Παρασκευή 1 Απριλίου 2016

FAP-dependent DR5 hyperclustering drives tumor cell death

Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor targeted induction of apoptosis, we engineered a bispecific antibody (BsAb) which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyper-clustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP-dependent, was independent of FcR crosslinking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis.



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dPCR and RAS pathway genotyping for mCRC anti-EGFR therapy

The clinical significance of low-frequent RAS pathway mutated alleles and the optimal sensitivity cut-off in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E) was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared to conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS) and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1 to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04 to 10.8%. An inverse correlation between the fraction of mutated alleles and radiological response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy.



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PTK2/FAK and radioresistance

Purpose: Head and neck squamous cell carcinoma (HNSCC) is commonly treated with radiotherapy, and local failure after treatment remains the major cause of disease-related mortality. To date human papillomavirus (HPV) is the only known clinically validated, targetable biomarkers of response to radiation in HNSCC. Experimental Design: We performed proteomic and transcriptomic analysis of targetable biomarkers of radioresistance in HPV-negative HNSCC cell lines in vitro, and tested whether pharmacologic blockade of candidate biomarkers sensitized cells to radiotherapy. Candidate biomarkers were then investigated in several independent cohorts of patients with HNSCC. Results: Increased expression of several targets was associated with radioresistance, including FGFR, ERK1, EGFR, and focal adhesion kinase (FAK), also known as PTK2. Chemical inhibition of PTK2/FAK, but not FGFR, led to significant radiosensitization with increased G2/M arrest and potentiated DNA damage. PTK2/FAK overexpression was associated with gene amplification in HPV-negative HNSCC cell lines and clinical tumors. In two independent cohorts of patients with locally advanced HPV-negative HNSCC, PTK2/FAK amplification was highly associated with poorer disease-free survival (DFS) (P=0.012 and P=0.034). PTK2/FAK mRNA expression was also associated with worse DFS (P=0.03). Moreover, both PTK2/FAK mRNA (P=0.021) and copy number (P=0.063) were associated with DFS in the Head and Neck Cancer subgroup of The Cancer Genome Atlas. Conclusion: Proteomic analysis identified PTK2/FAK overexpression is a biomarker of radioresistance in locally advanced HNSCC, and PTK2/FAK inhibition radiosensitized HNSCC cells. Combinations of PTK2/FAK inhibition with radiotherapy merit further evaluation as a therapeutic strategy for improving local control in HPV-negative HNSCC.



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Role of Extracellular Visfatin in Breast Cancer

Purpose: Visfatin is an adipocytokine involving in cellular metabolism, inflammation, and cancer. This study investigated the roles of extracellular visfatin in breast cancer, and explored underlying mechanisms in clinical and experimental settings. Experimental Design: Associations of serum visfatin with clinicopathological characteristics and patient survival were assessed with Cox regression models and Kaplan-Meier analyses. Effects of extracellular visfatin on cultured breast cancer cells were examined, followed by in vivo investigation of tumor growth and metastasis in xenograft animal models. Imatinib and Stattic were utilized to inhibit c-Abl and STAT3 activation, respectively. Results: Breast cancer patients with high serum visfatin levels were associated with advanced tumor stage, increased tumor size and lymph node metastasis, and poor survival. Elevated phosphorylation of c-Abl and STAT3 in breast tumor tissues were correlated with high serum visfatin levels in patients. Visfatin-promoted in vitro cell viability and metastatic capability were suppressed by imatinib (c-Abl inhibitor) and Stattic (STAT3 inhibitor). Increased in vivo cell invasiveness was observed in zebrafish xenografted with visfatin-pretreated breast cancer cells. Tumor growth and lung metastasis occurred in visfatin-administered mice xenografted with breast cancer cells. Tail vein-injected mice with visfatin-pretreated breast cancer cells showed increased lung metastasis, which was suppressed by imatinib. Conclusions: Serum visfatin levels in breast cancer patients reveal potential prognostic values, and our findings that visfatin promoted breast cancer through activation of c-Abl and STAT3 may provide an important molecular basis for future design of targeted therapies that take into account of different serum visfatin levels in breast cancer.



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Expression of miRNA-26b in the diagnosis and prognosis of patients with non-small-cell lung cancer

Future Oncology Ahead of Print.


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An Evaluation of Robotic and Conventional IMRT for Prostate Cancer: Potential for Dose Escalation

This study compares conventional and robotic intensity modulated radiation therapy (IMRT) plans for prostate boost treatments and provides clinical insight into the strengths and weaknesses of each. The potential for dose escalation with robotic IMRT is further investigated using the "critical volume tolerance" method proposed by Roach et al. Three clinically acceptable treatment plans were generated for 10 prostate boost patients: (1) a robotic IMRT plan using fixed cones, (2) a robotic IMRT plan using the Iris variable aperture collimator, and (3) a conventional linac based IMRT (c-IMRT) plan. Target coverage, critical structure doses, homogeneity, conformity, dose fall-off, and treatment time, were compared across plans. The average bladder and rectum V75 was 17.1%, 20.0%, and 21.4%, and 8.5%, 11.9%, and 14.1% for the Iris, fixed, and c-IMRT plans, respectively. On average the conformity index (nCI) was 1.20, 1.30, and 1.46 for the Iris, fixed, and c-IMRT plans. Differences between the Iris and the c-IMRT plans were statistically significant for the bladder V75 (P= .016), rectum V75 (P= .0013), and average nCI (P =.002). Dose to normal tissue in terms of R50 was 4.30, 5.87, and 8.37 for the Iris, fixed and c-IMRT plans, respectively, with statistically significant differences between the Iris and c-IMRT (P = .0013) and the fixed and c-IMRT (P = .001) plans. In general, the robotic IMRT plans generated using the Iris were significantly better compared to c-IMRT plans, and showed average dose gains of up to 34% for a critical rectal volume of 5%.



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A Study on Stereoscopic X-ray Imaging Data Set on the Accuracy of Real-Time Tumor Tracking in External Beam Radiotherapy

At external beam radiotherapy, stereoscopic X-ray imaging system is responsible as tumor motion information provider. This system takes X-ray images intermittently from tumor position (1) at pretreatment step to provide training data set for model construction and (2) during treatment to control the accuracy of correlation model performance. In this work, we investigated the effect of imaging data points provided by this system on treatment quality. Because some information is still lacking about (1) the number of imaging data points, (2) shooting time for capturing each data point, and also (3) additional imaging dose delivered by this system. These 3 issues were comprehensively assessed at (1) pretreatment step while training data set is gathered for prediction model construction and (2) during treatment while model is tested and reconstructed using new arrival data points. A group of real patients treated with CyberKnife Synchrony module was chosen in this work, and an adaptive neuro-fuzzy inference system was considered as consistent correlation model. Results show that a proper model can be constructed while the number of imaging data points is highly enough to represent a good pattern of breathing cycles. Moreover, a trade-off between the number of imaging data points and additional imaging dose is considered in this study. Since breathing phenomena are highly variable at different patients, the time for taking some of imaging data points is very important, while their absence at that critical time may yield wrong tumor tracking. In contrast, the sensitivity of another category of imaging data points is not high, while breathing is normal and in the control range. Therefore, an adaptive supervision on the implementation of stereoscopic X-ray imaging is proposed to intelligently accomplish shooting process, based on breathing motion variations.



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Pax5 Re-Expression In H460 Cells Treated With The Combination Of Demethylating Agent And Histone Deacetylase Inhibitor Is Associated With The Enhancement Of P53 Binding To Pax5 Promoter Region.

Related Articles

Pax5 Re-Expression In H460 Cells Treated With The Combination Of Demethylating Agent And Histone Deacetylase Inhibitor Is Associated With The Enhancement Of P53 Binding To Pax5 Promoter Region.

Curr Cancer Drug Targets. 2016 Mar 31;

Authors: Liang Y, Zeng J, Jelicks L, Ma S, Liu J, Mei J, Perez-Soler R, Zou Y

Abstract
The epigenetic combinations of DNA demethylating agents and histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits for non-small cell lung cancer (NSCLC) treatment, however, there are few studies uncovering the underlying molecular mechanism of the combinations. Our previous study showed that DNA demethylating agent Azacitidine (Aza) demethylated CpG sites in paired box gene 5 (pax5) promoter region, but did not induce pax5 mRNA or protein expression. In this study, we used epigenetic combination of Aza and HDAC inhibitor Vorinostat (SAHA) to treat NSCLC cells and tried to elucidate the underlying molecular mechanism. We treated pax5-silenced NSCLC H460 cells with Aza+SAHA combination at sub-toxic concentration and detected the re-expression of pax5 mNRA and protein. Our MassArray illustrated demethylation of CpG sites in pax5 promoter region by Aza treatment; and DNA-protein binding assay indicated increased DNA accessibility for protein binding by SAHA treatment. Chromatin DNA-protein binding test demonstrated that the combination of Aza+SAHA significantly increased p53 protein binding to DNA in pax5 promoter region (p<0.01). These results implied more efficient binding of the transcription factor p53 to pax5 promoter region likely because SAHA increased accessibility of the chromatin conformation and Aza-demethylated DNA was more permissive, allowing transcription factors to bind. Our study not only explained an underlying mechanism, that pax5 re-expression was induced by Aza+SAHA combination in H460 cells via p53, but also demonstrated a pattern showing that the combination of demethylating agent and HDAC inhibitor can re-activate tumor suppressor gene (TSG) which is associated with the enhancement of transcription factors binding to the promoter region of the TSG.

PMID: 27029827 [PubMed - as supplied by publisher]



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Level of arterial ligation in sigmoid colon and rectal cancer surgery

Abstract

Background

Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate, and it is unclear whether this confers a survival advantage. Accordingly, the IMA may be ligated at a point just below the origin of the left colic artery (LCA) "low tie" combined with lymph node dissection (LND) around the origin of the IMA (low tie with LND). However, no study has investigated the detailed prognostic results between "high tie" and "low tie with LND." The aim of this study was to assess the utility of "low tie with LND" on survival in patients with sigmoid colon or rectal cancer.

Methods

A total of 189 sigmoid colon or rectal cancer patients who underwent curative operation from 1997 to 2007 were enrolled in this study. The patient's medical records were reviewed to obtain clinicopathological information. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method, with differences assessed using log-rank test.

Results

Forty-two and 147 patients were ligated at the origin of the IMA (high tie) and just below the origin of the LCA combined with LND around the origin of the IMA (low tie with LND), respectively. No significant differences were observed in the complication rate and OS and RFS rates in the two groups. Further, no significant difference was observed in the OS and RFS rates in the lymph node-positive cases in the two groups.

Conclusions

"Low tie with LND" is anatomically less invasive and is not inferior to "high tie" with prognostic point of view.



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A recurrent epidermoid cyst of the spleen: report of a case and literature review

Abstract

Background

Splenic cysts are rare disease. Epidermoid cysts of the spleen belong to the primary nonparasitic splenic cysts group. They are an unusual event in surgical practice. Usually, epidermoid cysts occur in children and young female. Most often, they are asymptomatic, but they may present with abdominal discomfort.

Case presentation

We are reporting a rare case of a 23-year-old female came to our attention with history of intermittent pain and previously undergone two times to laparoscopic decapsulation of the cyst in others institutions. During hospitalization, serum and intracystic levels of tumor marker CA19-9 increased. Enhanced CT of the abdomen showed recurrent large cyst in the upper pole of the spleen with satellite nodules. Laparotomic total splenectomy was performed. Histopathological and immunoreactive examinations were executed, and they revealed stratified squamous epithelium on the inner surface of cystic wall, which was positive for EMA, CEA, and CA19-9. The diagnosis of epidermoid cyst was confirmed.

Conclusions

Recently, the surgical approach is changing towards conservative treatments in order to save the spleen in young patients for immunological reasons. Sometimes, this target is not achievable. In such circumstances, like recurrent large cyst, anomalous anatomical relationship to the surrounding tissues, total splenectomy is safe and necessary.



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BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer

This article summarises the evolving role and challenges of somatic BRCA mutations and BRCA methylation in ovarian cancer



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Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases



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In reply to the Letter to the Editor "Insertion of central venous catheters (CVCs): Any changes in the past ten years" by Biffi et al.



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Systematic review: brain metastases from colorectal cancer—Incidence and patient characteristics

Abstract

Background

Brain metastases (BM) from colorectal cancer (CRC) are a rare event. However, the implications for affected patients are severe, and the incidence has been reported to be increasing. For clinicians, knowledge about the characteristics associated with BM is important and could lead to earlier diagnosis and improved survival.

Method

In this paper, we describe the incidence as well as characteristics associated with BM based on a systematic review of the current literature, following the PRISMA guidelines.

Results

We show that the incidence of BM in CRC patients ranges from 0.6 to 3.2 %. BM are a late stage phenomenon, and young age, rectal primary and lung metastases are associated with increased risk of developing BM. Molecular markers such as KRAS, BRAF, NRAS mutation as well as an increase in CEA and CA19.9 levels are suggested predictors of brain involvement. However, only KRAS mutations are reasonably well investigated and associated with an increased risk of BM.

Conclusion

The incidence of BM from CRC is 0.6 to 3.2 % and did not seem to increase over time. Development of BM is associated with young age, lung metastases, rectal primary and KRAS mutation. Increased awareness of brain involvement in patients with these characteristics is necessary.



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Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments

Abstract

Background

Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets.

Results

Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival.

Conclusions

Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.



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miR-539 inhibits prostate cancer progression by directly targeting SPAG5

We conducted multiple microarray datasets analyses from clinical and xenograft tumor tissues to search for disease progression-driving oncogenes in prostate cancer (PCa). Sperm-associated antigen 5 (SPAG5) att...

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miR-539 inhibits prostate cancer progression by directly targeting SPAG5

Abstract

Background

We conducted multiple microarray datasets analyses from clinical and xenograft tumor tissues to search for disease progression-driving oncogenes in prostate cancer (PCa). Sperm-associated antigen 5 (SPAG5) attracted our attention. SPAG5 was recently identified as an oncogene participating in lung cancer and cervical cancer progression. However, the roles of SPAG5 in PCa progression remain unknown.

Methods

SPAG5 expression level in clinical primary PCa, metastatic PCa, castration resistant PCa, neuroendocrine PCa, and normal prostate tissues was investigated. We established multiple in vivo xenografts models using patient-derived tissues and investigated SPAG5 expression trend in these models. We also investigated the functions of SPAG5 in vivo and in vitro studies. Luciferase reporter assays were performed to investigate potential miRNAs that can regulate SPAG5.

Results

We identified that SPAG5 expression was gradually increased in PCa progression and its level was significantly associated with lymph node metastasis, clinical stage, Gleason score, and biochemical recurrence. Our results indicated that SPAG5 knockdown can drastically inhibit PCa cell proliferation, migration, and invasion in vitro and supress tumor growth and metastasis in vivo. We identified that miR-539 can directly target SPAG5. Ectopic overexpression of miR-539 can drastically inhibit SPAG5 expression and the restoration of SPAG5 expression can reverse the inhibitory effects of miR-539 on PCa cell proliferation and metastasis.

Conclusion

Our results collectively showed a progression-driving role of SPAG5 in PCa which can be regulated by miR-539, suggesting that miR-539/SPAG5 can serve as a potential therapeutic target for PCa.



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The Curie - Da Vinci connection: 5-years’ experience with laparoscopic (robot assisted) implantation for HDR brachytherapy of solitary T2 bladder tumors

Publication date: Available online 1 April 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Elzbieta M. van der Steen-Banasik, Geert Smits, Bernard J. Oosterveld, Theo Janssen, Andries G. Visser
PurposeTo report experience and early results of laparoscopic implantation for interstitial brachytherapy (BT) of solitary bladder tumors and the feasibility of a high dose rate (HDR) schedule.Materials and methodsFrom December 2009 till April 2015, 57 patients with a T2 solitary bladder tumor were treated in Arnhem with trans urethral bladder resection (TURB) followed by external beam irradiation (EBI), applied to the bladder and regional iliac lymph nodes, 40 Gy in 20 fractions, 5 fractions a week, and within one week interstitial high dose rate (HDR) BT, in selected cases combined with partial cystectomy and lymph node dissection. The BT catheters were placed via a trans-abdominal approach with robotic assistance from a Da Vinci Robot after a successful initial experience with non-robotic laparoscopic approach. The fraction schedule for HDR was 10 fractions of 2.5 Gy, 3 fractions a day. This is calculated to be equivalent to a reference low dose rate schedule of 30 Gy in 60h.Data for oncologic outcomes and toxicity ( Common Toxicity Criteria v.4) were prospectively collected.ResultsThese modifications resulted in an average postoperative hospitalization of 6 days, minimal blood loss and no wound healing problems. Two patients had severe acute toxicity: one pulmonary embolism grade 4 and one cardiac death. Late toxicity was mild (N=2 urogenital grade 3 toxicity). The median follow-up is 2 years. Using cumulative incidence competing risk analysis the 2-year overall , disease free and disease specific survival and local control are: 59%, 71%, 87% and 82%, respectively.ConclusionsThe benefits of minimally invasive surgery for implantation of BT catheters and the feasibility of HDR BT in bladder cancer are documented. The patient outcome and adverse events are comparable with the best results published for a bladder sparing approach.

Teaser

From 2009 till 2015 57 patients with solitary pT2 bladder tumors ≤5 cm, received TURB, EBI: 20 fractions of 2 Gy and HDR interstitial brachytherapy: 10 fractions of 2,5 Gy, 3 fractions a day. The implantation of brachytherapy catheters was performed with a robot assisted laparoscopic technique. Minimally invasive surgery was found beneficial in terms of postoperative toxicity and hospitalization time and HDR was found effective with 2-years LC: 82%, DSS: 87% and mild toxicity.


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Exposure to ionizing radiation and brain cancer incidence: The Life Span Study cohort

Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Nicolas R. Smoll, Zoe Brady, Katrina Scurrah, John D. Mathews
BackgroundIonizing radiation is a cause of cancer. This paper examines the effects of radiation dose and age at exposure on the incidence of brain cancer using data from the Life Span Study (LSS) of atomic bomb survivors.MethodsThe Radiation Effects Research Foundation website provides demographic details of the LSS population, estimated radiation doses at time of bomb in 1945, person years of follow-up and incident cancers from 1958 to 1998. We modelled brain cancer incidence using background-stratified Poisson regression, and compared the excess relative risk (ERR) per Gray (Gy) of brain dose with estimates from follow-up studies of children exposed to diagnostic CT scans.ResultsAfter exposure to atomic bomb radiation at 10 years of age the estimated ERR/Gy was 0.91 (90%CI 0.53, 1.40) compared with 0.07 (90%CI −0.27, 0.56) following exposure at age 40. Exposure at 10 years of age led to an estimated excess of 17 brain tumors per 100,000 person year (pyr) Gy by 60 years of age. These LSS estimates are substantially less than estimates based on follow-up of children exposed to CT scans.ConclusionEstimates of ERR/Gy for brain cancers in the LSS and haemangioma cohorts seem much smaller than estimates of risk for young persons in the early years after exposure to CT-scans. This could be due to reverse causation bias in the CT cohorts, diagnostic error, measurement error with radiation doses, loss of early follow-up in the LSS, or non-linearity of the dose-response curve.



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