Publications by authors named "Shirin Karimi"

49 Publications

Loss of H3K27me3 in meningiomas.

Neuro Oncol 2021 May 10. Epub 2021 May 10.

MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, ON, Canada.

Background: There is a critical need for objective and reliable biomarkers of outcome in meningiomas beyond WHO classification. Loss of H3K27me3 has been reported as a prognostically unfavorable alteration in meningiomas. We sought to independently evaluate the reproducibility and prognostic value of H3K27me3 loss by immunohistochemistry (IHC) in a multi-center study.

Methods: IHC staining for H3K27me3 and analyses of whole slides from 181 meningiomas across three centers was performed. Staining was analyzed by dichotomization into loss and retained immunoreactivity, and using a 3-tiered scoring system in 151 cases with clear staining. Associations of grouping with outcome was performed using Kaplan-Meier survival estimates.

Results: A total of 21 of 151 tumours (13.9%) demonstrated complete loss of H3K27me3 staining in tumour with retained endothelial staining. Overall, loss of H3K27me3 portended a worse outcome with shorter times to recurrence in our cohort, particularly for WHO grade 2 tumours which were enriched in our study. There were no differences in recurrence-free survival (RFS) for WHO grade 3 patients with retained versus loss of H3K27me3. Scoring by a 3-tiered system did not add further insights into the prognostic value of this H3K27me3 loss. Overall, loss of H3K27me3 was not independently associated with RFS after controlling for WHO grade, extent of resection, sex, age, and recurrence status of tumour on multivariable Cox regression analysis.

Conclusions: Loss of H3K27me3 identifies a subset of WHO grade 2 and possibly WHO grade 1 meningiomas with increased recurrence risk. Pooled analyses of a larger cohort of samples with standardized reporting of clinical definitions and staining patterns is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noab036DOI Listing
May 2021

TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy.

Acta Neuropathol Commun 2021 04 14;9(1):67. Epub 2021 Apr 14.

MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-021-01163-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048292PMC
April 2021

Clinical significance of checkpoint regulator "Programmed death ligand-1 (PD-L1)" expression in meningioma: review of the current status.

J Neurooncol 2021 Feb 21;151(3):443-449. Epub 2021 Feb 21.

MacFeeters-Hamilton Center for Neuro-Oncology Research, Princess Margaret Cancer Center, 14-701, Toronto Medical Discovery Tower (TMDT), 101 College St, Toronto, ON, M5G 1L7, Canada.

Introduction: Meningioma is the most common primary brain tumor. Most meningiomas are benign; however, a subset of these tumors can be aggressive, presenting with early or multiple tumor recurrences that are refractory to neurosurgical resection and radiotherapy. There is no standard systemic therapy for these patients, and post-surgical management of these patients is usually complicated due to lack of accurate prediction for tumor progression.

Methods: In this review, we summarise the crucial immunosuppressive role of checkpoint regulators, including PD-1 and PD-L1 interacting in the tumor microenvironment, which has led to efforts aimed at targeting this axis.

Results: Since their discovery, checkpoint inhibitors have significantly improved the outcome in many types of cancers. Currently, targeted therapy for PD-1 and PD-L1 proteins are being tested in several ongoing clinical trials for brain tumors such as glioblastoma. More recently, there have been some reports implicating increased PD-L1 expression in high-grade (WHO grades II and III) meningiomas. Several clinical trials are underway to assess the efficacy of checkpoint inhibitors in the therapeutic management of patients with aggressive meningiomas. Here, we review the immune suppressive microenvironment in meningiomas, and then focus on clinical and pathological characterization and tumor heterogeneity with respect to PD-L1 expression as well as challenges associated with the assessment of PD-L1 expression in meningioma.

Conclusion: We conclude with a brief review of ongoing clinical trials using checkpoint inhibitors for the treatment of high-grade and refractory meningiomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-020-03584-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897616PMC
February 2021

A case series of pediatric survivors of anaplastic pleomorphic xanthoastrocytoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa176. Epub 2021 Jan 30.

Division of Pediatric Hematology, Oncology and Bone Marrow Transplantation, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA.

Methods: Our institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs).

Results: Two patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children's Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%).

Conclusions: The natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849951PMC
January 2021

Epigenomic, genomic, and transcriptomic landscape of schwannomatosis.

Acta Neuropathol 2021 01 6;141(1):101-116. Epub 2020 Oct 6.

Princess Margaret Cancer Center and MacFeeters-Hamilton Center for Neuro-Oncology Research, University Health Network, Wilkins Family Chair in Brain Tumor Research, 14-701 PMCRT, 101 College St, Toronto, ON, M5G 1L7, Canada.

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-020-02230-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785562PMC
January 2021

Programmed death ligand-1 (PD-L1) expression in meningioma; prognostic significance and its association with hypoxia and NFKB2 expression.

Sci Rep 2020 08 24;10(1):14115. Epub 2020 Aug 24.

Princess Margaret Cancer Center, MacFeeters-Hamilton Center for Neuro-Oncology Research, 14-701, Toronto Medical Discovery Tower (TMDT), 101 College St, Toronto, ON, M5G 1L7, Canada.

Management of clinically aggressive meningiomas is a considerable challenge. PD-L1 induced immune suppression has increasingly gained attention in clinical management of cancer; however, to date, the clinical significance and regulatory mechanisms of PD-L1 in meningioma is not yet fully characterized. We sought to characterize PD-L1 expression in meningioma and elucidate its regulatory mechanisms. Immunohistochemical staining of PD-L1 expression in meningiomas showed 43% positivity in both tumor and immune cells and we observed intra and inter tumoral heterogeneity. Univariate and multivariate analyses confirmed that PD-L1 protein expression is an independent prognostic marker for worse recurrence free survival in meningioma. Furthermore, our transcriptomic analysis revealed a strong association between PD-L1 expression and that of NFKB2 and carbonic anhydrase 9 (CA9). We also demonstrated that both of these markers, when co-expressed with PD-L1, predict tumor progression. Our studies on several meningioma cell lines cultured in hypoxic conditions validated the association of CA9 and PD-L1 expression. Here we show the clinical significance of PD-L1 in meningioma as a marker that can predict tumor recurrence. We also show an association PD-L1 expression with NFKB2 expression and its induction under hypoxic conditions. These findings may open new avenues of molecular investigation in pathogenesis of meningioma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-70514-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445252PMC
August 2020

Successful treatment of peritoneal dialysis catheter exit-site granuloma with silver ion-based dressing.

J Vasc Access 2020 Jul 20:1129729820938216. Epub 2020 Jul 20.

Isfahan Kidney Diseases Research Center, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1129729820938216DOI Listing
July 2020

Clinical value of methylation testing: a case report of intraventricular schwannomas with associated molecular findings.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa029. Epub 2020 Mar 26.

Division of Neurosurgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212842PMC
March 2020

The central nervous system tumor methylation classifier changes neuro-oncology practice for challenging brain tumor diagnoses and directly impacts patient care.

Clin Epigenetics 2019 12 5;11(1):185. Epub 2019 Dec 5.

Division of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment.

Methods: Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions.

Results: Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment.

Conclusions: The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0766-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896594PMC
December 2019

Hypoxia Can Induce Migration of Glioblastoma Cells Through a Methylation-Dependent Control of Gene Expression.

Front Oncol 2019 10;9:1036. Epub 2019 Oct 10.

Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.

The transmembrane protein ODZ1 has been associated with the invasive capacity of glioblastoma (GBM) cells through upregulation of RhoA/ROCK signaling, but the mechanisms triggering the ODZ1 pathway remain elusive. In addition, it is widely accepted that hypoxia is one of the main biological hallmarks of the GBM microenvironment and it is associated with treatment resistance and poor prognosis. Here we show that hypoxic tumor regions express higher levels of ODZ1 and that hypoxia induces ODZ1 expression in GBM cells by regulating the methylation status of the ODZ1 promoter. Hypoxia-induced upregulation of ODZ1 correlates with higher migration capacity of GBM cells that is drastically reduced by knocking down ODZ1. methylation of the promoter decreases its transactivation activity and we found a functionally active CpG site at the 3'end of the promoter. This site is hypermethylated in somatic neural cells and mainly hypomethylated in GBM cells. Mutagenesis of this CpG site reduces the promoter activity in response to hypoxia. Overall, we identify hypoxia as the first extracellular activator of ODZ1 expression and describe that hypoxia controls the levels of this migration-inducer, at least in part, by regulating the methylation status of the ODZ1 gene promoter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795711PMC
October 2019

DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management.

Neuro Oncol 2019 07;21(7):901-910

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma.

Methods: DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts.

Results: The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications.

Conclusions: The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noz061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620635PMC
July 2019

Proteomic analysis of meningiomas reveals clinically distinct molecular patterns.

Neuro Oncol 2019 08;21(8):1028-1038

Princess Margaret Cancer Centre, MacFeeters Hamilton Centre for Neuro-Oncology Research, Toronto, Ontario, Canada.

Background: Meningiomas represent one of the most common brain tumors and exhibit a clinically heterogeneous behavior, sometimes difficult to predict with classic histopathologic features. While emerging molecular profiling efforts have linked specific genomic drivers to distinct clinical patterns, the proteomic landscape of meningiomas remains largely unexplored.

Methods: We utilize liquid chromatography tandem mass spectrometry with an Orbitrap mass analyzer to quantify global protein abundances of a clinically well-annotated formalin-fixed paraffin embedded (FFPE) cohort (n = 61) of meningiomas spanning all World Health Organization (WHO) grades and various degrees of clinical aggressiveness.

Results: In total, we quantify 3042 unique proteins comparing patterns across different clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic (n = 106 proteins, Welch's t-test, P < 0.01) and pathway-level (eg, Notch and PI3K/AKT/mTOR) differences between convexity and skull base meningiomas. Supervised comparative analyses of different pathological grades revealed distinct patterns between benign (grade I) and atypical/malignant (grades II‒III) meningiomas with specific oncogenes enriched in higher grade lesions. Independent of WHO grade, clinically aggressive meningiomas that rapidly recurred (<3 y) had distinctive protein patterns converging on mRNA processing and impaired activation of the matrisome complex. Larger sized meningiomas (>3 cm maximum tumor diameter) and those with previous radiation exposure revealed perturbed pro-proliferative (eg, epidermal growth factor receptor) and metabolic as well as inflammatory response pathways (mitochondrial activity, interferon), respectively.

Conclusions: Our proteomic study demonstrates that meningiomas of different grades and clinical parameters present distinct proteomic profiles. These proteomic variations offer potential future utility in helping better predict patient outcome and in nominating novel therapeutic targets for personalized care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noz084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682208PMC
August 2019

Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells.

Clin Cancer Res 2019 01 15;25(2):844-855. Epub 2018 Oct 15.

MacFeeters-Hamilton Center for Neuro-Oncology Research, Princess Margaret Cancer Center, Toronto, Ontario, Canada.

Purpose: Hexokinase II (HK2) protein expression is elevated in glioblastoma (GBM), and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient-derived glioma stem cells (GSCs), and mouse models of GBM. We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2-associated gene signature. We next determined the EC of the compounds by treating glioma cell lines and GSCs. Selected compounds showing significant impact were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on the metabolic activity in glioma cells was also assessed .

Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, ketoconazole and posaconazole displayed the greatest inhibitory effect on GBM both and . Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. In addition, treatment with azoles resulted in increased proportion of apoptotic cells.

Conclusions: Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM. Combined with existing literature and preclinical results, these data support the value of repurposing azoles in GBM clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103287PMC
January 2019

Correlation of Minichromosome Maintenance Protein 6 Expression Rate and Clinical Outcome in Patients With Hodgkin's Lymphoma.

Acta Med Iran 2017 Sep;55(9):550-555

Department of Molecular Pathology, Princess Margaret Hospital, University of Toronto, Toronto, Canada.

Minichromosome maintenance complex component 6 (MCM-6) is one of the six proteins of the MCM family, which are involved in the initiation of DNA replication, represents a marker of proliferating cells. The goal of this study was to evaluate the prognostic relevance of the neoplastic cell proliferation rate in patients with Hodgkin's lymphoma (HL). We evaluated the formalin-fixed paraffin-embedded lymph node biopsy specimens from 55 patients by using monoclonal antibody against MCM-6 and compared these findings with clinical data and treatment outcome. Median of MCM-6 expression was 85% (range: 35%-99%). In multivariate analysis, MCM-6 expression, B symptoms, and age were not statistically significant predictor for relapse in contrary to response (P=.001) and stage of disease (P=.048). Patients with lower MCM-6 expression rates showed higher relapse rate and lower disease-free survival (DFS). Meanwhile, patients with MCM-6 expression less than 85% showed shorter DFS (P=.031). We hypothesize that in group of patients with lower MCM-6 expression rate, a larger proportion of proliferating malignant cells are arrested in the very early phase of mitosis, in comparison to the group of patients with higher MCM-6 expression, and this could imply a shorter and probably higher relapse rate in the former group.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2017

Prognostic significance of preoperative neutrophilia on recurrence-free survival in meningioma.

Neuro Oncol 2017 Oct;19(11):1503-1510

MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.

Background: Meningioma is the most common primary intracranial tumor and recurrence is one of the important challenges in patient management. Prognostic factors for tumor recurrences in these patients especially before surgical resection are not fully characterized. Several studies have indicated an association between changes in hematologic laboratory parameters with patient outcomes in solid malignancies. We aimed to assess the association between hematologic parameters and tumor recurrence in patients with meningioma.

Methods: Preoperative complete blood count (CBC) data were analyzed in patients with newly diagnosed meningioma (n = 222). Clinical data, including history of corticosteroid therapy, tumor characteristics, and follow-up, were obtained. Recurrence-free survival (RFS) was evaluated using Cox proportional hazards models and log-rank tests.

Results: Using preoperative CBC data from patients prior to any steroid therapy, 51 (23%) patients had neutrophilia. In univariate analysis, neutrophilia was significantly associated with meningioma recurrence (hazard ratio [HR] 2.73; P < 0.01). Neither leukocytosis nor lymphocytosis was associated with RFS. In multivariate analysis, after adjusting for tumor grade, tumor size, and extent of resection, neutrophilia remained an independent prognostic factor for RFS (HR 2.23, P = 0.01). Forty-six (21%) patients had low hemoglobin levels indicative of anemia, and the presence of anemia showed a trend toward high risk for recurrence (HR 1.83; P = 0.06).

Conclusions: The presence of neutrophilia was associated with higher rate of tumor recurrence in patients with meningioma. Validation of these results and the biologic role of neutrophilic inflammatory/immune reaction in meningioma requires further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nox089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737603PMC
October 2017

Comparing the Effect of Dressing Versus No-dressing on Exit Site Infection and Peritonitis in Chronic Ambulatory Peritoneal Dialysis Patients.

Adv Biomed Res 2017 31;6. Epub 2017 Jan 31.

Isfahan Kidney Diseases Research Center, Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Bachground: Peritonitis and exit site (ES) infection are two main complications of peritoneal dialysis. There are some controversies regard to preventive strategies for ES care. In this study we compared peritonitis and ES infection rates in patients with and without dressing.

Materials And Methods: This historical cohort study carried out on 72 patients under continuous ambulatory peritoneal dialysis treatment, 54 with dressing versus 18 patients without dressing, followed from October 1, 2010 to March 31, 2011 for peritonitis and ES infection.

Results: A total of 17 episodes of ES infection occurred in 12 patients in dressing group, but no case was seen in no-dressing group ( = 0.02). Twenty-one episodes of peritonitis occurred in 15 patients in both groups (one episode every 20.6 patient-months). In no-dressing group two episodes occurred in only one patient (one episode every 54 patient-months), and in dressing group, 19 episode in 14 patients (one episode every 17.1 patient-months) ( = 0.03). Peritonitis was significantly more frequent in male versus female in overall patients (38% vs. 14%, = 0.025) and in dressing group (52% vs. 15%, = 0.003). In dressing group, peritonitis was more frequent in diabetics versus non-diabetics (48% vs. 11%, = 0.01). Odds ratio for developing peritonitis was 9.4 in dressing group (95% confidence interval [CI] =1.05 - 84.4; = 0.045), and 4.4 in men (95% CI = 1.26 - 15.19; = 0.02).

Conclusion: In this study, chronic ES care without dressing was associated with lower risk of peritonitis and ES infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/2277-9175.199263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309448PMC
January 2017

Immunohistochemical findings of the granulomatous reaction associated with tuberculosis.

Int J Mycobacteriol 2016 Dec 11;5 Suppl 1:S234-S235. Epub 2016 Nov 11.

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective/background: The histological diagnosis of Mycobacterium tuberculosis (MTB) has long been a diagnostic challenge in the anatomical pathology field despite availability of different laboratory methods. Immunohistochemistry (IHC) could not only confirm granulomatous tissue involvement but also demonstrate MTB antigen immunolocalization. This study tries to clarify the details of IHC staining for MTB with pAbBCG.

Methods: A total of 50 patients undergoing simultaneous biopsy and tissue culture with positive tissue culture for MTB during 2005-2009 were selected from the MRC Department at Masih Daneshvari Hospital, Tehran, Iran. Using the archives of the Pathology Department of this hospital, which is a referral center for pathological lung lesions, hematoxylin and eosin slides of the selected patients were evaluated. Twenty-three confirmed TB granulomatous tissue samples with adequate tissue and number of granulomas were chosen and studied by Ziehl-Neelsen and IHC staining with pAbBCG.

Results: A total of 23 cases were evaluated, of which 17 (73.9%) were males. The types of tissue obtained from study cases were as follows: pleura (9 cases, 39.1%), lymph node (cervical, axillary, and thoracic [9 cases, 39.1%]), and lung tissues (5 cases, 21.7%). IHC staining was positive in all samples, whereas Ziehl-Neelsen staining was positive in nine cases of 23 (39.1%). IHC showed positive coarse granular cytoplasmic and round, fragmented bacillary staining. In this study, epithelioid cells clearly showed more positive staining at the periphery rather than at the center of granuloma. There is also positive staining in endothelial cells, fibroblasts, plasma cells, macrophages, and lymphocytes outside the granuloma.

Conclusion: Detection of TB in tissue slides is still based on the histological pattern of the granuloma, which has several differential diagnoses with different treatments. Presence of mycobacterial antigens and tissue morphology can be evaluated using the IHC technique. Considering the criteria of positive IHC staining of TB granulomatous reactions, this stain not only highlights the presence of mycobacterial antigens for tissue diagnosis, but also could morphologically localize their distribution in different cells. Pathologists must be familiar with adequate staining pattern, elimination of background staining, and type of selected antibody. This method is especially important for application in countries with high prevalence of TB as a technique with early diagnostic value in tissue specimens. Early diagnosis using this technique can reduce related morbidity and mortality and decrease the rate of complications due to misdiagnosis and mistreatment of TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijmyco.2016.11.001DOI Listing
December 2016

Clinicopathological Characteristics of Iranian Patients with Lung Cancer: a Single Institute Experience.

Asian Pac J Cancer Prev 2016 ;17(8):3817-22

Medical Oncology, Tobacco Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran E-mail :

Background: Lung cancer has long been a leading cause of cancer related death in both women and men worldwide. The focus of this study was to review clinicopathological features of Iranian patients diagnosed with lung cancer.

Materials And Methods: Clinicopathological data of 1353 primary lung cancer patients diagnosed during 17 years (1997-2014) in the "National Institute of Tuberculosis and Lung Disease" (NRITLD), Tehran, Iran, were retrospectively reviewed.

Results: The median age of patients was 60 (mean: 58.95 years, range: 16- 99) and adenocarcinoma was the most prevalent pathology (45.2%). Male/female ratio was 3.22 and 57.2% of patients were smokers (men 70.3%, women 15%). The majority (85.3%) were referred in advanced stages (stage IIIB and IV).

Conclusions: Although some of our findings are in concordance with other studies in lung cancer there are some discrepancies particularly in terms of smoking status and median age of Iranian patients. Further clinical and epidemiological studies are warranted to elucidate etiologic and factors other than smoking contributing to development of lung cancer, such as environmental exposures or genetic predisposition.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2017

PIK3CA mutations in meningioma.

Neuro Oncol 2016 05;18(5):603-4

Department of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (G.Z.); Princess Margaret Cancer Centre and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, Ontario, Canada (S.K., K.D.A.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/now029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827051PMC
May 2016

Malignant Mesothelioma Versus Metastatic Carcinoma of the Pleura: A CT Challenge.

Iran J Radiol 2016 Jan 14;13(1):e10949. Epub 2016 Jan 14.

Department of Biostatistics, Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Malignant pleural mesothelioma (MPM) is a rare malignant neoplasm of the pleura that typically affects individuals occupationally exposed to asbestos through a variety of industries. MPM presents with several CT features similar to more common pleural diseases such as metastatic pleural malignancy.

Objectives: The aim of this study is to differentiate malignant pleural mesothelioma from metastatic carcinoma of the pleura by pathological and radiological assessment in order to investigate accuracy of CT scan in this regard and to compare CT features of these two malignancies.

Patients And Methods: Chest CT scans of 55 pleural malignancy patients including MPM and metastatic pleural malignancy were evaluated in this retrospective study. The pathologist made the definite diagnosis based on immunohistochemistry. A chest radiologist unaware of the pathology diagnosis observed all CT scans. Several parameters including pleural thickening, pleural effusion, thickening of inter lobar fissure, contralateral extension, contraction of involved hemithorax, parenchymal involvement (infiltration, nodules, fibrosis), pleural mediastinal involvement, lymphadenopathy, extrapleural invasion (hepatic, chest wall, diaphragm, intraperitoneal), and pericardial involvement were checked. Data analysis was carried out using SPSS version 16, and the ability of CT scan to differentiate malignant pleural mesothelioma and metastatic pleural diseases was investigated.

Results: Totally 29 males and 26 females were assessed in this study. Based on pathology, 17 MPM and 38 metastatic pleural malignancies were diagnosed. According to CT study, about 82% of the patients with MPM and about 79% of the patients with metastatic pleural diseases were correctly diagnosed by a radiologist. The most common findings suggestive of MPM were pleural thickening (88.2%), loculated effusion (58.8%), and thickening of the interlobar fissure (47.1%). Whereas free pleural effusion (71.7%), parenchymal infiltration (65.8%) and pleural thickening (63.2%) were most prevalent parameters among metastatic cases.

Conclusion: CT scan is highly accurate in differentiating malignant pleural mesothelioma and metastatic pleural diseases. Pleural thickening and thickening of interlobar fissure lead us to the diagnosis of MPM and massive free pleural effusion is more commonly seen in metastatic pleural malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5812/iranjradiol.10949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837229PMC
January 2016

Where Light Shines Through.

Authors:
Shirin Karimi

Conn Med 2016 Jan;80(1):49-51

View Article and Find Full Text PDF

Download full-text PDF

Source
January 2016

Gorham's Disease With Chest Wall Involvement: A Case Report and a Review of the Literature.

Iran Red Crescent Med J 2014 Nov 17;16(11):e12180. Epub 2014 Nov 17.

Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, IR Iran.

Introduction: Gorham's disease is a rare disorder characterized by osteolysis and abnormal vascular growth within bones. Diagnosis of Gorham's disease is often delayed and for accurate and early diagnosis high clinical suspicion is crucial. No specific treatment is available. Management options include surgery, radiation therapy and medical therapy. We aimed to present the first case of Gorham's disease with chest wall involvement in Iran. By review of the literature we discussed important issues of this rare disease including clinical findings, diagnosis and treatment options.

Case Presentation: We present a 48-year-old man with a history of dyspnea following a blunt chest trauma who was admitted to our clinic several times due to reaccumulation of pleural fluid and chylothorax. Gorham's disease was finally established according to clinical manifestations and radiological findings including massive osteolysis in his left ribs and also histological examination.

Discussion: According to review of the literature and considering all treatment modalities the patients was successfully treated with a combination of radiotherapy, pamidronate and thalidomide. We suggest that this disease should be considered among differential diagnoses of patients with chest pain, pleural effusion and/or chylothorax with an unknown reason and more importantly history of chest trauma. In suspected cases, it is essential to examine biopsy specimens of the bone adjacent to the inflammated tissues in order to confirm diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5812/ircmj.12180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329932PMC
November 2014

Evaluation of in-house polymerase chain reaction assay sensitivity, can it be utilized in limited-resources settings?

Med J Islam Repub Iran 2014 8;28:126. Epub 2014 Nov 8.

6. MD, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Polymerase chain reaction (PCR) assay has widely used for the detection of tuberculosis (TB). This study tried to compare in-house PCR with some well-known commercial PCR kits for detection of TB agent.

Methods: Clinical samples obtained from 620 TB suspected patients were analyzed for the diagnosis of Mycobacterium tuberculosis complex (MTC) by in-house PCR. All samples were obtained through pulmonary specimens consisted of 384 sputum, 148 bronchial aspirates and 88 pleural effusions.

Results: Considering culture as a golden criterion, in which its diagnostic sensitivity and specificity of PCR assay were 87.7% and 85.6%, respectively. The findings of this study also indicate 22.1% (137/620) of the specimens were detected as MTC by PCR. Both PCR and culture confirmed presence of MTC in 57 of the samples. In comparison to culture, the diagnostic sensitivity of PCR for sputum was 87.5% (42/48), bronchial aspirates 100% (12/12), and 60% (3/5) for pleural effusions. The sensitivity of in-house PCR method is comparable with the sensitivity of Amplicor and Cobas TaqMan for MTC.

Conclusion: The study illustrates the in-house PCR assay for detection of MTC has high sensitivity and specificity versus approved commercial kits. This could be reliable test in the diagnosis of MTC in resource-limited countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313456PMC
February 2015

Expression of two basic mRNA biomarkers in peripheral blood of patients with non-small cell lung cancer detected by real-time rt-PCR, individually and simultaneously.

Iran Biomed J 2015 ;19(1):17-22

Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.

Introduction: Although extensive research has been conducted on lung cancer markers, a singular clinically applicable marker has not been found yet. The objective of this study was to evaluate the sensitivity and the specificity of carcinoembryonic antigen (CEA) mRNA and lung-specific X protein (LUNX) mRNA biomarkers in peripheral blood to detect lung cancer individually and simultaneously.

Methods: Thirty patients affected by lung cancer and 30 healthy individuals were studied in this research. Three vials of cDNA were made from each sample after taking peripheral blood samples and extracting total RNA. Each sample was examined by the real-time RT-PCR technique. The result from each vial was then compared with the sensitivity of overall marker.

Results: The CEA mRNA was positive in 24 out of 30 lung cancer patients. Hence, its sensitivity was determined at 80%, differing significantly from that observed in healthy individuals, where 11 positive cases were seen. The overall sensitivity of this marker was significantly associated with positivity in vials 2 and 3 but not in vial 1. The LUNX mRNA was positive in 21 out of 30 patients, indicating 70% sensitivity. This finding significantly differed from that in healthy individuals. The overall sensitivity of this marker was significantly associated with positivity in vials 1 and 3, but not in vial 2. In 93.3% of the patients, at least one positive marker was observed.

Conclusion: The mentioned mRNA could be suggested as sensitive and specific markers in peripheral blood for primary diagnosis of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322228PMC
http://dx.doi.org/10.6091/ibj.1397.2014DOI Listing
October 2015

Manipulation of regulatory T cells and antigen-specific cytotoxic T lymphocyte-based tumour immunotherapy.

Immunology 2015 Feb;144(2):186-96

Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.

The most potent killing machinery in our immune system is the cytotoxic T lymphocyte (CTL). Since the possibility for self-destruction by these cells is high, many regulatory activities exist to prevent autoimmune destruction by these cells. A tumour (cancer) grows from the cells of the body and is tolerated by the body's immune system. Yet, it has been possible to generate tumour-associated antigen (TAA) -specific CTL that are also self-antigen specific in vivo, to achieve a degree of therapeutic efficacy. Tumour-associated antigen-specific T-cell tolerance through pathways of self-tolerance generation represents a significant challenge to successful immunotherapy. CD4(+)  CD25(+)  FoxP3(+) T cells, referred to as T regulatory (Treg) cells, are selected in the thymus as controllers of the anti-self repertoire. These cells are referred to as natural T regulatory (nTreg) cells. According to the new consensus (Nature Immunology 2013; 14:307-308) these cells are to be termed as (tTreg). There is another class of CD4(+) Treg cells also involved in regulatory function in the periphery, also phenotypically CD4(+)  CD25(±) , classified as induced Treg (iTreg) cells. These cells are to be termed as peripherally induced Treg (pTreg) cells. In vitro-induced Treg cells with suppressor function should be termed as iTreg. These different Treg cells differ in their requirements for activation and in their mode of action. The current challenges are to determine the degree of specificity of these Treg cells in recognizing the same TAA as the CTL population and to circumvent their regulatory constraints so as to achieve robust CTL responses against cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.12387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298413PMC
February 2015

No evidence for a role of Merkel cell polyomavirus in small cell lung cancer among Iranian subjects.

Pathol Res Pract 2014 Dec 2;210(12):836-9. Epub 2014 Sep 2.

Virology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Merkel cell polyomavirus (MCPyV), as a new member of polyomaviruses, has recently been discovered as a possible etiologic factor for human cancer. It was first detected in Merkel cell carcinoma (MCC). Small cell lung cancer (SCLC) is a malignant lung tumor which shares histopathological and genetic features with MCC, as both are of neuroendocrine origin. In this study, we investigated the presence of MCPyV DNA in SCLC specimens by real-time PCR. Our null hypothesis was that MCPyV is an etiologic factor in SCLC, as previously seen in MCC. Formalin-fixed and paraffin-embedded (FFPE) specimens were obtained from 50 patients, who underwent bronchoscopic biopsy and were diagnosed with SCLC between March 2010 and March 2012. Similarly, we obtained bronchoscopic biopsy specimens from 29 patients, who were diagnosed with non-small cell lung cancer (NSCLC). All samples were obtained at a single center (Masih Daneshvari Hospital, Tehran, Iran). Real-time PCR was done to detect the presence of MCPyV DNA. After excluding one specimen from the SCLC group due to loss of tumor tissue, we did not detect MCPyV DNA in samples from patients with either SCLC (the mean age 58.9 years, male/female ratio: 7.3/1) or NSCLC. Our results suggest that MCPyV does not play a role in the pathogenesis of SCLC, which is in accord with the results from other prior investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2014.08.011DOI Listing
December 2014

Comparing docetaxel plus Cisplatin with Paclitaxel plus Carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: a single institute study.

Iran J Pharm Res 2014 ;13(2):575-81

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran .

The backbone of treatment in advanced non-small cell lung cancer is platinum-based doublet chemotherapy. We intended to compare the effectiveness of two commonly used regimens in real world practice. This single institute, parallel comparative post marketing study included 100 patients with chemo-naïve advanced (stage IIIB, IV) non-small cell lung cancer and Eastern Cooperative Oncology Group performance status of 0 to 2. They were randomly assigned by stratified blocks to receive Docetaxel/Cisplatin (DC, n=50) on day 1 or Paclitaxel/Carboplatin AUC 5 (PC, n=50) on day 1, every 3 weeks for up to six cycles. Primary end point was progression free survival (PFS); secondary end points were objective response rate, overall survival (OS) and toxicity. The administered dosage could be modified according to clinician's discretion for each individual patient. PFS was similar between DC and PC arms (4.5 ± 0.3 v 4.6 ± 1.8 months, respectively; HR= 1.337; 95% CI: 0.874 to 2.046, P = 0.181). Although median overall survival for DC arm was longer (17.2 ± 4.4 m) than PC arm (10.6 ± 0.7 m) but was not statistically significant (P = 0.300). The 1-year survival rates were in favor of DC arm (53.1% v 37.9%). Objective response rates were similar in both groups. In our study, hematologic toxicity and neuropathy were more frequent in DC and PC arms, respectively. In our study two commonly used regimens of DC and PC showed statistically similar outcomes in terms of PFS and OS, albeit numerically results of OS and 1-year survival were in favor of DC arm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157033PMC
September 2014

Transbronchial lung biopsy: the pathologist's point of view.

Clin Respir J 2016 Mar 9;10(2):211-6. Epub 2014 Nov 9.

Tracheal Disease Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background And Aims: The efficacy of flexible cryoprobe in providing high-quality tissue specimens through bronchoscopy for making a diagnosis remains debatable. In this study, we have compared the diagnostic yield of cryoprobe with conventional sampling by forceps.

Methods: Forty-one patients scheduled to undergo transbronchial lung biopsy (TBLB) in a pulmonary hospital in Tehran, Iran. Each patient underwent conventional TBLB and flexible cryoprobe TBLB (FCLB) sequentially. Specimen adequacy was defined by the presence of at least 50 alveolar spaces or a positive diagnostic yield. Adequacy of specimens, number and percentage of alveolar spaces without artifact, type of artifact, presence of bronchiolar structures and the diagnosis made based on the results of the two methods separately were compared.

Results: The mean values of tissue section area obtained by forceps and cryoprobe were 6 mm(2) [standard deviation (SD) ± 6.7] and 22 mm(2) (SD ± 19.1), respectively (P < 0.001). Specimens were adequate in 26 cases of conventional TBLB and 40 cases of FCLB (P < 0.001). Of adequate specimens, 14 samples obtained by TBLB and 28 samples obtained via FCLB were diagnostic. A significant difference was also detected between diagnostic and non-diagnostic specimens (P = 0.04). Frequency of specimens with >75% artifact-free lung parenchyma was significantly higher in FCLB method.

Conclusion: FCLB method provides larger tissue samples with better quality compared with TBLB. Higher-quality specimens are associated with less artifact and higher diagnostic yield. Multisite randomized trials are required to improve our knowledge about the benefits and indications of TBLB with cryoprobe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/crj.12207DOI Listing
March 2016