Budgetary Impact of Treating Acute Promyelocytic Leukemia Patients with First-Line Arsenic Trioxide and Retinoic Acid from an Italian Payer Perspective

The objective of this study was to estimate the net cost of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) compared to ATRA plus chemotherapy when used in first-line acute promyelocytic leukemia (APL) treatment for low to intermediate risk patients from the perspective of the overall Italian healthcare systemA Markov model was developed with 3 health states: stable disease, disease event and death. Each month, patients could move from stable to disease event or die from either state. After a disease event, patients discontinued initial treatment and switched to the other regimen as second-line therapy. Treatment regimens, efficacy and adverse events were derived from published sources and expert opinion; unit costs were collected from standard Italian sources. Clinical outcomes and costs for pre-ATO and post-ATO scenarios were combined with population and product utilization information to calculate the total budgetary impact using a 3-year time horizon; one-way sensitivity analyses were conducted. Three-year cumulative pharmacy costs for ATO+ATRA were €46,700 per-patient versus €6,500 for ATRA+chemotherapy; however, medical costs for ATO+ATRA were €12,300 per-patient versus €30,200 for ATRA+chemotherapy. The total budgetary impact was estimated to be an additional €127,300, €312,500 and €477,800 in the first, second and third years, respectively. The model was most sensitive to changes in the cost of the ATO+ATRA regimen during the consolidation phase. Budgetary impact models are valuable to payers making formulary decisions regarding the access and affordability of new medicines. The cost of treatment analysis showed that pharmacy costs for ATO+ATRA were higher than for ATRA+chemotherapy, while all other evaluated costs were lower for ATO+ATRA treated patients. The average budgetary impact was €305,900 per year overall, representing a 3.5% increase. Further research is needed to determine the cost-effectiveness of ATO+ATRA compared to the current first-line standard of care in APL.     

ATO/ATRA/Anthracycline-Chemotherapy Sequential Consolidation Achieves Long-Term Efficacy in Primary Acute Promyelocytic Leukemia

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O₃, ATO) has been effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but the long-term efficacy and safety among newly diagnosed APL patients are unclear. In this retrospective study, total 45 newly diagnosed APL patients received ATRA/chemotherapy combination regimen to induce remission. Among them, 43 patients (95.6%) achieved complete remission (CR) after induction therapy, followed by ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment with a median follow-up of 55 months. In these patients, the estimated overall survival (OS) and the relapse-free survival (RFS) were 94.4%±3.9% and 94.6±3.7%, respectively. The toxicity profile was mild and reversible. No secondary carcinoma was observed. These results demonstrated the high efficacy and minimal toxicity of ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for APL.     

急性早幼粒细胞白血病巩固治疗现状及进展

急性早幼粒细胞白血病(APL)曾被认为是最迅速的致命白血病,特点为临床表现凶险,早期死亡率高,治愈率低。药物全反式维甲酸及亚砷酸的应用,使APL的治疗取得了很大成功,其完全缓解率可达90%。然而APL的复发率仍然较高,约15%-30%。降低复发率和提高长期生存已成为研究重点,如何选择合理的缓解后治疗策略至关重要。缓解后治疗一般包括巩固治疗和维持治疗,而最佳治疗方案的确定仍然有待商榷。因此,本文就APL缓解后巩固治疗回顾相关文献进行整合分析,综述APL巩固治疗的研究进展。     

Death-associated protein 5 (DAP5/p97/NAT1) contributes to retinoic acid-induced granulocytic differentiation and arsenic trioxide-induced apoptosis in acute promyelocytic leukemia

All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells. Here we investigated the role and regulation of death-associated protein-5 (DAP5/p97/NAT1), a novel inhibitor of translational initiation, in APL cell differentiation and apoptosis. We found that ATRA markedly induced DAP5/p97 protein and gene expression and nuclear translocation during terminal differentiation of APL (NB4) and HL60 cells but not differentiation-resistant cells (NB4.R1 and HL60R), which express very low levels of DAP5/p97. At the differentiation inducing concentrations, ATO (<0.5 μM), dimethyl sulfoxide, 1,25-dihydroxy-vitamin-D3, and phorbol-12-myristate 13-acetate also significantly induced DAP5/p97 expression in NB4 cells. However, ATO administered at apoptotic doses (1–2 μM) induced expression of DAP5/p86, a proapoptotic derivative of DAP5/p97. ATRA and ATO-induced expression of DAP5/p97 was associated with inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Furthermore, DAP5/p97 expression was upregulated by inhibition of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway via LY294002 and via rapamycin. Finally, knockdown of DAP5/p97 expression by small interfering RNA inhibited ATRA-induced granulocytic differentiation and ATO-induced apoptosis. Together, our data reveal new roles for DAP5/p97 in ATRA-induced differentiation and ATO-induced apoptosis in APL and suggest a novel regulatory mechanism by which PI3K/Akt/mTOR pathway inhibition mediates ATRA- and ATO-induced expression of DAP5/p97. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. B. Ozpolat and U. Akar contributed equally.     

Triterpenoid CDDO-Im downregulates PML/RARalpha expression in acute promyelocytic leukemia cells

The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of diverse human tumor cells. In the present study, we examined the effects of the CDDO imidazolide imide (CDDO-Im) on the NB4 acute promyelocytic leukemia (APL) cell line and primary APL cells. The results show that CDDO-Im selectively downregulates expression of the PML/retinoic receptor alpha fusion protein by a caspase-dependent mechanism and sensitizes APL cells to the differentiating effects of all-trans retinoic acid (ATRA). CDDO-Im treatment of APL cells was also associated with disruption of redox balance and activation of the extrinsic apoptotic pathway. In concert with these results, CDDO-Im sensitizes APL cells to arsenic trioxide (ATO)-induced apoptosis. Our findings indicate that CDDO-Im may be effective in the treatment of APL by: (i) downregulation of PML/RARalpha; (ii) enhancement of ATRA-induced differentiation; and (iii) sensitization of ATO-induced APL cell death.     

Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy

Background

Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitor (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ⅢA EGFR-mutated NSCLC.

Methods

Patients with surgically resected stage IB (with high risk factors) to ⅢA EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS).

Results

41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.

Conclusions

The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would think the preliminary result here was promising, and further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.

Trial Registration

ClinicalTrials.gov NCT02430974     

High-dose chemotherapy sensitizes locally advanced esophageal squamous cell carcinoma to PD-1 blockade for a higher pathological complete response rate and survival

BackgroundPD-1 inhibitor and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as the first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). The present study aimed to evaluate the efficacy of PD-1 inhibitors plus different dose intensity neoadjuvant chemotherapy in the treatment of locally advanced ESCC.MethodsPatients with locally advanced but resectable thoracic ESCC, staged as T3 or T4a, N0–3, and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes), were enrolled in this study. The eligible patients received tislelizumab plus different dose intensity chemotherapy for a 21-day cycle with repeated 2–4 cycles before surgery. The primary endpoints are pathological complete response (pCR) and major pathological response (MPR), and the secondary endpoints are objective response rate (ORR), disease control rate (DCR), and disease-free survival (DFS).ResultsFrom November 2019 to February 2022, 122 cases received at least two cycles neoadjuvant chemoimmunotherapy and were evaluated by imaging examination. Subsequently, 99 patients underwent surgery and were evaluated by pathological evaluation. According to chemotherapy dose intensity, the patients were divided into three cohorts: cohort 1 (<80% dose intensity), cohort 2 (80–90% dose intensity), cohort 3 (90–100% dose intensity). All surgery patients underwent minimally invasive esophagectomy (MIE). The average pCR was identified in 22.22%; 16% had pCR in cohort 1, 17.65% had pCR in cohort 2, and 30.00% had pCR in cohort 3. MPR was observed in 9 (36.00%) patients in cohort 1, 18 (52.94%) patients in cohort 2, 22 (55.00%) patients in cohort 3. In univariable and multivariable analysis, dose intensity was significantly associated with MPR (p = 0.048) in patients who underwent esophagectomy. For surviving patients, the median follow-up was 13.76 months after esophagectomy. Compared to cohort 1, cohorts 2 and 3 had better DFS (p = 0.056). In addition, the prognosis of patients with MPR was better than that of patients without MPR (p = 0.014).ConclusionsThe robust antitumor activity of neoadjuvant chemoimmunotherapy for locally advanced but resectable thoracic ESCC was confirmed. More than 80% of chemotherapy dose intensity combined with immunotherapy resulted in a high pCR rate and prolonged DFS.     

浅议与APL预后密切相关的因子

急性早幼粒细胞白血病(APL)是急性髓系白血病(AML)的一种特殊亚型。近年来随着全反式维甲酸和三氧化二砷的靶向治疗日益规范化,APL的预后已很大程度上得到提高,成为AML中预后最好的亚型,但仍有15%的患者发生复发。越来越的学者致力于研究影响APL预后的因素,以往很多人们关注过的因子在近来的研究中也发现在APL中起着重要的作用,如FLT3、CD56、Fas等,以及新近证实的一些特殊基因的表达也影响着APL的预后,BAALC低表达与APL预后正相关,与其相反Ets相关基因(ERG)高表达与APL预后负相关。在此本文总结了近年来人们在APL预后研究的进展,这些因素的发现,使人们对APL发病机制有了更深一层的了解,便于临床上早期对APL患者进行危险分层,对高风险的APL患者采用个体化治疗,也可成为日后治疗APL的新靶点。     

Evaluation of the prognostic value of lymphadenectomy for low-grade serous ovarian cancer: A case-control multicenter retrospective study

BackgroundThe prognostic value of lymphadenectomy in low-grade serous ovarian cancer (LGSOC) remains uncertain.Materials and methodsA retrospective analysis of 155 patients with LGSOC who underwent surgery over a ten-year period (2011–2020) was performed. The propensity score matching (PSM) algorithm was performed between the lymphadenectomy and no lymphadenectomy groups, and Kaplan-Meier analyses were conducted to evaluate clinical prognosis. Finally, univariate and multivariate Cox proportional hazards regression analyses were performed to analyze high-risk factors associated with clinical prognosis.ResultsIn the pre-PSM cohort, 110 (71.0%) patients underwent lymphadenectomy. Of these, 54 (34.8%) experienced recurrence, and 27 (17.4%) died. There were statistical differences in disease-free survival (DFS) (P = 0.018) and overall survival (OS) (P = 0.016) in the post-PSM cohort. In the subgroup analysis, there were no statistically significant differences in DFS (P = 0.449) or OS (P = 0.167) in the FIGO I/II cohort. However, in the FIGO III/IV cohort, DFS (P = 0.011) and OS (P = 0.046) were statistically different between the two groups. Age > 50 years, FIGO stage III/IV, and suboptimal cytoreductive surgery were risk factors associated with prognosis. In the lymphadenectomy group, the histological status of pelvic lymph nodes had no significant effect on DFS (P = 0.205) or OS (P = 0.114).ConclusionLymphadenectomy was associated with DFS and OS, particularly in patients with advanced LGSOC patients. Age > 50 years, advanced FIGO stage III/IV, and suboptimal cytoreductive surgery were high-risk factors associated with clinical prognosis in patients with LGSOC.     

Characterization of cytotoxicity induced by arsenic trioxide (a potent anti-APL drug) in rat cardiac myocytes

Arsenic, a known environmental toxicant, is ubiquitously present in the environment. Arsenic trioxide (ATO), an anti-acute promyelocytic leukemia (APL) drug, is associated with cardiac toxicity. It is reported to induce cardiac arrhythmia via altering various ion channels involved in the repolarization phase of cardiac action potential. The exact molecular mechanism of cardiovascular adverse effect due to ATO exposure has not been fully elucidated except for alteration on ion channels. To evaluate the cytotoxic effect of ATO on cardiac myocytes, primary culture of myocytes was treated with different doses (30, 60 and 90 μM) of ATO for various periods (24, 48 and 72 h). Cardiac toxicity was assessed by monitoring cell viability, mitochondrial and deoxyribonucleic acid (DNA) integrity, reactive oxygen species (ROS) generation, calcium overload and apoptosis. ATO exposure caused alteration in mitochondrial integrity, generation of ROS, calcium overload and apoptosis in cardiac cells in dose- and duration-dependent manner. There was no DNA fragmentation. Hence our results show that ATO causes apoptosis in cardiomyocytes by generation of ROS and the induction of calcium overload.     

Clinical significance of risk stratification of esophageal squamous cell carcinoma after neoadjuvant chemoradiation and surgery

ObjectiveNowadays, there were few studies reporting the risk stratification of patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiation (NCRT) and surgery. We aimed to establish a simple risk stratification to help postoperative detection and adjuvant treatment.MethodsWe included 146 patients with locally advanced ESCC who received NCRT followed by esophagectomy. The impacts of clinicopathological factors on overall survival (OS) and disease-free survival (DFS) were analyzed. The recurrence site, time, and frequency were recorded as well.ResultsThe median follow-up was 53 months. The pathological complete respond (pCR) group demonstrated better 5-year OS and DFS (78.6% and 77.0%) than the non-pCR group (44.8% and 35.2%, all P < 0.005). Multivariate analysis for the non-pCR group revealed perineural invasion (PNI) (HR:2.296, P = 0.013) and ypTNM stage (I/II vs III/IV) (HR:1.972, P = 0.046) were considered as independent unfavorable factors affecting OS, while PNI (HR:1.866, P = 0.045) and lymph vessel invasion (LVI) (HR:3.370, P < 0.001) were considered as independent adverse factors for DFS. Based on clinicopathological factors (including pCR, ypTNM stage, PNI, LVI), patients were divided into the low-risk (pCR), mediate-risk (non-pCR without PNI, LVI, stage III/IV), high-risk (non-pCR with one factor of PNI, LVI or stage III/IV (n = 45)), highest risk (non-pCR with two or more factors of PNI, LVI or stage III/IV) groups. The corresponding 5-year OS rates were 78.6%, 60.4%, 49.6%, 18.6%, respectively (P < 0.005) and 5-year DFS rates were 77.0%, 46.9%, 41.1%, 12.1%, respectively (P < 0.005). Adjuvant chemotherapy may improve survival in high or highest risk groups of patients with low prognostic nutritional index (< 49).ConclusionsA novel risk stratification based on clinicopathological factors may be conducive to postoperative surveillance and guide adjuvant chemotherapy.     

Preoperative albumin-to-globulin ratio predicts survival in patients with non-small-cell lung cancer after surgery

The prognostic value of the preoperative albumin-to-globulin ratio (AGR) has not been investigated in non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the clinical applicability of the preoperative AGR to predict the prognosis in patients with NSCLC. We retrospectively enrolled 545 patients with stage I/II/III NSCLC who underwent surgery at our institution. The cutoff value for preoperative AGR was calculated by using a receiver operating characteristic curve analysis. A low AGR was associated with several clinicopathological variables related to tumor progression. In the multivariate analyses, the preoperative AGR was identified as an independent prognostic factor for disease-free survival (DFS; P = 0.003) and overall survival (OS; P = 0.005). For patients with stage II and III with a preoperative AGR ≤ 1.43, the surgery plus chemotherapy group had a significantly longer DFS and OS than the surgery alone group (P = 0.002 and P = 0.001, respectively); however, a significant difference in DFS and OS between these two groups was not observed in patients with stage II and III with an AGR > 1.43 (P = 0.808 and P = 0.842, respectively). The preoperative AGR is an independent, significant predictor of DFS and OS in patients with NSCLC. Our results also demonstrate that the preoperative AGR might be a predictive marker of the therapeutic effect of postoperative chemotherapy in patients with stage II and III NSCLC.     

Comparison of Newly Diagnosed and Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide: Insight into Mechanisms of Resistance

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.     

Adjuvant Chemotherapy with Docetaxel,Cisplatin, and Continuous-Infusion 5-Fluorouracil for Gastric Cancer: A Phase II Study

PURPOSE: This study evaluated the efficacy and safety of adjuvant chemotherapy with the docetaxel plus cisplatin and 5-fluorouracil (5-FU) (DCF) regimen in patients with gastric cancer. PATIENTS AND METHODS: Thirty-two patients with gastric or gastroesophageal junction cancer were enrolled in this study after undergoing radical resection. The patients received the following chemotherapy: docetaxel (60 mg/m²) on day 1, cisplatin (12 mg/m² per day) on days 1 to 5, and 5-FU (2500 mg/m²) continuous infusion for 120 hours, repeated every 3 weeks for six cycles. The primary end point was disease-free survival (DFS). RESULTS: The median DFS was 17.0 months. The 1-year DFS was 72%, and the 2-year DFS was 37.5%. The median overall survival was 28.0 months. Using univariate analysis, the technique of lymph node dissection was a predictor for postoperative relapse. The median DFS was 15.0 months in the D1 group and 18.0 months in the D2 group (P = .043). The most frequent grade 3/4 adverse events were neutropenia (56.25%), diarrhea (9.38%), nausea (6.25%), and vomiting (6.25%); 12.5% of patients developed febrile neutropenia. There were no chemotherapy-related deaths. CONCLUSIONS: The modified DCF regimen is an effective adjuvant chemotherapy in gastric cancer. Hematologic toxicity was frequent but manageable. This regimen merits further investigation.     

Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis

We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E₂ analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.     

ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis

Arsenic trioxide (ATO) is a potent anti-leukemic chemotherapeutic agent for acute promyelocytic leukemia (APL) that results from a t (15, 17) chromosomal translocation that produces PML-RARalpha, a fusion protein between a tumor suppressor PML and the retinoic acid receptor RARalpha. APL patients are initially treated with retinoic acid, but most develop resistance and relapse. In contrast, ATO induces prolonged remissions even in the relapsed cases. However, the molecular mechanisms by which ATO kills the leukemic cells are not fully understood. We find that ATO induces apoptosis, at least in part, by activating proapoptotic kinase Chk2. ATO does this by stimulating ATR (ataxia telangiectasia mutated and Rad3-related) kinase, a Chk2-activating kinase. In conjunction, ATO degrades PML-RARalpha, resulting in the restoration of PML, which is required for autophosphorylation and full activation of Chk2. As a result, the p53-dependent apoptosis pathway is activated. Based on this, we propose that a pathway composed of ATR, PML, Chk2, and p53 plays a role in ATO-mediated apoptosis, a notion that is consistent with the observation that Chk2 is genetically intact and mutations in the p53 gene are extremely rare in APL.     

Effects of regional body temperature variation during asphyxial cardiac arrest on mortality and brain damage in a rat model

To date, hypothermia has focused on improving rates of resuscitation to increase survival in patients sustaining cardiac arrest (CA). Towards this end, the role of body temperature in neuronal damage or death during CA needs to be determined. However, few studies have investigated the effect of regional temperature variation on survival rate and neurological outcomes. In this study, adult male rats (12 week-old) were used under the following four conditions: (i) whole-body normothermia (37 ± 0.5 °C) plus (+) no asphyxial CA, (ii) whole-body normothermia + CA, (iii) whole-body hypothermia (33 ± 0.5 °C)+CA, (iv) body hypothermia/brain normothermia + CA, and (v) brain hypothermia/body normothermia + CA. The survival rate after resuscitation was significantly elevated in groups exposed to whole-body hypothermia plus CA and body hypothermia/brain normothermia plus CA, but not in groups exposed to whole-body normothermia combined with CA and brain hypothermia/body normothermia plus CA. However, the group exposed to hypothermia/brain normothermia combined with CA exhibited higher neuroprotective effects against asphyxial CA injury, i.e. improved neurological deficit and neuronal death in the hippocampus compared with those involving whole-body normothermia combined with CA. In addition, neurological deficit and neuronal death in the group of rat exposed to brain hypothermia/body normothermia and CA were similar to those in the rats subjected to whole-body normothermia and CA. In brief, only brain hypothermia during CA was not associated with effective survival rate, neurological function or neuronal protection compared with those under body (but not brain) hypothermia during CA. Our present study suggests that regional temperature in patients during CA significantly affects the outcomes associated with survival rate and neurological recovery.