Evaldo Soares - Academia.edu (original) (raw)

Papers by Evaldo Soares

A você meu filho, João Victor, que de mim esteve tão distante durante a realização deste trabalho... more A você meu filho, João Victor, que de mim esteve tão distante durante a realização deste trabalho, mas que ficou sempre presente em meus pensamentos. Que à distância nos aproxime e, o tempo vai mostrar que valeu a pena todo este sacrifício. v AGRADECIMENTOS A Deus, sempre presente em minhas orações nos momentos de maior aflição e que me deu forças para prosseguir quando as adversidades pareciam ser intransponíveis. A meus pais, Evandro e Ivete, que me apoiaram em todos os momentos e alicerçaram minha formação sem a qual não teria chegado até aqui. A minha tia Maria Helena Ferreira cujo apoio moral e emocional foram fundamentais no meu distanciamento para poder concretizar este trabalho. A minha orientadora, Prof a. Maria Clara pelo apoio e orientação dados ao longo de todo o trabalho e pela confiança em mim depositado na realização do mesmo.

Orientador: Maria Clara Filippini IerardiTese (doutorado) - Universidade Estadual de Campinas, Fa... more Orientador: Maria Clara Filippini IerardiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia MecanicaResumo: A melhoria nas propriedades superficiais dos materiais tem sido buscada incessantemente pelas indústrias de transformação. A utilização do laser para tratamento térmico e refusão, entre outros processos, tem possibilitado grandes avanços nesta área. Muito se tem trabalhado na determinação dos parâmetros operacionais do laser e a resultante destas influências sobre as propriedades dos materiais. Os objetivos deste trabalho são estudar os efeitos destes parâmetros operacionais sobre a profundidade da camada superficial e a caracterização microestrutural das amostras submetidas a tratamento térmico a laser. Foram feitos experimentos usando os aços AISI 1045 e AISI 4340, a partir de amostras recozidas, temperadas e nitretadas. Foi utilizado um laser de CO2, pertencente ao LNLS, com potência nominal de 1 kW, desfocado em 2 mm, velocidade de deslocamento d...

Revista Brasileira da Educação Profissional e Tecnológica

O objetivo é verificar como a prática de esportes adaptados favorece a inclusão de pessoas com de... more O objetivo é verificar como a prática de esportes adaptados favorece a inclusão de pessoas com deficiência visual nas aulas de educação física (EF). É um estudo qualitativo realizado em 2019 no campus Tucuruí do IFPA em uma turma do ensino médio, onde foram desenvolvidas as modalidades de goalball e futebol de 5. As aulas foram estruturadas conforme Dolz, Noverraz e Schneuwly (2004). Utilizou-se para a coleta de dados um questionário adaptado de Cunha (2013) e as respostas foram processadas e analisadas pelo software IRAMUTEQ. Os resultados demostraram reflexões positivas sobre a inclusão e que esses esportes possuem características inclusivas. Conclui-se que a prática de modalidades de esportes adaptados nas aulas de EF favorece na inclusão de pessoas com deficiência visual.

O presente trabalho tem como objetivo estudar as modificacoes mecânicas e microestruturais em um ... more O presente trabalho tem como objetivo estudar as modificacoes mecânicas e microestruturais em um aco de 0,6%C, submetido a diferentes meios de resfriamento, procurando verificar e comparar as mudancas em suas propriedades mecânicas bem como caracterizar e analisar a microestrutura de acordo com o tratamento empregado a cada corpo de prova.

Experimental and Molecular Therapeutics, 2020

Journal of Clinical Oncology, 2013

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histo... more e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/...

International Journal of Radiation Oncology*Biology*Physics, 2020

iScience, 2019

Aberrant RAS signaling activation is common in cancers with even few Ras mutations, indicating al... more Aberrant RAS signaling activation is common in cancers with even few Ras mutations, indicating alternative dysregulation other than genetic mutations. We identified a Ras GTPase-activating gene RASA5/SYNGAP1, at the common 6p21.3 deletion, methylated/downregulated in multiple carcinomas and different from other RASA family members (RASA1-RASA4), indicating its special functions in tumorigenesis. RASA5 mutations are rare, unlike other RASA members, whereas its promoter CpG methylation is frequent in multiple cancer cell lines and primary carcinomas and associated with patient's poor survival. RASA5 expression inhibited tumor cell migration/invasion and growth in mouse model, functioning as a tumor suppressor. RASA5 suppressed RAS signaling, depending on its Ras GTPase-activating protein catalytic activity, which could be counteracted by oncogenic HRas Q61L mutant. RASA5 knockdown enhanced Ras signaling to promote tumor cell growth. RASA5 also inhibited epithelial-mesenchymal transition (EMT) through regulating actin reorganization. Thus, epigenetic inactivation of RASA5 contributing to hyperactive RAS signaling is involved in Rasdriven human oncogenesis.

Journal of Clinical Oncology, 2015

4073 Background: Axitinib is a potent and specific inhibitor of VEGFRs. Elevation of VEGF level i... more 4073 Background: Axitinib is a potent and specific inhibitor of VEGFRs. Elevation of VEGF level in plasma and tumor is frequently observed after TACE treatment for HCC. We hypothesize that combining axitinib and TACE has synergism by inhibiting the VEGF surge after TACE. We conducted a phase II clinical trial to study the combination for treatment of inoperable HCC. Methods: This is an investigator-initiated, single-arm, phase II study. Key eligibility criteria include: diagnosis of inoperable HCC; Child’s A function; without main portal vein thrombosis/distant metastases. Patients (pts) were started axitinib 5mg bid followed by TACE at 5thweek. Assessment of further TACE is conducted every 2 months (m). TACE is given if there is viable HCC and pts are suitable for TACE. Axitinib is withheld 24 hours before and resumed 24 hours after TACE. CT Imaging is arranged every 8 weeks (mRECIST). The primary endpoint is 2-year survival rate. Secondary endpoints include determination of response, toxicity and clinic...

Journal of Clinical Oncology, 2014

3582 Background: The early determination of drug response is a keystone in oncology, and CTC is a... more 3582 Background: The early determination of drug response is a keystone in oncology, and CTC is a promising biomarker in mCRC. This study investigated the prognostic significance of a novel dual-endpoint of ‘PET and CTC response’ at 4 weeks (wk), and of the conventional RECIST response at 10 wks post-1stline chemotherapy (chemo). Methods: All pts had a whole-body (WB) PET-CT (contrast) and CTC analysis (7.5ml blood) at baseline, a plain PET-CT and CTC analysis at 4 wks, and a WB-CT at 10 wks after starting chemo. CTCs were isolated using the cancer cell enrichment and detection kit (Milenyi Biotech). A positive CTC is defined as having: a positive red staining, round-to-oval morphology, size = or > 2 times that of lymphocyte. Evaluable lesions must have a SUVmax = or > 2 on PET and be measurable based on RECIST (version 1.0 and 1.1). PET response is defined as = or > 30% drop in the sum of SUVmax of target lesions, and CTC response is defined as ‘any level of drop’, or a ‘CTC < 3 cells’ at 4 wks. Results:...

International Journal of Radiation Oncology*Biology*Physics, 2018

Journal of Clinical Oncology, 2004

4205 Background: Phase II clinical trials aim to assess anti-tumor activity of investigational th... more 4205 Background: Phase II clinical trials aim to assess anti-tumor activity of investigational therapies in order to detect promising agents for future phase III trials. A review of previous phase II studies on single agent doxorubincin (Dox) for HCC shows that response rates (RR) vary widely from 0% to 44%. A randomized phase II design is preferred but the decision theoretical approach by Simon picking the winner may not be appropriate in this circumstance. We proposed a new randomized phase II design using control as an adjustment for the efficacy of study treatment. METHOD A hypothesis similar to a single-arm phase II design will be stated, e.g. H0: p = p0 vs H1: p = p1. Patients (pts) randomized to control arm will receive standard treatment. The RR of the control arm (p0) with s0 responders from n0 pts will be used in a conditional model to adjust for the RR in the study arm (p1). The probability of the study arm with s1 responders from n1 pts given the null hypothesis, i.e. P(s1| n1, p0) has binomial distribution and the RR follows a dirichlet distribution h(p0|n0, s0). We determined the rejection regions (r) so that P(s1>r|n1, n0, s0) < 0.05. RESULTS Based on a randomized study comparing Dox versus combination chemotherapy (PIAF) for inoperable HCC, a RR of about 10% was found in the Dox arm where previous phase II study showed a RR of 26%. With 30 pts in each arm assuming a null hypothesis of p*=0.1 and a 5% type I error, the number of responders required to declare the study treatment effective is shown in the following table. The estimate RR for the study treatment is p=(p1-p0)+p*, a 95% confidence interval can be obtained in the analysis. CONCLUSION The new randomized phase II design provides a platform by which effective investigational agents for HCC can be detected without being camouflaged by the patient selection problem. Simulation on the properties of the design will be presented. [Figure: see text] No significant financial relationships to disclose.

Journal of Clinical Oncology, 2008

17015 Background: To investigate the impact of dose-volume parameters of skin on the severity of ... more 17015 Background: To investigate the impact of dose-volume parameters of skin on the severity of radiation dermatitis in a cohort of nasopharyngeal carcinoma (NPC) patients treated with concurrent cetuximab (C225), cisplatin, and intensity-modulated radiotherapy (IMRT). Method: 20 stage III-IVb NPC patients were treated with a loading dose of C225 (400 mg/m2), followed by IMRT (74 Gy to primary, 70 Gy to involved nodes, 62 Gy to subclinical region, 35 fractions) plus weekly cisplatin (30 mg/m2) and C225 (250 mg/m2) for 6–7 cycles during radiotherapy. The different level of worst skin toxicity (Grade 0–2 vs. 3–4) within 90 days from start of RT (NCI CTCAE v 3.0), and hyperpigmentation (mild or moderate) were compared with respect to various dose-volume parameters: total skin volume within radiation portal (Vt), volume of skin irradiated to different dose levels (Vdose), maximum (Dmax) and mean (Dmean) skin dose using Mann-Whitney test. Result: The incidence of grades 1, 2, 3 and 4 radiation dermatitis were...

Journal of Clinical Oncology, 2005

... Issue Date: 2005. Citation: MOK Shu Kam Tony, YEO Winnie, HUI Pun, CHAK Yin Mui Karen, CHAN A... more ... Issue Date: 2005. Citation: MOK Shu Kam Tony, YEO Winnie, HUI Pun, CHAK Yin Mui Karen, CHAN Anthony Tak Cheung, JOHNSON J. Philip, ZEE Benny, PAN Z. R, XU M, AU WC Paper presented in the 2005 ASCO Annual Meeting, 2005, p.8157. ...

Journal of Clinical Oncology, 2005

5501 Background: Severe xerostomia regularly occurs in NPC patients treated by 2-dimensional radi... more 5501 Background: Severe xerostomia regularly occurs in NPC patients treated by 2-dimensional radiotherapy (2DRT). Although IMRT reduces parotid gland irradiation in NPC, randomized data supporting its use is lacking. Methods: Patients with T1–2bN0–2M0 NPC were randomized to receive either IMRT or 2DRT, both 66Gy, without chemotherapy. Primary endpoint was RTOG xerostomia at 1 year after treatment. Secondary endpoints included RTOG xerostomia at 6 weeks post treatment, stimulated parotid flow rate (SPFR) and stimulated whole saliva flow rate (SWSFR). Post-RT saliva flow rate was expressed as percentage of residual flow rate over pre-RT baseline. Planned sample size was 27 patients in each arm, to detect a 40% reduction in incidence of severe (RTOG >=grade 2) xerostomia (assumed to occur in >=80% of 2DRT-treated patients) with 80% power for alpha=0.05. Categorical and continuous variables were analyzed with chi-square test and wilcoxon rank-sum test, respectively. Results: 60 patients were recruited, and 56...

Journal of Clinical Oncology, 2011

205 Background: Serum interleukin-10 (IL-10) is associated with active hepatitis in patients (pts... more 205 Background: Serum interleukin-10 (IL-10) is associated with active hepatitis in patients (pts) with hepatitis B viral (HBV) infection. In HBV-related HCC, elevation of serum IL-10 is frequently observed but its significance on the outcome of HCC is unclear. Methods: A prospective cohort of newly diagnosed and inoperable HCC was recruited from a multidisciplinary clinic from Prince of Wales Hospital from 2006 to 2008. The baseline demographics, tumor characteristics/stage, laboratory parameters, virologic factors (HBV DNA, antiviral therapy) and first-line treatment modality were documented at the time of diagnosis. Serum IL-10 was measured by enzyme-linked immunosorbent essay. Univariate and multivariate analyses were conducted. Overall survival (OS) was the primary endpoint. Results: Total 180 new cases of inoperable HCC were evaluated. The median follow-up time was 15.5 months. Median age was 60.5 years. Most (159 pts; 88.3%) were males. 81.1% of them were positive for HBsAg. ...

Nature communications, Jan 18, 2017

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Bar... more Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is sele...

Cancer research, 1999

Recently, cell-free EBV DNA has been detected in the plasma and serum of patients with nasopharyn... more Recently, cell-free EBV DNA has been detected in the plasma and serum of patients with nasopharyngeal carcinoma (NPC). We studied the relationship between plasma/serum EBV DNA and tumor recurrence. Using real-time quantitative PCR, the median plasma EBV DNA concentration in 10 patients with tumor recurrence was determined to be 32,350 copies/ml, whereas that in 15 patients in continuous remission for a mean period of 2 years was 0 copy/ml. Longitudinal follow-up of 17 NPC patients revealed 6 individuals with tumor recurrence and 11 patients who remained in remission. Significant elevations in serum EBV DNA, sometimes up to 6 months before detectable clinical deterioration, were observed in the patients who subsequently developed tumor recurrence. Continuously low or undetectable levels of serum EBV DNA were observed in the patients who remained in remission. These results suggest that plasma/serum cell-free EBV DNA may be a valuable tool for the monitoring of NPC patients for the ea...

PLoS ONE, 2013

Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-c... more Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.Trial Registration: ClinicalTrials.gov NCT00321594 http://clinicaltrials. gov/ct2/show/NCT00321594

A você meu filho, João Victor, que de mim esteve tão distante durante a realização deste trabalho... more A você meu filho, João Victor, que de mim esteve tão distante durante a realização deste trabalho, mas que ficou sempre presente em meus pensamentos. Que à distância nos aproxime e, o tempo vai mostrar que valeu a pena todo este sacrifício. v AGRADECIMENTOS A Deus, sempre presente em minhas orações nos momentos de maior aflição e que me deu forças para prosseguir quando as adversidades pareciam ser intransponíveis. A meus pais, Evandro e Ivete, que me apoiaram em todos os momentos e alicerçaram minha formação sem a qual não teria chegado até aqui. A minha tia Maria Helena Ferreira cujo apoio moral e emocional foram fundamentais no meu distanciamento para poder concretizar este trabalho. A minha orientadora, Prof a. Maria Clara pelo apoio e orientação dados ao longo de todo o trabalho e pela confiança em mim depositado na realização do mesmo.

Orientador: Maria Clara Filippini IerardiTese (doutorado) - Universidade Estadual de Campinas, Fa... more Orientador: Maria Clara Filippini IerardiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia MecanicaResumo: A melhoria nas propriedades superficiais dos materiais tem sido buscada incessantemente pelas indústrias de transformação. A utilização do laser para tratamento térmico e refusão, entre outros processos, tem possibilitado grandes avanços nesta área. Muito se tem trabalhado na determinação dos parâmetros operacionais do laser e a resultante destas influências sobre as propriedades dos materiais. Os objetivos deste trabalho são estudar os efeitos destes parâmetros operacionais sobre a profundidade da camada superficial e a caracterização microestrutural das amostras submetidas a tratamento térmico a laser. Foram feitos experimentos usando os aços AISI 1045 e AISI 4340, a partir de amostras recozidas, temperadas e nitretadas. Foi utilizado um laser de CO2, pertencente ao LNLS, com potência nominal de 1 kW, desfocado em 2 mm, velocidade de deslocamento d...

Revista Brasileira da Educação Profissional e Tecnológica

O objetivo é verificar como a prática de esportes adaptados favorece a inclusão de pessoas com de... more O objetivo é verificar como a prática de esportes adaptados favorece a inclusão de pessoas com deficiência visual nas aulas de educação física (EF). É um estudo qualitativo realizado em 2019 no campus Tucuruí do IFPA em uma turma do ensino médio, onde foram desenvolvidas as modalidades de goalball e futebol de 5. As aulas foram estruturadas conforme Dolz, Noverraz e Schneuwly (2004). Utilizou-se para a coleta de dados um questionário adaptado de Cunha (2013) e as respostas foram processadas e analisadas pelo software IRAMUTEQ. Os resultados demostraram reflexões positivas sobre a inclusão e que esses esportes possuem características inclusivas. Conclui-se que a prática de modalidades de esportes adaptados nas aulas de EF favorece na inclusão de pessoas com deficiência visual.

O presente trabalho tem como objetivo estudar as modificacoes mecânicas e microestruturais em um ... more O presente trabalho tem como objetivo estudar as modificacoes mecânicas e microestruturais em um aco de 0,6%C, submetido a diferentes meios de resfriamento, procurando verificar e comparar as mudancas em suas propriedades mecânicas bem como caracterizar e analisar a microestrutura de acordo com o tratamento empregado a cada corpo de prova.

Experimental and Molecular Therapeutics, 2020

Journal of Clinical Oncology, 2013

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histo... more e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/...

International Journal of Radiation Oncology*Biology*Physics, 2020

iScience, 2019

Aberrant RAS signaling activation is common in cancers with even few Ras mutations, indicating al... more Aberrant RAS signaling activation is common in cancers with even few Ras mutations, indicating alternative dysregulation other than genetic mutations. We identified a Ras GTPase-activating gene RASA5/SYNGAP1, at the common 6p21.3 deletion, methylated/downregulated in multiple carcinomas and different from other RASA family members (RASA1-RASA4), indicating its special functions in tumorigenesis. RASA5 mutations are rare, unlike other RASA members, whereas its promoter CpG methylation is frequent in multiple cancer cell lines and primary carcinomas and associated with patient's poor survival. RASA5 expression inhibited tumor cell migration/invasion and growth in mouse model, functioning as a tumor suppressor. RASA5 suppressed RAS signaling, depending on its Ras GTPase-activating protein catalytic activity, which could be counteracted by oncogenic HRas Q61L mutant. RASA5 knockdown enhanced Ras signaling to promote tumor cell growth. RASA5 also inhibited epithelial-mesenchymal transition (EMT) through regulating actin reorganization. Thus, epigenetic inactivation of RASA5 contributing to hyperactive RAS signaling is involved in Rasdriven human oncogenesis.

Journal of Clinical Oncology, 2015

4073 Background: Axitinib is a potent and specific inhibitor of VEGFRs. Elevation of VEGF level i... more 4073 Background: Axitinib is a potent and specific inhibitor of VEGFRs. Elevation of VEGF level in plasma and tumor is frequently observed after TACE treatment for HCC. We hypothesize that combining axitinib and TACE has synergism by inhibiting the VEGF surge after TACE. We conducted a phase II clinical trial to study the combination for treatment of inoperable HCC. Methods: This is an investigator-initiated, single-arm, phase II study. Key eligibility criteria include: diagnosis of inoperable HCC; Child’s A function; without main portal vein thrombosis/distant metastases. Patients (pts) were started axitinib 5mg bid followed by TACE at 5thweek. Assessment of further TACE is conducted every 2 months (m). TACE is given if there is viable HCC and pts are suitable for TACE. Axitinib is withheld 24 hours before and resumed 24 hours after TACE. CT Imaging is arranged every 8 weeks (mRECIST). The primary endpoint is 2-year survival rate. Secondary endpoints include determination of response, toxicity and clinic...

Journal of Clinical Oncology, 2014

3582 Background: The early determination of drug response is a keystone in oncology, and CTC is a... more 3582 Background: The early determination of drug response is a keystone in oncology, and CTC is a promising biomarker in mCRC. This study investigated the prognostic significance of a novel dual-endpoint of ‘PET and CTC response’ at 4 weeks (wk), and of the conventional RECIST response at 10 wks post-1stline chemotherapy (chemo). Methods: All pts had a whole-body (WB) PET-CT (contrast) and CTC analysis (7.5ml blood) at baseline, a plain PET-CT and CTC analysis at 4 wks, and a WB-CT at 10 wks after starting chemo. CTCs were isolated using the cancer cell enrichment and detection kit (Milenyi Biotech). A positive CTC is defined as having: a positive red staining, round-to-oval morphology, size = or > 2 times that of lymphocyte. Evaluable lesions must have a SUVmax = or > 2 on PET and be measurable based on RECIST (version 1.0 and 1.1). PET response is defined as = or > 30% drop in the sum of SUVmax of target lesions, and CTC response is defined as ‘any level of drop’, or a ‘CTC < 3 cells’ at 4 wks. Results:...

International Journal of Radiation Oncology*Biology*Physics, 2018

Journal of Clinical Oncology, 2004

4205 Background: Phase II clinical trials aim to assess anti-tumor activity of investigational th... more 4205 Background: Phase II clinical trials aim to assess anti-tumor activity of investigational therapies in order to detect promising agents for future phase III trials. A review of previous phase II studies on single agent doxorubincin (Dox) for HCC shows that response rates (RR) vary widely from 0% to 44%. A randomized phase II design is preferred but the decision theoretical approach by Simon picking the winner may not be appropriate in this circumstance. We proposed a new randomized phase II design using control as an adjustment for the efficacy of study treatment. METHOD A hypothesis similar to a single-arm phase II design will be stated, e.g. H0: p = p0 vs H1: p = p1. Patients (pts) randomized to control arm will receive standard treatment. The RR of the control arm (p0) with s0 responders from n0 pts will be used in a conditional model to adjust for the RR in the study arm (p1). The probability of the study arm with s1 responders from n1 pts given the null hypothesis, i.e. P(s1| n1, p0) has binomial distribution and the RR follows a dirichlet distribution h(p0|n0, s0). We determined the rejection regions (r) so that P(s1>r|n1, n0, s0) < 0.05. RESULTS Based on a randomized study comparing Dox versus combination chemotherapy (PIAF) for inoperable HCC, a RR of about 10% was found in the Dox arm where previous phase II study showed a RR of 26%. With 30 pts in each arm assuming a null hypothesis of p*=0.1 and a 5% type I error, the number of responders required to declare the study treatment effective is shown in the following table. The estimate RR for the study treatment is p=(p1-p0)+p*, a 95% confidence interval can be obtained in the analysis. CONCLUSION The new randomized phase II design provides a platform by which effective investigational agents for HCC can be detected without being camouflaged by the patient selection problem. Simulation on the properties of the design will be presented. [Figure: see text] No significant financial relationships to disclose.

Journal of Clinical Oncology, 2008

17015 Background: To investigate the impact of dose-volume parameters of skin on the severity of ... more 17015 Background: To investigate the impact of dose-volume parameters of skin on the severity of radiation dermatitis in a cohort of nasopharyngeal carcinoma (NPC) patients treated with concurrent cetuximab (C225), cisplatin, and intensity-modulated radiotherapy (IMRT). Method: 20 stage III-IVb NPC patients were treated with a loading dose of C225 (400 mg/m2), followed by IMRT (74 Gy to primary, 70 Gy to involved nodes, 62 Gy to subclinical region, 35 fractions) plus weekly cisplatin (30 mg/m2) and C225 (250 mg/m2) for 6–7 cycles during radiotherapy. The different level of worst skin toxicity (Grade 0–2 vs. 3–4) within 90 days from start of RT (NCI CTCAE v 3.0), and hyperpigmentation (mild or moderate) were compared with respect to various dose-volume parameters: total skin volume within radiation portal (Vt), volume of skin irradiated to different dose levels (Vdose), maximum (Dmax) and mean (Dmean) skin dose using Mann-Whitney test. Result: The incidence of grades 1, 2, 3 and 4 radiation dermatitis were...

Journal of Clinical Oncology, 2005

... Issue Date: 2005. Citation: MOK Shu Kam Tony, YEO Winnie, HUI Pun, CHAK Yin Mui Karen, CHAN A... more ... Issue Date: 2005. Citation: MOK Shu Kam Tony, YEO Winnie, HUI Pun, CHAK Yin Mui Karen, CHAN Anthony Tak Cheung, JOHNSON J. Philip, ZEE Benny, PAN Z. R, XU M, AU WC Paper presented in the 2005 ASCO Annual Meeting, 2005, p.8157. ...

Journal of Clinical Oncology, 2005

5501 Background: Severe xerostomia regularly occurs in NPC patients treated by 2-dimensional radi... more 5501 Background: Severe xerostomia regularly occurs in NPC patients treated by 2-dimensional radiotherapy (2DRT). Although IMRT reduces parotid gland irradiation in NPC, randomized data supporting its use is lacking. Methods: Patients with T1–2bN0–2M0 NPC were randomized to receive either IMRT or 2DRT, both 66Gy, without chemotherapy. Primary endpoint was RTOG xerostomia at 1 year after treatment. Secondary endpoints included RTOG xerostomia at 6 weeks post treatment, stimulated parotid flow rate (SPFR) and stimulated whole saliva flow rate (SWSFR). Post-RT saliva flow rate was expressed as percentage of residual flow rate over pre-RT baseline. Planned sample size was 27 patients in each arm, to detect a 40% reduction in incidence of severe (RTOG >=grade 2) xerostomia (assumed to occur in >=80% of 2DRT-treated patients) with 80% power for alpha=0.05. Categorical and continuous variables were analyzed with chi-square test and wilcoxon rank-sum test, respectively. Results: 60 patients were recruited, and 56...

Journal of Clinical Oncology, 2011

205 Background: Serum interleukin-10 (IL-10) is associated with active hepatitis in patients (pts... more 205 Background: Serum interleukin-10 (IL-10) is associated with active hepatitis in patients (pts) with hepatitis B viral (HBV) infection. In HBV-related HCC, elevation of serum IL-10 is frequently observed but its significance on the outcome of HCC is unclear. Methods: A prospective cohort of newly diagnosed and inoperable HCC was recruited from a multidisciplinary clinic from Prince of Wales Hospital from 2006 to 2008. The baseline demographics, tumor characteristics/stage, laboratory parameters, virologic factors (HBV DNA, antiviral therapy) and first-line treatment modality were documented at the time of diagnosis. Serum IL-10 was measured by enzyme-linked immunosorbent essay. Univariate and multivariate analyses were conducted. Overall survival (OS) was the primary endpoint. Results: Total 180 new cases of inoperable HCC were evaluated. The median follow-up time was 15.5 months. Median age was 60.5 years. Most (159 pts; 88.3%) were males. 81.1% of them were positive for HBsAg. ...

Nature communications, Jan 18, 2017

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Bar... more Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is sele...

Cancer research, 1999

Recently, cell-free EBV DNA has been detected in the plasma and serum of patients with nasopharyn... more Recently, cell-free EBV DNA has been detected in the plasma and serum of patients with nasopharyngeal carcinoma (NPC). We studied the relationship between plasma/serum EBV DNA and tumor recurrence. Using real-time quantitative PCR, the median plasma EBV DNA concentration in 10 patients with tumor recurrence was determined to be 32,350 copies/ml, whereas that in 15 patients in continuous remission for a mean period of 2 years was 0 copy/ml. Longitudinal follow-up of 17 NPC patients revealed 6 individuals with tumor recurrence and 11 patients who remained in remission. Significant elevations in serum EBV DNA, sometimes up to 6 months before detectable clinical deterioration, were observed in the patients who subsequently developed tumor recurrence. Continuously low or undetectable levels of serum EBV DNA were observed in the patients who remained in remission. These results suggest that plasma/serum cell-free EBV DNA may be a valuable tool for the monitoring of NPC patients for the ea...

PLoS ONE, 2013

Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-c... more Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.Trial Registration: ClinicalTrials.gov NCT00321594 http://clinicaltrials. gov/ct2/show/NCT00321594