TCR V α- and V ß-Gene Segment Use in T-Cell Subcultures Derived from a Type-III Bare Lymphocyte Syndrome Patient Deficient in MHC Class-II Expression

Previously, we and others have shown that MHC class-II deficient humans have greatly reduced numbers of CD4+CD8– peripheral T cells. These type-III Bare Lymphocyte Syndrome patients lack MHC class-II and have an impaired MHC class-I antigen expression. In this study, we analyzed the impact of the MHC class-II deficient environment on the TCR V-gene segment usage in this reduced CD4+CD8– T-cell subset. For these studies, we employed TcR V-region-specific monoclonal antibodies (mAbs) and a semiquantitative PCR technique with V α and V ß amplimers, specific for each of the most known V α- and V ß;-gene region families. The results of our studies demonstrate that some of the V α-gene segments are used less frequent in the CD4+CD8– T-cell subset of the patient, whereas the majority of the TCR V α- and V ß-gene segments investigated were used with similar frequencies in both subsets in the type-III Bare Lymphocyte Syndrome patient compared to healthy control family members. Interestingly, the frequency of TcR V α12 transcripts was greatly diminished in the patient, both in the CD4+CD8– as well as in the CD4–CD8+ compartment, whereas this gene segment could easily be detected in the healthy family controls. On the basis of the results obtained in this study, it is concluded that within the reduced CD4+CD8– T-cell subset of this patient, most of the TCR V-gene segments tested for are employed. However, a skewing in the usage frequency of some of the V α-gene segments toward the CD4–CD8+ T-cell subset was noticeable in the MHC class-II deficient patient that differed from those observed in the healthy family controls

Norse-Icelandic Skaldic Poetry of the Scandinavian Middle Ages - an electronic edition

This presentation aims to describe an international project to edit the corpus of Old Norse-Icelandic skaldic poetry and to outline some issues related to electronic aspects of the project, both in its organisation and in its publication. Prof. Clunies Ross will outline the nature of the project and the place of the electronic edition. Tarrin Wills will present information relating to the electronic encoding of the corpus. This will include explanation and discussion of issues related to the collation of electronic facsimiles of the manuscripts and the encoding of skaldic verse, in particular, the encoding of the native poetic devices known as 'kenningar' and 'heiti'.Hosted by the Scholarly Text and Imaging Service (SETIS), the University of Sydney Library, and the Research Institute for Humanities and Social Sciences (RIHSS), the University of Sydney

Retrospective methods to estimate radiation dose at the site of breast cancer development after Hodgkin lymphoma radiotherapy.

BACKGROUND: An increased risk of breast cancer following radiotherapy for Hodgkin lymphoma (HL) has now been robustly established. In order to estimate the dose-response relationship more accurately, and to aid clinical decision making, a retrospective estimation of the radiation dose delivered to the site of the subsequent breast cancer is required. METHODS: For 174 Dutch and 170 UK female patients with breast cancer following HL treatment, the 3-dimensional position of the breast cancer in the affected breast was determined and transferred onto a CT-based anthropomorphic phantom. Using a radiotherapy treatment planning system the dose distribution on the CT-based phantom was calculated for the 46 different radiation treatment field set-ups used in the study population. The estimated dose at the centre of the breast cancer, and a margin to reflect dose uncertainty were determined on the basis of the location of the tumour and the isodose lines from the treatment planning. We assessed inter-observer variation and for 47 patients we compared the results with a previously applied dosimetry method. RESULTS: The estimated median point dose at the centre of the breast cancer location was 29.75 Gy (IQR 5.8-37.2), or about 75% of the prescribed radiotherapy dose. The median dose uncertainty range was 5.97 Gy. We observed an excellent inter-observer variation (ICC 0.89 (95% CI: 0.74-0.95)). The absolute agreement intra-class correlation coefficient (ICC) for inter-method variation was 0.59 (95% CI: 0.37-0.75), indicating (nearly) good agreement. There were no systematic differences in the dose estimates between observers or methods. CONCLUSION: Estimates of the dose at the point of a subsequent breast cancer show good correlation between methods, but the retrospective nature of the estimates means that there is always some uncertainty to be accounted for

Long-Term Cause-Specific Mortality in Hodgkin Lymphoma Patients

BACKGROUND: Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients. METHODS: This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated. RESULTS: HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02). CONCLUSIONS: Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity

Functional definition of a transcription factor hierarchy regulating T cell lineage commitment

T cell factor 1 (Tcf1) is the first T cell-specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell-committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.Molecular Technology and Informatics for Personalised Medicine and Healt

Retrospective methods to estimate radiation dose at the site of breast cancer development after Hodgkin lymphoma radiotherapy.

Background:An increased risk of breast cancer following radiotherapy for Hodgkin lymphoma (HL) has now been robustly established. In order to estimate the dose-response relationship more accurately, and to aid clinical decision making, a retrospective estimation of the radiation dose delivered to the site of the subsequent breast cancer is required. Methods:For 174 Dutch and 170 UK female patients with breast cancer following HL treatment, the 3-dimensional position of the breast cancer in the affected breast was determined and transferred onto a CT-based anthropomorphic phantom. Using a radiotherapy treatment planning system the dose distribution on the CT-based phantom was calculated for the 46 different radiation treatment field set-ups used in the study population. The estimated dose at the centre of the breast cancer, and a margin to reflect dose uncertainty were determined on the basis of the location of the tumour and the isodose lines from the treatment planning. We assessed inter-observer variation and for 47 patients we compared the results with a previously applied dosimetry method. Results:The estimated median point dose at the centre of the breast cancer location was 29.75 Gy (IQR 5.8-37.2), or about 75% of the prescribed radiotherapy dose. The median dose uncertainty range was 5.97 Gy. We observed an excellent inter-observer variation (ICC 0.89 (95% CI: 0.74-0.95)). The absolute agreement intra-class correlation coefficient (ICC) for inter-method variation was 0.59 (95% CI: 0.37-0.75), indicating (nearly) good agreement. There were no systematic differences in the dose estimates between observers or methods. Conclusion:Estimates of the dose at the point of a subsequent breast cancer show good correlation between methods, but the retrospective nature of the estimates means that there is always some uncertainty to be accounted for

Colorectal cancer surveillance in Hodgkin lymphoma survivors at increased risk of therapy-related colorectal cancer: Study design

Background: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. Methods/Design: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived =8years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. Discussion: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. Trial registration: Registered at the Dutch Trial Registry (NTR): NTR4961

Infradiaphragmatic irradiation and high procarbazine doses increase colorectal cancer risk in Hodgkin lymphoma survivors

Background:Hodgkin lymphoma (HL) survivors are at increased risk of second malignancies, but few studies have assessed colorectal cancer (CRC) risk after HL treatment. We assessed long-term, subsite-specific CRC risk associated with specific radiation fields and chemotherapy regimens.Methods:In a Dutch cohort of 3121 5-year HL survivors treated between 1965 and 1995, subsite-specific CRC incidence was compared with general population rates. Treatment effects were quantified by Cox regression analyses.Results:After a median follow-up of 2