Volumetric response and pattern of failure of histone altered high grade glioma in adults following management with radiation therapy.

PURPOSE: H3K27M- and H3G34R-mutant gliomas are recently-classified subgroups of high-grade gliomas (HGGs) affecting younger adults. This study aimed to describe patterns of infiltration and failure, and the volumetric response of these tumours to radiotherapy. METHODS: Patients with histone-mutant gliomas aged 16-50 years, managed from 2009 to 2021 were identified and clinical, radiological and histopathological characteristics collected. Tumour volume was assessed on MRI at diagnosis, pre-radiotherapy, month + 1, + 3 and + 5 post-radiation and at relapse. RESULTS: Of 538 IDH1/2 wild-type HGGs, 18(15%) had a histone alteration. Eleven were H3K27M- and 7 H3G34R-mutant respectively. Median age at diagnosis was 20 years (range17-48 years). Median overall survival was 20 months (95%CI 14-29 months). Both H3K27M- and H3G34R-mutant tumours exhibited extensive T2F infiltration involving a median of 4 neuroanatomical subsites at diagnosis. Median volume of disease pre-radiotherapy on T1gd and T2F respectively was 0.5cm3 (IQR:0-1.7cm3) and 11.9 cm3 (IQR:7.5-29.6cm3) for H3K27M and 0.9cm3 (IQR:0-8.4cm3) and 43.8cm3 (IQR:25.2-86.6 cm3) for H3G34R tumours. T2F volume reduction > 50% was observed 3-months post-IMRT in 7(64%) patients with H3K27M and 1(14%) with H3G34R tumours. Fourteen patients had relapsed. Relapse was local-only, distant-only and both in 4(44%), 3(33%) and 2(22%) H3K27M-mutant and 1(20%), 2(40%), and 2(40%) H3G34R-mutant tumours. On last scan before death, leptomeningeal spread was present in 4/8(50%) and 1/5(20%) and subependymal spread in 4/8 (50%) and 0/5 H3K27M- and G34R-mutant cases respectively. CONCLUSION: H3K27M-mutant gliomas are highly responsive to radiotherapy but exhibit high propensity for subsequent leptomeningeal and subependymal spread. H3G34R-mutant tumours exhibit lesser early volumetric response to radiotherapy and propensity for distant in-brain failure.

Pattern of failure in anaplastic glioma patients with an IDH1/2 mutation.

PURPOSE: The current study aimed to assess patterns of failure (PoF) in anaplastic glioma (AG) patients managed with intensity-modulated radiation therapy (IMRT) and their relationship to molecular subtype. METHODS: The outcomes of AG patients managed between 2008 and 2014 and entered into a prospective database were assessed, including PoF. AG was initially defined using the WHO 2007 classification, but for analysis, patients were subsequently recategorised based on WHO 2016 as anaplastic oligodendroglioma (AOD), astrocytoma isocitrate dehydrogenase (IDH) mutant (AAmut) or astrocytoma IDH wildtype (AAwt). Management involved IMRT and temozolomide (TMZ), including from 2011 patients with an IDH mutation (IDHmut) planned with 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET). PoF was local, marginal or distant in relation to the IMRT volume. Relapse-free survival (RFS) was calculated from the start of IMRT. RESULTS: A total of 156 patients were assessed, with median follow-up of 5.1 years. Of these patients, 75% were IDHmut, 44% were managed at first or later relapse and 73% received TMZ. Relapse occurred in 68 patients, with 6­year RFS of 75.0, 48.8 and 2.5% for AOD, AAmut and AAwt, respectively (p < 0.001). There was a component of local relapse in 63%, of marginal relapse in 19% and of distant relapse in 37% of relapses. Isolated local, marginal and distant relapse was evident in 51, 9 and 22%, respectively. A distant relapse pattern was more frequent in IDHmut compared to IDHwt patients (26% vs. 45%, p = 0.005), especially within the first 2 years post-IMRT. In multivariate analysis, distant relapse remained associated with AAmut (p < 0.002) and delayed IMRT until the second relapse (p < 0.001). CONCLUSION: Although patients with IDH-mutated AG have improved outcomes, there was a higher proportion of distant relapses occurring during the 2 years after IMRT.

Proliferation Index Predicts Survival after Second Craniotomy within 6 Months of Adjuvant Radiotherapy for High-grade Glioma.

AIMS: To determine pathological features that predict survival in patients having repeat craniotomy within 6 months of radiotherapy for high-grade glioma (HGG). MATERIALS AND METHODS: HGG patients (World Health Organization grade 3/4) managed with repeat craniotomy within 6 months of completing radiotherapy between 2008 and 2012 were included. Based on the presence of residual tumour cells, the pathology was reported as pathological progression or pathological pseudoprogression. The proliferation index (Ki67) was reported and compared with initial pathology as a percentage change. Tumour necrosis was estimated as a percentage of the specimen. Overall survival was calculated in months. RESULTS: Of 327 patients managed with HGG, 27 patients underwent repeat craniotomy within 6 months of radiotherapy. The median survival after reoperation was 11 months (95% confidence interval 1-22). Ki67 at reoperation of 0%, 1-9% and >10% was associated with survival with a median survival of 13, 13 and 3 months, respectively (P = 0.007). Change in Ki67 was also associated with median survival, with <50% reduction median survival 3 months, 50-80% median survival 7 months and >80% reduction median survival 13 months, P = 0.02. Widespread treatment-related necrosis improved outcome, with >80% necrosis having a median survival of 13 months versus 3 months in those with <80% necrosis (P = 0.003). CONCLUSION: The presence of residual tumour at repeat craniotomy within 6 months of radiotherapy is not an independent indicator of prognosis. Patients with residual tumour that had a low Ki67 had a similar median survival as those with only treatment necrosis. Reduced proliferation of residual tumour cells and widespread necrosis may be more important indicators for future outcome.

Elderly patients aged 65-75 years with glioblastoma multiforme may benefit from long course radiation therapy with temozolomide.

To determine the outcome of elderly patients with glioblastoma managed with hypofractionated [40 Gray (Gy)] or long-course (60 Gy) radiation therapy (RT). Patients aged >60 years diagnosed with WHO grade IV glioma managed with RT between October 2006 and July 2012 were retrospectively identified. Baseline data including ECOG performance status, RT dose and use of temozolomide (TMZ) were recorded. Overall survival was calculated in months from date of diagnosis. 109 patients were included with age distribution from 61 to 88 years (13 % <65, 63 % 65-75, and 24 % >75). Median survival (MS) of total group was 12 months (95 % CI 11-13) with 12 % surviving beyond 2 years. For age groups <65, 65-75, >75 the survival was 17, 12, and 9 months respectively (p = 0.001). Near total resection (p = 0.027), but not ECOG 0-1 (p = 0.34) was associated with improved MS. For the 69 patients aged 65-75, 55 % were managed with 40 Gy and 45 % 60 Gy. Longer survival was associated with the use of 60 Gy (15 vs. 9 months, p < 0.0001), and use of TMZ (13 vs. 7 months, p < 0.0001). In the 48 patients (70 %) managed with TMZ, the MS was 15 months with 60 Gy (95 % CI 13-17) compared with 11 months (95 % CI 9-13) in those with 40 Gy. Performance status with ECOG 0-1 was not associated with improved survival (p = 0.25). Within the limitations of a retrospective study, we demonstrate improved MS in the elderly population when TMZ is added to RT. Those in the age group 65-75 may benefit from long-course RT with TMZ.

Employment following chemoradiotherapy in glioblastoma: a prospective case series.

PURPOSE: Radiotherapy (RT) and temozolomide (TMZ) for glioblastoma (GBM) has resulted in longer survival. Uncertainties exist regarding quality of survival. This study aims to determine the rate of patients returning to previous employment (EM) following treatment. METHODS: Eligible patients were diagnosed with GBM, aged 18-70 years, and treated with intensity-modulated radiotherapy to 60 Gray and TMZ (EORTC Protocol) between July 2007 and July 2011. EM was defined as paid work. Exclusion criteria included patients without histological confirmation of WHO grade IV glioblastoma, those not in paid employment in the 2-month period prior to diagnosis, or mothers of pre-school aged children not working. Data were collected on EM prior (EM pre) and after RT at 6 and 12 months (EM 6 m, EM 12 m). Rate of EM was analysed in regards to baseline performance status (ECOG), neurological deficits (MRC scale) and median survival. RESULTS: One hundred twelve patients were identified with median follow-up of 15.5 months and median survival 18 months (95%CI, 15-21 months). Seventy-one patients were working prior to diagnosis and eligible for analysis. Twenty patients returned to work (28 %) by EM 6 months and 19 patients (27 %) by EM 12 months. EM 6 months was strongly associated with ECOG and MRC status, with only 1 of 37 patients (3 %) with neurological deficit returning to work compared with 21 of 36 (58 %) intact patients. Of good performance status patients not returning to work, factors included presence of income insurance, family financial support or treatment-related symptoms. CONCLUSION: A modest proportion of patients with GBM return back to work at 6 and 12 months following radiotherapy with the majority demonstrating the lowest level of neurological deficit prior to RT. IMPLICATIONS FOR CANCER SURVIVORS: Return to work following treatment does occur but it is not a common outcome.

Immunopathogenesis of psoriasis: focus on natural killer T cells.

Psoriasis is a common inflammatory skin disease triggered by dysregulated immune response and characterized by hyperproliferation and altered differentiation of keratinocytes. Formation of psoriatic lesions is thought to be elicited by the complex cellular and cytokine network arising from the pathogenic interactions between keratinocytes and components of innate and acquired immune system. Natural killer T (NKT) cells are a heterogenous T-cell lineage that has been implicated in the pathogenesis of various autoimmune diseases including psoriasis. Due to the numerous functions of NKT cells that link innate and adaptive immunity, their role in psoriasis is complex and still elusive. We summarize the currently available literature data on this issue and discuss the possible role of NKT cells in the immunopathogenesis of this autoimmune disease.

Granuloma annulare--a genetic disorder that sustain an incomplete foreign-body granuloma reaction.

Granuloma annulare (GA) is a common dermatosis characterized by an annular arrangement of erythematous papules, plaques, rarely nodules or patches. It is a type of non-infectious granuloma with unknown etiology. Hypothesis. The immune reaction always begins with the foreign-body granuloma formation. However, if during the process the antigen is recognized as too small the immune reaction stops the granuloma development. In the case of GA the dysfunctional control mechanism continues to sustain the granulomatous formation. Because the target does not exist anymore, the initiated process starts the "search" for a new target (circular spreading). Different histological and clinical presentations depends on which gene of the control mechanism is dysfunctional, while the distribution depends on the type of antigen and its distribution at the start of the immune reaction. The disappearance of GA after biopsy, that occurs in some cases, could be attributable to the specific defective gene involved (the biopsy can disrupt only some type of GA). So, new therapies for solitary GA formations could be directed to the disruption and creation of a new and healthy immune response from the point of disruption. A comparative analysis of the gene expression of GA and the foreign-body granuloma in the same patient, and GA among different patients could clarify which genes are involved in granulomatous formations. The cells affected by those genetic defects are probably histiocytes and lymphocytes (both always present in GA). Because of some similarity, necrobiosis lipoidica could also be a specific type of GA.

Perforin expression is upregulated in the epidermis of psoriatic lesions.

BACKGROUND: There are currently very few data regarding the role of cell-mediated cytotoxicity in psoriasis. Both cytotoxic T lymphocytes and natural killer (NK) cells mediate cytotoxicity reactions, mainly by two distinct pathways, the perforin/granzyme and the Fas/Fas ligand pathway. OBJECTIVES: To study the expression and distribution of perforin, T- and NK-cell subsets in psoriatic lesional and nonlesional skin. METHODS: Skin biopsy specimens from both lesional and nonlesional skin of 11 patients with chronic plaque psoriasis and eight healthy controls were analysed by immunohistochemistry. RESULTS: We found a significant increase in CD4+ and CD8+ cells in psoriatic lesions compared with nonlesional and healthy skin. The expression of CD16+ NK cells was significantly lower in lesions compared with healthy skin. Perforin expression was significantly enhanced in the epidermis of psoriatic lesions. CONCLUSIONS: Perforin expression is upregulated in the epidermis of psoriatic lesions, suggesting a potential role for perforin in the creation of the psoriatic plaque.

Perforin expression in peripheral blood lymphocytes and skin-infiltrating cells in patients with lichen planus.

BACKGROUND: Current evidence suggests that lichen planus is a T-cell-mediated autoimmune disease in which cytotoxic mechanisms have been poorly investigated. OBJECTIVES: We investigated the expression of perforin in subpopulations of peripheral blood lymphocytes (PBL) in exacerbation and remission phases of the disease as well as in skin lesions. METHODS: We performed a simultaneous detection of perforin (intracellular molecule) and cell surface antigens on PBL by flow cytometry, and skin lesions were investigated by immunohistochemistry. RESULTS: The most interesting finding was a significant increase of perforin expression in cytotoxic T lymphocytes (CD3+ perforin+ cells) in the exacerbation phase of disease (P < 0.05), which was mostly located in the CD8+ subpopulation (CD8+ perforin+) (P < 0.01). Using immunohistochemistry we confirmed the infiltration of T lymphocytes in skin lesions, especially of CD4+ and CD8+ phenotypes, compared with uninvolved (P < 0.05) and healthy skin (P < 0.01). The expression of perforin was also significantly higher in lesional skin compared with nonlesional and healthy skin (P < 0.05). CONCLUSIONS: Our results clearly show the upregulation of perforin expression in peripheral blood as well as in lesions of patients with lichen planus and therefore suggest an important role for perforin in this autoimmune disease.

A new extended haplotype Cw*0602-B57-DRB1*0701-DQA1*0201-DQB1*0201 associated with psoriasis in the Croatian population.

In this study, we have analysed the distribution of HLA class II alleles and the extended haplotype HLA-Cw-B-DRB1-DQA1-DQB1 in Croatian patients with type I and type II psoriasis by hybridization with specific oligonucleotide probes. Type I psoriasis showed a significant association with the DRB1*0701 [P < 0.00001; relative risk (RR) = 5.83], DQA1*0201 (P < 0.00001; RR = 6.12), DQB1*0201 (P = 0.0006; RR = 3.29) and DQB1*0303 alleles (P = 0.0008; RR = 7.51). A negative correlation with type I disease was observed for the DQA1*0102 allele (P = 0.002; RR = 0.26). Type II psoriasis did not show any association with any class II alleles. The extended haplotype HLA-Cw*0602-B57-DRB1*0701-DQA1*0201-DQB1*0201 was present at a significantly higher frequency in type I patients (P < 0.00001; RR = 7.72). However, this haplotype was not detected at all in patients with type II psoriasis. In conclusion, the extended haplotype HLA-Cw*0602-B57-DRB1*0701-DQA1*0201-DQB1*0201 is a risk haplotype for type I disease in the Croatian population. This particular haplotype has not been reported previously in association with psoriasis in any other ethnic groups.

HLA class II haplotypic association and DQCAR microsatellite polymorphisms in Croatian patients with psoriasis.

The purpose of the present study was to investigate polymorphism of HLA class II haplotypic associations (HLA-DRB1, -DQA1, -DQB1) and DQCAR alleles in 78 Croatian patients with psoriasis. Patients were divided into two groups according to a family history of disease and age of onset: type I (positive family history and early onset) and type II (negative family history and late onset). The difference in frequency of HLA class II haplotypic associations between type I patients and controls was observed for the following combinations: HLA-DRB1*0701, -DQA1*0201, -DQB1*02 (23.6% vs. 7.2%; p < 0.001), HLA-DRB1*0701, -DQA1*0201, -DQB1*0303 (8.5% vs. 1.3%; p = 0.0018) and HLA-DRB1*1601, -DQA1*0102, -DQB1*0502 (2.8% vs. 9.3%; p = 0.06). The difference between type II psoriasis and controls for association: HLA-DRB1*1501, -DQA1*0102, -DQB1*0602 is not significant (20.0% vs. 8.9%; p = 0.06). The significantly higher frequency of DQCAR 113bp and 119bp alleles in patients with type Ipsoriasis is a result of linkage disequlibrium of these alleles with both HLA-DRB1*0701 haplotypic associations. Analysis ofDQCAR alleles in the HLA-DRB1*0701 haplotypic associations in patients with psoriasis vulgaris and matched controls did not reveal any difference in polymorphism of DQCAR alleles. These data suggest that HLA-DRB*0701 haplotypic combinations are associated with type I but not for type II psoriasis in the Croatian population. DQCAR polymorphism is not useful genetic marker to distinguish susceptible HLA class II haplotypic association.

Treatment of early syphilis with azithromycin.

An open, noncomparative study was performed to establish the efficacy of azithromycin in the treatment of early syphilis. Sixteen patients were treated with oral azithromycin: 1g the first day and then 500 mg for the following 8 days. Two patients were excluded from the study, leaving 14 patients for the evaluation of the efficacy. Venereal Disease Research Laboratory (VDRL) negativity was observed in 3 out of 6 patients treated for primary syphilis after 3 months and in all patients after 6 months. Two of 8 patients treated for manifest or early latent secondary syphilis had VDRL negativity after 3 months and 4 patients after 6 months. This study demonstrates that azithromycin is effective in the treatment of early syphilis. Two patients experienced gastrointestinal side effects which did not require treatment interruption.

Analysis of HLA antigens in Croatian patients with psoriasis.

In common with most autoimmune diseases, psoriasis is associated with some HLA antigens. We studied the distribution of HLA antigens in Croatian patients with psoriasis: 108 patients were divided into groups according to family history and age of disease onset. HLA antigens were analyzed serologically and HLA-C alleles were analyzed using polymerase chain reaction. We found significant increases in HLA-A2, -B17, -B37 and -B13 antigens and highly significant increases in HLA-Cw*0602 and DR7 antigens in psoriatic patients compared with controls. Patients with type I psoriasis (early onset, positive family history) showed highly significant associations with Cw*0602 [p < 0.00001; relative risk (RR) = 14.45] and DR7 (p < 0.00001; RR = 15.09) antigens. Patients with type II psoriasis (late onset, no family history) had a significant association with Cw*03 antigen (p = 0.008; RR = 0.17). In conclusion, HLA-B13, -B17, Cw*0602 and -DR7 antigens are associated with a significant risk of psoriasis in the Croatian population and the Cw*0602 allele has the strongest association, especially for type I psoriasis.

Jumping translocations involving 11q in a non-Hodgkin lymphoma.

This paper presents the results of a cytogenetic analysis in an 11-year-old boy with non-Hodgkin lymphoma. The investigation was performed on slides obtained from short-term culture of lymph node cells. The analyses revealed an abnormal clone with loss of Y, gain of an X chromosome, t(3;22), trisomy 11, and three cytogenetically-related subclones with jumping translocations involving 11q13 as the common breakpoint region. This region is an unusual site of chromosome breakage in jumping translocations, and has not been reported thus far. Contrary to most published reports, the jumping translocation in our patient is associated with long survival.

Immunocompetent cells and lymphocyte reactivity to mitogens in levamisole-treated brain tumor children.

This study investigated the influence of levamisole therapy on immunocompetent cells and lymphocyte reactivity to mitogens in 25 children with brain tumor. Eleven (11/25) patients were receiving chemotherapy and immunomodulating drug levamisole 3 months after neurosurgery, during maintenance chemotherapy, 2.5 mg/kg of body weight per os, for three consecutive days every 2 weeks, for 6-12 months. The proportion of lymphocytes, proportion and number of T- and B-lymphocytes and natural killer (NK) cells, as well as lymphocyte reactivity to mitogens were significantly lower in non-levamisole-treated patients than in the healthy controls (N = 18). Therapy with levamisole significantly augments the proportion of T lymphocytes, the number of T lymphocytes, NK cells, and the lymphocyte reactivity to concanavalin A (Con A). Depression of the NK cells and the lymphocyte reactivity to mitogens were much more pronounced in those patients who developed recurrences. Levamisole shortened the period of secondary immunodeficiency in immunocompromised children with brain tumor.

Azithromycin compared with minocycline in the treatment of acne comedonica and papulo-pustulosa.

This open study was conducted in 72 outpatients with acne vulgaris, to compare the clinical efficacy and tolerability of azithromycin and minocycline. Azithromycin was administered as a single oral dose (500 mg/day) for 4 days in four cycles every 10 days and minocycline was administered 100 mg daily for 6 weeks. Improvement was assessed 6 weeks after initiation of treatment with a four-graded scale. A satisfactory clinical response was observed in 75.8% of the patients treated with azithromycin and in 70.5% of those treated with minocycline. There were no significant differences between these two acne treatments in terms of reduction of the number of lesions (p> 0.05). Both agents were well tolerated and mild side effects were reported in 10.3% of azithromycin and 11.7% of minocycline treated patients. We conclude that azithromycin is at least as clinically effective and well tolerated as minocycline as treatment of facial comedonic and papulopustular acne.