Akihiro Hirakawa

Bio: Akihiro Hirakawa is an academic researcher from University of Tokyo. The author has contributed to research in topics: Medicine & Cancer. The author has an hindex of 25, co-authored 205 publications receiving 2722 citations. Previous affiliations of Akihiro Hirakawa include Tokyo University of Science & Tokyo Medical and Dental University.

Minocycline selectively inhibits M1 polarization of microglia

Abstract: Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1G93A mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1G93A mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer.

Abstract: BACKGROUND: Generally, the blood-brain barrier (BBB) of brain metastasis was thought to be disrupted. METHODS: We retrospectively performed immunohistochemical staining for glucose transporter 1 (GLUT1) and breast cancer resistance protein (BCRP) to evaluate the status of the BBB in resected brain metastases. Associations between expression of GLUT1 and/or BCRP and the immunohistochemical profiles of breast cancers, such as the statuses of hormone receptors, human epidermal growth factor receptor 2 (HER2/neu), and a basal-type marker (cytokeratin 5/6, HER1), were also analyzed. RESULTS: The study included 29 breast cancer patients with brain metastasis who had undergone brain tumor resections. Among the 29 patients, there was no expression of GLUT1 and BCRP in the intratumor microvessels of 9 (32%) and 11 (38%) patients, respectively. There was no expression of both GLUT1 and BCRP in 8 patients (28%). The expression of GLUT1 was significantly associated with that of BCRP (P < .001). A positive correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of HER2/neu-positive breast cancer (P = .012), while a negative correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of triple negative or basal-type breast cancer (P = .014 and P = .003 for triple negative and basal-type, respectively). CONCLUSIONS: Brain metastases of triple negative or basal-type breast cancers may often disrupt the BBB, whereas brain metastases of HER2/neu-positive breast cancer tend to preserve the BBB. Cancer 2010. © 2010 American Cancer Society.

Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer

Abstract: The long-term outcomes and risk factors of paclitaxel-induced peripheral neuropathy (PIPN) have not yet been fully elucidated. We identified 219 breast cancer patients who received paclitaxel as adjuvant chemotherapy between 2002 and 2009. We retrospectively analyzed the incidence, time to onset, duration, and risk factors for PIPN by chart review. Of the 219 patients, 212 developed PIPN (97%) during a median follow-up time of 57 months (range 5.3–95.5). Median time to PIPN onset was 21 days (range 11–101) for the entire patient population: 35 days (range 14–77) for weekly administration and 21 days (range 11–101) for tri-weekly administration. PIPN caused termination of paclitaxel treatment in 7 patients (4%). Median duration of PIPN was 727 days (range 14–2621 days). PIPN persisted in 64 and 41% of patients at 1 and 3 years after initiating paclitaxel, respectively. Age ≥60 years and severity of PIPN were significantly associated with PIPN duration. PIPN persists longer in older patients and in those who experience severe neuropathy. Further studies to identify the risk factors for PIPN are warranted.

Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose-derived regenerative cells: 1-year outcomes in 11 patients

Abstract: Objectives To assess the efficacy and safety of a novel cell therapy for male stress urinary incontinence consisting of periurethral injection of autologous adipose-derived regenerative cells, and to determine the 1-year outcomes. Methods A total of 11 male patients with persistent stress urinary incontinence after prostate surgery were included in the study. The Celution system was used to isolate adipose-derived regenerative cells from abdominal adipose tissue obtained by liposuction. Subsequently, these regenerative cells, and a mixture of regenerative cells and adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. The 1-year outcomes were assessed using a 24-h pad test, a validated patient questionnaire, urethral pressure profile, transrectal ultrasonography and magnetic resonance imaging. Results Stress urinary incontinence improved progressively in eight patients during the 1-year follow up, as determined by a 59.8% decrease in the leakage volume in the 24-h pad test, decreased frequency and amount of incontinence, and improved quality of life. One patient achieved total continence. The mean maximum urethral closing pressure and functional profile length increased from 35.5 to 44.7 cmH2O, and from 20.4 to 26.0 mm, respectively. Magnetic resonance imaging showed the sustained presence of the injected adipose tissue, and enhanced ultrasonography showed a progressive increase in blood flow to the injected area in all patients. No significant adverse events were observed peri- or postoperatively. Conclusion Periurethral injection of autologous adipose-derived regenerative cells might represent a safe and feasible treatment modality for male stress urinary incontinence.

Change in the hormone receptor status following administration of neoadjuvant chemotherapy and its impact on the long-term outcome in patients with primary breast cancer.

Abstract: To evaluate the impact of change in the hormone receptor (HR) status (HR status conversion) on the long-term outcomes of breast cancer patients treated with neoadjuvant chemotherapy (NAC). We investigated 368 patients for the HR status of their lesions before and after NAC. On the basis of the HR status and the use/non-use of endocrine therapy (ET), the patients were categorised into four groups: Group A, 184 ET-administered patients with HR-positive both before and after NAC; Group B, 47 ET-administered patients with HR status conversion; Group C, 12 ET-naive patients with HR status conversion; Group D, 125 patients with HR-negative both before and after NAC. Disease-free survival in Group B was similar to that in Group A (hazard ratio, 1.16; P=0.652), but that in Group C was significantly lesser than that in Group A (hazard ratio, 6.88; P<0.001). A similar pattern of results was obtained for overall survival. Our results indicate that the HR status of tumours is a predictive factor for disease-free and overall survival and that ET appears to be suitable for patients with HR status conversion. Therefore, both the CNB and surgical specimens should be monitored for HR status.

Multiple Imputation for Nonresponse in Surveys

Abstract: 25. Multiple Imputation for Nonresponse in Surveys. By D. B. Rubin. ISBN 0 471 08705 X. Wiley, Chichester, 1987. 258 pp. £30.25.

Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases

Abstract: One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease (AD), and amyotrophic lateral sclerosis, is microglia-mediated neuroinflammation. Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M1 phenotype and M2 phenotype. Depending on the phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects. In this review, we focus on the potential role of M1 and M2 microglia and the dynamic changes of M1/M2 phenotypes that are critically associated with the neurodegenerative diseases. Generally, M1 microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair process of M2 microglia are dampened. This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed β-amyloid (Aβ) plaque and tangles that are released into the extracellular space. The endogenous stimuli including aggregated α-synuclein, mutated superoxide dismutase, Aβ, and tau oligomers exist in the milieu that may persistently activate M1 pro-inflammatory responses and finally lead to irreversible neuron loss. The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.

Microglial and Macrophage polarization—new Prospects for Brain Repair

Abstract: The traditional view of the adult brain as a static organ has changed in the past three decades, with the emergence of evidence that it remains plastic and has some regenerative capacity after injury. In the injured brain, microglia and macrophages clear cellular debris and orchestrate neuronal restorative processes. However, activation of these cells can also hinder CNS repair and expand tissue damage. Polarization of macrophage populations toward different phenotypes at different stages of injury might account for this dual role. This Perspectives article highlights the specific roles of polarized microglial and macrophage populations in CNS repair after acute injury, and argues that therapeutic approaches targeting cerebral inflammation should shift from broad suppression of microglia and macrophages towards subtle adjustment of the balance between their phenotypes. Breakthroughs in the identification of regulatory molecules that control these phenotypic shifts could ultimately accelerate research towards curing brain disorders.

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

Abstract: Purpose To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors. Methods A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life. Results A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the ba...