Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Long-term effect of epidural injection with sustained-release lidocaine particles in a rat model of postoperative pain.

BACKGROUND: Single applications of sustained-release local anaesthetics may provide prolonged pain relief without requiring indwelling catheters, but have not yet been investigated for epidural postoperative pain management. We synthesized injectable sustained-release lidocaine particles (SRLPs) from biodegradable polymers and examined their effect in a rat model of postoperative pain. METHODS: Two types of polylactic acid particles, SRLP-10 and SRLP-25, containing 10% or 25% lidocaine, respectively, were generated and the lidocaine release was evaluated in vitro for 14 days. The SRLPs were then injected epidurally in the male Sprague-Dawley rats immediately before they received a hindpaw incision (the postoperative pain model), and hindpaw hypersensitivity was evaluated with the von Frey test. Motor paralysis and coordination were also assessed using a paralysis score and rota-rod test. Neurotoxicity and inflammation of the spinal cord, cauda equina, and tissue surrounding the injection site were histologically evaluated. RESULTS: In vitro, SRLP-10 and SRLP-25 released lidocaine over 7 and 3 days, respectively. The in vivo injection of SRLP-10 (80 mg) produced anti-hypersensitivity with no evidence of motor paralysis for 7 days after the paw incision, and SRLP-25 (60 mg) inhibited postoperative hypersensitivity for 7 days. Temporary motor paralysis (15 min) was observed after the injection of SRLP-25 (even with 40 mg). Foreign body reactions were observed around the SRLP injection site at 1 and 4 weeks after injection. No histopathological changes were observed at 1 or 4 weeks. CONCLUSIONS: The epidural injection of SRLPs produced prolonged anti-hypersensitivity in a rat model of postoperative pain with no major complications.

[Subscapular elastofibroma].

Elastofibroma is a tumor that is localized mainly at the subscapular region. We report 2 cases of subscapular elastofibromas. Case 1, 75-year-old woman was seen at the hospital because of a left dorsal tumor. Computed tomography (CT) scan revealed the tumor of 6 cm in diameter in the inferior angle of left scapula. The patient underwent excision of the tumor. Case 2, 90-year-old man underwent excision a tumor of 5 cm in diameter in the inferior angle of right scapula simultaneously with the operation of right lung cancer. Histological examinations showed increased elastic fiber with elastica van Gieson staining. These specimens confirmed the diagnosis of elastofibroma There have been no signs of recurrence after surgery.

Size-dependent cytotoxic effects of amorphous silica nanoparticles on Langerhans cells.

Amorphous silica nanoparticles (nSPs), are widely used in medicines, cosmetics and food. However, due to their reduced particle size they are suspected to pose new risks induced by changes in biological reactivity and kinetics, which differ from those of bulk materials. In a previous study, we showed that silica particles with a diameter of 70 nm penetrated the stratum corneum (SC) of mouse skin and were taken up by living cells such as keratinocytes and Langerhans cells. To clarify the relationship between particle size, distribution and cellular response, we have evaluated size-dependent intracellular localization and cytotoxicity of silica particles, using the mouse epidermal Langerhans cell line XS52. On treatment with silica particles of diameters 70, 300, and 1000 nm, cellular uptake and cytotoxicity increased with reduction in particle size. These results suggest that smaller sized silica particles induced greater cytotoxicity against Langerhans cells, which was correlated with the quantity of particle uptake into the cells.

The role of the ADC value in the characterisation of renal carcinoma by diffusion-weighted MRI.

The purpose of this study is to evaluate the role of diffusion-weighted imaging (DWI) in combination with T(1) and T(2) weighted MRI for the characterisation of renal carcinoma. The institutional review board approved the study protocols and waived informed consent from all of the patients. 47 patients (32 male and 15 female; age range, 21-85 years; median age, 65 years) who had suspected renal lesions on abdominal CT underwent MRI for further evaluation and characterisation of the lesions from April 2005 to August 2007 in our university hospital. A region of interest was drawn around the tumour area on apparent diffusion coefficient (ADC) maps. Final diagnosis was confirmed by histological examination of surgical specimens from all patients. The ADC value was significantly higher in renal cell carcinoma (RCC) than in transitional cell carcinoma (2.71+/-2.35 x 10(-3) mm(2) s(-1) vs 1.61+/-0.80 x 10(-3) mm(2) s(-1); p = 0.022). While analysing the histological subtypes of RCC, a significant difference in ADC values between clear cell carcinoma and non-clear cell carcinoma was found (1.59+/-0.55 x 10(-3) mm(2) s(-1) vs 6.72+/-1.85 x 10(-3) mm(2) s(-1); p = 0.0004). Similarly, ADC values of RCC revealed a significant difference between positive and negative metastatic lesions (1.06+/-0.38 x 10(-3) mm(2) s(-1) vs 3.02+/-2.44 x 10(-3) mm(2) s(-1); p = 0.0004), whereas intensity on T(1) and T(2) weighted imaging did not reach statistical significance. In conclusion, DWI has clinical value in the characterisation of renal carcinomas and could be applied in clinical practice for their management.

Early recurrence after surgical resection in patients with pathological stage I non-small cell lung cancer.

INTRODUCTION: Early recurrence is observed even in patients who undergo complete resection and had pathological (p-) stage I. Therefore, we focused on early recurrence, and attempted to elucidate the relationship between early recurrence and clinicopathological factors. METHODS: Between May 1993 and December 2005, 1201 patients with non-small cell lung cancer (NSCLC) underwent surgical treatment at our institution. Of these, 402 patients who underwent complete resection and had p-stage I NSCLC were retrospectively analyzed for clinicopathological factors. Patients were divided into four groups according to the period between surgery and recurrence (R): no recurrence (NR, n = 331), late recurrence (LR, n = 28, R > 2 years), intermediate recurrence (IR, n = 22, 1 year < R < or = 2 years), and early recurrence (ER, n = 21, R < or = 1 year). RESULTS: The overall 5-year survival rate for patients with p-stage I was 79.9 %. The overall 5-year survival rates were 91.0 %, 55.6 %, 17.1 %, and 7.5 % for the NR, LR, IR, and ER group, respectively. Preoperative high CEA level, lymphatic permeation, and pleural invasion were proven to be independent factors for overall recurrence. Moreover, multivariate analysis showed that preoperative CEA level, pathological T factor, lymphatic permeation, vascular invasion, and pleural invasion influenced early recurrence within one year. CONCLUSIONS: The present study demonstrated that preoperative CEA level, pathological T-factor, lymphatic permeation, vascular invasion, and pleural invasion were independent prognostic factors for early recurrence within one year, even in patients with pathological stage I. In patients with these factors, adjuvant therapy may be indicated since this may improve their survival.

[Development of fusion instruments (NT forceps) for video-assisted thoracic surgery].

A lobectomy is a standard surgical operation for lung cancer. Recently, the general surgical approach for this operation has been the use of a video-assisted procedure (video-assisted thoracic surgery: VATS). Almost all thoracoscopic instruments have been developed from classical instruments, scissors or forceps. We think that thoracoscopic instruments are often limited about the handling for the procedures, because the procedures are widely demanded to understand anatomical variations in an intrathoracic space. Fusion instruments (NT forceps) with atraumatic dispositions have been developed on our device, and they are so useful tools in all technical handlings for standard operations, lobectomy. And the forceps with a new device (such as LigaSure and Harmonic Scalpel) especially show a good combination technique.

Morbidity in video-assisted thoracoscopic lobectomy for clinical stage I non-small cell lung cancer: is VATS lobectomy really safe?

OBJECTIVE: The objective of this study was to compare video-assisted thoracoscopic lobectomy (VATS lobectomy) with standard thoracotomy in terms of morbidity and mortality. PATIENTS AND METHODS: Two-hundred and forty-nine consecutive patients with clinical (c) stage I non-small cell lung cancer who underwent surgery between 1999 and 2003 were retrospectively analyzed. All of the patients underwent surgical resection that was at least as extensive as lobectomy. VATS lobectomy was performed in 73 patients, and thoracotomy in 176 patients. RESULTS: The clinical stages were stage IA in 151 (60.6 %), and stage IB in 98 (39.4 %), and the pathological stages were I in 206 (82.7 %), II in 16 (6.4 %), and III in 27 (10.9 %). The mean operation time was 291 minutes for VATS and 215 minutes for thoracotomy ( P = 0.0 042). The mean blood loss was 160 ml and 191 ml ( P = 0.2 738), respectively. Mortality was 1.4 % (1/73) in the VATS group, and 2.3 % (4/176) in the thoracotomy group ( P = 0.6 438). Morbidity was 19.2 % (14/73), and 24.4 % (44/176), respectively ( P = 0.1 315). Air leakage was the most frequent complication. Anastomotic leakage was found in four patients who underwent thoracotomy. The incidence of pulmonary vessel injury was 8.2 % in the VATS group and 1.7 % in the thoracotomy group ( P = 0.0 361). While pulmonary vessel injury was observed frequently in the intermediate part of the study period, the incidence decreased in the late period. CONCLUSIONS: Pulmonary vessel injury, longer operation times, and greater blood loss have been frequently observed with VATS lobectomy. Proficiency is required to perform VATS lobectomy, and the procedure should be performed by a well-trained surgeon as indicated by the results of this study.

[Risk factors of recurrence in resected stage I non-small cell lung cancer].

We reviewed risk factors of recurrence in resected pathological stage I non-small cell lung cancer (I NSCLC). Objective is 229 complete resected I NSCLC in our department. Risk factors of recurrence were carcinoembryonic antigen (CEA), histology, differentiation, lymphatic invasion, blood vessel invasion, pleural invasion and tumor size. By univariate analysis, lymphatic invasion (p=0.009), blood vessel invasion (p=0.008), pleural invasion, p1 (p=0.013), p2 (p=0.001), and tumor size (value of cut off was 2 cm) were significant risk factors of recurrence. By multivariate analysis, blood vessel invasion (p=0.004), pleural invasion (p1 or p2) [p=0.001], were significantly risk factors of recurrence. It was suggested that I NSCLC presenting pathological blood vessel invasion and/or pleural invasion should be recognized as cases with a high risk of recurrence, and a strict follow-up and adjuvant therapy should be in consideration.

Unpleasant sweet taste: a symptom of SIADH caused by lung cancer.

A 56 year old woman with large cell lung carcinoma complained of an unpleasant sweet taste (dysgeusia). She developed hyponatraemia caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Dysgeusia disappeared when serum sodium normalised and recurred when hyponatraemia relapsed. Dysgeusia was the initial and only symptom of SIADH in this case.

Dysplastic ganglioneurocytoma with increased glucose metabolism: a heterotopia with unique histopathology.

A 1 year and 7 month old boy was incidentally found to have an intracranial mass lesion at the frontal base. The mass was 45 x 54 x 47 mm in size, contained a calcification, a few small cysts, and extended downward to the sphenoid sinus and upper pharynx. The signal intensity of the lesion on magnetic resonance imaging was iso-high on T1-weighted images, and slightly high on T2-weighted images, and it did not enhance with gadolinium injection. Although there was no obvious mass effect, 18F-fluorode-oxyglucose positron-emission tomography demonstrated increased uptake, and a surgical resection was performed suspecting a neoplastic lesion. Histologically, the lesion consisted of small to large anomalous neurons and glial cells but lacked normal cortical architecture. Cellularity was high in some portion with MIB-1 labeling index of 2%, but there was no cellular atypia suggestive of neoplasm. Therefore, this lesion was considered to be a dysplasia that does not fit into the previously described entity. We suggest this lesion would be better described as dysplastic ganglioneurocytoma.

Angiotensin-converting-enzyme inhibitors slow renal decline in IgA nephropathy, independent of tubulointerstitial fibrosis at presentation.

BACKGROUND: Tubulointerstitial fibrosis (TIF) is a marker of progression of diabetic and non-diabetic nephropathy, correlating with creatinine clearance (CCr), and functional outcome. Angiotensin-converting-enzyme inhibitors (ACEIs) slow the rate of decline of renal function in proteinuric patients. AIM: To examine whether ACEIs affect TIF, directly or indirectly. DESIGN: Prospective 3-year follow-up study. METHODS: We enrolled 49 patients with IgA nephropathy (IgAN), treating some with ACE inhibitors (n = 26, 1-2 mg/day temocapril or trandolapril) and some with calcium-channel blockers (CCB, n = 23, 2.5-5 mg/day amlodipine). Blood pressure, serum creatinine, and urinalysis were measured monthly, and 24-h endogenous creatinine clearance (CCr) at least once a year. RESULTS: In the CCB group, TIF was positively correlated with the rate of decline in CCr (dCCr), consistent with previous observations. In the ACEI group, dCCr was lower (0.02 +/- 0.02 vs. 0.06 +/- 0.03), and the TIF-dCCr correlation was absent. DISCUSSION: In the absence of post-treatment histological data, it is not possible to say whether ACEIs have an effect on TIF. However, ACEIs appear to slow the progression of renal failure in IgAN, regardless of the degree of TIF at presentation.

Expression of glucose transporter 5 by microglia in human gliomas.

Our previous studies indicate that glucose transporter 5 (GLUT5) is a microglial marker in routine paraffin sections, and is rarely present in monocytes/macrophages of the peripheral organs. We examined the expression of GLUT5 in 91 cases of human gliomas to characterize the microglial phenotype in glioma tissues. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections using such antibodies as a GLUT5 antibody, two markers for activated microglia: major histocompatibility complex (MHC) class II Ag and macrophage scavenger receptor class A (MSR-A), and MIB-1 antibody. The immunoreactivity of GLUT5 was present in three microglial phenotypes: ramified (resting), activated, and ameboid (macrophagic) microglia in most of the cases. A double-labelling study of astrocytic tumours using GLUT5 and MIB-1 antibodies demonstrated a proportion of proliferating microglia. However, no morphological difference between MIB-1-positive, microglial cells and MIB-1-negative, microglial cells was found. The number of GLUT5-positive microglia was significantly (P < 0.001) higher in astrocytic tumours than in oligodendroglial tumours. Many GLUT5-positive microglia (up to 52% in total cells) were often observed in pilocytic astrocytomas, where microglial cells were predominantly ramified, and the number of MHC class II- or MSR-A-positive microglia was less than GLUT5-positive microglia. Thus, the present study indicated that intrinsic microglia can be a source of microglia/macrophages cell populations in astrocytic tumours, and that pilocytic astrocytomas often have a high proportion of microglial cells with mild activation.

Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease.

BACKGROUND: Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. OBJECTIVE: To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. METHODS: Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. RESULTS: The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. CONCLUSION: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.