Use of a 2-year continuing professional development programme to change Japanese physicians' attitudes to learning primary care: a qualitative study.

OBJECTIVE: To evaluate changes in the learning attitudes of primary care physicians. DESIGN: Qualitative study through one focus group interview with the programme's participants. Analysis of the focus group content using the Steps for Coding and Theorization method. SETTING: Japan. PARTICIPANTS: Eight primary care physicians who completed a 2-year continuing professional development (CPD) programme using a problem-based learning (PBL) approach, focused on acquiring the skills needed to practise as primary care physicians in the community. RESULTS: Participants described positive changes in their attitudes and behaviours as a result of the training programme. These changes were grouped into three main themes: 'changes in learning methods regarding medical practice', 'encounters with diverse perspectives and values, and confidence gained from those encounters', and 'showing one's attitude towards learning and its influence on others'. The experienced practitioners participating in this study reported that the programme helped them apply their skills more broadly; for example, searching the literature for psychosocial aspects of practice and engaging more comfortably with diverse perspectives. They reported the positive impact of their learning on their coworkers. CONCLUSION: A 2-year CPD programme using PBL can influence primary care physicians' attitudes and learning-related behaviours. Further research is needed to determine which specific aspects of the programme are the most effective and whether the changes in attitudes and behaviours described affect patient care.

How a problem-based learning approach could help Japanese primary care physicians: a qualitative study.

OBJECTIVES: This study aimed to identify training needs among primary care physicians in Japan who had no formal primary care training. METHODS:  We conducted a focus group interview with seven Japanese primary care physicians who had not previously undergone specialist training in primary care and had been recruited to a family medicine training program that used a problem-based learning approach. At the start of the program, the physicians attended the interview. The discussion was recorded, and the transcribed interview was analyzed using the Steps for Coding and Theorization method. RESULTS:  Three main themes emerged. First, there is a lack of standard re-education programs for physicians who move away from their specializations into primary care. Second, there is insufficient training on primary care in undergraduate and postgraduate medical education in Japan. Third, continuing professional development programs should cover the communication skills, attitudes, and behaviors necessary for primary care practice. CONCLUSIONS:  This study clarified the needs to be addressed in our training program for primary care physicians involved in retraining in primary care. It is important to consider how to best include the communication skills, attitudes, and behaviors necessary for primary care among the topics covered in the program. As the program undergoes further iteration, it will be important to check whether it meets the needs of primary care practitioners. It will be necessary to investigate the needs of re-education programs for more physicians in many areas, and to emphasize the importance of primary care re-education in these abilities in undergraduate and postgraduate medical education.

Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma.

BACKGROUND: This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). METHOD: GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient's PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays. RESULTS: FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays. CONCLUSIONS: The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

BRAF V600E-mutated diffuse glioma in an adult patient: a case report and review.

Recent advances in genomic technology and genome-wide analysis have identified key molecular alterations that are relevant to the diagnosis and prognosis of brain tumors. Molecular information such as mutations in isocitrate dehydrogenase (IDH) genes or 1p/19q co-deletion status will be more actively incorporated into the histological classification of diffuse gliomas. BRAF V600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM. This mutation is relatively rare in other types of diffuse gliomas, especially in adult onset cases. Here, we present an adult onset case of IDH wild-type/BRAF V600E-mutated diffuse glioma, evolving from grade III to grade IV. The tumor displayed atypical exophytic growth and had unusual histological features not fully compatible with, but indicative of PXA and E-GBM. We discuss differential diagnosis of the tumor, and review previously described diffuse gliomas with the BRAF V600E mutation.

Parallel insertion endoscopic technique for precise catheter placement in cystic craniopharyngiomas.

BACKGROUND: Total removal of craniopharyngioma is the most acceptable therapeutic modality; however, there are cases in which radical excision is not possible. To reduce the cystic component volume, an Ommaya reservoir catheter can be placed endoscopically. However, there are certain complications and risks with this type of maneuver, such as misplacement of the catheter, which may result in leakage of cyst contents or installed fluids such as bleomycin. Thus, accurate placement of intracystic catheter is extremely important. PATIENTS AND METHODS: The authors placed Ommaya reservoir catheters running over the outer surface of a transparent endoscopic sheath in three cases. RESULTS: This neuroendoscopic procedure permits easier manipulation of the catheter and precise placement of the catheter tip. This technique was useful for placement of Ommaya reservoir catheters. CONCLUSIONS: This new technique of catheter placement with neuroendoscopy is more accurate, safer, and less invasive.

Clinicopathological Features of Growth Hormone-Producing Pituitary Adenomas in 242 Acromegaly Patients: Classification according to Hormone Production and Cytokeratin Distribution.

The aim of this study was to clarify the relationship between the histological features of GH-producing adenomas surgically resected at the Toranomon Hospital and the clinical features of the patients. Histological examinations, including immunohistochemistry for anterior pituitary hormones and cytokeratin (CK), were performed on 242 consecutively excised GH-producing pituitary adenomas. Immunohistochemistry showed 45% of the adenomas to be monohormonal and 55% to be plurihormonal, producing GH-PRL (77%), GH-TSH (13%), and GH-PRL-TSH (10%). One-fourth of the monohormonal GH adenomas had a dot-like pattern of CK immunoreactivity in the majority of the tumor cells (>80%); they were significantly more common in female or younger patients and usually tended to be larger and more invasive than monohormonal GH adenomas with perinuclear CK. Interestingly, CK-immunonegative adenomas were found in only 5% of the patients; they also showed a tendency to be larger, suggesting that they are a distinct type of GH adenoma with clinically aggressive features. Serum hormone levels correlated well with tumor size only in GH-producing adenomas with a perinuclear pattern of CK immunoreactivity. Each histological subtype of adenoma, classified according to the pattern of CK immunoreactivity, was associated with distinct clinical characteristics. This information is useful for understanding the pathophysiology of acromegaly-causing GH-producing adenomas.

Initial experience of real-time intraoperative C-arm computed-tomography-guided navigation surgery for pituitary tumors.

OBJECTIVE: We report our initial experience of real-time intraoperative C-arm computed tomography (C-arm CT: DynaCT)-guided navigation surgery for pituitary tumors. METHODS: Recent advancement in flat panel technology makes it possible to obtain CT-like images by using rotation of the C-arm of a digital subtraction angiography (DSA) system. A specially designed new suite, which has C-arm CT-imaging-capable DSA in combination with a navigation system (VectorVision Sky, BrainLAB AG, Munich, Germany), allows neurosurgeons to perform endoscopic transsphenoidal procedures under real-time navigation support. Thirty-one pituitary tumor patients were examined. During or after tumor removal, contrast-enhanced DynaCT was conducted to rule out residual tumor in 12 cases. When enhanced tumor was confirmed, additional removal was continued without moving the patients. RESULTS: DynaCT and subsequent image transfer to navigation system was performed in all cases without difficulties, requiring only an additional 15 minutes of surgical time. Sellar fenestration in relation to tumors and absence of hidden hematomas was confirmed in all cases. The contrast-enhanced DynaCT was found to be contributing to a better handling of the residual tumor. In 9 of these 12 cases (75%), residual tumor was detected on DynaCT; consequently, further removal was considered. In 2 cases (16%) there was no enhanced lesion, indicating complete removal. CONCLUSIONS: The proposed technique of intraoperative visualization in the hybrid operating room can be easy to perform and may be a useful adjunct to conventional transsphenoidal surgery for an improved resection rate and less cavernous sinus and internal carotid artery injury.

[Intracranial malignant glioma presenting as subarachnoid hemorrhage].

Cerebral aneurysms are the predominant cause of spontaneous subarachnoid hemorrhage (SAH). However, if an aneurismal cause has been excluded, there remains but a short list of meningiomas or metastatic lesions as possible causes. This article details a case of neoplasm that presented exclusively with SAH. A 31-year-old male presented with a SAH with normal cerebral angiography. The initial magnetic resonance image (MRI) revealed a lesion in the left uncus thought to be recovering hemorrhage. Subsequent MRI, however revealed the mass to be expanding. A neuroendoscopical biopsy of the lesion established a diagnosis of glioblastoma. An affirmation is made that patients experiencing "angiographically-negative" SAH should undergo MRI, occasionally on a serial basis, to exclude other etiologies for hemorrhage, including neoplasma.

A case of sphenoid sinus meningoencephalocele repaired by an image-guided endoscopic endonasal approach.

We report a Japanese patient with a complaint of unilateral watery nasal discharge. Analysis of the nasal discharge showed it to contain high levels of sugar and transferrin, which indicated cerebrospinal fluid (CSF) rhinorrhea. A diagnosis of sphenoid sinus meningoencephalocele was easily made on the basis of the CT, MRI and nasal discharge findings. We performed surgery by an image-guided endoscopic endonasal approach (IGEEA). An image guidance system (IGS) was used to confirm the position of the bone defect and the prolapsed brain lobe. We resected the brain lobe, and used fat tissue and fascia to create an extracranial-intracranial blockade. As of 18 months after the operation, there is no evidence of infection or CSF leakage. The IGEEA enabled us to successfully repair the middle skull base using a multi-layer sealing technique, while the IGS allowed us to confirm the anatomical structures and successfully avoid causing collateral damage to the surrounding tissues. This case exemplifies the beneficial effect that of the development of surgical support equipment on the operative approach that is now indicated for sphenoid sinus meningoencephaloceles: the endonasal approach has largely replaced other approaches, such as lateral rhinotomy.

Cotransfection of Poly(I: C) and siRNA of IL-10 into fusions of dendritic and glioma cells enhances antitumor T helper type 1 induction in patients with glioma.

Apart from generating T-helper (Th) effector responses, dendritic cells (DCs) are capable of initiating tolerance against the inciting antigens. Therefore, successful DC-based immunotherapy against malignant tumors requires an additional strategy to activate antigen-processing DCs. We studied the antitumor immune responses conferred by fusions of DCs and glioma cells in vitro. Fusion cells (FCs) were stimulated with polyriboinosinic polyribocytidylic acid [Poly(I:C)] and/or small interference RNA (siRNA) of IL-10 (IL-10-siRNA). Increased IFN-ß expression induced by Poly(I:C) transfection was accompanied by enhanced production of IL-10 and IL-12p70 in the FCs. We also found that the ability of Poly(I:C)-transfected FCs to produce IL-12p70, but not IFN-ß, was preserved when endogenous IL-10 was suppressed by IL-10-siRNA. To analyze the antigen-presenting function further, DCs, glioma cells, and peripheral lymphocytes were established from patients newly diagnosed with glioma. In this experiment, peripheral lymphocytes were stimulated with autologous FCs and restimulated with autologous glioma cells. CD4T cells isolated from the stimulated lymphocytes were subjected to the ELISPOT and WST-1 assays, which revealed that the IL-10-siRNA/Poly(I:C)-cotransfected FCs elicit an efficient tumor-specific Th1 response. These findings support the relevance of using Poly(I:C) and IL-10-siRNA in clinical immunotherapy protocols with an FC-based vaccine for patients with malignant glioma as a means of promoting Th1-induced tumor antigen presentation.

Robotic digital subtraction angiography systems within the hybrid operating room.

BACKGROUND: Fully equipped high-end digital subtraction angiography (DSA) within the operating room (OR) environment has emerged as a new trend in the fields of neurosurgery and vascular surgery. OBJECTIVE: To describe initial clinical experience with a robotic DSA system in the hybrid OR. METHODS: A newly designed robotic DSA system (Artis zeego; Siemens AG, Forchheim, Germany) was installed in the hybrid OR. The system consists of a multiaxis robotic C arm and surgical OR table. In addition to conventional neuroendovascular procedures, the system was used as an intraoperative imaging tool for various neurosurgical procedures such as aneurysm clipping and spine instrumentation. RESULTS: Five hundred one neurosurgical procedures were successfully conducted in the hybrid OR with the robotic DSA. During surgical procedures such as aneurysm clipping and arteriovenous fistula treatment, intraoperative 2-/3-dimensional angiography and C-arm-based computed tomographic images (DynaCT) were easily performed without moving the OR table. Newly developed virtual navigation software (syngo iGuide; Siemens AG) can be used in frameless navigation and in access to deep-seated intracranial lesions or needle placement. CONCLUSION: This newly developed robotic DSA system provides safe and precise treatment in the fields of endovascular treatment and neurosurgery.

Novel local drug delivery system using thermoreversible gel in combination with polymeric microspheres or liposomes.

BACKGROUND: The purpose of our study was to evaluate the application of thermoreversible gelation polymer (TGP) as a local drug delivery system for malignant glioma. MATERIALS AND METHODS: Polymeric microspheres or liposomes loaded with doxorubicin (sphere-dox or lipo-dox) were combined with TGP to provide continuous drug delivery of doxorubicin (dox) for kinetic release studies and cell viability assays on glioma cell lines in vitro. For in vivo studies, TGP loaded with dox alone (TGP-dox) was combined with sphere-dox or lipo-dox. Their antitumor effects on subcutaneous human glioma xenografts were evaluated in nude mice. RESULTS: In vitro, TGP combined with sphere-dox or lipo-dox released dox for up to 30 days. In vivo, TGP-dox combined with sphere-dox or lipo-dox inhibited subcutaneous glioma tumor growth until day 32 and day 38, respectively. CONCLUSION: TGP in combination with microspheres or liposomes successfully prolonged the release of dox and its antitumor effects.

Volumetric analysis of a rhabdoid meningioma during preoperative follow-up. A case report.

The authors describe a case of rhabdoid meningioma (RM) in a 17-year-old boy that was determined by measuring the tumor volume during preoperative follow-up. The volume of the tumor located in the left occipital lobe, was measured every 1-5 months, using an image analysis software. The tumor volume doubling time (Td) ranged from 1.0 to 4.9 years in the first 11 months, but became 0.3 years in the last two months. The tumor grew rapidly in the last two months at which time surgery was performed. Pathological examination of the surgical specimen showed that the tumor contained rhabdoid cells (RCs). RCs were heterogeneously distributed in the tumor admixed with spindle-shaped cells. The areas where RCs were predominant had malignant histological features, with necrosis and high proliferation indices, whereas the areas with few RCs lacked the malignant features. The tumor grew slowly in the initial phase, possibly because components with low proliferation rates occupied most of the tumor. The tumor began to grow rapidly when the malignant component containing abundant RCs became predominant. To the authors' knowledge, this is the first report monitoring the volumetric change of RM periodically. Our investigation indicated that volumetric analysis is useful to decide surgical intervention of the meningiomas with potential malignancy.

[Intraoperative photodynamic diagnosis for spinal ependymoma using 5-aminolevulinic acid: technical note].

OBJECTIVE: The fluorescence-guided resection using 5-aminolevulinic acid (5-ALA) is a well established method for the treatment of brain tumor, especially malignant glioma. However, there is no report on photodynamic diagnosis (PDD) for spinal tumor. In the present study, we evaluated the usefulness of PDD for spinal ependymoma using 5-ALA. METHODS: Three patients with spinal ependymoma received oral doses of 5-ALA (20 mg/kg body weight) 2 hours before anesthesia induction. Intraoperatively, fluorescence was observed with a 420 nm sharp cut filter after excitation with a violet semiconductor laser (405 nm) and was verified by analysis of fluorescent spectra. Residual fluorescent samples taken from the tumor cavity were examined histologically RESULTS: Fluorescence peaked at 636nm in the removed tumors in all cases. Fluorescent tissue tended to exist at the cranial and caudal portion in the tumor cavity or around the anterior median fissure. The residual fluorescent tissue was not detected after removal of the tumor in case 1. The residual fluorescent tissue was composed of tumor cells and ependymal lining in case 2 or the infiltrated inflammatory cells and vascular endothelial cells in case 3. Postoperative magnetic resonance (MR) imaging showed no residual tumor in any of the cases. CONCLUSION: The results of this study indicate the usefulness of 5-ALA-induced tumor fluorescence in guiding resection of spinal ependymoma. 5-ALA-induced porphyrin fluorescence may label spinal ependymomas easily and clearly enough to enhance the completeness of tumor removal.

Novel drug delivery system using thermoreversible gelation polymer for malignant glioma.

Many approaches to local tumor treatment have been reported and their efficacy demonstrated in patients with malignant glioma. We studied thermoreversible gelation polymer (TGP) as a novel drug delivery system (DDS) for treating this type of tumor. TGP exhibits sol-gel transition i.e., is water-soluble in the sol phase below the chosen sol-gel transiting temperature and water-insoluble in the gel phase above this temperature. We conjugated doxorubicin with TGP to prepare doxorubicin-TGP (DXR-TGP), then studied the kinetics of doxorubicin release from TGP and the antitumor activity of DXR-TGP in vitro and in vivo. The diffusive speed of doxorubicin from TGP was 9.4x10(-7) cm(2)/s and doxorubicin was reliably released from TGP. DXR-TGP showed antitumor activity against the human glioma cell lines T98G and U87MG and in a subcutaneous tumor model in nude mice. Pathologically, detection of the proliferation marker Ki-67 was considerably lower in the DXR-TGP group than in the control group (30-40% vs. 60-70%, respectively). This is to the best of our knowledge the first report of TGP as a novel drug delivery system, and further we provide evidence that TGP exhibits potential for use as a novel DDS for malignant glioma.

[An autopsy case with cerebral histoplasmoma: case report].

Histoplasma capsulatum infection is, for the most part, asymptomatic or of little clinical consequence. Disseminated infection due to H. capsulatum is rather uncommon. Clinically apparent infection of central nervous system (CNS) is rare, and involves in 10 to 50% of patients with disseminated histoplasmosis. Although CNS histoplasmosis is frequently fetal or only discovered as an autopsy, some patients can be effectively treated with anti-fungal agents. We describe a 44-year-old civil man who is engineering contractor with headache without evidence of systemic infection. Magnetic resonance imaging showed enhancing masses in the third and forth ventricles, right interpeduncular cistern, and right cerebello-pontine angle. After biopsy of what was presumed to be a malignant lymphoma, the patient died of rapidly progressive multiple cerebral infarctions. The autopsy revealed the CNS histoplasmoma disseminating systemically. And we finally diagnosed him as histoplasmoma by gene analysis. It was extremely difficult to make a diagnosis based on his physical and radiological findings because it should be included in the differential diagnosis of a well or ring enhanced lesion. It is very important to ask patients about their birthplace, past illness, occupation, and where they had traveled. In the present case, the patient working for the construction has visited many countries including the African Continent and Central America. Clinicians should maintain a high index of suspicion in patients who are from any area endemic for histoplasmosis. The clinical, radiological and pathological features of this infection were reviewed in this report.

Neuroendoscopic placement of Ommaya reservoir into a cystic craniopharyngioma.

INTRODUCTION: Total removal of the tumor is the most acceptable therapeutic modality in the management of craniopharyngioma; however, there are innumerable factors that can upset treatment plans. Unresectable lesions are often treated with gamma knife surgery (GKS). Reduction of the cystic volume is necessary, to decrease the area to be treated with GKS. An Ommaya reservoir system is usually placed during open surgery or by stereotactic access. MATERIALS AND METHODS: The authors use a neuroendoscope for safer and less invasive placement of the Ommaya reservoir into deep-seated cystic lesions. The cystic component is aspirated, and the Ommaya reservoir tube is precisely guided and placed into the cyst cavity under neuroendoscopic control with a newly developed two-burr-hole technique. This neuroendoscopic procedure could make it easier to reduce cystic volume prior to GKS as the final procedure. This technique may also be used for instillation of chemotherapeutic agents and for repeat aspirations, making the achievement of cystic control more likely. This type of neuroendoscopic management is a safe and effective procedure and could be considered as an alternative management technique for some stubborn cystic craniopharyngiomas.