Determination of doripenem penetration into human prostate tissue and assessment of dosing regimens for prostatitis based on site-specific pharmacokinetic-pharmacodynamic evaluation.

Prostatic hypertrophy patients prophylactically received a 0.5-hour infusion of doripenem (250 or 500 mg) before transurethral resection of the prostate. Doripenem concentrations in plasma and prostate tissue were measured chromatographically, and analysed pharmacokinetically using a three-compartment model. The approved doripenem regimens were assessed based on the time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24 hours), an indicator for antibacterial effects, at the prostate. The prostate tissue/plasma ratios were 17.3% for the maximum drug concentration and 18.7% for the area under the drug concentration-time curve, and they were irrespective of the dose. Against Escherichia coli and Klebsiella species isolates, 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue.

Treatment of upper urinary tract stones with extracorporeal shock wave lithotripsy (ESWL) Sonolith vision.

BACKGROUND: The aim was to retrospectively assess the results of treatment of upper urinary tract stones with the Sonolith vision manufactured by EDAP, and purchased in 2004. METHODS: The subjects were 226 Japanese patients who underwent extracorporeal shock wave lithotripsy (ESWL) alone as an initial treatment and could be followed up for at least 3 months, selected from 277 candidate patients who underwent this therapy between 2004 and 2006. Treatment effect was evaluated by kidney, ureter, and bladder X-ray or renal ultrasonography at 1 and 3 months after treatment. A stone-free status or status of stone fragmentation to 4 mm or smaller was considered to indicate effective treatment. RESULTS: At 3 months after treatment, the stone-free rate was 69.4% and the efficacy rate was 77.4% for renal stones, while these rates were 91.5 and 93.3%, respectively for ureteral stones. Assessment of treatment effect classified by the location of stones revealed a stone-free rate of 94.6% and an efficacy rate of 94.6% for lower ureteral stones (4.0 mm or smaller, 1 subject; 4.1-10.0 mm, 31 subjects; 10.1-20.0 mm, 5 subjects: number of treatment sessions, 1 or 2 sessions [mean: 1.03 sessions]). Complications of this therapy included renal subcapsular hematoma and pyelonephritis in 1 case each. CONCLUSIONS: ESWL with the Sonolith vision manufactured by EDAP produced a treatment effect equivalent to those achieved with other models of ESWL equipment. ESWL seems to be an effective first-line treatment also in patients who have lower ureteral stones 10 mm or larger but do not wish to undergo TUL, if measures such as suitable positioning of the patient during treatment are taken.

Inflammatory pseudotumors of the kidney and the lung presenting as immunoglobulin G4-related disease: a case report.

INTRODUCTION: It has been reported that immunoglobulin G4-related systemic disease can spread to nearly every organ, and often presents as an inflammatory mass or masses at those sites. In the kidney, this disease is often diagnosed after a radical or partial nephrectomy following the discovery of an inflammatory mass which is often suspected to be a malignant tumor. Here, we present a rare case of inflammatory pseudotumors of the kidney and the lung presenting as immunoglobulin G4-related disease, which were diagnosed by computed tomography-guided biopsies. CASE PRESENTATION: A 54-year-old Japanese man was referred to our hospital with suspected bilateral renal cancer, multiple lung metastases and autoimmune pancreatitis. His serum immunoglobulin G4 level was high. We used computed tomography-guided biopsies and histopathological examinations of the biopsied specimens to diagnose the tumors as immunoglobulin G4-related bilateral renal and lung inflammatory pseudotumors. Our patient was treated with oral prednisolone, and after one month of treatment, contrast-enhanced computed tomography demonstrated a general improvement, as noted by a reduction in size of the masses. CONCLUSION: Renal masses that are formed due to immunoglobulin G4-related disease require comprehensive diagnosis to prevent unnecessary surgical resections from being performed. Further consideration should be paid to immunoglobulin G4-related diseases in the future.

A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system.

Molecular targeting agents have become formidable anticancer weapons showing much promise against refractory tumors and functional peptides and are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms the basis for a potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. We examine the growth suppression efficiency of human renal cell carcinoma (RCC) by single-peptide targeting. We simultaneously introduced p16INK4a tumor suppressor peptides by Wr-T-mediated peptide delivery. Wr-T-mediated transport of p16INK4a functional peptide into 10 RCC lines, lacking expression of the p16INK4a molecule, reversed the specific loss of p16 function, thereby drastically inhibiting tumor growth in all but 3 lines by >95% within the first 96 h. In vivo analysis using SK-RC-7 RCC xenografts in nude mice demonstrated tumor growth inhibition by the p16INK4a peptide alone, however, inoculation of Wr-T and the p16INK4a functional peptide mixture, via the heart resulted in complete tumor regression. Thus, restoration of tumor suppressor function with Wr-T peptide delivery represents a powerful approach, with mechanistic implications for the development of efficacious molecular targeting therapeutics against intractable RCC.

Lactate dehydrogenase, Gleason score and HER-2 overexpression are significant prognostic factors for M1b prostate cancer.

It has not been elucidated whether certain types of M1b prostate cancer (M1b PC) are associated with a poor outcome. The present study retrospectively identified predictive factors related to the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC. The observation period ranged from 4 to 122 months (median, 43 months). The parameters investigated were: T classification, N classification, Gleason score (GS), pretreatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium, and hemoglobin (Hb) levels, platelet count, and the status of HER-2 overexpression as determined with a Hercep Test(TM) Kit using initial needle biopsy specimens for diagnosis. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pretreatment PSA ≥ 192, N1, GS ≥ 8, EOD grade 3+4, high LDH, high ALP, low Hb, and HER-2 overexpression. Multivariate Cox proportional hazard analysis identified the factors GS ≥ 8, high LDH, and HER-2 overexpression with significant differences. The hazard ratio was 5.962, 2.465, and 2.907, respectively, and the probability value was P=0.0218, P=0.0207 and P=0.0090, respectively. When the subjects with GS ≥ 8, high LDH, and HER-2 over-expression were classified as the high-risk group, the 5-year cause-specific survival rate was 51.2, 29.6, and 20.0%, respectively. The present study showed that M1b PC patients with GS ≥ 8, high LDH, and HER-2 overexpression have a very poor outcome and thus, should be treated as a high-risk group requiring close follow-up.

Significant prognostic factor of immunohistochemical HER-2 expression using initial prostate biopsy specimens with M1b prostate cancer.

BACKGROUND: We examined whether human epidermal growth factor-2(HER-2) overexpression could be a useful marker of outcome after hormone therapy in patients with M1b prostate cancer (PC). SUBJECTS AND METHODS: The subjects were 102 patients who were diagnosed with M1b PC at Aichi Medical University Hospital. HER-2 expression was determined by immunohistochemical (IHC) staining using initial needle biopsy specimens for diagnosis. The results were classified into four grades (0, 1+, 2+, 3+), and scores of 1+ or greater were considered overexpression and defined as positive. RESULTS: The results showed a rating of 0 in 72 subjects, 1+ in 10, 2+ in 14, and 3+ in 6; 30 subjects (29.4%) were classified as HER-2 positive. Comparison of clinical data of HER-2 positive and negative subjects obtained at baseline revealed many of the subjects with high-grade tumors by Gleason score were HER-2 positive (P = 0.030). The prostate-specific antigen (PSA) relapse was observed in 76 subjects and cause-specific death occurred in 44. A significant difference was observed only in the item HER-2 (negative vs. positive) by multivariate Cox proportional hazard analysis. The 5-year PSA relapse-free rate was 0% in subjects with HER-2 positive (26/30), and 43.9% in subjects with HER-2 negative (50/72, P = 0.0192). The 5-year cause-specific survival rate was 40.9% in subjects with HER-2 positive (30/102), and 67.3% in subjects with HER-2 negative (72/102, P = 0.0301). CONCLUSION: HER-2 overexpression as determined by IHC staining using needle biopsy specimens for diagnosis with M1b PC is a significant prognostic factor for PSA relapse after hormone therapy and unfavorable outcome.

Contrast-enhanced ultrasound using a time-intensity curve for the diagnosis of renal cell carcinoma.

OBJECTIVE: • To evaluate the usefulness of contrast-enhanced ultrasound (CEUS) for the diagnosis of renal cell carcinoma by employing a time-intensity curve (TIC). PATIENTS AND METHODS: • From May 2008 to October 2009, CEUS was performed prior to surgery in 30 patients with renal masses. • In all, 10 of the 30 patients had cystic renal masses. The final diagnoses of all patients were pathologically confirmed. Contrast enhancement as a function of time was measured in two (tumour or solid component of cystic lesions and normal parenchyma) regions of interest (ROI) and TICs were obtained. • The time to the contrast enhancement peak (TTP), intensity change from the baseline to peak (ΔI) and ΔI/TTP of the tumour and the normal parenchyma were measured from the TIC. RESULTS: • Pathological diagnoses were renal cell carcinoma in 30 patients. • The TTP of the cancer was shorter than that of the normal parenchyma in all cases (6.0 ± 2.0 vs 10.4 ± 3.0 s; P < 0.0001). • The ΔI did not differ between the cancer and normal parenchyma [21.3 ± 5.9 vs 20.9 ± 7.0 decibels (db); P= 0.68]; the ΔI/TTP of the cancer was significantly higher than that of the normal parenchyma (3.9 ± 1.4 vs 2.2 ± 0.94 db/s; P < 0.0001). • TIC patterns of solid cancer and cystic cancer were very similar. CONCLUSIONS: • An objective and quantitative diagnosis of renal cell carcinoma by CEUS using a second-generation ultrasound contrast agent can be made by employing a TIC. • The TIC patterns of solid and cystic cancers were very similar, despite their morphological and vascular differences. • CEUS using TIC is a promising tool in the diagnosis of cystic renal cancer.

Intravesical administration of pirarubicin against superficial bladder cancer: Relationship between tumor tissue concentration and exposure time in the bladder or therapeutic effect.

The aim of this study was to investigate the relationship between tissue concentrations and exposure times or therapeutic effect of an anthracycline anticancer drug, pirarubicin, in bladder cancer tissue after single intravesical administration against superficial bladder cancer. The concentrations of pirarubicin in tumor tissues and serum were measured at designated collection times after a single intravesical administration of pirarubicin (30 mg) in 22 patients with superficial bladder cancer. A wide range of concentrations of pirarubicin in bladder cancer tissue was observed (2.3-125 µg/g of tissue), although serum pirarubicin concentrations were not detected in any of the patients. Recurrence of superficial bladder cancer after transurethral resection of the bladder tumor (TUR-BT) was observed in 2 patients (9%). The concentration of pirarubicin in the tumor tissue tended to be higher as the exposure time increased. There was a weak relationship between the pirarubicin tissue concentration and tumor size. However, no significant relationship between tissue pirarubicin concentrations and the prophylactic effect against intravesical recurrence of bladder cancer after TUR-BT was observed. All patients had no adverse events, such as bladder irritation and local toxicity, caused by the treatment with pirarubicin. These findings suggest that prior to single intravesical administration of pirarubicin to patients with superficial bladder cancer the exposure time and tumor size should be considered.

A rare case of metastatic renal carcinoid.

BACKGROUND: Carcinoid is an endocrine cell tumor with low-grade atypia, which is generally a low-grade malignant cancer with a good prognosis. Metastatic renal carcinoid is even rarer than primary carcinoids. CASE PRESENTATION: We present our experience of a patient with metastatic renal carcinoid from the gastrointestinal tract. CONCLUSIONS: The carcinoid tumor of the kidney in our patient, who had a history of liver metastasis from rectal carcinoid, was considered metastatic based on the pathological findings.

Potential of molecular targeted therapy of HER-2 and Cox-2 for invasive transitional cell carcinoma of the urinary bladder.

Expression of HER-2 and COX-2 was determined to assess the potential of molecular-targeted therapy against human epidermal growth factor receptor-2 (HER-2) and cyclooxygenase-2 (COX-2) for the treatment of invasive bladder cancer. The subjects were 46 patients who attended Aichi Medical University Hospital between January 2001 and August 2008, underwent total cystectomy with a diagnosis of M0 bladder cancer, and received a pathological diagnosis of invasive transitional cell carcinoma of the urinary bladder (pT2-pT4). Expression of HER-2 and COX-2 was determined by immunohistochemical staining, and the results were interpreted by two pathologists by classifying HER-2 expression into four grades, and considering COX-2 positive when 10% or more of the tumor cells were stained. In HER-2 immunostaining, 10 subjects (21.7%) were positive, all of whom had a Grade 3 tumor. Staging classification identified 2 subjects (2/22, 9.1%) with pT2 stage, 3 (3/16, 18.8%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was a correlation between HER-2 positivity and tumor stage (P=0.007). Lymph node metastasis was detected in 13 subjects, 3 of them (3/8, 37.5%) with pN2 metastasis were HER-2 positive. The 5-year cause-specific survival rate was 51.4% for HER-2-positive subjects and 83.4% for HER-2-negative subjects. The outcome was poorer in HER-2-positive subjects, but the difference in survival rate was not statistically significant (P=0.218). In COX-2 immunostaining, 27 subjects (58.7%) were found to be positive. Three (3/4, 75.0%) showed a Grade 2 tumor and 24 (24/42, 57.1%) a Grade 3 tumor. Staging classification identified 13 subjects (13/22, 59.1%) with pT2 stage, 9 (9/16, 56.3%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was no correlation between COX-2 positivity and tumor grade or stage (P=0.488 and 0.089, respectively). Classification by the extent of lymph node metastasis revealed that 6 subjects (6/8, 75.0%) with pN2 were COX-2 positive. There was a correlation between COX-2 positivity and the extent (pN1 or pN2) of lymph node metastasis (P=0.008). The 5-year cause-specific survival rate was 84.0% for COX-2-positive subjects and 71.7% for COX-2-negative subjects. However, the difference in survival rate was not significant (P=0.407). Seven subjects (7/46, 15.2%) were positive for both HER-2 and COX-2, and there was no statistically significant correlation between the status of HER-2 expression and that of COX-2 expression (P=0.2195). The present study failed to show any association between HER-2 or COX-2 positivity and outcome in subjects with invasive bladder cancer. However, HER-2-positive subjects tended to have a poorer outcome. This finding suggests that molecular-targeted therapy against HER-2 could be an effective therapy. Further studies involving a larger number of subjects are required.

Association between gefitinib and hemorrhagic cystitis and severely contracted bladder: a case report.

BACKGROUND: Gefitinib remains an excellent treatment option for patients with a variety of cancers, including non small cell lung cancer (NSCLC). However, clinicians must be aware of the potential of gefitinib to cause an inflammatory reaction in the skin, lungs and bladder. CASE PRESENTATION: We present a case on hemorrhagic cystitis and severely contracted bladder in a patient with NSCLC on gefitinib. CONCLUSIONS: Further studies are needed to substantiate the association of gefitinib therapy with hemorrhagic cystitis and contracted bladder.

Penetration of doripenem into prostatic tissue following intravenous administration in prostatectomy patients.

This study examined the prostatic penetration of doripenem in prostatectomy patients. Doripenem 500 mg was administered by a 0.5-h infusion and venous blood and prostatic tissue samples were obtained up to 5h afterwards. Drug concentrations in plasma and prostatic tissue were measured chromatographically. The observed maximum concentration (C(max)) (mean+/-standard deviation; n=9) was 27.5+/-5.1 microg/mL in plasma and 5.09+/-1.94 microg/g in prostate tissue and the prostate/plasma C(max) ratio was 0.189+/-0.078. The area under the drug concentration-time curve (AUC) was 49.7+/-6.9 microg h/mL in plasma and 3.93+/-1.89 microg h/g in prostate tissue and the prostate/plasma AUC ratio was 0.081+/-0.047. Based on a three-compartment pharmacokinetic analysis, average drug exposure times above 0.25 microg/mL (the minimum inhibitory concentration for isolates of common pathogens) in the prostate were 23.2% for 500 mg once daily, 46.2% for 500 mg twice daily and 69.9% for 500 mg three times daily. The 500-mg regimens all achieved the drug exposure time target (bacteriostatic 20% or bactericidal 40%) in the prostate, despite the relatively low penetrability of doripenem.

The use of zoledronic acid in Japanese men with stage D2 prostate cancer.

Zoledronic acid (ZOL) is a new generation bisphosphonate with improved efficacy benefits over pamidronate in preclinical testing. In addition, ZOL is superior to pamidronate in the treatment of hypercalcemia of malignancy. ZOL is also the first bisphosphonate to demonstrate efficacy in patients with bone metastases from solid tumors other than breast cancer, such as prostate cancer. In this study, we investigated ZOL treatment in 17 Japanese men with advanced prostate cancer, treated at the Aichi Medical University Hospital between August 2006 and November 2007. The 17 patients had biopsy-confirmed prostate cancer and were found to harbor bone metastasis upon bone scintigraphy. ZOL was administered intravenously at a dose of 4 mg over 15 min every 4 weeks. ZOL was well tolerated with mild renal dysfunction in 2 patients (11.8%), while 1 patient (5.8%) developed skin rash. No significant side effects were observed. Subjective improvement in bone pain was reported in 14 patients (32.4%). ZOL, therefore, is a safe and effective drug that remains an important component of the urologist's armamentarium against advanced prostate cancer.

Investigation of risk factors for prostate cancer patients with bone metastasis based on clinical data.

It has not yet been determined whether certain types of prostate cancer with bone metastasis (M1b PC) are associated with a poor outcome. The present study retrospectively assessed the potential significance of various clinical data in predicting the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC between January 1998 and December 2006. The age of the subjects ranged from 51 to 91 years (median 74). The observation period ranged from 4 to 122 months (median 43). The parameters investigated were T classification, N classification, Gleason score (GS), pre-treatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium and hemoglobin (Hb) levels and platelet count. The 5-year cause-specific survival rate was 56.6% and the 10-year cause-specific survival rate was 34.9%. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pre-treatment PSA level ≥192, N1, GS ≥8, EOD grade 3+4, high LDH, high ALP and low Hb. Multivariate Cox proportional hazard analysis identified the factors GS ≥8 and high LDH with significant differences. The hazard ratio was 4.967 and 2.728, respectively, and the probability value (P) was 0.029 and 0.004, respectively. When the subjects with GS ≥8 and high LDH were classified as the high-risk group, the 5-year cause-specific survival rate was 24.6%. The outcome was significantly poorer in this group (P<0.0001) than in the other group, which had a 5-year cause-specific survival rate of 67.7%. The present study showed that patients with M1b PC with GS ≥8 and high LDH have a very poor outcome and thus should be treated as a high-risk group requiring close follow-up.

Holmium YAG laser ablation of a hemangioma involving a lower pole renal calyx - using the new-generation flexible ureteroscope URF type P5: a case report.

Hemangioma of the renal calyx is a rare disease, which is difficult to diagnose and an even greater challenge to treat. We report the use of the new-generation flexible ureteroscope, in the management of a 37-year-old Asian male with a lower pole renal calyx hemangioma, which was previously inaccessible.

Preliminary results of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium.

OBJECTIVE: We evaluated the efficacy and safety of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional cell carcinoma of the urothelium. SUBJECTS AND METHODS: The subjects were 12 patients diagnosed with advanced metastatic transitional cell carcinoma of the urothelium. For mild hyperthermia, the patients' oral temperature was elevated to about 38 degrees C by heating for 20 min and retaining the heat for 20 min with a far-infrared heater. The antitumor effect was evaluated according to the RECIST, while adverse drug reactions were assessed based on the NCI-CTC. RESULTS: The antitumor effect was rated as partial remission (PR) in 10 of the 12 patients and stable disease in 2 patients, with an efficacy rate of 83% (10/12). All 10 patients who had achieved PR received three courses of treatment. Of the 12 patients, 5 died during the observation period, with survival for 9-23 months (mean: 15.6 months). Adverse drug reactions included myelosuppression in all patients (Grade 3 in 4 patients, Grade 4 in 8), and gastrointestinal toxicity, such as nausea or vomiting, which was mild (Grade 0 in 2 patients, Grade 1 in 8, Grade 2 in 1, Grade 3 in 1). CONCLUSIONS: The results of the present study suggest that M-VAC chemotherapy combined with mild hyperthermia, which potentiates the anticancer effect and reduces adverse drug reactions such as gastrointestinal symptoms, is a useful and safe method for the treatment of advanced transitional cell carcinoma of the urothelium.

Long-term results and management of ureteral transitional cell carcinoma using the holmium: YAG laser via rigid-ureteroscopy.

The standard operative procedure for ureteral transitional cell carcinoma is nephrouterectomy with partial cystectomy at the affected ureteral orifice. However, nephron-sparing surgery and endoscopic surgery and management have become common practice for low-grade and low-stage cases. We investigated the follow-up results of patients who underwent endoscopic surgery using the holmium:YAG laser, and evaluated its treatment effect. The patients were 4 men and 3 women aged from 68 to 87 years (mean: 74.7 years). Two were imperative cases and 5 were elective cases. The tumor size ranged from 8 to 25 mm (mean: 15.4 mm). Hydronephrosis was not found in any case, and urinary cytology was negative in all cases. Biopsy revealed 5 cases of grade 1, and 2 of grade 2. A Versa Pulse Select 80 laser generator, a 365-microm slim line laser fiber, and a rigid ureteroscope with 8F-point diameter were used. A 6F double J catheter was placed postoperatively for 3 weeks. Pulse energy was set at 0.5-1.0 J (mean: 0.8 J) with a frequency of 10 Hz. The total amount of energy was 0.9-11.22 KJ (mean: 2.89 KJ) and the operation time including ureteral stent placement was 20-97 min (mean: 66 min). Neither urinary tract perforation nor ureteral stricture associated with laser irradiation was observed. The postoperative follow-up period ranged from 23-88 months (mean: 67.8 months). Patients underwent urinary cytological examination once a month, and cystoscopy, retrograde pyelography and urethroscopy once every 3 months for 2 years, then once every 6 months thereafter. One patient developed tumor recurrence 23 months after surgery and received another laser treatment, but no recurrence has been observed in the other 6 patients (85.7%). Transurethral endoscopic surgery and management using the holmium:YAG laser is safe and effective nephron-sparing surgery for ureteral transitional cell carcinoma, and good long-term treatment results can be expected even in elective cases if the indications are carefully selected.

Pharmacokinetic-pharmacodynamic target attainment analysis of doripenem in infected patients.

This study was a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of doripenem. Drug concentration data in plasma (115 samples) and urine (61 samples) from 18 infected patients were concurrently analysed to develop a more accurate population PK model for doripenem. In the final PK model, creatinine clearance (CL(Cr)) was the most significant covariate: CL(r) (L/h)=0.137xCL(Cr); CL(nr) (L/h)=2.49; V(1) (L)=8.29; Q (L/h)=8.10; and V(2) (L)=9.37, where CL(r) and CL(nr) are the renal and non-renal clearances, V(1) and V(2) are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central-peripheral) clearance. Based on the PK model, a Monte Carlo simulation predicted the probabilities of attaining the bactericidal exposure target (40% of the time above the minimum inhibitory concentration (MIC)) in plasma and defined the PK-PD breakpoints (the highest MIC values at which the target attainment probabilities were >or=90%). The breakpoint for 500 mg every 8h (q8h) (1-h infusion) with a CL(Cr) of 80 mL/min (1 microg/mL) corresponded to those for 250 mg q8h with a CL(Cr) of 40 mL/min and 250 mg every 12h with a CL(Cr) of 20 mL/min. Prolonging the infusion time was a more effective strategy than dose escalation to increase the breakpoint. These results provide guidance for constructing a PK-PD-based strategy for dosing guidance for tailoring doripenem regimens.

Combining anti-tumor drugs with mild hyperthermia increases the cytotoxic effects of drugs on human leukemia cells in vitro.

Although the benefits of using a combination of hyperthermia and chemotherapy or radiotherapy in the treatment of cancer have been theoretically established, the use of such combination therapy is not widespread at the clinical level, as the application of hyperthermia is complex and maintaining a tumor temperature of 43°C or higher is exceedingly difficult. Consequently, in the present study, the effects of chemotherapy combined with mild hyperthermia at 41°C (which is easier to apply than standard hyperthermia) were examined in the NALM-6 leukemia cell line. The results were as follows: i) NALM-6 leukemia cells, like most cells, survived mild hyperthermia at 41°C, but were killed at temperatures over 43°C. ii) Low concentrations of adriamycin (0.1 µg/ml) or mild hyperthermia applied separately did not have a visible effect on the survival rate of NALM-6 cells, whereas combined treatment with these therapies decreased the survival rate of NALM-6 cells in a time-dependent manner. The anti-tumor effect after 5 h of the combination of 0.1 µg/ml adriamycin and mild hyperthermia was the same as that observed with a 10-fold higher concentration (1 µg/ml) of adriamycin alone. iii) Another anti-tumor drug, vincristine, exhibited the same behavior as adriamycin. The anti-tumor effect after 1 h of the combination of 5x10-11 M vincristine and mild hyperthermia was the same as that observed with a 10-fold higher concentration (5x10-10 M) of vincristine alone. The results indicate that it may be possible to reduce the required concentrations of anti-tumor drugs by using them in combination with mild hyperthermia. In this way, the side effects of chemotherapy may be reduced in clinical settings. Mild hyperthermia is a useful and practical heating method, and could result in the increasing clinical application of hyperthermia in the treatment of cancer.

Retrospective study comparing six- and twelve-core prostate biopsy in detection of prostate cancer.

OBJECTIVE: We compared the safety and efficacy of the 12-core biopsy with those of the conventional systematic 6-core biopsy with PSA levels between 4.1 and 20.0 ng/mL. MATERIALS AND METHODS: This study included 428 patients who underwent a 6-core biopsy and 128 patients who underwent a 12-core biopsy. Biopsies were performed transrectally under ultrasound guidance. The 12-core biopsy scheme involved obtaining 6 far lateral cores. RESULTS: For patients with PSA level between 4.1 and 10.1 ng/mL, 47 of the 265 patients who underwent 6-core biopsy and 32 of the 91 patients who underwent a12-core biopsy were diagnosed with prostate cancer (p = 0.0006). Among the patients with a PSA level between 10.1 and 20.0 ng/mL, 48 of 163 patients who underwent the 6-core biopsy and 16 of 37 patients who underwent the 12-core biopsy were diagnosed with prostate cancer (p = 0.0606). Three of the 95 patients who were diagnosed with prostate cancer through the 6-core biopsy and 12 of the 48 patients who were diagnosed through the 12-core biopsy had cancer located in the anterior apex. The 12-core biopsy increased the diagnostic rate in the apex (p = 0.001). No statistically significant differences were found in incidence of complications. CONCLUSION: We concluded that the 12-core biopsy is a safe and more effective procedure for increasing the diagnostic rate of prostate cancer than the 6-core biopsy in patients with PSA level between 4.1 and 10.0 ng/mL, and the most useful anatomical area to be added was found to be cores from the anterior apex.