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1.
Hematol Oncol ; 40(4): 763-776, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35368106

RESUMO

Second allogeneic stem cell transplantation (allo-SCT2) represents a rescue option for selected patients (pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML). Still, relapse rates post-allo-SCT2 remain high and effective anti-relapse strategies and predictive biomarkers remain to be defined. We here analyzed a cohort of 41 AML patients (pts) undergoing allo-SCT2 in our center. Allo-SCT2 induced a third hematologic complete remission (CR) in 37 pts, at costs of a 36% non-relapse mortality rate. Furthermore, 19 pts eventually relapsed post allo-SCT2. Addressing relapse after allo-SCT2, 14 pts (74%) underwent cell-based anti-relapse strategies, including third allogeneic transplantation (allo-SCT3; 3/14), donor lymphocyte infusions (DLIs) combined with either 5-azacytidin and venetoclax (4/14) or chemotherapeutic agents (7/14). Notably, six of seven pts (86%) who received either allo-SCT3 or a combination therapy of DLIs, 5-azacytidine and venetoclax achieved CR despite poor cytogenetics post-allo-SCT2 (e.g., TP53). Finally, 11 of 41 pts were alive at the last follow-up (seven CR2, three CR3, one partial remission) resulting in estimated 2- and 5-year overall survival of 35% and 25%, respectively.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/terapia , Recidiva , Estudos Retrospectivos , Sulfonamidas
2.
Eur J Haematol ; 107(5): 529-542, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34270825

RESUMO

OBJECTIVE: A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. METHODS: Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation. RESULTS: Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569). CONCLUSIONS: Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Quimioterapia de Consolidação/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Idoso , Terapia Combinada , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Estudos Retrospectivos , Transplante Autólogo
3.
Eur J Haematol ; 103(3): 255-267, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31231828

RESUMO

OBJECTIVE: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). METHODS: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. RESULTS: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. CONCLUSION: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Terapia Combinada , Quimioterapia de Consolidação , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
4.
Br J Haematol ; 179(4): 586-597, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28961309

RESUMO

We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55·5 months); median progression-free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P < 0·0001), and median OS was 54·7 months versus not reached (P = 0·0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long-term follow-up, cytogenetic high risk is associated with markedly reduced PFS and OS post-ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Indução/métodos , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Quimioterapia de Consolidação , Ciclofosfamida/administração & dosagem , Citogenética , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Medição de Risco/métodos , Transplante de Células-Tronco , Análise de Sobrevida , Transplante Autólogo , Adulto Jovem
5.
Acta Haematol ; 137(1): 51-54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27923223

RESUMO

Pneumatosis intestinalis (PI), defined as intestinal intra- and extramural gas accumulation, is a rare radiographic finding in conditions of intestinal wall damage of varied etiology. Here, we report on a 56-year-old female with multiple myeloma who presented with undulating fever, fluctuating abdominal symptoms, and a distended abdomen 5 months after allogeneic hematopoietic stem cell transplantation (HSCT). Abdominal X-ray and CT scan documented PI with gas accumulation both in the intestinal and colonic bowel walls. Concurrently, thoracic CT revealed mediastinal and bihilar lymphadenopathy associated with bilateral pleural effusions. Microscopy of bronchoalveolar lavage fluid (BALF) revealed acid-fast bacilli, which were identified as Mycobacterium tuberculosis. Tuberculostatic treatment resulted in timely clinical improvement, a complete clearance of the radiological and clinical findings of PI, and the control of the tuberculosis (Tbc), determined by multiple negative BALF results. Taken together, PI occurred as the initial symptom of Tbc in an allogeneic stem cell recipient, achieving complete recovery by tuberculostatic treatment only.


Assuntos
Antituberculosos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Derrame Pleural/diagnóstico por imagem , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Tuberculose Pulmonar/diagnóstico por imagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Humanos , Isoniazida/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/isolamento & purificação , Derrame Pleural/tratamento farmacológico , Derrame Pleural/etiologia , Pneumatose Cistoide Intestinal/tratamento farmacológico , Pneumatose Cistoide Intestinal/etiologia , Rifampina/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/etiologia
6.
Haematologica ; 101(11): 1398-1406, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27662018

RESUMO

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741).


Assuntos
Mieloma Múltiplo/terapia , Transplante de Células-Tronco/métodos , Idoso , Citogenética , Intervalo Livre de Doença , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Quimioterapia de Indução/métodos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Transplante de Células-Tronco/mortalidade , Transplante Autólogo , Resultado do Tratamento
8.
Med Educ ; 50(7): 711-20, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27295475

RESUMO

CONTEXT: Clinical reasoning is an essential skill, the foundations of which should be acquired during undergraduate medical education. Student performance in clinical reasoning can be assessed using key feature examinations. However, within a paradigm of test-enhanced learning, such examinations may also be used to enhance long-term retention of procedural knowledge relevant to clinical reasoning. OBJECTIVES: This study tested the hypothesis that repeated testing with key feature questions is more effective than repeated case-based learning in fostering clinical reasoning. METHODS: In this randomised crossover trial, Year 4 medical students attended 10 weekly computer-based seminars during which patient case histories covering general medical conditions were displayed. The presentation format was switched between groups every week. In the control condition, students studied long case narratives. The intervention condition used the same content but augmented case presentation with a sequence of key feature questions. Using a within-subjects design, student performance on intervention and control items was assessed at 13 weeks (exit examination) and 9 months (retention test) after the first day of term. RESULTS: A total of 87 of 124 eligible students provided complete data for the longitudinal analysis (response rate: 70.2%). In the retention test, mean ± standard deviation student scores on intervention items were significantly higher than those on control items (56.0 ± 25.8% versus 48.8 ± 24.7%; p < 0.001). The results remained unchanged after accounting for exposure time in a linear regression analysis that also adjusted for sex and general student performance levels. CONCLUSIONS: This is the first study to demonstrate an effect of test-enhanced learning on clinical reasoning as assessed with key feature questions. In this randomised trial, repeated testing was more effective than repeated case-based learning alone. Curricular implementation of longitudinal key feature testing may considerably enhance student learning outcomes in relevant aspects of clinical medicine.


Assuntos
Tomada de Decisão Clínica , Educação de Graduação em Medicina/métodos , Adulto , Competência Clínica/normas , Instrução por Computador , Estudos Cross-Over , Avaliação Educacional , Feminino , Feedback Formativo , Alemanha , Humanos , Masculino , Estudantes de Medicina , Ensino , Fatores de Tempo
9.
JMIR Med Educ ; 7(4): e30607, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34779777

RESUMO

BACKGROUND: The COVID-19 pandemic necessitated the rapid expansion of novel tools for digital medical education. At our university medical center, an Instagram account was developed as a tool for medical education and used for the first time as a supplement to the hematology and medical oncology teaching module of 2020/2021. OBJECTIVE: We aimed to evaluate the acceptance and role of Instagram as a novel teaching format in the education of medical students in hematology and medical oncology in the German medical curriculum. METHODS: To investigate the role of Instagram in student education of hematology and medical oncology, an Instagram account was developed as a tie-in for the teaching module of 2020/21. The account was launched at the beginning of the teaching module, and 43 posts were added over the 47 days of the teaching module (at least 1 post per day). Five categories for the post content were established: (1) engagement, (2) self-awareness, (3) everyday clinical life combined with teaching aids, (4) teaching aids, and (5) scientific resources. Student interaction with the posts was measured based on overall subscription, "likes," comments, and polls. Approval to conduct this retrospective study was obtained from the local ethics commission of the University Medical Center Goettingen. RESULTS: Of 164 medical students, 119 (72.6%) subscribed to the Instagram account, showing high acceptance and interest in the use of Instagram for medical education. The 43 posts generated 325 interactions. The highest number of interactions was observed for the category of engagement (mean 15.17 interactions, SD 5.01), followed by self-awareness (mean 14 interactions, SD 7.79). With an average of 7.3 likes per post, overall interaction was relatively low. However, although the category of scientific resources garnered the fewest likes (mean 1.86, SD 1.81), 66% (27/41) of the student participants who answered the related Instagram poll question were interested in studies and reviews, suggesting that although likes aid the estimation of a general trend of interest, there are facets to interest that cannot be represented by likes. Interaction significantly differed between posting categories (P<.001, Welch analysis of variance). Comparing the first category (engagement) with categories 3 to 5 showed a significant difference (Student t test with the Welch correction; category 1 vs 3, P=.01; category 1 vs 4, P=.01; category 1 vs 5, P=.001). CONCLUSIONS: Instagram showed high acceptance among medical students participating in the hematology and oncology teaching curriculum. Students were most interested in posts on routine clinical life, self-care topics, and memory aids. More studies need to be conducted to comprehend the use of Instagram in medical education and to define the role Instagram will play in the future. Furthermore, evaluation guidelines and tools need to be developed.

10.
Front Immunol ; 12: 746996, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691055

RESUMO

Purpose: Extrinsic factors and genetic predisposition contribute to the etiology of sarcoidosis, converging in a phenotype of altered immune response associated with multisystemic inflammatory granulomatous tissue infiltration. Immunological reconstitution after hematopoietic stem cell transplantation (HSCT) may represent a unique window for the pathogenesis of the disease. We describe the incidence, clinicopathological features, and HLA associations of sarcoidosis after HSCT in a single-center cohort of patients, together with data from previously published cases. Methods: We retrospectively analyzed clinical characteristics and HLA haplotypes from allogeneic (allo) or autologous (auto) HSCT patients from January 2001 through May 2021 at the University Medicine Goettingen (UMG), and data from previously published cases. Results: A total number of 19 patients was identified. These included 4 patients from our center (3 allo HSCT and 1 auto HSCT) and 15 patients from the literature review. Thirteen patients had received an allo HSCT, and six patients had received an auto HSCT. Sarcoidosis occurred after a median interval of 20 (after allo HSCT) and 7 (after auto HSCT) months, respectively. The predominant HLA allele associated with sarcoidosis was HLA DRB1*03:01. Sarcoidosis involved the respiratory tract in 15 patients (three unknown, one without pulmonary involvement), and it was associated with graft-versus-host disease in 7 of 13 patients receiving allo HSCT. None of the donors or patients had a history of sarcoidosis before transplantation. Disease manifestations resolved with standard glucocorticoid treatment without long-term sequelae. Conclusion: Sarcoidosis may occur at low frequency during reconstitution of the immune system after HSCT. HLA allele associations reflect the associations observed in the general population, particularly with DRB1*03:01. Further insights into the interplay between Tcell reconstitution and the development of sarcoidosis could also provide novel approaches to an improved understanding of the pathogenesis in sarcoidosis.


Assuntos
Antígenos HLA , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Sarcoidose/etiologia , Adulto , Idoso , Antígenos HLA/genética , Haplótipos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sarcoidose/epidemiologia
11.
Cancers (Basel) ; 13(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809431

RESUMO

BACKGROUND: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. RESULTS: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). CONCLUSIONS: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.

12.
Bone Marrow Transplant ; 54(6): 877-884, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30413811

RESUMO

Salvage chemotherapy induces disease remissions in patients with relapsed or refractory (r/r) T-cell lymphomas, but fails to provide lasting tumor control. We analyzed the outcome after peripheral blood stem and bone marrow transplantation (PBSCT, n = 80; BMT, n = 4) from matched related (MRD, n = 22) or matched and unmatched unrelated donors (MUD and MMD, n = 53 and n = 9, respectively) following conditioning with fludarabine, busulfan, and cyclophosphamide (FBC) for 84 consecutive patients with r/r T-cell malignancies. At start of conditioning LDH was elevated in 50% of cases, and residual tumor (PD, SD, PR) was detectable in 84% of patients. In total, 38% (95% CI 33-44) of the patients were alive and disease-free after a median observation time of 14.5 (range 1.8 to 114) months. Univariate and multivariate analyses identified low ECOG status, as well as occurrence of acute GvHD as favorable factors for outcome. Lymphoma-directed conditioning with fludarabin, busulfan and cyclophosphamid (FBC-12), and allogeneic stem cell transplantation resulted in long-term survival for a proportion of patients with r/r peripheral T-cell lymphoma, including those with PR and SD only after salvage therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Células T Periférico/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto , Idoso , Feminino , Humanos , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Salvação , Análise de Sobrevida
13.
Leukemia ; 33(11): 2710-2719, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31462732

RESUMO

This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36-0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.


Assuntos
Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Transplante Homólogo , Adulto , Deleção Cromossômica , Citogenética , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro , Antígenos HLA/química , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Condicionamento Pré-Transplante , Resultado do Tratamento
15.
Lancet Haematol ; 5(10): e462-e473, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290903

RESUMO

BACKGROUND: Although intensified chemotherapy regimens have improved tumour control and survival in advanced-stage Hodgkin's lymphoma, data on the long-term sequelae are scarce. We did preplanned follow-up analyses of the German Hodgkin Study Group (GHSG) trials HD9 and HD12 to assess whether the primary results of these trials-which had shown that intensive initial therapy in advanced-stage Hodgkin's lymphoma has a beneficial effect on treatment outcomes-would continue with longer follow-up. METHODS: In HD9 (Feb 1, 1993, to March 10, 1998), 1282 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight alternating cycles of COPP and ABVD (COPP/ABVD), eight cycles of bBEACOPP, or eight cycles of eBEACOPP. In HD12 (Jan 4, 1999, to Jan 13, 2003; registered with ClinicalTrials.gov [NCT00265031]), 1670 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy, to analyse two non-inferiority objectives. In both trials, randomisation was done centrally in the GHSG trial coordination centre using the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease. Patients and investigators were not masked to treatment allocation. All analyses were done on the intention-to-treat principle. The primary endpoint of this follow-up analysis was progression-free survival (time from first diagnosis to progressive disease, relapse, or death from any cause or censoring at the date of last information on disease status). To assess whether long-term outcome might be impaired by long-term sequelae, we analysed overall survival and second primary malignant neoplasm incidence as key secondary endpoints. FINDINGS: Median observation time was 141 months (IQR 101-204) in HD9 and 97 months (69-143) in HD12. For HD9 trial patients, 15-year progression-free survival was 57·0% (95% CI 50·0-64·0) for COPP/ABVD, 66·8% (61·9-71·8) for bBEACOPP, and 74·0% (69·0-79·0) for eBEACOPP, 15-year overall survival was 72·3% (95% CI 66·5-78·1), 74·5% (70·1-78·9), and 80·9% (76·7-85·0), respectively. Progression-free survival and overall survival in the eBEACOPP group remained significantly better than in the COPP/ABVD group (hazard ratio [HR] 0·53, 95% CI 0·41-0·69, p<0·0001, and 0·68, 0·50-0·93, p=0·015, respectively). The 15-year cumulative incidence of second primary malignant neoplasms was 7·2% (95% CI 3·7-10·7) after COPP/ABVD, 13·0% (9·1-16·9) after bBEACOPP, and 11·4% (7·6-15·1) after eBEACOPP. For HD12 trial patients, non-inferiority of 4 + 4 was shown, with 10-year progression-free survival of 82·6% (95% CI 79·6-85·6) for eBEACOPP and 80·6% (77·4-83·7) for 4 + 4 (HR 1·13 [0·89-1·43], within non-inferiority margin of 1·50), and 10-year overall survival of 87·3% (95% CI 84·7-89·9) and 86·8% (84·2-89·4), respectively (HR 1·02 [95% CI 0·77-1·36]). Among 555 (37%) patients with residual disease after chemotherapy, omission of radiotherapy was associated with significantly worse 10-year progression-free survival (89·7% [95% CI 85·8-93·6] radiotherapy vs 83·4% [78·2-88·5] for no radiotherapy; p=0·027) and 10-year overall survival (94·4% [91·4-97·3] vs 88·4% [83·8-93·0]; p=0·025). 10-year cumulative second primary malignant neoplasms incidence was 6·4% (95% CI 3·3-9·5) for 4 + 4 and 8·8% (5·2-12·4) for eBEACOPP. INTERPRETATION: Long-term follow-up of HD9 and HD12 shows an ongoing benefit of intensive first-line treatment and consolidation radiotherapy to residual disease in terms of progression-free survival and overall survival. Our results support the use of eBEACOPP in advanced-stage Hodgkin's lymphoma. However, because late toxicities such as second primary malignant neoplasms contribute to mortality, less toxic but equally effective treatments need to be developed to further improve overall survival. FUNDING: Deutsche Krebshilfe e.V.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Prednisona , Procarbazina , Análise de Sobrevida , Resultado do Tratamento , Vincristina , Adulto Jovem
16.
J Clin Virol ; 38(2): 146-8, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17182277

RESUMO

BACKGROUND: Reactivation of a hepatitis B virus (HBV) infection after transplantation is associated with a high morbidity and mortality. HBV infections generally result in anti-HBc persisting lifelong. CASE REPORT: A 44-year-old female presented 10 years after allogeneic stem cell transplantation with a chronic hepatitis B. The infection was reactivated from a resolved (anti-HBs and anti-HBc positive) HBV infection acquired some years prior to transplantation. Interestingly, she lost all antibodies to HBV including anti-HBc and is upto now anti-HBc negative. The sequence of the surface and the core gene did not reveal any escape mutations. Thus, the loss of anti-HBc might suggest an immunotolerance of the donor's immune system against HBcAg. CONCLUSION: This data illustrate that an HBV infection might be reactivated despite high anti-HBs levels prior to transplantation. Furthermore, this is the first patient in which a complete loss of anti-HBc could be documented. Moreover, since anti-HBc is often used as a screening marker for HBV it should be kept in mind that anti-HBc negative patients with high viremic HBV infection may occur.


Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Transplante de Células-Tronco , Adulto , Feminino , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/imunologia , Hepatite B Crônica/virologia , Humanos , Transplante Homólogo , Ativação Viral
17.
Case Rep Rheumatol ; 2016: 8605274, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28018698

RESUMO

Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year-old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high-spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV-infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases.

18.
Leuk Lymphoma ; 44(9): 1587-96, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14565663

RESUMO

Recently, comparative genomic hybridization (CGH)- and fluorescence in situ hybridization (FISH)-analyses of native Hodgkin and Reed-Sternberg (H&RS) cells extracted from Hodgkin lymphoma (HL) revealed a recurrent amplification of the HDM2 locus on chromosome 12. HDM2 is known to target, inactivate and to degrade p53. Wild type (wt) p53 protein is detected in high levels in HL. Simultaneously, stabilized wt p53 and spliced hdm2 transcripts have been observed in different tumors. Therefore, we examined the expression and structure of HDM2 in HL cell lines and possible effects on components of the p53 pathway. DNA integrity and induction potential of p53 was verified by DNA sequencing and detection of potential effector proteins (p21(WAF/CIP), HDM2) using immunofluorescence, respectively. All HL cell lines show an overexpression of HDM2 protein. Furthermore, several different spliced hdm2 transcripts (mdm-sv) including five new variants lacking a functional p53 binding site were characterized. If expressed, corresponding proteins were shown to be not restricted to the nucleus. Co-localization of the potential binding partners HDM2/p14(ARF) and HDM2/p53 was found in HL cell lines. We suggest that HDM2-sv have no significant disturbing influence on the interaction of these proteins.


Assuntos
Processamento Alternativo , Doença de Hodgkin/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral/metabolismo , Núcleo Celular/metabolismo , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ciclinas/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Hibridização in Situ Fluorescente , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/farmacologia , Reação em Cadeia da Polimerase , Ligação Proteica , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2 , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Células de Reed-Sternberg/metabolismo , Deleção de Sequência , Proteína Supressora de Tumor p14ARF/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores
19.
Anticancer Res ; 24(6): 4121-5, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15736462

RESUMO

A 69-year-old female patient was treated for primary CNS-lymphoma (PCNSL) starting from August 2002. As her general condition allowed no high-dose methotrexate (MTX) therapy, radiotherapy was administered as a first-line treatment. CSF involvement could be managed by intrathecal Ara-C. Her general condition and cognitive status stabilized, but did not improve for 3 months. Therefore, oral chemotherapy with Temozolomide 200 mg/m2 was initiated. After two courses, which were tolerated without any problems, the patient's Karnofsky performance index had improved from 40% to 50%, the Mini-Mental Status rose from 16 to 27/30. The CSF-cell count was elevated again to 23 cells/l without signs of meningeal relapse. Unfortunately, the patient died unexpectedly from suspected pulmonary embolism. We conclude that adjuvant Temozolomide chemotherapy can improve the general condition and cognition in patients with PCNSL even when the general condition is poor. Long-term effects and neurotoxicity remain to be analysed in prospective trials, as well as the efficacy in leptomeningeal disease.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Administração Oral , Idoso , Quimioterapia Adjuvante , Feminino , Humanos , Temozolomida
20.
Int J Hematol ; 100(5): 425-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25258193

RESUMO

T-cell prolymphocytic leukemia is a rare aggressive malignancy with low susceptibility to conventional chemotherapy. The anti-CD52 antibody alemtuzumab induces remission, which requires consolidation by stem cell transplantation in eligible patients. In this case series, three chemotherapy-naïve T-PLL patients received alemtuzumab for remission induction and allogeneic SCT after reduced-intensity conditioning. While primary hematopoietic engraftment occurred in a timely fashion, donor chimerism declined in all patients between day 28 and day 290 post-transplantation. Loss of chimerism was not associated with disease recurrence, and full chimerisms were regained on donor leukocyte infusion. In six B-CLL patients, treated with identical regimens of alemtuzumab and SCT, a similar pattern of failing chimerism was not observed. We surmise that an accumulation of uncleared alemtuzumab in the plasma may impede the incoming graft after allogeneic SCT, which would indicate the need for close monitoring and management of engraftment to secure complete donor chimerism and putative cure in T-PLL patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T/terapia , Quimeras de Transplante , Alemtuzumab , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento
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