Outcome Of MDS and AML With MDS-Related Changes: Treatment Versus Prognostic Factors

Abstract The significance of host- and disease-related prognostic factors on outcome in patients (pts) with MDS and AML with MDS-related changes (sAML) depends on the treatment given. The impact of therapy opposed to prognostic variables on the heterogeneity of MDS and sAML was investigated. Patients and methods From January, 2004-August, 2012, 367 pts (MDS, n=208; sAML, n=159) consecutively treated (median age 63y) at the University of Leipzig were included. Patients (84%) with marrow blasts >10% received induction chemotherapy (CT; 59%) or azacitidine (AZA; 25%) (after its approval in the EU in January, 2009) with the intention of performing a subsequent allogeneic hematopoietic cell transplantation (HCT) in pts <70y. Up-front HCT was scheduled if blasts were <10% (n=56). Cytogenetics were categorized according to Schanz et al, JCO 2012 for MDS and the WHO classification for sAML. As confounders in the estimation of therapy, host- and disease-related features were investigated in a multistep process. 38% of pts had >2 comorbidities with no difference between MDS and sAML. The sAML group (median blasts 40%) included 69 and 81 pts with previous MDS and MDS-related cytogenetic abnormality respectively. Cytogenetics were poor and very poor in 34% of MDS. Outcome at two years are presented. Results Median interval between diagnosis of MDS and therapy was 3.6 months. Median survival time for sAML was 15 vs 72 months for MDS (p<0.0005). Overall, age was higher (median 68y) and blasts lower (median 13%) in the AZA group compared to CT (62y and 27%) (p<0.0005). Cytogenetics and the comorbidity burden (CB) were comparable. OS with AZA was similar to up-front HCT (68%) and superior to CT (48%) (p=0.01). OS was 50% if HCT was performed after CT (136 pt) compared to CT alone (p=0.01). In the 20% of pts >70y, AZA was given to 52% and CT to 48%. OS was 55% and best with AZA (p=0.01). Median survival times were 30 for AZA/MDS, 27 for AZA/AML, 15 for CT/AML, and 5 months for CT/MDS. Of the 110 pts <70y with MDS, AZA was given to 50 (45%) and CT to 60 (55%). The IPSS, cytogenetics, CB, BM blasts (10% vs 11.5%) were similar in both groups. With a median age of 63y, the AZA/MDS group was older than the CT/MDS group (median age 60y) (p=0.005). OS for both groups was 68%. NRM (16%) and RI (38% vs 34%) were alike. For the 114 pts <70y with sAML (median age 62%; median blasts 44%) treated with CT, OS was 40% and inferior to MDS (AZA/MDS, p=0.007; CT/MDS, p=0.01) due to higher RI (57%) (p=0.008). Overall, 218 (78%) pts <70y received HCT (after a median of 3 AZA cycles for AZA/MDS). Ferritin, cytogentics, CB, type of donor, and blasts at HCT (median 4%) were comparable in the transplant groups (AZA/MDS, CT/MDS, HCT up-front, CT/sAML). Irrespective of prior therapy (p=0.6), interval between therapy and HCT, and blasts <5 vs >5-<10%, outcome in the MDS groups (OS, 60%, NRM 29%, RI, 32%) was similar. In multivariate analysis, >2 comorbidities and very poor cytogenetics were associated with an inferior OS (p=0.001)and a higher RI (p=0.003). With a median survival time of 11 months for sAML and a RI of 49%, outcome after HCT for sAML was inferior to MDS (p=0.005). In multivariate analysis, blasts <5%, >2 comorbidities were associated with a poor outcome. For MDS/CT and sAML/CT, a complex karyotype (38%) tended to decrease OS (p=0.06) and increase RI (p=0.01) after HCT. Conclusions Treatment was able to reduce the significance of most negative host- and disease-specific prognostic factors on outcome in MDS. AZA is superior to CT in elderly patients and equal to CT in younger patients with MDS and seems to have no negative impact on outcome after HCT. Despite the improvement achieved with allogeneic HCT, AML with MDS-related changes remains a distinct clinic-pathologic entity associated with a worse outcome. Genetics rather than marrow blasts are an important determinant of prognosis after treatment including allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

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Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative Disorders

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.3.772 ◽

2001 ◽

Vol 19 (3) ◽

pp. 772-778 ◽

Cited By ~ 162

Author(s):

Véronique Leblond ◽

Nathalie Dhedin ◽

Marie-France Mamzer Bruneel ◽

Sylvain Choquet ◽

Olivier Hermine ◽

...

Keyword(s):

Prognostic Factors ◽

Complete Remission ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Univariate Analysis ◽

Lymphoproliferative Disorders ◽

Long Term Outcome ◽

Pathologic Features ◽

Risk Patients

PURPOSE: Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkin’s lymphoma International Prognostic Index (IPI) in 61 patients with PTLD. PATIENTS AND METHODS: We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates. RESULTS: In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) ≥ (P = .0001) and nondetection of Epstein-Barr virus (EBV) in the tumor (P = .01). Only a negative link with PS ≥ 2 was observed in multivariate analysis. In univariate analysis, factors predictive of lower survival were PS ≥ 2, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy. The IPI failed to identify a patient subgroup with better survival and was less predictive of the response rate than was a specific index using two risk factors (PS and number of involved sites), which defined three groups of patients: low-risk patients whose median survival time has not yet been reached, intermediate-risk patients with a median survival time of 34 months, and high-risk patients with a median survival time of 1 month. CONCLUSION: PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.

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Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study

Nutrients ◽

10.3390/nu12041076 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1076 ◽

Cited By ~ 1

Author(s):

Shigeo Shimose ◽

Takumi Kawaguchi ◽

Hideki Iwamoto ◽

Masatoshi Tanaka ◽

Ken Miyazaki ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Nutritional Status ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Rank Test ◽

Multicenter Cohort Study ◽

The Impact ◽

Conut Score

We aimed to investigate the impact of the controlling nutritional status (CONUT) score, an immuno-nutritional biomarker, on the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). This retrospective study enrolled 164 patients with HCC and treated with LEN (median age 73 years, Barcelona Clinic Liver Cancer (BCLC) stage B/C 93/71). Factors associated with overall survival (OS) were evaluated using multivariate and decision tree analyses. OS was calculated using the Kaplan–Meier method and analyzed using the log–rank test. Independent factors for OS were albumin–bilirubin grade 1, BCLC stage B, and CONUT score <5 (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.58–5.31, p < 0.001). The CONUT score was the most important variable for OS, with OS rates of 70.0% and 29.0% in the low and high CONUT groups, respectively. Additionally, the median survival time was longer in the low CONUT group than in the high CONUT group (median survival time not reached vs. 11.3 months, p < 0.001). The CONUT score was the most important prognostic variable, rather than albumin–bilirubin grade and BCLC stage, in patients with HCC treated with LEN. Accordingly, immuno-nutritional status may be an important factor in the management of patients with HCC treated with LEN.

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CXCR4 Invalidation Limits the MLL-ENL Induced Leucemogenesis in Vivo

Blood ◽

10.1182/blood.v120.21.4089.4089 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4089-4089

Author(s):

Yanyan Zhang ◽

Hadjer Abdelouahab ◽

Aline Betems ◽

Monika Wittner ◽

William Vainchenker ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Abstract 4089 The receptor CXCR4 and its ligand SDF-1 play major physiological roles especially on hematopoietic stem cells homing and retention. Many studies have implicated CXCR4 in the invasion by tumor cells of organs that produce SDF-1. In acute myeloid leukemia, the physiological role of CXCR4 is not fully understood. We used retrovirus to express MLL-ENL oncogene in CXCR4+/+ and CXCR4−/− hematopoietic primitive cells (Lin- isolated from fetal liver) and showed that CXCR4 is dispensable for generation of immortalized colonies in vitro. To determine CXCR4 function in vivo, CXCR4+/+ and CXCR4−/− transformed cells were transplanted into lethally irradiated mice. Whatever their phenotype, the recipient developed a myelo-monocytique leukemia characterized by their expression of Gr-1 and Mac-1. As expected, all recipients of MLL-ENL transduced CXCR4+/+ cells were moribund within 35 to 80 days post transplant (median survival time: 50 days). Strikingly, recipients of MLL-ENL transduced CXCR4−/− cells showed significantly increased lifespan, with a median survival time of 90 days. The cellularity of the peripheral blood of recipients of MLL-ENL transduced cells displayed considerable increases over time although this increase was much lower in CXCR4−/− than in CXCR4+/+ chimera. Bone marrow of MLL-ENL transduced CXCR4−/− chimera had moderately decreased numbers of mononuclear cells. There were important numbers of leukemic CD45.2+/Gr1+/Mac1+/c-kit+ cells in spleen from MLL-ENL CXCR4+/+ chimera which suggested that CXCR4 is important for leukemic progenitors cells retention in the bone marrow and especially in the spleen. The homing capacity of transduced CXCR4+/+ cells is comparable to the CXCR4−/− cells. Finally, more DNA damages were found in the BM cells of MLL-ENL CXCR4−/− chimera. All these results were confirmed by treating of MLL-ENL CXCR4+/+ chimera with CXCR4 inhibitor (TN140). These results demonstrated that in absence of CXCR4, the cells transduced by oncogene MLL-ENL are capable of generating leukemia in the recipients. However, mice transplanted with MLL-ENL transduced CXCR4−/− FL cells developed acute myeloid leukemia with reduced aggressiveness and organ infiltration, which is associated with induced differentiation and DNA instability. These results indicated that the MLL-ENL progenitors are dependent on CXCR4 for their maintenance in the BM and spleen suggesting that CXCR4 inhibitors might have potential therapeutic applications. Disclosures: No relevant conflicts of interest to declare.

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Impact of surgery and chemotherapy on survival in patients with advanced cholangiocarcinoma: A multivariate analysis in a cohort of 242 consecutive patients

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4133 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4133-4133

Author(s):

C. Dreyer ◽

C. Le Tourneau ◽

S. Faivre ◽

V. Paradis ◽

Q. Zhan ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Lymph Node ◽

Median Survival ◽

Tumor Size ◽

Positive Impact ◽

Univariate Analysis ◽

Lymph Node Involvement ◽

Node Involvement ◽

The Impact

4133 Background: Cholangiocarcinoma remains an orphan disease for which prospective studies are missing to evaluate the impact of systemic chemotherapy on survival. Methods: Univariate and multivariate analysis of parameters that might impact survival were analyzed in a cohort of 242 consecutive patients with cholangiocarcinoma treated in a single institution between 2000 and 2004. Variables were WHO performance status (PS), age, symptoms, tumor size, extent of the disease, lymph node involvement, site of metastasis, tumor markers, pathology, and type of treatment including surgery, chemotherapy and radiotherapy. Results: Statistically significant prognostic factors of survival in univariate analysis are displayed in the table : In multivariate analysis, PS, tumor size and surgery were independent prognostic factors. Subgroup analysis demonstrated that in patients with advanced diseases (lymph node involvement, peritoneal carcinomatosis and/or distant metastasis), patients who had no surgery benefited of chemotherapy (median survival 13.1 versus 7.4 months in patients with/without chemotherapy, p = 0.006). Moreover, survival was further improved when patients could benefit of chemotherapy following total and/or partial resection (median survival 22.9 versus 13.0 months in patients with/without chemotherapy, p = 0.03). Conclusions: This study strongly suggests the positive impact on survival of multimodality approaches including surgery and chemotherapy in patients with advanced cholangiocarcinoma. [Table: see text] No significant financial relationships to disclose.

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Hypercalcemia- Leukocytosis Syndrome: A Rare Ominous Indicator in Lung Cancer

Blood ◽

10.1182/blood-2018-99-112705 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4966-4966

Author(s):

Taylor Hanson ◽

Ravi Patel ◽

Nitasa Sahu ◽

Zain Ayaz ◽

Julie Caler ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Lactic Acid ◽

Cell Carcinoma ◽

Survival Time ◽

Median Survival ◽

Squamous Cell ◽

Median Survival Time ◽

Poor Prognosis ◽

Conflicts Of Interest

Abstract Introduction: Paraneoplastic syndromes are signs and symptoms that occur in association with malignancy at sites distant from the primary tumor or metastases. They occur in approximately 10% of patients with lung cancer (1). Case: A 59-year-old male with a history of tobacco abuse, COPD, and Stage IV Lung Adenosquamous cancer with brain metastases status post chemotherapy presented with weakness and lethargy. Patient was normotensive and on room air. Clinical exam was significant for confusion with noted chronic cachexia. Labs most prominent were a WBC count of 46.8 (16.3 1mo prior, 44.6 3wks prior) , Cr of 1.9, Ca of 11.9 , and Lactic acid of 3.7. Imaging was consistent with an increase in his RUL cavitary lesion with pleural based lesions and 11 metastatic deposits throughout the brain. He was admitted and started on aggressive intravenous fluids. Furthermore, infectious workup was initiated and empiric antibiotics administered for possible pneumonia. By day 3 of admission his creatinine, calcium, and lactic acid normalized but his wbc continued to trend up to 98.6 despite negative infectious workup. His severe metastatic disease burden along with his failure to thrive carried a poor prognosis. Subsequently, a family meeting was held and he was transitioned to comfort measures. Patient passed away shortly thereafter. Discussion: The case clearly demonstrates poor prognostic indicators with hypercalcemia and severe leukocytosis in the setting of end stage lung adenosquamous carcinoma. Classically, paraneoplastic hypercalcemia is associated with PTHrP production in Squamous Cell carcinoma. Overall incidence of hypercalcemia in lung cancer ranges from to 8%-12% with median survival time (MST) of 3.8 months (1,2).Paraneoplastic Leukocytosis meanwhile is most often associated with adenocarcinoma (42%) and squamous cell carcinoma (36%) with incidence ranging between 16 and 30% and MST of 1.9 months (1,2). Nonetheless, the combination of these two known as Hypercalcemia-Leukocytosis syndrome has been identified an independent clinical entity with an even shorter median survival time in comparison with leukocytosis or hypercalcemia alone of 1.5 months (2). The incidence of this was studied to be 0.5% over a 10 year interval (2). Given this rare occurrence, it is prudent for clinicians to recognize this clinical syndrome and the very poor prognosis it bears . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127595/ G.R. Mundy, K.J. Ibbotson, S.M. D'Souza, E.L.Simpson, J.W. Jacobs, T.J. MartinThe hypercalcemia of cancer. Clinical implications and pathogenic mechanismsN Engl J Med, 310 (1984), pp. 1718-1727 .https://www.sciencedirect.com/science/article/pii/S0169500203004549?via%3Dihub Hypercalcemia-leukocytosis syndrome associated with lung cancer Disclosures No relevant conflicts of interest to declare.

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Marker Chromosomes Are a New Cytogenetic Adverse Risk Factor in AML after Allo-HCT

Blood ◽

10.1182/blood-2018-99-113251 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5260-5260

Author(s):

Kyoko Fuse ◽

Tomoyuki Tanaka ◽

Shun Uemura ◽

Tatsuya Suwabe ◽

Takayuki Katagiri ◽

...

Keyword(s):

Multivariate Analysis ◽

Risk Factor ◽

Median Survival ◽

Poor Prognosis ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Marker Chromosome ◽

Disease Stage ◽

Poor Prognostic Factor ◽

The Impact

Abstract [Background] Chromosome analysis is indispensable for the diagnosis and risk classification of acute myeloid leukemia (AML). A marker chromosome (MC) is a fragmented chromosome that cannot be identified as originating from an existing autosomal or sex chromosome. Although often observed, the significance of MC in hematological malignancies is unknown. Recently, MC was found to be the result of chromothripsis (CT). CT is a catastrophic phenomenon by which chromosomes are shattered into tens to hundreds of fragments. Half of all CT cases are related to TP53 mutation. In addition to MC, complex karyotype (CK), monosomal karyotype (MK) and existing sub-clone (SC) have also been noted as the result of CT. Previous studies reported that MC was a poor prognostic factor in AML. These studies included AML patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT). However, the influence of MC on AML after allo-HCT was not clarified. [Purpose] In this study, we evaluated the impact of MC on the outcome of AML patients after allo-HCT. [Method] This retrospective analysis included 166 AML patients who received allo-HCT at Niigata University Hospital (n=129) or Nagaoka Red Cross Hospital (n=37) between 1990 and 2017. The median age of patients at allo-HCT was 38 years old (range 14-67 y). The median follow-up period was 2.0 y (range 0.0-22.2 y). According to the revised Medical Research Council (rMRC) criteria for cytogenetic risk categories, 26 (15.7%), 104 (62.7%) and 36 (21.7%) patients were categorized as favorable, intermediate and adverse-risk, respectively. Myeloablative conditioning was used for 128 (77.1%) and reduced-intensity was used for 38 (22.9%) patients. Donors were related for 83 (59.3%) and unrelated for 57 (40.7%) patients. The Kaplan-Meier method (log-rank test) and Gray's test were used to estimate the probabilities of overall survival (OS) and cumulated incidence of relapse (CIR). The impact of several variables was assessed by multivariate analysis using a Cox regression model and Fine-Gray test with backward stepwise selection based on the p-value. For the comparison of clinical phenotypes, category variables were evaluated by Fisher's exact test. [Results] MC was detected in 14 (8.4%) of 166 patients. Eleven (78.6%) were grouped as adverse-risk by rMRC criteria. CK, MK and SC were observed in 26 (16.3%), 20 (12.0%) and 23 (13.9%) patients, respectively. The median age of AML/MC+ (n=14) and AML/MC-(n=152) patients were similar (38.5 y, range 19-64 y vs 38 y, range 14-64 y, P=0.812). Twelve AML/MC+ patients (85.7%) received allo-HCT at the advanced stage (³3 CR or non-remission) and 10 (71.4%) had primary induction failure (PIF). Compared with AML/MC- patients, those with AML/MC+ had a higher incidence of MK (78.6% vs. 5.9%, p<0.001), sub-clone (64.3% vs. 9.2%, p<0.001) and CK (85.7% vs. 9.9%, p<0.001). On univariate analysis, the 2-y OS and median survival period of AML/MC+ patients were shorter than those of AML/MC- patients (26.8% vs. 61.3% and 0.78 y vs. 4.9 y, p=0.0126). The 2-y CIR of AML/MC+ patients was higher than that of AML/MC- patients (80.4% vs. 37.2%, p<0.01). To further investigate the impact of MC on the outcome, we compared AML patients with/without MC who had the cytogenetic adverse-risk karyotype. The 2-y OS of adverse-risk AML/MC+ patients (n=11) was shorter than that of adverse-risk AML/MC- patients (n=25) (9.1% vs 58.3%, p=0.003). The median survival periods were 0.58 y and 4.0 y, and the 2-y CIR was 89.6% and 44.7% (p=0.002), respectively. The 2-y OS based on the other risk factors in adverse-risk AML patients were as follows: CK+ 33.2%, MK+ 26.9% and SC+ 34.7%. As these results suggested MC to be a poorer risk factor, we performed multivariate analysis for confirmation. In the multivariate analysis adjusted for CK, MK, SC, donor, conditioning and disease stage before allo-HCT, only MC was an independent poor risk factor for OS (HR 3.547, 95%CI: 1.46-8.63, p=0.005) and CIR (HR 3.90, 95%CI: 1.47-10.33, p=0.006) among adverse-risk AML patients using the rMRC criteria. [Conclusion] It is very difficult for AML/MC+ patients to achieve complete remission, leading to a markedly poor prognosis after allo-HCT. The outcome for AML/MC+ was inferior to that for AML with CK, MK, SC or the current adverse-risk karyotype by rMRC. This analysis revealed MC as a new independent factor that further indicates a poor prognosis after allo-HCT, especially in high-risk AML patients. Disclosures No relevant conflicts of interest to declare.

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Onodera’s prognostic nutritional index is a strong prognostic indicator for patients with hepatocellular carcinoma after initial hepatectomy, especially patients with preserved liver function

10.21203/rs.3.rs-28900/v1 ◽

2020 ◽

Author(s):

Akihiro Tanemura ◽

Shugo Mizuno ◽

Aoi Hayasaki ◽

Kazuyuki Gyoten ◽

Takehiro Fujii ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Prognostic Factor ◽

Liver Function ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Prognostic Nutritional Index ◽

Nutritional Index ◽

Initial Hepatectomy

Abstract Background Several inflammation-based scores are used to assess the surgical outcomes of hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the prognostic value of the prognostic nutritional index (PNI) in HCC patients who underwent hepatectomy with special attention to preoperative liver functional reserve.Methods Preoperative demographic and tumor-related factors were analyzed in 189 patients with HCC undergoing initial hepatectomy from August 2005 to May 2016 to identify significant prognostic factors.Results Multivariate analysis for overall survival (OS) revealed that female gender (p=0.005), tumor size (p<0.001) and PNI (p=0.001) were independent prognostic factors. Compared to the High PNI group (PNI ≥37, n=172), the Low PNI group (PNI <37, n=17) had impaired liver function and significantly poorer OS (13% vs. 67% in 5-year survival, p=0.001) and recurrence-free survival (RFS) (8 vs. 25 months in median survival time, p=0.002). In the subgroup of patients with a preserved liver function of LHL15 ≥0.9, PNI was also independent prognostic factor, and OS (21% vs. 70% in 5-year survival, p=0.008) and RFS (8 vs. 28 months in median survival time, p=0.018) were significantly poorer in the Low PNI group than the High PNI group.Conclusions PNI was an independent prognostic factor for HCC patients who underwent hepatectomy. Patients with PNI lower than 37 were at high risk for early recurrence and poor patient survival, especially in the patients with preserved liver function of LHL ≥0.9.

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Deficiency of Either Carboxypeptidase B2 or Carboxypeptidase N Exacerbated Disease Activity in a Mouse Model of Hemolytic Uremic Syndrome

Blood ◽

10.1182/blood.v128.22.3758.3758 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3758-3758

Author(s):

Lawrence L. Leung ◽

Zhifei Shao ◽

Toshihiko Nishimura ◽

Qin Zhou ◽

Laura Gigliello ◽

...

Keyword(s):

Mouse Model ◽

Hemolytic Uremic Syndrome ◽

Survival Time ◽

Median Time ◽

Median Survival ◽

Median Survival Time ◽

Conflicts Of Interest ◽

Uremic Syndrome ◽

Carboxypeptidase N ◽

C5a Anaphylatoxin

Abstract Two different basic carboxypeptidases circulate in blood - carboxypeptidase N (CPN) and proCPB2. CPN is constitutively active, while proCPB2 is a zymogen, (also termed thrombin activatable fibrinolysis inhibitor, TAFI), and is activated by the endothelial thrombin/thrombomodulin complex to CPB2. Their kinetics of substrate cleavage are distinct but both can efficiently inactivate the complement anaphylatoxins, C3a and C5a. Hemolytic uremic syndrome (HUS) is caused by Shiga toxin (stx) producing strains of E. coli and is characterized by the triad of hemolysis, thrombocytopenia and uremia. We hypothesized that in a mouse model of HUS, Cpb2-/- and Cpn-/- mice would have prolonged C5a anaphylatoxin activity thus causing disease exacerbation. HUS was induced by stx2 and LPS administration in WT, Cpn-/- and Cpb2-/- mice. In Cpb2-/- mice, median time to death was earlier (60 hours, n=15) than in WT mice (96 hours: n=42, p<0.0001), and had greater kidney and liver damage shown by increases in ALT, AST, BUN and creatinine levels at 48 hours (creatinine Cpb2-/-: 1.01 mg/dL, WT: 0.25 mg/dL; Cpb2-/- control: 0.20 mg/dL and WT control: 0.19 mg/dL; Cpb2-/- p<0.0001 vs. all other groups, n>9). An increase in hemolysis was demonstrated by reduced RBC count and hemoglobin level plus an increase in total bilirubin and LDH. Profound thrombocytopenia (Cpb2-/-: 121,000/μL vs. WT: 217,000/μL; p=ns) developed in both genotypes (control Cpb2-/-: 1,001,000/μL vs. control WT: 1,141,000/μL; p=ns but vs. either Cpb2-/- or WT with HUS, p<0.0001) and thus the HUS clinical triad was present. Histology showed tubular epithelial necrosis in the kidney ante-mortem. Administration of either toxin separately caused milder disease without the characteristics of HUS and with no observed mortality. Induction of the disease depended on co-administration of both toxins. Treatment with anti-murine C5 antibody (0.75 mg every 24 hours from 3 hours before disease initiation) improved survival of both WT and Cpb2-/- mice with a median survival time of 168 hours for both genotypes (n=11, p=0.003 and <0.0001 respectively) and normalized the outcomes between the genotypes. Cpn-/- mice also died sooner (median time to survival 81.5 hours, n=28) than WT mice (96 hours, n=42, p=0.0002). The median survival time between Cpb2-/- and Cpn-/- mice was also significantly different (60 vs. 81.5 hours, p=0.0083). This is a first direct comparison of the role of CPN vs. CPB2 in regulating C5a activity in a disease relevant mouse model. Our study suggests that both CPB2 and CPN protect against HUS by inactivation of C5a with CPB2 having a greater effect than CPN. When Cpb2+/-/Cpn+/- mice are crossed, all expected genotypes are recovered in the expected Mendelian ratios including double deficient Cpb2-/-/Cpn-/- mice. Thus absence of both plasma basic carboxypeptidases is not essential for murine life. We are currently evaluating the Cpb2-/-/Cpn-/- mice in our HUS model. Disclosures No relevant conflicts of interest to declare.

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Survival Benefit of Intervention Treatment in Advanced Anaplastic Thyroid Cancer

International Journal of Surgical Oncology ◽

10.1155/2021/5545127 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Pornthep Kasemsiri ◽

Pimpika Chaisakgreenon ◽

Patravoot Vatanasapt ◽

Supawan Laohasiriwong ◽

Watchareeporn Teeramatwanich ◽

...

Keyword(s):

Prognostic Factors ◽

Survival Rate ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Anaplastic Thyroid Cancer ◽

Overall Survival Rate ◽

Intervention Treatment ◽

One Year ◽

Postoperative Chemoradiation

Background. The management of anaplastic thyroid cancer (ATC) is controversial; thus, proper treatment and prognostic factors should be investigated. Objectives. To compare the survival outcomes of the intervention and palliative treatment in ATC patients. Methods. A hospital-based retrospective study was conducted at a single tertiary university hospital. The medical record charts were retrieved from November 20, 1987, to December 31, 2016. The final follow-up ended by December 31, 2017. The patients’ demographic data, laboratory data, clinical presentation, and treatment modality results were analyzed. Results. One hundred twenty-one records were analyzed with a one-year overall survival rate of 3.5% (median survival time: 77 days); however, 16 cases had insufficient data to classify staging and treatment modalities. Therefore, 105 ATC patients (37 with stage IVa, 39 with stage IVb, and 29 with stage IVc disease) were included with a one-year overall survival rate of 4.0% (median survival time of 82 days). Intervention treatment allowed longer median survival times ( p < 0.05 ) and a better survival rate ( p < 0.05 ). Among the interventional treatment groups, postoperative chemoradiation yielded the longest median survival time (187 days) and the highest survival rate (20%) ( p < 0.05 ). The intervention modality allowed a better median survival time at all stages, particularly in stage IVa ( p < 0.05 ). Unfavorable prognostic factors were adjusted for in a multiple Cox regression model showing that significant factors included age ≥65 years (hazard ratio HR: 2.57), palliative treatment (HR: 1.85), and leukocytosis ≥10,000 cells/mm3 (HR: 2.76). Conclusions. Intervention treatment provided a better survival outcome in all stages, particularly in stage IVa, with a significantly better median survival time. Among interventional treatments, postoperative chemoradiation led to the longest survival rate, suggesting that this treatment should be considered in ATC patients with resectable tumors and no poor prognostic factors, such as older age and leukocytosis.

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Impact Of Dysplasia On Outcome Of Patients With Acute Myeloid Leukemia and Response To Allogeneic Hematopoetic Stem Cell Transplantation

Blood ◽

10.1182/blood.v122.21.5551.5551 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5551-5551

Author(s):

Shatha Farhan ◽

Catherine Carroll ◽

Danielle Pelland ◽

Jose Carlos Velasco ◽

Susan Wautelet ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Survival Time ◽

Median Survival ◽

Peripheral Blood ◽

Median Survival Time ◽

Myeloid Leukemia ◽

Median Number ◽

The Impact ◽

Acute Myeloid

Abstract Background Myelodysplastic syndromes (MDS) are a heterogeneous group of malignancies characterized by dysplasia, cytopenia, ineffective hematopoiesis and by an increased risk of transformation to acute myeloid leukemia (AML). Recurrent aberrant karyotypes cannot entirely account for the genetic defects that are at the basis of the pathogenesis of MDS, as they are detected only in approximately 50% of patients. Allogeneic hematopoietic cell transplantation (HCT) likely prolongs survival in patients with AML and MDS. In this report, we evaluated the impact of presence of dyspoesis in paients with AML with or without cytogenetic (CG) abnormality on outcome in our center. Methods We retrospectively reviewed all patients who were diagnosed with AML (non promyelocytic) in our center between 2002 and 2012. Primary objective was to study the impact of MDS with or without CG abnormalities on outcome of patients with AML. Demographics and disease-related variables were collected. OS was defined as the time from diagnosis to the time of death or last contact. Results Between 2002 and 2012, 123 patients with high or intermediate risk AML patients were treated at our center. Median age at diagnosis was 60 (range 19-89). Median OS for all patients was 368 days. Of 123 patients, 51 had MDS while 73 did not. CG abnormalities were present in 35 (68%) of patients with dyspoetic changes. Median age of AML patients with MDS was 59 while median age of AML without MDS patients was 55. Median number of blasts in bone marrow and peripheral blood in AML patients with MDS was 38% and 6% respectively. While median number of blasts in bone marrow and peripheral blood in AML patients without MDS was 67% and 39% respectively. Of 51 AML patients with MDS, 14 received HCT with median age of 56. Half of these received myeloablative regimen while the other half received reduced toxicity regimen. The median survival time for AML patients without MDS was 401 days while the median survival time for AML patients with MDS was 278 days (p = 0.0201), Fig1. For AML with MDS who received HCT, the median survival time was 586 days while it was 164.5 days for AML patient with MDS who did not receive HCT (p = 0.0013), Fig2. Conclusion In this small cohort from a single center, the results suggest that AML patients with dyspoetic changes do have a worse prognosis despite having lower percentage of blasts in bone marrow or peripheral blood. This can be explained by what Walter et al reprted, using next-generation sequencing, that the proportion of neoplastic marrow cells is indistinguishable in MDS and secondary-AML even with myeloblast count of zero. HCT can be performed in those patients including older patients with promising results. Disclosures: No relevant conflicts of interest to declare.

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