The Outcome of CLL Patients with 97% Identity to Germline Is Inferior to Other ‘Mutated’ Cases Defined by a 98% Cut off

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2842-2842
Author(s):  
Zadie Davis ◽  
Anton Parker ◽  
Daniel Catovsky ◽  
David Oscier
Keyword(s):  
Cox Regression ◽  
Conflicts Of Interest ◽  
Early Stage ◽  
Prognostic Significance ◽  
Published Data ◽  
Early Stage Disease ◽  
Ighv Gene ◽  
Significant Difference ◽  
Gene Usage ◽  
The Uk

Abstract Abstract 2842 IGHV gene mutational load and use of specific IGHV genes and stereotypes have all been reported to have prognostic significance in CLL. In the UK CLL4 trial there were significant differences in response rate and progression free survival regardless of whether a 97% or 98% cut off was used, and the percentage of mutations which correlates best with clinical outcome remains controversial. We performed IGHV gene sequencing on 1071 patients with CLL or ‘clinical’ MBL (n= 153) in whom biomarkers, time to first treatment (TTFT) and overall survival (OS) were available. Four hundred and ninety six cases were entered into the UK CLL4 trial and 575 presented or were referred to the Royal Bournemouth Hospital. TTFT and OS were determined for cases with <96% identity and for each mutational point from 96% – 100% identity separately, excluding cases utilising IGHV3-21 assigned to stereotype subset 2. There was a significant difference in median TTFT and median OS between those with 97% identity (TTFT-20.9 and OS-99.3 months) and <97% identity (TTFT-118 and OS-191 months; p<0.001 and p<0.001), but not between cases with 97% and >97% identity (TTFT -13.1 months p=0.052 and OS-84.5 months p=0.177). When TTFT was determined for patients with early stage disease only (stage A CLL or CLL-like MBL, n=571), those with 97% identity, determined using either leader sequence or BIOMED 2 primers, had a significantly longer median TTFT than those with >97% identity (92.0 and 36.4 months respectively; p=0.012) and significantly shorter than those cases with <97% identity (273.1 months; p=0.012). If only stage A cases were analysed, those with 97% identity had a significantly longer median TTFT than those with >97% identity (TTFT; 68 vs. 26 months p=0.034). However, when compared to cases with <97% identity, there was a trend towards a shorter TTFT but significance was not reached (68 vs. 128 months p=0.060). A series of Cox Regression analyses were conducted to see if the prognostic value of the 98% cut off in MBL/stage A cases could be improved. In univariate analyses a model which incorporated <97%, 97%, >97% identity and stereotype subset 2 was the best discriminator of TTFT (p=0.0011) (Figure 1).Figure 1.Four subgroups of MBL/stage A CLL with differing TTFT based on stereotype subset 2 and relationship to 97% germline identityFigure 1. Four subgroups of MBL/stage A CLL with differing TTFT based on stereotype subset 2 and relationship to 97% germline identity Multivariate analysis, selected 97% and >97% identity as independent predictors of shorter TTFT (HR 2.5; 95% CI 1.3–4.9; p=0.007 and HR 4.2; 95% CI 2.9–6.1; p<0.001 respectively) in a model including <97%, 97%, >97% identity to germline, age at diagnosis, gender, expression of ZAP70, expression of CD38, del11q, del17p, stereotypy and stereotype subset 2 (Table 1). Further analyses were performed to investigate whether the differences in TTFT between cases with <97%, 97% or >97% identity could be explained by differences in IGHV gene usage. Sixty-one percent of cases with 97% identity to germline utilised only five genes; IGHV3-21, IGHV3-23, IGHV3-48, IGHV3-53 and IGHV1-18 and these genes were significantly over-represented in cases with 97% compared to either, cases with <97% (p>0.001) or >97% (p>0.001). When subset 2 cases were excluded, there was no difference in TTFT between cases using the above 5 genes and all other IGHV genes at this identity (p=0.288). In contrast to previously published data we found no difference in TTFT between mutated IGHV3-23 cases and other mutated cases (using a 98% cut-off), but IGHV3-23 cases with 97% identity had a shorter TTFT than cases with <97% identity (p<0.001). In conclusion the clinical course of cases with 97% identity, especially if diagnosed early in their disease, appears distinct from other cases defined as having mutated IGHV genes using the conventional 98% cut off. This is not accounted for by differences in IGHV gene usage, the incidence of stereotypy or other biomarkers and may reflect differences in response to BCR stimulation between cases with 97% and <97% identity.Table.Multivariate analysis for TTFT in MBL/stage A CLLOutcomeCovariateHazard Ratio (HR)95% CI for HRSignificance (p)TTFT97% identity2.51.3–4.90.007>97% identity4.22.9–6.1<0.001Subset 23.71.8–7.4<0.001Del11q1.71.1–2.70.014CD381.51.0–2.00.028Age at diagnosis0.980.96–0.99<0.001 Only covariates selected as significant are listed above. Disclosures: No relevant conflicts of interest to declare.

Unmutated IGHV1-69/D3-16/J3 Stereotyped HCDR3 Rearrangements (Subset 6) Are Associated with Indolent Disease Course and Have Outcome Independent of Mutational Status In Early Stage CLL (Rai 0)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1371-1371 ◽  
Author(s):  
Francesco Forconi ◽  
Emanuele Cencini ◽  
Davide Rossi ◽  
Riccardo Bomben ◽  
Elisa Sozzi ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Early Stage ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
B Cell Receptors ◽  
Cell Receptors ◽  
Differential Outcomes ◽  
Mutational Status ◽  
Ighv Gene

Abstract Abstract 1371 Background: IGHV1-69 gene identifies the most frequent IGHV gene in chronic lymphocytic leukemia (CLL) and identifies the paradigm of unmutated CLL (U-CLL), being used in roughly 1/3 U-CLL. It is often rearranged to form subsets of stereotyped HCDR3 patterns, likely selected and transformed from the natural naïve B-cell repertoire (Blood. 2010; 115:71-7). Being unmutated, IGHV1-69 CLL are hypothetically expected to have competent tumor B-cell receptors (BCR) and to progress more rapidly. However, it has not been investigated if progression occurs similarly in all the subsets. Aims: we aimed to investigate the prognostic significance of mutational status and of stereotypic B-cell receptors in IGHV1-69+ CLL. Methods: Nucleotide sequences of the tumor IGHV1-69/D/J rearrangement, clinical and molecular prognostic parameters at diagnosis and clinical status at follow-up of 294 IGHV1-69+ CLL patients were obtained from 22 hematological Institutions in Italy. CLL B-cell derived IGHV1-69 rearrangements were scanned for HCDR3 stereotypic patterns and assigned to subsets according to the criteria by Murray et al (Blood. 2008; 111: 1524–1533). Enpoint of outcome was time to progression requiring first treatment according to NCI criteria (TTFT) in Rai stage 0 CLL. Results: Of 294 IGHV1-69+ CLL, 264 (89,8%) were unmutated, 168 (57,1%) were assigned to subsets, of which subsets 7 (n=23, 7,8%), 6 (17, 5,8%), 3 (13, 4,4%), 5 (10, 3,4%) and 9 (10, 3,4%) were the most frequent. CD38, ZAP70, normal or sole del13, +12, del11 and del17p scored positive in 109/264 (58,7%), 139/245 (56,7%), 128/248 (50,5%), 51/248 (20,6%), 43/248 (17,3%) and 34/248 (13,7%). CLLs were reclassified as 18 (6,1%) clinical MBL, 101 (34,4%) Rai 0, 155 (52,7%) Rai I-II and 20 (6,8%) Rai III-IV CLL. Subset 6 was also UM in 16/17 (94,1%) cases. Prevalence of CD38 (p<.001), ZAP70 (p=.016), normal or sole del13 (p<.001), +12 (p=.026), del11 (p=.011), and clinical high risk CLL (p=.025) were lower in IGHV1-69 M-CLL than in IGHV1-69 U-CLL. TTFT was significantly shorter in stage 0 IGHV1-69 U-CLL than in IGHV1-69 M-CLL (49 vs 144 months, p<.001, while it was not different between CLL assigned or not to subsets (65 vs 55 months, p=.346). However, specific analysis of individual subsets revealed differential outcomes (p=.005). Among all, it emerged that subset 6 had a TTFT equivalent to IGHV1-69 M-CLL (p=.29) and significantly longer than stage 0 IGHV1-69 U-CLL (median not reached vs 48 months, p=.017). Conclusions: our analysis documents and confirms that unmutated status of IGHV, and not stereotypy, is a relevant prognosticator of outcome (TTFT) in CLL. In the IGHV1-69 CLL it exclude a role of IGHV gene use for CLL progression. However, the good prognosis of Rai 0 U-CLL assigned to subset 6 suggests a differential clinical benign course of this particular subset, irrelevant of unmutated status. One possibility is that the IGHV1-69/D3-16/J3 rearrangements of subset 6 produce a tumor-specific BCR with stereotypic HCDR3 patterns that are anergized by antigen while circulating in the peripheral blood in early stage (Rai 0) CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Relationship Between Co-morbidity, Screen-Detection and Outcome in Patients Undergoing Resection for Colorectal Cancer

2021 ◽  
Author(s):  
Mark S. Johnstone ◽  
Donald C. McMillan ◽  
Paul G. Horgan ◽  
David Mansouri
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Early Stage ◽  
Univariate Analysis ◽  
Charlson Index ◽  
Early Stage Disease ◽  
Neutrophil Lymphocyte Ratio ◽  
Co Morbidity ◽  
Significant Difference ◽  
The Relationship

Abstract Background Bowel cancer screening increases early stage disease detection and reduces cancer-specific mortality. We assessed the relationship between co-morbidity, screen-detection and survival in colorectal cancer. Methods A retrospective, observational cohort study compared screen-detected (SD) and non-screen-detected (NSD) patients undergoing potentially curative resection (April 2009–March 2011). Co-morbidity was quantified using ASA, Lee and Charlson Indices. Systemic inflammatory response was measured using the neutrophil lymphocyte ratio (NLR). Covariables were compared using crosstabulation and the χ2 test for linear trend. Survival was analysed using Cox Regression. Results Of 770 patients, 331 had SD- and 439 NSD-disease. A lower proportion of SD patients had a high ASA (≥3) compared to NSD (27.2% vs 37.3%; p = 0.007). There was no significant difference in the proportion of patients with a high (≥2) Lee Index (16.3% SD vs 21.9% NSD; p = 0.054) or high (≥3) Charlson Index (22.7% SD vs 26.9% NSD; p = 0.181). On univariate analysis, NSD (HR 2.182 (1.594–2.989;p < 0.001)), emergency presentation (HR 3.390 (2.401–4.788; p < 0.001)), advanced UICC-TNM (III or IV) (p < 0.001), high ASA (≥3) (HR 1.857 (1.362–2.532; p < 0.001)), high Charlson Index (≥3) (HR 1.800 (1.333–2.432; p < 0.001)) and high (≥3) NLR (HR 1.825 (1.363–2.442; p < 0.001)) were associated with poorer overall survival (OS). NSD predicted poorer cancer-specific survival (CSS) (HR 2.763 (1.776–4.298; p < 0.001)). On multivariate analysis, NSD retained significance as an independent predictor of poorer OS (HR 1.796 (1.224–2.635; p = 0.003)) and CSS (HR 1.924 (1.193–3.102; p = 0.007)). Conclusions Patients with SD cancers have significantly lower ASA scores. After adjusting for ASA, co-morbidity and a broad range of covariables, SD patients retain significantly better OS and CSS.

Prognostic Significance of Telomere Length in Chronic Lymphocytic Leukemia Patients in Early Stage Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3890-3890
Author(s):  
Sonia Fabris ◽  
Mirjam Hoxha ◽  
Luca Agnelli ◽  
Laura Dioni ◽  
Valentina Bollati ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Conflicts Of Interest ◽  
Early Stage ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
Limited Information ◽  
Early Stage Disease ◽  
Variable Regions

Abstract Abstract 3890 Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease with a variable outcome. The identification of factors that could predict the clinical course of early-stage CLL represents a crucial objective. Although previous studies indicated that telomere length may be a useful independent prognostic factor in the risk stratification of CLL, limited information has been reported in asymptomatic early stage patients (Binet stage A). We investigate the association of telomere length with the major biological and cytogenetic markers known to predict clinical outcome in CLL. The global DNA methylation levels of Alu and LINE sequences, was also investigated. Correlation with disease progression, measured as the time elapsed from diagnosis to first treatment, was evaluated. We measured relative telomere length (RTL) by real-time PCR in a panel of highly purified (>90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 untreated CLLs. All the cases were characterized by FISH for the most frequent chromosomal aberrations (Fabris et al. GCC, 2008). Molecular markers including mutation status of the heavy chain variable regions of immunoglobulin genes (IGVH), the expression of the 70-kd zeta-chain T-cell receptor-associated protein kinase (ZAP-70) and CD38 cell surface antigen protocols were previously reported (Cutrona et al., Haematologica, 2008). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu and LINE-1. We found a significantly lower RTL values in CLLs (median RTL=0.4 IQR 0.3–0.6) as compared with controls (median RTL=1.0 IQR 0.9–1.3) (P <0.001). A progressive and significant RTL decrease in low (13q- and normal karyotype), intermediate (+12) and high (11q- and 17p-) cytogenetic risk categories (P for trend =0.008) was observed. Patients with IGVH mutated genes had longer telomeres than patients with unmutated genes (P <0.001). No significant association between telomere length and either CD38 or ZAP-70 expression was found. Telomere shortening was significantly correlated with hypomethylation of Alu (P =0.048) and LINE-1 (P =0.001), indicating a contribution to chromosome instability. Finally, follow-up analysis showed a significantly higher risk of starting treatment for patients with shorter telomeres (P =0.0037). Our results extended previous evidence that telomere length could be used as marker for the identification of CLLs with a different prognostic risk. Disclosures: No relevant conflicts of interest to declare.

Early Stage Follicular Lymphoma: Is There a Clinical Impact of First Line Treatment?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2722-2722
Author(s):  
Anne-Sophie Michallet ◽  
Laure L Lebras ◽  
Deborah D Bauwens ◽  
Fadhela F bouafia-Sauvy ◽  
Gilles Salles ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Early Stage ◽  
Stage I ◽  
Stage Ii ◽  
Watch And Wait ◽  
First Line ◽  
Early Stage Disease ◽  
Bulky Disease ◽  
Significant Difference

Abstract Abstract 2722 Introduction Follicular lymphoma (FL) is the commonest type of indolent lymphomas and is considered as an incurable malignancy with a relapsing and remitting course. Most patients are diagnosed with FL when they have an advanced stage of disease, only less than 20% presenting with stage I or II. Initial management of early stage (Ann Arbor stage I or II) FL remains undefined. Numerous options exist but radiotherapy appeared to be the standard of care for early stage disease based on single institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the era of rituximab. Patients and Methods We analyzed 145 patients treated in our institution with early stage (I or II) FL between January 01/1967 and 01/2011. Patients were retrospectively divided into six groups according to their initial treatment: watch and wait (WW), chemotherapy alone (CT), radiotherapy alone (RT), combination of radiotherapy and chemotherapy (RT-CT), Rituximab alone (Ri) and immuno-chemotherapy (Ri-CT). Results Of the 145 patients (79 females and 66 males), 84 (57.9%) patients had stage I disease and 61 (42.1%) a stage II. Median age was 55 years (20% of patients > 65 years). Only 22 (15.2%) of them had a bulky disease (> 7cm). FLIPI score was 0–1 in 116 pts, 2 in 29 pts and none had a score >2. The management of patients significantly varied over the different time (period I: <1990; period II: 1991–2000 and period III: 2001–2011) Use of RT decreased (43% for period I versus 24% for period III) whereas watchful waiting increased from 19.5% for period I up to 75% for the period III. Rituximab and Ri- CT use increased rapidly to 86% for the period III. Patients characteristics were similar in terms of age between the 6 groups but differed in term of stage and prognostic factors, essentially more stage II (61%) and bulky disease (42%) in the Ri-CT group compared to the others. The CR rate varied from 57% for the Ri group to 95% for the RT-CT group with 69% for CT, 75% for Ri-CT and 81% for RT alone. As expected, the proportion of PR was higher in the Ri group (43%). With a median follow-up of 7 years, the relapse rate was significantly lower in the Ri-CT group (40% versus 90.5% RT, 84% RT-CT, 69% CT and 58% WW respectively). According to the modifications of management over time, OS and PFS are analyzed according to two period of time: < year 2000 and ≥ 2000. OS at 7.5 years for the patients managed after >2000 was better (75%) than for those managed <2000 (59%) (not statistically significant, p= 0.29). OS according to the different treatments did not show any difference: 72% WW, 74% CT, 74% Ri-CT, 67% RT-CT, 66% RT, and 100% for Ri, respectively. By contrast, a significant difference was found for PFS at 7.5 years in favor of the combination of Ri-CT (60%) versus the others (19% RT, 26% RT-CT, 23% CT and 26% for the WW strategy, respectively) (p= 0.00135) as described in Figure 1. Conclusion Within the inherent limits of this retrospective study, delayed start of therapy was associated with a similar OS than the one observed in patients receiving immediate intervention, and PFS was not different between WW versus RT or RT-CT. Thus, the “watch and wait” strategy could be proposed as first line therapy, like it is in stage III and IV follicular lymphoma patients with a low tumor burden. However, when a treatment is required, the combination of immunochemotherapy seems to be the best option. Legends: R-CT: Ri CT or immunochemotherapy Others regimens: WW, RT, RT+CT, CT Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improved renal allograft survival for pre-emptive paediatric renal transplant recipients in the UK

2021 ◽  
pp. archdischild-2020-321277
Author(s):  
Matko Marlais ◽  
Kate Martin ◽  
Stephen D Marks
Keyword(s):  
Peritoneal Dialysis ◽  
Renal Transplant ◽  
Renal Allograft ◽  
Cox Regression ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Allograft Survival ◽  
Significant Difference ◽  
Donor Type ◽  
The Uk

BackgroundThe aim of this study was to investigate whether being on dialysis at the time of renal transplantation affected renal allograft survival in paediatric renal transplant recipients (pRTRs).MethodsRetrospective study of UK Transplant Registry (National Health Service Blood and Transplant) data on all children (aged <18 years) receiving a kidney-only transplant from 1 January 2000 to 31 December 2015. Kaplan-Meier estimates of patient and renal allograft survival calculated and Cox regression modelling accounting for donor type. The relationship between time on dialysis and renal allograft survival was examined.Results2038 pRTRs were analysed: 607 (30%) were pre-emptively transplanted, 789 (39%) and 642 (32%) on peritoneal dialysis and haemodialysis, respectively, at the time of transplantation. Five-year renal allograft survival was significantly better in the pre-emptively transplanted group (90.6%) compared with those on peritoneal dialysis and haemodialysis (86.4% and 85.7%, respectively; p=0.02). After accounting for donor type, there was a significantly lower hazard of 5-year renal allograft failure in pre-emptively transplanted children (HR 0.742, p=0.05). Time spent on dialysis pre-transplant negatively correlated with renal allograft survival (p=0.002). There was no significant difference in 5-year renal allograft survival between children who were on dialysis for less than 6 months and children transplanted pre-emptively (87.5% vs 90.5%, p=0.25).ConclusionsPre-emptively transplanted children have improved 5-year renal allograft survival, compared with children on dialysis at the time of transplantation. Although increased time spent on dialysis correlated with poorer renal allograft survival, there was no evidence that short periods of dialysis pre-transplant affected renal allograft survival.

scholarly journals Radiomics is feasible for prediction of spread through air spaces in patients with nonsmall cell lung cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuki Onozato ◽  
Takahiro Nakajima ◽  
Hajime Yokota ◽  
Jyunichi Morimoto ◽  
Akira Nishiyama ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Predictive Model ◽  
Cell Lung Cancer ◽  
Early Stage ◽  
Characteristic Curve ◽  
Sublobar Resection ◽  
Tumor Spread ◽  
Early Stage Disease ◽  
Significant Difference ◽  
Spread Through Air Spaces

AbstractTumor spread through air spaces (STAS) in non-small-cell lung cancer (NSCLC) is known to influence a poor patient outcome, even in patients presenting with early-stage disease. However, the pre-operative diagnosis of STAS remains challenging. With the progress of radiomics-based analyses several attempts have been made to predict STAS based on radiological findings. In the present study, patients with NSCLC which is located peripherally and tumors ≤ 2 cm in size on computed tomography (CT) that were potential candidates for sublobar resection were enrolled in this study. The radiologic features of the targeted tumors on thin-section CT were extracted using the PyRadiomics v3.0 software package, and a predictive model for STAS was built using the t-test and XGBoost. Thirty-five out of 226 patients had a STAS histology. The predictive model of STAS indicated an area under the receiver-operator characteristic curve (AUC) of 0.77. There was no significant difference in the overall survival (OS) for lobectomy between the predicted-STAS (+) and (−) groups (p = 0.19), but an unfavorable OS for sublobar resection was indicated in the predicted-STAS (+) group (p < 0.01). These results suggest that radiomics with machine-learning helped to develop a favorable model of STAS (+) NSCLC, which might be useful for the proper selection of candidates who should undergo sublobar resection.

scholarly journals Tumor Characteristics and Treatment Outcomes of Older Women with Breast Cancer in Jordan

2019 ◽  
Author(s):  
Hikmat Abdel-Razeq ◽  
Fadwa Abdel Rahman ◽  
Hanan Al-Masri ◽  
Hazem Abdulelah ◽  
Mahmoud Abu Nasser ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Outcomes ◽  
Metastatic Disease ◽  
Cox Regression ◽  
Early Stage ◽  
Poor Performance Status ◽  
Tumor Characteristics ◽  
Early Stage Disease ◽  
Node Positive ◽  
Stage Disease

Abstract Background : Less than 10% of newly diagnosed breast cancer in our region are diagnosed in women 70 years or older. Treatment plans of such patients is less clear and have poor outcomes. In this paper, we describe clinical presentation, tumor characteristics and treatment outcomes in such patients. Methods : Consecutive patients aged 65 years or older with pathologically-confirmed diagnosis of breast cancer were included. Medical records and hospital databases were searched for patients’ characteristics and treatment outcomes. Results : A total of 553 patients, median age 70 (range: 65-91) years, were included. On presentation, 114 (20.6%) patients had metastatic disease and was mostly visceral (81; 71.1%). Patients with non-metastatic disease had poor pathological features including node-positive in 244 (55.6%), GIII in 170 (38.7%) and lymphovascular invasion in 173 (39.4%). Patients were treated less aggressively; 144 (32.8%) patients with early-stage disease and 98 (86.0%) with metastatic disease never had chemotherapy. After a median follow up of 45 months, 5-year overall survival for the whole group was 67.6%. Survival was better for patients with non-metastatic disease (78.8% vs. 25.4%, P<0.001) and for those with node-negative compared to node-positive disease (85.4% vs. 74.1%, P=0.002). On Cox regression, only positive lymph nodes were associated with poor outcome in patients with non-metastatic disease (Hazard Ratio [HR], 1.75; 95% CI: 1.006-3.034, P=0.048). Conclusions : Older Jordanian women with breast cancer present with more aggressive features and advanced-stage disease that reflect poorly on treatment outcomes. Because of comorbidities and poor performance status, some patients were not aggressively treated.

A Complex Karyotype but Not Monosomy 7 Is an Independent Prognostic Factor in Advanced Childhood MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2452-2452
Author(s):  
Gudrun Gohring ◽  
Kyra Michalova ◽  
Berna Beverloo ◽  
David Betts ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Chromosome Aberrations ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Prognostic Significance ◽  
Complex Karyotype ◽  
Similar Frequency ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Significant Difference ◽  
Secondary Mds

Abstract Disclosure: No relevant conflicts of interest to declare. To study the clinical significance of recurrent chromosome aberrations in childhood MDS, cytogenetic data of 394 consecutive children with refractory cytopenia (RC) (N=215), RAEB (N=141) and RAEB-T (N=38) analyzed in the regional cytogenetic reference centers and registered in the prospective study EWOG-MDS 98 between 1998 and 2005 were evaluated. At diagnosis, a karyotype could be defined in 279/394 patients (pts) (71%). No karyotype was obtained in 16% of pts with RC compared to 8% pts with RAEB and RAEB-t (p&lt;0.001). Clonal chromosome aberrations were more common in pts with advanced MDS (RAEB and RAEB-T, 61%) compared to RC (29%), and in pts with secondary (69%) compared to primary MDS (36%) (p&lt;0.001). Monosomy 7 was the most frequent aberration occurring with similar frequency in RC (47% of abnormal karyotypes) compared to advanced MDS (49%) and in primary (53%) compared to secondary (41%) MDS. In addition, aberrations typical for de novo AML such as aberrations involving 11q23 or 3q, t(6;9) and del(9q) were noted in morphologically and clinically unequivocal MDS cases. Recurrent aberrations of adult MDS like isolated del(5q), del(20q) and -Y were very uncommon indicating a different pathogenesis of these cases. In pts with advanced MDS, there was no significant difference in overall survival (OS) of pts with normal karyotype (44% ± 18) compared to pts with monosomy 7 (58% ± 19) and patients with other karyotypes (61% ± 22). However, pts with advanced MDS and a complex karyotype (defined by ≥ 3 chromosome aberrations, presence of structural aberrations and excluding clonal evolution of monosomy 7) had a shorter OS (16% ±15, p&lt;0.01). OS and event-free survival after hematopoietic stem cell transplantation (HSCT) in pts with complex karyotypes was inferior compared to that of pts with other cytogenetic aberrations (p=0.012 and 0.039, respectively). Within the group of pts with secondary MDS, complex karyotypes were found in MDS evolving from inherited bone marrow failure disorders or after radio-/ chemotherapy, but absent in familial MDS and cases evolving from acquired aplastic anemia. As shown in a multivariate Cox analysis, advanced MDS, secondary MDS, the presence of a complex karyotype and HSCT were identified as independent prognostic factors for OS. Thus, this study demonstrates the prognostic significance of cytogenetic findings in advanced childhood MDS independent of HSCT.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

Promising Efficacy with the 308 Nm Excimer Laser Phototherapy in Early Stage Mycosis Fungoides

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4990-4990
Author(s):  
Darcie Deaver ◽  
Ashley Cauthen ◽  
George Cohen ◽  
Lubomir Sokol ◽  
L. Frank Glass
Keyword(s):  
Mycosis Fungoides ◽  
Excimer Laser ◽  
Conflicts Of Interest ◽  
Uv Light ◽  
Short Pulse ◽  
Early Stage ◽  
Common Type ◽  
Topical Steroids ◽  
Serious Adverse Events ◽  
Early Stage Disease

Abstract Abstract 4990 Background: Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. Early stage disease is effectively managed with skin directed therapies such as UV light and topical steroids. Excimer laser (EL) delivers monochromatic, UVB light at a wavelength of 308 nm via hand held device that covers an area of 2 × 2 cm. It generates a short-pulse radiation that is concentrated on an affected area of skin, thereby allowing a delivery of higher dose on precisely targeted tissue. In contrast to other phototherapy techniques such as narrow band UV light, the EL is ideally suited for patients with small number of patch lesions. Although EL was successfully utilized in the management of psoriasis and vitiligo, there is not extensive experience with this modality in patients with CTCL. Objectives: To assess safety and efficacy of EL therapy in patients with early stage MF who failed ≥1 skin directed therapy. Design and Methods: This is a retrospective analysis of seven consecutive patients with stage 1 MF treated with EL phototherapy between January 2011 and August 2011 in a single institution. Seven patients with histologically confirmed common type MF, and one patient with folliculotropic MF received 308 nm EL therapy after failure of at least one prior skin directed therapy. The median age was 48 years (range 24–77 yrs). Four (57%) were male, 3 (43%) were female, six (86%) were Caucasian, and 1(14%) were African American. Biopsies and photos were obtained at diagnosis and after the completion of 24 treatments. Results: Treatment was initiated at a dose of 200 millijoules (mJ) and was increased by 10–15% each subsequent treatment. The max dose of treatment ranged from 240 mJ to 850 mJ. The total number of administered treatments was 24 delivered over period of 3 months. The median number of treated lesions was 2 (range 1–5). The surface area of treated lesions was <10%. Six patients achieved clinical improvement in appearance of lesions and intensity of pruritis; 2 (29%) achieved clinical remission as confirmed with photos and post-treatment biopsies. One (14%) patient developed first degree burn and 1 (14%) patient developed pruritis. These resolved by the second treatment with EL. There were no treatment-related serious adverse events observed. Conclusion: Our results suggest that EL is effective and well tolerated skin-directed treatment modality for selected patients with early stage MF. However, longer follow-up will be required to assess durability of responses. Advantages of this approach include shorter treatment duration and lower risk of carcinogenesis in the non-affected areas of skin. Prospective study with a larger cohort of patients is necessary to further assess efficacy and safety of this approach. Disclosures: No relevant conflicts of interest to declare.

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