The Prognostic Significance of the Absolute Lymphocyte to Monocyte Count Ratio (ALC/AMC-dx) at Diagnosis in Hodgkin´s Lymphoma

Abstract Background. In Classic Hodgkin's lymphoma (cHL), malignant cells constitute only about 1% of the bulk of tumor tissue, the rest constitutes the microenvironment and is made up of a compound of inflammatory cells. Lymphocytopenia and increased CD68+ tumor-associated macrophages (TAMs) are adverse prognostic factors in cHL. TAMs are derived from circulating monocytes and are possibly related to absolute monocyte count (AMC). We have sought to investigate the relationship of circulating lymphocytes and monocytes with response and survival in patients. Recently, Porrata et al. reported that a low absolute lymphocyte count/absolute monocyte count at diagnosis [ALC/AMC-Dx] (<1.1) is an independent prognostic factor in cHL. Subsequent studies used different cutoffs for ALC/AMC (1.5 and 2.9). Currently, there are no studies that evaluate the usefulness of the index relative to the overall response. Aim To determine the prognostic value of ALC /AMC at diagnosis in patients with cHL and its impact on treatment response to therapy, progression and overall survival. Methods: We evaluated 262 consecutive individuals with cHL, referred and treated at the National Cancer Institute in Mexico between 2006 to 2013. The great majority of patients were treated with ABVD with or without radiotherapy, and all had available data for ALC/AMC determined at diagnosis. It was made a multivariate analysis and ROC curves for cutoff point of ALC/AMC. Results: Median age was 35 y (14-89), 59.2% of patients were male, 77% had B-symptoms, 36.3% had stage IV disease, 85% had advanced stage (IB,IIB,III,IV), 51.5% had IPS ≥3, 46.2% nodular sclerosing histology and 45.4% mixed cellularity. The overall response (CR + PR) was obtained in 188 patients (72%) and failure (stable disease or progressive disease) in 73 patients (28%). A new cutoff point, 1.77 in ALC/AMC-Dx ratio with area under the curve of 0.62. Multivariate analysis showed that the ALC/AMC-Dx index was an independent predictor for response to treatment, progression as well as overall survival (Table 1). Additionally the IPS≥3 showed to be an independent factor for response 68.8% vs 41.7% in low and high risk, respectively (p<0.0000). Conclusion: In our population ALC/AMC-Dx index was established with a cutoff of 1.77. The group of patient with < 1.77 had a less overall response and overall survival. It proves that ALM/AMC-Dx is an independent predictor of response, progression and overall survival in patients with classical cHL. That differs of other reviews where the cutoff was lower. Table 1. Multivariate analysis according to ALC/AMC-DX ratio ALC/AMC -Dx index p Low< 1.77 High >1.77 Overall Response 58.1% 79.8% OR 0.25-.0.84p 0.011 Overall Survival8 years 81% 94% p 0.004 Disclosures No relevant conflicts of interest to declare.

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Correlation of Erythropoietin Stimulating Agents (ESAs) with the Post-Therapy Micro-Vessel Density (MVD) in Newly Diagnosed Myeloma Patients: a Possible Mechanism of ESAs Association with Reduced Survival Rates.

Blood ◽

10.1182/blood.v114.22.4873.4873 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4873-4873

Author(s):

Eirini Katodritou ◽

Evangelos Terpos ◽

Vassiliki Kaloutsi ◽

Evgenia Verrou ◽

Vassiliki Gastari ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Conflicts Of Interest ◽

Independent Predictor ◽

Survival Rates ◽

Response To Treatment ◽

Newly Diagnosed ◽

Bone Marrow Biopsies ◽

Group Post ◽

Post Therapy

Abstract Abstract 4873 Angiogenesis plays a significant role in the biology of multiple myeloma (MM). Erythropoiesis stimulating agents (ESAs) have been recently associated with reduced survival in a subset of cancer patients who receive ESAs, including MM but the etiology for this correlation has not been sufficiently explored. It is known that the endothelial cells produce angiogenic factors, promote the growth and survival of MM cells and carry erythropoietin receptors which in hypoxic conditions they transport the signal for their own proliferation and expansion under the influence of the endogenous erythropoietin. The aim of this study was to investigate the possible impact of ESAs administration on post-therapy angiogenesis. We studied 84 newly diagnosed MM patients (47M/37F; median age: 65 years, range: 39-82 years) who underwent conventional anti-myeloma therapy: 62 patients received VAD (53 of whom within the context of the randomized study VAD vs. TVAD, conducted by the Greek Myeloma Study Group) and 22 patients received MP. Fifty-two patients received ESAs for at least 8 weeks (ESA group), while 32 did not receive ESA (non-ESA group). MVD was assessed in bone marrow biopsies at baseline and at the time of best response by using monoclonal antibodies targeting CD34. The number of microvessels expressing the CD34 antibody was counted by two experienced pathologists through a grid at a magnification of 400x and was finally divided to the number of the high power fields used for screening the whole marrow surface. The counts were finally expressed as number of vessels per mm2 area of the involved marrow. Fifteen individuals with normal findings in the bone marrow were used as controls. Furthermore, the following cytokines that are involved in the angiogenesis process in MM were measured in the serum of both patients and controls on the day of the trephine biopsy performance: VEGF, bFGF, TGF-b, IL-6, soluble IL-6R (sIL-6R), IL-1b and TNF-α, using an ELISA methodology (R&D, Minneapolis, MN, USA). Patients characteristics between the ESA and non-ESA groups at baseline were well balanced except of Hb which was, as expected, significantly lower in the ESA-group (p<0.001). The median follow-up was 84 months (range 5-154). The median number of baseline MVD in the ESA group was 18.5/mm2 (range: 1-29.3) and in the non-ESA group 17.7/mm2 (range: 2-28.5; p=NS) and was higher compared to controls (median 1.2/mm2, range: 0-9; p<0.001 for both comparisons). The post-therapy MVD in the two groups were 16/mm2 (range: 1.8-26) for ESA and 12.8/mm2 (range: 2-29) for non-ESA group, respectively (p=0.03); the % reduction between baseline and post-therapy value was significantly greater in the non-ESA group (non-ESA group: 24.9%, range -36% to +76.6%, ESA group: 14.5%, range -410% to +85.6%, p=0.04). Myeloma patients before treatment had increased serum levels of VEGF (p=0.029), bFGF (p=0.012), IL-6 (p=0.007) and sIL-6R (p=0.047) compared to controls and showed no differences between ESA and non-ESA groups and no alterations post-therapy. Post-therapy, MVD positively correlated with the baseline MVD and baseline β2-microglobulin and negatively correlated with baseline Hb, response to treatment and PFS (p<0.05). In the ESA group but not in the non-ESA group, post-therapy MVD was negatively correlated with response to treatment (p<0.05). In the multivariate analysis, age and post-therapy MVD were the only independent predictors for OS (p=0.04 and p=0.005, respectively; Hz ratio for post-therapy MVD: 1.2, 95% CI: 1.04-1.28). In the ESA group, the multivariate analysis showed that post-therapy MVD >14/mm2 was the only independent predictor for survival (p=0.04; Hz ratio 0.136, 95% CI: 0.02-0.9) whereas in the non-ESA group, post-therapy MVD did not show any significant prognostic value, either used as a continuous or a dichotomous variable. The median PFS for patients with post-therapy MVD >14/mm2, was 13 months (95% CI: 8.5-17.5) and for patients with MVD <14/mm2 was 33 months (95% CI: 25-41; p=0.001). The median OS in patients with MVD >14/mm2 was 37 months (95% CI: 29-45) and for those with MVD <14/mm2 was 63 months (95% CI: 50-75; p=0.04). These results suggest that ESAs may negatively influence the post-therapy MVD. In the ESA group MVD negatively correlated with disease response and MVD >14/mm2 was the only independent predictor for OS. These findings could partially explain the possible association of ESAs with reduced survival rates in newly diagnosed MM patients. Prospective studies are required in order to fully investigate this current issue. Disclosures No relevant conflicts of interest to declare.

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Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk

Blood ◽

10.1182/blood.v122.21.1910.1910 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1910-1910 ◽

Cited By ~ 2

Author(s):

Chrystal Landry ◽

Dory Londono ◽

Sean M. Devlin ◽

Alex Lesokhin ◽

Nikoletta Lendvai ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Disease Risk ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Protein Translation ◽

Response To Therapy ◽

Cytogenetic Abnormality ◽

Newly Diagnosed

Abstract Background Multiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods We identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. Results In unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). Conclusions Karyotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures: No relevant conflicts of interest to declare.

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Younger Adult Acute Myeloid Leukemia (AML) Patients with IDH2-R140 Mutations Have a Significantly Better Prognosis Than Those with Either IDH2-R172 or IDH1 Mutations

Blood ◽

10.1182/blood.v116.21.100.100 ◽

2010 ◽

Vol 116 (21) ◽

pp. 100-100 ◽

Cited By ~ 1

Author(s):

Claire L Green ◽

Catherine M Evans ◽

Robert Hills ◽

Lu Zhao ◽

Alan Burnett ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Prognostic Significance ◽

Response To Therapy ◽

Specific Gene ◽

Npm1 Mutation ◽

Long Term Outcome ◽

Idh1 Mutations ◽

The Impact ◽

Idh2 Mutation

Abstract Abstract 100 The prognostic implications of specific gene mutations in AML can be dependent on their interaction with other mutations so that large cohorts of patients are required for detailed analyses. For example, we have recently reported that the prognostic significance of IDH1 mutations is dependent on FLT3/ITD but not NPM1 mutant status (Green et al, Blood 2010). To explore the impact of IDH2 mutations we have therefore studied a cohort of 1473 well characterized younger adult patients (median age 43 yrs) entered into the UK MRC AML 10 and 12 trials. 10% had an IDH2 mutation and, as with IDH1 mutations, most of them (92%) had intermediate-risk cytogenetics; 64% had a normal karyotype. Remission rates did not differ between IDH2-mut and IDH1/2-WT patients, 78% vs 75% respectively. The cumulative incidence of relapse (CIR) was significantly lower in IDH2-mut than IDH1/2-WT patients (35% vs 50% respectively at 5 yrs, with a hazard ratio [HR] in multivariate analysis of 0.66 (0.48-0.91), P=.02). There was an accompanying trend to improved overall survival (OS) in all patients with IDH2 mutations (50% vs 37%, HR=0.77 [0.60-0.99], P=.1 in multivariate analysis). There was some evidence of interaction between IDH2 and NPM1 mutation status (test for heterogeneity P=.08 for relapse, P=.03 for OS), with a significant beneficial impact of an IDH2 mutation on both CIR and OS only in the 61% of IDH2-mut patients with an NPM1 mutation (CIR at 5 years in the IDH2-mut and IDH2-WT patients: 24% vs 45% respectively, P=.003; OS: 63% vs 47%, P=.02), and no impact of an IDH2 mutation on either relapse or survival in NPM1-WT patients (CIR: 54% vs 55%, P=.4; OS: 29% vs 31%, P=.8). There was no difference in the impact of an IDH2 mutation by FLT3/ITD status. Of the 148 IDH2-mut cases, 119 (80%) had an R140 and 29 (20%) an R172 alteration. There were striking differences between patients with these two mutations. The median presenting white cell count was 30.9 vs 3.6 (× 109/l) for IDH2-R140 and IDH2-R172 cases respectively (P<.0001), the incidence of NPM1 mutations 75% vs 3% respectively (P<.0001), and of FLT3/ITDs 24% vs 7% (P=.05). Response to therapy and long-term outcome were all significantly worse in the IDH2-R172 cases. Remission rate was 86%, 48% and 75% for IDH2-R140, IDH2-R172 and IDH2-WT cases, CIR was 28%, 70% and 50% respectively at 5 years (P=.004 in multivariate analysis) and OS 56%, 24% and 37% (P=.02 in multivariate analysis). The prognosis of IDH2-R172 mutant disease is therefore comparable to that in adverse-risk cytogenetic cases. Overall, these results illustrate that different mutations in the same gene may have significantly different prognostic effects, that the impact of mutations in the IDH2 gene are different from those in the IDH1 gene and that the impact of both IDH1 and IDH2 mutations is dependent on the presence of other cooperating mutations. It should also be noted that the overall survival of NPM1-mut FLT3/ITD-WT cases with an IDH2 R140 mutation (67% at 5 years) is comparable to the CBF leukemia cases in the same trials and such patients should therefore not be considered for transplantation in first remission. Disclosures: No relevant conflicts of interest to declare.

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Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.3.1110 ◽

1997 ◽

Vol 15 (3) ◽

pp. 1110-1117 ◽

Cited By ~ 346

Author(s):

P Brice ◽

Y Bastion ◽

E Lepage ◽

N Brousse ◽

C Haïoun ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

Alkylating Agents ◽

Intensive Therapy ◽

Tumor Burden ◽

Interferon Alfa ◽

Response To Therapy ◽

Response To Treatment ◽

Survival Duration ◽

Overall Response

PURPOSE To evaluate prospectively in patients with follicular lymphoma and a low tumor burden three therapeutic options: delay of any treatment until clinically meaningful progression, immediate treatment with an oral alkylating agent, or treatment with a biologic response modifier, interferon alfa-2b. PATIENTS AND METHODS Newly diagnosed follicular lymphoma patients with a low tumor burden (n = 193) were randomly assigned to one of three arms: arm 1, no initial treatment (n = 66); arm 2, prednimustine 200 mg/m2/d for 5 days per month for 18 months (n = 64); or arm 3, interferon alfa 5 MU/d for 3 months then 5 MU three times per week for 15 months (n = 63). Clinical characteristics were similar in the three arms. RESULTS Overall response rates with prednimustine and interferon alfa were 78% and 70%, respectively. The overall response to therapy, when deferred, was similar at 70%. With a median follow-up duration of 45 months after randomization, the median freedom-from-treatment (FFT) interval was 24 months in arm 1 and the interval of freedom from treatment failure (FFTF) was 40 months in arm 2 and 35 months in arm 3. The median overall survival time was not reached and the overall survival rate at 5 years was 78% in arm 1, 70% in arm 2, and 84% in arm 3. Therefore, deferred treatment does not adversely influence survival at 5 years. Patients who progressed within 1 year had a significantly shorter survival duration (median, 48 months). CONCLUSION Delayed treatment is feasible in patients with follicular lymphoma and a low tumor burden. For patients with early progression, more intensive therapy should be considered. For others, because delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment, the long-term toxicity of alkylating agents can be reduced.

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Survival Analysis of Additional Chromosomal Aberrations in Philadelphia Chromosome Positive and Negative Cells: A Single Institutional

Blood ◽

10.1182/blood.v118.21.2523.2523 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2523-2523

Author(s):

William Bulkeley ◽

Bijal D. Shah ◽

Monique A Hartley ◽

John M. Bennett ◽

Rami S. Komrokji ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Disease Progression ◽

Cox Regression ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Philadelphia Chromosome ◽

Response To Therapy ◽

Blast Phase ◽

Clone Group

Abstract Abstract 2523 Background: Chronic myeloid leukemia (CML) is a clonal stem cell malignancy associated with the Philadelphia chromosome, t(9;22)(q34q31)/BCR-ABL gene fusion. Additional cytogenetic abnormalities have been known to emerge in Philadelphia (Ph) positive cells (additional Ph+ clones) or Ph negative cells (Ph- clones) at diagnosis, or during or post tyrosine kinase inhibitor (TKI) therapy. Many studies have elucidated that the presence of some Ph+ clones were frequently associated with disease progression, while presence of Ph- clones were unrelated to disease outcome. A majority of studies have shown a waxing and waning of Ph- clonality in response to therapy. However, there remains no solid data regarding overall survival comparing Ph+ and Ph- clones over a long term period. This study focuses on the observation of clonal evolution in various phases of CML, and the relationship to overall survival, disease resistance, kinase domain mutation (KDM) and progression to accelerated or blast phase in patients with CML. Materials and Methods: Data from 318 patients who were diagnosed with CML was retrieved from Moffitt Cancer Center during January 1990-December 2010. Patients are divided into three groups based on the presence of additional ph+ clone (A), ph- clone (B) and absence of both (C). Clinicopathologic results including initial diagnosis date, nature and frequency of clone, copy of clone at karyotyping, disease status in response to treatment and overall outcome were documented and statistically analyzed. All patients with Ph- and Ph+ clones have been treated with TKIs since 2001. Median overall survival and median disease progression survival were compared between conal ph- and clonal ph+ group by the log-rank test. Survival curves were generated using the Kaplan–Meier method. All reported P values are two-sided. Cox Regression (multivariate analysis) was also performed for time to progression. Results: Of 318 (average age 57, range: 19 to 89, M:F=1:1), 17 carried ph- clones (5.3%) and 41 showed additional ph+ clones (12.9%) and the rest (258) lacked additional ph+ or ph- clones. Additional clonal cytogenetic aberrations were random with the most frequent occurrence of trisomy 8 (7 of 17 ph- and 14 of 41 ph+ clones, respectively) and isochromosome 17q (4 in ph+ clone only). There is a higher rate of transformation to accelerated/blast phase in Ph+ additional clones (36.6%,15 of 41) as compared to Ph- additional clone (17.6%, 3 of 17) and Ph+ without additional clones(11.1%, 29 of 260) (p=0.015). The overall median survival is shorter in patients with ph+ clones (133.4 months) than in those with ph- clones (172 months) (p<0.005). KDM were observed in 27 of 110 tested patients (24.5%), and many of them fell into the Ph+ clone group (10 of 22 tested) and fewer into ph- clone group (3 of 10 tested) (p<0.005). Statistical analysis proved that there is a higher rate of transformation to accelerated/blast phase in the presence of a KDM (p<0.005). Of note, most of those with ph- clones had only one episode (59%) with 41% having more than one occurrence and lasting from 6–58 months (average 21.1 months), while in those 41 patients with Ph+ clone; a subset (18 of 41, 43.9%) showed a long-lasting ph+ clone over months (ranging from 2 months to 70 months, average 14.5 months) and the remaining only occurred one occasion (23 of 41, 56.1%). Multivariate analysis for disease progression demonstrated statistical significance with regards to both the ph+ clone and kinase mutation categories (p=0.003 and 0.034). Conclusion: Most Ph+ or Ph- clones are occasionally observed during the long course of CML, with a minor subset of clones showing persistency, especially in Ph- ones. The presence of an additional Ph+ clone is correlated with disease progression, drug resistance and shorter overall survival in comparison to a Ph- clone. A relatively long overall survival is observed in patients with ph- clones. Ph- clones were often identified during disease remission regardless of frequency of clonal copy or clonal persistence. The outcome of patients with concurrent Ph+ and Ph- clones was dictated by the Ph+ clone. Disclosures: No relevant conflicts of interest to declare.

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Clinicopathological Characteristics and Prognostic Factors in Axial Chondroblastomas: A Retrospective Analysis of 61 Cases and Comparison with Extra-Axial Chondroblastomas

10.21203/rs.3.rs-1242480/v1 ◽

2022 ◽

Author(s):

Bo-Wen Zheng ◽

Bo-Yv Zheng ◽

Hua-Qing Niu ◽

Xiao-Bin Wang ◽

Guo-Hua Lv ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Univariate Analysis ◽

Prognostic Significance ◽

Clinicopathological Characteristics ◽

Motor Dysfunction ◽

Surrounding Tissue ◽

Wide Resection ◽

Tissue Specimens

Abstract Background The clinical characteristics and prognostic factors of axial chondroblastoma (ACB) are still poorly understood. Purpose To characterize clinicopathological characteristics in a large ACB cohort and investigate their correlation with survival. We also sought to compare these results with extra-axial CB (EACB). Methods Our institution's local database was retrospectively reviewed and included a total of 132 CB patients, including 61 ACB patients and 71 EACB patients. Immunohistochemistry was used to assess the expression levels of Vimentin (Vim), S100, and cytokeratin (CK) on tumor cells in 132 tissue specimens. Results Overall, ACB and EACB had similar characteristics, except for older age and tumor size, as well as higher Vim expression, incidence of surrounding tissue invasion and postoperative sensory or motor dysfunction. Whereas wide resection and absence of invasion of surrounding tissues were consistently associated with favorable survival in the ACB and EACB cohorts in univariate analysis, most parameters showed differential prognostic significance between the 2 groups. Significant prognostic factors for local recurrence-free survival in multivariate analysis included the type of resection and chicken-wire calcification in the ACB cohort. Multivariate analysis of overall survival demonstrated that the type of resection was a significant predictor in the ACB cohort, whereas the type of resection and postoperative sensory or motor dysfunction were predictive of overall survival in the EACB group. Conclusion These data suggest that there may be distinct biological behaviors between ACB and EACB and may provide useful information to better understand the prognostic characteristics of patients with ACB and to improve outcome prediction in patients with ACB.

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The Clinical and Prognostic Significance of Protein Arginine Deiminases 2 and 4 in Colorectal Cancer

Pathobiology ◽

10.1159/000518414 ◽

2021 ◽

pp. 1-11

Author(s):

Mohamed Gijon ◽

Rachael L. Metheringham ◽

Michael S. Toss ◽

Samantha J. Paston ◽

Lindy G. Durrant

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Survival Time ◽

Patient Survival ◽

Prognostic Significance ◽

High Expression ◽

Related Protein ◽

Post Translational Modification

Introduction: Protein arginine deiminases (PADIs) are a family of enzymes that catalyse the post-translational modification of proteins. Association between PADI expression and clinicopathology, protein expression, and outcome was determined. Methods: PADI2 and PADI4 expression was assessed immunohistochemically in a cohort of colorectal cancer (CRC) patients. Results: CRC tissues expressed variable levels of PADI2 which was mainly localised in the cytoplasm and correlated with patient survival (p = 0.005); high expression increased survival time from 43.5 to 67.6 months. Expression of cytoplasmic PADI2 correlated with the expression of nuclear β catenin, PADI4, and alpha-enolase. In contrast, expression of nuclear PADI2 correlated with a decrease in survival (p = 0.010), with high expression decreasing survival from 76.4 to 42.9 months. CRC tissues expressed variable levels of PADI4 in both the nucleus and cytoplasm. Expression of cytoplasmic PADI4 correlated with survival (p = 0.001) with high expression increasing survival time from 48.1 to 71.8 months. Expression of cytoplasmic PADI4 correlated with expression of nuclear β catenin, alpha-enolase (p ≤ 0.0001, p = 0.002), and the apoptotic related protein, Bcl-2. Expression of nuclear PADI4 also correlated with survival (p = 0.011), with high expression of nuclear PADI4 increasing survival time from 55.4 to 74 months. Expression of nuclear PADI4 correlated with p53, alpha-enolase, and Bcl-2. Multivariate analysis showed that TNM stage, cytoplasmic PADI2, and PADI4 remained independent prognostic factors in CRC. Both PADI2 and PADI4 are good prognostic factors in CRC. Conclusion: High expression of cytoplasmic PADI2, PADI4, and nuclear PADI4 were associated with an increase in overall survival.

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CD23 Receptor Positivity Has No Prognostic Implication in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.4397.4397 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4397-4397

Author(s):

Jahan Aghalar ◽

Charles Chu ◽

Rajendra N Damle ◽

Che-Kai Tsao ◽

Nina Kohn ◽

...

Keyword(s):

Flow Cytometry ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Prognostic Markers ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Mutation Status ◽

Percent Positivity ◽

Cd23 Expression

Abstract Abstract 4397 BACKGROUND Chronic Lymphocytic Leukemia (CLL) phenotypically expresses CD23, although the percentage of positive cells measured by flow cytometry is variable. We sought to analyze whether the percent of CD23 positive cells in the CLL clone correlates with time to treat (TTT), overall survival (OS) and prognostic markers CD38, ZAP-70, and IGHV mutation status. METHODS We retrospectively analyzed the flow cytometry data of 332 CLL patients on the gated population of cells that were CD5 and CD19 positive. Percentage positivity for CD23, CD38, and ZAP-70 was noted. CD38 and ZAP-70 were considered positive at cut-offs of >= 30% and >=20%, respectively. CD23 was considered negative at <30% and positive at >= 30%. IGHV sequence was determined from cDNA and then compared to germline to assess mutation status using IMGT/V-QUEST. The distributions of time from diagnosis until start of treatment and overall survival were stratified by CD23 positivity, estimated using the product limit method, and compared using the log rank test. Those who had expired without treatment or were alive and not treated at this time point were censored in the TTT analysis. Those who were still alive were censored in the OS analysis. Associations of CD23 positivity with IGHV mutation status, ZAP-70, and CD38 positivity were examined using the chi-square test. RESULTS Out of 332 patients, 25 had diminished CD23 expression (<30%) whereas 307 had normal CD23 expression (>30%). There was no difference in time until start of treatment or overall survival based on CD23 %positivity. CD23 %positivity showed no associations with IGHV mutation status, ZAP-70 or CD38 positivity. CONCLUSION CD23 percent positivity has no prognostic significance in CLL. There is no correlation between CD23 percent positivity and poor prognostic markers such as CD38, ZAP-70, or IGHV mutation status. Disclosures: No relevant conflicts of interest to declare.

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Clinical Monoclonal B Lymphocytosis (cMBL), Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): Diagnostic Criteria, Features At Diagnosis and Natural History

Blood ◽

10.1182/blood.v122.21.5273.5273 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5273-5273

Author(s):

Rodrigo Santacruz ◽

Julio Delgado ◽

Tycho Baumann ◽

Maria Rozman ◽

Martha Aymerich ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

B Cells ◽

B Cell ◽

Cell Count ◽

Diagnostic Criteria ◽

Conflicts Of Interest ◽

Consistent Difference ◽

Transformation Rate ◽

Mutational Status

Abstract Introduction CLL, SLL and cMBL are considered to be part of the same spectrum of clonal expansions of CD5+ B cells. Clinically, the transition from one to another of these forms over time is a well recognized event. Diagnostic criteria to separate these disorders have been proposed (IWCLL, 2008; WHO, 2008). Aim To compare presenting and evolving features of three groups of patients with cMBL, Rai 0 CLL or SLL and to ascertain the usefulness of current diagnostic criteria for these disorders. Patients and Methods Retrospective study of clinical, biologic and evolving characteristics of patients diagnosed with cMBL, Rai 0 CLL or SLL according to current criteria (CLL: ≥5x109 clonal B cells/L in peripheral blood; SLL <5x109/L clonal B cells with lymphadenopathy, organomegaly, cytopenia or disease-related symptoms; cMBL <5x109 clonal B cells with no signs or symptoms). Results Baseline characteristics of the patients are shown in the Table. Median age was 68 years (range, 24-94) and 57% of patients were males. Out of 1,093 patients, 79 had cMBL (7.2%), 522 Rai 0 CLL (48%) and 94 SLL (8.6%). Overall, adverse biomarkers such as high LDH (p<0.001), high B2M (p<0.001), increased ZAP70 (p<0.001), high CD38 (p<0.001), unmutated IGHV status (p=0.002), +12 (p=0.02) and 11q- (p=0.01) were significantly more frequent in SLL. In subgroup analyses, the only difference between cMBL and Rai 0 CLL was a higher proportion of cases with mutated IGHV in cMBL (p=0.008). Furthermore, when SLL was compared to Rai I to IV CLL no differences were observed (data not shown). The actuarial risk for transformation from cMBL or SLL to CLL was 4.2% and 4.4 % per year (p=0.5), respectively. Median TTFT was significantly shorter in the SLL group (12 m.) than in Rai 0 CLL (174 m.) or cMBL (244 m.) (p<0.001). Median overall survival was also significantly shorter for SLL (94 m.) compared with Rai 0 CLL and cMBL (153 and 157 m., respectively) (p=0.028). Multivariate analysis of 695 patients (cMBL/Rai 0-CLL/SLL) revealed four variables independently correlated with shorter TTFT: diagnosis of SLL vs. Rai 0 CLL vs. cMBL (HR 2.28; p=0.008), high ZAP70 (HR 4.08; p<0.001), high CD38 (HR 4.68; p=0.001) and increased serum B2M levels (HR 1.54; p = 0.031). Importantly, however, when the multivariate analysis was restricted to patients with cMBL and Rai 0 CLL, variables correlated with TTFT were the clonal B-cell count (HR 3.76; p=0.01), ZAP70 (HR 3.31; p<0.001), and CD38 (HR 4.61; p=0.02). FISH cytogenetics, IGHV mutational status,NOTCH1 or SF3B1 mutations were not included in the analysis because of missing data. Conclusions Disparities in biologic and clinical features of cMBL, CLL and SLL mainly reflect the different tumor burden in this spectrum of CD5+ monoclonal B cell disorders. In this study, the transformation rate from either cMBL or SLL to CLL was around 4% per year. As a result of differences in tumor mass, the need for therapy was shorter in SLL than in Rai 0 CLL and cMBL, and the overall survival poorer. Biologically, the only consistent difference between cMBL and Rai O CLL was a higher proportion of mutated IGHV in cMBL. Clinically, however, no differences in median survival were observed. Moreover, the clonal B cell count was the most reliable predictor of disease outcome in both cMBL and Rai 0 CLL. Therefore, the distinction between cMBL and Rai 0 CLL seems hardly justified. Disclosures: No relevant conflicts of interest to declare.

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ASXL1 Mutations in AML: Molecular Biomarker for Secondary AML?

Blood ◽

10.1182/blood.v124.21.2343.2343 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2343-2343

Author(s):

Jingmei Hsu ◽

Anita J. Kumar ◽

Martin P. Carroll ◽

Noelle V. Frey ◽

Nirav N. Shah ◽

...

Keyword(s):

Overall Survival ◽

De Novo ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Myeloproliferative Neoplasm ◽

Molecular Characteristics ◽

Intermediate Risk ◽

Kaplan Meier ◽

The Impact

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.

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