Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning ...risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC.
We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT.
All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions.
The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.
Abstract Background Studies with long-term follow-up of patients with myelodysplastic syndromes (MDS) based on data from nationwide population-based cancer registries are lacking. We conducted a ...nationwide population-based study to assess trends in incidence, initial treatment and survival in MDS patients diagnosed in the Netherlands from 2001 to 2010. Methods We identified 5144 MDS patients (median age, 74 years) from the Netherlands Cancer Registry (NCR). The NCR only includes MDS cases that were confirmed by bone marrow examinations. Information regarding initial treatment decisions was available in the NCR. Results The age-standardised incidence rate of MDS was 2.3/100,000 in 2001–2005 and 2.8/100,000 in 2006–2010. The incidence increased with older age, with the highest incidence among those aged ⩾80 years (32.1/100,000 in 2006–2010). Forty-nine percent of all MDS cases were unspecified. Of all patients, 89% receive no treatment or only supportive care and 8% were started on intensive therapy as initial treatment. Survival did not improve over time. The 5-year relative survival was 53%, 58%, 48%, 38% and 18% in patients with refractory anaemia (RA), RA with ringed sideroblasts, 5q-syndrome, refractory cytopenia with multilineage dysplasia, and RA with excess blasts, respectively. Conclusion The incidence of MDS increased over time due to improved notification and better disease awareness, and has stabilised since 2007. The classification of MDS seems challenging as almost half of the pathologically confirmed cases were unspecified. The lack of improvement in survival might be explained by the limited availability of therapeutic agents. Therefore, ameliorated management and new treatment options are warranted.
In paraneoplastic neurological syndromes (PNS) associated with small cell lung cancer (SCLC) and Hu antibodies (Hu-PNS), Hu antigens expressed by the tumour hypothetically trigger an immune response ...that also reacts with Hu antigens in the nervous system, resulting in tumour suppression and neuronal damage. To gain more insight into the hypothesized CD8(+ )T cell-mediated immune pathogenesis of these syndromes, we searched for circulating HuD-specific CD8(+) T cells in a large cohort of Hu-PNS patients and controls.
Blood was tested from 43 Hu-PNS patients, 31 Hu antibody negative SCLC patients without PNS and 54 healthy controls. Peripheral blood mononuclear cells (PBMC) were stimulated with HuD protein-spanning peptide pools (15-mers) and individual HuD-derived peptides (9-mers) and analysed by cytokine flow cytometry and interferon-gamma ELISPOT-assays. Additionally, HuD-based Class I HLA multimers were used to visualize HuD-specific CD8(+) T cells.
No HuD-specific CD8(+ )T cells could be detected in the blood of Hu-PNS patients or controls.
Our results do not support a role for HuD-specific CD8(+) T cells in Hu-PNS. Further studies should focus on the detection of circulating HuD-specific CD4(+ )T cells and examine the antigen specificity of T cells in affected tissues.
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While recent studies showed that the allogeneic graft versus leukemia (GVL) effect is operational in poor-risk acute myeloid leukemia (AML), the relapse rate remains high. In order to exploit GVL ...more effectively, we explored the early initiation of epigenetic therapy after alloHSCT, interspersed with successive, low dosage DLI in patients (pts) with AML, characterized as poor- or very poor-risk, according to the latest (2015) HOVON-SAKK AML risk classification. This study started as a phase I study in very poor-risk AML pts exploring the feasibility of combination epigenetic therapy at dose levels 1, 2, and 3, consisting of either panobinostat (PNB) alone (20 mg at days 1, 4, 8, 11 of a 4 wk-cycle) or PNB combined with decitabine (DCB, 10 or 20 mg/m2 at days 1-3 of every 4 wk-cycle). DLI consisted of 106 CD3 T-cells/kg at day 90 and 3 x 106 at day 180 in case of a matched sibling (sib) donor and 30% of that dose in case of a matched unrelated donor (MUD). Reduced intensity conditioning was applied by a combination of cyclophosphamide, fludarabine, and reduced-dose total body irradiation (TBI). Graft versus host disease (GVHD) prophylaxis consisted of post-transplant (PT) cyclophosphamide and short course cyclosporine. Phase II is focusing on actual delivery of transplantation, epigenetic therapy, and subsequent DLI in newly diagnosed AML pts upon confirmation of poor-risk or very poor-risk status, at which time point pts are registered for the study. Secondary endpoints include toxicities, GVHD, non-relapse mortality (NRM), relapse, overall survival (OS), and relapse free survival (RFS) as from transplantation. Pts lacking a sib or MUD proceeded off-protocol to alloHSCT with an alternative donor.
Currently (July 2016), 94 pts are registered early after diagnosis during induction chemotherapy and so far 59 of them have actually proceeded to alloHSCT by either a MUD or sib donor. Interim results refer to 54 pts actually transplanted, and with sufficient follow-up (median: 9 months, range: 2-25 after transplantation). Pts received their transplant at a median number of 109 days (range: 69-200) after diagnosis. After 2 cycles of induction therapy, 35 pts were in hematological CR, 16 in CR without complete blood recovery, and 3 in PR. Median percentage of blasts prior to alloHSCT was 2 (range: 0-10). Median age was 54 years (18-70), 48 pts were classified as very poor-risk, 6 pts as poor-risk AML. Donors included 23 sib and 31 MUD. OS at 12 months from transplantation is 81% (±7). 10 pts died, including 5 due to NRM and 5 due to relapse. RFS at 12 months is 66% (±9). A historical HOVON control group of very poor-risk AML CR1 recipients of alloHSCT showed OS of 52% ±6 at 12 months and RFS of 43% ±5.
Forty-one out of 54 pts received PT epigenetic therapy, including 13 PNB alone, 13 PNB/DCB (20 mg/m2), and 15 PNB/DCB. Pts started at a median time point of 33 days (range: 27-54) after transplantation. Combining PNB with DCB at a dose of 20 mg/m2 proved not feasible due to cytopenia, causing extension of successive cycles of PNB/DCB, which was considered a dose limiting toxicity (DLT). CTC grade 3 and 4 side-effects after the first cycle of PNB/DCB included gastrointestinal nausea in 2 pts (grade 3), neutropenia in 3 pts and general fatigue in 1 pt. After the second cycle PNB/DCB, 1 pt experienced nausea (grade 3), and 1 pt fatigue (grade 3). No opportunistic CTC grade 3 and 4 infections were observed after the first 2 cycles of PNB/DCB. DLI could so far be administered in 34 pts, including 19 receiving 2 DLI's, and 9 pts a third DLI. None of the pts developed grade 3 or 4 acute GVHD before DLI. Out of 34 recipients of DLI, severe chronic GVHD occurred in 5 (15%) pts.
Collectively, these results suggest that: 1. alloHSCT with GVHD-prophylaxis by cyclophosphamide PT allows for early initiation of epigenetic therapy and DLI, and 2. as compared to historical HOVON-data in very poor-risk AML pts receiving alloHSCT, encouraging results with respect to relapse, DFS, and OS are observed in patients actually receiving PNB alone or PNB combined with DCB, followed by DLI. 3. Limited side effects were observed in recipients of PNB alone or the combination of PNB and DCB at a dose of 10 mg/m2; the incidence GVHD also appeared limited. Altogether these results might suggest enhanced GVL and, therefore, have set the stage for an international prospective randomized study in (very) poor-risk AML patients.
Maertens:Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy.
► Time series analyses of road safety and risk can be improved by using demographic data. ► Distance travelled per person is often more smooth over time than total distance travelled for drivers of ...that age. ► This smoothness can be used to obtain forecasts of distance travelled and thus of road safety risk. ► This smoothness can be used to average out year-to-year fluctuations of data of distance travelled and risk. ► Fatalities forecasts with models including population data, with or without data of distance travelled, are alike.
The purpose of this paper is to show that time series analyses of road safety and risk can be improved by using demographic data. We demonstrate that the distance travelled by drivers or riders of a certain age reflects the fluctuations over the years of the number of people of that age within the population. We further demonstrate that the change over time of per capita distance travelled, i.e. distance travelled per person, is often less subject to stochastic fluctuations, and therefore more smooth than the total distance travelled for drivers of that age. This smoothness is used to obtain forecasts of distance travelled, or to average out year-to-year fluctuations of data of distance travelled. Analysis of such data stratified by age group, gender or both reveals that, for most travel modes, per capita distance travelled is to a large extent constant or slowly changing over time. The consequences for the evaluation of risk, i.e. casualties per distance travelled, with and without the use of population data, are explored. Dutch data are used to illustrate the model concept.
It is shown that the analyses and forecasts of distance travelled could gain substantially by incorporating demographic data, as compared to an analysis with data of distance travelled alone. The paper further shows that, for an analysis of risk and therefore for traffic safety forecasts in the absence of any data of distance travelled, stratified analysis of mortality, i.e. casualties per inhabitant, may be a reasonable alternative.
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, ...we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error SE 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post–allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.
•Epigenetic therapy after allo-HSCT with panobinostat alone and in combination with low-dose decitabine is feasible in poor-risk AML.•Results did not suggest a synergistic or additive effect of combining panobinostat with decitabine.
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