Efficacy of therapeutic drug monitoring-based antibiotic regimen in critically ill patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of therapeutic drug monitoring (TDM)-based antimicrobial dosing optimization strategies on pharmacokinetics/pharmacodynamics and specific drug properties for critically ill patients is unclear. Here, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the effectiveness of TDM-based regimen in these patients. METHODS: Articles from three databases were systematically retrieved to identify relevant randomized control studies. Version two of the Cochrane tool for assessing risk of bias in randomized trials was used to assess the risk of bias in studies included in the analysis, and quality assessment of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcome was the 28-day mortality and secondary outcome were in-hospital mortality, clinical cure, length of stay in the intensive care unit (ICU) and target attainment at day 1 and 3. RESULTS: In total, 5 studies involving 1011 patients were included for meta-analysis of the primary outcome, of which no significant difference was observed between TDM-based regimen and control groups (risk ratio [RR] 0.94, 95% confidence interval [CI]: 0.77-1.14; I2 = 0%). In-hospital mortality (RR 0.96, 95% CI: 0.76-1.20), clinical cure (RR 1.23, 95% CI: 0.91-1.67), length of stay in the ICU (mean difference 0, 95% CI: - 2.18-2.19), and target attainment at day 1 (RR 1.14, 95% CI: 0.88-1.48) and day 3 (RR 1.35, 95% CI: 0.90-2.03) were not significantly different between the two groups, and all evidence for the secondary outcomes had a low or very low level of certainty because the included studies had serious risk of bias, variation of definition for outcomes, and small sample sizes. CONCLUSION: TDM-based regimens had no significant efficacy for clinical or pharmacological outcomes. Further studies with other achievable targets and well-defined outcomes are required. TRIAL REGISTRATION: Clinical trial registration; PROSPERO ( https://www.crd.york.ac.uk/prospero/ ), registry number: CRD 42022371959. Registered 24 November 2022.

Efficacy of antimicrobial therapy in patients with uncomplicated acute colonic diverticulitis: an updated systematic review and meta-analysis.

The need for antimicrobial therapy for uncomplicated acute diverticulitis of the colon remains controversial. We conducted a systematic review of the efficacy of antimicrobial agents against this disease, including new randomized controlled trials (RCTs) reported in recent years, and evaluated their efficacy using a meta-analytic approach. RCTs were searched using PubMed, EMBASE, Google Scholar, Cochrane Library, Ichushi-Web, and eight registries. Keywords were 'colonic diverticulitis', 'diverticulitis', 'antimicrobial agents', ''antibiotics, 'complication', 'abscess', 'gastrointestinal perforation', 'gastrointestinal obstruction', 'diverticular hemorrhage', and 'fistula'. Studies with antimicrobial treatment in the intervention group and placebo or no treatment in the control group were selected by multiple reviewers using uniform inclusion criteria, and data were extracted. Prevention of any complication was assessed as the primary outcome, and efficacy was expressed as risk ratio (RR) and risk difference (RD). A meta-analysis was performed using 5 RCTs of the 21 studies that were eligible for scrutiny in the initial search and which qualified for final inclusion. Three of these studies were not included in the previous meta-analysis. Subjects included 1039 in the intervention group and 1040 in the control group. Pooled RR = 0.86 (95% confidence interval, 0.58-1.28) and pooled RD = -0.01 (-0.03 to 0.01) for the effect of antimicrobial agents in reducing any complications. Recurrences, readmissions, and surgical interventions did not significantly show the efficacies of using antimicrobial agents. A meta-analysis of recently reported RCTs did not provide evidence that antimicrobial therapy improves clinical outcomes in uncomplicated acute diverticulitis of the colon.

A Cluster of Japanese Spotted Fever Cases Associated with Cemetery Visits in Wakayama City, Japan.

Japanese spotted fever (JSF) is a tick-borne rickettsiosis caused by Rickettsia japonica. Although the number of JSF cases has been increasing, exceeding 300 per year since 2017, clusters of cases are rare. Here, we report a cluster of seven JSF cases, the first nonfamilial cluster of the disease documented in the Japanese literature, and describe the management of the outbreak through prompt investigation and control-and-prevention measures performed collaboratively by members from the clinical, laboratory, and public health fields. All seven cases in the cluster had visited a cemetery in September or October of 2019. R. japonica was detected in whole-blood and/or skin samples from six patients and in the larvae of Haemaphysalis hystricis collected in a field survey. The evidence suggested that this cluster of cases was caused by the conjunction of two circumstances within a short period of time: an increase in the number of visitors to a cemetery during a Buddhist event and an increase in the number of infectious tick larvae in the cemetery through hatching (vertical transmission from infected females). Delays in the treatment of JSF can lead to severe manifestations. Early interventions through collaborative efforts among members from the clinical, laboratory, and public health fields are important for controlling outbreaks, raising the awareness of the public, and diagnosing and treating patients.

Diagnostic accuracy of rapid antigen tests in cerebrospinal fluid for pneumococcal meningitis: a systematic review and meta-analysis.

BACKGROUND: Streptococcus pneumoniae is a leading cause of bacterial meningitis worldwide. Conventional microbiological assays take several days and require the use of various drugs for empirical treatment. Rapid antigen tests in cerebrospinal fluid (CSF) may be useful to triage pneumococcal meningitis immediately. OBJECTIVES: To elucidate whether rapid antigen tests in CSF are useful in the triage of pneumococcal meningitis. METHODS: Data sourcesCochrane CENTRAL, MEDLINE, EMBASE, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov databases were searched. Study eligibility criteriaAll types of cohort studies except multiple-group studies, where the sensitivity and specificity of rapid antigen tests in CSF compared with CSF culture can be extracted. ParticipantsPatients with suspected meningitis. TestsRapid antigen tests in CSF. Reference standardsOne or more of the following: blood culture, CSF culture, and polymerase chain reaction in CSF. Assessment of risk of biasThe methodological quality of the included studies was assessed using QUADAS-2. Methods of data synthesisWe used a random-effects bivariate model for the meta-analysis. We conducted a subgroup analysis by dividing studies into types of antigen tests, adults and children, low-income and high-income countries, and with or without exposure to antibiotics before lumbar puncture. RESULTS: Forty-four studies involving 14 791 participants were included. Most studies had a moderate-to-low methodological quality. Summary sensitivity and specificity were 99.5% (95% confidence interval (CI), 92.4-100%) and 98.2% (95% CI, 96.9-98.9%), respectively. Positive predictive values and negative predictive values at the median prevalence (4.2%) in the included studies were 70.8% (95% CI, 56.6-79.9%) and 100% (95% CI, 99.7-100%), respectively. The diagnostic accuracy was consistent across the various subgroups, except for slightly reduced sensitivity in high-income countries. CONCLUSIONS: Rapid antigen tests in CSF would be useful in triaging pneumococcal meningitis. Further studies are warranted to investigate the clinical benefit of ruling out pneumococcal meningitis based on the results of rapid antigen tests.

Serologic Evidence of Human Exposure to Ehrlichiosis Agents in Japan.

In retrospective analyses, we report 3 febrile patients in Japan who had seroconversion to antibodies against Ehrlichia chaffeensis antigens detected by using an immunofluorescence and Western blot. Our results provide evidence of autochthonous human ehrlichiosis cases and indicate ehrlichiosis should be considered a potential cause of febrile illness in Japan.

Non-severe COVID-19 complicated by cytotoxic lesions of the corpus callosum (mild encephalitis/encephalopathy with a reversible splenial lesion): a case report and literature review.

BACKGROUND: Coronavirus disease 2019- (COVID-19-) associated cytotoxic lesions of the corpus callosum (CLOCCs) have been reported as a rare neurological abnormality in severe cases. Here, a case of CLOCCs in the early stages of mild COVID-19 infection during the Omicron BA.1 epidemic is reported along with a literature review. CASE REPORT: A Japanese woman with COVID-19 presented to the emergency department with altered consciousness and cerebellar symptoms a day after fever onset. Magnetic resonance imaging (MRI) revealed a lesion with restricted diffusion in the corpus callosum. She exhibited no complications of pneumonia, her neurological symptoms resolved after two days, and after 10 days, the brain lesion was not detected on MRI. LITERATURE REVIEW: The PubMed database was searched for case reports that met the CLOCC definition proposed by Starkey et al. The search yielded 15 COVID-19-associated cases reported as CLOCCs and 13 cases described under former terms, including mild encephalitis/encephalopathy with a reversible splenial lesion. Adult cases with a documented course were accompanied by pneumonia or hypoxemia, whereas pediatric cases were mostly accompanied by a multisystem inflammatory syndrome. CONCLUSION: COVID-19-associated CLOCCs can occur, even at an early, non-severe stage. Therefore, this condition may be underdiagnosed if MRI is not performed.

Chemical analysis of amyloid ß aggregation inhibitors derived from Geranium thunbergii.

Amyloid ß (Aß) aggregates in the brains of patients with Alzheimer's disease (AD) and accumulates via oligomerization and subsequent fiber elongation processes. These toxicity-induced neuronal damage and shedding processes advance AD progression. Therefore, Aß aggregation-inhibiting substances may contribute to the prevention and treatment of AD. We screened for Aß42 aggregation inhibitory activity using various plant extracts and compounds, and found high activity for a Geranium thunbergii extract (EC50 = 18 µg/mL). Therefore, we screened for Aß42 aggregation inhibitors among components of a G. thunbergii extract and investigated their chemical properties in this study. An active substance was isolated from the ethanol extract of G. thunbergii based on the Aß42 aggregation inhibitory activity as an index, and the compound was identified as geraniin (1) based on spectral data. However, although geraniin showed in vitro aggregation-inhibition activity, no binding to Aß42 was observed via saturation transfer difference-nuclear magnetic resonance (STD-NMR). In contrast, the hydrolysates gallic acid (2) and corilagin (5) showed aggregation-inhibiting activity and binding was observed via STD-NMR. Therefore, the hydrolysates produced under the conditions of the activity test may contribute to the Aß42 aggregation-inhibition activity of G. thunbergii extracts. Geraniin derivatives may help prevent and treat AD.

Effectiveness and safety of a program for appropriate urinary catheter use in stroke care: A multicenter prospective study.

OBJECTIVES: Since patients with stroke frequently develop bladder dysfunction, a careful approach is required to reduce unnecessary indwelling urinary catheter (IUC) for preventing catheter-associated urinary tract infection (CAUTI). This study aimed to assess the effectiveness and safety of a program to promote appropriate IUC use in stroke care. METHODS: We conducted a prospective interrupted time series study in three tertiary care hospitals in Japan. Adult patients with acute stroke were eligible. The study consisted of three phases: baseline, education and implementation. Our program included an assessment of IUC indications, educational meetings among healthcare professionals, reminders for removal of inappropriate IUC and a urinary retention protocol. The primary outcome was the proportion of inappropriate IUC use to assess effectiveness. The device utilization ratio and incidence of CAUTI were examined to assess effectiveness, and incidences of urinary retention and all symptomatic urinary tract infection (UTI) were examined to assess safety. RESULTS: Among 976 patients who met the inclusion criteria, 738 were analysed. Inappropriate IUC use decreased from 50.1% in the baseline phase to 22.5% in the implementation phase (absolute risk reduction in interrupted time series analysis 42.4% [95% confidence interval, 19.2%-65.6%]). The device utilization ratio decreased from 0.302 to 0.194 (p < 0.001), whereas CAUTI did not change significantly (from 8.81 to 8.28 per 1000 catheter-days; incidence rate ratio 0.95 [0.44-1.94]). All symptomatic UTI decreased from 9.5% to 4.9% (p = 0.015), with no increase in urinary retention. CONCLUSIONS: Our program improved the appropriateness of IUC use in stroke care while ensuring safety.

Short- versus prolonged-course antibiotic therapy for sepsis or infectious diseases in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: The 2016 International Guidelines for the Management of Sepsis and Septic Shock recommend antibiotic therapy for 7-10 days for most patients with sepsis. However, evidence on critically ill patients is limited. Thus, we conducted the first systematic review and meta-analysis comparing the effectiveness and adverse events of shorter- (≤1 week) with longer-course antibiotics in adults with critical infections including sepsis. METHODS: We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases for randomised controlled trials (RCTs) and observational studies (OSs) from inception to 31 March 2021. RESULTS: We included 6 of 3,766 identified articles, incorporating data from 4 RCTs and 2 OSs (1,721 patients) in meta-analyses. Three RCTs and one OS focussed on ventilator-associated pneumonia, and one RCT and one OS investigated intra-abdominal infections. The severity score levels were similar to that of sepsis, but no study comprehensively focussing on sepsis was found. There were no significant differences in mortality at a maximum follow-up of 30 days (RR 1.08, 95%CI 0.80-1.46); 28-day mortality, clinical cure, the occurrence of new events, and the emergence of resistant organisms between the groups in the RCTs. The OSs findings were consistent. The quality of evidence was assessed as very low to moderate using the GRADE approach, with no uniform description of severity scores, sepsis, or adverse events. CONCLUSIONS: Shorter, fixed-duration antibiotic therapy for clinically heterogeneous sepsis or severe infections was not associated with poorer outcomes, but the overall quality of evidence was poor.

Urethral Tuberculosis: A Forgotten Cause of Urethral Stricture.

We describe the clinical features of a 75-year-old man who presented to our hospital with frequent urination for 3 months. Retrograde urethrography showed extended and continuous narrowing of the stricture in the anterior urethra. Cystourethroscopy showed extended narrowing of the urethral lumen without normal membrane. Urine acid-fast bacillus culture and polymerase chain reaction assays indicated a diagnosis of urethral tuberculosis. Anti-tuberculosis therapy was initiated. Urethral tuberculosis is a very rare cause of urethral stricture in developed countries that can be diagnosed by cystourethroscopy. Urethral tuberculosis should be considered in the differential diagnosis of urethral stricture.

A case of postpartum thyroiditis following SARS-CoV-2 infection.

Postpartum thyroiditis (PPT) is characterized by mild thyrotoxicosis occurring within one year of parturition commonly followed by transient hypothyroidism. Having genetic background of autoimmune thyroid disorders is a risk factor for it because the immune reactivation during postpartum period is a trigger for PPT. Pandemic of COVID-19: caused by SARS-CoV-2 infection is a global health problem, and occurrence of Graves' disease and Hashimoto's thyroiditis after the viral infection have been reported but occurrence of PPT with COVID-19 has never been reported. A 29-year-old woman developed general fatigue four and a half months after parturition, and was diagnosed as having PPT: one month before, she had COVID-19. Hereafter, we define the date of delivery as Day 0 to make timeline clear. SARS-CoV-2 infection was diagnosed by PCR on Day 103, its disappearance from the upper airway confirmed on Day 124, and the thyroiditis diagnosed on Day 136. She had been euthyroid on Day 0 and 95, but thyrotoxic on Day 136. Serum thyroglobulin (Tg) concentration was normal in the presence of anti-Tg antibody, other thyroid-related autoantibodies were negative, and by ultrasonography, the thyroid gland was normal in size and no evidence of increased vascularity. Thyroid function returned to normal by Day 172 without any specific drug therapy. In conclusion, although a clear causal relationship could not be found, we documented the world's first case of PPT developed following COVID-19.

Clinical Characteristics of Patients With Coronavirus Disease 2019 in Japan: A Single-Center Case Series.

We report a case series of 6 patients with confirmed coronavirus disease 2019 (COVID-19) in Wakayama prefecture, Japan. All 6 of the patients tested positive via pharyngeal swab polymerase chain reaction (PCR) tests, and 2 of the 6 were still positive at 3 weeks after onset. All of the patients exhibited bilateral ground glass opacities on computed tomography (CT). This article also reports narrative information on the spectrum of symptoms collected directly from the patients. It would be difficult to triage patients with COVID-19 based on the typical symptoms of fever and/or cough, although PCR and CT are definitive in diagnosis.

Diagnostic performance of chest CT to differentiate COVID-19 pneumonia in non-high-epidemic area in Japan.

PURPOSE: To evaluate the diagnostic performance of chest CT to differentiate coronavirus disease 2019 (COVID-19) pneumonia in non-high-epidemic area in Japan. MATERIALS AND METHODS: This retrospective study included 21 patients clinically suspected COVID-19 pneumonia and underwent chest CT more than 3 days after the symptom onset: six patients confirmed COVID-19 pneumonia by real-time reverse-transcription polymerase chain reaction (RT-PCR) and 15 patients proved uninfected. Using a Likert scale and its receiver operating characteristic curve analysis, two radiologists (R1/R2) evaluated the diagnostic performance of the five CT criteria: (1) ground glass opacity (GGO)-predominant lesions, (2) GGO- and peripheral-predominant lesions, (3) bilateral GGO-predominant lesions; (4) bilateral GGO- and peripheral-predominant lesions, and (5) bilateral GGO- and peripheral-predominant lesions without nodules, airway abnormalities, pleural effusion, and mediastinal lymphadenopathy. RESULTS: All patients confirmed COVID-19 pneumonia had bilateral GGO- and peripheral-predominant lesions without airway abnormalities, mediastinal lymphadenopathy, and pleural effusion. The five CT criteria showed moderate to excellent diagnostic performance with area under the curves (AUCs) ranging 0.77-0.88 for R1 and 0.78-0.92 for R2. The criterion (e) showed the highest AUC. CONCLUSION: Chest CT would play a supplemental role to differentiate COVID-19 pneumonia from other respiratory diseases presenting with similar symptoms in a clinical setting.

Numerical simulations of particle behaviour in a realistic human airway model with varying inhalation patterns.

OBJECTIVES: For dry powder inhalers, the airflow properties in the airways could affect the deposition of inhaled particles; the flow patterns vary inherently between patients. This paper provides an evaluation of the effects of six airflow patterns on the behaviour of inhaled particles, as determined by using numerical simulations. METHODS: Constant-velocity and unsteady inhalation flows were employed. The unsteady inhalation flow was set as an inhalation curve with a peak inspiratory flow rate. Under a constant flow of 28.3 l/min, the total flow rates were calculated to confirm the validity of the numerical simulation. The effects of different inhalation patterns on the particle behaviour in a realistic human airway model were revealed via numerical simulation. KEY FINDINGS: Different flow rates affected the behaviour and deposition of the inhaled particles. Under an inhalation flow pattern, different airflow tendencies were observed between the right and left bronchi. Particle deposition in the airways was promoted by a vortex following terminal-velocity-like breath-holding. The inhalation flow pattern affected the behaviour and deposition of inhaled particles in the airway. CONCLUSIONS: Our results indicated that particle deposition in a realistic human airway model was promoted by a vortex formation following the terminal-velocity-like breath-holding. Moreover, the inhalation flow pattern significantly influenced the behaviour and deposition of inhaled particles in the airways. Additionally, the effect of flow patterns on the particle deposition in each airway position was quantitatively evaluated by numerical simulations for a realistic human airway model.

Erysipelothrix rhusiopathiae bacteremia following a cat bite.

Erysipelothrix rhusiopathiae is a major causative organism of swine erysipelas, but the infection has rarely occurred in humans. A soft-tissue infection with this organism is described as "erysipeloid." Most reported cases in human are related to occupational exposure. Endocarditis is a common complication of E. rhusiopathiae bacteremia in human. We report the case of a previously healthy 52-year-old Japanese female who presented with fever and an inflamed hand after being bitten by a stray cat. Blood culture was positive for E. rhusiopathiae, but no sign of infective endocarditis was observed. It may be prudent to consider E. rhusiopathiae infection in patients with animal bites.

Clinical and Molecular Characteristics of Klebsiella pneumoniae Isolates Causing Bloodstream Infections in Japan: Occurrence of Hypervirulent Infections in Health Care.

Although hypervirulent Klebsiella pneumoniae (hvKp) has been associated with severe community-acquired infections that occur among relatively healthy individuals, information about hvKp infections in health care settings remains limited. Here, we systematically analyzed the clinical and molecular characteristics of K. pneumoniae isolates causing bloodstream infections in a cross-sectional study. Clinical characteristics of K. pneumoniae bloodstream infections from hospitals across Japan were analyzed by a review of the medical records. Whole-genome sequencing of the causative isolates was performed. Bacterial species were confirmed and hvKp were identified using whole-genome sequencing data. Clinical characteristics of hvKp infections were compared with those of non-hvKp infections by bivariate analyses. Of 140 cases of K. pneumoniae bloodstream infections, 26 cases (18.6%) were caused by various clones of hvKp defined by the carriage of cardinal virulence genes. Molecular identification revealed that 24 (17.1%) and 14 (10%) cases were caused by Klebsiella variicola and Klebsiella quasipneumoniae, respectively. Patients with hvKp infections had higher proportions of diabetes mellitus (risk ratio [RR], 1.75; 95% confidence interval [CI], 1.05 to 2.94), and their infections had significantly higher propensity to involve pneumonia (RR, 5.85; 95% CI, 1.39 to 24.6), liver abscess (RR, 5.85; 95% CI, 1.39 to 24.6), and disseminated infections (RR, 6.58; 95% CI, 1.16 to 37.4) than infections by other isolates. More than one-half of hvKp infections were health care associated or hospital acquired, and a probable event of health care-associated transmission of hvKp was documented. hvKp isolates, which are significantly associated with severe and disseminated infections, are frequently involved in health care-associated and hospital-acquired infections in Japan.

Antibacterial Properties of Silicone Membranes after a Simple Two-Step Immersion Process in Iodine and Silver Nitrate Solutions.

　Silicone is widely used in packing materials, medical equipment, and separation membranes. Since microbial cells easily adhere to the surface of silicone materials and form biofilms, techniques for incorporating antimicrobial activity into silicone materials are in high demand. This study describes the preparation of silver (Ag)/silicone composite membranes through a simple two-step immersion process, utilizing an iodine solution followed by a silver nitrate solution at room temperature. Scanning electron microscopy (SEM) observations revealed that particles with sizes of several nanometers to several tens of nanometers were present on the silicone membrane surface; these particles were identified as silver iodide using energy-dispersive X-ray spectroscopy (EDS) . The Ag/silicone membrane possessed excellent antibacterial efficacy against Escherichia coli and Staphylococcus aureus, and the antibacterial efficacy (R) against both types of bacteria was R > 4, even after stomacher treatment or acidic treatment of pH 2-6 for 24 h. The mechanical strength of the silicone membrane was also maintained after antibacterial treatment, with Young's modulus values of 7.9±1.2 MPa and 8.3±1.5 MPa for the untreated membrane and Ag/silicone membrane, respectively (p > 0.05) . In addition, the reduction in permeation performance of the Ag/silicone membrane was only 20%, despite the antibacterial treatment on the membrane surface. This antibacterial treatment method of silicone membranes can be conducted at room temperature (25℃) without special equipment, and may be applied to other types of silicone materials.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501).

BACKGROUND: The incidences of metastatic brain tumors from malignant melanomas have increased and survival has been prolonged by novel molecular targeted agents and immunotherapy. However, malignant melanomas are uncommon in Asian populations. OBJECTIVES: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in Japanese melanoma patients with brain metastases treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 177 patients with 1,500 tumors who underwent GKRS for brain metastases from malignant melanomas. This study was conducted by the Japanese Leksell Gamma Knife Society (JLGK1501). RESULTS: Six and 12 months after GKRS, the cumulative incidences of local tumor recurrence were 9.2 and 13.8%. Intratumoral hemorrhage (p < 0.0001) and larger tumor volume (p = 0.001) in GKRS were associated with significantly poorer local control outcomes. The use of immune checkpoint inhibitors before GKRS was significantly associated with symptomatic adverse events (p = 0.037). The median overall survival time after the initial GKRS was 7.3 months. Lower Karnofsky performance status scores (p = 0.016), uncontrolled primary cancer (p < 0.0001), and multiple brain metastases (p = 0.014) significantly influenced unfavorable overall survival outcomes. The cumulative incidences of neurological death 6 and 12 months after GKRS were 9.7 and 17.4%, those of neurological deterioration were 14.2 and 19.6%, and those of new tumor appearance were 34.5 and 40.5%. CONCLUSIONS: The results of the present multicenter study suggest that GKRS is a relatively effective and safe modality for control of tumor progression in Japanese patients with brain metastases from malignant melanomas.