Effect of body mass index on the prognosis of children and adolescents with high-grade mature B-cell non-Hodgkin lymphoma.

BACKGROUND: Little progress has been made in determining the prognostic factors for children and adolescents with high-grade mature B-cell non-Hodgkin lymphoma (HG B-NHL). Based on the important role of body mass index (BMI) in cancer, this study explored the effect of BMI on the prognosis of patients with HG B-NHL. METHODS: Patients aged <18 years with newly diagnosed HG B-NHL were enrolled. Patients were divided into normal, overweight, obese, and emaciated BMI groups according to the growth criteria for children and adolescents. RESULTS: In total, 435 patients were enrolled in this study. There were 329 (75.6%), 46 (10.6%), 13 (3.0%), and 47 (10.8%) patients stratified into the normal, overweight, obese, and emaciated BMI groups, respectively. The event-free survival and overall survival rates of the entire cohort were 89.3% and 92.4%, respectively. The 5-year event-free survival rate for the patients with obese BMI was worse than those with overweight BMI (76.2% vs. 95.6%, p = .04). The 5-year overall survival rate for the patients with emaciated BMI was worse than those with normal (84.5% vs. 93.1%, p = .04) or overweight BMI (84.5% vs. 97.7%, p = .03). Cox multivariate analysis showed that obese or emaciated BMI at diagnosis was associated with an increased risk of death (p = 0.04; HR, 2.26) and was identified as an independent adverse prognostic factor in pediatric HG B-NHL. CONCLUSION: Obese or emaciated BMI at diagnosis is associated with poor prognosis in pediatric HG B-NHL and can be used for risk stratification.

Searching for Two-Neutrino and Neutrinoless Double Beta Decay of

^{134}Xe is a candidate isotope for neutrinoless double beta decay (0νßß) search. In addition, the two-neutrino case (2νßß) allowed by the standard model of particle physics has not yet been observed. With the 656-kg natural xenon in the fiducial volume of the PandaX-4T detector, which contains 10.4% of ^{134}Xe, and its initial 94.9-day exposure, we have established the most stringent constraints on 2νßß and 0νßß of ^{134}Xe half-lives, with limits of 2.8×10^{22} yr and 3.0×10^{23} yr at 90% confidence level, respectively. The 2νßß (0νßß) limit surpasses the previously reported best result by a factor of 32 (2.7), highlighting the potential of large monolithic natural xenon detectors for double beta decay searches.

Search for Light Dark Matter from the Atmosphere in PandaX-4T.

We report a search for light dark matter produced through the cascading decay of η mesons, which are created as a result of inelastic collisions between cosmic rays and Earth's atmosphere. We introduce a new and general framework, publicly accessible, designed to address boosted dark matter specifically, with which a full and dedicated simulation including both elastic and quasielastic processes of Earth attenuation effect on the dark matter particles arriving at the detector is performed. In the PandaX-4T commissioning data of 0.63 tonne·year exposure, no significant excess over background is observed. The first constraints on the interaction between light dark matter generated in the atmosphere and nucleus through a light scalar mediator are obtained. The lowest excluded cross section is set at 5.9×10^{-37} cm^{2} for a dark matter mass of 0.1 MeV/c^{2} and mediator mass of 300 MeV/c^{2}. The lowest upper limit of η to the dark matter decay branching ratio is 1.6×10^{-7}.

Search for Dark-Matter-Nucleon Interactions with a Dark Mediator in PandaX-4T.

We report results of a search for dark-matter-nucleon interactions via a dark mediator using optimized low-energy data from the PandaX-4T liquid xenon experiment. With the ionization-signal-only data and utilizing the Migdal effect, we set the most stringent limits on the cross section for dark matter masses ranging from 30 MeV/c^{2} to 2 GeV/c^{2}. Under the assumption that the dark mediator is a dark photon that decays into scalar dark matter pairs in the early Universe, we rule out significant parameter space of such thermal relic dark-matter model.

Treatment outcomes for response-based radiotherapy in children and adolescents with central nervous system germinoma: a prospective study.

PURPOSE: The optimal dose and range of radiotherapy for central nervous system (CNS) germinoma have not yet been established. This study aimed to investigate the effects of individualized radiotherapy on the prognosis of patients with germinoma. METHODS: Based on imaging examination, tumor markers, and pathologic results, patients with germinoma received different radiotherapy strategies, including R1 (24 Gy whole ventricular irradiation + tumor-bed boost to 40 Gy), R2 (24-30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy), R3 (24 Gy craniospinal irradiation + tumor-bed boost to 40 Gy), and R4 (30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy with 45 Gy to spinal metastasis). RESULTS: A total of 77 patients were enrolled in this study between January 2015 and March 2021. The 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 94.7% ± 2.6% and 96.0% ± 2.3%, respectively. The 3-year EFS for patients with localized and metastatic disease were 96.6% ± 2.4% and 89.2% ± 7.2%, respectively. The 3-year EFS of patients receiving R1, R2, R3, and R4 radiotherapy were 100%, 94.1% ± 5.7%, 100%, and 86.2% ± 9.1%, respectively. CONCLUSION: Good prognosis was still achieved after reducing dose and extent of radiation for the patients who achieved complete response (CR) after induction chemotherapy or pathological CR after second-look surgery.

The association between team resilience and team performance in nurses during COVID-19 pandemic: a network analysis.

BACKGROUND: Compared to other healthcare workers, nurses are more vulnerable to the potentially devastating effects of pandemic-related stressors. Studies have not yet investigated the deeper characteristics of the relationship between team resilience and team performance among nurses during the COVID-19 pandemic. This study aimed to elucidate the characteristics of team resilience and performance networks among nurses during the pandemic. METHODS: A cross-sectional study involving 118 nursing teams comprising 1627 practice nurses from four tertiary-A and secondary-A hospitals in Shandong Province, China, was conducted. Analyzing and Developing Adaptability and Performance in Teams to Enhance Resilience Scale and the Team Effectiveness Scale were used to measure team resilience and performance, respectively. The estimation of the network model and calculation of related metrics, network stability and accuracy, and network comparison tests were performed using R 4.0.2. RESULTS: Node monitoring had the highest centralities in the team resilience and performance network model, followed by node anticipation, cooperation satisfaction, and cooperation with other departments. Moreover, node cooperation satisfaction and learning had the highest levels of bridge centrality in the entire network. CONCLUSION: Monitoring, anticipation, cooperation satisfaction, cooperation with other departments, and learning constituted core variables maintaining the team resilience-performance network structure of nurses during the pandemic. Clinical interventions targeting core variables may be effective in maintaining or promoting both team resilience and performance in this population.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.

Epstein-Barr virus-derived circular RNA LMP2A induces stemness in EBV-associated gastric cancer.

Cancer stem cells (CSCs) are cancer-initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5-fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU-4th, which displays properties of CSCs and mainly consists of CD44+ CD24- cells. In SNU-4th cells, an EBV-encoded circRNA, ebv-circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR-3908/TRIM59/p53 axis. Additionally, high expression of ebv-circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv-circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.

Association between Gestational Age, Birth Weight, Parental Age at Childbirth, Mode of Delivery, and Infantile Esotropia.

SIGNIFICANCE: This study investigated the potential perinatal risk factors associated with infantile esotropia in a Chinese population, including advanced parental age at childbirth and mode of delivery. The findings may be significant in developing better intervention strategies for infantile esotropia. PURPOSE: This study aimed to investigate the associations between gestational age, birth weight, parental age at childbirth, mode of delivery, family history of strabismus, and infantile esotropia in the Chinese population. METHODS: Ninety-nine patients with infantile esotropia and 117 control subjects were enrolled between March 2018 and March 2021. Detailed questionnaires were administered to parents to collect relevant information. Univariate and multivariate logistic regression models were used to identify possible risk factors of infantile esotropia. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Infantile esotropia was associated with low birth weight (<2500 g; OR, 4.235; 95% CI, 1.460 to 12.287; P = .008) and emergency cesarean delivery (OR, 2.230; 95% CI, 1.127 to 4.413; P = .02). CONCLUSIONS: The findings suggest that low birth weight and emergency cesarean deliveries are risk factors for infantile esotropia, highlighting a need for collaborative care between obstetricians, pediatricians, and vision care providers.

Validation of a Chinese version of the Analysing and Developing Adaptability and Performance in Teams to Enhance Resilience Scale in nurses in China.

AIM: This study examined the validity and reliability of the Analysing and Developing Adaptability and Performance in Teams to Enhance Resilience (ADAPTER) Scale in a sample of Chinese nurses. BACKGROUND: Nurse shortage caused by job stress in China is becoming more acute, while research on team resilience training among nurses is still rising. To accurately and consistently describe team resilience status prior to training and evaluate the effects of resilience interventions at the team level among nurses, it is critical to develop a valid and reliable Chinese measure. METHODS: This was a cross-sectional study of 838 nurses. The scale was translated into Chinese according to Brislin's guidelines. Validity was evaluated by content validity, discriminative validity, exploratory and confirmatory factor analyses and convergent validity. Reliability was estimated by item-to-total correlations, internal consistency and test-retest reliability. RESULTS: Exploratory and confirmatory factor analyses revealed a four-factor model. Content validity was good and discriminative validity showed a significant discriminative ability. The concurrent validity was acceptable. The reliability was demonstrated with item-to-total correlations of greater than .40, Cronbach's alpha of .97 and intraclass correlation coefficients of .946. CONCLUSIONS: The Chinese version of the scale is a valid and reliable instrument. IMPLICATIONS FOR NURSING MANAGEMENT: The scale can provide insight into nurses' team resilience and thereby inform the development of specific interventions aimed at improving the team resilience of nurses.

Novel fully human anti-CD47 antibodies stimulate phagocytosis and promote elimination of AML cells.

Although most patients with acute myeloid leukemia (AML) enter remission after induction chemotherapy, the risk of relapse remains considerable. Therefore, some novel therapeutic strategies are still required. This study found that the overexpression of CD47 on AML cells was at least twofold more than that on normal bone marrow (NBM) cells in 81% (17/21) of the investigated patients; no patients had lower expression level of CD47 compared with healthy donors. The study also demonstrated that blocking the CD47/SIRPα (signal regulatory protein α) signal with the established novel fully human anti-CD47 monoclonal antibodies increased the phagocytosis of AML cells by macrophages in vitro. Furthermore, in vivo experiments showed that the novel fully human anti-CD47 monoclonal antibodies could significantly prolong the survival time of mice. Overall, the novel fully human anti-CD47 antibodies could block CD47/SIRPα interaction, increase macrophage-mediated phagocytosis, and enhance the elimination of AML cells.

Comparison of chemotherapy with or without asparaginase for extranodal nasal NK/T-cell lymphoma in children and adolescents.

PURPOSE: As extranodal natural killer/T-cell lymphoma (ENKTL) occurs rarely in children and adolescents, standardized therapy is yet to be determined. This study aimed to describe the clinical features and determine the optimal chemotherapy regimen for childhood ENKTL. METHODS: The treatment outcomes of radiotherapy combined with asparaginase-based (P-GEMOX or P-GMED) or asparaginase-absent chemotherapy regimens (CHOP, EPOCH, or NHL-BFM-90/95) in patients aged ≤18 years with newly diagnosed ENKTL from December 2006 to December 2018 were compared. RESULTS: Among the 34 patients included in the study, 21 had stage I/II disease. The overall response rates of chemotherapy with or without asparaginase were 85.0% and 78.6%, respectively. With a median follow-up of 54 months, the 5-year event-free survival (EFS) rates of patients with stage I/II and III/IV disease were 66.2 ± 11.3% and 26.0 ± 12.8%, respectively (P = .027). In stage III/IV patients treated with asparaginase-based or asparaginase-absent regimens, the 5-year EFS rates were 40.0 ± 17.4% and 0%, respectively (P = .236). The 5-year EFS rates of stage III/IV patients who received or did not receive hematopoietic stem cell transplant were 66.7 ± 27.2% and 11.1 ± 10.5%, respectively (P = .054). In addition, chemotherapy-associated side effects were significantly less in patients treated with asparaginase-based regimens as compared to asparaginase-absent regimens in this cohort. CONCLUSION: P-GEMOX and P-GMED regimens are effective and safe for treating childhood ENKTL.

Multimodal Treatment of Children With Sacrococcygeal Yolk Sac Tumor: Retrospective Analysis of Clinicopathology Characteristics and Relapse-free Survival.

The aim of the study was to explore the clinicopathologic characteristics of sacrococcygeal yolk sac tumor (SYST) associated with relapse and the role of sensitivity to neoadjuvant chemotherapy in predicting outcome. The authors investigated prognostic factors of age, stage, initial tumor size, pathologic response to neoadjuvant chemotherapy, and alfa fetoprotein. A total of 26 patients with SYST were enrolled. Neoadjuvant chemotherapy was administered to 20 cases. Six patients underwent resection as initial therapy. Recurrence occurred in 12 patients. Nine patients with specimens exhibiting no malignant component after chemotherapy did not experience recurrence. By contrast, relapses occurred in 7 of 11 patients with viable residual tumor after neoadjuvant chemotherapy. All relapsed patients still achieved partial remission or complete remission after salvage therapy. Five-year relapse-free survival and overall survival rates were 55.2% and 100%, respectively (median follow-up, 59.5 mo; range, 16 to 155). Patients with complete necrosis after neoadjuvant chemotherapy had a better outcome compared with children with viable residual tumor. Relapse-free survival of pediatric SYSTs in this cohort were still low and warrants the multidisciplinary effort.

The prognosis of prechemotherapy blastemal predominant histology subtype in Wilms tumor: A retrospective study in China.

PURPOSE: This study aimed to retrospectively analyze survival outcomes for Chinese patients with prechemotherapy blastemal predominant histology type Wilms tumors (WTs). METHODS: We collected and analyzed clinical data concerning patients aged <15 years with favorable histology (FH) WTs treated at the Sun Yat-Sen University Cancer Center from December 2005 to May 2016, based on the Children's Oncology Group protocol. Pathological specimens were collected through biopsy or surgical resection before initiation of chemotherapy. We analyzed survival outcomes involving different prechemotherapy histology subtypes. RESULTS: We enrolled 97 patients with FH WTs (median follow-up, 71.5 months; range, 22.2-170.7). The total recurrence rate was 17.5%, and the subtype recurrence rates were as follows: blastemal predominant (45.5%), mixed (7.5%), epithelial (14.3%), and mesenchymal (9.5%) (P = .010). Five-year event-free survival (EFS) and overall survival (OS) rates were 84.9% and 81.4%, respectively. Respective 5-year EFS and OS rates for subtypes were as follows: blastemal predominant (54.5% and 68.2%), mixed (90.0% and 88.9%), epithelial (85.7% and 85.1%), and mesenchymal (90.5% and 94.7%). Multivariate survival analyses showed that the blastemal predominant subtype was an independent prognostic factor of EFS (P = .001) and OS (P = .017). CONCLUSIONS: Our findings showed that prechemotherapy blastemal predominant WTs had higher recurrence and lower EFS and OS rates. Our findings suggested that, albeit with some deficiencies, blastemal predominant histology WT-diagnosed prechemotherapy may have prognostic relevance. Further research into other potential confounding variables are required to determine whether such patients warrant altered risk-stratified therapy.

The effectiveness of the Internet-based self-management program for cancer-related fatigue patients: a systematic review and meta-analysis.

OBJECTIVE: To systematically investigate how fatigue, depression, anxiety, sleep quality, and life quality are influenced by the Internet-based self-management program (IBSMP) among cancer patients. DATA SOURCES: Eight databases (Cochrane Library, Ovid, Web of Science, Medline, Embase, Chinese biomedical database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang) were systematically searched from inception to January 2019. METHODS: The aim of this study is to identify randomized controlled trials (RCTs) associated with the IBSMP among cancer-related fatigue (CRF) patients. Two reviewers independently screened 1128 records and selected 13 articles, including 1603 patients for inclusion. The quality of the evidence was assessed at the study level and at the outcome level. RESULTS: The meta-analysis showed that the IBSMP was effective for ameliorating fatigue and related symptoms among cancer survivors (the Brief Fatigue Index, relative risk = 0.74, 95% confidence interval (CI; 0.69, 0.79), P < 0.01; the Cancer Fatigue Scale or the Multidimension Fatigue Scale, weighted mean difference = -10.15, 95% CI (-11.42, -8.89), P < 0.01; the Self-rating Anxiety scale, relative risk = 1.07, 95% CI (0.55, 2.05), P < 0.01; the Self-rating Depression scale, relative risk = 0.70, 95% CI (0.60, 0.81), P < 0.01; the Pittsburgh Sleep Quality Index, relative risk = 0.46, 95% CI (0.33, 0.62), P < 0.01; and the Function Assessment of Cancer Therapy-General scale or the Function Assessment of Cancer Therapy-Breast, weighted mean difference = 13.76, 95% CI (3.38, 24.14), P < 0.01.). CONCLUSION: This meta-analysis demonstrates that the IBSMP, as one of the rehabilitation forms, can reduce the incidence of fatigue, depression, and anxiety and improve sleep quality and life quality among CRF patients.

Rituximab is highly effective in children and adolescents with Burkitt lymphoma in Risk Groups R2 to R4.

Data regarding the use of rituximab in children and adolescents with Burkitt's lymphoma (BL) is limited. This study retrospectively analyzed the effect of rituximab on children and adolescents with BL in risk group (R) 2 to R4. Patients underwent chemotherapy according to the revised NHL-BFM-95 protocol. Rituximab was administered at the dose of 375 mg/m2 on day 0 of each cycle. A total of 106 patients were included. Stratified by the number of doses of rituximab, there were 49, 16, and 41 patients in group 1 (no rituximab), group 2 (1-3 doses of rituximab) and group 3 (≥4 doses of rituximab), respectively. The 3-year event-free survival (EFS) rates were 83.2% (95% CI = 72.6%-93.8%), 81.2% (95% CI = 52.3%-93.5%) and 96.8% (95% CI = 78.8%-99.6%) in group 1, group 2 and group 3, respectively (p = 0.077). In R2/R3, the relapse rates were 0 in patients treated with rituximab and 11.8% in those treated without rituximab (p = 0.516). In R4, the relapse rates were 18.8%, 21.4% and 3.0% in group 1, group 2 and group 3, respectively (p = 0.048). Rituximab is highly effective in children and adolescents with BL in R2 to R4. The optimal number of doses was 4-6 in patients with BL in R4.

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era.

BACKGROUND: Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL). METHODS: We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels. RESULTS: Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0-1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001). CONCLUSIONS: The prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.

Synthesis and biological evaluation of novel N3-substituted dihydropyrimidine derivatives as T-type calcium channel blockers and their efficacy as analgesics in mouse models of inflammatory pain.

Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson's disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the CaV3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of CaV3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated CaV3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in CaV3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Cav3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.

Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects.

As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10µM concentration and exhibited cytotoxic effect (IC50=5.9µM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels.

Effect of chemotherapy alone with adult chemotherapy regimens on prognosis of children and adolescents with Hodgkin's disease.

OBJECTIVE: A current focus on the treatment of children and adolescents with Hodgkin's disease is identification of subgroups of patients for whom radiotherapy can be omitted without compromising clinical outcome. We evaluated the feasibility of using adult chemotherapy regimens alone to treat children and adolescents with Hodgkin's disease. METHODS: Recruitment inclusion criteria were children and adolescents ≤18 years old who were newly diagnosed as Hodgkin's disease. Chemotherapy comprised four cycles of ABVD, six cycles of ABVD or COPP/ABV and six cycles of BEACOPP/ABVD chemotherapy regimens in the low-, intermediate- and high-risk groups, respectively. Radiotherapy was omitted for patients with low-risk, nonbulky disease who had achieved complete remission after chemotherapy and patients who failed to undergo the scheduled radiotherapy due to various reasons beyond the disease. RESULTS: Seventy-five children and adolescents were recruited, including 28, 24 and 23 patients in the low-, intermediate- and high-risk groups, respectively. With a median follow-up of 48 months, 4-year event-free survival and 4-year overall survival were 77.6% ± 5% and 95.3% ± 3%, respectively, in the whole cohort. The 4-year event-free survival in the low-, intermediate- and high-risk groups were 88.2% ± 6%, 78.1% ± 9% and 66.2% ± 11%, respectively (P = 0.062). Sixteen patients (21.3%) relapsed and four died from tumor progression. CONCLUSIONS: Over three-quarters of children and adolescents with Hodgkin's disease achieved long-term event-free survival after receiving chemotherapy alone with adult chemotherapy regimens, and radiotherapy-related toxicity was avoided.