scholarly journals Can Allo-HSCT Improve the Poor Clinical Outcome of the “Internal Tandem Duplication” of the FLT3 Gene?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5938-5938
Author(s):  
Paolo Bernasconi ◽  
Catherine Klersy ◽  
Anna Amelia Colombo ◽  
Daniela Caldera ◽  
Francesco Ripamonti ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Tandem Duplication ◽  
Cox Model ◽  
High Dose ◽  
Internal Tandem Duplication ◽  
Relapse Risk

Abstract AML patients (pts) with a normal chromosome pattern and the “Internal Tandem Duplication” (ITD) of the FLT3 gene have an overall and event-free survival (OS, EFS) inferior than those of pts with a FLT3 “wild-type” gene because of a higher relapse risk, are placed in the intermediate-1 prognostic category, and when in complete remission (CR) are candidates to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the role of allo-HSCT in ITD+ pts is still debated and a recent retrospective analysis has stated that FLT3/ITD adversely affected allo-HSCT outcome in the same direction as it does after chemotherapy. Thus, the present study was aimed to compare the OS, EFS and relapse risk of pts submitted to allo-HSCT in first CR or in initial relapse, defined by a 5-10% bone marrow blast cell percentage, with those of pts submitted to chemotherapy alone. The study cohort consisted of 54 chromosomally normal, ITD+ consecutive non-M3 AML pts who were included in 168 AML pts aged 18-66 years who came to our observation in the period January 2007-December 2013. At diagnosis median age was 48.6 years (range 18-66), 25 pts were males and 29 females. Median follow-up was 16.2 months (0.4-68.8): median follow-up for responsive pts was 7.15 months (range 0.26-27.6), for relapsed pts was 18.1 (range 1.9-68.8) and for transplanted pts was 9.1 months (range 2.9-26.8). All pts received the same induction treatment that consisted of standard Idarubicine+Ara-c “3+7” followed by two consolidation courses with high-dose Ara-c. Those who failed induction received other treatment schedules among which Fludarabine+Ara-c+Idarubicine was the most common. At the end of consolidation 38 pts were in first CR, achieved after 3+7 in 27 pts and after a second different course in 11. Sixteen pts had a resistant disease. After a median time of five months (range 1-21) 21/38 pts (55.2%) relapsed. All received a re-induction and 8/21 (38.1%) attained a second CR. Allo-HSCT was performed in a total of 23 pts: 12 first CRs, 6 second CRs and 5 initial relapses. The donor was a sibling in 7 pts, an unrelated donor in 13 and an haplo-identical donor in 3; the HSC source was the marrow in 6 pts, the peripheral blood in 16 and the cord blood (CB) in one. The Conditioning regimen was myeloblative (mainly Busulfan+Fludarabine) in 21 and non-myeloblative in 2; GvHD prophylaxis consisted of Cyclosporine A, steroids and methotrexate “short course”. The median number of CD34+ cells infused was 5.14x106/kg (1.3-12.7). All pts except that who received CB engrafted after a median time of 15 days (12-28); 21 were complete chimeras, two partial chimeras. Thirteen pts developed acute GvHD (grade I in 3 pts, grade II in 5, grade III in 2 and grade IV in 3) which totally/partially recovered after high dose steroids along with different immunosuppressive drugs in 4 and 9 pts respectively. Eleven pts developed a chronic GvHD which was the evolution of an aGvHD in 9, targeted different organs, was stable in 3 pts and completely/partially recovered in 4 and 2 pts respectively. Post-transplant relapse occurred in 3/12 first CRs, in none second CRs and in 3/5 initial relapse. The estimated response rate for CR pts submitted to allo-HSCT was 422.1 (95% CI: 262.4-679.1) versus 64.6 (95% CI: 40.7-102.6) for those submitted to chemotherapy alone with a median survival time of 7.2 months (range 5.3-8.8) versus not reached (1.9-not available); on univariable Cox model the HR of allo-HSCT pts was 37.9 (95% CI: 9.4-152.0) with p=0.0000. The estimated relapse rate for CR pts submitted to allo-HSCT was 8.6 (95% CI: 2.1-34.4) versus 44.3 (95% CI: 25.7-76.3) for those submitted to chemotherapy alone with a median survival time not reached (range not available) versus 13.2 (7.2-not available); on univariable Cox model the HR of allo-HSCT pts was 0.5 (95% CI: 0.2-1.1) with p=0.06. The estimated death rate for CR pts submitted to allo-HSCT was 28.7 (95% CI: 13.7-60.4) versus 49.7 (95% CI: 32.1-77.1) for those submitted to chemotherapy alone with a median survival time of 18.3 months (range 14.2-not available) versus 12.2 (8.8-18.9); on univariable Cox model the HR for allo-HSCT pts was 0.48 (95% CI: 0.2-1.1) with p=0.09. In conclusion, our series suggests that in ITD+ pts allo-HSCT significantly strengthens CR in pts who had already responded to conventional chemotherapy, but it presents only a trend towards significance when its superiority to prevent relapse was considered. Disclosures Castagnola: Gilead Sciences: Research Funding.

Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid.

1986 ◽  
Vol 4 (5) ◽  
pp. 685-696 ◽  
Author(s):  
D Machover ◽  
E Goldschmidt ◽  
P Chollet ◽  
G Metzger ◽  
J Zittoun ◽  
...  
Keyword(s):  
Survival Time ◽  
Folinic Acid ◽  
Disease Progression ◽  
Median Time ◽  
Gastric Adenocarcinoma ◽  
Median Survival ◽  
Median Survival Time ◽  
Single Agent ◽  
High Dose ◽  
Gastric Adenocarcinomas

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.

Survival of multiple myeloma patients who are potential candidates for early high-dose therapy intensification/ autotransplantation and who were conventionally treated.

1996 ◽  
Vol 14 (7) ◽  
pp. 2167-2173 ◽  
Author(s):  
J Bladé ◽  
J F San Miguel ◽  
M Fontanillas ◽  
A Alcalá ◽  
J Maldonado ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
L 62

PURPOSE To analyze the outcome of patients with multiple myeloma (MM) who were potential candidates for early high-dose therapy (HDT) intensification followed by autotransplantation from a series treated with conventional chemotherapy. PATIENTS AND METHODS From January 1985 through December 1989, 487 patients with symptomatic MM were entered onto a randomized study to compare melphalan and prednisone (MP) versus vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) /vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). The sub-group of 77 patients who could have been candidates for early intensification with HDT followed by stem-cell support (ie, < 65 years of age, stage II or III disease, performance status < 3, and objective or partial response to initial chemotherapy) are the subjects of this report. RESULTS Seventy-seven of 487 patients could have been candidates for early intensification. The median age was 56 years (range, 27 to 64). At diagnosis, 12% had abnormal renal function, 16% hypercalcemia, and 42% serum beta 2-microglobulin level > or = 6 mg/L; 62% had stage III disease at diagnosis. Thirty-six patients were initially treated with MP and 41 with VCMP/VBAP. The median response duration to initial chemotherapy was 22 months, and the actuarial probability of being in continued first response at 5 years was 14%. After a median follow-up time of 58 months, 59 patients have died, one was lost to follow-up evaluation, and 17 are still alive 69 to 119 months after initial chemotherapy. The median survival time from initiation of treatment was 60 months and from the time when autotransplantation would be considered, 52 months. The only independent prognostic parameter for survival was renal function at diagnosis. CONCLUSION The median survival time of patients with MM who are less than 65 years of age and who respond to initial chemotherapy is 5 years. This survival duration is similar to that reported in selected series of patients given early HDT and stresses the importance of ongoing randomized trials to determine the role of HDT in the treatment of younger myeloma patients.

scholarly journals An Evaluation of Survival of Space Maintainers: A Six-year Follow-up Study

2005 ◽  
Vol 6 (1) ◽  
pp. 74-84 ◽  
Author(s):  
Ozlem Tulunoglu ◽  
Tezer Ulusu ◽  
Yasemin Genç
Keyword(s):  
Survival Time ◽  
Success Rate ◽  
Median Survival ◽  
Median Survival Time ◽  
Age Groups ◽  
Age Group ◽  
Follow Up Study ◽  
Different Types ◽  
Lost To Follow Up

Abstract The aim of this study was to evaluate the median survival time of fixed and removable space maintainers related to age groups, gender, and their distribution in upper and lower dental arches. The adherence of patients to a periodic recall program and the success rate of different types of space maintainers related to different arches were also evaluated. This study included 663 patients aged between 4-15 years old that were treated between the years of 1997 and 2002. The patients were categorized into four main groups: lost to follow-up, failed, successful, and censored at the end of study. Three hundred forty-five space maintainers were considered lost to follow-up, 83 were considered failed, 206 successful, and 20 censored-at-end. The overall median survival time of the appliances was 6.51 months. Median survival time was 7.25 months in the 4-6 age group, 6.35 months in the 7-12 age group, and 7.0 months in the 13+ age groups. Median survival time was 5.76 months in girls and 7.11 months in boys. Median survival time of space maintainers was 7.17 months for maxilla and 6.69 months in the mandible. Median survival time was 5.25 months for space maintainers fabricated in both arches. Citation Tulunoglu Ö, Ulusu T, Genç Y. An Evaluation of Survival of Space Maintainers: A Six-year Follow-up Study J Contemp Dent Pract 2005 February;(6)1:074-084.

Repeat decompression surgery for recurrent spinal metastases

2010 ◽  
Vol 13 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Ilya Laufer ◽  
Andrew Hanover ◽  
Eric Lis ◽  
Yoshiya Yamada ◽  
Mark Bilsky
Keyword(s):  
Spinal Cord ◽  
Survival Time ◽  
Median Survival ◽  
Spinal Cord Compression ◽  
Median Survival Time ◽  
Eastern Cooperative Oncology Group ◽  
Cord Compression ◽  
Decompression Surgery ◽  
High Grade

Object In this paper, the authors' goal was to determine the outcome of reoperation for recurrent epidural spinal cord compression in patients with metastatic spine disease. Methods A retrospective chart review was conducted of all patients who underwent spine surgery at the Memorial Sloan-Kettering Cancer Center between 1996 and 2007. Thirty-nine patients who underwent reoperation of the spine at the level previously treated with surgery were identified. Only patients whose reoperation was performed because of tumor recurrence leading to high-grade epidural spinal cord compression or recurrence with no further radiation options were included in the study. Patients who underwent reoperations exclusively for instrumentation failure were excluded. All patients underwent additional decompression via a posterolateral approach without removal of the spinal instrumentation. Results Patients underwent 1–4 reoperations at the same level. A median survival time of 12.4 months was noted after the first reoperation, and a median survival time of 9.1 months was noted after the last reoperation. At last follow-up 22 (65%) of 34 patients were ambulatory at the time of last follow-up or death, and the median time between loss-of-ambulation and death was 1 month. Functional status was maintained or improved by one Eastern Cooperative Oncology Group grade in 97% of patients. A major surgical complication rate of 5% was noted. Conclusions Reoperation represents a viable option in patients with high-grade epidural spinal cord compression who have recurrent metastatic tumors at previously operated spinal levels. In carefully selected patients, reoperation can prolong ambulation and result in good functional and neurological outcomes.

scholarly journals Effect of Hemoglobin on the Prognosis of Patients with Advanced Cancer in Palliative Care Settings

2021 ◽  
Author(s):  
xinghe liao ◽  
Cihang Bao ◽  
Minghui Liu ◽  
Menglei Chen ◽  
Xiaoli Gu ◽  
...  
Keyword(s):  
Survival Time ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Median Survival ◽  
Median Survival Time ◽  
Palliative Treatment ◽  
Treatment Center ◽  
Cancer Center ◽  
Advanced Cancer Patients

Abstract Background: Hemoglobin is a prognostic factor for many cancer patients. However, its effect on the prognosis of patients with advanced cancer receiving palliative treatment is still unclear.Objective: The aim of this study was to assess whether hemoglobin can be used as a prognostic indicator for patients with advanced cancer receiving palliative treatment.Methods: From July 2013 to October 2015, 368 consecutive patients were treated in the palliative treatment center of the Shanghai Cancer Center of Fudan University. The data for 105 patients were extended in the follow-up. The cut-off value selected for hemoglobin was 100 g/L.Results: The median survival time of patients with low hemoglobin was shorter than that of patients with high hemoglobin (41 days vs. 84 days). In the follow-up readmission cohort (n = 105), the median survival time for patients with high hemoglobin (HHb → HHb) was 3.44 times longer than that of patients with low hemoglobin (HHb → LHb). Thus, both low hemoglobin and decreased hemoglobin were identified as independent prognostic factors for poor prognosis.Conclusions: In palliative treatment, hemoglobin can be used as a stratification factor to determine the prognosis of advanced cancer patients.

scholarly journals Primary Squamous Cell Carcinomas Arising in Intracranial Epidermoid Cysts: A Series of Nine Cases and Systematic Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Pengcheng Zuo ◽  
Tao Sun ◽  
Yi Wang ◽  
Yibo Geng ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Squamous Cell ◽  
Median Survival Time ◽  
Postoperative Radiotherapy ◽  
Squamous Cell Carcinomas ◽  
Epidermoid Cysts ◽  
Pubmed Database ◽  
Intracranial Epidermoid

ObjectivePrimary squamous cell carcinomas (PSCCs) arising in intracranial epidermoid cysts (IECs) are very rare, and their management and prognostic factors remain unclear. This study aimed to enunciate the clinical features and suggest a treatment protocol based on cases from the literature and the cases from our institution.MethodsThe clinicoradiological data were obtained from nine patients with PSCCs arising in IECs, who underwent surgical treatment at Beijing Tiantan Hospital between July 2012 and June 2018. We also searched the PubMed database using the keywords “epidermoid cyst(s)” or “epidermoid tumor(s)” combined with “malignant” or “malignancy” or “intracranial” or “brain” or “squamous cell carcinoma” between 1960 and 2020. Risk factors for overall survival (OS) were evaluated in the pooled cohort.ResultsThe mean age of our cohort was 51.2 ± 8.3 years (range: 39–61 years), which included eight males and one female. Gross total resection (GTR) was achieved in three patients, while non-GTR was achieved in six patients. Radiotherapy was administered to five patients. After a median follow-up of 16.7 ± 21.6 months (range: 3–72 months), eight patients died with a mean OS time of 9.75 ± 6.6 months (range: 3–23 months). In the literature between 1965 and 2020, 45 cases of PSCCs arising in IECs were identified in 23 males and 22 females with a mean age of 55.2 ± 12.4 years. GTR, non-GTR, and biopsy were achieved in six (13.3%), 36 (80%), and three (6.7%) cases, respectively. After a mean follow-up of 12.7 ± 13.4 months (range: 0.33–60 months), 54.1% (20/37) patients died, and recurrence occurred in 53.6% (15/28) patients. A multivariate analysis demonstrated that postoperative radiotherapy (p = 0.002) was the only factor that favored OS. The Kaplan–Meier analysis showed that, compared with no radiotherapy (median survival time: 4 months), radiotherapy (median survival time: 24 months) had significantly prolonged OS (p = 0.0011), and GTR could not improve OS (p = 0.5826), compared with non-GTR. The 1-year OS of patients with or without radiotherapy was 72.5% or 18.2%, respectively.ConclusionMalignant transformation of IEC into PSCC was prevalent in elderly patients, with slight male predominance. GTR of previous benign IECs is recommended. For remnant benign IECs, close follow-up should be performed. Postoperative radiotherapy for PSCCs could bring survival benefit. GTR of these malignant intracranial tumors is difficult when they involve important brain structures. Future studies with larger cohorts are necessary to verify our findings.

scholarly journals Influence of chemiotherapeutic protocol and neuroendocrine differentiation on metastatic non-small cell lung cancer treatment results

2007 ◽  
Vol 64 (9) ◽  
pp. 591-596 ◽  
Author(s):  
Ilija Tomic ◽  
Marina Petrovic ◽  
Goran Plavec ◽  
Srbislav Ilic
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Therapeutic Response ◽  
Neuroendocrine Differentiation ◽  
Survival Period ◽  
Small Cell Lung ◽  
Metastatic Nsclc ◽  
One Year

Background/Aim. In 40-50% of patients with non-small cell lung cancer (NSCLC) at the time of making a diagnosis, the disease is yet at IIIb and IV stage. Standard in the treatment of these patient is the application of systemic chemiotherapy based on CIS/Carboplatin preparations. The aim of this study was to determine the influence of two different chemiotherapeutic protocols and neuroendocrine differentiation on treatment response and survival in patients with metastatic NSCLC. Methods. We examined 85 patients with metastatic NSCLC, of which 51 with stage IIIb, and 34 with stage IV of the disease. The histologic diagnosis of NSCLC was determined by tissue assays using hematoxylin eosin method. Neuroendocrine differentiation was determined by immunohistochemical analysis of neuron- specific enolase (NSE), chromogranin A, and synapthophysin expression using monoclonal mouse anti- human bodies (DAKO, Denmark). According to chemiotherapeutic protocol, the patients were randomly assigned into combined Taxol + Cisplatin group (Tax + Cis, n = 35), and Cyclophosphamide + Etoposide + Carboplatin group (CEP, n = 50). The treatment was conducted within 4-6 chemiotherapeutic cycles. The efficacy was assessed after the therapy regimen and median survival time was assessed after the randomization. Results. A total of 31 (36.47%) patients had a favourable therapeutic response, both partial and complete response (54.2% in the Tax + Cis group and 24% in CEP group of patients, respectively, p < 0.001). The median survival time in both groups was 13.1 months (15.3 months in the Tax + Cis group and 10.6 months in the CEP group, respectively, p < 0.001). A one-year follow-up survival period was confirmed in 40% of patients (60% only in the Tax + Cis group). A total of 23 (27.05%) patients with metastatic NSCLC had neuroendocrine differentiation. The disease progression or stable disease was noted only in patient with NSCLC without neuroendocrine differentiation (n = 42, 67.7%, p < 0.001). The median survival time in patients with NSCLC and neuroendocrine differentiation was 14.8 months, without neuroendocrine differentiation 10.7 months (p < 0.001). The patients with NSCLC and neuroendocrine differentiation in the CEP group had a longer one-year follow-up survival period than patients in Tax + Cis group (p < 0.001). In Tax-Cis group of patients, there was no significant difference in one-year follow-up survival period with neuroendocrine differentiation. Conclusion. Better therapeutic response and longer median survival time in metastatic NSCLC was obtained using Tax + Cis as compared to CEP protocol. Similar effect was noted using CEP protocol in patients with NSCLC and neuroendocrine differentiation. .

Long-Term Prognostic Value of Hematological and “Old” Biological Parameters in CLL. Reflexions on 156 Patients with a Median Follow-Up Time More Than 6.5 Years.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4951-4951
Author(s):  
Réda Garidi ◽  
Ioana Vaida ◽  
Jean-Claude Capiod ◽  
Salhia Sid Idris ◽  
Bernard Desablens
Keyword(s):  
Prognostic Factors ◽  
Survival Time ◽  
Median Survival Time ◽  
Prognostic Value ◽  
Cox Model ◽  
Hematological Parameters ◽  
Biological Parameters ◽  
Prognostic System ◽  
System P

Abstract Waiting for a standardization of “modern” biological prognostic factors in CLL, such as mutational status, ZAP-protein, CD38… we review with a long median delay of survey, the prognostic value of classical hematological data and “old” biological parameters such as seric LDH, β2-microglobuline, sCD23 and sCD25. At time of diagnosis our 156 pts were aged from 39 to 80 yrs (median=66 yrs) and sex-ratio shows as usually a male predominance (M/F=1.40). According to Binet’s system we note 131 stages A (95 stages A0), 14 stages B and 11 stages C. With a median follow-up time more than 6.5 yrs, median survival time is 9.5 yrs and median “corrected” (i.e., without not CLL-related deaths including those due to a solid tumor because this complication is independent of initial prognostic factors of CLL) survival time is 10.2 yrs. When looking at “corrected” survival, best cut-off values for “old” biological factors are 1.25 N for LDH, 3 mg for β2-m, 33 U (=10 N) for sCD23 and 2282.5 U (=1.25 N) for sCD25. Cox model with these 4 pejorative factors (PF) retains sCD23 (p=0.00004), β2-m (p=0.00002) and LDH (p=0.001). When adding these 3 PF, we can build a very strong prognostic system: median survival time of the 117 pts with 0 or 1 PF is more than 11 yrs versus 4 yrs for the 39 pts with 2 PF or more (p<10−6). Among hematological parameters, Cox model retains 3 of them: platelets level at 2 cut-off values 150 and 100 G (p=0.000005 and 0.02); 3 or more lymphoid area according to Binet’s classification (p=0.0002) and hemoglobin level at cut-off value 120 g (p=0.03). DLT is also a strong prognostic factor (p= 0.002) but this value was missing for 47 pts. However Cox model done with DLT retains 3 factors: DLT (p=0.0003); hemoglobin at cut-off value 100 g (p=0.0003) and platelets at cut-off value 150 G (p=0.001). Cox model including “old” biological PF and classical hematological parameters without DLT, retains sCD23 (p=0.0003), platelet at cut-off value 150 G (p=0.0005) and 3 or more lymphoid areas (p = 0.003). Finally we test 3 clinical classifications (Rai, Binet and our local classification based on clinical examination, hemoglobin and platelet levels, and medullary examination) and 2 biological classifications (LDH+β2-m system and this new PF system). Cox model retains the sCD23+LDH+β2-m system (p=0.00009) and our local system (p=0.003) and when looking at global survival our prognostic system seems more performing than PF system: p=0.0007 and 0.001. Addition of LDT does not modify our results but this parameter is kept in Cox model too. We conclude on the necessity to clearly determine the best cut-off values for all prognostic parameters, classical and “old” and “new” biological ones. We also claim the usefulness to compare all prognostic factors of CLL together because “old” clinical system and DLT are perhaps more useful for clinical practice when patients are out of a prospective therapeutic trial.

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

Blood ◽  
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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