daily administration of SM-108 exhibited poor efficacy, the intermittent multiple administration of SM-108 exhibited potent antitumor activity against a wide variety of tumors, such as Ehrlich carcinoma, P388, 6-mercaptopurine-sensitive and -resistant L1210, Lewis lung carcinoma, Colon 26 adenocarcinoma, and Sarcoma 180. Among them, Ehrlich carcinoma showed the most prominent susceptibility to SM-108. With the intermittent multiple administration of SM-108, complete suppression was obtained in both the ascitic and solid forms of this tumor over a wide dose range. The schedule dependency of the antitumor effect of SM-108 described above was reasonably explained by its in vitro growth-inhibitory effects and pharmacokinetics in the mice.

Antitumor activities of newly synthesized 5-carbamoyl-1 H-imidazol-4yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4yl piperonylate.

In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.

High dose of Garcinia cambogia is effective in suppressing fat accumulation in developing male Zucker obese rats, but highly toxic to the testis.

We investigated the ability of Garcinia cambogia extract containing (-)-hydroxycitric acid (HCA) to suppress body fat accumulation in developing male Zucker obese (fa/fa) rats. We also examined histopathologically the safety of its high doses. Diets containing different levels of HCA (0, 10, 51, 102 and 154 mmol/kg diet) were fed to 6-week-old rats for 92 or 93 days. Each diet group was pair-fed to the 154 mmol HCA/kg diet group. Epididymal fat accumulation and histopathological changes in tissues were observed. The highest dose of HCA-containing Garcinia cambogia (154 mmol HCA/kg diet) showed significant suppression of epididymal fat accumulation in developing male Zucker obese rats, compared with the other groups. However, the diets containing 102 mmol HCA/kg diet and higher (778 and 1244 mg HCA/kg BW/d, respectively) caused potent testicular atrophy and toxicity, whereas diets containing 51 mmol HCA/kg diet (389 mg HCA/kg BW/d) or less did not. Accordingly, 51 mmol HCA/kg diet (389 mg HCA/kg BW/d) was deemed to be the no observed adverse effect level (NOAEL).

Improved graft survival in ABO-incompatible living donor kidney transplantation.

INTRODUCTION: We reviewed ABO-incompatible living donor kidney transplantations (LDKT) performed in our institute. PATIENTS: Fourteen ABO-incompatible LDKT were carried out in the first era (September 1990-August 1996) and 13 were in the second era (October 2001-July 2004). All patients were treated with sessions of plasmapheresis before transplantation to reduce antibody titers <1:8. In the second era, those with rebound increase of antibody titers >1:64 after repeated plasmapheresis were not subjected to transplantation. Posttransplantation immunosuppression consisted of cyclosporin, predonisone, azathioprine, gusperimus hydrochloride (DSG), and antilymphocyte globulin (ALG) in the first era, and tacrolimus, mycophenolate mofetil, predonisone, and DSG in the second era. Splenectomy was performed during the transplantation. Anticoagulant therapy was introduced in the second era. RESULTS: One-, 2-, and 5-year graft survival in the first era was 57%, 57%, and 50%, respectively, values that were significantly lower than those of ABO-compatible cases in the same period (n = 101), namely, 1-, 3-, and 5-year graft survival rates 93%, 83%, and 76%, respectively. The main reason for graft and patient losses was infectious complications. In the second era, no recipient suffered a severe infectious complication and 1- and 2-year graft survival rates were both 100%. Four patients in the first era and 1 in the second era experienced a graft rejection episode between 10 days and 14 months after transplantation, but they were successfully treated with steroid pulse therapy. CONCLUSION: Although patients with high blood group antibody titers remain problematic, ABO-incompatible LDKT is an increasingly viable option for patients whose only donor is blood group-incompatible.

Therapeutic drug monitoring of mycophenolic acid in renal transplant recipients.

Immunosuppressive regimens including mycophenolate mofetil (MMF, Cellcept) were used in a renal transplant transplant program since May 2000 including 67 patients in whom it was the primary drug. Acute rejection (AR) occurred in 9 cases (13%) with 1-year graft survival rate of 96.8%. Pharmacokinetic (PK) studies of mycophenolic acid (MPA) were performed in 46 recent patients (total, 127 times). There was no correlation between dose (mg/kg) and blood concentration (AUC0-9: r2= 0.27). AUC0-9 was well correlated with AUC0-4 (r2= 0.91), but not with a single timepoint concentration. MPA AUC0-9 level was significantly higher among the AR-negative group (n = 33; 34.2 +/- 16.8 ng.hr/mL) compared with AR-positive group (n = 3; 28.2 +/- 1.9 ng.hr/mL; P = .04085) over the 2 weeks after transplantation. MPA AUC0-9 level was higher among the adverse event (AE-positive) group (n = 15; 39.2 +/- 22.8 ng.hr/mL) compared with the negative group (n = 21; 30.1 +/- 8.0 ng.hr/mL; P = .08772) within 2 weeks after transplantation. These results suggest the necessity of measuring AUC for therapeutic drug monitoring (TDM) of MMF-containing immunosuppressive therapy. The possible target level of MPA AUC0-9 would be approximately 30 ng.hr/mL using the present immunosuppressive regimen.