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Meenakshi Devidas

Publications and source records attributed to Meenakshi Devidas.

15 recordsLinked to original sources

Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG).

The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.

Adolescent↗

Resolution of ambiguous low-level positive quantitative polymerase chain reaction results in TEL-AML1 positive ALL using a post-PCR fluorescent oligoligation method.

The interpretation of low-level or non-reproducible amplification results in clinical quantitative polymerase chain reaction (Q-PCR) assays can be difficult to definitively resolve. Concerning minimal residual disease detection in leukaemia, indeterminate low-level results might create prognostic or therapeutic dilemmas. We evaluated low-level, ambiguous Q-PCR results in a study of paired diagnostic and end-induction (day 29) TEL-AML1 positive acute lymphoblastic leukaemia samples utilising a novel fluorescent primer ligation detection assay. The data presented here indicate that a significant number of low-level apparent Q-PCR positive results may be spurious or non-specific in nature, requiring additional technical manoeuvres for confirmation of true positive cases.

Child↗

Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study.

PURPOSE: Prognosis and outcome of children with isolated CNS relapse of acute lymphoblastic leukemia (ALL) has depended on duration of first complete remission (CR1). This study intensified systemic therapy by delaying CNS radiation for 12 months and tailored CNS radiation by CR1 duration. PATIENTS AND METHODS: Seventy-six children with first isolated CNS relapse of ALL were treated with systemic chemotherapy that effectively penetrates into the CSF and intrathecal chemotherapy for 12 months. Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CR1 of 18 months or more received cranial radiation only (18 Gy), followed by maintenance chemotherapy. Additionally, asymptomatic patients were enrolled in a thiotepa up-front therapeutic window. RESULTS: Seventy-four (97.4%) of 76 eligible patients achieved a second remission. Overall 4-year event-free survival (EFS) for the 71 precursor B-cell patients was 70.1% +/- 5.8%. CR1 duration and National Cancer Institute (NCI; National Institutes of Health, Bethesda, MD) risk group at initial diagnosis predicted outcome. Patients with CR1 of less than 18 months and 18 months or more had a 4-year EFS of 51.6% +/- 11.3% and 77.7% +/- 6.4% (P = .027), respectively. NCI high- versus standard-risk 4-year EFS was 51.4% +/- 10.8% and 80.2% +/- 6.3% (P = .0018), respectively. A significant difference in EFS between standard risk/CR1 of at least 18 months and both high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups was detected (P = .0068 and .0314, respectively). Response rate to thiotepa was 78%. Most relapses involved the bone marrow, and three second malignancies were reported. CONCLUSION: Twelve months of intensive systemic chemotherapy with reduced dose cranial radiation (18 Gy) is highly effective for children with isolated CNS relapse and CR1 of 18 months or more. Novel strategies are needed for patients with CR1 of less than 18 months.

Adolescent↗

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research.

The best treatment approach for children with B-precursor acute lymphoblastic leukemia (ALL) in second clinical remission (CR) after a marrow relapse is controversial. To address this question, we compared outcomes in 188 patients enrolled in chemotherapy trials and 186 HLA-matched sibling transplants, treated between 1991 and 1997. Groups were similar except that chemotherapy recipients were younger (median age, 5 versus 8 years) and less likely to have combined marrow and extramedullary relapse (19% versus 30%). To adjust for time-to-transplant bias, treatment outcomes were compared using left-truncated Cox regression models. The relative efficacy of chemotherapy and transplantation depended on time from diagnosis to first relapse and the transplant conditioning regimen used. For children with early first relapse (< 36 months), risk of a second relapse was significantly lower after total body irradiation (TBI)-containing transplant regimens (relative risk [RR], 0.49; 95% confidence interval [CI] 0.33-0.71, P < .001) than chemotherapy regimens. In contrast, for children with a late first relapse (> or = 36 months), risks of second relapse were similar after TBI-containing regimens and chemotherapy (RR, 0.92; 95% CI, 0.49-1.70, P = .78). These data support HLA-matched sibling donor transplantation using a TBI-containing regimen in second CR for children with ALL and early relapse.

Adolescent↗

Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group.

PURPOSE: Prognosis is poor for Ewing sarcoma patients with metastasis at diagnosis. We intensified a five-drug therapy (ifosfamide, etoposide alternated with vincristine, doxorubicin, and cyclophosphamide) using filgrastim but not stem-cell support. We studied topotecan alone and combined with cyclophosphamide in therapeutic windows before the five-drug therapy. A randomly assigned proportion of patients received amifostine as a cytoprotective agent. PATIENTS AND METHODS: Eligible patients were < or = 30 years old and had histologically proven Ewing sarcoma or primitive neuroectodermal tumor (PNET) and metastasis at diagnosis. Chemotherapeutic cycles began every 21 days, after recovery from toxicities. RESULTS: One hundred ten of the 117 patients enrolled were eligible. Thirty-six patients received initial topotecan. Three had partial responses (PRs), and 17 had progressive disease (PD). Thirty-seven patients were administered topotecan and cyclophosphamide; 21 of these patients achieved PR, and one patient had PD. In a randomly assigned group of 69 patients, amifostine did not provide myeloprotection, which was measured by absolute neutrophil count, platelet count, or cycle intervals. The best responses to the overall therapy included 45 complete responses, 41 PRs, stable disease in 14 patients, and PD in five patients. For all patients, the 2-year event-free survival (EFS) rate was 24% (+/- 4%), and the overall survival rate was 46% (+/- 5%). For the 39 patients with isolated pulmonary metastases, the 2-year EFS rate was 31% (+/- 7%) compared with 20% (+/- 5%) for patients with more widespread disease. CONCLUSION: Topotecan had limited activity in patients with Ewing sarcoma or PNET metastatic at diagnosis. The topotecan-cyclophosphamide combination was active. Amifostine was not myeloprotective. Overall results showed no improvement compared with previous studies.

Adolescent↗

Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia: a report of POG study 9296.

PURPOSE: A previous Pediatric Oncology Group (POG) study showed high incidence of secondary acute myelogenous leukemia (AML) in children treated for T-cell acute lymphoblastic leukemia (T-ALL) or higher-stage lymphoblastic lymphoma. To prevent secondary neoplasms, induce prolonged asparagine depletion, and maintain high event-free survival (EFS) in children with newly diagnosed T-ALL or higher-stage non-Hodgkins lymphoma (NHL), we designed this pilot study to determine feasibility and safety of substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase. PATIENTS AND METHODS: Forty-five patients were entered, 29 with T-ALL and 16 with higher-stage NHL. Forty-two of 45 patients achieved complete remission (CR), and 27 completed the therapy in continuous CR. Treatment consisted of 4-week induction then 6 weeks consolidation and ten 9-week maintenance cycles. Therapy primarily comprised antimetabolites, anthracyclines, alkylating agents, and asparaginase. Expected chemotherapy duration was 100 weeks. RESULTS: Forty-two of 45 patients achieved CR, and 27 completed therapy. The most common toxicities were Grade 3 or 4 myelosuppression after cyclophosphamide/cytarabine and allergic reactions to asparaginase. Two died of sepsis early in maintenance. Five-year EFS was 68.5% (SE 9.1%) for T-ALL and 81.3% (SE 9.8%) for NHL. Five-year EFS was 73.1% (SE 6.8%) for the entire cohort. No patients treated entirely on this study developed secondary neoplasms. One patient taken off study for asparaginase toxicity was treated with multiagent therapy that contained teniposide, and died from secondary myelodysplasia (sMDS)/AML. CONCLUSION: Substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase in a dose-intensive regimen was feasible in children and young adults with newly diagnosed T-ALL or higher-stage NHL. EFS was not compromised and secondary neoplasms were decreased.

Adolescent↗

Hematopoietic stem cell transplantation after first marrow relapse of non-T, non-B acute lymphoblastic leukemia: a pediatric oncology group pilot feasibility study.

BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) in children is associated with a poor outcome, especially for those patients whose relapse occurs during the first 36 months after diagnosis. The best therapy for these patients is not known. This study was designed to evaluate the feasibility of enrolling children with recurrent ALL in a standardized treatment protocol that included receipt of a hematopoietic stem cell transplant (HSCT). PROCEDURE: Eligible patients with a bone marrow relapse of non-T, non-B ALL underwent a common induction and consolidation followed by receipt of either an allogeneic HSCT from a human leukocyte antigen (HLA)-identical sibling or an autologous HSCT purged with B-4 blocked ricin. A common conditioning regimen was used for all patients. RESULTS: Twenty-eight patients from eight institutions were enrolled. Fourteen patients did not receive a transplant during the study, because of toxicity (4), relapse (1), inadequate purging (1), and parental or physician preference for an alternative donor transplant (8). Six patients received allogeneic HSCTs. Five of them have remained in remission for a median of 78 months. Eight patients received autologous HSCTs purged with B4-blocked ricin. Four have remained in remission for a median of 94 months. Of the nine patients who received alternative donor transplants, only two remain in remission. CONCLUSION: We conclude that well designed and controlled prospective studies are necessary to define the role of HSCTs in children with recurrent ALL. In order to be successful, such studies must have the full support of participating centers. Autologous HSC transplantation may have a role in the treatment of relapsed ALL, but further studies are needed.

Adolescent↗

Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group.

PURPOSE: Nelarabine (compound 506U78), a water soluble prodrug of 9-b-d-arabinofuranosylguanine, is converted to ara-GTP in T lymphoblasts. We sought to define the response rate of nelarabine in children and young adults with refractory or recurrent T-cell disease. PATIENTS AND METHODS: We performed a phase II study with patients stratified as follows: stratum 1: > or = 25% bone marrow blasts in first relapse; stratum 2: > or = 25% bone marrow blasts in > or = second relapse; stratum 3: positive CSF; stratum 4: extramedullary (non-CNS) relapse. The initial nelarabine dose was 1.2 g/m2 daily for 5 consecutive days every 3 weeks. There were two dose de-escalations due to neurotoxicity on this or other studies. The final dose was 650 mg/m2/d for strata 1 and two patients and 400 mg/m2/d for strata 3 and four patients. RESULTS: We enrolled 121 patients (106 assessable for response) at the final dose levels. Complete plus partial response rates at the final dose levels were: 55% in stratum 1; 27% in stratum 2; 33% in stratum 3; and 14% in stratum 4. There were 31 episodes of > or = grade 3 neurologic adverse events in 27 patients (18% of patients). CONCLUSION: Nelarabine is active as a single agent in recurrent T-cell leukemia, with a response rate more than 50% in first bone marrow relapse. The most significant adverse events associated with nelarabine administration are neurologic. Further studies are planned to determine whether the addition of nelarabine to front-line therapy for T-cell leukemia in children will improve survival.

Adolescent↗

Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study.

PURPOSE: To describe the response rate and survival of children and adolescents with unresected or metastatic nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) treated with vincristine, ifosfamide, and doxorubicin. PATIENTS AND METHODS: Between September 1996 and June 2000, 39 eligible patients received vincristine (1.5 mg/m(2) weekly for 13 doses), ifosfamide (3 g/m(2) daily for 3 days every 3 weeks for seven cycles), doxorubicin (30 mg/m(2) daily for 2 days for six cycles), and mesna (750 mg/m(2) for four doses after ifosfamide). Granulocyte colony-stimulating factor was administered daily (5 mug/kg) after each cycle of chemotherapy. Radiotherapy was administered from weeks 7 through 12. RESULTS: The median patient age at diagnosis was 11.7 years; the most common primary tumor site was lower extremity (36%); and synovial sarcoma was the predominant histology. More than three fourths of all tumors were 5 cm or greater at their largest diameters. The overall objective combined partial and complete response rate was 41% (95% CI, 25.7% to 56.7%). The estimated 3-year overall survival and progression-free survival rates (+/- standard deviation) for eligible patients were 59% +/- 8.2% and 43.6% +/- 7%, respectively. Patients with clinical group III disease had significantly better 3-year and progression-free survival rates compared with patients who presented with metastatic disease. CONCLUSION: The vincristine, ifosfamide, and doxorubicin regimen was moderately active against pediatric NRSTS. Patients with synovial sarcoma had higher response rates than other patients, and patients with unresected disease had improved outcomes. Patients with metastatic disease continue to fare poorly, and newer approaches are indicated for these patients.

Adolescent↗

Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651.

PURPOSE: Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously. PATIENTS AND METHODS: Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin. RESULTS: One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy). CONCLUSION: Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.

Adolescent↗

Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy.

OBJECTIVE: To establish outcome and optimal timing of local control for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the chest wall. METHODS: Patients < or =30 years of age with ES/PNET of the chest wall were entered in 2 consecutive protocols. Therapy included multiagent chemotherapy; local control was achieved by resection, radiotherapy, or both. We compared completeness of resection and disease-free survival in patients undergoing initial surgical resection versus those treated with neoadjuvant chemotherapy followed by resection, radiotherapy, or both. Patients with a positive surgical margin received radiotherapy. RESULTS: Ninety-eight (11.3%) of 869 patients had primary tumors of the chest wall. Median follow-up was 3.47 years and 5-year event-free survival was 56% for the chest wall lesions. Ten of 20 (50%) initial resections resulted in negative margins compared with 41 of 53 (77%) negative margins with delayed resections after chemotherapy (P = 0.043). Event-free survival did not differ by timing of surgery (P = 0.69) or type of local control (P = 0.17). Initial chemotherapy decreased the percentage of patients needing radiation therapy. Seventeen of 24 patients (70.8%) with initial surgery received radiotherapy compared with 34 of 71 patients (47.9%) who started with chemotherapy (P = 0.061). If a delayed operation was performed, excluding those patients who received only radiotherapy for local control, only 25 of 62 patients needed radiotherapy (40.3%; P = 0.016). CONCLUSION: The likelihood of complete tumor resection with a negative microscopic margin and consequent avoidance of external beam radiation and its potential complications is increased with neoadjuvant chemotherapy and delayed resection of chest wall ES/PNET.

Adult↗

Sequence alterations in the reduced folate carrier are observed in osteosarcoma tumor samples.

High-dose methotrexate is a standard component of therapy for high-grade osteosarcoma. Its effectiveness may be limited by intrinsic and acquired resistance. Decreased reduced folate carrier (RFC) expression has been shown in approximately half of osteosarcomas at diagnosis. Mutations and polymorphisms in the RFC gene have been reported in various cell lines. The purpose of this study was to investigate sequence alterations in the RFC gene in osteosarcoma tumor samples. The entire coding region of the RFC gene in samples from 162 osteosarcoma patients was screened by DNA single-stranded conformational polymorphism, followed by direct sequencing of any region with altered mobility. A previously identified polymorphism at cDNA position number 174 of RFC exon 2 was observed. Sixty-one samples (37.6%) were heterozygous with both A/G at this position (His(27)/Arg(27)), 52 samples (32.2%) were homozygous with G (Arg(27)), and 49 samples (30.2%) were homozygous with A (His(27)). Fifteen (9.2%) samples were identified with other RFC sequence variants in exon 2, none of which have been reported. The sequence variants in exon 2 included a G to A substitution at cDNA position 231, a G to A substitution at cDNA position 155, a C to T substitution at cDNA position 114, and a T to C substitution at cDNA position 104, resulting in a serine to asparagine substitution at amino acid 46, a glutamate to lysine substitution at amino acid 21, an alanine to valine substitution at amino acid 7, and a serine to proline substitution at amino acid 4, respectively. A deletion of A at cDNA position 126 resulting in a frameshift was also observed. Some of these variants were observed in multiple samples. Eight samples had altered single-stranded conformational polymorphism patterns in exon 3 that were associated with nucleotide changes that altered the amino acid sequence. All of these RFC sequence variants appeared to be heterozygous. Heterozygous C/T and homozygous C also were observed at RFC cDNA position 790 in exon 3, which does not alter the amino acid coding sequence. This study shows that RFC sequence alterations are frequent in samples from osteosarcoma patients. Additional studies are under way to determine the clinical significance of these sequence alterations and their effect on methotrexate transport and resistance.

Amino Acid Sequence↗

Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial.

PURPOSE: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma. PATIENTS AND METHODS: Eligible patients received infusions of 100 mg/m(2) per day of etoposide and 3.5 g/m(2) per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor. RESULTS: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% +/- 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% +/- 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% +/- 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi's syndrome was observed in five patients. CONCLUSION: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.

Adolescent↗

Functional outcome after thoracoabdominal aortic aneurysm repair.

OBJECTIVE: Repair of thoracoabdominal aortic aneurysms (TAAAs) is performed for the improvement of long-term survival and the preservation of function. The determination of functional outcome and the identification of predictors of survival and functional recovery after TAAA repair are key to proper patient selection. METHODS: This retrospective review of clinical data was performed in an academic medical center. The demographics, Crawford aneurysm type (I-18, II-33, III-22, IV-28), preoperative risk factors, operative characteristics, and postoperative complications and outcomes were recorded from the medical records for 101 consecutive patients who underwent TAAA repair (58 elective and 43 urgent/emergent). Functional status and living situation at hospital discharge and 12 months after discharge were determined from follow-up examination records or telephone contact with surviving patients. The patients then were categorized into "good" (survival, home, discharge to rehabilitation center, ambulatory) or "bad" (death, discharge to or residence in a long-term care facility, non-ambulatory) outcomes. RESULTS: The postoperative mortality rate was 17.8% (10% in elective cases and 28% in urgent cases), and significant postoperative complications occurred in 77% of the cases (pulmonary complications in 41%, renal complications in 28%, and cord injury in 12%). The mean length of stay was 22.8 + 23.6 days, and at discharge, 80% of the patients were sent to home or rehabilitation and 20% were sent to long-term care facilities. At 1 year, 15 additional patients had died. All but two patients who had been initially discharged to rehabilitation had returned home, but only two patients who had been discharged to long-term care facilities had returned home and both were nonambulatory. Therefore, the survival rate at 1 year was 67%, and only 52.4% of the patients had a "good" outcome at 1 year (survival rate was 78% and rate of "good" outcome was 63% in patients who underwent elective TAAA repair). Independent predictors of postoperative death and "bad" outcome were age more than 75 years, preoperative heart disease, duration of visceral ischemia, use of left atrial femoral bypass graft, postoperative renal dysfunction, and number of organs failing after surgery. CONCLUSION: Survival and good functional outcome after TAAA repair is significantly less common than expected and is primarily predicted with intraoperative factors and postoperative complications. Improved operative techniques and limitation of visceral ischemia reperfusion injury may improve outcome after TAAA repair.

Aged↗