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1.
Cancer Lett ; 465: 1-11, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31465840

RESUMO

In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the Glioma-Associated Oncogene Homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family member MCL-1 by A-1210477 synergistically induces cell death in HH-driven cancers, i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB) cells. Combined genetic and pharmacological inhibition emphasized that co-treatment of GANT61 and A-1210477 indeed relies on inhibition of GLI1 (by GANT61) and MCL-1 (by A-1210477). Mechanistic studies revealed that A-1210477 triggers the release of BIM from MCL-1 and its shuttling to BCL-xL and BCL-2. Indeed, BIM proved to be required for GANT61/A-1210477-induced cell death, as genetic silencing of BIM using siRNA significantly rescues cell death upon GANT61/A-1210477 co-treatment. Similarly, genetic silencing of NOXA results in a significant reduction of GANT61/A-1210477-mediated cell death. Also, overexpression of MCL-1 or BCL-2 significantly protects RMS cells from GANT61/A-1210477-triggered cell death. Addition of the pan-caspase inhibitor zVAD.fmk significantly decreases GANT61/A-1210477-stimulated cell demise, indicating apoptotic cell death. In conclusion, GANT61 and A-1210477 synergize to engage mitochondrial apoptosis. These findings provide the rationale for further evaluation of dual inhibition of HH signaling and MCL-1 in HH-driven cancer.

2.
Pediatr Blood Cancer ; 66 Suppl 3: e27884, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393080

RESUMO

BACKGROUND: Ewing tumors are the most frequent malignant tumors of the chest wall in children and young adults. Surgical management of these tumors can be challenging. Optimal local control remains controversial. The aim of this study was to analyze treatment, outcome, and surgical procedures in patients with thoracic tumors of the Ewing sarcoma family (TES) treated within four Cooperative Soft-Tissue Sarcoma (CWS) trials and one registry. PATIENTS AND METHODS: Sixty-two patients from 0 to 21 years treated between 1981 and 2014 were selected for this analysis. A retrospective chart analysis was carried out. Institutional review board approval was obtained for all trials. RESULTS: The median age of the patients was 7 years. The 5-year overall (OS) and event-free survival (EFS) rates were 58.7% (52.7-64.7) and 52.8% (46.8-58.8). Patients with intrathoracic tumor localization (n = 24) had a worse outcome (EFS: 37.5%; 27.5-37.5) compared with those with chest wall tumors (n = 38; EFS: 62.3%; 54.3-70.3, P = 0.008). Patients ≤10 years (n = 38) had a better survival compared with those > 10 years (EFS: 65.7%; 57.7-73.7 vs 31.3%; 21.3-41.3, P = 0.01). Tumor size ≤5 cm (n = 15) was associated with significantly better survival compared with a size > 5 cm (n = 47, EFS: 93.3%; 87.3-99.3 vs 40%; 33-47, P = 0.002). Primary resections were carried out in 36 patients, of which 75% were incomplete resulting in inferior EFS (P = 0.006). Complete secondary resections were performed in 22 of 40. CONCLUSIONS: Positive predictive factors for outcome are age ≤10 years, size ≤5 cm, and localization at the chest wall. Diverse IRS groups require individual treatment.

3.
Pediatr Blood Cancer ; 66(9): e27879, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31215116

RESUMO

BACKGROUND: Epithelioid sarcoma (ES) is a rare malignant soft-tissue tumor. Little is known about the optimal treatment of primary localized (LD), metastatic (MD), and relapsed disease (RD). METHODS: Characteristics, treatment, and outcome of 67 patients registered within the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, -2002P trials and the registry SoTiSaR were analyzed (1981-2016). RESULTS: The median age was 14 years (range, 0.7-26.9); 53 patients had localized disease (LD) and 14 metastatic disease (MD). A total of 58 of 67 patients were treated with primary resection. Resection was microscopically complete (R0) in 35, microscopically incomplete (R1) in 12, macroscopically incomplete (R2) in 20 patients. Radiotherapy (RT) was administered to 33 of 67 patients and 49 of 67 patients received chemotherapy (CHT). Complete remission (CR) was achieved in 45 of 53 (85%) patients with LD. Twenty-seven of 53 patients relapsed after a median time of 0.9 years (range, 0.1-2.3). Relapse therapy consisted of resection (n = 19/27), RT (n = 10/27), CHT (n = 12/27), and limb perfusion (n = 3/27). The five-year event-free survival and overall survival of patients with LD, MD, and RD was 35% (± 12, CI 95%) and 58% (± 14, CI 95%), 7% (± 14, CI 95%), and 9% (± 16, CI 95%), 24% (± 17, CI 95%), and 40% (± 20, CI 95%), respectively. Tumor size, IRS group, tumor invasiveness, nodal status, and best resection correlated with a favorable prognosis in patients with LD while best resection was the only significant factor in patients with RD. CONCLUSIONS: Complete tumor resection correlates with long-term survival in patients with ES.

4.
Front Immunol ; 10: 1218, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214182

RESUMO

Cytokine-induced killer (CIK) cells are an immunotherapeutic approach to combat relapse following allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia or myelodysplastic syndrome (MDS) patients. Prompt and sequential administration of escalating cell doses improves the efficacy of CIK cell therapy without exacerbating graft vs. host disease (GVHD). This study addresses manufacturing-related issues and aimed to develop a time-, personal- and cost-saving good manufacturing process (GMP)-compliant protocol for the generation of ready-for-use therapeutic CIK cell doses starting from one unstimulated donor-derived peripheral blood (PB) or leukocytapheresis (LP) products. Culture medium with or without the addition of either AB serum, fresh frozen plasma (FFP) or platelet lysate (PL) was used for culture. Fresh and cryopreserved CIK cells were compared regarding expansion rate, viability, phenotype, and ability to inhibit leukemia growth. Cell numbers increased by a median factor of 10-fold in the presence of FFP, PL, or AB serum, whereas cultivation in FFP/PL-free or AB serum-free medium failed to promote adequate CIK cell proliferation (p < 0.01) needed to provide clinical doses of 1 × 106 T cells/kG, 5 × 106 T cells/kG, 1 × 107 T cells/kG, and 1 × 108 T cells/kG recipient body weight. CIK cells consisting of T cells, T- natural killer (T-NK) cells and a minor fraction of NK cells were not significantly modified by different medium supplements. Moreover, neither cytotoxic potential against leukemic THP-1 cells nor cell activation shown by CD25 expression were significantly influenced. Moreover, overnight and long-term cryopreservation had no significant effect on the composition of CIK cells, their phenotype or cytotoxic potential. A viability of almost 93% (range: 89-96) and 89.3% (range: 84-94) was obtained after freeze-thawing procedure and long-term storage, respectively, whereas viability was 96% (range: 90-97) in fresh CIK cells. Altogether, GMP-complaint CIK cell generation from an unstimulated donor-derived PB or LP products was feasible. Introducing FFP, which is easily accessible, into CIK cell cultures was time- and cost-saving without loss of viability and potency in a 10-12 day batch culture. The feasibility of cryopreservation enabled storage and delivery of sequential highly effective ready-for-use CIK cell doses and therefore reduced the number of manufacturing cycles.

5.
Clin Microbiol Rev ; 32(3)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31092507

RESUMO

SUMMARYInvasive fungal diseases carry high morbidity and mortality in patients undergoing chemotherapy for hematological malignancies or allogeneic hematopoietic stem cell transplantation. In order to prevent these life-threatening infections, antifungal chemoprophylaxis plays an important role in daily clinical practice. Broad-spectrum antifungal triazoles are widely used but exhibit disadvantages such as relevant drug-drug interactions. Therefore, amphotericin B products or echinocandins can be an alternative in selected patient populations. As these compounds are available as intravenous formulations only, there is growing interest in extended dosing regimens. Although not approved for these agents, this strategy is a rational option, as these compounds have properties suitable for this strategy, including dose-proportional pharmacokinetics, prolonged elimination half-life, and a large therapeutic window. As the use of extended dosing regimens in antifungal prophylaxis is expanding in clinical practice, we reviewed the pharmacokinetic and pharmacodynamic rationale for this strategy, animal model data, dose escalation studies, and clinical trials supporting this concept.

6.
BMC Infect Dis ; 19(1): 357, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035966

RESUMO

BACKGROUND: Overcrowding, reduced nurse to patient ratio, limited distance between incubators and absence of microbiological surveillance have been shown to promote spread of multidrug-resistant gram-negative organisms (MDRGN) in patients with birthweight < 1500 g. Patients > 1500 g treated on an intermediate care unit are unrepresented in recent literature. We therefore intended to present data obtained from a short-term overcrowded neonatal intermediate care unit (NIMCU) at a level III (international categorization) perinatal center at University Hospital Frankfurt, Germany. METHODS: During a 25 day overcrowding (OV) and 28 day post-overcrowding period (POST-OV) on NIMCU, epidemiological data obtained from continuously hold microbiological surveillance were investigated and compared to the last 12 months of ward-regular bed occupancy preceding OV (PRAE-OV). RESULTS: During OV, the number of patients simultaneously treated at the NIMCU increased from 18 to 22, resulting in a reduced bed-to-bed space. Nurse: patient ratio was 4:22 during OV compared to 3:18 during PRAE-OV. Cumulative incidence of MDRGN was 4.7% in OV and 2.4% POST-OV compared to 4.8% to PRAE-OV, respectively, without any significant variations. During OV and POST-OV, septic episodes due to MDRGN were not observed. In one case, potential nosocomial transmission of Enterobacter cloacae resistant to Piperacillin and 3rd/4th generation cephalosporins was observed. CONCLUSIONS: Prevention of nosocomial spread of MDRGN in an overcrowded NIMCU is based on staff's diligent training and adequate staffing. Concise microbiological surveillance should be guaranteed to escort through overcrowding periods. In our setting, impact of bed-to-bed distance on MDRGN transmission seemed to be less strong.


Assuntos
Infecção Hospitalar/diagnóstico , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , DNA Bacteriano/metabolismo , Enterobacter cloacae/genética , Enterobacter cloacae/isolamento & purificação , Feminino , Alemanha/epidemiologia , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Hospitais Universitários , Humanos , Incidência , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino
7.
Biol Blood Marrow Transplant ; 25(7): 1281-1292, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30878607

RESUMO

Well-established donor lymphocyte infusion (DLI) and novel cytokine-induced killer (CIK) cell therapy for the treatment of relapsing hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were compared with respect to feasibility, safety, and efficacy. Altogether, a total of 221 infusions were given to 91 patients (DLI, n = 55; CIK, n = 36). T cell recovery was significantly improved after CIK cell therapy (P < .0001). Although patients with CIK cell treatment showed a significantly worse prognosis at the time of HSCT (risk score, 1.7 versus 2.1; P < .0001), DLI and CIK cell therapy induced complete remission (CR) in 29% and 53% patients, respectively, whereas relapse occurred in 71% and 47%. In both groups, all patients with overt hematologic relapse at the time of immunotherapy (DLI, n = 11; CIK, n = 8) succumbed to their disease, while 36% and 68% patients with DLI or CIK cell therapy applied due to molecular relapse or active disease at the time of transplantation achieved CR. The 6-month overall survival rate in the latter patients was 57% and 77%, respectively, with a median follow-up of 27.9 months (range, .9 to 149.2 months). The 6-month cumulative incidence of relapse was 55% and 22% in patients who received DLI and CIK cell therapy, respectively (P = .012). Acute graft-versus-host disease developed in 35% of the patients who received DLI and in 25% of those who received CIK. No transfusion-related deaths occurred. These data, while underscoring the therapeutic value of conventional DLI, suggest the improved safety and to a certain extent efficacy of CIK cell therapy for patients at high risk for post-transplantation relapse of various hematologic malignancies.

8.
Pediatr Blood Cancer ; 66(6): e27652, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30762282

RESUMO

BACKGROUND: Rhabdomyosarcoma (RMS) diagnosed during the first year of life is reported to have poor outcome. Little is known about treatment and outcome data of relapsed disease (RD). METHODS: Characteristics, treatment, and outcome of 155 patients ≤ 12 months registered within the Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 2016 were evaluated. RESULTS: Localized disease (LD) was diagnosed in 144 patients and metastatic disease (MD) in 11. The histological diagnosis was alveolar (RMA) (n = 38, 23/25 examined patients PAX7/3:FOXO1-positive), embryonal (RME) (n = 100), botryoid (n = 10), anaplastic (n = 1), and spindle-cell RMS (n = 6). Multimodal treatment including conventional (age-adjusted) chemotherapy (CHT) (n = 150), resection (n = 137), and radiotherapy (RT) (n = 37) was administered. Complete remission was achieved in 129 of 144 patients with LD. RD occurred in 51 infants at a median age of 1.7 years (range, 0.3-8.8). Sixty-three percent of patients with RMA suffered RD, in contrast to 28% of patients with RME. Relapse treatment consisted of conventional CHT (n = 48), resection (n = 28), and RT (n = 21). The pattern of relapse and best resection were significant prognostic factors for patients with RD (P = 0.000 and P = 0.002). Late effects occurred as secondary malignancies in 6%, long-term toxicity in 21%, and resection-related impairment in 33% of the 105 surviving patients. The 5-year event-free survival and overall survival for infants with initial LD were 51% and 69%, 14% and 14% for patients with initial MD and 39% and 41% for relapsed patients, respectively. CONCLUSION: Multimodal treatment including microscopically complete resection is strongly recommended to achieve a good prognosis in LD and RD of infants with RMS.

9.
Sci Rep ; 9(1): 1774, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30742027

RESUMO

In the current study we compared the molecular signature of expanded mesenchymal stromal cells (MSCs) derived from selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs derived from non-selected bone marrow mononuclear cells by plastic adherence (PA-MSCs). Transcriptome analysis demonstrated for the first time the upregulation of 115 and downregulation of 131 genes in CD271-MSCs. Functional enrichment analysis showed that the upregulated genes in CD271-MSCs are significantly enriched for extracellular matrix (tenascin XB, elastin, ABI family, member 3 (NESH) binding protein, carboxypeptidase Z, laminin alpha 2 and nephroblastoma overexpressed) and cell adhesion (CXCR7, GPNMB, MYBPH, SVEP1, ARHGAP6, TSPEAR, PIK3CG, ABL2 and NCAM1). CD271-MSCs expressed higher gene transcript levels that are involved in early osteogenesis/chondrogenesis/adipogenesis (ZNF145, FKBP5). In addition, increased transcript levels for early and late osteogenesis (DPT, OMD, ID4, CRYAB, SORT1), adipogenesis (CTNNB1, ZEB, LPL, FABP4, PDK4, ACDC), and chondrogenesis (CCN3/NOV, CCN4/WISP1, CCN5/WISP2 and ADAMTS-5) were detected. Interestingly, CD271-MSCs expressed increased levels of hematopoiesis associated genes (CXCL12, FLT3L, IL-3, TPO, KITL). Down-regulated genes in CD271-MSCs were associated with WNT and TGF-beta signaling, and cytokine/chemokine signaling pathways. In addition to their capacity to support hematopoiesis, these results suggest that CD271-MSCs may contain more osteo/chondro progenitors and/or feature a greater differentiation potential.

10.
Cancer Med ; 8(2): 527-542, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30652419

RESUMO

BACKGROUND: To evaluate optimal therapy and potential risk factors. METHODS: Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed. RESULTS: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. CONCLUSION: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.

11.
Transfusion ; 59(3): 1061-1068, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30610749

RESUMO

BACKGROUND: Autologous stem cell transplantation remains an integral treatment tool for certain childhood malignancies. In children, a central venous catheter is typically necessary to provide adequate flow rates for preparative apheresis. In this study, the feasibility and efficiency of collecting CD34+ cells via an indwelling Hickman catheter, preimplanted for chemotherapy, instead of placing an additional temporary central venous catheter was evaluated. STUDY DESIGN AND METHODS: Forty-eight pediatric leukaphereses for autologous hematopoietic stem cell transplantation using Spectra Optia MNC, Version 3.0 were reviewed. We compared preimplanted Hickman catheters with a temporary Shaldon catheter, inserted for apheresis. Apheresis was considered successful if a dose of 2 × 106 CD34+ peripheral blood stem cells/kg BW was achieved. RESULTS: In 43 (89.6%) of the 48 patients, a Hickman catheter was used for leukapheresis. Only 5 patients (10.4%) received a temporary Shaldon catheter. In both groups, apheresis was performed without apparent adverse reactions. The dose of collected CD34+ peripheral blood stem cells was 12.7 × 106 (range, 2.3-70.7 × 106 ) cells/kg BW in the Hickman group and 16.2 × 106 (range, 3.8-48.4 × 106 ) cells/kg BW in the Shaldon group, showing no statistically significant difference (p = 0.58). In both groups, the primary endpoint of a minimal CD34+ cell concentration of 2 × 106 cells/kg BW was achieved at a maximum of two leukapheresis sessions. Apheresis efficacy was further confirmed by the collection efficiency of 40.2% in the Hickman group and 27.8% in the Shaldon group (p = 0.32). CONCLUSION: These data indicate the reliable feasibility and efficacy of mobilized apheresis via an indwelling Hickman catheter. In light of this, the routine insertion of a dialysis catheter for the purpose of leukapheresis should be critically reconsidered.

12.
J Surg Oncol ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30421433

RESUMO

BACKGROUND: Synovial sarcoma of the foot/ankle is rare. Mutilating surgery is often discussed. METHODS: Patients registered from 1981 to 2013 were analyzed. Cooperative Weichteilsarkom Studiengruppe (CWS) protocols recommend chemotherapy for all synovial sarcoma patients. RESULTS: Thirty-two of 330 patients with localized synovial sarcoma had their tumor at the foot/ankle. Eleven of thirty-two tumors were >5 cm. Twenty were T1, 11 T2, and one TX, respectively. Eight (25%) patients underwent primary complete resection with free margins (Intergroup Rhabdomyosarcoma Study [IRS] I), 12 of 32 (38%) primary complete resection with positive margins (IRS II), and 12 of 32 (38%) had macroscopic residuals (IRS III). The best surgical result at any time was R0 in 19, R1 in 10 and R2 in one patient, and missing in two. Mutilation was documented in 14 of 32 (44%). Radiotherapy was conducted in 20 patients. All patients achieved a first complete remission. Five-year-event-free survival and overall survival rates were 80% and 86%, respectively. Four patients suffered local and four other metastatic recurrences. IRS and the best surgical result at any time did not correlate with survival. There was no prognostic difference between R0- and R1-resection. CONCLUSION: Survival expectancies for patients with localized synovial sarcomas of the foot/ankle compare favorably to that of those with other affected sites. DISCUSSION: Further studies are needed to set the limits of minimally required aggressiveness of local therapies.

13.
Pediatr Blood Cancer ; : e27537, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30421578

RESUMO

BACKGROUND: Ewing tumors are the most frequent malignant tumors of the chest wall in children and young adults. Surgical management of these tumors can be challenging. Optimal local control remains controversial. The aim of this study was to analyze treatment, outcome, and surgical procedures in patients with thoracic tumors of the Ewing sarcoma family (TES) treated within four Cooperative Soft-Tissue Sarcoma (CWS) trials and one registry. PATIENTS AND METHODS: Sixty-two patients from 0 to 21 years treated between 1981 and 2014 were selected for this analysis. A retrospective chart analysis was carried out. Institutional review board approval was obtained for all trials. RESULTS: The median age of the patients was 7 years. The 5-year overall (OS) and event-free survival (EFS) rates were 58.7% (52.7-64.7) and 52.8% (46.8-58.8). Patients with intrathoracic tumor localization (n = 24) had a worse outcome (EFS: 37.5%; 27.5-37.5) compared with those with chest wall tumors (n = 38; EFS: 62.3%; 54.3-70.3, P = 0.008). Patients ≤10 years (n = 38) had a better survival compared with those > 10 years (EFS: 65.7%; 57.7-73.7 vs 31.3%; 21.3-41.3, P = 0.01). Tumor size ≤5 cm (n = 15) was associated with significantly better survival compared with a size > 5 cm (n = 47, EFS: 93.3%; 87.3-99.3 vs 40%; 33-47, P = 0.002). Primary resections were carried out in 36 patients, of which 75% were incomplete resulting in inferior EFS (P = 0.006). Complete secondary resections were performed in 22 of 40. CONCLUSIONS: Positive predictive factors for outcome are age ≤10 years, size ≤5 cm, and localization at the chest wall. Diverse IRS groups require individual treatment.

14.
Cancers (Basel) ; 10(10)2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30336605

RESUMO

GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m²/d; d8⁻18) combined with s.c. IL-2 (6 × 106 IU/m²/d; d1⁻5, d8⁻12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.

15.
Lancet Haematol ; 5(10): e450-e461, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290902

RESUMO

BACKGROUND: Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, treatment of relapsed or refractory disease remains challenging. The aims of this study were to assess the safety, tolerability, recommended phase 2 dose, and efficacy of brentuximab vedotin in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. METHODS: This open-label, dose-escalation phase 1/2 study was done at 12 centres across eight countries (France, Germany, Italy, Mexico, The Netherlands, Spain, UK, and USA). We recruited paediatric patients aged 7-18 years with relapsed or refractory classical Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, for whom standard treatment was unavailable or no longer effective. Participants were allocated to receive brentuximab vedotin at 1·4 mg/kg (phase 1) or 1·8 mg/kg (phases 1 and 2) via intravenous infusion once every 3 weeks for up to 16 cycles. Dose escalation was done via a 3+3 design. Key exclusion criteria were stem-cell transplantation less than 3 months before administration of the first dose of study drug, presence of cytomegalovirus infection after allogeneic stem-cell transplantation, previous treatment with an anti-CD30 antibody, and concurrent immunosuppressive or systemic therapy for chronic graft-versus-host disease. Primary outcomes were safety profile in the safety-evaluable population and maximum tolerated dose, recommended phase 2 dose, pharmacokinetics (phase 1), and proportion of patients who achieved best overall response (phase 2; evaluated by an independent review facility) in the response-evaluable population. This trial is registered with ClinicalTrials.gov, number NCT01492088. FINDINGS: Between April 16, 2012, and April 4, 2016, we screened 41 paediatric patients and enrolled 36 (aged 7-18 years), of whom 19 had relapsed or refractory classical Hodgkin's lymphoma and 17 had relapsed or refractory systemic anaplastic large-cell lymphoma. At the data cutoff (Oct 12, 2016), all 36 patients had discontinued study drug treatment; the most common reason was progressive disease (15 patients). The maximum tolerated dose was not reached. The recommended phase 2 dose was 1·8 mg/kg. The proportion of patients who achieved overall response was 47% (95% CI 21-73) for classical Hodgkin's lymphoma and 53% (28-77) for systemic anaplastic large-cell lymphoma. All 36 patients had a treatment-emergent adverse event and 16 patients (44%) had at least one grade 3 or worse treatment-emergent adverse event. The most common treatment-emergent adverse events were pyrexia (16 [44%] of 36) and nausea (13 [36%]). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (four [11%]), increased γ-glutamyl transpeptidase (two [6%]), and pyrexia (two [6%]). 12 (33%) patients had transient, limited-severity peripheral neuropathy. Eight patients (22%) had a serious adverse event; three (8%) had a drug-related serious adverse event. One patient died of cardiac arrest (disease progression of a large huge mediastinal mass, unrelated to the study drug). Paediatric pharmacokinetic profiles were consistent with those from studies of adult patients. INTERPRETATION: Brentuximab vedotin has manageable toxicity and is associated with clinically meaningful responses in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, and could allow subsequent stem-cell transplantation in some patients who were initially ineligible for stem-cell transplantation. FUNDING: Millennium Pharmaceuticals Inc.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Recidiva
16.
Int J Radiat Oncol Biol Phys ; 102(3): 584-592, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30244879

RESUMO

PURPOSE: There is no standard treatment procedure for relapsed Ewing sarcoma (EwS). This retrospective analysis evaluates the survival outcome in patients with an isolated pulmonary relapse of EwS treated with whole lung irradiation (WLI) in addition to second line chemotherapy (Ctx). METHODS AND MATERIALS: In our study, 136 patients with pulmonary relapsed EwS who were registered in the relapse register of the Cooperative Ewing Sarcoma Study group or the Sarcoma Relapse Registry for relapsed sarcoma of bone and soft tissues were analyzed. All patients received relapse Ctx or an additional total resection of lung metastasis. Of these patients, 88 (median age, 21 years; range, 7-52 years) achieved a second remission by the relapse treatment. Of these 88 patients, 48 patients received an additional WLI. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were analyzed (median follow-up, 3 years; range, 7 months to 11 years and 9 months). Additional prognostic factors for survival outcomes, including the response of lung metastases to Ctx, were also estimated. RESULTS: The survival outcome was significantly improved after WLI when analyzing the entire group of pulmonary relapsed patients: 3-year PFS 36% (+WLI) versus 14% (-WLI) (P = .001); 3- year OS 47% (+WLI) versus 33% (-WLI) (P = .007). The 3-year PFS in patients with complete remission of lung relapse receiving WLI (n = 48) compared with those without WLI (n = 40), was 37% (+WLI) versus 21% (-WLI) (P = .18). The site of the primary tumor and the response of pulmonary lesions to Ctx were significant prognostic indicators for survival in patients treated with WLI. No severe pulmonary function disorders or lung toxicities were observed after WLI treatment in both pediatric and adult patients. CONCLUSIONS: The WLI does not correlate with improved OS in patients with pulmonary relapsed EwS. However, a marginal trend toward superior PFS and improved local control of pulmonary disease suggests the application of WLI in patients with EwS with isolated lung relapse and second clinical remission.

17.
J Clin Oncol ; : JCO2018782516, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30188789

RESUMO

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30258130

RESUMO

Allogeneic hematopoietic stem cell transplantation (alloHSCT) has become a well-established treatment option for many patients suffering from malignant and non-malignant diseases. In the past decade, high-resolution HLA-typing, remission surveillance, pre-emptive immune intervention, and standardisation in supportive care measures have substantially improved transplant outcomes. This retrospective study evaluated transplant procedures in 162 paediatric patients with acute lymphoblastic leukaemia (n = 124) or acute myeloid leukaemia (n = 38) who received their first alloHSCT in our institution over an 11-year period. We observed a significant reduction in risk of non-relapse mortality (NRM) over time (HR = 0.34, 95% CI 0.12-0.98; P = 0.05), the 4-year NRM estimate decreased from 20% in 2005-2008 to 7% in 2012-2016 (P = 0.02) and an increase in survival after relapse. There was no significant difference in patients who received a graft from a sibling, haplo, or an unrelated donor with regard to their overall survival (P = 0.45), event-free survival (P = 0.61), and non-relapse mortality (P = 0.19). Our data suggest that a specific transplant infrastructure with a highly experienced team in an accredited transplant centre likely contributes to better transplant outcomes for acute leukaemia patients in complete remission regardless of donor type.

19.
Pediatr Blood Cancer ; 65(12): e27405, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30124238

RESUMO

BACKGROUND: Patients with metastatic alveolar soft-part sarcoma (ASPS) are known to have a very poor prognosis. Little is known about best treatment of primary metastatic disease (MD) or relapsed metastatic disease (rMD). PATIENTS AND METHODS: Patients with localized disease (LD), primary MD, and metastatic recurrence after complete remission (CR) treated within the CWS-86, -91, -96, -2002P trials and the recent registry SoTiSaR (1985-2016) were analyzed. RESULTS: Fifteen of 61 patients had primary metastases at initial diagnosis at the age of 14.6 years (range, 7.8-19.7). Nine of 46 patients with initial LD suffered of rMD at a median age of 9.9 years (range, 3.5-30), 3.75 years (0.75-21) after CR of primary disease. Complete resection (microscopically or macroscopically) was possible in 2 of 15 patients with MD and in 5 of 9 with rMD. RT was administered in 4 of 15 MD and 1 of 9 rMD. Chemotherapy was administered to 11 of 15 MD and 3 of 9 rMD, targeted therapy to 3 of 15 MD and 1 of 9 rMD. Median time to progression of patients treated with targeted therapy (n = 4), CHT (n = 14), and resection only (n = 6) was 56, 17, and 23 months, respectively. The 5-year event-free survival and overall survival (OS) rates were 19.8% and 61%, respectively, for patients with MD compared with 79% and 98% for patients with LD. The 5-year progression-free survival and OS were 67% and 100% for patients with rMD. CONCLUSIONS: Complete tumor resection correlates with long-term survival in patients with primary and relapsed MD.

20.
Front Immunol ; 9: 1841, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30154788

RESUMO

Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.

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