Summary Background Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 ...weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14. Methods 1222 elderly patients (aged 61–80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243. Findings 3-year event-free survival was 47·2% after six cycles of CHOP-14 (95% CI 41·2–53·3), 53·0% (47·0–59·1) after eight cycles of CHOP-14, 66·5% (60·9–72·0) after six cycles of R-CHOP-14, and 63·1% (57·4–68·8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5·8% (−2·8–14·4) for eight cycles of CHOP-14, 19·3% (11·1–27·5) for six cycles of R-CHOP-14, and 15·9% (7·6–24·2) for eight cycles of R-CHOP-14. 3-year overall survival was 67·7% (62·0–73·5) for six cycles of CHOP-14, 66·0% (60·1–71·9) for eight cycles of CHOP-14, 78·1% (73·2–83·0) for six cycles of R-CHOP-14, and 72·5% (67·1–77·9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by −1·7% (−10·0–6·6) after eight cycles of CHOP-14, 10·4% (2·8–18·0) after six cycles of R-CHOP-14, and 4·8% (−3·1–12·7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR relative risk 0·76 0·60–0·95, p=0·0172; six cycles of R-CHOP-14: RR 0·51 0·40–0·65, p<0·0001; eight cycles of R-CHOP-14: RR 0·54 0·43–0·69, p<0·0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0·50 0·38–0·67, p<0·0001), and eight cycles of R-CHOP-14 (RR 0·59 0·45–0·77, p=0·0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0·63 0·46–0·85, p=0·0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles. Interpretation Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.
To evaluate the utility of high-resolution magnetic resonance imaging (MRI) in assessing the normal and refilled lens geometry in rabbits after lens-refilling surgery.
University of Rostock, Rostock, ...Germany.
Experimental study.
High-resolution ocular MRIs were acquired (7.1 T ClinScan) using a 2-channel coil with 4 coil elements and T2-weighted turbo spin-echo sequences (slice thickness 700 μm, field of view 40 mm × 40 mm) in rabbits after lens refilling surgery combined with intraoperative treatment to prevent lens epithelial cell proliferation. Single slices were used to assess the refilled lenses 3 years postoperatively.
The entire geometry (cross-sectional area, radius of curvature, axial and equatorial diameters) of the crystalline and refilled lenses was visualized by in vivo 7.1T MRI 3 years postoperatively (in-plane resolution: 125 μm × 125 μm). In refilled eyes, the capsule and the homogenous silicone polymer remained in close contact with no visible interface. The dimensions of the refilled lens were significantly smaller than those of the crystalline lens of the contralateral eye.
High-resolution MRI allows in vivo visualization and analysis of the spatial arrangement of the lens in rabbit eyes after lens refilling surgery and overcomes a number of major limitations in the quantitative evaluation of the lens shape. Further efforts are required to optimize the amount of polymer injected during lens refilling to achieve a predictable refractive outcome after lens refilling surgery.
Drs. Stachs, Langner, Sternberg, Martin, Schmitz, Hosten and Guthoff have no financial or proprietary interest in any material or method mentioned. Additional financial disclosure is found in the footnotes.
Summary Background The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based ...chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. Methods We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. Findings We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75–86), 62% (55–70), and 25% (20–34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)—which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories—significant associations with overall survival were noted (81% 95% CI 75–87%, 55% (44–66), and 28% (18–40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. Interpretation PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. Funding Samsung Biomedical Research Institute.
Summary Background High-dose therapy (HDT) followed by transplantation of autologous haemopoietic stem cells is frequently done as part of first-line therapy in young patients with high-risk ...aggressive B-cell lymphoma. We investigated whether HDT with cytotoxic agents identical to those used for conventional therapy followed by autologous stem-cell transplantation (ASCT) improved survival outcome compared with conventional chemotherapy when rituximab was added to both modalities. Methods We did an open-label, randomised trial comparing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and rituximab (R-CHOEP-14) with dose-escalated sequential HDT and rituximab (R-MegaCHOEP) followed by repetitive ASCT in high-risk (age-adjusted International Prognostic Index IPI 2 or 3) patients aged 18–60 years with aggressive B-cell lymphoma. Eligible patients received radiotherapy for bulky, extranodal disease, or both. Randomisation (1:1) used the Pocock minimisation algorithm; patients were stratified by age-adjusted IPI factors, bulky disease, and centre. The primary endpoint was event-free survival. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00129090. Findings 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months (IQR 29–59), 3-year event-free survival was 69·5% (95% CI 61·3–77·7) in the R-CHOEP-14 group and 61·4% (52·8–70·0) in the R-MegaCHOEP group (p=0·14; hazard ratio 1·3, 95% CI 0·9–2·0). All 128 evaluable patients treated with R-MegaCHOEP had grade 4 leucopenia, as did 48 (58·5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. All 128 evaluable patients in the R-MegaCHOEP group had grade 3–4 thrombocytopenia, as did 26 (33·8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 96 (75·0%) of 128 patients treated with R-MegaCHOEP and in 40 (31·3%) of 128 patients treated with R-CHOEP-14. Interpretation In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy. Funding Deutsche Krebshilfe.
Summary Background Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding ...rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen. Methods We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m2 ), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m2 on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2–4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov , number NCT00785330. Findings Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2–4 acute graft-versus-host disease was 46% (95% CI 32–62) in the rituximab group and 42% (95% CI 29–59) in the no rituximab group (hazard ratio HR 0·91, 95% CI 0·52–1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41–62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four). Interpretation The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival. Funding Hoffmann-La Roche, Amgen, Astellas Pharma.
As outlined earlier, publication of negative findings is essential to interpreting the overall significance of a field of research. However, papers with negative findings are less likely to be highly ...cited than papers with positive findings and less likely overall to be noticed in the scientific commun - ity.
Summary Background Most allogeneic haematopoietic stem cell transplants now use peripheral blood progenitor cell transplantation (PBPCT) instead of bone-marrow transplantation (BMT). Long-term data ...on outcome and late effects of PBPCT compared with BMT are scarce. Here we present long-term data from a randomised study comparing PBPCT with BMT. Methods Between February, 1995, and September, 1999, 329 patients with leukaemia received either PBPCT (n=163) or BMT (n=166) from HLA-identical sibling donors after central randomisation accounting for stratification criteria. Follow-up data were collected via questionnaires from 87% (176 of 202; 84 PBPCT, 92 BMT) patients who survived for more than 3 years (median of 9·3 years) after transplantation. Efficacy analyses included all patients who received treatment. This study is registered with ClinicalTrials.gov , number NCT01020175. Findings 10-year overall survival was 49·1% for patients who underwent PBPCT and 56·5% for patients who underwent BMT (HR 0·83, 95% CI 0·60–1·15; p=0·27). Leukaemia-free survival was 28·3% with BMT versus 13·0% with PBPCT (0·61, CI 0·32–1·16; p=0·12) for acute lymphoblastic leukaemia; 62·3% with BMT versus 47·1% with PBPCT for acute myeloid leukaemia (0·67, 0·39–1·16; p=0·16); and 40·2% with BMT versus 48·5% with PBPCT for chronic myeloid leukaemia (1·12, 0·73–1·74; p=0·60). More patients developed chronic graft-versus-host disease after PBPCT (n=56, 73%) than after BMT (n=46, 56%; p=0·021), with more frequent involvement of skin, liver, and oral mucosa, and more patients who underwent PBPCT needed immunosuppressive treatment 5 years after transplantation (n=20, 26%) than patients who had BMT (n=10, 12%; p=0·024). Nonetheless, there was no difference in performance status, return to work, incidence of bronchiolitis obliterans, and haematopoietic function between the two groups. 14 cases of secondary malignancies occurred (five after BMT, nine after PBPCT), resulting in a cumulative incidence of 3% and 7% after BMT and PBPCT (p=0·17), respectively. Interpretation More than 9 years after transplantation, overall and leukaemia-free survival remain similar in patients who underwent BMT and PBPCT. Differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression exist, but do not affect survival, general health status, or late events. Funding No external funding was received.
Besides their extracellular activity crucial for several pathophysiological conditions, human cysteine cathepsins, in particular cathepsins K and S, represent important intracellular targets for drug ...development. In the present study, a prototypic dipeptide nitrile inhibitor structure was equipped with a coumarin moiety to function as a fluorescent reporter group. In a second inhibitor, a PEG linker was introduced between the dipeptide nitrile and the fluorophore. These tool compounds 6 and 7 were characterized by kinetic investigations as covalent reversible inhibitors of human cathepsins L, S, K and B. Probe 6 showed a pronounced inhibitory activity against cathepsins K and S, which was corroborated by modeling of inhibition modes. Probe 7 was highly potent (Ki = 93 nM) and selective for cathepsin S. To examine the ability of both probes to enter living cells, human embryonic kidney 293 cells were targeted. At a concentration of 10 μM, cellular uptake of probe 6 was demonstrated by fluorescence measurement after an incubation time of 30 min and 3 h, respectively. The probe's concentration in cell lysates was ascertained on the basis of the emission at 492 nm upon excitation at 450 nm, and the results were expressed as concentrations of probe 6 relative to the protein concentration originating from the lysate. After incubation of 10 μM of probe 6 for 3 h, the cellular uptake was confirmed by fluorescence microscopy. HPLC was used to assess the probes’ lipophilicity, and the obtained
Abstract Objective The study purpose was to examine the association between changes in depressive symptoms and changes in lifestyle-related indicators among adults with type 2 diabetes. Methods A ...longitudinal survey was conducted among individuals with type 2 diabetes in Quebec. The sample consisted of 1183 subjects who responded to the baseline and 1-year follow-up telephone interviews, with complete data for depressive symptoms (Patient Health Questionnaire 9). Regression models were used to determine associations between changes in depressive symptoms and changes in lifestyle-related indicators (physical activity, body mass index (BMI)) and, perception-related indicators (control of body weight and of amount of food eaten). Results After 1 year, 136 subjects (11.5%) developed depression (major or minor), 118 (10%) remained depressed, 829 (70%) remained not depressed and 100 (8.5%) reverted to not depressed. Subjects who developed depression, compared with those who remained not depressed, were more likely to be inactive at baseline, remain inactive at 1 year, report a worsening of their perception of controlling body weight, report maintaining a poor perception of controlling amount of food eaten and report maintaining a poor perception of controlling body weight (p<0.05). The same factors were associated with maintenance of depression at 1 year (p<0.05). Changes in BMI were not associated with changes in depressive symptoms. Conclusions Physical inactivity, perception of poor control of body weight and amount of food eaten have been found to be associated prospectively with the development and persistence of depression and, therefore, should be considered priority targets for diabetes treatment. Depression is related to the continuation of poor lifestyle and perception-related indicators.
PDF
