Klinik und Poliklinik für Augenheilkunde am Universitätsklinikum Carl Gustav Carus

The diagnosis of Parkinson’s disease (PD) follows the UK Brain Bank Criteria, which demands bradykinesia and one additional symptom, i.e. rigidity, resting tremor or postural instability. The latter is not a useful sign for the early diagnosis of PD, because it does not appear before Hoehn and Yahr stage 3. Early symptoms of PD which precede the onset of motor symptoms are hyposmia, REM sleep behavioral disorder, constipation, and depression. In addition, an increasing number of patients whose PD is related to a genetic defect are being described. Thus, genetic testing may eventually develop into a tool to identify at-risk patients. The clinical diagnosis of PD can be supported by levodopa or apomorphine tests. Imaging studies such as cranial CT or MRI are helpful to distinguish idiopathic PD from atypical or secondary PD. SPECT and PET methods are valuable to distinguish PD tremor from essential tremor if this is clinically not possible. Using all of these methods, we may soon be able to make a premotor diagnosis of PD, which will raise the question whether early treatment is possible and ethically and clinically advisable.

Myeloid sarcoma in acute myeloid leukemia has been clearly defined by the World Health Organization but studies regarding the prevalence and the prognostic impact of extramedullary acute myeloid leukemia have not been conducted. We performed 18Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography scans in 10 patients with de novo and relapsed acute myeloid leukemia and histologically proven extramedullary disease. The scans were able to detect the known extramedullary lesions in 9 out of 10 patients (90%). Furthermore, additional extramedullary sites were detected in 6 patients (60%). Thus, it is possible to identify known and clinically undetectable extramedullary manifestations of acute myeloid leukemia. Since most of these patients relapsed within a short period of time after initiation of therapy or had refractory disease, the detection of extramedullary disease with 18Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography might be helpful in the development of individual treatment algorithms for these high-risk patients. (ClinicalTrials.gov Identifier: NCT01278069).

The prognosis of patients with de novo myelodysplastic syndrome (MDS) who are red blood cell transfusion–dependent (TD) and receive supportive care is inferior to that of patients who do not require transfusions. Whether TD also affects outcome after allogeneic transplantation is unknown. Consequently, in 172 de novo MDS patients (median age, 51 years), we analyzed the impact of TD on outcome after high-dose conditioning and allogeneic peripheral blood stem cell transplantation (PBSCT). With a median follow-up of 37 months, the probability of 3-year overall survival (OS) did not differ significantly between patients who were TD and those who were not TD before PBSCT (P = .1); however, transfusion burden, as reflected by ferritin levels, was correlated with a greater probability of severe acute graft-versus-host disease (aGVHD; P = .03) and a higher comorbidity index (P = .01), and OS was inferior in those patients with a ferritin level >1000 μg/L before PBSCT (P = .03). In multivariate analysis, only marrow myeloblast count (P = .01) and comorbidity index (P = .001) had a significant impact on OS. Our data do not identify TD as an independent negative prognostic factor for outcome after allogeneic PBSCT' however, iron overload (presumably transfusion-related) may contribute to poor transplantation success by adding to the overall comorbidities. Whether clinical intervention in the form of iron chelation can improve the outcome of allogeneic PBSCT in TD patients with MDS remains to be determined. The prognosis of patients with de novo myelodysplastic syndrome (MDS) who are red blood cell transfusion–dependent (TD) and receive supportive care is inferior to that of patients who do not require transfusions. Whether TD also affects outcome after allogeneic transplantation is unknown. Consequently, in 172 de novo MDS patients (median age, 51 years), we analyzed the impact of TD on outcome after high-dose conditioning and allogeneic peripheral blood stem cell transplantation (PBSCT). With a median follow-up of 37 months, the probability of 3-year overall survival (OS) did not differ significantly between patients who were TD and those who were not TD before PBSCT (P = .1); however, transfusion burden, as reflected by ferritin levels, was correlated with a greater probability of severe acute graft-versus-host disease (aGVHD; P = .03) and a higher comorbidity index (P = .01), and OS was inferior in those patients with a ferritin level >1000 μg/L before PBSCT (P = .03). In multivariate analysis, only marrow myeloblast count (P = .01) and comorbidity index (P = .001) had a significant impact on OS. Our data do not identify TD as an independent negative prognostic factor for outcome after allogeneic PBSCT' however, iron overload (presumably transfusion-related) may contribute to poor transplantation success by adding to the overall comorbidities. Whether clinical intervention in the form of iron chelation can improve the outcome of allogeneic PBSCT in TD patients with MDS remains to be determined. IntroductionSeveral therapeutic modalities for patients with myelodysplastic syndrome (MDS) have been developed over the past few years, some of which may change the natural course of the disease [1Fenaux P. Mufti G.J. Santini V. et al.Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): results of the AZA-001 phase III study.Blood. 2007; 110: 250A-251AGoogle Scholar]. With the rare exception of patients who achieve long-lasting remission with chemotherapy, allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only modality with proved curative potential [2Deeg H.J. Appelbaum F.R. Hemopoietic stem cell transplantation for myelodysplastic syndrome.Curr Opin Oncol. 2000; 12: 116-120Crossref PubMed Scopus (12) Google Scholar]. But given the heterogeneity of MDS and the potential complications associated with HSCT, deciding when and in whom to perform allogeneic HSCT often is difficult. The decision model presented by Cutler et al. [3Cutler C.S. Lee S.J. Greenberg P. et al.A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.Blood. 2004; 104: 579-585Crossref PubMed Scopus (541) Google Scholar] showed a survival advantage with early transplantation in patients with MDS classified as intermediate-2 or high risk based on International Prognostic Scoring System (IPSS) criteria [4Greenberg P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar]; however, that analysis was based largely on observations antedating the availability of new drugs and did not incorporate more recent information on factors that might affect the disease course, such as comorbidity, transfusion dependence (TD), or iron overload. The identification of additional clinical markers that might help in selecting patients likely to benefit from allogeneic HSCT and in determining the optimum time point for HSCT is desirable.The need for red blood cell transfusion support regardless of IPSS score has been shown to have a negative impact on overall survival (OS) in patients who did not undergo transplantation [5Malcovati L. Porta M.G. Pascutto C. et al.Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.J Clin Oncol. 2005; 23: 7594-7603Crossref PubMed Scopus (725) Google Scholar]. The reason for this is not entirely clear. Patients who become TD may have a more aggressive disease biology. They also may experience adverse effects related to transfusion-induced allosensitization or may suffer toxic organ effects related to iron overload. The finding of a negative impact of TD on prognosis has led to the development of a new proposed scoring system for patients with de novo MDS: the World Health Organization International Prognostic Scoring System (WPSS), which merges the parameters of the World Health Organization's (WHO) classification of MDS with the IPSS, essentially by having TD replace the “cytopenia” category of the IPSS [6Malcovati L. Germing U. Kuendgen A. et al.Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes.J Clin Oncol. 2007; 25: 3503-3510Crossref PubMed Scopus (880) Google Scholar].Whether TD also is an independent risk factor in patients undergoing allogeneic HSCT remains unknown. A potential negative effect of TD on transplantation outcome has been derived indirectly from a study by Armand et al. [7Armand P. Kim H.T. Cutler C.S. et al.Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation.Blood. 2007; 109: 4586-4588Crossref PubMed Scopus (370) Google Scholar] in 103 patients with MDS (including therapy-related MDS, for which the scoring systems have not been validated) that suggested a possible link between pretransplantation ferritin level and outcome after allogeneic HSCT using conventional conditioning regimens. In that study, the negative impact of iron overload appeared to be independent of the effects of graft-versus-host disease (GVHD). Other possibilities are that transfusion needs and ferritin levels were related to disease stage or disease duration and, associated with this, a long history of transfusion support.We performed a retrospective study involving 6 transplantation centers in Germany, Austria, and the United States to analyze results in 172 patients with de novo MDS undergoing allogeneic HSCT using granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral blood stem cells (PBSCs) after high-intensity conditioning.Materials and MethodsPatient and disease characteristicsThe study cohort comprised 172 patients with de novo MDS (Table 1). The patients were classified according to French-American-British (FAB), WHO, IPSS, and WPSS criteria at the time of transplantation. According to Malcovati et al. [6Malcovati L. Germing U. Kuendgen A. et al.Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes.J Clin Oncol. 2007; 25: 3503-3510Crossref PubMed Scopus (880) Google Scholar], TD was defined as having received at least one unit of red blood cells within the 8-week period before PBSCT. The precise number of units of red blood cells transfused was not consistently available. Only 4 patients underwent transplantation within 2 months of diagnosis. The most recent ferritin level, obtained not more than 6 weeks before PBSCT, was considered for analysis. Pretransplantation comorbidities were assessed using the hematopoietic cell transplantation comorbidity index (HCT-CI) [8Sorror M.L. Maris M.B. Storb R. et al.Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.Blood. 2005; 106: 2912-2919Crossref PubMed Scopus (1926) Google Scholar]. Comorbidity scores could be assigned to 164 patients; the breakdown by score was as follows: 0, 74 patients; 1, 31 patients; 2, 19 patients; 3, 20 patients; 4, 13 patients; and ≥ 5, 7 patients.Table 1Disease and Patient CharacteristicsAll Patients (n = 172), nNon-TD (n = 41), n (%)TD (n = 131), n (%)PFAB classificationNS RA/RARS8518 (44)67 (51) RAEB5218 (44)34 (26) RAEB-t162 (5)14 (11) MDS/AML193 (7)16 (12)WHO classification.004 5q syndrome50 (0)5 (4) RA/RARS140 (0)14 (11) RCMD/RCMD-RS6419 (46)45 (34) RAEB-1247 (17)17 (13) RAEB-22710 (24)17 (13) AML355 (12)30 (23) MDS-U30 (0)3 (2)IPSS classification.01 LOW92 (5)7 (6) INT-17718 (47)58 (53) INT-24216 (43)26 (24) HIGH212 (5)19 (17)WPSS classificationNS Very low00 (0)0 (0) Low218 (22)13 (12) Intermediate3810 (27)27 (25) High6617 (47)48 (45) Very high101 (4)9 (8)Median age at treatment, years (range)51 (10-68)53 (21-64)50 (10-68)NSMedian time from diagnosis to treatment, months (range)8.5 (0.1-243)8.7 (0.4-35)8.5 (0.1-243)NSRelated/unrelated donor, n90/8218/2372/59NSHLA mismatch, n101 (2)9 (7)NSMedian CD34 cells/kg (range)6.76 (1.3-32.2)7.49 (2.07-18.7)6.67 (1.3-32.2)NSCMV seropositivity, n541539NSMedian follow-up, months (range)37 (0.5-135)49.1 (0.5-97)37.1 (0.8-135)NSCMV indicates cytomegalovirus.Note. The patients were grouped according to red blood cell transfusion dependence and the current classification and scoring systems used in MDS, including FAB, WHO, IPSS, and WPSS. Open table in a new tab DNA-based HLA-typing of donor and recipient was performed for and and by for patients received patients had received before PBSCT, of whom remission regimens were over 4 or In was with over 2 n = of n = or over n = patients received as of the conditioning as H.J. et of acute and graft-versus-host disease with the of to a 12: PubMed Scopus Google Scholar]. were on with a n = or = with n = (n = or n = was using the and were and using criteria P. et on acute Google et graft-versus-host syndrome in a study of 20 PubMed Scopus Google Scholar]. after was defined as a to regardless of the was classified as a was as the of when a or was the of in patients who had not was considered a to was at the time of from in the of patients and were according to at the retrospective study was performed within the MDS with the in in with the of of survival and survival were obtained by the patients were at follow-up P. from Scopus Google Scholar]. The of and were using for in 1997; PubMed Scopus Google Scholar]; the was used to in of Cox were to the effects of on were analyzed as of 1, outcome by FAB, WHO, and IPSS a median follow-up of 37 months, the 3-year OS was with an for patients patients were grouped by outcome as most in with patients OS was in patients with more including with P = and in P = and for patients MDS had to acute P = not significant The outcome in the was related to the that most of patients received before undergoing by WHO for a of with compared with (Table however, some only of patients and are not in patients with with and the few patients with MDS the 3-year OS was and The 3-year OS was for patients with with with for those with for those with and for those with The between patients with and (P = .01) or (P = were with which showed that the IPSS risk outcome in patients with MDS H.J. et with and for stem cell transplantation from related and in patients with myelodysplastic PubMed Scopus Google Scholar], was a significant between patients in risk category and those in risk category (P = and P = impact of TD on survival after shown in 1, of the 172 patients were TD before PBSCT. the were by did differ by WHO classification (P = was related to the that the TD patients based on had a such as patients with or who not have transplantation were not In were significantly more patients (P = .01) in the cohort that was not Patient and transplantation including [8Sorror M.L. Maris M.B. Storb R. et al.Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.Blood. 2005; 106: 2912-2919Crossref PubMed Scopus (1926) Google Scholar] not were in (Table of and patients were for and the developed was between the (P = data not The was for (P = data not which in of TD significantly more patients with risk WHO and IPSS and to have OS compared with the In as shown in the 3-year OS was in the compared with in the TD (P = were significant between and not P = and was a for survival in of patients in the P = of patients according to transfusion TD (n = TD (n = (P = WPSS TD the classification and grouped patients according to the developed WPSS were patients in WPSS risk the of patients for allogeneic HSCT in clinical shown in the 3-year OS was for and for and for patients by WPSS criteria (P = TD is an of the WPSS the impact of TD was not analyzed 3-year OS for IPSS and patients who were TD or was (P = (P = and (P = The risk few patients to a analysis. of risk IPSS in of TD significant a was in the risk in of patients n = compared with TD patients n = (P = by risk and risk (P = risk (P = .1); poor risk (P = level and transplantation pretransplantation ferritin levels have been shown to be associated with a significantly inferior OS to [7Armand P. Kim H.T. Cutler C.S. et al.Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation.Blood. 2007; 109: 4586-4588Crossref PubMed Scopus (370) Google Scholar], we as a of was correlated with outcome in MDS patients had received before The median pretransplantation ferritin for patients was μg/L to was a significant in ferritin levels between TD and patients (median ferritin levels P In clinical μg/L often as a to chelation patients were grouped by ferritin levels or Patients with a ferritin μg/L (n = had a significantly 3-year OS than patients with levels P = .03). was a higher of and in the with ferritin the did not (P = The analysis was to patients with ferritin μg/L [7Armand P. Kim H.T. Cutler C.S. et al.Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation.Blood. 2007; 109: 4586-4588Crossref PubMed Scopus (370) Google Scholar]. shown in 3-year survival was significantly inferior patients with ferritin levels this P = .03). The was for the 2 not a a link between higher ferritin levels and which was by the of a of disease stage with ferritin levels not In to be higher in patients with ferritin (P = compared the of in patients with to ferritin The of in patients with ferritin μg/L not >1000 P = was significantly higher than in patients with ferritin levels P = were in the patients with not and of were on pretransplantation ferritin level P = P = iron overload can to in et al. [8Sorror M.L. Maris M.B. Storb R. et al.Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.Blood. 2005; 106: 2912-2919Crossref PubMed Scopus (1926) Google Scholar] have shown that pretransplantation including of by the have a impact on transplantation Consequently, we analyzed ferritin levels were correlated with the given in 5, that iron overload was significantly associated with a higher (P = ferritin level and comorbidity index (HCT-CI) (P = A significant (P = .01) was between pretransplantation ferritin level and the shown in 2, only the (P = .001) and the classification (P = .01) significant for outcome in multivariate analysis. Patient age years), IPSS number of cells ferritin level mismatch, or donor had significant of or Open table in a new tab of this retrospective analysis was to as a negative prognostic factor in patients with de novo MDS with supportive also affects prognosis in patients who have allogeneic PBSCT. The data significant overall for TD the of a retrospective analysis, the data that the negative prognostic impact of TD in patients who did not undergo transplantation can be by PBSCT. be however, that in the on TD by Malcovati et al. [5Malcovati L. Porta M.G. Pascutto C. et al.Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.J Clin Oncol. 2005; 23: 7594-7603Crossref PubMed Scopus (725) Google Scholar], the median age was years, compared with 51 years in the patients are more likely to have organ and may be more to organ and related to the additional iron as a of transfusions. the of MDS may be aggressive in patients than in those over age years A. C. et syndromes in patients than age Clin Oncol. PubMed Scopus Google TD cohort significantly more patients with MDS as by conventional In the of TD patients was in the cohort with more MDS, in those patients disease was more and parameters than TD the of is by the impact of risk on PBSCT In patients with the TD did not affect the negative impact of the appeared to be the in with recent et al.Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute from myelodysplastic in patients with de novo disease and disease or 2007; 110: PubMed Scopus Google P. Kim H.T. et of and on outcome of and MDS after allogeneic transplantation.Blood. Scholar]. The data that patients with a or those not was for the category a of that may have prognostic et al.Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute from myelodysplastic in patients with de novo disease and disease or 2007; 110: PubMed Scopus Google Scholar], and TD may as an additional an to TD with iron we analyzed the data also on ferritin In with the of Armand et al. [7Armand P. Kim H.T. Cutler C.S. et al.Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation.Blood. 2007; 109: 4586-4588Crossref PubMed Scopus (370) Google Scholar] and A. P. et severe iron overload after stem cell transplantation and possible with 2004; PubMed Scopus Google Scholar], the current data suggested that elevated ferritin levels had a negative impact on related to higher of and more severe Our results that the negative effect of as reflected by elevated ferritin levels, was at ferritin levels of is in chelation is not levels of or higher are and in the of iron 2007; PubMed Scopus Google Scholar]. the study TD as as ferritin level, the data that TD can be a negative risk the retrospective analysis did not a significant data in patients with modalities improved life expectancy with chelation in TD patients C. et impact of iron chelation on survival in transfused MDS a analysis by the 2007; 110: Scholar]. data are for patients undergoing have shown an between iron overload and an of A. P. et severe iron overload after stem cell transplantation and possible with 2004; PubMed Scopus Google et of the in marrow Google Scholar], in et and outcome of in hematopoietic stem cell PubMed Scopus Google Scholar]. TD were a risk factor for transplantation might be considered a and impact could be analyzed in the of the [8Sorror M.L. Maris M.B. Storb R. et al.Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.Blood. 2005; 106: 2912-2919Crossref PubMed Scopus (1926) Google Scholar]. of a of iron overload with the may be that iron chelation can in of which may affect after treatment, such as PBSCT. the of transplantation conditioning affects be of to the analysis to patients undergoing allogeneic HSCT after conditioning U. et conditioning by allogeneic hematopoietic cell transplantation in PubMed Scopus Google R. et PBSCT with conditioning in patients with and MDS: results of a et outcome of and myeloablative conditioning in allogeneic stem cell transplantation for patients than years of age with acute a retrospective from the of the for and 2005; PubMed Scopus Google et allogeneic transplantation for patients with myelodysplastic syndrome or acute with a retrospective PubMed Scopus Google A. et hematopoietic stem cell transplantation in and MDS using myeloablative the of PubMed Scopus Google C. et stem cell transplantation using a conditioning has the to and survival in patients with acute and Clin Oncol. 2005; 23: PubMed Scopus Google et and conditioning for patients with undergoing allogeneic cell transplantation.Blood. PubMed Scopus Google A. et allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute with using and 2004; 104: PubMed Scopus Google et stem cell transplantation after a conditioning in patients with myelodysplastic syndrome or acute PubMed Scopus Google this retrospective study some pretransplantation iron and transplantation TD was not shown to be an independent risk this to iron which to in also to of and, or higher levels be the currently used Patients who are considered for PBSCT may benefit from iron chelation at iron overload. allogeneic PBSCT be considered in the disease course in patients with MDS who are IntroductionSeveral therapeutic modalities for patients with myelodysplastic syndrome (MDS) have been developed over the past few years, some of which may change the natural course of the disease [1Fenaux P. Mufti G.J. Santini V. et al.Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): results of the AZA-001 phase III study.Blood. 2007; 110: 250A-251AGoogle Scholar]. With the rare exception of patients who achieve long-lasting remission with chemotherapy, allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only modality with proved curative potential [2Deeg H.J. Appelbaum F.R. Hemopoietic stem cell transplantation for myelodysplastic syndrome.Curr Opin Oncol. 2000; 12: 116-120Crossref PubMed Scopus (12) Google Scholar]. But given the heterogeneity of MDS and the potential complications associated with HSCT, deciding when and in whom to perform allogeneic HSCT often is difficult. The decision model presented by Cutler et al. [3Cutler C.S. Lee S.J. Greenberg P. et al.A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.Blood. 2004; 104: 579-585Crossref PubMed Scopus (541) Google Scholar] showed a survival advantage with early transplantation in patients with MDS classified as intermediate-2 or high risk based on International Prognostic Scoring System (IPSS) criteria [4Greenberg P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar]; however, that analysis was based largely on observations antedating the availability of new drugs and did not incorporate more recent information on factors that might affect the disease course, such as comorbidity, transfusion dependence (TD), or iron overload. The identification of additional clinical markers that might help in selecting patients likely to benefit from allogeneic HSCT and in determining the optimum time point for HSCT is desirable.The need for red blood cell transfusion support regardless of IPSS score has been shown to have a negative impact on overall survival (OS) in patients who did not undergo transplantation [5Malcovati L. Porta M.G. Pascutto C. et al.Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.J Clin Oncol. 2005; 23: 7594-7603Crossref PubMed Scopus (725) Google Scholar]. The reason for this is not entirely clear. Patients who become TD may have a more aggressive disease biology. They also may experience adverse effects related to transfusion-induced allosensitization or may suffer toxic organ effects related to iron overload. The finding of a negative impact of TD on prognosis has led to the development of a new proposed scoring system for patients with de novo MDS: the World Health Organization International Prognostic Scoring System (WPSS), which merges the parameters of the World Health Organization's (WHO) classification of MDS with the IPSS, essentially by having TD replace the “cytopenia” category of the IPSS [6Malcovati L. Germing U. Kuendgen A. et al.Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes.J Clin Oncol. 2007; 25: 3503-3510Crossref PubMed Scopus (880) Google Scholar].Whether TD also is an independent risk factor in patients undergoing allogeneic HSCT remains unknown. A potential negative effect of TD on transplantation outcome has been derived indirectly from a study by Armand et al. [7Armand P. Kim H.T. Cutler C.S. et al.Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation.Blood. 2007; 109: 4586-4588Crossref PubMed Scopus (370) Google Scholar] in 103 patients with MDS (including therapy-related MDS, for which the scoring systems have not been validated) that suggested a possible link between pretransplantation ferritin level and outcome after allogeneic HSCT using conventional conditioning regimens. In that study, the negative impact of iron overload appeared to be independent of the effects of graft-versus-host disease (GVHD). Other possibilities are that transfusion needs and ferritin levels were related to disease stage or disease duration and, associated with this, a long history of transfusion support.We performed a retrospective study involving 6 transplantation centers in Germany, Austria, and the United States to analyze results in 172 patients with de novo MDS undergoing allogeneic HSCT using granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral blood stem cells (PBSCs) after high-intensity

BACKGROUND: Keratectasia is one of the most severe complications after refractive laser surgery. Usually penetrating keratoplasty is the treatment of choice to achieve an optical rehabilitation in such cases. PATIENTS AND METHODS: We report on a female patient who developed keratectasia in both eyes 4 weeks after LASIK. Due to a severe keratectasia 10 months after LASIK, a treatment with riboflavin/UVA cross-linking was performed. RESULTS: Due to the induced collagen cross-linking the biomechanical status of the cornea was stabilized and a progression of the keratectasia was prevented. The postoperative refraction and corneal topography have been stable for 18 months. CONCLUSION: Collagen cross-linking leads to a stiffening of the anterior parts of the corneal stroma. The increase of biomechanical stability can stop the progression of a keratectasia after LASIK by means of a simple procedure.

BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. METHODS: Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed. RESULTS: Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011). CONCLUSIONS: This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.

PURPOSE: Overactivation of TGF-β signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-β receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. PATIENTS AND METHODS: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. RESULTS: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%). CONCLUSIONS: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.

PURPOSE: To assess the outcomes of the intravitreal administration of methotrexate in uveitis. METHODS: Multicenter, retrospective interventional case series of patients with noninfectious uveitis. Thirty-eight eyes of 30 patients were enrolled, including a total of 54 intravitreal injections of methotrexate at a dose of 400 µg in 0.1 mL. The primary outcome measure was visual acuity. Secondary outcome measures included control of intraocular inflammation and cystoid macular edema, time to relapse, development of adverse events, and levels of systemic corticosteroid and immunosuppressive therapy. RESULTS: Methotrexate proved effective in controlling intraocular inflammation and improving vision in 30 of 38 eyes (79%). The side effect profile was good, with no reported serious ocular adverse events and only one patient having an intraocular pressure of >21 mmHg. Of the 30 eyes that responded to treatment, 8 relapsed, but 22 (73%) entered an extended period of remission, with the Kaplan-Meier estimate of median time to relapse for the whole group being 17 months. The eight eyes that relapsed were reinjected and all responded to treatment. One eye relapsed at 3 months, but 7 eyes again entered extended remission. Of the 14 patients on systemic therapy at the start of the study, 8 (57%) were able to significantly reduce this following intravitreal methotrexate injection. CONCLUSION: In patients with uveitis and uveitic cystoid macular edema, intravitreal MTX can effectively improve visual acuity and reduce cystoid macular edema and, in some patients, allows the reduction of immunosuppressive therapy. Some patients relapse at 3 to 4 months, but a large proportion (73%) enter an extended period of remission of up to 18 months. This larger study extends the results obtained from previous smaller studies suggesting the viability of intravitreal methotrexate as a treatment option in uveitis.

OBJECTIVES: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. METHODS: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. RESULTS: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. CONCLUSIONS: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music.

BACKGROUND: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. METHODS: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. FINDINGS: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. INTERPRETATION: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.

BACKGROUND: Epstein-Barr virus(EBV)-associated posttransplant lymphoproliferative disease (PTLD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Especially in cases with involvement of the central nervous system (CNS) treatment is difficult because the efficacy of most chemotherapeutic agents as well as EBV-specific cytotoxic donor T cells in liquor is uncertain. In the last years the anti-CD20 monoclonal antibody Rituximab was intensively investigated in the treatment of EBV-PTLD. However, only 8 patients with B-cell lymphoma and CNS involvement treated with Rituximab were reported. CASE REPORT: A 24-year-old female patient with acute T-lymphoblastic leukemia in second complete remission had received allogeneic, unrelated, T-cell depleted HSCT. 10 months later an EBV-associated PTLD was diagnosed. Beside peripheral lymphomas and B symptoms the patient showed neurological symptoms. Examination of the cerebrospinal fluid (CSF) revealed a meningeosis lymphoblastica caused by the EBV lymphoma. Treatment with Rituximab and the antiviral drug Cidofovir led to complete remission with regression of the peripheral lymphomas and disappearance of the neurological symptoms. In addition, the PCR control on EBV DNA became negative in the plasma as well as in CSF. CONCLUSION: The combination of Rituximab and Cidofovir appears as an interesting alternative treatment in patients with EBV-associated PTLD and CNS involvement.

OBJECTIVE: To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). METHODS: We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty-one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total-body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose-reduced conditioning with fludarabine-based regimens. RESULTS: The incidence of grades II-IV and III-IV graft-versus-host disease was 66% and 38% respectively. The probability of overall survival (OS), disease-free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non-relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine-based conditioning therapy, age > or = 40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. CONCLUSION: These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant-related mortality.

This retrospective study describes the outcome of patients with chronic myeloid leukaemia after allografting using dose-reduced conditioning with fludarabine and busulphan. Forty-four Philadelphia chromosome (Ph)-positive patients were transplanted in nine German centres; 26 patients were in chronic phase, 11 in accelerated phase and seven in blast crisis. Thirty-four patients achieved complete remission, with 18 alive and disease-free at a median follow-up of 562 d (range 244-922 d). Grade II-IV acute graft-versus-host disease (GVHD) incidence was 43%. Twenty patients died, 15 of causes unrelated to relapse. Risk factors predisposing to graft failure by univariate analysis were an unrelated donor (8/23 compared with a related donor 2/21, P = 0.07) and interferon therapy within 90 d of transplant (4/6 versus 3/17, P = 0.025). At the last follow-up, of 31 patients for whom molecular or cytogenetic data were available, 16 (52%) were polymerase chain reaction-negative, and seven (23%) were Ph-negative by fluorescent in situ hybridization. These findings demonstrate that dose-reduced conditioning with fludarabine and busulphan provides durable engraftment and a low rate of relapse. However, in this population, many of whom were not eligible for high-dose conditioning due to age, reduced performance status, previous complications or extensive pre-treatment, these data highlight the need for effective anti-infectious and GVHD prophylaxis. In addition, this study supports the discontinuation of interferon therapy at least 90 d before transplant

Since the first description of Wohlfahrtiimonas chitiniclastica in 2008, a number of well described case reports demonstrating its pathogenic role in humans have been published. Infections may be closely linked to flies, such as Wohlfahrtia magnifica, Lucilia sericata, Chrysomya megacephala or Musca domestica. These insects are potent vectors for the distribution of W. chitiniclastica causing local or systemic infections originating from wounds infested with fly larvae. However, other potential sources of transmission of W. chitiniclastica have been described such as soil or chicken meat. Infections in humans reported to date comprise wound infections, cellulitis, osteomyelitis and sepsis. This review summarizes all the literature available up to now and gives the current knowledge about this emerging human pathogen. Additionally, four patients with proven W. chitiniclastica infections treated at Dresden University Hospital between 2013 and 2015, are included. Special focus was placed on microbiological identification and antibiotic susceptibility testing of the pathogen.

We report a 20 year old man with short stature, microcephaly, unusual facies, numerous pigmented naevi, hypodontia, immunodeficiency, and a high pitched voice. Tympner et al had assumed that the patient had a new syndrome of "progressive combined immunodeficiency and ectomesodermal dysplasia". We show here that the condition is identical to the Mulvihill-Smith syndrome (McKusick 176690), a progeroid disorder described in four or possibly five sporadic cases to date. We describe his clinical progress up to the age of 20 years. Our patient suffered from severe viral infections, allergic rhinitis and conjunctivitis, delayed puberty, visual loss, modest achievement in high school, and reactive depression. The immunological, facioskeletal, and dental abnormalities are presented in detail.

Allogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications, including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCR-α repertoire and its clinical relevance in patients following stem cell transplantation. Using next-generation sequencing we examined the TCR-α repertoire of CD8(+) T cells and CMV-specific CD8(+) T cells in four patients. Additionally, we performed single-cell TCR-αβ sequencing of CMV-specific CD8(+) T cells. The TCR-α composition of human leucocyte antigen (HLA)-A*0201 CMVpp65- and CMVIE -specific T cells was oligoclonal and defined by few dominant clonotypes. Frequencies of single clonotypes reached up to 11% of all CD8(+) T cells and half of the total CD8(+) T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCR-α clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8(+) T cells was consistent with chronically activated effector memory T cells. The CD8(+) T cell response to CMV reactivation resulted in an expansion of a few TCR-α clonotypes to dominate the CD8(+) repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective anti-viral T cell response in this setting.

BACKGROUND: Primary urethral carcinoma is a very rare condition, and no large-scale experience with such cases has been published. Treatment will therefore have to follow rules established for the treatment of similar conditions. PATIENTS: Six cases of primary urethral carcinoma (5 male, 1 female) who had been treated at our institution between 1995 and 1999 were retrospectively analyzed. In 3 male cases, a primary urothelial carcinoma of the distal urethra was treated by distal urethrectomy only. In 3 other cases with locally advanced tumors and/or lymph node metastases surgical treatment was followed by adjuvant cisplatinum-containing chemotherapy. RESULTS: In the 3 cases with distal urethral carcinoma, partial urethrectomy with preservation of the penis resulted in cure, with a follow-up of 12-71 months. In the cases with advanced disease, adjuvant chemotherapy after surgery has resulted in complete remissions in all 3 cases, with a follow-up of 4-47 months at present. CONCLUSIONS: In localized, noninvasive carcinoma of the distal male urethra, partial urethrectomy seems adequate and the avoidance of penile amputation justified. In advanced cases, after local excision and lymphadenectomy adjuvant chemotherapy which by necessity must follow the guidelines established for the treatment of other urothelial or squamous cell malignancies seems to be beneficial.

TNF-receptor-associated periodic syndrome (TRAPS) is a recently recognized disorder characterized by prolonged attacks of high fever and severe localized inflammation. TRAPS is caused by dominant mutations in the 55 kDa TNF receptor gene (TNFRSF1A). We here describe three German TRAPS patients of two families with Cys30-->Arg and Thr50-->Met mutations, respectively. Both mutations have already been observed before in other nonrelated families. The Thr50-->Met amino acid exchange, caused by an ACG-->ATG transition, has been reported in two other families of different ethnic background. The possibility that the ACG-->ATG sequence alteration is a mutational hot spot causing TRAPS is discussed. Furthermore, we describe and discuss the symptoms of our patients, possible inducers of febrile attacks, and treatments which the patients had received when their diagnoses were still unknown.

PURPOSE: To clinically evaluate the effect of blue light-filtering intraocular lenses (IOLs) on disease progression in patients with geographic atrophy (GA). METHODS: Clinical data from 66 eyes of 40 patients were investigated, 27 with a blue filter and 39 with a non-blue filter IOL. Spectral-domain optical coherence tomography technology and the advanced retinal pigment epithelium analysis software tool were used to measure lesion size and monitor its progression over 1 year. RESULTS: The mean and median baseline area of GA for the total sample was 5.55 ± 4.72 mm2 and 4.40 mm2, respectively. There was a statistically significant difference of the mean (p = 0.0002) and median (p&lt;0.0001) GA progression in 1 year between the blue filter and non-blue filter IOL group (0.72 ± 0.39 SD mm2 mean and 0.70 mm2 median compared to 1.48 ± 0.88 SD mm2 and 1.30 mm2, respectively). CONCLUSIONS: The clinical data strongly support a photoprotective role of blue light-filtering IOLs on the progression of the atrophic form of dry age-related macular degeneration after cataract surgery.

Mastocytoses are characterized by clonal proliferation of mast cells in various tissues. In childhood, cutaneous mastocytosis (CM) occurs almost exclusively. It is confined to the skin, and has a good prognosis. The most common form is the maculopapular cutaneous mastocytosis (MPCM), formerly called urticaria pigmentosa. A distinction is made between a monomorphic variant of MPCM with multiple small, roundish maculopapular skin lesions and the - more common - polymorphic variant with larger lesions of variable size. One quarter of CM diagnosed in childhood are mastocytomas, which often occur solitary or at multiple sites. The diffuse variant of CM (DCM), which affects 5% of children with CM, should be distinguished from these forms. Systemic mastocytoses (SM) with mast cell infiltrates in the bone marrow or other extracutaneous tissues, such as the gastrointestinal tract, occur predominantly in adults. The diagnosis of CM is usually made clinically: Manifestation in infancy, typical morphology and distribution, pathognomonic Darier sign. Basal serum tryptase is determined if DCM or systemic mastocytosis are to be diagnosed. Children with mastocytosis should be managed in a specialized outpatient clinic. For affected families, detailed information about the clinical picture including prognosis assessment is essential. Mast cell mediated symptoms are controlled by oral non-sedating antihistamines if needed.

BACKGROUND: The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). METHODS: Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal-Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. RESULTS: Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). CONCLUSION: In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.