Single-nucleotide polymorphism in the 5-α-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors

Publication date: February 2016
Source:European Journal of Cancer, Volume 54
Author(s): Hink Boer, Nico-Derk L. Westerink, Renske Altena, Janine Nuver, D.A. Janneke Dijck-Brouwer, Martijn van Faassen, Frank Klont, Ido P. Kema, Joop D. Lefrandt, Nynke Zwart, H.Marike Boezen, Andries J. Smit, Coby Meijer, Jourik A. Gietema
PurposeChemotherapy-treated testicular cancer survivors are at risk for development of the metabolic syndrome, especially in case of decreased androgen levels. Polymorphisms in the gene encoding steroid 5-α-reductase type II (SRD5A2) are involved in altered androgen metabolism. We investigated whether single-nucleotide polymorphisms (SNPs) rs523349 (V89L) and rs9282858 (A49T) in SRD5A2 are associated with cardiometabolic status in testicular cancer survivors.MethodsIn 173 chemotherapy-treated testicular cancer survivors, hormone levels and cardiometabolic status were evaluated cross-sectionally (median 5 years [range 3–20] after chemotherapy) and correlated with SNPs in SRD5A2.ResultsThe metabolic syndrome was more prevalent in survivors who were homozygous or heterozygous variant for SRD5A2 rs523349 compared to wild type (33% versus 19%, P = 0.032). In particular, patients with lower testosterone levels (<15 nmol/l) and a variant genotype showed a high prevalence of the metabolic syndrome (66.7%). Mean intima-media thickness of the carotid artery and urinary albumin excretion, both markers of vascular damage, were higher in the group of survivors homozygous or heterozygous variant for rs523349 (0.62 versus 0.57 mm, P = 0.026; 5.6 versus 3.1 mg/24 h, P = 0.017, respectively). No association was found between cardiometabolic status and SNP rs9282858 in SRD5A2.ConclusionMetabolic syndrome develops more frequently in testicular cancer survivors homozygous or heterozygous variant for SNP rs523349 in SRD5A2. Altered androgen sensitivity appears to be involved in the development of adverse metabolic and vascular changes in testicular cancer survivors and is a target for intervention.



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Rationale for anti-CD137 cancer immunotherapy

Publication date: February 2016
Source:European Journal of Cancer, Volume 54
Author(s): Amani Makkouk, Cariad Chester, Holbrook E. Kohrt
The consideration of the complex interplay between the tumour microenvironment (TME) and the immune response is the key for designing effective immunotherapies. Therapeutic strategies that harness co-stimulatory receptors have recently gained momentum in the clinic. One such strategy with promising clinical applications is the targeting of CD137, a member of the tumour necrosis factor receptor superfamily. Its expression on both innate and adaptive immune cells, coupled with its unique ability to potentiate antitumour responses through modulating the TME and to ameliorate autoimmune responses, has established it as an appealing target. In this review, we will discuss the various CD137-targeted immunotherapeutics that have reached clinical development, with a focus on recent advances and novel modalities such as CD137 chimeric antigen receptors and CD137 bispecific antibodies. We will also highlight the effect of CD137 targeting on the TME and discuss the importance of probing TME changes for predicting and testing the efficacy of CD137-mediated immunotherapy.



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Comment on “Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: A Bayesian network meta-analysis”, published in Eur J Cancer 51 (2015), 1570–1579

Publication date: Available online 2 January 2016
Source:European Journal of Cancer
Author(s): Pierre Blanchard, Laureen Ribassin-Majed, Anne Lee, Jean Pierre Pignon




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Prospective Randomized Trial of Prone Accelerated Intensity Modulated Breast Radiotherapy with a Daily versus Weekly Boost to the Tumor Bed

Publication date: Available online 29 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): B.T. Cooper, G.F. Formenti-Ujlaki, X. Li, S.M. Shin, M. Fenton-Kerimian, A. Guth, D.F. Roses, C.J. Hitchen, B.S. Rosenstein, J.K. Dewyngaert, J.D. Goldberg, S.C. Formenti
PurposeTo report the results of a prospective randomized trial comparing a daily versus weekly boost to the tumor cavity during the course of accelerated radiation to the breast in the prone position.Methods and MaterialsFrom 2009-2012, 400 stage 0-II breast cancer patients who had undergone segmental mastectomy participated in an IRB-approved trial testing prone breast radiotherapy to 40.5 Gy/15 fractions to the whole breast, five days a week after randomization to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy, on Friday. This non-inferiority trial tested the primary hypothesis that a weekly boost produced no more acute toxicity than a daily boost. Recurrence Free Survival (RFS) was estimated for both treatment arms using the Kaplan-Meier method; the relative risk of recurrence or death was estimated and the two arms were compared with the log-rank test.ResultsAt a median follow-up of 45 months, there were no deaths related to breast cancer. The weekly boost regimen produced no more grade ≥ 2 acute toxicity than the daily boost regimen (8.1% vs 10.4%; non-inferiority Z = -2.52; p = 0.006). There was no statistical difference in cumulative incidences of long term fibrosis or telangiectasia ≥2 between the two arms (log-rank p=0.923). There were 2 local and 2 distant recurrences in the daily arm. There were 3 local and 1 distant recurrences in the weekly arm, with no difference in 4-year RFS between the two arms (98% in both arms).ConclusionsA tumor bed boost delivered either daily or weekly is similarly tolerated during accelerated prone breast radiotherapy, with excellent control of disease and comparable cosmetic results.

Teaser

We conducted a prospective trial randomizing women with early stage breast cancer to accelerated prone, whole breast radiotherapy with a weekly versus daily boost to the tumor bed. At a median follow-up of 45 months, there was no difference in toxicity or efficacy between the two treatment arms. There was a trend towards more patients reporting good/excellent cosmesis among those treated with the weekly boost.


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A prospective comparison of the effects of interfractional variations on proton therapy and IMRT for prostate cancer

Publication date: Available online 29 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M. Moteabbed, A. Trofimov, G.C. Sharp, Y. Wang, A.L. Zietman, J. Efstathiou, H.-M. Lu
PurposeTo quantify and compare the impact of interfractional setup and anatomy variations on proton therapy (PT) and intensity modulated radiotherapy (IMRT) for prostate cancer.Methods and MaterialsTwenty patients with low- or intermediate-risk prostate cancer randomized to receive passive-scattering PT (n=10) and IMRT (n=10) were selected. For both modalities, clinical treatment plans included 50.4 Gy(RBE) to prostate and proximal seminal vesicles, and prostate-only boost to 79.2 Gy(RBE) in 1.8 Gy(RBE) per fraction. Implanted fiducials were used for prostate localization, and endorectal balloons for immobilization. Patients in PT and IMRT arms received weekly CT and cone-beam CT (CBCT) scans, respectively. The planned dose was re-calculated on each weekly image, scaled and mapped onto the planning CT using deformable registration. The resulting accumulated dose distribution over the entire treatment course was compared with the planned dose using dose-volume histogram (DVH) and gamma analysis.ResultsThe target conformity index remained acceptable after accumulation. The largest decrease in the average prostate D98 was 2.2 and 0.7 Gy for PT and IMRT, respectively. On average, the mean dose to bladder increased by 3.26±7.51 Gy and 1.97±6.84 Gy for PT and IMRT, respectively. These values were 0.74±2.37 and 0.56±1.90 for rectum. Differences between changes in DVH indices were not statistically significant between the two modalities. All volume indices remained within the protocol tolerances after accumulation. The average pass rate in gamma analysis, assuming tolerances of 3 mm and 3%, for PT/IMRT for CTV, bladder, rectum and whole patient were 100/100, 92.6/99, 99.2/100 and 97.2/99.4, respectively.ConclusionThe difference in target coverage and OAR dose deviations for PT and IMRT was not statistically significant under the guidelines of this protocol.

Teaser

The impact of setup and anatomy variations on the dose distribution was compared between proton therapy and IMRT for prostate cancer. Although both modalities were robust to interfractional variations with no statistically significant differences, it is desirable to minimize the remaining sources of uncertainty mainly in setup accuracy and bladder size consistency.


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Clinicopathologic features of small cell glioblastomas

Abstract

Small cell glioblastoma (SCGBM) is a variant of glioblastomas characterized by a predominant population of small and monomorphic glial cells. The aim of the present study was to investigate clinical, neuroimaging, pathologic, and genetic features of SCGBM. The clinicopathologic and genetic features were evaluated in 14 patients with SCGBM. All cases were divided into multifocal and solitary type by MRI, and extent of microvascular proliferation, intratumoral necrosis, and perivascular lymphocytic accumulation were investigated. IDH1 mutations by immunohistochemistry (IDH1 R132H) and 1p 19q codeletion by fluorescence in situ hybridization were detected. Patients ranged from 23 to 92 years of age (median: 71 years), with three females and eleven males. The overall survival time of the patients ranged from 7 to 23 months (mean: 11 months). Nine patients (64 %) were the multifocal type. Pathologic study revealed that the microvascular proliferation, necrosis, and lymphocytic infiltration were limited in SCGBM. Immunohistochemically, tumor cells were negative for IDH1 R132H in all patients. FISH analysis demonstrated that no SCGBM had 1p/19q codeletion in informative patients. Our investigation suggested that an elderly onset and multifocal lesions were characteristics of SCGBM associated with degradation of the immune response, infiltrative feature of tumor cells, and an unfavorable prognosis.

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Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy

Abstract

Survival of patients with glioblastoma (GBM) remains poor, and novel treatment methods are urgently needed. In this study, we tested the effects of a combination of fasudil, a ROCK inhibitor, and clioquinol, an 8-hydroxyquinoline derivative with antimicrobial properties, on human GBM U87 cells. Combination treatment synergistically inhibited the viability of glioma cells but not mouse normal neuron HT22 cells and significantly induced mitochondria-mediated apoptosis. Moreover, the combination was also found to trigger macro-autophagy (henceforth referred to as autophagy) by increasing the expression levels of several proteins involved in the induction of autophagy. Further studies showed that 3-methyladenine (3-MA) or chloroquine (CQ), two autophagy inhibitors, abrogated the cytotoxic effects of the combination treatment as well as the autophagy. Overall, we demonstrated that fasudil and clioquinol show synergistic anti-cancer effects, providing evidence for the further development of combination therapy for GBM.

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