Cytogenetic features in myelodysplastic syndromes Myelodysplastic syndromes -LRB- MDS -RRB- comprise a group of bone marrow diseases characterized by profound heterogeneity in morphologic presentation , clinical course , and cytogenetic features . Roughly 50 % of patients display clonal chromosome abnormalities . In several multicentric studies , the karyotype turned out to be one of the most important prognostic parameters and was incorporated into statistical models aiming for a better prediction of the individual prognosis like the International Prognostic Scoring System . However , due to the profound cytogenetic heterogeneity , the impact of many rare abnormalities as well as combinations of anomalies occurring in a substantial portion of patients with MDS is still unknown and can only be delineated on the basis of large international multicentric cooperations . Recently , the German -- Austrian MDS Study Group presented cytogenetic findings in 2,072 patients with MDS , which serve as a basis for the characterization of the cytogenetic subgroups discussed in this article . The availability of new therapeutic options for low - and high-risk MDS targeted against distinct entities characterized by specific chromosome abnormalities , like 5q-deletions , monosomy 7 , and complex abnormalities underlines the important role of cytogenetics for the clinical management of MDS . This article thus focuses on the clinical and prognostic relevance , the molecular background , and therapeutic perspectives in these three cytogenetic subgroups . Introduction The profound heterogenetity of myelodysplastic syndromes -LRB- MDS -RRB- is well-known from morphological and clinical studies , which finally lead to the establishment of classification , and prognostic scoring systems . It is becoming increasingly obvious that this heterogeneity also manifests itself against the background of genetic heterogeneity of MDS . In sharp contrast to the situation in chronic myeloid leukemia -LRB- CML -RRB- where one single cytogenetic abnormality , the translocation t -LRB- 9 ; 22 -RRB- -LRB- q34 ; q11 -RRB- , is the genetic hallmark of the disease , there is an enormous variability of cytogenetic abnormalities in MDS hampering not only the prognostic classification but also the delineation of the molecular background of cytogenetic aberrations in MDS . As an example in our recent multicentric cytogenetic analysis of patients with MDS , we observed 684 different types of chromosome abnormalities in a cohort of 1,080 patients with MDS and an abnormal karyotype -LSB- 1 -RSB- . The cytogenetic profile of MDS In general , MDS show a characteristic genetic profile with an overweighing of unbalanced abnormalities . Most frequently , a loss of genetic material in the form of deletions and monosomies can be observed . A gain of genetic material with the appearance of total or partial trisomies is less frequent . Loss or gain of genetic material can also be the result of unbalanced translocations , which are frequently observed in MDS with multiple abnormalities . Taken together , it is thus obvious to assume that a prime molecular mechanism in MDS is the loss or inactivation of tumor suppressor genes , while the activation of oncogenes seems to be less relevant in myelodysplasia . In contrast to AML , balanced structural abnormalities like translocations and inversions are rare in MDS . Due to the profound genetic heterogeneity , the knowledge about distinct cytogenetic alterations was mainly restricted to the most frequent abnormalities -LRB- − 5/5q − , − 7/7q − , +8 , 20q − , and − Y -RRB- , although , in MDS , rare chromosome abnormalities are present in a substantial portion of patients . In a recent analysis of the German -- Austrian MDS Study Group , 59 % of all 2,370 abnormalities observed in 1,080 patients with MDS where rare ; that is , they occurred with a frequency of less than 2 % -LSB- 1 -RSB- . In this situation , prognostic knowledge can only be deepened by large-scale multicentric studies with a high enough number of abnormal cases with follow-up data . This development was initiated by the International MDS Risk Assessment Working Group -LRB- IMRAW -RRB- ending up with the establishment of the International Prognostic Scoring System -LRB- IPSS -RRB- , which was based upon the analysis of 816 patients with de novo MDS of whom 327 had abnormal karyotypes -LSB- 2 -RSB- . A next step forward was the study of the Spanish cooperative group with 500 abnormal cases -LSB- 3 -RSB- followed by our German -- Austrian dataset with 1,080 patients with chromosome abnormalities -LSB- 1 -RSB- . The situation is furthermore complicated by the fact that chromosome abnormalities in principle can occur in three different conditions : as isolated abnormality , together with one additional change , and as part of complex abnormalities with at least two additional cytogenetic alterations . Table 1 shows the incidence of the 21 most frequent abnormalities according to the number of accompanying alterations occurring in our German -- Austrian patient cohort . Table 1Incidence of chromosome abnormalities in MDS related to 2,072 patients examined successfullyAnomalytotal , n -LRB- % of all cases -RRB- Isolated , n -LRB- % a -RRB- With one additional abnormality , n -LRB- % a -RRB- As part of complex abnormalities , n -LRB- % a -RRB- 5q − 312 -LRB- 15.1 -RRB- 146 -LRB- 47 -RRB- 52 -LRB- 17 -RRB- 114 -LRB- 36 -RRB- − 7/7q − 230 -LRB- 11.1 -RRB- 86 -LRB- 37.5 -RRB- 31 -LRB- 13.5 -RRB- 113 -LRB- 49 -RRB- +8173 -LRB- 8.4 -RRB- 81 -LRB- 46.8 -RRB- 37 -LRB- 21.4 -RRB- 55 -LRB- 31.8 -RRB- − 18/18q − 78 -LRB- 3.8 -RRB- 3 -LRB- 3.8 -RRB- 2 -LRB- 2.6 -RRB- 73 -LRB- 93.6 -RRB- 20q − 74 -LRB- 3.6 -RRB- 36 -LRB- 48.6 -RRB- 10 -LRB- 13.5 -RRB- 28 -LRB- 37.8 -RRB- − 569 -LRB- 3.3 -RRB- 1 -LRB- 1.4 -RRB- 4 -LRB- 5.8 -RRB- 64 -LRB- 92.8 -RRB- − Y58 -LRB- 2.8 -RRB- 41 -LRB- 70.7 -RRB- 5 -LRB- 8.6 -RRB- 12 -LRB- 20.7 -RRB- +2145 -LRB- 2.2 -RRB- 5 -LRB- 11.1 -RRB- 18 -LRB- 40 -RRB- 22 -LRB- 48.9 -RRB- − 17/17p − 42 -LRB- 2.0 -RRB- 1 -LRB- 2.4 -RRB- 1 -LRB- 2.4 -RRB- 40 -LRB- 95.2 -RRB- inv/t -LRB- 3q -RRB- 41 -LRB- 2.0 -RRB- 16 -LRB- 39 -RRB- 8 -LRB- 19.5 -RRB- 17 -LRB- 41.5 -RRB- − 13/13q − 40 -LRB- 1.9 -RRB- 5 -LRB- 12.5 -RRB- 6 -LRB- 15 -RRB- 29 -LRB- 72.5 -RRB- +1 / +1 q37 -LRB- 1.8 -RRB- 3 -LRB- 8.1 -RRB- 6 -LRB- 16.2 -RRB- 28 -LRB- 75.7 -RRB- − 2133 -LRB- 1.6 -RRB- 3 -LRB- 9.1 -RRB- 4 -LRB- 12.1 -RRB- 26 -LRB- 78.8 -RRB- +1128 -LRB- 1.4 -RRB- 6 -LRB- 21.4 -RRB- 4 -LRB- 14.3 -RRB- 18 -LRB- 64.3 -RRB- − 1226 -LRB- 1.3 -RRB- 02 -LRB- 7.7 -RRB- 24 -LRB- 92.3 -RRB- 12p − 25 -LRB- 1.2 -RRB- 7 -LRB- 28 -RRB- 6 -LRB- 24 -RRB- 12 -LRB- 48 -RRB- t -LRB- 5q -RRB- 24 -LRB- 1.2 -RRB- 6 -LRB- 25 -RRB- 3 -LRB- 12.5 -RRB- 15 -LRB- 62.5 -RRB- 11q − 23 -LRB- 1.1 -RRB- 8 -LRB- 34.8 -RRB- 4 -LRB- 17.4 -RRB- 11 -LRB- 47.8 -RRB- 9q − 23 -LRB- 1.1 -RRB- 8 -LRB- 34.8 -RRB- 3 -LRB- 13 -RRB- 12 -LRB- 52.2 -RRB- t -LRB- 7q -RRB- 22 -LRB- 1.1 -RRB- 6 -LRB- 27.3 -RRB- 6 -LRB- 27.3 -RRB- 10 -LRB- 45.5 -RRB- − 2022 -LRB- 1.1 -RRB- 0022 -LRB- 100 -RRB- aOf cases with the respective abnormality Cytogenetic prognosis The first large-scale cytogenetic studies in patients with MDS encompassing more than 100 patients where published more than 20 years ago -LSB- 4 -- 7 -RSB- . In the following years , the patients cohorts increased step by step from nearly 250 patients -LSB- 8 -RSB- to some 400 patients -LSB- 9 , 10 -RSB- . In 1997 , Greenberg published a collaborative multicentric international data set of more than 800 patients with de novo MDS , which was the basis for the establishment of the IPSS -LSB- 2 -RSB- . This database was further surmounted by the analyses of the Spanish cooperative group with 968 patients examined -LRB- Table 2 -RRB- , which represented the largest number of patients with MDS karyotyped so far -LSB- 3 -RSB- . Recently , the German -- Austrian Study Group published their multicentric analyses of more than 2,100 patients with MDS -LSB- 1 -RSB- . Table 2Cytogenetic prognostic findings in publications with greater than 100 patients examinedAuthor , yearNumber of patientsAbnormal -LRB- % -RRB- FavorableIntermediateUnfavorableKnapp 198517466 -LRB- 38 -RRB- Normal -LRB- NN -RRB- ComplexNowell 1986 -- 198914463 -LRB- 44 -RRB- 5q − , 20q − +8 − 7/7q − Billström 198816974 -LRB- 44 -RRB- NN , 5q − +8 − 7/7q − Pierre 1989247106 -LRB- 43 -RRB- NNComplexMorel 1993408151 -LRB- 37 -RRB- NN , 5q − , − Y , − 7/7q − , 20q − +8 ComplexToyama 1993401200 -LRB- 50 -RRB- +8 − 7/7q − ComplexWhite 199419875 -LRB- 38 -RRB- NN , 5q − 12p − , +21 Complex , +8 , 20q − Greenberg 1997816327 -LRB- 40 -RRB- NN , 5q − , 20q − , − YAll othersComplex , abnormal # 7Solé 2005968500 -LRB- 51 -RRB- NN , 5q − , 20q − , − Y , 11q − , 12p − rea 3q , + 8 , +9 , t11q , 17p − Complex , − 7/7q − , i17qHaase 20072,0721,080 -LRB- 51 -RRB- NN , +1 / +1 q , t -LRB- 1q -RRB- , 5q − , t -LRB- 7q -RRB- , 9q − , 12p − , abnormal # 15 , t -LRB- 17q -RRB- , 20q − , − 21 , + 21 , − X , − Yrea 3q , − 7 , 7q − , +8 , 11q − , t -LRB- 11q23 -RRB- , +19 , complex -LRB- = 3 -RRB- Complex -LRB- > 3 -RRB- , t -LRB- 5q -RRB- rea Rearranged What has changed and what has been achieved during these last 25 years of cytogenetic analyses in MDS ? If the aberration rate is considered , there is a gradual increase in the portion of abnormal cases from under 40 % in the most earlier studies to 50 % in the more recent analyses of Toyama , Solé , and Haase -LSB- 1 , 3 , 10 -RSB- . Although the composition of the patient cohorts may play a role for the portion of clonal abnormalities in a given collective , other factors like the improvement of culture conditions possibly due to the use of recombinant myeloid growth factors -LSB- 11 -RSB- might have contributed to the increase in the aberration rate in cytogenetic studies . To date , an aberration rate of 50 % can be regarded as an international standard . Prognostic relevance of chromosome abnormalities The prognostication of patients with MDS has become an important means for the development of therapeutic strategies based on more individualized risk assessment . Even in the most recent prognostic scoring system , the World Health Organization classification-based Prognostic Scoring System , cytogenetics play a decisive role -LSB- 12 -RSB- . In general , three to four prognostic cytogenetic categories can be distinguished . In several multicentric investigations , cytogenetics have been proven to be highly relevant independent prognostic parameters -LRB- -LSB- 2 , 3 , 13 -RSB- , see also Table 2 -RRB- . Good prognosis Even in the earliest study considered here , Knapp et al. -LSB- 4 -RSB- described the prognostic relevance of cytogenetic findings with a normal karyotype as favorable and complex abnormalities as being associated with bad prognosis . The good prognosis of a normal karyotype was confirmed by nearly all other groups . Thus , in contrary to the situation in AML where patients with a normal karyotype have an intermediate outcome and prognosis is significantly influenced by additional molecular alterations , in MDS , a normal karyotype is undisputedly associated with good prognosis . Further , well-established abnormalities defining good-risk subgroups are deletions of 5q and 20q as well as loss of the Y-chromosome , although the question whether this latter abnormality is age related , or a real clonal marker is unsolved as yet . The Spanish group identified further new cytogenetic abnormalities with a good prognosis -LRB- 12p − and 11q − -RRB- -LSB- 3 -RSB- . In the German -- Austrian multicentric study , the following abnormalities were associated with a favorable clinical course with a median survival between more than 9 years and 32 months : normal karyotype , t -LRB- 1q -RRB- , 5q − , t -LRB- 7q -RRB- , 9p − , 12q − , t -LRB- 15q -RRB- , t -LRB- 17q -RRB- , 20q − , +21 , − 21 , − X , − Y. However , prognosis was only favorable when not more than one additional abnormality was present -LSB- 1 -RSB- . Intermediate prognosis In most studies , patients with trisomy 8 displayed an intermediate clinical course . Until the Spanish group published their results on more than 980 patients , the knowledge of cytogenetic findings with an intermediate prognosis was very limited . In the IPSS , all abnormalities neither belonging to the good-risk group -LRB- isolated 5q − , 20q − , and loss of Y-chromosome -RRB- nor to the bad risk cohort -LRB- complex -LSB- greater than or equal to three abnormalities -RSB- or any chromosome 7 abnormality -RRB- were designated to be of intermediate prognosis not by availability of survival data but by definition -LSB- 2 -RSB- . In their large Spanish dataset , Solé et al. delineated new abnormalities associated with an intermediate clinical course -LRB- 3q abnormalities , trisomy 9 , 11q translocations , and 17p deletions -RRB- -LSB- 3 -RSB- . The results of White et al. -LSB- 14 -RSB- and Toyama et al. -LSB- 10 -RSB- who identified − 7/7q − and 12p − and trisomy 21 , respectively , as abnormalities with an intermediate prognosis were not confirmed by other groups . Recently , the multicentric database of the German -- Austrian MDS Study Group revealed several infrequent abnormalities with an intermediate prognosis . A median survival time of 23 -- 26 months was observed in patients with trisomy 8 and 11q − -LRB- called Intermediate-I -RRB- . A more worse prognosis with a median survival time between 20 and 14 months was found for 11q23 translocations , chromosome 3q aberrations , trisomy 19 , 7q deletions , and complex abnormalities with three different chromosomal alterations and monosomy 7 -LRB- called Intermediate-II -RRB- -LSB- 15 -RSB- . Poor prognosis There is a great consensus in all publications on cytogenetic prognosis in MDS that complex abnormalities characterize a MDS subgroup with bad prognosis and a median survival time significantly below 1 year , although the threshold at which the number of abnormalities confers bad prognosis is a matter of debate . While in most publications , the term `` complex '' is used for three or more abnormalities , in the Medical Research Council AML trials , bad prognosis was assigned to cases with five or more abnormalities -LSB- 16 -RSB- . Recently , we clearly could show that , in patients with MDS , median survival is significantly reduced only when more than three abnormalities are present , reducing the median survival from 17 months in cases with three abnormalities to less than 9 months in cases with four or more anomalies -LSB- 1 -RSB- . Besides complex changes , partial and total monosomy 7 was ranked to the cytogenetic findings with an unfavorable clinical course -LSB- 3 , 5 -- 7 -RSB- . Within the IPSS , any chromosome 7 abnormality was counted to the bad prognostic findings -LSB- 2 -RSB- . As mentioned above , in the German -- Austrian dataset , − 7/7q − showed a significant better prognosis -LRB- 14 and 19 months median survival time , respectively -RRB- as compared to the complex abnormality group defined by four or more chromosomal changes -LRB- 8.7 months -RRB- and was thus attributed to the intermediate-II group -LSB- 15 -RSB- . The findings of Toyama et al. -LSB- 10 -RSB- who observed an unfavorable course in patients with trisomy 8 or 20q deletions was not confirmed by any other group . Solé et al. described a median survival of under 12 months in ten patients with an isochromosome of 17q -LSB- 3 -RSB- . Since , in the German -- Austrian dataset , this abnormality was too infrequent for a statistically meaningful analysis , the Spanish findings are convincing but still need further confirmation . Prognostic scoring In the IPSS , three different cytogenetic subgroups were established and weighted against bone marrow blast counts and cytopenias by multivariate analysis -LSB- 2 -RSB- . Applying the cytogenetic part of the IPSS to our German -- Austrian dataset , 59 % of the patients had a good risk karyotype -LRB- normal , isolated 5q − , 20q − , or loss of Y-chromosome -RRB- with a median survival of 54 months , 19 % of the collective had an intermediate prognosis -LRB- neither good risk nor bad risk cytogenetics -RRB- with a median survival of 31 months , and 22 % displayed a dismal prognosis -LRB- any chromosome 7 anomaly , complex -LSB- ≥ 3 -RSB- changes -RRB- with a median survival of 11 months -LSB- 1 -RSB- . The application of the new cytogenetic findings derived from the German -- Austrian dataset allows the definition of four different cytogenetic prognostic subgroups -LRB- Table 3 and Fig. 1 -RRB- . The low-risk group covers 73 % of patients with 14 cytogenetic categories and a median survival of 55 months , the intermediate groups I and II -LRB- 15.5 % of patients -RRB- with eight cytogenetic categories and a median survival of 29 -LRB- intermediate-I -RRB- and 15 months -LRB- intermediate-II -RRB- , and the high-risk group -LRB- 11.5 % of patients -RRB- with a median survival of 8 months -LSB- 15 -RSB- . In comparison to the IPSS , our new cytogenetic prognostication splits the intermediate group into two distinctly separate subgroups with significantly different median survival . The bad-risk group is more strictly defined with a lower median survival time -LRB- 8 vs. 11 months -RRB- . While the IPSS assigned an intermediate risk by exclusion and not by knowledge , our intermediate cytogenetic subgroup was based exclusively on available survival data of patients treated with supportive care only thus reflecting the natural course of the disease . Taking into account only those patients with a known prognosis -LRB- in IPSS only good - and bad-risk patients -RRB- , 81 % of our patients could be categorized by the IPSS in comparison to 93 % by the German -- Austrian prognostic system . Fig. 1Kaplan -- Meier survival curves according to the cytogenetic prognostic classification of the German -- Austrian MDS Study Group . Log-rank test : p < 0.0001 -LRB- 3 degrees of freedom -RRB- -LSB- 15 -RSB- Table 3New cytogenetic prognostic subgroups of the German -- Austrian MDS Study Group in 1,202 patients treated with supportive care onlyCytogenetic riskCytogenetic findingNumber -LRB- % -RRB- Median survival -LRB- months -RRB- Good12p − 7 -LRB- 0.6 -RRB- n.r. 9q − 6 -LRB- 0.5 -RRB- n.r.t -LRB- 15q -RRB- 6 -LRB- 0.5 -RRB- n.r. 15q − 5 -LRB- 0.4 -RRB- n.r. +2113 -LRB- 1.1 -RRB- 100.85 q − 132 -LRB- 11 -RRB- 77.220 q − 24 -LRB- 2 -RRB- 71.0 − X6 -LRB- 0.5 -RRB- 56.4 normal karyotype622 -LRB- 51.7 -RRB- 53.4 − Y33 -LRB- 2.8 -RRB- 39.4 t -LRB- 1q -RRB- 7 -LRB- 0.6 -RRB- 34.7 t -LRB- 7q -RRB- 7 -LRB- 0.6 -RRB- 34.7 t -LRB- 17q -RRB- 6 -LRB- 0.5 -RRB- 32.1 − 216 -LRB- 0.5 -RRB- 32.0Intermediate-I11q − 11 -LRB- 0.9 -RRB- 26.1 +864 -LRB- 5.3 -RRB- 23.0Intermediate-IIt -LRB- 11q23 -RRB- 6 -LRB- 0.5 -RRB- 20.0 Any 3q abnormality16 -LRB- 1.3 -RRB- 19.9 +195 -LRB- 0.4 -RRB- 19.87 q − 11 -LRB- 0.9 -RRB- 19.0 Complex -LRB- = 3 anomalies -RRB- 32 -LRB- 2.7 -RRB- 17.0 − 742 -LRB- 3.5 -RRB- 14.0 PoorComplex -LRB- > 3 anomalies -RRB- 134 -LRB- 11.1 -RRB- 8.7 t -LRB- 5q -RRB- 7 -LRB- 0.6 -RRB- 4.4 n.r. Median survival not reached A further element of the IPSS , the weighting of cytogenetics in comparison to other relevant parameters like the bone marrow blast counts , has become questionable . According to the IPSS , 0 scoring points are attributed to good-risk cytogenetics and blasts less than 5 % , intermediate cytogenetics as well as 5 -- 10 % blasts get 0.5 scoring points , and bad-risk cytogenetic findings are scored with 1.0 . Eleven to 20 % blasts are scored with 1.5 and 21 -- 30 % blasts with 2.0 points . Thus , bad-risk cytogenetics with a median survival of 11 months get less scoring points than patients with 11 -- 20 % blasts and a median survival in our cohort of 16.5 months . According to our observations , only patients with 21 -- 30 % blasts -LRB- 11.7 months median survival -RRB- had a prognosis comparable to patients with bad-risk cytogenetics . Thus in a revision of the IPSS the weight of bad-risk cytogenetics has to be readjusted -LSB- 17 -RSB- . Delineation of the most relevant cytogenetic subgroups 5q − , monosomy 7 , and complex abnormalities 5q deletions Deletions within the long arm of chromosome 5 are the most frequent cytogenetic changes in MDS accounting for roughly 30 % of abnormal cases -LSB- 1 , 2 , 3 -RSB- . The deletions can have variable size ; however , the common deleted region always spans the chromosome band 5q31 . Due to intensive research during the last decade , our knowledge of the molecular background of these abnormalities is increasing . It is generally accepted that not the illegitimate fusion of deoxyribonucleic acid -LRB- DNA -RRB- sequences at the variable breakpoints of the deletions but loss of genetic information represents the relevant pathomechanism . There could be two different deleted regions in 5q31 . One that is located more centromeric is possibly associated with bad prognosis , complex abnormalities , and high-risk , as well as therapy-related , MDS . A second area is located more telomeric in the vicinity of band 5q32 and is supposed to be related to the good-risk 5q − syndrome -LSB- 18 -- 21 . Recently , it has been convincingly shown by the means of sophisticated systematic knockout experiments on 41 candidate genes in the critical 5q − region that the gene for a ribosomal subunit protein , RPS41 , seems to be a relevant gene in patients with 5q − syndrome on the basis of haploinsufficiency -LSB- 22 -RSB- . The 5q − syndrome has been first described by Van den Berghe in 1974 -LSB- 23 -RSB- . It is cytogenetically characterized by an isolated deletion of chromosome 5q . A female preponderance is well documented . The clinical appearance is characterized by a refractory macrocytic anemia , normal or elevated platelets , and mild leukocytopenia . The clinical course is mild and long lasting with a very low risk for leukemic transformation . The bone marrow smears reveal less than 5 % blasts , while dysplasia of the erythroid and granulocytic lineages usually are discrete or even absent . Megakaryopoesis shows profound and characteristic dysplasias with either separated multiple nuclei , hypolobulation , microkaryocytes , and most characteristically monolobulated megakaryocytes with a round nucleus . The prognosis of 5q deletions in MDS is generally favorable if they are not part of complex abnormalities ; however , it is significantly modified by single additional cytogenetic changes -LSB- 1 , 24 -RSB- . Figure 2 shows the Kaplan -- Meier survival curves for patients treated with supportive care only with isolated 5q − , 5q − plus one additional abnormality , and 5q − as part of complex abnormalities derived from the German -- Austrian database -LSB- 1 -RSB- . Fig. 2Median survival according to accompanying abnormalities in patients with 5q deletions . Log-rank test : p ≤ 0.0001 -LRB- 2 degrees of freedom -RRB- , p = 0.30 -LRB- isolated vs. +1 -RRB- , p ≤ 0.0001 -LRB- isolated vs. complex -RRB- , p = 0.0001 -LRB- +1 vs. complex -RRB- It is evident that additional abnormalities negatively influence survival in patients with 5q deletions . However , due to cytogenetic heterogeneity , the additive prognostic impact of distinct single additional abnormalities remains obscure as yet -LRB- Table 4 -RRB- . Table 4Frequencies -LRB- in percent of all cases with the respective primary abnormality -RRB- of accompanying abnormalities5q − -LRB- n = 59 -RRB- − 7/7q − -LRB- n = 38 -RRB- trisomy 8 -LRB- n = 44 -RRB- Additional anomalyPercentAdditional anomalyPercentAdditional anomalyPercent +817 +21105 q − 23 +21135 q − 10 +2111 − 20/20q − 8 +810 der -LRB- 3q21/q26 -RRB- 7 − 77inv -LRB- 3q -RRB- 5 +117 der/del -LRB- 12p -RRB- 7del -LRB- 12p -RRB- 5 − 75der/del -LRB- 3p -RRB- 5t -LRB- 11q23 -RRB- 5del -LRB- 12p -RRB- 5der/t -LRB- 21q -RRB- 5iso -LRB- 17 -RRB- -LRB- q10 -RRB- 5 +135 t -LRB- 11q23 -RRB- 3Others50 +145 Others35 +8 * 5del -LRB- 1p -RRB- 5Others22 Over a long period , the therapeutic standard in patients with noncomplex 5q deletions was supportive care only . In clinical trials , retinoic acid turned out to be inefficient , and low-dose cytarabine was more effective but led to a pronounced increase in severe neutropenic infections -LSB- 25 -RSB- . A preferential response to other modern therapeutic strategies like immunosuppression and suppression of DNA methyltransferase or histone deacetylase was not reported as yet . However , recently , List et al. reported a remarkably high response rate to the immunomodulating agent lenalidomide , which was especially pronounced in MDS patients with 5q deletions . Nine out of 12 patients with a 5q deletion displayed complete cytogenetic remissions , and 10 out of 12 experienced an erythroid response -LSB- 26 -RSB- . Thus , a new promising agent may target cell clones in MDS bearing 5q deletions . These results could recently be confirmed on the basis of a large muliticentric trial -LSB- 27 -RSB- . Monosomy 7 Monosomy 7 is the second most frequent distinct chromosome abnormality in MDS occurring in some 25 % of abnormal cases . It can present as total or partial monosomy . In the latter case , variable deletions of parts of the long arm lead to loss of genetic material of different size . As yet , no significant differences concerning the prognostic relevance have been observed between total and partial monosomy 7 . In the German -- Austrian dataset , 36 % of monosomy 7 were isolated ones , 14 % displayed one additional abnormality , and 50 % occurred as part of complex abnormalities -LSB- 1 -RSB- . Comparable to the situation in 5q , also in 7q , at least two and maybe more distinct regions of common deletions have been identified : the band 7q22 and the more telomeric regions 7q31 -- 32 and 7q36 . It is interesting to note that interstitial as well as terminal deletions might be due to cryptic unbalanced translocations . In single individuals , more than one different deletion has been found in one and the same patient , either within the same copy of chromosome 7 with retention of sequences between the deleted regions or within different cell clones -LSB- 28 , 29 -RSB- . These observations clearly underline the regional genetic instability of the long arm of chromosome 7 , which makes this region especially prone to deletions of different size and localization as well as to structural abnormalities . On the other hand , it can be assumed that there must be a cluster of genes with tumor-suppressive features distributed over several chromosome bands in 7q with the same or very similar consequences when being inactivated by chromosomal abnormalities . However , in contrast to some presumptions in the 5q deletions , as yet , no prognostic differences have been elaborated between different regions of deletions -LRB- reviewed in -LSB- 20 -RSB- -RRB- . Investigations of the molecular background of monosomy 7 MDS are on the way . An association of this cytogentic subgroup with RAS mutations , mutations of AML1 , and hypermethylation of p15INK4B have been reported -LSB- 30 , 31 -RSB- . In an analysis of gene expression profiles in CD34 + cells from MDS patients with monosomy 7 , a malignant phenotype with highly proliferative potential was found with an overexpression of HOX9A , PRAME , BMI-1 , PLAB , and the DNA repair gene BRCA2 . Parallelly , downregulation of the tumor suppressor gene p21 , GATA2 , and MAP was observed -LSB- 32 -RSB- . Clinically , monosomy 7 is characterized by a lower median age of the affected patients as compared to 5q deletions , severe refractory cytopenias , and a proneness to life-threatening infections . Predisposing conditions recurrently observed in cases with monosomy 7 are antecedent aplastic anemia , Fanconi 's anemia , neurofibromatosis type I , cyclic neutropenia , and long-term treatment with granulocyte colony-stimulating factor -LRB- G-CSF -RRB- , as well as Schwachman 's syndrome . It is of special interest that myeloid cells harboring monosomy 7 seem to be preferentially responsive to a stimulation by myeloid growth factors like G-CSF and granulocyte -- macrophage CSF in vitro -LSB- 33 , 34 -RSB- as well as in vivo -LSB- 35 -RSB- . Although being obvious , this phenomenon never was exploited therapeutically for a targeted priming strategy for patients with monosomy 7 . In extremely rare cases , for the so-called monosomy 7 syndromes , the abnormality has a familiar background . In a substantial portion of patients , a mutagen exposition -LRB- benzene , solvents , irradiation , or radio - and/or chemotherapy -RRB- was documented . In contrast to the situation in 5q deletions , in monosomy 7 , additional abnormalities do not have such a profound impact on outcome as seen in 5q deletions , since monosomy 7 even as an isolated abnormality confers a significantly bad prognosis . In our Austrian -- German dataset , median survival times were 14 months for the isolated abnormality , 11 months for cases with one additional change , and 8 months for monosomy 7 as part of complex abnormalities -LRB- Fig. 3 -RRB- -LSB- 1 -RSB- . Fig. 3Median survival according to accompanying abnormalities in patients with − 7/7q − . Log-rank test : p = 0.03 -LRB- 2 degrees of freedom -RRB- , p = 0.94 -LRB- isolated vs. +1 -RRB- , p = 0.07 -LRB- isolated vs. complex -RRB- , p = 0.43 -LRB- +1 vs. complex -RRB- Therapeutic options in the monosomy 7 subgroup are unsatisfying as yet . If age and clinical condition are adequate , patients should be treated with allogeneic stem cell transplantation whenever possible . Conventional intensive chemotherapy bears a high risk of early death and nonresponse . Even if a complete remission can be achieved , this frequently is of only short duration with a high risk of early relapse . In a recent report on 34 patients with MDS or AML treated with 5-azacytidine , the group of Mufti observed a preferentially good response of MDS patients with monosomy 7 to the demethylating agent 5-azacytidine . In this trial , five of the seven -LRB- 71 % -RRB- complete responders had isolated chromosome 7 abnormalities and achieved a continuous complete remission -LRB- 10 months follow-up -RRB- in contrast to patients with other karyotype abnormalities like trisomy 8 who relapsed within the first 6 months -LSB- 36 -RSB- . Supporting results have been recently published for the use of decitabine by Lübbert et al. -LSB- 37 -RSB- . Future multicentric therapy trials are needed to verify this observation in a higher number of patients . Complex abnormalities According to the International System for Human Cytogenic Nomenclature criteria , complex chromomosome abnormalities are defined by the simultaneous occurrence of at least three independent abnormalities within one cell clone -LSB- 38 -RSB- . This cytogenetic subtype is present in some 15 % of all patients with MDS -LRB- roughly 30 % of all abnormal cases -RRB- and thus occurs in a frequency comparable to 5q deletions -LSB- 1 -- 3 -RSB- . Complex abnormalities may be the result of a multistep process with sequential accumulation of abnormalities , called karyotype evolution . In some cases , karyotype evolution can be observed if repeated cytogenetic analyses are performed , unraveling the stepwise accumulation of secondary abnormalities with the starting point of a primary abnormality . In a few patients , cytogenetic analysis detects cell clones with primary and others with primary and secondary and possibly further abnormalities at one and the same time point . However , frequently , this process can not be proven in the individual patient who presents with multiple chromosomal changes at first diagnosis . In most of these cases , complexity is profound with aberration numbers exceeding the threshold of three by far . Frequently , in these cases , cell-to-cell variations occur , and the chromosomal complement presents with a chaotic , mutator-like shape resembling cytogenetics of solid tumors and malignancies in chromosomal breakage syndromes . Thus , it is conceivable that , in these cases , the process leading to complex abnormalities and genetic instability must proceed rapidly on the one hand and must involve mechanisms like DNA repair and cell cycle control comparable to the situation in DNA repair deficiency syndromes . Recent results of gene expression analyses in patients with MDS and complex chromosome abnormalities support these assumptions and are considered below in more detail -LSB- 39 -RSB- . In a substantial portion of patients with complex abnormalities , an exposition to therapeutically applied mutagens , like anthracyclines , topoisomerase II inhibitors , alkylating agents , and/or irradiation , can be traced in the medical history -LSB- 40 -RSB- . Within the subgroup of patients with complex changes , a broad range of the number of abnormalities with the majority of patients displaying greater than or equal to five chromosomal changes can be observed -LSB- 39 -RSB- . There is a strong association with unbalanced structural abnormalities affecting most frequently chromosomes 5q and 7q . Chromosomes less frequently involved in loss of genetic material were chromosomes 3 -LRB- p - and q-arms -RRB- , 12p , 13q , 16q , 17p , 18q , and 20q . Genomic gains were observed for chromosome 8/8q , 11q , and 21q -LSB- 41 -RSB- . Mutations of p53 have been observed in up to 90 % of patients with AML and complex abnormalities -LSB- 39 -RSB- . Matrix comparative genomic hybridization -LRB- CGH -RRB- analyses in patients with complex abnormalities revealed an association of complex karyotype changes with amplifications in the chromosomal regions 8q24 , 9p24 , ,11 q23 , 12p13 , 13q12 , 20q11 , and 2q1q22 -LSB- 42 -RSB- . Recently , characteristic profiles of complex abnormalities in AML were delineated by gene expression analyses . In this respect , a significant overexpression of RAD21 , a double-strand-break DNA repair enzyme , as well as overexpression of other genes related to DNA-repair , apoptotic mechanisms , and cell-cycle control -LRB- RAD1 , RAD 9A , RAD23B , RAD51AP1 , NBS1 , MSH6 , SUMO1 , and PARP2 -RRB- was observed -LSB- 39 -RSB- . Taken together , these data might help to understand complex abnormalities as a maximum manifestation of genetic instability by allowing cells with significant DNA damages to circumvent physiologically protective apoptosis and to escape cytotoxicity of chemotherapy by intensified DNA repair . This model is also compatible with the high extent of chemo-resistance of hematopoietic cells with complex chromosome abnormalities , which is a well-known and severe problem in the clinical management of high-risk MDS . Further clinical associations are the high median age of patients within this cytogenetic subgroup -LSB- 43 -RSB- and , related to conventional intensive chemotherapy , short remission durations and a high risk for early relapse -LSB- 44 -RSB- . Allogeneic stem cell transplantation , the only curative option for these patients , will only be feasible for a minority of individuals with complex chromosomal changes due to age-related multimorbidity and organ dysfunctions . New therapeutic strategies targeting hypermethylation , deacetylation , and immunomodulation , which have proven their tolerability also in aged patient populations , are now available for the treatment of patients with high-risk MDS . In this respect , two studies have to be mentioned . Cytogenetic responses in a substantial portion of patients with high-risk MDS have been observed in a multicentric study of decitabine , a potent demethylating agent . Major cytogenetic responses -LRB- MajCR -RRB- were observed in 38 % of 50 patients . Remarkably , 10 out of 26 patients -LRB- 38 % -RRB- with high-risk cytogenetics displayed a MajCR ; five of them had complex chromosome abnormalities . In the patients ' group with MajCR , median survival time was 24 months as compared to the significantly shorter median survival time of 11 months in patients with persisting cytogenetic aberrations -LSB- 45 -RSB- . These observations are further supported by observations of our group . Within a cohort of 14 patients with high-risk MDS , we recently observed hematologic and cytogenetic responses to 5-azacytidine according to the modified International Working Group criteria -LSB- 46 -RSB- in three out of four patients with complex abnormalities -LSB- 47 -RSB- . Another new therapeutic mechanism , immunomodulation , might be effective in cases with complex karyotypic changes too . In this connection , a complete cytogenetic response to the immunomodulatory drug lenalidomide has been reported in patients with high-risk MDS with complex chromosome abnormalities harboring 5q deletions -LSB- 48 -RSB- . Further multicentric clinical trials are needed to confirm these observations . Conclusions In contrast to CML where the bcr -- abl fusion forms the homogenous genetic basis of the disease -LSB- 49 -RSB- , MDS show a profound heterogeneity , not only on the morphologic and clinical level but also on the genetic presentation . Three cytogenetic subgroups with prognostic relevance have been identified and were incorporated into prognostic scoring by the IPSS . However , in the great majority of cytogenetic changes , the prognostic relevance is still obscure . Genetic heterogeneity in MDS leads to the paradox situation that rare abnormalities can be observed frequently -LSB- 1 -RSB- with the consequence that , for a relevant portion of abnormalities , their prognostic impact is still unknown . The only chance to overcome these shortcomings is to establish multicentric cooperations , which are the goals of the German -- Austrian MDS Study Group , which is now cooperating with the MD Anderson Cancer Centre as well as the IMRAW group -LSB- 50 -- 52 -RSB- . New therapeutic strategies targeting immunomodulation and epigenetic changes proved to be of outstanding effectiveness and tolerability in comparison to established therapies not only for the low-risk 5q syndrome but also for high-risk MDS with as yet deleterious cytogenetic alterations like monosomy 7 and complex abnormalities . However , what about the subgroup of nearly 50 % of patients presenting with a normal karyotype ? New techniques will help to further delineate the genetic background in these cases . Thus , very recently , two groups published their results of single nucleotide polymorphism analyses in MDS -LSB- 53 , 54 -RSB- . The group of Mufti performed high-resolution single-nucleotide polymorphism -LRB- SNP -RRB- array analyses in 119 low-risk MDS patients of whom 32 % displayed clonal chromosome abnormalities to search for cryptic chromosomal aberrations not detectable by chromosomal banding analyses . They found uniparental disomy -LRB- UPD -RRB- , a copy number neutral loss of heterozygosity , in 46 % of patients , small deletions in 10 % , and amplifications in 8 % of the cohort . The changes of copy numbers were acquired while UPDs were constitutional . The former aberrations were associated with a worsened outcome of the patients . The authors speculated that the high frequency of UPD may be indicative for a constitutional genomic instability in these patients -LSB- 53 -RSB- . This could be a predisposing factor for MDS . Maciejewski et al. applied 250 K SNP arrays to 94 patients with MDS and observed SNP aberrations in 75 % of patients as compared to 59 % clonal chromosomal abnormalities detected by metaphase analyses . Previously unknown lesions were found in patients with a normal -- as well as in others with an abnormal -- karyotype . In this study , UPD occurred in 20 % of the MDS patients -LSB- 54 -RSB- . New analytical tools like matrix CGH , microarray gene expression analyses , proteomics , and methylation profiling will add substantially to the understanding of pathogenesis , delineation of therapeutic targets , and individualization of therapy in MDS . Taken together cytogenetics is still the gold standard of genetic diagnosis in MDS providing `` labels '' like 5q − , monosomy 7 , or complex abnormalities for disease entities with a common biological behavior and clinical as well as prognostic impact . In the future , scientific progress will depend on the ability to combine established and newly developed methods to gain a comprehensive understanding of MDS , which will translate into an individualized and highly effective and well-tolerable treatment for all patients with MDS .

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O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B I B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O 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mds
cytogenetics
karyotype
prognosis
monosomy 7
complex abnormalities


Isolated

Limb

Perfusion

and

External

Beam

Radiotherapy

for

Soft

Tissue

Sarcomas

of

the

Extremity

Long-Term

Effects

on

Normal

Tissue

According

to

the

LENT-SOMA

Scoring

System

Background

With

the

combined

treatment

procedure

of

isolated

limb

perfusion

-LRB-

ILP

-RRB-

delayed

surgical

resection

and

external

beam

radiotherapy

-LRB-

EBRT

-RRB-

for

locally

advanced

soft

tissue

sarcomas

-LRB-

STS

-RRB-

of

the

extremities

limb

salvage

rates

of

more

than

can

be

achieved

However

long-term

damage

to

the

healthy

surrounding

tissue

can

not

be

prevented

We

studied

the

late

effects

on

the

normal

tissue

using

the

LENT-SOMA

scoring

system

In

the

and

the

effectiveness

of

-LRB-

neo

-RRB-

adjuvant

isolated

limb

perfusion

-LRB-

ILP

-RRB-

with

various

cytostatics

was

explored

in

the

limb

salvage

treatment

of

extremity

sarcomas

The

practice

of

performing

extremity

perfusions

for

sarcomas

ended

after

Rosenberg

showed

the

effectiveness

of

adjuvant

radiation

treatment

in

limb

salvage

Amputations

or

exarticulations

of

the

affected

limb

did

not

result

in

higher

survival

rates

There

was

a

renewed

interest

in

neoadjuvant

ILP

in

the

early

when

Lejeune

and

co-workers

added

tumor

necrosis

factor

alpha

-LRB-

TNFα

-RRB-

to

Melphalan

in

the

ILP

treatment

of

locally

advanced

extremity

melanomas

and

sarcomas

This

resulted

in

high

local

response

rates

and

high

limb

salvage

rates

with

an

acceptable

local

and

systemic

toxicity

Currently

an

established

limb

salvage

strategy

for

primarily

irresectable

soft

tissue

sarcomas

-LRB-

STSs

-RRB-

of

the

limbs

consists

of

induction

treatment

with

hyperthermic

ILP

with

TNFα

and

Melphalan

followed

by

delayed

surgical

resection

and

in

case

of

marginal

or

non-radical

resection

adjuvant

external

beam

radiotherapy

-LRB-

EBRT

-RRB-

With

this

combined

treatment

modality

short-term

limb

salvage

rates

of

more

than

are

achieved

with

long-term

rates

of

However

as

the

number

of

long-term

cancer

survivors

increases

late

complications

of

therapy

will

become

an

increasingly

important

concern

Long-term

damage

to

the

healthy

surrounding

tissue

can

not

be

prevented

Toxic

effects

of

pre

or

postoperative

EBRT

and

intra-arterial

chemotherapy

have

been

extensively

described

in

previous

literature

and

include

edema

fibrosis

neuropathy

limited

mobility

impaired

wound

healing

and

less

commonly

pain

bone

fractures

and

second

tumors

Moreover

during

ILP

normal

tissue

in

the

limb

skin

subcutaneous

tissue

muscle

nerves

blood

vessels

bone

and

cartilage

is

exposed

to

the

same

concentrations

of

cytostatic

agents

active

against

the

tumor

causing

regional

toxic

effects

which

lead

to

comparable

late

complications

Recently

we

described

the

late

vascular

complications

that

occur

after

the

TNF

ILP

treatment

procedure

Functional

morbidity

and

symptoms

such

as

edema

and

pain

can

also

be

extremely

invalidating

sometimes

necessitating

aggressive

treatment

To

evaluate

all

toxic

long-term

effects

we

used

the

uniform

generally

accepted

toxicity

scoring

system

LENT-SOMA

This

system

not

only

allows

late

damage

to

be

classified

in

different

gradations

but

also

allows

data

acquisition

using

three

different

methods

-LRB-

-RRB-

subjective

the

injury

is

recorded

as

perceived

by

the

patient

-LRB-

-RRB-

objective

morbidity

is

assessed

during

a

clinical

examination

and

-LRB-

-RRB-

management

indicates

the

active

steps

made

to

ameliorate

the

symptoms

In

order

to

provide

an

overview

of

all

late

toxic

effects

on

the

limb

treated

with

ILP

delayed

surgical

resection

and

adjuvant

high-dose

EBRT

a

retrospective

study

was

conducted

to

evaluate

long-term

morbidity

using

the

LENT-SOMA

scoring

system

Patients

and

Methods

Between

and

patients

with

locally

advanced

STSs

underwent

perfusions

with

a

combination

of

TNFα

and

Melphalan

with

-LRB-

n

-RRB-

or

without

-LRB-

n

-RRB-

interferon-gamma

-LRB-

IFNγ

-RRB-

at

the

Division

of

Surgical

Oncology

of

the

University

Medical

Center

Groningen

-LRB-

UMCG

-RRB-

The

perfusion

technique

has

been

previously

described

extensively

Currently

patients

are

still

alive

and

in

follow-up

There

were

patients

who

were

unable

to

participate

because

of

severe

or

advanced

-LRB-

co

-RRB-

morbidity

-LRB-

n

-RRB-

or

non-medical

reasons

-LRB-

n

-RRB-

Consequently

patients

males

-LRB-

-RRB-

and

females

-LRB-

-RRB-

median

age

-LRB-

range

-RRB-

years

could

be

evaluated

-LRB-

response

rate

-RRB-

Of

all

the

patients

had

STSs

of

the

upper

extremity

-LRB-

-RRB-

treated

with

an

axillary

perfusion

In

the

remaining

they

were

located

in

the

lower

limb

-LRB-

-RRB-

and

were

treated

with

iliacal

-LRB-

n

-RRB-

femoral

-LRB-

n

-RRB-

or

popliteal

-LRB-

n

-RRB-

perfusion

There

were

primary

-LRB-

-RRB-

and

recurrent

-LRB-

-RRB-

STSs

After

a

median

post-perfusion

duration

of

-LRB-

range

-RRB-

weeks

all

patients

underwent

a

delayed

local

resection

of

the

tumor

remnant

Of

the

patients

had

clear

microscopic

surgical

margins

-LRB-

resection

-RRB-

and

had

histologically

positive

microscopic

margins

-LRB-

resection

-RRB-

No

patient

had

macroscopic

residual

disease

A

total

of

patients

-LRB-

-RRB-

with

marginal

-LRB-

cm

n

-RRB-

or

microscopically

positive

resection

-LRB-

n

-RRB-

margins

received

adjuvant

high

dose

-LRB-

Gy

-RRB-

postoperative

EBRT

in

fractions

of

Gy

followed

by

a

boost

of

Gy

One

patient

with

a

recurrent

STS

received

EBRT

at

the

time

of

treatment

of

the

primary

tumor

but

not

after

ILP

and

resection

of

the

recurrence

Adjuvant

systemic

chemotherapy

was

given

to

patients

due

to

the

definite

histopathological

classification

of

the

tumor

-LRB-

one

embryonal

rhabdomyosarcoma

and

one

extraosseal

osteosarcoma

-RRB-

as

part

of

an

EORTC

trial

-LRB-

EORTC

-RRB-

and

in

a

palliative

setting

because

of

distant

metastasis

All

patients

received

a

tailored

post-surgical

rehabilitation

program

during

and

after

the

radiation

treatment

until

a

final

result

was

achieved

All

patients

were

treated

after

informed

consent

was

obtained

according

to

institutional

guidelines

A

total

of

different

histological

types

of

STS

were

distinguished

The

pathological

grade

and

stage

of

the

tumor

were

scored

according

to

the

criteria

of

Coindre

et

al.

and

the

American

Joint

Committee

on

Cancer

-LRB-

AJCC

-RRB-

respectively

Patient

and

tumor

characteristics

are

summarized

in

Table

Table

of

patients

PNET

primitive

neuroectodermal

tumor

PUS

pleiomorphic

undifferentiated

sarcoma

MPNST

malignant

peripheral

nerve

sheath

tumor

FU

follow-up

in

months

not

availableAge

-LRB-

years

-RRB-

SexHistologyGradeAJCC

Myxoid

Synovial

Myxoid

Local

status

of

the

treated

limb

was

first

globally

assessed

using

a

checklist

including

the

following

items

lymphedema

color

stiffness

hypesthesia

paresthesia

muscle

atrophy

pain

scar

status

function

and

use

of

aids

Late

effects

on

surrounding

tissue

were

graded

according

to

the

subjective

objective

and

management

portions

of

the

LENT-SOMA

scales

as

proposed

by

the

EORTC

and

RTOG

Late

Effects

Working

Group

in

Four

LENT-SOMA

scales

were

used

muscle/soft

tissue

peripheral

nerves

skin/subcutaneous

tissue

and

vessels

Not

all

patients

could

be

scored

on

all

four

items

since

in

patients

-LRB-

-RRB-

the

affected

limb

was

amputated

Results

After

a

median

follow-up

of

-LRB-

range

-RRB-

months

patients

-LRB-

-RRB-

mentioned

one

or

more

locoregional

complaints

in

the

treated

leg

mainly

consisting

of

pain

spasm

and

limitation

of

mobility

Scoring

the

local

status

using

a

checklist

deviating

symptoms

and

signs

were

documented

and

are

summarized

in

Table

Only

patients

-LRB-

-RRB-

did

not

use

any

aids

the

remaining

-LRB-

-RRB-

needed

elastic

compression

stockings

braces

prostheses

or

crutches

Table

status

in

patients

deviating

symptoms

and

signsSymptomNo

Severely

LENT-SOMA

Scales

Results

of

scoring

late

tissue

effects

according

to

the

LENT-SOMA

scoring

system

are

listed

below

and

illustrated

in

Table

Grade

represents

the

most

minor

symptoms

which

do

not

require

treatment

Grade

represents

moderate

symptoms

requiring

only

conservative

treatment

Grade

represents

severe

symptoms

which

have

a

significant

negative

impact

on

daily

activities

and

require

more

aggressive

treatment

Grade

represents

irreversible

functional

damage

necessitating

major

therapeutic

intervention

SOMA

stands

for

S

subjective

complaints

O

objective

symptoms

and

M

management

and

therapy

Table

LENT-SOMA

scoresMaximum

grade

of

soft

tissue

-LRB-

n

-RRB-

Peripheral

nerves

-LRB-

n

-RRB-

Skin/subcutaneous

tissue

-LRB-

n

-RRB-

Vessels

-LRB-

n

-RRB-

a

n

Muscle/Soft

Tissue

Of

the

patients

experienced

no

subjective

toxic

effects

-LRB-

-RRB-

scored

maximum

grade

-LRB-

-RRB-

scored

grade

-LRB-

-RRB-

and

had

a

maximum

of

toxicity

-LRB-

-RRB-

When

scored

objectively

a

maximum

of

toxicity

was

found

in

patients

-LRB-

-RRB-

and

grade

in

patients

-LRB-

-RRB-

No

patient

had

only

minor

or

no

symptoms

No

treatment

was

required

in

patients

-LRB-

-RRB-

patient

-LRB-

-RRB-

scored

grade

-LRB-

occasional

physiotherapy

-RRB-

scored

grade

-LRB-

-RRB-

and

-LRB-

-RRB-

needed

continued

medical

intervention

-LRB-

grade

-RRB-

for

edema

and

extremity

malfunction

A

detailed

overview

of

all

items

is

provided

in

Table

Table

scores

for

muscle/soft

tissue

-LRB-

n

-RRB-

Grade

of

Objective

Mobility

and

extremity

Management

Mobility

and

extremity

Peripheral

Nerves

No

subjective

toxic

effects

were

observed

in

patients

-LRB-

-RRB-

scored

maximum

toxicity

-LRB-

-RRB-

scored

grade

-LRB-

-RRB-

and

toxicity

-LRB-

-RRB-

When

scored

objectively

patients

experienced

no

toxicity

-LRB-

-RRB-

and

scored

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

toxic

effects

Of

the

patients

did

not

require

any

treatment

-LRB-

-RRB-

-LRB-

-RRB-

scored

-LRB-

occasional

non-narcotic

-RRB-

-LRB-

-RRB-

-LRB-

regular

non

narcotic

-RRB-

and

-LRB-

-RRB-

-LRB-

physical

or

medical

intervention

because

of

severe

motor

dysfunction

-RRB-

toxicity

A

detailed

overview

is

provided

in

Table

Table

scores

for

peripheral

nerves

-LRB-

n

-RRB-

Grade

of

Motor

Objective

Motor

Sensory

Management

Motor

Sensory

Skin/Subcutaneous

Tissue

No

subjective

symptoms

were

observed

in

patients

-LRB-

-RRB-

scored

maximum

toxicity

-LRB-

-RRB-

grade

-LRB-

-RRB-

and

-LRB-

-RRB-

grade

-LRB-

scaliness/roughness

requiring

constant

attention

-RRB-

Only

patient

experienced

no

objective

toxicity

-LRB-

-RRB-

while

scored

grade

-LRB-

-RRB-

grade

-LRB-

-RRB-

and

grade

-LRB-

-RRB-

No

treatment

was

required

in

patients

-LRB-

-RRB-

but

-LRB-

-RRB-

required

medical

intervention

because

of

edema

and

dryness

-LRB-

toxicity

-RRB-

and

-LRB-

-RRB-

scored

toxicity

surgical

intervention

due

to

massive

fibrosis

and

a

persistent

ulcer

requiring

surgical

therapy

A

detailed

overview

is

provided

in

Table

Table

scores

for

skin/subcutaneous

tissue

-LRB-

n

-RRB-

Grade

of

Scaliness

Objective

Alopecia

-LRB-

scalp

-RRB-

Pigmentation

Ulcer

Fibrosis

Atrophy

Management

Fibrosis

Vessels

No

subjective

symptoms

were

observed

in

patients

-LRB-

-RRB-

while

scored

maximum

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

toxicity

clinical

symptoms

of

ischemia

at

rest

Objective

symptoms

were

absent

in

patients

-LRB-

-RRB-

but

patients

scored

toxicity

-LRB-

-RRB-

scored

grade

-LRB-

-RRB-

grade

-LRB-

intense

ischemia

-RRB-

-LRB-

-RRB-

and

grade

-LRB-

necrosis

-RRB-

-LRB-

-RRB-

No

form

of

management

was

needed

in

patients

-LRB-

-RRB-

However

patients

scored

grade

-LRB-

-RRB-

-LRB-

-RRB-

grade

-LRB-

conservative

surgery

because

of

arterial

disease

-RRB-

and

-LRB-

-RRB-

required

amputation

-LRB-

toxicity

-RRB-

because

of

critical

leg

ischemia

A

detailed

overview

is

provided

in

Table

Table

scores

for

vessels

-LRB-

n

-RRB-

Grade

of

Objective

Management

Overall

outcomes

from

the

Subjective

and

Objective

symptoms

are

different

from

those

of

the

Management

part

of

the

LENT-SOMA

scales

According

to

the

subjective

and

objective

parts

of

the

scale

two-thirds

of

patients

had

serious

late

toxic

side

effects

concerning

any

of

the

surrounding

normal

tissue

A

toxicity

was

scored

by

patients

-LRB-

-RRB-

on

one

or

more

items

of

the

subjective

parts

of

the

four

used

scales

They

experienced

their

long-term

morbidity

as

severe

and

with

a

negative

impact

on

daily

activities

or

toxicity

was

scored

by

patients

-LRB-

-RRB-

on

the

objective

parts

of

the

scoring

scales

showing

severe

or

irreversible

damage

during

a

clinical

examination

However

according

to

the

management

parts

patients

-LRB-

-RRB-

scored

no

toxicity

-LRB-

grade

-RRB-

on

all

management

items

of

the

four

used

LENT-SOMA

scales

and

did

not

require

any

treatment

Moreover

patients

-LRB-

-RRB-

scored

a

maximum

or

toxicity

and

only

needed

conservative

treatment

In

less

than

a

quarter

of

patients

-LRB-

n

-RRB-

aggressive

treatment

e.g.

continuous

medical

intervention

or

surgery

was

necessary

due

to

long-term

effects

of

the

combined

treatment

procedure

Discussion

The

limb-sparing

treatment

strategy

of

ILP

using

TNF

and

Melphalan

with

or

without

adjuvant

EBRT

is

increasingly

being

pursued

for

locally

advanced

STS

of

the

extremities

after

the

publication

of

the

results

of

a

European

multi-center

trial

performed

in

the

Using

this

combined

treatment

modality

excellent

short-term

limb

salvage

rates

of

more

than

and

long-term

rates

of

can

be

achieved

with

no

negative

impact

on

survival

While

at

first

selected

groups

of

patients

were

often

excluded

from

undergoing

this

procedure

limb

preservation

has

now

become

a

major

challenge

for

all

patients

with

a

locally

advanced

STS

It

seems

to

be

a

safe

and

highly

effective

procedure

in

elderly

patients

for

whom

every

attempt

to

avoid

an

amputation

that

may

end

their

independence

must

be

considered

It

can

also

be

used

in

a

palliative

setting

for

patients

who

present

with

distant

metastasis

at

the

time

of

diagnosis

as

better

local

control

improves

the

quality

of

life

In

patients

with

multifocal

primary

or

multiple

recurrent

extremity

sarcomas

ILP

also

provides

excellent

local

control

and

limb

salvage

rates

of

more

than

are

achieved

However

acute

toxicity

and

long-term

morbidity

due

to

the

combined

treatment

procedure

of

ILP

surgical

resection

and

EBRT

can

not

be

prevented

In

ILP

normal

tissue

in

the

limb

is

exposed

to

the

same

concentrations

of

cytostatic

agents

as

the

tumor

The

effects

of

the

perfusate

on

normal

tissue

vary

widely

among

individuals

and

long-term

morbidity

also

varies

widely

in

severity

As

far

as

we

know

this

is

the

first

study

to

assess

late

functional

morbidity

with

the

LENT-SOMA

scales

in

patients

treated

for

STS

with

ILP

surgical

resection

and

EBRT

Neurotoxicity

Neuropathy

is

particularly

important

and

is

mainly

seen

after

the

use

of

specific

cytostatic

perfusion

agents

such

as

cisplatin

carboplatin

and

doxorubicin

Furthermore

nerve

damage

can

be

caused

by

initial

tumor

swelling

or

pressure

from

the

tight

tourniquet

A

prophylactic

fasciotomy

can

prevent

the

occurrence

of

a

persistent

neurotoxicity

with

motor-sensory

neuropathy

and

is

routinely

performed

in

our

series

Radiotherapy

also

plays

an

important

role

especially

when

patients

have

received

a

boost

All

our

patients

received

a

boost

of

Gy

EBRT

Despite

the

fact

that

neurotoxicity

was

subjectively

found

to

be

severe

in

of

patients

only

in

could

it

be

objectified

and

in

only

was

physical

or

medical

intervention

needed

of

the

patients

had

paralysis

or

complete

anesthesia

or

needed

surgical

intervention

Functional

Morbidity

Functional

outcome

after

limb-sparing

treatment

with

ILP

has

been

analyzed

previously

but

mostly

in

melanoma

patients

and

not

using

a

uniform

scoring

system

Other

studies

show

limitations

in

ankle

joint

mobility

in

of

patients

compared

with

no

significant

objective

limitations

in

previous

investigations

in

our

study

population

The

routinely

performed

fasciotomy

combined

with

an

intensive

physiotherapy

program

might

explain

these

better

outcomes

because

the

regional

toxic

effects

of

ILP

are

hereby

reduced

In

this

study

we

found

muscle

atrophy

in

almost

all

patients

-LRB-

-RRB-

which

may

be

due

to

an

extensive

surgical

resection

having

been

performed

after

ILP

for

deep-seated

STSs

in

contrast

to

the

mostly

superficial

resection

in

melanoma

patients

Only

patients

-LRB-

-RRB-

still

needed

medical

intervention

occasional

or

regular

physiotherapy

However

patients

-LRB-

-RRB-

found

that

their

limb

function

interfered

with

daily

activities

In

only

patients

-LRB-

-RRB-

could

no

functional

impairment

be

objectified

Scoring

Systems

Most

previous

studies

evaluating

functional

outcome

after

treatment

for

STS

included

no

ILP

but

consisted

of

wide

local

excision

with

or

without

postoperative

EBRT

and/or

adjuvant

chemotherapy

Gerrand

et

al.

found

a

significant

decrease

in

functional

scores

when

the

revised

Musculoskeletal

Tumor

Society

Rating

Scale

-LRB-

MSTS

-RRB-

and

Toronto

Extremity

Salvage

Score

-LRB-

TESS

-RRB-

were

used

after

treatment

of

deep-seated

In

two

studies

the

LENT-SOMA

scales

were

used

to

assess

functional

morbidity

after

wide

local

excision

and

EBRT

sometimes

combined

with

chemotherapy

for

STS

The

LENT-SOMA

scales

were

found

to

be

time-consuming

but

reliable

for

a

detailed

description

of

late

toxicity

To

evaluate

the

long-term

morbidity

in

our

study

we

used

this

generally

accepted

LENT-SOMA

scoring

system

According

to

Denekamp

et

al.

no

overall

LENT

score

is

calculated

but

all

criteria

are

separately

described

in

order

to

prevent

the

high

scores

being

filtered

out

thus

giving

a

falsely

optimistic

picture

Although

primarily

developed

to

analyze

late

radiation

effects

it

can

also

be

used

to

score

the

toxicity

of

chemotherapy

In

this

study

of

the

patients

analyzed

-LRB-

-RRB-

received

EBRT

The

patients

who

scored

toxicity

on

one

or

more

items

all

received

EBRT

Overall

there

was

no

patient

who

did

not

experience

any

late

toxic

effect

Quality

of

Life

All

functional

complaints

can

have

a

substantial

negative

impact

on

daily

functioning

which

brings

into

question

whether

expectations

of

the

time-consuming

technically

demanding

limb-sparing

treatment

are

upheld

Previous

studies

showed

no

improved

quality

of

life

with

limb-sparing

surgery

compared

with

that

after

amputation

The

long

rehabilitation

period

is

a

disadvantage

of

a

limb-sparing

treatment

strategy

but

the

impact

of

a

prosthesis

should

not

be

underestimated

Thijssens

et

al.

recently

showed

a

worse

physical

functioning

and

more

role

limitations

in

amputated

patients

in

this

study

population

Attention

to

collaborative

decision

making

and

communication

with

the

patient

seem

very

important

Future

Perspectives

Every

effort

should

be

made

to

prevent

long-term

morbidity

in

the

future

As

long-term

morbidity

seems

to

be

correlated

to

acute

regional

toxic

reactions

these

acute

reactions

should

be

reduced

as

far

as

possible

Improved

perfusion

technique

and

enhanced

technical

insights

have

led

to

the

following

suggestions

reduce

the

doses

of

TNFα

decrease

systemic

leakage

reduce

maximum

temperatures

and

strictly

regulate

perfusion

pressures

To

prevent

the

significant

toxicity

related

to

muscle

and

nerve

damage

a

prophylactic

fasciotomy

should

be

performed

in

all

cases

and

the

isolating

tourniquet

should

not

be

applied

too

tightly

Furthermore

all

patients

should

receive

an

individualized

rehabilitation

program

to

achieve

an

optimum

functional

situation

Finally

a

lot

of

long-term

morbidity

after

EBRT

is

subscribed

to

the

occurrence

of

radiation-induced

fibrosis

which

was

thought

to

be

irreversible

Thanks

to

the

pioneering

work

of

Delanian

et

al.

there

is

growing

knowledge

that

radiation-induced

fibrosis

is

at

least

partially

reversible

by

administering

drugs

with

antioxidant

and

anti-fibrotic

properties

such

as

pentoxifylline

and

vitamin

E.

Large

randomized

trials

are

however

needed

to

confirm

these

findings

In

conclusion

the

Subjective

Objective

and

Management

parts

of

the

LENT-SOMA

scoring

system

confirm

late

toxic

effects

on

surrounding

normal

tissue

in

all

patients

treated

with

a

combined

treatment

modality

for

locally

advanced

STS

of

the

extremity

Two-thirds

of

the

patients

have

severe

Subjective

or

Objective

damage

but

half

of

all

patients

do

not

require

any

Management

for

their

symptoms

To

prevent

long-term

morbidity

in

the

future

efforts

should

be

made

to

reduce

acute

toxic

reactions

after

ILP

and

a

fasciotomy

and

a

customized

rehabilitation

program

are

recommended

Furthermore

anti-fibrotic

therapies

might

be

considered

O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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