To investigate the association between serum TSH, total T4 and various patient characteristics when hypothyroidism is diagnosed in a population, and to study how age, sex and serum T4 levels ...influenced pituitary TSH response.
A computer-based register linked to laboratory databases prospectively identified all patients with new, biochemically overt hypothyroidism (n = 685) in an open cohort in Denmark. The diagnosis was verified in each patient, and disease was classified into nosological type. Serum TSH and total T4 were recorded at the time of diagnosis in untreated patients with spontaneous autoimmune hypothyroidism (n = 578).
In untreated primary, spontaneous autoimmune hypothyroidism, we observed a four fold difference in average serum TSH levels between the youngest (0-20 years: TSH = 100 mU/l) and the oldest (80+ years: TSH = 24.4 mU/l) group of patients. No age dependent variation was observed in serum total T4. Log TSH showed an inverse linear correlation with age. An inverse linear correlation was present between log TSH and total T4 in both young and old patients, but for all total T4 values we observed lower median serum TSH values in elderly patients.
For the same degree of thyroid failure, the serum TSH is lower among the elderly. This is most likely caused by a decrease in the hypothalamic/pituitary response to low serum T4. A certain increase in serum TSH may indicate more severe hypothyroidism in an old than in a young patient, and longer time may be needed after thyroid hormone withdrawal before elderly patients with thyroid cancer reach sufficiently high TSH values to allow for an effective radio-iodine treatment.
Nordic MCL2 trial update Geisler, Christian H.; Kolstad, Arne; Laurell, Anna ...
British journal of haematology,
2012, Volume:
158, Issue:
3
Journal Article
Peer reviewed
Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early based on the median observation time of 4 years results ...of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6.5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7.4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
During the past decades, the outcome of Mantle Cell Lymphoma (MCL) treatment has improved substantially in younger patients. In a recent update of the Nordic MCL2 trial we show very long response ...durations after a median follow-up of 11.4 years, but we also observe a continuous pattern of relapses even after 10 years of remission.(Eskelund et al, 2016) The course of this disease remains very heterogeneous, and with the current prognostic indexes we are unable to identify patients who might be cured by the current standard-of-care and others who would possibly benefit from alternative frontline approaches. Recently, next-generation sequencing (NGS) studies have explored the mutational landscape of MCL, however, in inhomogeneous and diversely treated cohorts or with short follow-up. Still, TP53 and NOTCH1/2 mutations have been shown to be prognostic markers. In our current study we examine the prognostic impact of aberrations in the most frequently mutated genes in MCL in a homogenously and optimally treated patient cohort, with a long-term follow-up.
Freshly frozen DNA from diagnostic bone marrow samples from patients included in two prospective Nordic trials, MCL2 and MCL3 were analysed. In both trials patients received intensified first line induction therapy with alternating courses of R-CHOP and R-HD-Cytarabine and consolidation with high-dose therapy and ASCT. All patients signed an informed consent.(Geisler et al, 2008; Kolstad et al, 2014). NGS was performed using the Ion Torrent Technology. A targeted panel of 8 genes frequently mutated in MCL was constructed on the basis of previous NGS studies.(Bea et al, 2013; Zhang et al, 2014) The panel included all coding regions of the following genes: ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3. Cut-off for calling a mutation was set to a variant allele frequency >3%. Mean depth was >1500X in all patients.
So far, we have mutational data from 72 patients. Patients were previously untreated and <66 years (median 58, range 37-65). Fifty-three percent were either MIPI intermediate or high risk. Eighty-five percent of patients had bone marrow involvement at diagnosis. After a median follow-up of 11.6 years, median overall (OS) and progression-free survival (PFS) of all 72 patients were 12.4 and 9.8 years, respectively.
Of the 72 patients, mutations were detected in 33 cases. Twenty-one patients carried 1 mutation and 12 patients had >1 mutation (2-4). Mutations were distributed as follows: ATM 15 (21%), KMT2D 11 (15%), WHSC1 7 (10%), TP53 6 (8%), CCND1 5 (7%), NOTCH2 4 (6%), NOTCH1 3 (4%), BIRC3 2 (3%). In univariate analyses, mutations in TP53 were highly predictive of an inferior outcome (median OS and PFS were 14 and 10 months, respectively; p<0.0001 for both outcomes) (Fig). Likewise, patients with either NOTCH1 or NOTCH2 mutations displayed worse OS (median OS 8.1 years, p=0.023), and there was a trend towards inferior PFS (median PFS 4.5years, p=0.087). No other mutations predicted better or worse outcomes, nor did carrying any one or >1 mutations. In multivariate analyses, the only prognostic significant mutations were TP53 (p<0.0001, HR=15.9) and NOTCH1 (p=0.012, HR=5.3).
TP53 mutations were associated with increased Ki67 expression, median 30% (range 20-80%), higher risk MIPI/MIPI-B/MIPI-C, and 4 out of 6 patients had blastoid morphology at diagnosis. All 6 TP53 mutations were found in the DNA-binding domain, and 5 were missense mutations while the last was a frameshift mutation. Patients with missense mutations all died within 3 years (range 6-34 months) due to relapsing or progressive disease, while PFS and OS of the latter patient was 4.6 years and 8.4 years, respectively.
We found no predictors for late relapses.
Here we evaluate the prognostic impact of mutations in eight genes that are commonly involved in MCL in a cohort of 72 younger patients who received intensified induction therapy and ASCT in the Nordic MCL2 trial. In line with previous reports, we demonstrate a negative prognostic impact of TP53 and NOTCH1/2 mutations; however, in multivariate analyses only TP53 and NOTCH1 mutations held significance. Missense mutations in the DNA binding domain of TP53 seem to predict an exceedingly poor short term outcome. At the annual meeting, we will present mutational analyses and long term follow up of >150 patients from the combined MCL2 and MCL3 cohort.
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Jerkeman:Amgen: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Minimal residual disease monitoring has been shown to be of relevance in mantle cell lymphoma (MCL) to evaluate quality of remission and predict clinical relapse. The main objectives of ...the present study were to determine the value of minimal residual disease (MRD) monitoring to guide pre-emptive treatment with rituximab, and to predict clinical relapse in MCL following autologous stem cell transplantation (ASCT) in two prospective trials (MCL2 and MCL3) with long-term follow-up conducted by the Nordic Lymphoma Group.
Methods: Patients treated in the two studies received a total of 6 alternating cycles with R-CHOP and R-Ara-C followed by a peripheral blood stem cell harvest and high-dose therapy with ASCT. Additionally, responding patients not in CR before ASCT in the MCL3 trial received yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) as intensification one week prior to the standard conditioning with BEAM/C. Staging included physical examination, blood tests, computed tomography (CT) scans and bone marrow (BM) aspiration and biopsy. Clinical and molecular response evaluation was repeated 2-3 months and 6 months after transplant, and then every 6 months until relapse or 5 years follow-up. A combined standard nested and quantitative real-time PCR assay was used to estimate MRD involvement in consecutive post-transplant BM/PB samples. Molecular relapse after ASCT was defined as; 1. Conversion from standard nested PCR negative to standard nested PCR positive, or 2. For patients who were MRD positive post-ASCT, a significant (>5 fold) increase of the real time quantitative PCR detectable MRD level in two consecutive BM samples. Patients in clinical remission who developed a molecular relapse in both studies received 4 weekly doses of rituximab (375 mg/m2). This treatment could be repeated in case of recurrent molecular relapses.
Results: An MRD marker for Bcl-1 or IgH rearrangement was obtained for 94 out of 160 patients (59%) recruited in the Nordic MCL2 trial, and for 121 out of 160 (76%) in the consecutive MCL3 trial. 183 patients, who had completed induction therapy and autologous stem cell transplantation (ASCT) in the two studies and where a PCR marker in blood or bone marrow was obtained, were included in the current analysis. Median follow-up from inclusion was 8.5 years among survivors. Patients who were MRD negative post-ASCT had significantly longer relapse-free survival (RFS) and overall survival (OS) compared to those who were MRD positive (P<0.001). Eighty-six patients remained in continuous molecular remission. Of those, 73% also remained in clinical remission after 10 years. For all patients, median time from ASCT to molecular relapse was 55 months and with no signs of a plateau on the curve (Figure 1). Fifty-eight patients with MRD relapse received pre-emptive treatment with 4 weekly doses of rituximab (375 mg/m2) on one or more occasions. Conversion back to MRD negative state was achieved in the majority (82%) of cases after rituximab treatment. Median time from molecular relapse to clinical relapse in patients who received pre-emptive rituximab was 55 months (Figure 2). In a multivariate analysis, significant predictors for molecular relapse were MIPI high risk category at diagnosis (HR 1.91, 95% CI 1.37-2.66, P=0,0001) and detection of MRD prior to ASCT (HR 2.47, 95% CI 1.49-4.09, P=0.0005). Late MRD relapses continued to occur 5-10 years after ASCT even in lower risk groups.
Conclusion: We observed a continuous pattern of MRD relapses that did not subside even after 5-10 years and included all risk groups. Hence, it is fair to consider MCL as a chronic incurable lymphoma entity and novel approaches will be necessary to change the natural course of this disease. Detection of MRD was shown to be a predictor for clinical relapse and inferior survival. Additionally, the data strongly suggests that pre-emptive rituximab treatment delayed clinical relapse in MCL. We recommend MRD monitoring post-ASCT in MCL as a useful approach to select the MRD positive patients for novel strategies in future trials and as an alternative to maintenance therapy for all patients. The MCL2 and MCL3 trials were registered at www.isrctn.com as ISRCTN 87866680 and at www.clinicaltrials.gov as NTC 00514475, respectively.
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Kolstad:Nordic Nanovector: Other: Membership of Scientific Advisory Board. Jerkeman:Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Mundipharma: Research Funding; Gilead: Research Funding. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The relationship between fatty acids in plasma and basal (B), interleukin-2-(IL-2), and interferon-alpha (IFN-alpha)-stimulated natural killer (NK) cell activity was studied in healthy elderly men ...aged on average 70.5 y (65-81 y). B-NK correlated significantly with the fraction of plasma fatty acids consisting of total polyunsaturated fatty acids (PUFAs), total n-6 fatty acids, and linoleic acid (r = -0.68, r = -0.62, and r = -0.52, respectively). Significant negative correlations were also found between IFN-alpha stimulated NK cells and the three groups of fatty acids and between IL-2-stimulated NK cells and PUFAs. Likewise, negative correlations between PUFAs in the diet and B-NK, IL-2, and IFN-alpha stimulated NK cell activity were found. The number of NK cells increased significantly but NK cell activity did not change after 5 wk on a diet lower in fat but higher in PUFAs than the subjects' habitual diet. It is concluded that the amount and type of dietary fatty acids influence in vitro measures of immune function in elderly men. From an immunological point of view, a high intake of n-6 PUFAs may be inadvisable
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