Impact of Tumor Grade Distribution on Genetic Alterations in Clear Cell Renal Cell Carcinoma and Prostate Cancer.

BACKGROUND/AIM: A genomic analysis based on next-generation sequencing is important for deciding cancer treatment strategies. Cancer tissue sometimes displays intratumor heterogeneity and a pathologic specimen may contain more than two tumor grades. Although tumor grades are very important for the cancer prognosis, the impact of higher tumor grade distribution in a specimen used for a genomic analysis is unknown. PATIENTS AND METHODS: We retrospectively analyzed the data of 61 clear cell carcinoma and 46 prostate cancer patients that were diagnosed between December 2018 and August 2022 using the GeneRead Human Comprehensive Cancer Panel or SureSelect PrePool custom Tier2. Genome annotation and curation were performed using the GenomeJack software. RESULTS: Tumor mutation burden (TMB) was increased in proportion to the higher tumor grade distribution in grade 2 clear cell renal cell carcinoma (ccRCC). In PC, Grade Group 3/4 specimens that included an increased distribution of Gleason pattern 4 had more frequent gene mutations. CONCLUSION: Our results suggest the importance of selecting the maximum distribution of higher tumor grade areas to obtain results on the precise gene alterations for genomics-focused treatments.

Evaluation of the Microbiological Efficacy of a Single 2-Gram Dose of Extended-Release Azithromycin by Population Pharmacokinetics and Simulation in Japanese Patients with Gonococcal Urethritis.

The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the Neisseria gonorrhoeae isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated N. gonorrhoeae in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an N. gonorrhoeae eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain.

Postoperative infectious complications in patients undergoing holmium laser enucleation of the prostate: Risk factors and microbiological analysis.

OBJECTIVES: To examine the incidence of postoperative bacteriuria and febrile complications, and to investigate bacterial strains in the urine of patients undergoing holmium laser enucleation of the prostate. METHODS: We retrospectively analyzed 190 evaluable patients treated with holmium laser enucleation of the prostate at the Gifu University Hospital, Gifu, Japan, between September 2005 and May 2014. All patients presented with lower urinary tract symptoms as a result of benign prostatic hyperplasia. We also evaluated the causative bacteria and compared the findings with the results of preoperative urine cultures. We analyzed the relationship between the emergence of postoperative febrile complications, antibiotic prophylaxis, patient background and surgical procedure. RESULTS: The frequency of bacterial isolation in preoperative and postoperative urine cultures was 41% and 23%, respectively. Preoperatively, Enterococcus faecalis was the most frequently cultured bacteria, second was methicillin-resistant Staphylococcus epidermidis, and third was Escherichia coli. Postoperatively, Enterococcus faecalis was still the most frequently cultured bacteria, whereas the second was Escherichia coli. Risk factors for postoperative bacteriuria were evaluated. Multivariate analysis showed that the rate of postoperative bacteriuria in patients who had taken dutasteride preoperatively was significantly lower than that in the other patients. Risk factors for febrile complications could not be identified. CONCLUSIONS: The use of perioperative prophylactic antibacterial agents for holmium laser enucleation of the prostate keeps the rate of postoperative infectious complications low. Dutasteride treatment administered before surgery might reduce the risk of postoperative bacteriuria.

[Three Patients with Acute Myocardial Infarction Associated with Targeted Therapy of Sorafenib for Metastatic Renal Cell Carcinoma : Case Report].

Sorafenib is a tyrosine kinase inhibitor (TKI) of the vascular endothelial growth factor receptor (VEGFR) used for advanced renal cell carcinoma. Treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal cell carcinoma. However, in spite of its therapeutic efficacy, sorafenib causes a wide range of adverse events. Cardiovascular adverse events have been observed when sorafenib was used with targeted agents. Although these adverse events like hypertension, reduced left ventricular ejection fraction, cardiac ischemia or infarction were manageable with standard medical therapies in most cases, some had a poor clinical outcome. We report three cases of acute myocardial infarction associated with sorafenib in patients with metastatic renal cell carcinoma.

[Study of tolerability of capecitabine in postoperative adjuvant chemotherapy in colon cancer].

OBJECTIVE: Based on the results of the X-ACT study, capecitabine has become one of the standard postoperative adjuvant chemotherapies for colon cancer. However, few studies of tolerability have been conducted in Japan. METHOD: In this study, we retrospectively examined treatment continuation, and the adverse events that occurred during eight courses of postoperative adjuvant chemotherapy with capecitabine, in 34 patients with colon cancer who had undergone curative resection. RESULT: The completion rate for eight courses of treatment with capecitabine was 79. 4%(27 of 34 subjects), the median relative dose intensity was 94. 4%(13% to 106%), and the proportion of subjects with relative dose intensity B 60% was 82. 4%(28 of 34 subjects). The following Grade 3 or higher adverse events were reported: hand-foot syndrome, in 11. 8%(4 of 34 subjects); mucositis oral, in 2. 9%(1 of 34 subjects); diarrhea, in 2. 9%(1 of 34 subjects); and glans penis ulcer, in 2. 9%(1 of 34 subjects). CONCLUSION: In our hospital, a high rate of capecitabine treatment continuation comparable to that reported in the X-ACT study was obtained, suggesting that capecitabine adjuvant chemotherapy would be well tolerated in clinical practice as well.

Antimicrobial chemotherapy of Mycoplasma genitalium-positive non-gonococcal urethritis.

Mycoplasma genitalium is an important pathogen of acute non-gonococcal urethritis (NGU) in men and plays a significant role in persistent or recurrent NGU. In the management of patients with M. genitalium-positive NGU, eradication of the mycoplasma from the urethra is necessary to prevent persistent or recurrent NGU. Therefore, M. genitalium should be considered for antimicrobial chemotherapy of NGU. This article reviews the in vitro antimicrobial activities of antibiotics against M. genitalium and the efficacies of various antibiotic regimens against M. genitalium-positive NGU, including the doxycycline and azithromycin regimens recommended as first-line treatments for NGU in the guidelines. Selection of macrolide-resistant M. genitalium by treatment with the single-dose regimen of 1-g azithromycin and mechanisms of macrolide resistance in M. genitalium are discussed. The effectiveness of the moxifloxacin regimen against persistent or recurrent NGU, unsuccessfully treated with azithromycin and/or doxycycline regimens, is emphasized.

Selection of Mycoplasma genitalium strains harbouring macrolide resistance-associated 23S rRNA mutations by treatment with a single 1 g dose of azithromycin.

OBJECTIVE: A single 1 g dose regimen of azithromycin has been recommended for the treatment of Mycoplasma genitalium infections. The authors evaluated whether this regimen could select M genitalium strains with macrolide resistance after treatment for M genitalium-positive non-gonococcal urethritis. METHODS: In seven men with non-gonococcal urethritis, who were infected with M genitalium without macrolide resistance-associated mutations but experienced microbiological azithromycin treatment failure, M genitalium DNAs in their post-treatment urine specimens were examined for mutations in the 23S rRNA gene and the ribosomal protein genes of L4 and L22. To assess the relatedness of M genitalium strains before and after treatment, their DNAs in pretreatment and post-treatment urine were genotyped by analysing short tandem repeats of an AGT/AAT unit in the MG309 gene and single nucleotide polymorphisms in the MG191 gene. RESULTS: In four of seven patients, M genitalium in post-treatment urine had an A-to-G transition at nucleotide position 2071 or 2072, corresponding to 2058 or 2059 in the 23S rRNA gene of Escherichia coli. In one of the four strains, Pro81Ser in the ribosomal protein L4 accompanied the mutation in the 23S rRNA gene. The genotyping of M genitalium DNAs suggested that these four post-treatment strains were selected from the respective closely related or identical pretreatment strains without macrolide resistance-associated mutations by the treatment. CONCLUSIONS: The single 1 g dose treatment of azithromycin could select M genitalium strains harbouring macrolide resistance-associated mutations. For M genitalium, this regimen might increase the risk of macrolide resistance selection after treatment.

In vitro activity of azithromycin against Mycoplasma genitalium and its efficacy in the treatment of male Mycoplasma genitalium-positive nongonococcal urethritis.

Many recent studies have shown that Mycoplasma genitalium is among the pathogens responsible for Chlamydia trachomatis-negative nongonococcal urethritis (NGU). A single 1-g dose of azithromycin (AZM) has been recommended for the treatment of NGU, including M. genitalium-positive NGU, irrespective of whether it is positive or negative for Chlamydia trachomatis. The purpose of this study was to determine the minimal inhibitory concentrations of AZM against Mycoplasma genitalium strains, and to assess its clinical efficacy against Mycoplasma genitalium-positive NGU. Seven Mycoplasma genitalium strains were obtained from the American Type Culture Collection, and susceptibility testing of seven antimicrobial agents was performed using a broth microdilution method. Thirty men with M. genitalium-positive NGU were enrolled in this study and treated with a single 1-g dose of AZM. AZM and clarithromycin (CAM) were highly active against M. genitalium strains. Fluoroquinolone activities were moderate, and of the three fluoroquinolones tested, gatifloxacin (GFLX) and sparfloxacin (SPFX) were more active than levofloxacin (LVFX). In 25 of 30 (83.3%) men treated with a single 1-g dose of AZM, M. genitalium was eradicated from first-void urine samples, as determined by polymerase chain reaction. AZM was highly active against M. genitalium, and a single 1-g dose of AZM for M. genitalium-positive NGU was tolerated in Japan. These findings may be helpful in establishing optimal treatment for M. genitalium-positive NGU.

[Clinical usefulness of chlormadinone acetate as an alternative antiandrogen therapy for prostate cancer relapse after combined androgen blockade therapy].

We prospectively studied the usefulness of chlormadinone acetate (CMA) as an alternative therapy for prostate cancer relapse after combined androgen blockade (CAB) therapy. Sixteen patients with relapsed prostate cancer after treatment with CAB, including surgical or medical castration and nonsteroidal antiandrogens, 80 mg bicalutamide daily or 375 mg flutamide daily, were enrolled. After discontinuing the antiandrogen for evaluating the patient for the antiandrogen withdrawal syndrome, we administered 100 mg CMA daily as alternative antiandrogen and estimated its effect. Four patients showed a > or = 50% decline in prostate-specific antigen (PSA) levels and another 4 patients showed a < 50% decline in PSA levels but residual 8 patients showed no decline in PSA levels. In 8 patients with a decline in PSA levels, the median duration of alternative CMA therapy was 11.4 months. Patients with a PSA level of < 1 ng/ml at the start of CMA therapy showed the tendency of decline in PSA levels. In contrast, patients with a nadir PSA level of > or = 0.2 ng/ml during pretreatment showed no effectiveness of the alternative CMA therapy. The alternative CMA therapy may be useful in a part of patients with prostate cancer relapse after CAB therapy.

[Case of urachal cancer treated by neoadjuvant chemotherapy with FOLFOX4 (oxaliplatin, 5-FU and leukovolin)].

A 52-year-old woman was referred to our hospital for treatment of urachal cancer. She complained of supurapubic dull pain and gross hematuria. Computed tomography and magnetic resonance imaging showed a non-papillary sessile tumor, which was located on the dome of the bladder and invaded the small intestine. The tumor was diagnosed as Sheldon's stage IIIC urachal cancer. After three courses of neoadjuvant chemotherapy with FOLFOX4 (oxaliplatin, 5-FU and leukovolin), the tumor was reduced from 7 x 6 cm to 5.5 x 5 cm in size. Consequently, the patient underwent an en-bloc resection of the urachal tumor with the dome of the bladder and the parts of the ileum invaded by the tumor. One course of adjuvant chemotherapy (FOLFOX4) was performed. Surgical specimen revealed histologically well differentiated squamous carcinoma and invasion to the propria of the ileum. The surgical margins were negative for the cancer. For 1.5 years after the surgery, no local recurrence or distant metastasis has been observed.

Comparison of two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia: a randomized crossover study.

OBJECTIVES: To compare the efficacy of two alpha(1)-adrenoceptor antagonists, alpha(1A)-adrenoceptor-selective tamsulosin hydrochloride and alpha(1D)-adrenoceptor-selective naftopidil, in the treatment of lower urinary tract symptoms (LUTS) with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Thirty-four patients (mean age 72.4 years, sd 4.3, range 66-79) with LUTS (International Prostate Symptom Score, IPSS >8) secondary to BPH were enrolled in a randomized crossover study. Seventeen patients were initially prescribed naftopidil 50 mg for 4 weeks, followed by tamsulosin 0.2 mg for 4 weeks (group A); another 17 were initially prescribed tamsulosin 0.2 mg, followed by naftopidil 50 mg (group B). Patients changed to the alternative treatment after a 1-week washout period. Efficacy criteria were improvement in LUTS (IPSS), quality of life (QoL), uroflowmetry, and pressure-flow study (PFS) values based on the treatment with each agent. RESULTS: At baseline there were no significant differences between the groups in IPSS, QoL, uroflowmetry values or PFS values, except for the volume at maximum desire to void. After treatment with each agent, the IPSS and QoL were significantly improved and the reduction in bladder outlet obstruction confirmed by PFS. Naftopidil was significantly more effective than tamsulosin in relieving nocturia. The increases from baseline (before treatment) to the endpoint (after treatment with each agent) in the volume at first desire and maximum desire to void were significantly higher with naftopidil than with tamsulosin. Involuntary contractions disappeared in two patients with relief of nocturia with naftopidil, but not with tamsulosin. The decrease in other symptoms of the IPSS, QoL, increase in uroflowmetry values and changes in other PFS values were similar for both agents. CONCLUSIONS: The two agents provided similar efficacy in the treatment of LUTS with BPH. However, naftopidil was better than tamsulosin for nocturia. The disappearance of involuntary contraction and the greater increase in first-desire volume with naftopidil may be associated with the relief of nocturia. The alpha(1D)-adrenoceptor antagonist is effective in alleviating both voiding and storage symptoms. The alpha(1D)-adrenoceptor antagonist may be more effective than the alpha(1A)-adrenoceptor antagonist in LUTS with BPH.

Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval.

The efficacy of antimicrobial regimens for the treatment of uncomplicated gonococcal urethritis depends partially upon the period of time (therapeutic time) during which the drug concentration in the blood after the concentration peak is greater than four times the minimum inhibitory concentration for 90% of clinical isolates of Neisseria gonorrhoeae (MIC(90)). A therapeutic time of at least 10 h is suggested as an important determinant for elimination of 95% or more of the infection. In this study, therapeutic times for a single 400-mg dose of cefixime at various MIC(90)s were calculated, and pharmacokinetic profiles of double-dosing of 200 mg cefixime at various intervals were simulated. Subsequently, a dosing interval of 6 h was tested in 6 healthy Japanese men, and then 93 Japanese men with gonococcal urethritis were treated with a regimen of two 200-mg doses of cefixime given at a 6-h interval. For a single dose of 400 mg cefixime, therapeutic times were calculated to be 12.8, 9.1, 5.4, and 1.7 h for MIC(90)s of 0.06, 0.125, 0.25, and 0.5 microg/ml, respectively. In the simulation study of double-dosing of 200 mg cefixime at a 6-h interval, the therapeutic times for the MIC(90)s of < or =0.125 microg/ml were longer than 10 h. Of the 93 patients, 68 were evaluated for microbiological outcome, and N. gonorrhoeae was eradicated in 60 (88.2%). The MIC(90) of cefixime for the 61 isolates tested was 0.125 microg/ml. All strains with MICs of < or =0.06 microg/ml were eradicated, whereas 8 of 16 strains with MICs of > or =0.125 microg/ml persisted after treatment. This regimen would not be effective against infection by strains exhibiting cefixime MIC(90)s of > or =0.125 microg/ml. For such strains, a different regimen with a higher dose of cefixime would be required.