Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good potency and oral activity for the treatment of solid tumors.

Although KRAS protein had been classified as an undruggable target, inhibitors of KRAS G12C mutant protein were recently reported to show clinical efficacy in solid tumors. In our previous report, we identified 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivative (1) as a KRAS G12C inhibitor that covalently binds to Cys12 of KRAS G12C protein. Compound 1 exhibited potent cellular pERK inhibition and cell growth inhibition against a KRAS G12C mutation-positive cell line and showed an antitumor effect on subcutaneous administration in an NCI-H1373 (KRAS G12C mutation-positive cell line) xenograft mouse model in a dose-dependent manner. In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.

α(PS)-γ(Ge) digital anti-coincidence spectroscopy and its application to activity measurement of 225Ac.

Activity of 225Ac was measured by the digital anti-coincidence spectroscopy technique using a 4πα-γ detector configuration, composed of a sandwich type 4π plastic scintillator and Ge detectors. Ultrathin plastic scintillators were used for selective detection of α-particles emitted from 225Ac and its progenies, and the α-counting efficiencies of a 4π plastic scintillation detector for individual nuclides in the decay chain were determined as well. A list-mode multichannel analyzer was employed to record coincidence/anti-coincidence events for off-line analyses. The time difference distribution spectra revealed α-particle emission following 213Po decay without ß-particle interference from 213Bi.

Comprehensive Genome profile testing in head and neck cancer.

OBJECTIVE: Head and neck cancer (HNC) is a tumor occurring in various primary sites with limited chemotherapy options for its treatment. Recently, comprehensive genomic profiling (CGP) testing has become clinically widespread. In this study, we examined the utility of CGP in diagnosing and treating HNC. METHODS: This study included 29 patients with HNC who underwent CGP testing at the Gifu University Hospital between December 2019 and April 2022. We analyzed the types of gene mutations and tumor mutational burden (TMB) based on the CGP results. Squamous cell carcinoma accounted for 55.2%, and other cancers accounted for 44.8%. And we investigated the correlation of prognosis with gene mutations and TMB. RESULTS: Gene mutations were detected in TP53(48.3%), CDKN2A (27.6%), CDKN2B (17.2%), NOTCH1 (17.2%), PIK3CA (17.2%), ARID1A (13.8%), and NF1 (13.8%). TP53, CDKN2A and CDKN2B mutations significantly decreased survival rate in HNC. Five cases (17.2%) were TMB-high and 82.8% were TMB-low. In SCC cases treated with immune checkpoint inhibitors, TMB-high had better Overall survival than TMB-low. And all patients with TMB-high were oropharyngeal cancer. CONCLUSION: Although there were no cases in which effective treatment was actually performed based on the results of CGP, many gene mutations have been detected and several gene mutations correlated with prognosis. Furthermore, TMB can be used as a biomarker to predict the therapeutic effects of immune checkpoint inhibitors in cases of SCC.

An agroecological structure model of compost-soil-plant interactions for sustainable organic farming.

Compost is used worldwide as a soil conditioner for crops, but its functions have still been explored. Here, the omics profiles of carrots were investigated, as a root vegetable plant model, in a field amended with compost fermented with thermophilic Bacillaceae for growth and quality indices. Exposure to compost significantly increased the productivity, antioxidant activity, color, and taste of the carrot root and altered the soil bacterial composition with the levels of characteristic metabolites of the leaf, root, and soil. Based on the data, structural equation modeling (SEM) estimated that amino acids, antioxidant activity, flavonoids and/or carotenoids in plants were optimally linked by exposure to compost. The SEM of the soil estimated that the genus Paenibacillus and nitrogen compounds were optimally involved during exposure. These estimates did not show a contradiction between the whole genomic analysis of compost-derived Paenibacillus isolates and the bioactivity data, inferring the presence of a complex cascade of plant growth-promoting effects and modulation of the nitrogen cycle by the compost itself. These observations have provided information on the qualitative indicators of compost in complex soil-plant interactions and offer a new perspective for chemically independent sustainable agriculture through the efficient use of natural nitrogen.

Nonsurgical Treatment Strategies for Elderly Head and Neck Cancer Patients: An Emerging Subject Worldwide.

Consistent with the increasing rate of head and neck cancers among elderly adults, there has been an increase in the rate of those receiving nonsurgical treatments to maintain their function and quality of life. However, various problems, such as poor tolerance to chemoradiotherapy-related toxicity, are of greater concern in elderly adults than in younger individuals. In this review, we describe adverse events that should be particularly noted in elderly patients and provide an overview of countermeasures in nonsurgical treatments. We mainly focus on cisplatin-based chemoradiotherapy-the primary treatment for head and neck squamous cell carcinoma (HNSCC). Furthermore, we review the molecular targeted drugs and immune checkpoint inhibitors for elderly patients with HNSCC. Although the number of older patients is increasing worldwide, clinical trials aimed at determining the standard of care typically enroll younger or well-conditioned elderly patients. There is still very little evidence for treating elderly HNSCC older patients, and the question of optimal treatment needs to be explored.

Discovery and biological evaluation of 1-{2,7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one derivatives as covalent inhibitors of KRAS G12C with favorable metabolic stability and anti-tumor activity.

RAS protein plays a key role in cellular proliferation and differentiation. RAS gene mutation is a known driver of oncogenic alternation in human cancer. RAS inhibition is an effective therapeutic treatment for solid tumors, but RAS protein has been classified as an undruggable target. Recent reports have demonstrated that a covalent binder to KRAS protein at a mutated cysteine residue (G12C) is effective for the treatment of solid tumors. Here, we report a series of 1-{2,7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one derivatives as potent covalent inhibitors against KRAS G12C identified throughout structural optimization of an acryloyl amine moiety to improve in vitro inhibitory activity. From an X-ray complex structural analysis, the 1-{2,7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one moiety binds in the switch-II pocket of KRAS G12C. Further optimization of the lead compound (5c) led to the successful identification of 1-[7-[6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)amino]quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]prop-2-en-1-one (7b), a potent compound with high metabolic stabilities in human and mouse liver microsomes. Compound 7b showed a dose-dependent antitumor effect on subcutaneous administration in an NCI-H1373 xenograft mouse model.

l-Tryptophan-starved cultivation enhances S-allyl-l-cysteine synthesis in various food-related microorganisms.

S-Allyl-l-cysteine (SAC) has received much interest due to its beneficial effects on human health. To satisfy the increasing demand for SAC, this study aims to develop a valuable culturing method for microbial screening synthesizing SAC from readily available materials. Although tryptophan synthase is a promising enzyme for SAC synthesis, its expression in microorganisms is strictly regulated by environmental l-tryptophan. Thus, we constructed a semisynthetic medium lacking l-tryptophan using casamino acids. This medium successfully enhanced the SAC-synthesizing activity of Lactococcus lactis ssp. cremoris NBRC 100676. In addition, microorganisms with high SAC-synthesizing activity were screened by the same medium. Food-related Klebsiella pneumoniae K-15 and Pantoea agglomerans P-3 were found to have a significantly increased SAC-synthesizing activity. The SAC-producing process established in this study is shorter in duration than the conventional garlic aging method. Furthermore, this study proposes a promising alternative strategy for producing food-grade SAC by microorganisms.

Integrating Incompatible Assay Data Sets with Deep Preference Learning.

A large amount of bioactivity assay data is already accumulated in public databases, but the integration of these data sets for quantitative structure-activity relationship (QSAR) studies is not straightforward due to differences in experimental methods and settings. We present an efficient deep-learning-based approach called Deep Preference Data Integration (DPDI). For integrating outcome variables of different assay types, a surrogate variable is introduced, and a neural network is trained such that the total order induced by the surrogate variable is maximally consistent with given data sets. In a task of predicting efficacy of factor Xa inhibitors, DPDI successfully integrated 2959 molecules distributed in 129 assay data sets. In most of our experiments, data integration improved prediction accuracy strongly in interpolation and extrapolation tasks, indicating that DPDI is an effective tool for QSAR studies.

Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated preclinical models.

BACKGROUND: KRAS is one of the most frequently mutated oncogenes in various cancers, and several novel KRAS G12C direct inhibitors are now in clinical trials. Here, we characterised the anti-tumour efficacy of ASP2453, a novel KRAS G12C inhibitor, in preclinical models of KRAS G12C-mutated cancer. METHODS: We evaluated the in vitro and in vivo activity of ASP2453, alone or in combination with targeted agents and immune checkpoint inhibitors, in KRAS G12C-mutated cancer cells and xenograft models. We also assessed pharmacological differences between ASP2453 and AMG 510, another KRAS G12C inhibitor, using an SPR assay, washout experiments and an AMG 510-resistant xenograft model. RESULTS: ASP2453 potently and selectively inhibited KRAS G12C-mediated growth, KRAS activation and downstream signalling in vitro and in vivo, and improved the anti-tumour effects of targeted agents and immune checkpoint inhibitors. Further, ASP2453 had more rapid binding kinetics to KRAS G12C protein and showed more potent inhibitory effects on KRAS activation and cell proliferation after washout than AMG 510. ASP2453 also induced tumour regression in an AMG 510-resistant xenograft model. CONCLUSIONS: ASP2453 is a potential therapeutic agent for KRAS G12C-mutated cancer. ASP2453 showed efficacy in AMG 510-resistant tumours, even among compounds with the same mode of action.

A Case of Carcinoid Tumors in the Ear Canal With Long-Term Postoperative Follow-Up.

Carcinoid tumors in the ear canal are very rare. In this report, we experienced a case of carcinoid tumor of the ear canal that underwent total tumor resection. This study included a 39-year-old man presented with a chief complaint of right-sided hearing loss. Computed tomography scan showed a shadow from the ear canal to the right tympanic chamber. There were no suspicious findings of metastasis in the cervical lymph nodes or other organs. At the time of surgery, the tumor was simply removed because it was small and there was no adhesive invasion. Postoperatively, the patient has been under observation for 11.5 years without any recurrence. Carcinoid tumors in the ear canal can rarely metastasize or recur after more than 10 years. It is important to follow up with the patient for a long time after surgery, using the Ki-67 index of the removed tissue as a prognostic reference.

Effects of dutasteride in a rat model of chemically induced prostatic inflammation-Potential role of estrogen receptor ß.

BACKGROUND: Dutasteride administration reportedly improves lower urinary tract symptoms in patient with chronic, histologically-identified prostatic inflammation, potentially through estrogen receptor ß (ERß), activation of which has anti-inflammatory effects in the prostate tissue. Therefore, we investigated the effect of dutasteride on intraprostatic inflammatory responses and bladder activity using a rat model of chemically induced prostatic inflammation. METHODS: Male Sprague-Dawley rats at 10 weeks old were used. Prostatic inflammation was induced by 5% formalin injection into ventral lobes of the prostate and saline was injected in the control group (control, n = 5). Rats with prostatic inflammation were divided into dutasteride therapy (dutasteride, n = 5) and placebo groups (placebo, n = 5). Dutasteride was administrated at a dose of 0.5 mg/kg daily from 2 days before induction of prostatic inflammation whereas placebo rats received vehicle only. Twenty-eight days later, cystometry was performed in a conscious condition to measure non-voiding contractions (NVCs), intercontraction intervals (ICI) and postvoid residual volume (RV). After cystometry, the prostate was excised for analysis of messenger RNA (mRNA) expression levels of ERα, ERß, interleukin-1ß (IL-1ß), and IL-18 by quantitative polymerase chain reaction. RESULTS: The mean number of NVCs was significantly greater in placebo group than that of control group without prostatic inflammation (p < .05), and ICI were significantly decreased in placebo group compared with control group (p < .05). On the contrary, there was no significant change in NVCs or ICI between control and dutasteride groups. RV was not significantly different among three groups. Gene expression levels of ERα, IL-1ß, and IL-18 was significantly increased in placebo rats compared with control rats (p < .05), but not significantly different between control and dutasteride rats. On the other hand, the mRNA expression level of ERß was significantly decreased in placebo rats (p < .05), but not in dutasteride rats, compared with control rats. CONCLUSION: Dutasteride treatment improved not only prostatic inflammation evident as increased gene expression levels in IL-1ß and IL-18, but also bladder overactivity shown by increased NVCs during bladder filling. These therapeutic effects were associated with the restored expression of anti-inflammatory ERß. Therefore, dutasteride might be effective via ERß modulation for the treatment of prostatic inflammation in addition to its previously known, anti-androgenic effects on benign prostatic hyperplasia.

Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations.

Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer.

Gastric cancer remains one of the leading causes of cancer death worldwide. Despite intensive investigations of treatments over the past three decades, the poor prognosis of patients with unresectable advanced or recurrent gastric cancer has not significantly changed, and improved therapies are required. Here, we report the identification of an oncogenic mutation in FGFR4 in a human gastric tumour that leads to constitutive activation of its product, FGFR4. The G636C-FGFR4 tyrosine kinase domain mutation was found in 1 of 83 primary human gastric tumours. The G636C mutation increased FGFR4 autophosphorylation, and activated FGFR4 downstream signalling molecules and enhanced anchorage-independent cell growth when expressed in NIH/3T3 cells. 3D-structural analysis and modelling of FGFR4 suggest that G636C destabilizes an auto-inhibitory conformation and stabilizes an active conformation, leading to increased kinase activation. Ba/F3 cell lines expressing the G636C-FGFR4 mutant were significantly more sensitive to ASP5878, a selective FGFR inhibitor, than the control. Oral administration of ASP5878 significantly inhibited the growth of tumours in mice engrafted with G636C-FGFR4/3T3 cells. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncoprotein. These findings support the therapeutic targeting of FGFR4 in gastric cancer.

The long-term prognosis of nephropathy in operated reflux.

OBJECTIVE: To investigate the postoperative long-term prognosis and the factors predicting the renal function of patients with reflux nephropathy. As the serum creatinine (s-Cr) level tends to increase during infancy, the degree of reflux and renal parenchymal damage are thought to be more important factors in pediatric patients than in older patients. MATERIALS AND METHODS: This study examined s-Cr, urinary protein, and blood pressure of patients who underwent anti-reflux surgery 10 years before. It also calculated the postoperative estimated glomerular filtration rate (eGFR) and examined the correlation between the eGFR and preoperative factors (age, gender, number of urinary tract infections [UTIs], primary diagnosis, reflux grade, percentage of dimercaptosuccinic acid uptake, degree of renal parenchymal damage, s-Cr abnormality, proteinuria, and hypertension), and analyzed the factors associated with the long-term prognosis. RESULTS: The study population was 51 infants (37 boys and 14 girls). The mean age of the patients before surgery and at the follow-up examination was 3.41 ± 3.61 and 14.63 ± 3.74 years, respectively. After surgery, the s-Cr, urinary protein, and blood pressure values showed (44.7%, 26.7%, and 18.2%, respectively) were abnormal. The postoperative eGFR was a mean 90.27 ± 20.42 ml/min/1.73 m2 and primary correlated with an older age (P = 0.0361), no UTI at the primary diagnosis (P = 0.0044), reflux grade ≥8 (P = 0.0180), degree of renal parenchymal damage (group ≥2b, P < 0.0001), s-Cr abnormality (P < 0.0001), and proteinuria (P = 0.0001) at baseline. A total of 20 patients had chronic kidney disease (CKD; Fig. 1). The multiple regression analysis of these factors revealed that an older age (P = 0.0021), reflux grade ≥8 (P = 0.0134), and degree of renal parenchymal damage (group ≥2b, P < 0.0001) were significantly associated with the long-term postoperative prognosis of reflux nephropathy. Using these three factors, this study derived a multiple regression equation estimating eGFR in the 10th year after surgery (Fig. 1). DISCUSSION: In this study, severe vesico-ureteral reflux (reflux grade ≥8) and severe renal parenchymal damage (group ≥2b) were associated with a long-term decrease in the eGFR. In particular, renal parenchymal damage was closely correlated with the postoperative eGFR; thus, this was clearly a critical factor. The age at surgery showed a better correlation with the postoperative eGFR in the multiple regression analysis; thus, age was regarded as an independent prognostic factor. CONCLUSIONS: The age, reflux grade, and degree of renal parenchymal damage at baseline were factors that affected the long-term postoperative prognosis of reflux nephropathy. Patients with high-grade reflux and severe renal parenchymal damage were more likely to show a reduced CKD level at 10 years after anti-reflux surgery.

The role of prostaglandin and E series prostaglandin receptor type 4 receptors in the development of bladder overactivity in a rat model of chemically induced prostatic inflammation.

OBJECTIVES: To evaluate, using a rat model of non-bacterial prostatic inflammation, the prostaglandin production and expression profiles of E-series prostaglandin (EP) receptor subtypes, which are reportedly implicated in the development of overactive bladder, in the bladder mucosa, and to investigate the effect of EP receptor type 4 (EP4) blockade on bladder overactivity after prostatic inflammation. METHODS: Male Sprague-Dawley rats were used. Prostatic inflammation was induced by formalin injection (5%; 50 µL per lobe) into the bilateral ventral lobes of the prostate. At 10 days after induction of prostatic inflammation or vehicle injection, bladder tissues from the deeply anaesthetized rats were harvested and separated into mucosal and detrusor layers. Then, prostaglandin E2 (PGE2) concentrations and protein levels of PGE2 receptors (EP1-4) in the bladder mucosa and detrusor were measured by ELISA and Western blotting, respectively. In separate groups of control and formalin-treated rats, awake cystometry was performed to evaluate the changes in bladder activity after prostatic inflammation. In addition, the effect of intravesical administration of a selective EP4 antagonist (ONO-AE3-208; 30 µm) on bladder activity was evaluated in control rats and rats with prostatic inflammation. RESULTS: PGE2 concentration and protein levels of EP4, but not other EP receptor subtypes, in the bladder mucosa and detrusor layers were significantly increased in formalin-injected rats vs vehicle-injected control rats. In cystometry, rats with prostatic inflammation exhibited a significant decrease in intercontraction intervals (ICIs) compared with control rats. Intravesical application of ONO-AE3-208 (30 µm), but not vehicle application, significantly increased ICIs in rats with prostatic inflammation, whereas ONO-AE3-208 at this concentration did not significantly affect any cystometric values in control rats. CONCLUSIONS: Because intravesical administration of an EP4 antagonist effectively improved bladder overactivity after prostatic inflammation, EP4 activation, along with increased PGE2 production in the bladder mucosa, seems to be an important contributing factor to bladder overactivity induced by prostatic inflammation. Thus, blockade of EP4 in the bladder could be a therapeutic approach to male lower urinary tract symptoms attributable to benign prostatic hyperplasia with prostatic inflammation.

Cedar Pollinosis and Mortality: A Population-Based Prospective Cohort Study in Japan.

BACKGROUND: Cedar pollinosis is one of the most prevalent forms of seasonal allergic reaction in Japan. Only one prospective study has examined the association between cedar pollinosis and mortality. Using a symptom-based questionnaire on cedar pollinosis, we investigated the association of cedar pollinosis with all-cause and cause-specific mortality. METHODS: Data came from the Takayama Study, which recruited residents aged ≥35 years in 1992 from Takayama city in Gifu Prefecture, Japan. The current study used information on cedar pollinosis that was obtained from the second survey in 2002. A total of 12,471 persons who were 45-80 years old and had no history of cancer, coronary heart disease, or stroke responded to a questionnaire asking about four symptoms related to cedar pollinosis. Mortality and migration data were obtained throughout the follow-up period up to March 2013. Cox proportional hazard models were used to examine the relation between cedar pollinosis and mortality. RESULTS: A total of 1,276 persons died during follow-up period. Among these, there were 504 neoplasm, 278 cardiovascular, and 181 respiratory deaths. After adjusting for potential confounders, cedar pollinosis was associated with significantly lower all-cause mortality (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95) and respiratory mortality (HR 0.38; 95% CI, 0.18-0.82). There was no significant association between cedar pollinosis and mortality due to neoplasm or cardiovascular disease. CONCLUSIONS: We found an inverse association between cedar pollinosis and the risk of all-cause and respiratory mortality. Further research is needed to elucidate the association between cedar pollinosis and mortality.

The effect of herpes simplex virus vector-mediated gene therapy of protein phosphatase 1α on bladder overactivity and nociception.

AIMS: We studied the effect of herpes simplex virus (HSV) vectors-based gene transfer of protein phosphatase 1α (PP1α) on bladder hypersensitivity in rats. METHODS: Using adult female Sprague-Dawley rats, non-replicating HSV vectors carrying PP1α or green fluorescent protein (GFP) were injected into the bladder wall. At one week after vector inoculation, cystometry and Western blot assay were performed, whereas the other experiments were performed at 2 weeks after vector inoculation. RESULTS: GFP-expressing cells were identified in the bladder as well as in L6/S1 dorsal root ganglia at 14 days. In cystometry, intercontraction intervals (ICI) after resiniferatoxin (RTx; TRPV1 agonist) irrigation was significantly reduced in the PP1α group in comparison with the GFP group. Moreover, RTx-induced freezing behavior events were observed significantly more frequently in the PP1α group than the GFP group. The number of c-Fos positive cells in the L6 spinal dorsal horn was significantly less in the PP1α group than in the GFP group. Western blot assay revealed lower levels of phosphorylated inositol 1, 4, 5-triphosphate receptor (p-IP3 R), and phosphorylated TRPV1 in the PP1α compared with the GFP group. CONCLUSIONS: HSV vectors-mediated PP1α gene therapy may be an alternative treatment modality for cystitis-related hypersensitive bladder condition at least in part via modulation of the IP3 R signaling pathway.

Discovery of N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor.

Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.

Laparoendoscopic single-site nephrectomy for hemodialysis patients with dialysis-related renal tumors.

PURPOSE: The purpose of this study is to assess the efficacy of laparoendoscopic single-site (LESS) nephrectomy in hemodialysis patients, we compared outcomes between LESS nephrectomy and conventional laparoendoscopic nephrectomy in hemodialysis patients with dialysis-related renal tumors. MATERIAL AND METHODS: A total of 16 hemodialysis patients who underwent LESS nephrectomy (LESS-N; n = 8) or conventional laparoendoscopic nephrectomy (C-N; n = 8) between November 2003 and July 2012 were retrospectively evaluated. Outcomes were compared between the two groups. RESULTS: Patient and tumor characteristics were similar between the LESS-N and C-N groups. The mean operative duration was longer in the LESS-N than in the C-N group (231.0 ± 26.7 min versus 188.6 ± 36.4 min; p = .025). The mean estimated blood loss was lower in the LESS-N compared with the C-N group (26.4 ± 14.4 ml versus 65.6 ± 45.2 ml; p = .047). Postoperative complications were observed in three cases, comprising one case of retroperitoneal hematoma in the LESS-N group and one case each of peritoneal hematoma and retroperitoneal abscess in the C-N group. Surgical scarring was minimal in the LESS-N group. CONCLUSIONS: Although there is a little extension of the operating time, LESS nephrectomy in hemodialysis patients is a feasible procedure compared with the conventional method.

Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia.

Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML. Initial kinase studies showed that gilteritinib, a type I tyrosine kinase inhibitor, was highly selective for both FLT3 and AXL while having weak activity against c-KIT. Gilteritinib demonstrated potent inhibitory activity against the internal tandem duplication (FLT3-ITD) and FLT3-D835Y point mutations in cellular assays using MV4-11 and MOLM-13 cells as well as Ba/F3 cells expressing mutated FLT3. Gilteritinib also inhibited FLT3-F691 mutations, although to a lesser degree, in these assays. Furthermore, gilteritinib decreased the phosphorylation levels of FLT3 and its downstream targets in both cellular and animal models. In vivo, gilteritinib was distributed at high levels in xenografted tumors after oral administration. The decreased FLT3 activity and high intratumor distribution of gilteritinib translated to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. No overt toxicity was seen in mouse models treated with gilteritinib. These results indicate that gilteritinib may be an important next-generation FLT3 inhibitor for use in the treatment of FLT3 mutation-positive AML.