Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Increased plasma LIGHT levels in patients with atopic dermatitis.

LIGHT [the name of which is derived from 'homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator (HVEM), and expressed by T lymphocytes'], is a member of the tumour necrosis factor superfamily that is involved in various inflammatory diseases. We aimed to estimate the relevance of plasma LIGHT levels as a biomarker for atopic dermatitis (AD). In order to understand the putative role of LIGHT in AD pathogenesis, we also investigate the effects of LIGHT on a monocytic cell line, human acute monocytic leukaemia cell line (THP-1). We examined plasma LIGHT levels, total serum IgE, serum value of CCL17 and peripheral blood eosinophil counts in patients with AD and healthy subjects. The effects of LIGHT on activation and apoptosis in THP-1 cells were also investigated. The plasma concentrations of LIGHT in AD patients were significantly higher than those in healthy individuals and the concentrations decreased as the symptoms were improved by treatment. The LIGHT plasma concentrations correlated with IgE levels and the Severity Scoring of AD (SCORAD) index. In addition, LIGHT stimulation increased expression of CD86 and induced production of interleukin-1ß in THP-1 cells. Apoptosis was inhibited, the Bcl-2 level increased and the caspase-3 level decreased in THP-1 cells stimulated with LIGHT, compared to unstimulated control cells. These results suggest that plasma LIGHT levels may be one of the promising biomarkers for AD.

Skin autofluorescence is associated with severity of vascular complications in Japanese patients with Type 2 diabetes.

AIMS: Skin autofluorescence, a non-invasive measure of the accumulation for advanced glycation end products, has been reported to be a useful marker for diabetic vascular risks in the Caucasian population. The aim of this study was to evaluate associations between skin autofluorescence and vascular complications in non-Caucasian patients with Type 2 diabetes. METHODS: Subjects in this cross-sectional study comprised 130 Japanese patients with Type 2 diabetes. Skin advanced glycation end products were assessed by skin autofluorescence using an autofluorescence reader. Association between skin autofluorescence and severity of vascular complications was evaluated. RESULTS: Of the 130 patients, 60 (46.2%) had microvascular complications such as diabetic retinopathy, neuropathy and nephropathy, 10 (7.7%) had macrovascular complications and 63 (48.5%) had micro- and/or macrovascular complications. Skin autofluorescence increased with severity of vascular complications. Independent determinants of skin autofluorescence were age (ß = 0.24, P < 0.01), mean HbA(1c) in previous year (ß = 0.17, P = 0.03), microvascular complications (ß = 0.44, P < 0.01) and macrovascular complications (ß = 0.27, P < 0.01). Multiple logistic regression analysis revealed that diabetes duration (odds ratio 1.15, P < 0.01), systolic blood pressure (odds ratio 1.04, P = 0.01), skin autofluorescence (odds ratio 3.62, P = 0.01) and serum albumin (odds ratio 0.84, P < 0.01) were independent factors for the presence of vascular complications in these patients. CONCLUSIONS: Skin autofluorescence had independent effects on vascular complications in Japanese patients with Type 2 diabetes. This indicates that skin advanced glycation end products are a surrogate marker for vascular risk and a non-invasive autofluorescence reader may be a useful tool to detect high-risk cases in non-Caucasian patients with diabetes.

Astrocytes co-express aquaporin-1, -4, and vascular endothelial growth factor in brain edema tissue associated with brain contusion.

INTRODUCTION: Brain edema may be life threatening. The mechanisms underlying the development of traumatic brain edema are still unclear; however, mixed mechanisms including vasogenic, ischemic, and neurotoxic types of edema may be contributors. Recent studies indicate that astrocytes, aquaporins (AQPs; a protein family of water channels), and vascular endothelial growth factor (VEGF) may have important roles in the formation and resolution of brain edema. We studied the expression of AQPs and VEGF in the edematous brain. METHODS: We investigated the expression of AQP1, AQP4, and vascular endothelial growth factor (VEGF) in contusional brain tissue surgically obtained from 6 patients. Glial fibrillary acidic protein (GFAP) was also stained to detect astrocytes and to clarify the location of those proteins. The specimens received immunohistological staining and 3-color immunofluorescent staining, and were observed using confocal laser scanning microscopy. RESULTS: AQP1, AQP4, and VEGF were co-expressed in GFAP-positive astrocytes. AQP1 and AQP4 were expressed strongly in astrocytic end-feet. The astrocytes were located in the edematous tissue, and some cells surrounded cerebral capillaries. CONCLUSION: Our results suggest that AQP1, AQP4, and VEGF are induced in astrocytes located in and surrounding edematous tissue. Those astrocytes may regulate the water in- and out-flow in the injured tissue.

Congenital malignant melanoma: a case report.

Congenital malignant melanoma (MM) is an uncommon condition that is defined as MM recognized at birth. Its incidence is difficult to determine because of the small number of reported cases and because of problems associated with diagnosis. Generally, Spitz naevus and melanoma have many clinical and histopathological similarities, so it is difficult to differentiate between the two. We describe a rare case of congenital MM in which differential diagnosis from Spitz naevus was problematic. In addition, we review the literature and comment on the prognostic differences among the three types of congenital and infantile MM.

Tissue reconstruction process in the area of peri-tumoural oedema caused by glioblastoma--immunohistochemical and graphical analysis using brain obtained at autopsy.

BACKGROUND: In the area of peri-tumoural oedema, proteolytic agents derived from the tumour cause tissue degradation, which promotes tumour cell invasion. METHOD: We investigated the biological processes in the area of peri-tumoural oedema, using a brain obtained at autopsy from a patient who died from glioblastoma. Immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF), c-myc, p53, paternally expressed gene-3 (PEG-3), transforming growth factor beta (TGFB), and tumour necrosis factor alpha (TNFA). The data were translated into colour graphics and the localization of these proteins was analyzed. FINDINGS: In the area of peri-tumoural oedema, Ki-67 and p53 positive cells were observed with TGFB expression. Moreover, c-myc, PEG-3, VEGF, and TNFA were also expressed strongly in the glial cells or extra-cellular spaces in the area of peri-tumoural oedema. INTERPRETATION: These data suggest that in the area of peri-tumoural oedema, tissue reconstruction processes take place with concomitant anti-tumour activities. The expression of c-myc, VEGF, and TNFA in the area of peri-tumoural oedema may indicate that these proteins are not utilized for tumour growth, but may be used to guard the brain against tumour invasion. Peri-tumoural oedema does not only indicate the tissue damage caused by tumour, but many tissue reconstruction processes take place in these areas against tumour cell invasion.

Very early expression of vascular endothelial growth factor in brain oedema tissue associated with brain contusion.

BACKGROUND: Brain oedema associated with cerebral contusion can be life-threatening. Mechanisms of the development of brain oedema are still unclear. METHOD: We investigated the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (KDR/Flk-1) in the contusional brain tissue obtained during neurosurgery from 5 patients. FINDINGS: VEGF is expressed in some but not all the astrocytes, and KDR/Flk-1 is expressed in vascular endothelial cells in the con-tusional tissue as early as 3 hours after onset. CONCLUSION: The results suggested that the VEGF is induced in the contusional tissue in the very early period after onset, and that it increases capillary permeability via KDR/Flk-1 resulting in vasogenic type brain oedema.

Different distribution of c-myc and MIB-1 positive cells in malignant meningiomas with reference to TGFs, PDGF, and PgR expression.

We investigated the expression of transforming growth factors (TGFs), platelet-derived growth factor (PDGF), progesterone receptor (PgR), and c-myc in 20 cases of meningioma of various grades: 17 benign, 2 atypical, and 1 anaplastic. All cases of atypical and anaplastic meningioma were positive for c-myc, whereas all 17 benign meningiomas were negative for c-myc immunostaining. Expression of TGF-alpha, TGF-beta, and PDGF-BB proteins was seen in more than 80% of the meningioma cases and was not restricted to their histological grade of meningioma. PgR was expressed mainly in benign meningiomas. Moreover, the cells expressing c-myc protein were not usually stained by MIB-1. These results indicate that c-myc does not directly work on the proliferation of meningioma cells, and even in homogeneous meningioma cells, there may be many functional variations that lead the meningioma cells to their growth.

Exclusively epidural arteriovenous fistula in the cervical spine with spinal cord symptoms: case report.

OBJECTIVE AND IMPORTANCE: We describe the case of an epidural arteriovenous fistula (AVF) in the cervical spine draining only into the epidural and paravertebral plexus. An entirely epidural AVF having such drainage is extremely rare. CLINICAL PRESENTATION: A 24-year-old man presented with a 4-month history of gradually progressive sensory and motor disturbances of the upper and lower extremities. Magnetic resonance imaging and magnetic resonance angiography revealed a peridural vascular lesion within the canal compressing the spinal cord from C5 to T2. Diagnostic angiography revealed a perimedullary and/or dural high-flow AVF, fed mainly by branches of ascending cervical and deep cervical arteries. The fistula drained into the epidural and paravertebral venous plexus without reflux into intradural venous systems. INTERVENTION: Multiple feeders of the AVF were embolized with a Liquid coil and n-butylcyanoacrylate via a two-step procedure. One week after embolization, the AVF was surgically removed. CONCLUSION: Interesting points of this case were the exclusively epidural location of the lesion, the exclusively epidural drainage of the AVF, and the etiology of the symptoms. Venous drainage of the fistula had no relation to any dural or intradural veins. Initially, spinal cord and nerve root compression by extradural veins with varicose dilation seemed to cause the radiculopathy and/or the myelopathy, and subsequent myelopathy caused by spinal venous hypertension was believed to be the main etiology in this case.

Immunohistochemical and immunogenetic analyses of ocular adnexal lymphoid proliferation.

PURPOSE: To compare polymerase chain reaction (PCR) results with histological, immunohistochemical, and clinical findings to understand the nature of ocular adnexal lymphoid proliferation. METHODS: We examined 20 cases (21 specimens) of ocular adnexal lymphoid proliferation, using histological, immunohistochemical, and molecular genetic methods. The latter two types of experiments were performed to examine the light chain restriction of immunoglobulin using the peroxidase-antiperoxidase method, and the clonality of immunoglobulin heavy chains using the PCR method. RESULTS: Although in 8 cases it could not be determined morphologically whether the tumors were neoplastic or not, clonality was revealed in 1 case by immunohistochemistry and in 4 cases by PCR. Two cases showed disparate results between immunohistochemistry and PCR, probably due to somatic mutation of the framework region of the immunoglobulin heavy chain gene. CONCLUSION: Examination using these methods contributes to a better understanding of the nature of the ocular adnexal lymphoid proliferation. Furthermore, the immunoglobulin gene PCR method is very useful in practice for examination of specimens, as it can be used with formalin-fixed and paraffin-embedded specimens.

[Avascular necrosis of the femoral head caused by steroid treatment in neurosurgery].

Steroid induced avascular necrosis of the femoral head is a well known disease, but, there are few reports about the disease in neurosurgical patients. In the neurosurgical field, the use of steroids has become prevalent since the 1960's. Recently, the adverse effect of steroids and the limitation of its effect have been highlighted, but its use against neurosurgical diseases is still a common treatment to prevent cerebral edema or to counteract hypo-pituitarism caused by hypophyseal lesions. We reviewed 250 patients of avascular necrosis treated between 1985 and 1997 in our institute. Within these patients, 11 (4.4%) were treated with steroid during neurosurgical treatment. Six patients were treated for brain tumors near hypophyseal lesions, and 5 patients were treated for head injury or cerebro-vascular disease. It is concluded that total steroid dose over 5000 mg such as hydrocortisone may become a high risk for causing avascular necrosis of the femoral had in neurosurgical disease, and it may occur even with the supplemental steroid treatment against hypo-pituitarism. The onset is usually 2 or 3 years after the neurosurgical treatment, when neurosurgical care is no longer needed. Therefore, it tends to be ignored in the neurosurgical field. The treatments against avascular necrosis of the femoral head were femoral head osteotomy or conservative management, and good results were obtained. Early diagnosis and early treatment is essential. Further consideration concerning steroid treatment in neurosurgical patients may be required.

[Irinotecan (topoisomerase-I inhibitor) for the treatment of recurrent primary intracranial malignant lymphoma].

Primary intracranial malignant lymphoma is a fetal disease with poor prognosis, and there is no effective treatment against recurrent primary intracranial malignant lymphomas. We report 3 cases of malignant lymphoma treated with irinotecan (topoisomerase-I inhibitor, camptothecin derivatives), an aromatic drug extracted from camptotheca acuminata. After the initial diagnosis, surgical resection followed by radiation therapy was performed for one cerebral, and two cerebellar malignant lymphomas. The tumors recurred 1 month, 18 months, and 18 months after the initial treatment, respectively. The former two cases were treated with additional radiation therapy and/or radiosurgery for the recurrent tumors; however, the tumors recurred again. All cases were treated finally with a combination therapy of irinotecan and cis-platinum followed by a maintenance therapy with irinotecan only. All cases showed a sharp roentgenographical response to the chemotherapy even after cumulative recurrences. One patient died of systemic infection, and another died of intracranial tumor recurrence 11 and 29 months after the initial diagnosis, respectively. Autopsies revealed multiple tumor recurrences in both these cases. The other patient died 31 months after the initial diagnosis, also due to intracranial tumor recurrences. These results indicate the usefulness of irinotecan for the treatment of recurrent primary intracranial malignant lymphoma; however, further investigation is necessary to establish a better protocol for irinotecan treatment against primary intracranial malignant lymphoma.

Graphic analysis of microscopic tumor cell infiltration, proliferative potential, and vascular endothelial growth factor expression in an autopsy brain with glioblastoma.

BACKGROUND: Growth of brain tumors requires tumor-cell attachment to adjacent structures, degradation of surrounding matrixes, migration of tumor cells, proliferation of vasculature, and tumor cell proliferation. Comparison of the findings on neuroimaging, degrees and patterns of tumor invasion, regional tumor cell viability detected by Ki-67 immunohistochemistry, and regional vascular endothelial growth factor (VEGF) expression in whole-brain specimen of glioblastoma therefore is of great interest, and will facilitate study of the host reaction against the glioblastoma. METHODS: We graphically analyzed microscopic tumor-cell infiltration, regional differences in Ki-67 labeling indices (LI), and immunohistochemical expression of VEGF in an autopsy brain with glioblastoma. RESULTS: Glioblastoma cells infiltrated the brain far beyond the gross limits of the tumor and the areas with high signal intensity on T2-weighted magnetic resonance images. A wide range of histologic malignancy was apparent from hematoxylin-eosin staining and the Ki-67 labeling indices. VEGF was highly expressed in normal astrocytes located outside the tumor. CONCLUSION: Graphic analysis of histologic and immunohistochemical patterns is a useful method of investigating the mechanisms of glioma growth, tumor cell infiltration in the brain, and the host reaction of the brain against neoplasms.

Fluorescence automatic cell sorter and immunohistochemical investigation of CD68-positive cells in meningioma.

Infiltration of brain neoplasms by mononuclear cells including monocytes/macrophages has attracted little attention since they have marked morphological heterogeneity. Twenty-seven meningiomas were studied by anti-CD68 antibody-gated flow cytometry and by immunohistochemical analysis using the anti-CD68 antibodies. Flow cytometric analysis divided cells contained within tumor tissues into CD68-positive and -negative cells. In addition, eight gliomas, eight metastatic brain tumor, and 12 pituitary adenomas were investigated in the same way to compare meningiomas. The mean contents of CD68-positive cells were 24.0 +/- 3.7% in meningiomas, 4.4 +/- 1.4% in gliomas, 9.5 +/- 3.9% in metastatic brain tumors, and 4.5 +/- 1.8% in pituitary adenomas. Immunohistochemically, CD68-positive cells showed significant heterogeneity and were detected as round, rod-shaped, ameboid and ramified cells in meningiomas. Although the infiltrated mononuclear cells in gliomas have been investigated to some degree and showed that they express cytokines and/or growth factors, these infiltrated cells in meningioma have barely been studied. The CD68-positive cells detected in this study are likely to be monocytes, macrophages and microglias, and are presumed to be in various functional stages and to play important roles in growth regulation in meningioma.

[A case of spontaneous middle cerebral artery occlusion associated with a cerebral aneurysm angiographically disappearing after STA-MCA anastomosis].

We report a case of a rapidly growing cerebral aneurysm in the basal abnormal vascular network associated with spontaneous middle cerebral artery (MCA) occlusion. The aneurysm disappeared spontaneously shortly after performing STA-MCA anastomosis. A 54-year-old female was admitted to our hospital because of repeated attacks of right hemisensory disturbance and dysarthria. CT scan and MRI images showed the infarcted focus in the left parieto-occipital lobe. Bilateral MCAs were undetectable on MRI images. Cerebral angiography revealed that the bilateral MCAs were occluded in their proximal origin with basal abnormal vascular networks. The distal MCA branches were perfused via the vascular networks. A small aneurysm was detected in the distal portion of the left Heubner's artery. There were no abnormalities in the bilateral internal carotid arteries, the anterior cerebral arteries, and the basilar artery. The follow-up angiography performed 29 days after admission revealed a growing aneurysm with a diameter of 3 mm in the distal enhanced lesion consistent with the aneurysm observed in the angiography. An STA-MCA anastomosis was performed for improvement of cerebral misery perfusion. Single photon emission tomography (SPECT) performed 9 days after the bypass operation revealed improvement of cerebral blood flow in the left parieto-occipital lobe, and her TIA attacks disappeared. The aneurysm was undetected in the cerebral angiography performed 24 days after the bypass operation. Spontaneous MCA occlusion is a rare condition of chronic cerebrovascular occlusive diseases. Diagnostic criteria of the disease includes the MCA occlusions or stenosis with basal abnormal vascular networks. Usually the phenomenon is seen unilaterally, which differs from moyamoya disease. Diagnosis must exclude diseases caused by the etiologies such as those of arteriosclerotic origin. There have been 24 reported cases of spontaneous MCA occlusion including our case. Among them, 9 cases presented cerebral aneurysm located in abnormal vascular networks, and all the reported cases presented cerebral hemorrhage at their onset. The abnormal basal vascular network may be developed as collateral vessels to supply blood to the ischemic regions in this disease. An increased hemodynamic stress in the abnormal basal vascular network may produce a true aneurysm in the distal portion of the perforating arteries. STA-MCA anastomosis reduced the TIA attacks, but also decreased the hemodynamic stress on the abnormal basal vascular network and resulted in reduction in size or thrombosis of the aneurysm. STA-MCA anastomosis can be considered effective to treat cerebral aneurysms located in vessels with increased hemodynamic stress.

Meningoencephalocele associated with Tripterygium wilfordii treatment.

We treated a male infant with occipital meningoencephalocele associated with the taking of Tripterygium wilfordii. The infant was delivered normally at 38 weeks of gestation with a huge cystic mass protruding from the occiput. He was diagnosed with occipital meningoencephalocele and cerebellar agenesis. His mother had taken T. wilfordii for rheumatoid arthritis early in her pregnancy. T. wilfordii is a herbal medicine used for rheumatoid arthritis and male contraception. Since its toxicity is high and its use during pregnancy is restricted, it is the most likely cause of this infant's anomalies.

[Immunohistochemical and immunogenetic analysis of ocular adnexal lymphoid proliferations].

We examined 20 cases (21 specimens) of ocular adnexal lymphoid proliferations, using the histological, immunohistochemical and molecular genetic methods. The latter two protocols were performed to detect the light chains restriction of immunoglobulin with peroxidase-antiperoxidase (PAP) methods, and the clonality of immunoglobulin heavy chain gene with the hemi-nested polymerase chain reaction (PCR) method, respectively. Although in 8 cases it could not be morphologically determined whether they were neoplastic or not, clonality was revealed in 1 case with immunohistochemistry and in 4 cases with PCR. Two cases showed discordant results between immunohistochemistry and PCR probably due to somatic mutation of the framework region of the immunoglobulin heavy chain gene. Therefore, we, concluded that examination with these methods contribute to a better understanding of the nature of the ocular adnexal lymphoid proliferations. Furthermore, the immunoglobulin gene PCR method is very useful in practical examination, as it can be used with formalin-fixed paraffin-embedded specimens.