Search

Competing Interests: The authors report no conflicts of interest.

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution., (© 2022. The Author(s).)

Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker., (© 2021 American Association of Neuropathologists, Inc.)

Graft-versus-host disease (GVHD) is a major barrier to the widespread use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treating hematologic malignancies. Myeloid-derived suppressor cells (MDSCs) have been recognized as crucial immunosuppressive cells in various pathologic settings. Here, we investigated whether the unique functional properties of MDSCs could be harnessed to control allo-HSCT-associated GVHD. Using multiple murine GVHD/GVL models including both MHC-mismatched and miHA-mismatched, we demonstrated that treatment with CD115+ MDSCs efficiently suppressed GVHD but did not significantly impair graft-versus-leukemia (GVL) activity, leading to 80 and 67% protection in treated mice in GVHD and GVL models, respectively. The mechanism for this dissociation of GVHD from GVL, specifically the emergence of donor-derived NKG2D + CD8 T cells with a memory phenotype in MDSC-treated recipient mice, was identified. NKG2D expression on donor T cells was required for eradication of allogeneic lymphoma cells. Furthermore, long-term surviving MDSC recipients that exhibited cytolytic activities against allogeneic leukemia cells had a significantly increased percentage of T regulatory cells and, more importantly, NKG2D + CD8 T cells. These findings indicate that MDSCs can be used as a novel cell-based therapy to suppress GVHD while maintaining GVL activities through selective induction of NKG2D + CD8 memory T cells.

Muscle atrophy with weakness is a core feature of amyotrophic lateral sclerosis (ALS) that has long been attributed to motor neuron loss alone. However, several studies in ALS patients, and more so in animal models, have challenged this assumption with the latter providing direct evidence that muscle can play an active role in the disease. Here, we examined the possible role of cell autonomous pathology in 148 skeletal muscle samples from 57 ALS patients, identifying phosphorylated TAR DNA-binding protein (pTDP-43) inclusions in the muscle fibers of 19 patients (33.3%) and 24 tissue samples (16.2% of specimens). A muscle group-specific difference was identified with pTDP-43 pathology being significantly more common in axial (paraspinous, diaphragm) than appendicular muscles (P = 0.0087). This pathology was not significantly associated with pertinent clinical, genetic (c9ALS) or nervous system pathologic data, suggesting it is not limited to any particular subgroup of ALS patients. Among 25 non-ALS muscle samples, pTDP-43 inclusions were seen only in the autophagy-related disorder inclusion body myositis (IBM) (n = 4), where they were more diffuse than in positive ALS samples (P = 0.007). As in IBM samples, pTDP-43 aggregates in ALS were p62/ sequestosome-1-positive, potentially indicating induction of autophagy. Phospho-TDP-43-positive ALS and IBM samples also showed significant up-regulation of TARDBP and SQSTM1 expression. These findings implicate axial skeletal muscle as an additional site of pTDP-43 pathology in some ALS patients, including sporadic and familial cases, which is deserving of further investigation.

Context: - Autopsy studies of the older population (≥65 years of age), and particularly of the "oldest-old" (≥85 years of age), have identified a significant proportion (∼20%) of cognitively impaired patients in which hippocampal sclerosis is the major substrate of an amnestic syndrome. Hippocampal sclerosis may also be comorbid with frontotemporal lobar degeneration, Alzheimer disease, and Lewy body disease. Until recently, the terms hippocampal sclerosis of aging or hippocampal sclerosis dementia were applied in this context. Recent discoveries have prompted a conceptual expansion of hippocampal sclerosis of aging because (1) cellular inclusions of TAR DNA-binding protein 43 kDa (TDP-43) are frequent; (2) TDP-43 pathology may be found outside hippocampus; and (3) brain arteriolosclerosis is a common, possibly pathogenic, component., Objective: - To aid pathologists with recent recommendations for diagnoses of common neuropathologies in older persons, particularly hippocampal sclerosis, and highlight the recent shift in diagnostic terminology from HS-aging to cerebral age-related TDP-43 with sclerosis (CARTS)., Data Sources: - Peer-reviewed literature and 5 autopsy examples that illustrate common age-related neuropathologies, including CARTS, and emphasize the importance of distinguishing CARTS from late-onset frontotemporal lobar degeneration with TDP-43 pathology and from advanced Alzheimer disease with TDP-43 pathology., Conclusions: - In advanced old age, the substrates of cognitive impairment are often multifactorial. This article demonstrates common and frequently comorbid neuropathologic substrates of cognitive impairment in the older population, including CARTS, to aid those practicing in this area of pathology.

Glioblastoma (GBM) is the most common type of malignant tumor found in the brain, and acts very aggressively by quickly and diffusely infiltrating the surrounding brain parenchyma. Despite its aggressive nature, GBM is rarely found to spread extracranially and develop distant metastases. The most common sites of these rare metastases are the lungs, pleura and cervical lymph nodes. There are also a few case reports of skin metastasis. We present the clinical, imaging and pathologic features of a case of a GBM with metastasis to the soft tissue scar and skin near the original craniotomy site. In addition, we discuss the details of this case in the context of the previously reported literature.

To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0.07), though no association with disease duration or progression rate was seen. Shorter disease duration (p = 0.0016), more severe striatal pathology (p = 0.0029), and a trend toward greater whole brain TDP-43 pathology (p = 0.059) were found in c9ALS. Cluster analysis identified "TDP43-limited," "TDP43-moderate," and "TDP43-severe" subgroups. The TDP43-limited group contained more cognitively intact (p = 0.005) and lower extremity onset site (p = 0.019) patients, while other subgroups contained more cognitively impaired patients. We conclude that TDP-43 pathologic burden in ALS is associated with cognitive impairment and c9ALS, but not duration of disease or rate of progression. Further, we demonstrate a subgroup of patients with low TDP-43 burden, lower extremity onset, and intact cognition, which requires further investigation., (© 2017 American Association of Neuropathologists, Inc.)

Chronic hepatitis B (CHB) treatment aims at long-term suppression of HBV replication and improvement in clinical outcomes. We describe the data of a pilot, non-profit study in which patients with CHB were treated with de novo combination lamivudine-adefovir (LAM-ADV) for at least four years with a view to HBV suppression and resistance prevention, and shifted to tenofovir (TDF) when new antiviral agents were available. Fifty-one HBeAg negative patients were enrolled. Histology was available for 39 patients and data of liver stiffness (LS) for 24 patients at baseline. Serum quantification of HBsAg and HBVDNA was obtained regularly during the follow-up. In 10 and 7 patients, a paired histology and LS were available at the end of LAM-ADV treatment, respectively. The de novo LAM-ADV combination was able to obtain HBVDNA suppression and ALT normalization in one year in most of the patients and in the second year in the remaining. Histology improved in patients with paired biopsy, but tissue HBsAg was present in all but one patient after 48 months of therapy. TDF maintained biochemical and virological response throughout the follow-up. Renal impairment during LAM-ADV therapy improved on shifting to TDF; only in 4 cases was a second shift to entecavir needed. TDF was safe and effective in maintaining HBV DNA suppression achieved by a long-term course of LAM-ADV de novo combination for the treatment of HBeAg-negative CHB.

The histologic expression of epithelial and organ-related immunohistochemical markers in primary sellar region tumors has received little attention to date. This lack of empirical data may lead to mistaken assumptions in the evaluation of sellar region neoplasms. To address this issue, the frequency and specificity of epithelial (cytokeratin 7(CK7), CK20) and organ-related differentiation markers (gross cystic disease fluid protein-15 (GCDFP-15), thyroid transcription factor-1 (TTF-1), Napsin A, paired box 8 (PAX-8), hepatocyte paraffin 1 (HepPar1) and estrogen receptor (ER)) were studied in 40 patients with adenomas comprising five hormonal sub-types. Non-parametric statistical procedures were used to examine associations between marker expression and tumor sub-type. CK7 and CK20 immunoreactivity were seen in 48% and 8% of tumors, respectively, although never in a diffuse pattern. CK20 expression was nearly exclusive to corticotrophs, whereas CK7 frequently highlighted cells with dendritic-type morphology. The specificity of organ-related differentiation markers was 100% (monoclonal Napsin A, GCDFP-15 and TTF-1), 97% (HepPar1 and PAX-8), 90% (polyclonal Napsin A) and 72% (ER); no tumors demonstrated significant co-expression of these organ-related markers with either CK7 or CK20. The first major conclusion of this study is that CK7 staining in adenoma is more frequent than has been previously than has been previously described. CK7 immunoreactive cells often displayed a dendritic-type morphology, including within large macroadenomas, which raises the question as to whether these represent tumor cells with folliculo-stellate cell-type differentiation, as these also have dendritic cell-type morphology and express CK7 in non-neoplastic glands. The second major conclusion, which confirms earlier findings, is that CK20 staining is a very infrequent immunohistochemical finding in adenomas that is virtually limited to corticotrophs and thus is helpful in diagnostic confirmation of that sub-type. The final conclusion is in regard to those features that separate adenomas from sellar region metastases: adenomas do not demonstrate significant expression of TTF-1, monoclonal Napsin A, PAX-8, HepPar1 or GCDFP-15, nor do they exhibit diffuse expression of CK7 and CK20., (© 2016 Japanese Society of Neuropathology.)

Background: Anaplastic oligodendroglial tumors are rare, and median survival varies widely. Analysis of 1p19q deletion is performed commonly and is an important prognostic factor. However, age and other clinical variables also carry prognostic value, and it is unclear how to incorporate them into clinical decision making or to combine them for prognostication., Methods: We compiled a retrospective database of 1013 patients with newly diagnosed anaplastic oligodendrogliomas or oligoastrocytomas and performed a recursive partitioning analysis to generate independent prognostic classes among 587 patients with informative 1p19q status. Variables included for survival classification were age (continuous), history of prior low-grade glioma, 1p19q deletion status, histology (presence or absence of an astrocytic component), tumor lobe, tumor hemisphere, gender, extent of resection, postresection treatment, and performance status at diagnosis., Results: Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age <60 y, 1p19q codeleted), class II (age <43 y, not codeleted), class III (age 43-59 y, not codeleted, frontal lobe tumor or age ≥60 y, codeleted), class IV (age 43-59 y, not codeleted, not frontal lobe tumor or age 60-69 y, not codeleted), and class V (age ≥70 y, not codeleted). Survival differences were highly significant (P < .0001), with medians ranging from 9.3 years (95% CI: 8.4-16.0) for class I to 0.6 years (95% CI: 0.5-0.9) for class V., Conclusions: These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Robotic telepathology (RT) allows a remote pathologist to control and view a glass slide over the internet. This technology has been demonstrated to be effective on several platforms, but we present the first report on the validation of RT using the iScan Coreo Au whole slide imaging scanner., Methods: One intraoperative touch preparation slide from each of 100 cases were examined twice (200 total cases) using glass slides and RT, with a 3 week washout period between viewings, on two different scanners at two remote sites. This included 75 consecutive neuropathology cases and 25 consecutive general surgical pathology cases. Interpretations were compared using intraobserver variability., Results: Of the 200 total cases, one failed on RT. There were 47 total interpretive variances. Most of these were the result of less specific interpretations or an inability to identify scant diagnostic material on RT. Nine interpretive variances had potentially significant clinical implications (4.5%). Using the final diagnosis as a basis for comparison to evaluate these nine cases, three RT interpretations and three glass slide interpretations were considered to be discrepant. In the other three cases, both modalities were discrepant. This distribution of discrepancies indicates that underlying case difficulty, not the RT technology, probably accounts for these major variances. For the subset of 68 neoplastic neuropathology cases, the unweighted kappa of agreement between glass slides and RT was 0.68 (good agreement). RT took 225 s on average versus only 71 s per glass slide., Conclusions: This validation demonstrates that RT using the iScan Coreo Au system is a reasonable method for supplying remote neuropathology expertise for the intraoperative interpretation of touch preparations, but is limited by the slowness of the robotics, crude focusing, and the challenge of determining where to examine the slide using small thumbnail images.

Background: Collagen proportionate area (CPA) has a better correlation with hepatic venous pressure gradient (HVPG) than with Ishak stage. Liver stiffness measurement (LSM) is proposed as non invasive marker of portal hypertension/disease progression. Our aim was to compare LSM and CPA with Ishak staging in chronic viral hepatitis, and HVPG in HCV hepatitis after transplantation., Methods: One hundred and sixty-nine consecutive patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections pre/post liver transplantation (LT), had a liver biopsy combined with LSM (transient elastography), CPA (biopsies stained with Sirius Red and evaluated by digital image analysis and expressed as CPA) and HVPG (measured contemporaneously with transjugular biopsies in LT HCV patients)., Results: LSM was dependent on CPA in HBV (r (2) = 0.61, p < 0.0001), HCV (r (2) = 0.59, p < 0.0001) and LT groups (r (2) = 0.64, p < 0.0001). In all three groups, CPA and Ishak were predictors of LSM, but multivariately CPA was better related to LSM (HBV: r (2) = 0.61, p < 0.0001; HCV: r (2) = 0.59, p < 0.0001; post-LT: r (2) = 0.68, p < 0.0001) than Ishak stage. In the LT group, multiple regression analysis including HVPG, LSM, aspartate aminotransferase to platelet ratio index (APRI) and Ishak stage/grade, showed that only CPA was related to HVPG (r (2) = 0.41, p = 0.01), both for HVPG ≥6 mmHg (OR 1.34, 95 % CI 1.14-1.58; p < 0.0001) or ≥10 mmHg (OR 1.25, 95 % CI 1.06-1.47; p = 0.007)., Conclusion: CPA was related to LSM in HBV or HCV hepatitis pre/post-LT. CPA was better related to LSM than Ishak stage. In the LT HCV group, CPA was better related to HVPG than Ishak stage/grade, LSM or APRI. CPA may represent a better comparative histological index for LSM, rather than histological stages.

The histopathological diagnosis of diffuse gliomas often lacks the precision that is needed for tailored treatment of individual patients. Assessment of the molecular aberrations will probably allow more robust and prognostically relevant classification of these tumors. Markers that have gained a lot of interest in this respect are co-deletion of complete chromosome arms 1p and 19q, (hyper)methylation of the MGMT promoter and IDH1 mutations. The aim of this study was to assess the prognostic significance of complete 1p/19q co-deletion, MGMT promoter methylation and IDH1 mutations in patients suffering from diffuse gliomas. The presence of these molecular aberrations was investigated in a series of 561 diffuse astrocytic and oligodendroglial tumors (low grade n=110, anaplastic n=118 and glioblastoma n=333) and correlated with age at diagnosis and overall survival. Complete 1p/19q co-deletion, MGMT promoter methylation and/or IDH1 mutation generally signified a better prognosis for patients with a diffuse glioma including glioblastoma. However, in all 10 patients with a histopathological diagnosis of glioblastoma included in this study complete 1p/19q co-deletion was not associated with improved survival. Furthermore, in glioblastoma patients >50 years of age the favorable prognostic significance of IDH1 mutation and MGMT promoter methylation was absent. In conclusion, molecular diagnostics is a powerful tool to obtain prognostically relevant information for glioma patients. However, for individual patients the molecular information should be interpreted with caution and weighed in the context of parameters such as age and histopathological diagnosis.

In amyotrophic lateral sclerosis (ALS) mice, regulatory T-lymphocytes (Tregs) are neuroprotective, slowing disease progression. To address whether Tregs and FoxP3, a transcription factor required for Treg function, similarly influence progression rates of ALS patients, T-lymphocytes from patients were assessed by flow cytometry. Both numbers of Tregs and their FoxP3 protein expressions were reduced in rapidly progressing ALS patients and inversely correlated with progression rates. The mRNA levels of FoxP3, TGF-β, IL4 and Gata3, a Th2 transcription factor, were reduced in rapidly progressing patients and inversely correlated with progression rates. Both FoxP3 and Gata3 were accurate indicators of progression rates. No differences in IL10, Tbx21, a Th1 transcription factor or IFN-γ expression were found between slow and rapidly progressing patients. A 3.5-year prospective study with a second larger cohort revealed that early reduced FoxP3 levels were indicative of progression rates at collection and predictive of future rapid progression and attenuated survival. Collectively, these data suggest that Tregs and Th2 lymphocytes influence disease progression rates. Importantly, early reduced FoxP3 levels could be used to identify rapidly progressing patients., (Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

Selected patients with hepatocellular carcinoma are candidates to receive potentially curative treatments, such as hepatic resection or liver transplantation, but nevertheless there is a high risk of tumor recurrence. Microvascular invasion is a histological feature of hepatocellular carcinoma related to aggressive biological behavior. We systematically reviewed 20 observational studies that addressed the prognostic impact of microvascular invasion, either after liver transplantation or resection. Outcomes were disease-free survival and overall survival. In liver transplantation, the presence of microvascular invasion shortened disease-free survival at 3 years (relative risk (RR)=3.41 [2.05-5.7]; five studies, n=651) and overall survival both at 3 years (RR=2.41 [1.72-3.37]; five studies, n=1,938) and 5 years (RR=2.29 [1.85-2.83]; six studies, n=2,003). After liver resection, microvascular invasion impacted disease-free survival at 3 and 5 years (RR=1.82 [1.61-2.07] and RR=1.51 [1.29-1.77]; four studies, n=1,501 for both comparisons). However inter/intraobserver variability in reporting and the lack of definition and grading of microvascular invasion has led to great heterogeneity in evaluating this histological feature in hepatocellular carcinoma. Thus, there is an urgent need to clarify this issue, because determining prognosis and response to therapy have become important in the current management of hepatocellular carcinoma. In this systematic review, we summarize the diagnostic and prognostic data concerning microvascular invasion in hepatocellular carcinoma and present a basis for consensus on its definition.

Traditional radiotherapy is only effective in treating hepatocellular cancer (HCC) in doses above 50 Gy, but this is above the recommended liver radiation exposure of about 35 Gy, which is an important limitation making this treatment unsuitable for routine clinical practice. Trans-arterial radio-embolisation (TARE), consists of delivery of compounds linked to radio-emitter particles which end up in hepatic end-arterioles or show affinity for the neoplasm itself, allowing localised delivery of doses beyond 120 Gy. These are well tolerated in patients treated with this type of internal radiation therapy. TARE for HCC is used for palliative treatment of advanced disease which cannot be treated in other ways, or for tumour down-staging before liver transplantation, or as adjuvant therapy for surgically resected HCC. Tumour response after TARE is between 25% and 60% if assessed by using RECIST criteria, and 80% by EASL criteria. In this review we outline the advantages and limitations of radio-emitter therapy including 131-I, 90-Y and 188-Re. We include several observational, and all comparative studies using these compounds. In particular we compare TARE to trans-arterial chemo-embolisation and other intra-arterial techniques., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981-2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980-1984 vs 5% in 2005-2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980-1984 vs 38% in 2005-2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005-2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005-2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.

Primary intracranial squamous cell carcinomas (SCCs) are rare and mostly associated with an intracranial epidermoid or dermoid cyst. Sarcomatoid carcinoma is a rare biphasic tumor composed of both carcinomatous and sarcomatous components and has not previously been reported as a primary intracranial tumor. Here, we present a case of a 60-year-old man with a primary intracranial sarcomatoid carcinoma, arising from the remnants of the previously resected epidermoid cyst in the cerebellopontine angle. The resected material had portions of an epidermoid cyst lined by normal and dysplastic squamous epithelia and invasive keratinizing SCC. This area was in continuity with areas of highly pleomorphic, anaplastic sarcomatoid cells. Brisk mitotic activity and extensive areas of necrosis were found. On immunohistochemical staining, the cells of the conventional SCC were positive for cytokeratin 5/6, pancytokeratin, epithelial membrane antigen, p63, and p53. The sarcomatoid cells were diffusely and strongly positive for vimentin, p53, smooth muscle actin, and, focally, muscle-specific actin. Occasional sarcomatoid cells coexpressed cytokeratin 5/6, pancytokeratin, p63, and S100 protein. The patient subsequently developed leptomeningeal spread and died 4 months after the second surgery. This rare entity expands the morphologic spectrum encountered in primary intracranial carcinoma.

Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

Hemangioblastomas (HBs) account for nearly a tenth of all posterior fossa neoplasms and can be the presenting finding in patients with von Hippel-Lindau (VHL) syndrome. HB must be differentiated from renal cell carcinoma (RCC), also seen in VHL, as the distinction between these lesions dictates the management of these patients. Currently inhibin A and RCC marker have been used in the diagnosis of HB and metastatic RCC, both with inconsistent results. Additional immunohistochemical markers including CD10, PAX-2, D2-40, and FLi-1 have been shown to have potential for the distinction of these two entities. Fifteen cerebellar HBs and 17 metastatic clear cell RCCs to the brain were selected for the study. All cases were immunostained with RCC marker, inhibin, CD10, PAX-2, D2-40, and Fli-1. The staining patterns were scored based on intensity and extent of tumor staining. In the differentiation of HB and metastatic RCC, D2-40 and RCC marker proved to be poor markers with less than 50% of HBs and RCCs, respectively, showing positive staining. PAX-2 and CD10 were superior to RCC marker in the diagnosis of metastatic RCC, with PAX-2 having better specificity. Fli-1 failed to stain tumor cells in both HBs and RCC. Inhibin A, in combination with PAX-2, showed to be the most useful markers to differentiate HB from metastatic RCC., (© 2010 Japanese Society of Neuropathology.)

Early and very early stage hepatocellular cancers (HCC) when staged clinically, if they are coincident with histological early HCC, have the best outcome in terms of recurrence rates and survival after potential curative therapy. This is because predictors of HCC recurrence such as microscopic vascular invasion and satellite metastases, are rarely present in histological early HCC. Other predictors of HCC recurrence are size of the principal lesion, numbers of lesions, histological grade, several gene signature patterns that are promising for future clinical practice, and other less constantly predictive features such as high alpha-fetoprotein and transaminase concentrations, and cellular aneuploidia. Adjuvant and neo-adjuvant therapies have been proposed to reduce the risk of HCC recurrence after potentially curative treatments. These preventative therapies are focused on extra-tumoural therapies, such as retinoids or interferon, possibly effective in preventing late recurrence by influencing the premalignant field in cirrhosis, and on tumour related therapies, by utilising several procedures able to downstage tumours, such as neo-adjuvant and "bridge to transplant" therapies, which influence mainly early recurrence. Both strategies have been combined for example with using sorafenib which may treat both the patient's premalignant liver and malignant liver cells themselves., (Copyright 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.)

The majority of primary CNS tumors in adults are comprised of gliomas (astrocytomas, oligodendrogliomas and ependymomas). The diagnosis has historically been based on the histologic appearance of these tumors. However, as molecular data have accumulated over the years, there is considerable evidence that the molecular diversity (even within the same diagnostic entity) may account for the heterogeneity of clinical outcomes, such as response to treatment, time to progression and overall survival after diagnosis. These molecular markers are becoming more useful in the field of neuro-oncology. They can assist in diagnosis, provide prognostic information and potentially predict response to therapy. Perhaps the greatest potential for these molecular aberrations is that they may represent therapeutic targets themselves. In this article, we summarize the findings of important, published biomarker studies in adult gliomas and provide an overview of the practical uses of these markers in the clinical setting, as well as the current understanding of molecular gliomagenesis.

Most hepatocellular carcinomas (HCC) are diagnosed in patients with cirrhosis and/or when tumor burden is too advanced for surgical treatment. In many of these cases the only suitable therapy is locoregional, percutaneous and/or intraarterial treatment. Moreover, the best way to guide and assess response to locoregional HCC treatment are two issues under discussion today. First-generation and subsequent second-generation microbubble contrast agents, together with contrast-enhanced ultrasound (US) imaging, have expanded the role of US techniques in HCC treatments. In this review our purpose is to illustrate the advantages, limits and potential of contrast-enhanced US application for locoregional HCC treatment., (Copyright (c) 2010 S. Karger AG, Basel.)

Hypermethylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) gene has been shown to be associated with improved outcome in glioblastoma (GBM) and may be a predictive marker of sensitivity to alkylating agents. However, the predictive utility of this marker has not been rigorously tested with regard to sensitivity to other therapies, namely radiation. To address this issue, we assessed MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy as a component of adjuvant treatment. Formalin-fixed, paraffin-embedded tumor samples from 225 patients with newly diagnosed GBM were analyzed via methylation-specific, quantitative real-time polymerase chain reaction following bisulfite treatment on isolated DNA to assess MGMT promoter methylation status. In patients who received radiotherapy alone following resection, methylation of the MGMT promoter correlated with an improved response to radiotherapy. Unmethylated tumors were twice as likely to progress during radiation treatment. The median time interval between resection and tumor progression of unmethylated tumors was also nearly half that of methylated tumors. Promoter methylation was also found to confer improved overall survival in patients who did not receive adjuvant alkylating chemotherapy. Multivariable analysis demonstrated that methylation status was independent of age, Karnofsky performance score, and extent of resection as a predictor of time to progression and overall survival. Our data suggest that MGMT promoter methylation appears to be a predictive biomarker of radiation response. Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM.

Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy.

Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF.

In this study, we test the reliability of chromogenic in situ hybridization (CISH) for the detection of epidermal growth factor receptor (EGFR) gene amplification in glioblastoma. Earlier reports have described EGFR CISH in glioblastoma multiforme, but a comparison of CISH with a "gold standard" testing method, such as fluorescence in situ hybridization (FISH), has not been described. Therapies targeting the EGFR-signaling pathway might increase the importance of assessment of EGFR-amplification status. CISH is a potential alternative to FISH as a testing method. To test its reliability, EGFR-amplification status by CISH was assessed in 89 cases of glioblastoma and compared with FISH results, and correlated with the protein expression using immunohistochemistry (IHC) for EGFR. FISH was scored as being EGFR-amplified in 47/89 tumors, CISH as being amplified in 43/89 tumors. The CISH and FISH results were in agreement in 83/89 cases (93%). Four glioblastomas were scored as being amplified by FISH, but not by CISH; whereas amplification was detected in 2 tumors by CISH that were not amplified using FISH. Forty-eight of the 89 cases were positive for EGFR expression by IHC. EGFR amplification was highly correlated with protein expression by IHC, as 40/48 (83%) EGFR IHC-positive cases were found to be EGFR-amplified. The high concordance of CISH and FISH for the assessment of EGFR gene-amplification status indicates that CISH is a viable alternative to FISH for the detection of EGFR gene amplification in glioblastoma. Detectable EGFR expression by IHC can occur in the absence of gene amplification, but is uncommon.

Thoracic actinomycosis is uncommon, indolent, and often not considered in children with chest wall masses, pneumonia, or empyema. We present a 27-month-old girl without risk factors for thoracic actinomycosis whose initial diagnosis was malignancy. She recovered completely after lobectomy, debridement, and antimicrobial therapy. Literature review since 1975 identified 54 additional cases; most were male, older, and had underlying risk factors.

The ovarian hormones, estradiol (E) and progesterone (P) facilitate the expression of sexual behavior in female rats. E and P mediate many of these behavioral effects by binding to their respective intracellular receptors in specific brain regions. Nuclear receptor coactivators, including Steroid Receptor Coactivator-1 (SRC-1) and CREB Binding Protein (CBP), dramatically enhance ligand-dependent steroid receptor transcriptional activity in vitro. Previously, our lab has shown that SRC-1 and CBP modulate estrogen receptor (ER)-mediated induction of progestin receptor (PR) gene expression in the ventromedial nucleus of the hypothalamus (VMN) and hormone-dependent sexual receptivity in female rats. Female sexual behaviors can be activated by high doses of E alone in ovariectomized rats, and thus are believed to be ER-dependent. However, the full repertoire of female sexual behavior, in particular, proceptive behaviors such as hopping, darting and ear wiggling, are considered to be PR-dependent. In the present experiments, the function of SRC-1 and CBP in distinct ER- (Exp. 1) and PR- (Exp. 2) dependent aspects of female sexual behavior was investigated. In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior. In Exp. 2, antisense to SRC-1 and CBP mRNA around the time of P administration reduced PR-dependent ear wiggling and hopping and darting. Taken together, these data suggest that SRC-1 and CBP modulate ER and PR action in brain and influence distinct aspects of hormone-dependent sexual behaviors. These findings support our previous studies and provide further evidence that SRC-1 and CBP function together to regulate ovarian hormone action in behaviorally-relevant brain regions.

Hepatitis-associated aplastic anemia is an only recently recognised syndrome. We present a case whereby a month after an episode of fever, a 17-year-old boy was recovered with liver enzyme elevation and circulating platelet reduction. All the acute viral hepatitis markers were negative. After bone marrow aspiration a severe aplastic anemia was diagnosed and all the findings were consistent with hepatitis-associated aplastic anemia. The disorder was initially treated with glucocorticoids and platelet transfusion, obtaining the normalization of the liver enzymes but worsening of the aplastic anemia. An HLA-identical related marrow donor was not found. The patient responded to immunosuppressive treatment but died of multi-organ failure due to severe sepsis.

Phytoestrogens are a diverse group of plant-derived compounds that structurally or functionally mimic mammalian estrogens and show potential benefits for human health. The number of articles published on phytoestrogens has risen dramatically in the past couple decades. Further research continues to demonstrate the biological complexity of phytoestrogens, which belong to several different chemical classes and act through diverse mechanisms. This paper discusses the classification of phytoestrogens, methods of identification, their proposed mechanisms of action and botanical sources for phytoestrogens. The effects of phytoestrogens on breast and prostate cancers, cardiovascular disease, menopausal symptoms and osteoporosis will also be examined including research on benefits and risks., (Copyright 2003 John Wiley & Sons, Ltd.)

This ethnobotanical literature survey is part of an on-going study in New York City investigating Dominican and Chinese healing systems and the herbal treatments used for the following women's conditions: uterine fibroids (benign tumors of uterine smooth muscle); menorrhagia (excessive uterine bleeding); endometriosis (growth of endometrial tissue outside of the uterus); and hot flashes (sudden brief sensations of heat commonly experienced during menopause). The objectives of this survey were: (1) to search literature on medicinal plants used in the Dominican Republic and identify those used for the above listed conditions and their symptoms; (2) to compare the use between herbal treatments reported in the literature with those prescribed by Dominican healers in New York City; and (3) to evaluate the extent to which healers may have changed their use of plants in order to adapt to availability in the New York City environment. A total of 87 plant species were reported in the Dominican literature for these conditions and symptoms. Nineteen species overlapped from the literature survey and the fieldwork with Dominican healers in New York City, representing 29% (n=65) of the plants prescribed by healers in New York City. This study offers a model to investigate changes in plant use as people migrate to urban centers where they are surrounded by diverse cultures, healing systems, and new environments.

Gonadal steroid hormones act in the brain to elicit changes in gene expression that result in profound effects on behavior and physiology. A variety of in vitro studies indicate that nuclear receptor coactivators are required for efficient transcriptional activity of steroid receptors. Two nuclear receptor coactivators, steroid receptor coactivator-1 (SRC-1) and cAMP response element binding protein-binding protein (CBP), have been shown to act in concert to enhance ER activity in vitro. In the present study, we investigated the function of these important nuclear receptor coactivators in estrogen action in rodent brain. Reduction of SRC-1 and CBP protein in brain disrupted ER-mediated activation of the behaviorally relevant progestin receptor gene. Furthermore, we found that SRC-1 and CBP function in brain to modulate the expression of hormone-dependent female sexual behavior. These findings indicate that these nuclear receptor coactivators function in brain to modulate ER transcriptional activity and the expression of hormone-dependent behavior.