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Philip J. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Systemic therapy for hepatocellular carcinoma: Cytotoxic Chemotherapy, targeted therapy and immunotherapy.
Annals of Surgical Oncology, 2008Co-Authors: Melanie B. Thomas, Ghassan K. Abou-alfa, James O'beirne, Junji Furuse, Anthony T.c. Chan, Philip J. JohnsonAbstract:Conventional Cytotoxic Chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. This review summarizes the results of prospective clinical trials of several categories of systemic therapy, with emphasis on the more promising results from recent trials of biologically targeted therapeutic agents in HCC.
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high hepatitis b virus hbv dna viral load is an important risk factor for hbv reactivation in breast cancer patients undergoing Cytotoxic Chemotherapy
Journal of Viral Hepatitis, 2004Co-Authors: Sheng Zhong, Winnie Yeo, Paul K S Chan, C Schroder, W L Wong, B Zee, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation during Cytotoxic Chemotherapy for cancer may complicate treatment and cause liver damage. The complication has been reported to occur in 10% to over 50% of HBV carriers, but the factors that determine which patients will develop reactivation remain unclear. The objective of the study is to test the hypothesis that the preChemotherapy HBV DNA level is a risk factor for the development of HBV reactivation. We studied 41 women undergoing Cytotoxic Chemotherapy for breast cancer, 17 of whom developed reactivation and 24 who did not. We developed a novel, ultra-sensitive, real-time polymerase chain reaction assay for the measurement of HBV DNA. The sera of 37 patients (16 who developed reactivation and 21 who did not) were available for measurement of HBV DNA using this technique. The results showed that patients in the reactivation group had a significantly higher median HBV DNA load (1.03 x 10(6) copies/mL; range <2.9 x 10(3) to 8.723 x 10(7)) than did the nonreactivation group (<2.9 x 10(3) copies/ml; range <2.9 x 10(3) to 6.331 x 10(7)) (P < 0.001). The optimal cut-off between the two groups was found to be at serum HBV DNA level of 3 x 10(5), which gave a sensitivity of 81.0% and a specificity of 85.0%. In conclusion, for breast cancer patients receiving standard Cytotoxic Chemotherapy, a high HBV viral load prior to the administration of Cytotoxic Chemotherapy is a significant predictive factor for the development of HBV reactivation. Such information may be useful in determining which patients would benefit most from prophylactic antiviral therapy during Cytotoxic Chemotherapy.
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hepatitis b virus reactivation in breast cancer patients receiving Cytotoxic Chemotherapy a prospective study
Journal of Medical Virology, 2003Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Kwok Chi Lam, W H Kwan, Sheng Zhong, Philip J. JohnsonAbstract:Breast cancer is a rapidly increasing problem in many developing countries, and Cytotoxic Chemotherapy is now an integral part of its management. In several developing countries, the carriage of hepatitis B virus (HBV) in cancer patients may be as high as 12%, and such patients are at risk of developing fatal HBV reactivation during Chemotherapy. HBV reactivation is well recognized in patients with hematological malignancies, but limited data are available on patients with other, more common, cancers, such as breast cancer. Recent data have suggested that increased viral replication, an indication of HBV reactivation, may precede clinical hepatitis. In the absence of serial HBV DNA monitoring, HBV reactivation during Chemotherapy may have been underestimated. In this prospective study, breast cancer patients who were hepatitis B surface antigen (HBsAg) seropositive were followed up during Chemotherapy. The main objectives were to determine the incidence of HBV reactivation in breast cancer patients undergoing conventional Chemotherapy; to investigate whether "serial HBV DNA monitoring" improves the accuracy of diagnosing HBV reactivation when compared with previous schema that only measured HBV DNA at the time of clinical hepatitis ("conventional monitoring"); and to assess the clinical consequences as a result of developing the condition. The secondary objective was to identify risk factors associated with this condition. Over an 18-month period, 41 patients were studied. Ten developed HBV reactivation by conventional monitoring criteria, but with serial HBV DNA monitoring, seven additional patients were diagnosed when increased HBV DNA levels were detected before, but not concomitant with, clinical hepatitis. Thus, a total of 17 patients (41%) developed HBV reactivation. Premature termination of Chemotherapy or delay in treatment schedules occurred in 71% of the patients who developed viral reactivation, as compared with 33% in those who did not develop the condition (P = 0.019). No risk factors associated with the development of HBV reactivation could be identified. Serial monitoring of HBV DNA, in addition to liver function, increases the sensitivity of diagnosing of HBV reactivation, and helps explain some cases that would otherwise be labeled as "cryptogenic hepatitis," for which concomitant HBV DNA measured at the time of hepatitis was undetectable. The present study highlights the importance of monitoring HBsAg-seropositive patients who are receiving Chemotherapy for common solid tumors such as breast cancer.
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frequency of hepatitis b virus reactivation in cancer patients undergoing Cytotoxic Chemotherapy a prospective study of 626 patients with identification of risk factors
Journal of Medical Virology, 2000Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Sheng Zhong, B Zee, Joyce Steinberg, John S Tam, Nancy Leung, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive Cytotoxic Chemotherapy and may result in varying degrees of liver damage. As Chemotherapy is used increasingly in cancer patients, HBV reactivation during Cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during Chemotherapy. However, corresponding data for patients with other malignancies undergoing Cytotoxic Chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received Cytotoxic Chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of Chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during Chemotherapy. It is concluded that in patients with chronic HBV infection under Chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving Cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.
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hepatitis b virus reactivation in patients undergoing Cytotoxic Chemotherapy for solid tumours precore core mutations may play an important role
Journal of Medical Virology, 2000Co-Authors: Joyce Steinberg, Winnie Yeo, Paul K S Chan, Sheng Zhong, John Y H Chan, John S Tam, Nancy W Y Leung, Philip J. JohnsonAbstract:Reactivation of the hepatitis B virus (HBV) is a rare, but well described complication of Cytotoxic Chemotherapy that may result in hepatic failure. Patients who are chronic carriers of the HBV and who have a G to A mutation at nucleotide 1896 in the precore region may develop more severe liver disease, possibly because of rapid selection and enhanced replication ability of the mutant strain. Such mutant viruses have been implicated occasionally in Chemotherapy induced reactivation of hepatitis B virus. In this report, 5 patients with solid tumours were identified to have developed severe hepatitis B virus related liver disease during treatment with Cytotoxic agents (with dexamethasone as anti-emetic). All had clinical and serological evidence of reactivation of the HBV. Three patients developed icteric hepatitis; 2 fully recovered, and 1 had died from progressive metastatic disease while recovering from the reactivation. The other two died from progressive liver failure. Direct sequencing of the polymerase chain reaction (PCR) products of the precore (preC) and precore promoter region of the HBV-DNA was carried out on the patients' serum samples taken during the episode of reactivation. In each case, similar mutations (G to A) in nucleotide 1896 of the preC region were found, together with additional mutations in the preC promoter. The present findings suggest that reactivation involving a mutant hepatitis B virus may lead to liver failure, which is possibly more severe than that caused by wild type HBV, and can be triggered by Cytotoxic Chemotherapy, or the administration of corticosteroids. In Eastern Asia the HBV carriage rate in adults is high. HBV reactivation and severe liver disease during Cytotoxic treatment may become a serious and common problem in this region as Cytotoxic Chemotherapy is more widely used. Patients should be screened routinely for HBsAg in endemic areas of chronic hepatitis B virus infection prior to receiving Cytotoxic treatment. The possibility of HBV reactivation should be considered in patients developing liver dysfunction. Patients who are HBeAg negative/Anti-HBe positive, and are suspected to be having an HBV reactivation, should have HBV-DNA levels measured for confirmation as they may carry a mutant HBV. J. Med. Virol. 60:249–255, 2000. © 2000 Wiley-Liss, Inc.
Winnie Yeo - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing Cytotoxic Chemotherapy
British Journal of Cancer, 2004Co-Authors: Winnie Yeo, Paul K S Chan, Kwok Chi Lam, Sheng Zhong, W L Wong, B Zee, P J JohnsonAbstract:For cancer patients with chronic hepatitis B virus (HBV) infection, who receive Cytotoxic Chemotherapy, HBV reactivation is a well-described complication, which may result in varying degrees of liver damage. Several clinical features and the pre-Chemotherapy HBV viral load have been suggested to be associated with an increased risk of developing the condition: (1) to assess the clinical and virological factors in a comprehensive manner and thereby identify those that are associated with the development of HBV reactivation; (2) to develop a predictive model to quantify the risk of HBV reactivation. In all, 138 consecutive cancer patients who were HBV carriers and undergoing Chemotherapy were studied, of which 128 patients had sera available for real-time PCR HBV DNA measurement. They were followed up throughout their course of Chemotherapy and the HBV reactivation rate was determined. The clinical and virological features between those who did and did not develop viral reactivation were compared. These included age, sex, baseline liver function tests, HBeAg status and viral load (HBV DNA) prior to the Chemotherapy, and the use of specific Cytotoxic agents. In all, 36 (26%) developed HBV reactivation. Multivariate analysis revealed pre-Chemotherapy HBV DNA level, the use of steroids and a diagnosis of lymphoma or breast cancer to be significant factors. Based on real-time HBV DNA PCR assay, detectable baseline HBV DNA prior to the administration of Cytotoxic Chemotherapy, the use of steroids and a diagnosis of lymphoma or breast cancer are predictive factors for the development of HBV reactivation. A predictive model was developed from the current data, based on a logistic regression method.
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lamivudine for the prevention of hepatitis b virus reactivation in hepatitis b s antigen seropositive cancer patients undergoing Cytotoxic Chemotherapy
Journal of Clinical Oncology, 2004Co-Authors: Winnie Yeo, Anthony T.c. Chan, Paul K S Chan, Kwok Chi Lam, Tony Mok, Benny Chungying Zee, Kenny I K Lei, Jam J Lee, Thomas W T Leung, Sheng ZhongAbstract:Purpose For cancer patients receiving Cytotoxic Chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during Chemotherapy. Patients and Methods Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing Chemotherapy. The historical controls consisted of 193 consecutive patients who underwent Chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. Results In the ...
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high hepatitis b virus hbv dna viral load is an important risk factor for hbv reactivation in breast cancer patients undergoing Cytotoxic Chemotherapy
Journal of Viral Hepatitis, 2004Co-Authors: Sheng Zhong, Winnie Yeo, Paul K S Chan, C Schroder, W L Wong, B Zee, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation during Cytotoxic Chemotherapy for cancer may complicate treatment and cause liver damage. The complication has been reported to occur in 10% to over 50% of HBV carriers, but the factors that determine which patients will develop reactivation remain unclear. The objective of the study is to test the hypothesis that the preChemotherapy HBV DNA level is a risk factor for the development of HBV reactivation. We studied 41 women undergoing Cytotoxic Chemotherapy for breast cancer, 17 of whom developed reactivation and 24 who did not. We developed a novel, ultra-sensitive, real-time polymerase chain reaction assay for the measurement of HBV DNA. The sera of 37 patients (16 who developed reactivation and 21 who did not) were available for measurement of HBV DNA using this technique. The results showed that patients in the reactivation group had a significantly higher median HBV DNA load (1.03 x 10(6) copies/mL; range <2.9 x 10(3) to 8.723 x 10(7)) than did the nonreactivation group (<2.9 x 10(3) copies/ml; range <2.9 x 10(3) to 6.331 x 10(7)) (P < 0.001). The optimal cut-off between the two groups was found to be at serum HBV DNA level of 3 x 10(5), which gave a sensitivity of 81.0% and a specificity of 85.0%. In conclusion, for breast cancer patients receiving standard Cytotoxic Chemotherapy, a high HBV viral load prior to the administration of Cytotoxic Chemotherapy is a significant predictive factor for the development of HBV reactivation. Such information may be useful in determining which patients would benefit most from prophylactic antiviral therapy during Cytotoxic Chemotherapy.
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hepatitis b virus reactivation in breast cancer patients receiving Cytotoxic Chemotherapy a prospective study
Journal of Medical Virology, 2003Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Kwok Chi Lam, W H Kwan, Sheng Zhong, Philip J. JohnsonAbstract:Breast cancer is a rapidly increasing problem in many developing countries, and Cytotoxic Chemotherapy is now an integral part of its management. In several developing countries, the carriage of hepatitis B virus (HBV) in cancer patients may be as high as 12%, and such patients are at risk of developing fatal HBV reactivation during Chemotherapy. HBV reactivation is well recognized in patients with hematological malignancies, but limited data are available on patients with other, more common, cancers, such as breast cancer. Recent data have suggested that increased viral replication, an indication of HBV reactivation, may precede clinical hepatitis. In the absence of serial HBV DNA monitoring, HBV reactivation during Chemotherapy may have been underestimated. In this prospective study, breast cancer patients who were hepatitis B surface antigen (HBsAg) seropositive were followed up during Chemotherapy. The main objectives were to determine the incidence of HBV reactivation in breast cancer patients undergoing conventional Chemotherapy; to investigate whether "serial HBV DNA monitoring" improves the accuracy of diagnosing HBV reactivation when compared with previous schema that only measured HBV DNA at the time of clinical hepatitis ("conventional monitoring"); and to assess the clinical consequences as a result of developing the condition. The secondary objective was to identify risk factors associated with this condition. Over an 18-month period, 41 patients were studied. Ten developed HBV reactivation by conventional monitoring criteria, but with serial HBV DNA monitoring, seven additional patients were diagnosed when increased HBV DNA levels were detected before, but not concomitant with, clinical hepatitis. Thus, a total of 17 patients (41%) developed HBV reactivation. Premature termination of Chemotherapy or delay in treatment schedules occurred in 71% of the patients who developed viral reactivation, as compared with 33% in those who did not develop the condition (P = 0.019). No risk factors associated with the development of HBV reactivation could be identified. Serial monitoring of HBV DNA, in addition to liver function, increases the sensitivity of diagnosing of HBV reactivation, and helps explain some cases that would otherwise be labeled as "cryptogenic hepatitis," for which concomitant HBV DNA measured at the time of hepatitis was undetectable. The present study highlights the importance of monitoring HBsAg-seropositive patients who are receiving Chemotherapy for common solid tumors such as breast cancer.
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frequency of hepatitis b virus reactivation in cancer patients undergoing Cytotoxic Chemotherapy a prospective study of 626 patients with identification of risk factors
Journal of Medical Virology, 2000Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Sheng Zhong, B Zee, Joyce Steinberg, John S Tam, Nancy Leung, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive Cytotoxic Chemotherapy and may result in varying degrees of liver damage. As Chemotherapy is used increasingly in cancer patients, HBV reactivation during Cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during Chemotherapy. However, corresponding data for patients with other malignancies undergoing Cytotoxic Chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received Cytotoxic Chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of Chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during Chemotherapy. It is concluded that in patients with chronic HBV infection under Chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving Cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.
Sheng Zhong - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing Cytotoxic Chemotherapy
British Journal of Cancer, 2004Co-Authors: Winnie Yeo, Paul K S Chan, Kwok Chi Lam, Sheng Zhong, W L Wong, B Zee, P J JohnsonAbstract:For cancer patients with chronic hepatitis B virus (HBV) infection, who receive Cytotoxic Chemotherapy, HBV reactivation is a well-described complication, which may result in varying degrees of liver damage. Several clinical features and the pre-Chemotherapy HBV viral load have been suggested to be associated with an increased risk of developing the condition: (1) to assess the clinical and virological factors in a comprehensive manner and thereby identify those that are associated with the development of HBV reactivation; (2) to develop a predictive model to quantify the risk of HBV reactivation. In all, 138 consecutive cancer patients who were HBV carriers and undergoing Chemotherapy were studied, of which 128 patients had sera available for real-time PCR HBV DNA measurement. They were followed up throughout their course of Chemotherapy and the HBV reactivation rate was determined. The clinical and virological features between those who did and did not develop viral reactivation were compared. These included age, sex, baseline liver function tests, HBeAg status and viral load (HBV DNA) prior to the Chemotherapy, and the use of specific Cytotoxic agents. In all, 36 (26%) developed HBV reactivation. Multivariate analysis revealed pre-Chemotherapy HBV DNA level, the use of steroids and a diagnosis of lymphoma or breast cancer to be significant factors. Based on real-time HBV DNA PCR assay, detectable baseline HBV DNA prior to the administration of Cytotoxic Chemotherapy, the use of steroids and a diagnosis of lymphoma or breast cancer are predictive factors for the development of HBV reactivation. A predictive model was developed from the current data, based on a logistic regression method.
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lamivudine for the prevention of hepatitis b virus reactivation in hepatitis b s antigen seropositive cancer patients undergoing Cytotoxic Chemotherapy
Journal of Clinical Oncology, 2004Co-Authors: Winnie Yeo, Anthony T.c. Chan, Paul K S Chan, Kwok Chi Lam, Tony Mok, Benny Chungying Zee, Kenny I K Lei, Jam J Lee, Thomas W T Leung, Sheng ZhongAbstract:Purpose For cancer patients receiving Cytotoxic Chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during Chemotherapy. Patients and Methods Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing Chemotherapy. The historical controls consisted of 193 consecutive patients who underwent Chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. Results In the ...
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high hepatitis b virus hbv dna viral load is an important risk factor for hbv reactivation in breast cancer patients undergoing Cytotoxic Chemotherapy
Journal of Viral Hepatitis, 2004Co-Authors: Sheng Zhong, Winnie Yeo, Paul K S Chan, C Schroder, W L Wong, B Zee, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation during Cytotoxic Chemotherapy for cancer may complicate treatment and cause liver damage. The complication has been reported to occur in 10% to over 50% of HBV carriers, but the factors that determine which patients will develop reactivation remain unclear. The objective of the study is to test the hypothesis that the preChemotherapy HBV DNA level is a risk factor for the development of HBV reactivation. We studied 41 women undergoing Cytotoxic Chemotherapy for breast cancer, 17 of whom developed reactivation and 24 who did not. We developed a novel, ultra-sensitive, real-time polymerase chain reaction assay for the measurement of HBV DNA. The sera of 37 patients (16 who developed reactivation and 21 who did not) were available for measurement of HBV DNA using this technique. The results showed that patients in the reactivation group had a significantly higher median HBV DNA load (1.03 x 10(6) copies/mL; range <2.9 x 10(3) to 8.723 x 10(7)) than did the nonreactivation group (<2.9 x 10(3) copies/ml; range <2.9 x 10(3) to 6.331 x 10(7)) (P < 0.001). The optimal cut-off between the two groups was found to be at serum HBV DNA level of 3 x 10(5), which gave a sensitivity of 81.0% and a specificity of 85.0%. In conclusion, for breast cancer patients receiving standard Cytotoxic Chemotherapy, a high HBV viral load prior to the administration of Cytotoxic Chemotherapy is a significant predictive factor for the development of HBV reactivation. Such information may be useful in determining which patients would benefit most from prophylactic antiviral therapy during Cytotoxic Chemotherapy.
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hepatitis b virus reactivation in breast cancer patients receiving Cytotoxic Chemotherapy a prospective study
Journal of Medical Virology, 2003Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Kwok Chi Lam, W H Kwan, Sheng Zhong, Philip J. JohnsonAbstract:Breast cancer is a rapidly increasing problem in many developing countries, and Cytotoxic Chemotherapy is now an integral part of its management. In several developing countries, the carriage of hepatitis B virus (HBV) in cancer patients may be as high as 12%, and such patients are at risk of developing fatal HBV reactivation during Chemotherapy. HBV reactivation is well recognized in patients with hematological malignancies, but limited data are available on patients with other, more common, cancers, such as breast cancer. Recent data have suggested that increased viral replication, an indication of HBV reactivation, may precede clinical hepatitis. In the absence of serial HBV DNA monitoring, HBV reactivation during Chemotherapy may have been underestimated. In this prospective study, breast cancer patients who were hepatitis B surface antigen (HBsAg) seropositive were followed up during Chemotherapy. The main objectives were to determine the incidence of HBV reactivation in breast cancer patients undergoing conventional Chemotherapy; to investigate whether "serial HBV DNA monitoring" improves the accuracy of diagnosing HBV reactivation when compared with previous schema that only measured HBV DNA at the time of clinical hepatitis ("conventional monitoring"); and to assess the clinical consequences as a result of developing the condition. The secondary objective was to identify risk factors associated with this condition. Over an 18-month period, 41 patients were studied. Ten developed HBV reactivation by conventional monitoring criteria, but with serial HBV DNA monitoring, seven additional patients were diagnosed when increased HBV DNA levels were detected before, but not concomitant with, clinical hepatitis. Thus, a total of 17 patients (41%) developed HBV reactivation. Premature termination of Chemotherapy or delay in treatment schedules occurred in 71% of the patients who developed viral reactivation, as compared with 33% in those who did not develop the condition (P = 0.019). No risk factors associated with the development of HBV reactivation could be identified. Serial monitoring of HBV DNA, in addition to liver function, increases the sensitivity of diagnosing of HBV reactivation, and helps explain some cases that would otherwise be labeled as "cryptogenic hepatitis," for which concomitant HBV DNA measured at the time of hepatitis was undetectable. The present study highlights the importance of monitoring HBsAg-seropositive patients who are receiving Chemotherapy for common solid tumors such as breast cancer.
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frequency of hepatitis b virus reactivation in cancer patients undergoing Cytotoxic Chemotherapy a prospective study of 626 patients with identification of risk factors
Journal of Medical Virology, 2000Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Sheng Zhong, B Zee, Joyce Steinberg, John S Tam, Nancy Leung, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive Cytotoxic Chemotherapy and may result in varying degrees of liver damage. As Chemotherapy is used increasingly in cancer patients, HBV reactivation during Cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during Chemotherapy. However, corresponding data for patients with other malignancies undergoing Cytotoxic Chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received Cytotoxic Chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of Chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during Chemotherapy. It is concluded that in patients with chronic HBV infection under Chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving Cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.
Alex Toker - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple negative breast cancer cells to Cytotoxic Chemotherapy
Journal of Biological Chemistry, 2020Co-Authors: Renee C Geck, Jackson R Foley, Tracy Murray Stewart, John M Asara, Robert A Casero, Alex TokerAbstract:Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care Chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the Cytotoxic Chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to Chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to Chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to Chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.
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inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple negative breast cancer cells to Cytotoxic Chemotherapy
bioRxiv, 2020Co-Authors: Renee C Geck, Jackson R Foley, Tracy Murray Stewart, John M Asara, Robert A Casero, Alex TokerAbstract:Treatment of triple-negative breast cancer (TNBC) is limited by a lack of effective molecular targeted therapies. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care Chemotherapy regimens. We found that exposure of TNBC cells to Cytotoxic Chemotherapy drugs leads to alterations in arginine and polyamine metabolites due to a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase (ODC). The reduction in ODC was mediated by its negative regulator, antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor DFMO sensitized TNBC cells to Chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines showed greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. Alterations in polyamine metabolism in response to Chemotherapy, as well as preferential sensitization of TNBC cells to Chemotherapy by DFMO, suggest that ODC may be a targetable metabolic vulnerability in TNBC.
Paul K S Chan - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing Cytotoxic Chemotherapy
British Journal of Cancer, 2004Co-Authors: Winnie Yeo, Paul K S Chan, Kwok Chi Lam, Sheng Zhong, W L Wong, B Zee, P J JohnsonAbstract:For cancer patients with chronic hepatitis B virus (HBV) infection, who receive Cytotoxic Chemotherapy, HBV reactivation is a well-described complication, which may result in varying degrees of liver damage. Several clinical features and the pre-Chemotherapy HBV viral load have been suggested to be associated with an increased risk of developing the condition: (1) to assess the clinical and virological factors in a comprehensive manner and thereby identify those that are associated with the development of HBV reactivation; (2) to develop a predictive model to quantify the risk of HBV reactivation. In all, 138 consecutive cancer patients who were HBV carriers and undergoing Chemotherapy were studied, of which 128 patients had sera available for real-time PCR HBV DNA measurement. They were followed up throughout their course of Chemotherapy and the HBV reactivation rate was determined. The clinical and virological features between those who did and did not develop viral reactivation were compared. These included age, sex, baseline liver function tests, HBeAg status and viral load (HBV DNA) prior to the Chemotherapy, and the use of specific Cytotoxic agents. In all, 36 (26%) developed HBV reactivation. Multivariate analysis revealed pre-Chemotherapy HBV DNA level, the use of steroids and a diagnosis of lymphoma or breast cancer to be significant factors. Based on real-time HBV DNA PCR assay, detectable baseline HBV DNA prior to the administration of Cytotoxic Chemotherapy, the use of steroids and a diagnosis of lymphoma or breast cancer are predictive factors for the development of HBV reactivation. A predictive model was developed from the current data, based on a logistic regression method.
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lamivudine for the prevention of hepatitis b virus reactivation in hepatitis b s antigen seropositive cancer patients undergoing Cytotoxic Chemotherapy
Journal of Clinical Oncology, 2004Co-Authors: Winnie Yeo, Anthony T.c. Chan, Paul K S Chan, Kwok Chi Lam, Tony Mok, Benny Chungying Zee, Kenny I K Lei, Jam J Lee, Thomas W T Leung, Sheng ZhongAbstract:Purpose For cancer patients receiving Cytotoxic Chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during Chemotherapy. Patients and Methods Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing Chemotherapy. The historical controls consisted of 193 consecutive patients who underwent Chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. Results In the ...
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high hepatitis b virus hbv dna viral load is an important risk factor for hbv reactivation in breast cancer patients undergoing Cytotoxic Chemotherapy
Journal of Viral Hepatitis, 2004Co-Authors: Sheng Zhong, Winnie Yeo, Paul K S Chan, C Schroder, W L Wong, B Zee, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation during Cytotoxic Chemotherapy for cancer may complicate treatment and cause liver damage. The complication has been reported to occur in 10% to over 50% of HBV carriers, but the factors that determine which patients will develop reactivation remain unclear. The objective of the study is to test the hypothesis that the preChemotherapy HBV DNA level is a risk factor for the development of HBV reactivation. We studied 41 women undergoing Cytotoxic Chemotherapy for breast cancer, 17 of whom developed reactivation and 24 who did not. We developed a novel, ultra-sensitive, real-time polymerase chain reaction assay for the measurement of HBV DNA. The sera of 37 patients (16 who developed reactivation and 21 who did not) were available for measurement of HBV DNA using this technique. The results showed that patients in the reactivation group had a significantly higher median HBV DNA load (1.03 x 10(6) copies/mL; range <2.9 x 10(3) to 8.723 x 10(7)) than did the nonreactivation group (<2.9 x 10(3) copies/ml; range <2.9 x 10(3) to 6.331 x 10(7)) (P < 0.001). The optimal cut-off between the two groups was found to be at serum HBV DNA level of 3 x 10(5), which gave a sensitivity of 81.0% and a specificity of 85.0%. In conclusion, for breast cancer patients receiving standard Cytotoxic Chemotherapy, a high HBV viral load prior to the administration of Cytotoxic Chemotherapy is a significant predictive factor for the development of HBV reactivation. Such information may be useful in determining which patients would benefit most from prophylactic antiviral therapy during Cytotoxic Chemotherapy.
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hepatitis b virus reactivation in breast cancer patients receiving Cytotoxic Chemotherapy a prospective study
Journal of Medical Virology, 2003Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Kwok Chi Lam, W H Kwan, Sheng Zhong, Philip J. JohnsonAbstract:Breast cancer is a rapidly increasing problem in many developing countries, and Cytotoxic Chemotherapy is now an integral part of its management. In several developing countries, the carriage of hepatitis B virus (HBV) in cancer patients may be as high as 12%, and such patients are at risk of developing fatal HBV reactivation during Chemotherapy. HBV reactivation is well recognized in patients with hematological malignancies, but limited data are available on patients with other, more common, cancers, such as breast cancer. Recent data have suggested that increased viral replication, an indication of HBV reactivation, may precede clinical hepatitis. In the absence of serial HBV DNA monitoring, HBV reactivation during Chemotherapy may have been underestimated. In this prospective study, breast cancer patients who were hepatitis B surface antigen (HBsAg) seropositive were followed up during Chemotherapy. The main objectives were to determine the incidence of HBV reactivation in breast cancer patients undergoing conventional Chemotherapy; to investigate whether "serial HBV DNA monitoring" improves the accuracy of diagnosing HBV reactivation when compared with previous schema that only measured HBV DNA at the time of clinical hepatitis ("conventional monitoring"); and to assess the clinical consequences as a result of developing the condition. The secondary objective was to identify risk factors associated with this condition. Over an 18-month period, 41 patients were studied. Ten developed HBV reactivation by conventional monitoring criteria, but with serial HBV DNA monitoring, seven additional patients were diagnosed when increased HBV DNA levels were detected before, but not concomitant with, clinical hepatitis. Thus, a total of 17 patients (41%) developed HBV reactivation. Premature termination of Chemotherapy or delay in treatment schedules occurred in 71% of the patients who developed viral reactivation, as compared with 33% in those who did not develop the condition (P = 0.019). No risk factors associated with the development of HBV reactivation could be identified. Serial monitoring of HBV DNA, in addition to liver function, increases the sensitivity of diagnosing of HBV reactivation, and helps explain some cases that would otherwise be labeled as "cryptogenic hepatitis," for which concomitant HBV DNA measured at the time of hepatitis was undetectable. The present study highlights the importance of monitoring HBsAg-seropositive patients who are receiving Chemotherapy for common solid tumors such as breast cancer.
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frequency of hepatitis b virus reactivation in cancer patients undergoing Cytotoxic Chemotherapy a prospective study of 626 patients with identification of risk factors
Journal of Medical Virology, 2000Co-Authors: Winnie Yeo, Paul K S Chan, Pun Hui, Sheng Zhong, B Zee, Joyce Steinberg, John S Tam, Nancy Leung, Philip J. JohnsonAbstract:Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive Cytotoxic Chemotherapy and may result in varying degrees of liver damage. As Chemotherapy is used increasingly in cancer patients, HBV reactivation during Cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during Chemotherapy. However, corresponding data for patients with other malignancies undergoing Cytotoxic Chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received Cytotoxic Chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of Chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during Chemotherapy. It is concluded that in patients with chronic HBV infection under Chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving Cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.
