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.

Heat-stable spores of carotenoid-producing Bacillus marisflavi and non-pigmented Bacillus subtilis cooperatively promote growth, quality, and gut microbiota of white-leg shrimp.

We evaluated the benefits of heat-stable carotenoid-producing Bacillus marisflavi SH8 spores individually and in combination with non-pigmented Bacillus subtilis SH23 spores on growth, colour change, nutritional content, innate immunity, and gut microbiota of white-leg shrimp. White-leg shrimp (Litopenaeus vannamei; n = 30 per tank; 2 tanks per group) were provided feed without (control group) or with SH8, SH23, or mixed spores (total, 1 × 106 cfu/g pellet) for 28 d. The SH8 and SH8-23 combination groups had significantly higher specific growth rates (9.6 and 11.0%), improved red-colour score (4 scores), astaxanthin concentration (1.8- and 2.3-fold), lipid contents (30 and 50%), and superoxidase dismutase activity (8.5 and 12.3%) than that of the control group. Analysis of shrimp's gut microbiome using 16S rRNA metagenome sequencing revealed increased abundance of four useful species and reduced abundance of four harmful species in the combination group than in the control group. Heat-stable Bacillus spore combination improved growth parameters, nutrient content, red-colour score, live counts, and abundance of useful bacteria in the gut of L. vannamei. This is the first study to show the benefits of combining highly heat-stable pigmented and non-pigmented Bacillus spores and their possible mechanisms in a shrimp model.

Spinal cord hemangioblastomas in von Hippel-Lindau disease.

STUDY DESIGN: Retrospective data analysis. OBJECTIVE: To clarify the clinical features and surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease (VHL). SETTING: Clinical VHL Research Group in Japan, Japan. METHODS: Forty-eight out of 66 patients with associated spinal cord hemangioblastoma among 142 VHL patients were retrospectively examined with respect to clinical features, accompanying lesions and outcome of surgical treatment. RESULTS: Among these 48 patients, 46 of them (95.8%) also had a central nervous system (CNS) hemangioblastoma at another site: 42 (87.5%) with cerebellar hemangioblastoma and 11 (22.9%) with brain stem hemangioblastoma. Twenty-three patients (47.9%) had more than one spinal cord hemangioblastoma. The 48 patients with spinal cord hemangioblastomas collectively had a total of 74 tumors. The tumor was accompanied with a syrinx in 64 and without it in 10 patients. Forty of the 48 patients underwent surgical treatment for their spinal cord hemangioblastomas, and 7 of these 40 underwent surgical treatment twice. When functional changes in the patients after these 47 operations were examined by postoperative evaluation by McCormick's classification, 39 of these operations (83.0%) resulted in improvement/no change and 8 (17.0%) in aggravation of symptoms. CONCLUSION: Von Hippel-Lindau disease patients bearing spinal cord hemangioblastomas mostly had a CNS hemangioblastoma at another site. These tumors can be removed in the majority of VHL patients without aggravation. In these patients, when the timing of treatment for spinal cord hemangioblastoma is determined, the probability of occurrence and treatment of other lesions should be considered.

Nationwide surveillance of IC anterior (or dorsal) wall aneurysm: with special reference to its dissecting nature.

Two hundred and twenty-one cases of IC dorsal aneurysm (ICDA) with subarachnoid hemorrhage (SAH) from 365 cases in the nationwide surveillance of ICDA (NSICDA) data bank were studied with special reference to the dissecting type. Dissection of the internal carotid artery (ICA) was confirmed in 50 out of 221 SAH cases. In 193 surgically treated cases, 40 were of the certified dissecting type. Including those with clinical features which strongly suggests the existence of dissecting changes in the ICA wall, 97 cases (55.6% of operated) were thought to be a dissecting type. Incidence of intraoperative bleeding is significantly higher and surgical outcome is significantly worse in the dissecting type than in the non-dissecting type. Treatment options for this peculiar and formidable aneurysm (An) are described.

The factors associated with fascicular block in acute anteroseptal infarction.

To elucidate the genesis and effect of fascicular block, 131 patients with acute Q-wave anteroseptal infarction were studied. Thirty-seven patients had new onset of fascicular block in the coronary care unit. The hospital mortality rate was 16%. Multivariate analysis was performed to determine the important variables related to the occurrence of fascicular block and hospital mortality based on 17 clinical variables obtained at the time of hospital admission. Serum potassium level and heart rate were the significant factors predicting the occurrence of fascicular block, whereas cardiac output and arterial oxygen tension were important for hospital mortality. Therefore, not only the rise in the heart rate but also the effect of the serum potassium level on the conduction system are independent factors related to the occurrence of fascicular block, and fascicular block in itself has no significant influence on the hospital mortality.

Management of severe subarachnoid hemorrhage; significance of assessment of both neurological and systemic insults at acute stage.

In order to elucidate mutual interrelationship between neurological and systemic dysfunctions in patients with subarachnoid hemorrhage (SAH) at acute stage, neurological condition, systemic complications and plasma catecholamine (CA) level were studied in 1431 consecutive cases admitted within 72 hours after the onset. Five hundred and twenty-four cases with Glasgow Coma Scale (GCS) score 8 or less were assigned to the group of severely ill cases (G-ill), 907 cases with GCS score 9 or more to that of the less ill group (G-well). Plasma CA level was extremely high at super-acute stage within an hour after bleeding and lowered fairly quickly within 24 hours to the normal range. Assuming the value obtained from a formula of [blood sugar level (mg/dl)/serum potassium concentration (mEq/L)] as stress index (SI), SI correlates well (r = 0.4-0.6) with serum catecholamine level at acute stage. Thus, sympathetic hyperactivity after SAH can be grossly estimated with SI. SI over 40 means that patients might have considerable neurological insults as well as systemic ones. For patients in G-well, SI over 50 means that there may be risks for systemic complications even in cases with good neurological condition.

Common regions of deletion on chromosome 22q12.3-q13.1 and 22q13.2 in human astrocytomas appear related to malignancy grade.

Approximately 30% of human astrocytomas have been reported to display allelic loss of the long arm of chromosome 22, suggesting the presence of a chromosome 22q astrocytoma suppressor gene. To define the most likely location for this putative tumor suppressor, we performed deletion mapping on 141 tumors using 16 chromosome 22q microsatellite markers. Allelic loss of 22q was observed in 2/12 (17%) of astrocytomas, 9/29 (31%) of anaplastic astrocytomas, and 38/100 (38%) of glioblastomas, consistent with a role for chromosome 22q loss in astrocytoma progression as well as formation. Twenty-two tumors exhibited allelic loss at every informative locus, consistent with loss of the entire arm of 22q. Twenty-seven tumors showed partial deletions, with one common region of deletion at 22q12.3-q13.1 between markers D22S280 and D22S282, and a second candidate region at 22q13.2 near the marker D22S1170. For the proximal candidate region, the incidence of allelic loss was similar between grades; for the distal locus, the incidence increased with grade, raising the possibility that the distal locus is involved in a later stage of astrocytoma tumorigenesis.

High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme.

BACKGROUND AND PURPOSE: Although glioblastoma multiforme is clearly radiation-resistant, there is evidence of a dose-dependent response relationship. The purpose of the study was to evaluate the impact of higher dose by rotational multileaf collimator (MLC) conformal radiation therapy. MATERIALS AND METHODS: From 1984 to 1995, 38 consecutive cases with intracranial glioblastoma multiforme were treated using the rotational MLC conformal therapy. There were 25 men and 13 women with a median age of 47 years (12-73 years, mean 46.5 years). Median Karnofsky performance score was 80 (30-100, mean 78.2). Median tumor volume was 64 cc (8-800 cc, mean 110.3 cc). All underwent surgical intervention (only biopsy in 1, partial resection in 13, subtotal resection in 21, and gross total resection in 3). Radiation dose to was 60 to 80 Gy (median 68.5 Gy, mean 68.3 Gy) in 21 patients treated before 1990 and 90 Gy in the 17 patients thereafter. Biweekly i.v. chemotherapy was also administered for both arms. RESULTS: The 1-year, 2-year, 5-year, and 10-year overall survival rates were 75%, 42%, 20%, and 15%, respectively. Univariate analysis showed the initial tumor volume, residual tumor volume, and Karnofsky performance score were statistically significant factors for survival. Only the residual tumor volume was statistically significant by multivariate analysis. The 5-year survival rate of patients with residual tumors of 5 cc or less in volume was as good as 37%. Survival of the 90-Gy Group appeared inferior to that of the Low-Dose Group, though no statistical difference was seen (the 3-year survival was 40% vs. 22%). Local failure was observed in 16 of the 19 recurrences in the Low-Dose Group, whereas it was observed in only 4 of the 13 recurrences in the 90-Gy Group. The difference in pattern of failure was statistically significant. Two patients of the High-Dose Group developed radiation necrosis and one died of it. CONCLUSIONS: The high-dose conformal radiotherapy did not improve survival in the disease, but did change the pattern of failure.

Effects of fixation time and enzymatic digestion on immunohistochemical demonstration of bromodeoxyuridine in formalin-fixed, paraffin-embedded tissue.

We studied the effects of fixation time and enzymatic digestion on immunohistochemical staining for bromodeoxyuridine (BUdR) in excised rat and human gastrointestinal tissues and human brain tumors which had been fixed in formalin after intravenous administration of BUdR shortly before biopsy of tissue. In formalin-fixed rat gastrointestinal tissues not treated with proteinase, the reaction products were insufficient to identify BUdR-positive cells. Results similar to those in ethanol-fixed tissue were obtained when formalin-fixed tissue sections were treated with protease, pepsin, or trypsin. The longer the material had been fixed in formalin, the longer the incubation in proteinase required to identify BUdR-labeled nuclei. The BUdR labeling indices of formalin-fixed human brain tumor specimens treated with protease were comparable to those of ethanol-fixed tissues. Sufficient BUdR staining was obtained even in tissues fixed in formalin for prolonged periods. Therefore, the BUdR labeling index can be determined retrospectively in clinical materials stored in formalin.

Effect of exercise on ventricular diastolic time in coronary artery disease.

To evaluate diastolic time during uninterrupted upright exercise, 28 normal volunteers (group 1) and 12 men with coronary artery disease (group 2) were studied by ear densitography. Electromechanical systole-heart rate and diastolic time-heart rate regression equations during upright exercise were obtained from group 1. Electromechanical systole-heart rate had an inverse linear relation (electromechanical systole = 480 - 1.4 heart rate) and diastolic time-heart rate had an inverse nonlinear relation (diastolic time = 1206e-0.02 heart rate). Although there were no significant differences in electromechanical systole and diastolic time at 1 minute of exercise between patients with and without CAD, at peak exercise prolongation of electromechanical systole and consequent shortening of diastolic time in patients with CAD were observed. This disproportionate shortening of diastole with lengthening of systole at peak exercise tends to decrease myocardial perfusion and, hence, oxygen supply, while increasing myocardial oxygen demand, contributing to aggravation of ischemia in patients with CAD.

Factors associated with persistent and transient fascicular blocks in anterior wall acute myocardial infarction.

To determine the factors associated with persistent and transient fascicular blocks, 144 patients with Q-wave anterior wall acute myocardial infarction (AMI) were studied. Thirty-three patients had new onset of fascicular block considered to be a consequence of AMI. Multivariate analysis using 16 clinical variables revealed that the number of asynergic segments, serum potassium level and pericardial rub were significant factors related to the occurrence of fascicular block. Among the 33 patients with fascicular block, 18 had persistent (group 1) and 15 had transient (group 2) fascicular blocks. When the 2 groups with fascicular block were compared, group 1 had significantly more asynergic segments than group 2 (4.7 +/- 1.2 vs 3.7 +/- 1.6, respectively), whereas pericardial rubs were observed significantly more in group 2 (67%) than in group 1 (28%). Therefore, the inflammatory process of AMI was 1 of the mechanisms related to the occurrence of a transient fascicular block and a more extensive myocardial necrosis was associated with a persistent fascicular block.

Effect of cilostazol in preventing restenosis after percutaneous transluminal coronary angioplasty.

This study sought to evaluate the effect of cilostazol in preventing restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) in 68 patients: 35 patients received cilostazol immediately after PTCA and 33 patients received aspirin or ticlopidine. Repeat coronary angiography was performed 4 to 6 months after PTCA and the incidence of restenosis was significantly lower (17%) in the cilostazol group than in the non-cilostazol group (40%) (p < 0.05), which indicates that cilostazol has the potential to prevent restenosis after PTCA.

Diastolic time and left ventricular performance during one- and two-handed weight holding.

To evaluate the difference in DT and systolic time intervals during one-handed and two-handed weight holding with the same total load, the DT-heart rate relationship was studied in 12 patients and ten normal volunteers. Heart rate, blood pressure, and pressure-rate product were significantly higher in one-handed compared with two-handed weight-holding exercise in patients with MI. Although there were no significant differences in QS2 and DT between the two types of weight-holding exercise in normal volunteers, QS2 was significantly longer and DT was significantly shorter in one-handed compared with two-handed weight-holding exercise in patients with MI. Disproportionate shortening of DT with higher pressure-rate product during one-handed compared with two-handed weight-holding exercise can initiate an imbalance of myocardial oxygen supply and demand in patients with MI.

Disturbance of pulmonary gas exchange in patients with right ventricular infarction.

To evaluate the difference in pulmonary gas exchange in patients with and without right ventricular infarction, 147 consecutive patients with their first inferior wall Q-wave acute myocardial infarction were studied. Thirty-nine patients (group 1) had electrocardiographic evidence of right ventricular infarction and it was absent in 108 patients (group 2). A significantly wider alveolar arterial oxygen difference and higher roentgenographic scores were observed in group 1 compared with group 2. Although there were no significant differences in pulmonary artery wedge pressure and colloid osmotic pressure between groups 1 and 2, mean right atrial pressure was significantly higher, while cardiac output and mixed venous oxygen saturation were lower in group 1 compared with group 2. Patients in group 1 had significantly more left ventricular segments with advanced asynergy and higher incidence of proximal right coronary artery lesions than those in group 2. Thus, our data suggest that disorder of pulmonary gas exchange in patients with right ventricular infarction may be explained by increased permeability of the alveolar capillary membrane secondary to larger extent of ischemic myocardium and by hemodynamic abnormalities associated with right ventricular infarction.

Clinical significance of pericardial rub with regional ventricular dilatation.

To elucidate the clinical characteristics associated with regional ventricular dilatation in the early phase of myocardial infarction (MI), 228 patients with acute Q-wave anterior MI were studied. Forty-nine patients (21 percent) had echocardiographically demonstrated regional ventricular dilatation (an abnormal bulge in the left ventricular contour during both systole and diastole) on the third hospital day. Careful auscultation revealed that a pericardial rub was present in 49 patients (21 patients with and 28 patients without regional ventricular dilatation) during the first three days after hospital admission. Multivariate analysis was performed to determine the relative importance of pericardial rub with six other clinical variables related to regional ventricular dilatation. Pericardial rub and cardiac output were the significant factors related to the presence of regional ventricular dilatation. Thus, a pericardial rub, in concert with impaired left ventricular function, is a physical sign associated with regional ventricular dilatation, and anatomically transmural infarction is the possible factor explaining their association.

Diastolic time during static and dynamic exercise in myocardial infarction.

To evaluate the difference in the response of DT in the early phase of static (sustained weight load) and dynamic (treadmill) exercise, the relation of DT and HR was studied by ear densitography in 11 patients with myocardial infarction. None of the patients had an ischemic electrocardiographic response during exercise. Despite an increase in HR and the pressure-HR product with both types of exercise, the pressure-HR product was significantly higher at three minutes of dynamic exercise, which was associated with a significant lengthening of left ventricular ejection time. Diastolic blood pressure rose significantly during static exercise, but it remained unchanged with dynamic exercise. Electromechanical systole and HR had a linear inverse relation at three minutes of exercise, and DT and HR had a nonlinear inverse relation (DT = e7.29-0.0156 x HR, and DT = e7.07-0.0142 x HR for static and dynamic exercises, respectively). A significant prolongation of QS2 with a consequent shortening of DT (p less than 0.05) was observed in dynamic exercise. In addition to a higher pressure-HR product, the disproportionate shortening of diastole in the early phase of dynamic exercise has a potential for initiating imbalance of myocardial oxygen supply and demand.

Participation of poly(ADP-ribose) polymerase in the drug sensitivity in human lung cancer cell lines.

Poly(ADP-ribose) polymerase has been generally assumed to be involved in DNA repair. The level of the enzyme in various lung cancer cell lines was examined to determine if it is involved in drug resistance. Among nine cell lines of lung cancer tested, small-cell lung cancer lines, which showed higher sensitivity to cisplatin and etoposide, were unexpectedly found to contain significantly higher poly(ADP-ribose) polymerase activity than five non-small-cell lung cancer cell lines. This activity inversely correlated with IC50 values of lung cancer cell lines to etoposide, an inhibitor of topoisomerase II. The polymerase activity was also examined in several cisplatin-resistant variants of the cell lines. However, no difference was observed between parental and cisplatin-resistant cells. There was no significant relation between poly(ADP-ribose) polymerase activity and IC50 values for cisplatin and carboplatin. Although this enzyme was considered to play some role in the resistance to specific drugs, it might not be a critical factor in cisplatin-induced cytotoxicity.

Successful treatment of recurrent malignant germ cell tumors: report of two cases.

We report two patients with recurrent malignant germ cell tumors who were successfully treated with radiation therapy and cisplatin combination chemotherapy. Patient 1, who had a suprasellar mixed yolk sac tumor, had been free of tumor for 3.5 years after cisplatin/vinblastine/bleomycin combination chemotherapy alone but showed a recurrent tumor in the pineal region. In Patient 2, who had a pineal alpha-fetoprotein-producing tumor, recurrent tumors appeared in the lateral ventricle 3 years after the tumor was controlled by radiation and cisplatin/vinblastine/bleomycin therapy. They were treated successfully again by radiation therapy, followed by cisplatin and etoposide combination therapy, and they have been free of tumor for 5.5 and 7 years after recurrence, respectively. The total dose of cisplatin in both patients exceeded 1,000 mg/m2, which would have contributed to the control of the recurrent tumors. Anterior pituitary dysfunction observed in Patient 1 did not improve, even after tumor disappearance by chemotherapy, suggesting severe damage to the neurohypophysis by direct invasion of the tumor.

Malignant growth hormone-secreting pituitary adenoma with hematogenous dural metastasis: case report.

A rare case of growth hormone-secreting pituitary adenoma with hematogenous metastasis to the dura mater of the cerebral convexity is presented. Immunohistological staining was essential to the diagnosis. The histological findings demonstrated that the metastasis was blood-borne. Extensive removal of the tumor and postoperative chemotherapy resulted in partial remission. The mechanism of metastasis, the histological findings, the treatment, and the prognosis are discussed.

Successful combination chemotherapy (cisplatinum, vinblastine, and bleomycin) in the treatment of medulloblastoma disseminated by cerebrospinal fluid: case report.

A case of successful combination chemotherapy using cisplatinum, vinblastine, and bleomycin (PVB therapy) to treat medulloblastoma disseminated by cerebrospinal fluid is presented. In this case, a locally recurrent tumor and several disseminated tumors were seen to decrease in size on CT examinations. Pain in the lower extremities and urinary incontinence improved during three courses of PVB therapy administered during a period of 9 weeks. These results suggest that combination PVB therapy may offer one of the treatments of choice for recurrent or disseminated medulloblastoma.