This pilot study examined the effectiveness of high-dose zidovudine plus valganciclovir for treating Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD) in 14 HIV-infected patients. The drugs target two KSHV lytic genes, ORF36 and ORF21, whose proteins activate ganciclovir and zidovudine. A total of 86% of patients achieved a major clinical response and 50% achieved a major biochemical response, with a median progression-free survival of 6 months and overall survival of 86% at 12 months. The treatment was generally well-tolerated with hematologic toxicities being most common. The
Autologous Cord Blood Transplantation in the Treatment of a Child with Leukemialifextechnologies
This document describes the first reported case of autologous cord blood transplantation to treat a child with leukemia. A 3-year-old girl developed isolated central nervous system relapse of acute lymphoblastic leukemia after initial treatment. She achieved a second remission with additional chemotherapy. She then underwent myeloablative chemotherapy and radiation followed by infusion of her own previously banked umbilical cord blood. At 20 months post-transplant, she remained in complete remission, demonstrating the potential safety and feasibility of autologous cord blood transplantation to treat childhood leukemia relapse. However, concerns remain about the possibility of the leukemic clone being present in the cord blood.
Austin Transplantation Sciences is an open access, peer reviewed, scholarly journal dedicated to publish articles covering all areas of Transplantation Sciences.
The journal aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Transplantation Sciences. Austin Transplantation Sciences accepts original research articles, reviews, mini reviews, case reports and rapid communication covering all aspects of Transplantation Sciences.
Austin Transplantation Sciences strongly supports the scientific up gradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Lombardi et al: XMRV/CFS Inflammatory Signaturedegarden
This document summarizes a study that identified a signature of 10 cytokines and chemokines that can correctly identify patients with chronic fatigue syndrome (CFS) associated with xenotropic murine leukemia virus-related virus (XMRV) infection. The study used Luminex multi-analyte profiling to measure cytokine and chemokine levels in the plasma of 118 CFS patients who tested positive for XMRV, compared to 138 healthy controls. Analysis identified a cytokine/chemokine signature that diagnosed XMRV-associated CFS with 93% specificity and 96% sensitivity. This signature provides immunological evidence for the role of XMRV in CFS pathology and the associated inflammatory response.
This document describes a study that analyzed the frequency of cells with a PIG-A mutant phenotype (PNH phenotype) in samples from 19 patients with acute lymphoblastic leukemia (ALL) and immortalized B cell lines (BLCLs) from healthy donors. The BLCLs showed a median frequency of 11 x 10-6, while the ALL samples showed two distinct populations - about half of samples had a median frequency of 13 x 10-6, similar to controls, while the other half had a significantly higher median frequency of 566 x 10-6. This suggests that in ALL, there are two phenotypes with respect to hypermutability, which may correlate with the number of mutations required to cause the leukemia.
Hematopoietic stem cell transplantation (HSCT) can cure thalassemia major by replacing diseased bone marrow. The process involves intensive preparation using chemotherapy and/or radiation to ablate the recipient's marrow. Healthy stem cells from a donor's bone marrow or umbilical cord blood are then infused. While HSCT from an HLA-identical sibling donor yields the best results, outcomes from unrelated donors are improving. Gene therapy clinical trials also aim to cure thalassemia by delivering healthy globin genes directly to the patient's stem cells.
This study investigated whether changes in complement regulatory proteins (CD55 and CD59) on red blood cells contributes to malaria-induced anemia. The study found:
1) Levels of CD55 and CD59 decreased with increased red blood cell age.
2) CD55 levels were lower in children with malaria-induced anemia compared to non-anemic children, and this difference was seen across all red blood cell age groups.
3) CD55 levels correlated positively with hemoglobin levels in anemic children, but CD59 levels did not.
4) The extensive and early loss of CD55 from red blood cells of all ages in malaria-induced anemia, as well as
Cord blood is a naturally discarded tissue that contains a high proportion of circulating hematopoietic stem cells. It allows HLA mismatch transplantation, providing cure to hematological malignancies with an attenuated risk of severe graft-versus-host disease through a graft-versus-leukemia effect. Cord blood transplantation is unique in its immunogenetics profile, preserving the immune cells carried in the cord blood graft, including T-regulatory cells and natural killer cells. Early reconstitution of lymphocytes from cord blood grafts predicts better outcomes. Advances in cord blood transplantation aim to take advantage of its immunological properties through donor selection accounting for HLA matching, maternal antigens, and cell dose to maximize graft-versus-leuke
C4d positivity in Renal transplant rejectionimrana tanvir
This document discusses C4d positivity in renal transplant rejection. It begins by introducing antibody-mediated rejection (AMR) and the classification of AMR. It describes the role of C4d as a marker in transplant rejection and reviews the pros and cons of using C4d. Donor specific antibodies (DSA) are also discussed. Alternative markers to C4d are emerging from genomics and endothelial transcripts. The document concludes by addressing some limitations of C4d and developments in other biomarkers for AMR.
Autologous Cord Blood Transplantation in the Treatment of a Child with Leukemialifextechnologies
This document describes the first reported case of autologous cord blood transplantation to treat a child with leukemia. A 3-year-old girl developed isolated central nervous system relapse of acute lymphoblastic leukemia after initial treatment. She achieved a second remission with additional chemotherapy. She then underwent myeloablative chemotherapy and radiation followed by infusion of her own previously banked umbilical cord blood. At 20 months post-transplant, she remained in complete remission, demonstrating the potential safety and feasibility of autologous cord blood transplantation to treat childhood leukemia relapse. However, concerns remain about the possibility of the leukemic clone being present in the cord blood.
Austin Transplantation Sciences is an open access, peer reviewed, scholarly journal dedicated to publish articles covering all areas of Transplantation Sciences.
The journal aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Transplantation Sciences. Austin Transplantation Sciences accepts original research articles, reviews, mini reviews, case reports and rapid communication covering all aspects of Transplantation Sciences.
Austin Transplantation Sciences strongly supports the scientific up gradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Lombardi et al: XMRV/CFS Inflammatory Signaturedegarden
This document summarizes a study that identified a signature of 10 cytokines and chemokines that can correctly identify patients with chronic fatigue syndrome (CFS) associated with xenotropic murine leukemia virus-related virus (XMRV) infection. The study used Luminex multi-analyte profiling to measure cytokine and chemokine levels in the plasma of 118 CFS patients who tested positive for XMRV, compared to 138 healthy controls. Analysis identified a cytokine/chemokine signature that diagnosed XMRV-associated CFS with 93% specificity and 96% sensitivity. This signature provides immunological evidence for the role of XMRV in CFS pathology and the associated inflammatory response.
This document describes a study that analyzed the frequency of cells with a PIG-A mutant phenotype (PNH phenotype) in samples from 19 patients with acute lymphoblastic leukemia (ALL) and immortalized B cell lines (BLCLs) from healthy donors. The BLCLs showed a median frequency of 11 x 10-6, while the ALL samples showed two distinct populations - about half of samples had a median frequency of 13 x 10-6, similar to controls, while the other half had a significantly higher median frequency of 566 x 10-6. This suggests that in ALL, there are two phenotypes with respect to hypermutability, which may correlate with the number of mutations required to cause the leukemia.
Hematopoietic stem cell transplantation (HSCT) can cure thalassemia major by replacing diseased bone marrow. The process involves intensive preparation using chemotherapy and/or radiation to ablate the recipient's marrow. Healthy stem cells from a donor's bone marrow or umbilical cord blood are then infused. While HSCT from an HLA-identical sibling donor yields the best results, outcomes from unrelated donors are improving. Gene therapy clinical trials also aim to cure thalassemia by delivering healthy globin genes directly to the patient's stem cells.
This study investigated whether changes in complement regulatory proteins (CD55 and CD59) on red blood cells contributes to malaria-induced anemia. The study found:
1) Levels of CD55 and CD59 decreased with increased red blood cell age.
2) CD55 levels were lower in children with malaria-induced anemia compared to non-anemic children, and this difference was seen across all red blood cell age groups.
3) CD55 levels correlated positively with hemoglobin levels in anemic children, but CD59 levels did not.
4) The extensive and early loss of CD55 from red blood cells of all ages in malaria-induced anemia, as well as
Cord blood is a naturally discarded tissue that contains a high proportion of circulating hematopoietic stem cells. It allows HLA mismatch transplantation, providing cure to hematological malignancies with an attenuated risk of severe graft-versus-host disease through a graft-versus-leukemia effect. Cord blood transplantation is unique in its immunogenetics profile, preserving the immune cells carried in the cord blood graft, including T-regulatory cells and natural killer cells. Early reconstitution of lymphocytes from cord blood grafts predicts better outcomes. Advances in cord blood transplantation aim to take advantage of its immunological properties through donor selection accounting for HLA matching, maternal antigens, and cell dose to maximize graft-versus-leuke
C4d positivity in Renal transplant rejectionimrana tanvir
This document discusses C4d positivity in renal transplant rejection. It begins by introducing antibody-mediated rejection (AMR) and the classification of AMR. It describes the role of C4d as a marker in transplant rejection and reviews the pros and cons of using C4d. Donor specific antibodies (DSA) are also discussed. Alternative markers to C4d are emerging from genomics and endothelial transcripts. The document concludes by addressing some limitations of C4d and developments in other biomarkers for AMR.
Transplantation of organs and tissues has become common for treating diseases. Complications include graft-versus-host disease (GVHD) and increased risk of infection and cancer due to lifelong immunosuppression. GVHD occurs when transplanted immune cells attack the recipient's body, commonly affecting the skin, bowel and liver. Opportunistic infections are frequent due to weakened immunity, including viruses like CMV and fungi such as Candida. Cancer risk is elevated 100-fold, with lymphoproliferative disorders, Kaposi's sarcoma and skin cancers being most common.
Successful Treatment of Severe Aplastic Anemia with Autologous Cord Blood Tra...lifextechnologies
1) A 20-month-old boy developed severe aplastic anemia after receiving a liver transplant for unknown fulminant hepatic failure.
2) He was treated with an autologous cord blood transplant using the cord blood that had been stored at his birth.
3) He had a successful engraftment and remains in remission 3 years later, demonstrating autologous cord blood transplantation can treat severe aplastic anemia in rare cases.
This document summarizes research on the immunobiology of chronic lymphocytic leukemia (CLL). Key points include:
1) CLL results from the transformation of B lymphocytes expressing antigen receptors (BCRs) of restricted structure that can be polyreactive and autoreactive.
2) These BCRs bind both natural antigens and novel autoantigens generated during apoptosis.
3) CLL subgroups differ in retention of polyreactivity, with retention associated with worse clinical outcomes.
This document summarizes research on the immunobiology of chronic lymphocytic leukemia (CLL). Key points include:
1. CLL results from the selection and transformation of B cells expressing B-cell receptors (BCRs) of restricted structure that can be polyreactive and autoreactive.
2. These BCRs bind to natural antigens as well as novel autoantigens generated during apoptosis.
3. CLL subgroups differ in retention of polyreactivity, with retention associated with worse clinical outcomes. Binding to autoantigens on apoptotic cells correlates with poor survival.
Cellular Immune Therapy with Allogeneic Stem Cell Transplantationspa718
This document discusses cellular immune therapy approaches using hematopoietic stem cell transplantation. It notes that high-dose chemotherapy alone does not fully eradicate malignancies and relapse remains a major treatment failure. The graft-versus-malignancy effect provided by allogeneic transplantation is responsible for residual disease eradication but is associated with graft-versus-host disease. The document reviews approaches to enhance the graft-versus-malignancy effect through donor lymphocyte infusions, antigen-specific cytotoxic T-cells, and chimeric antigen receptor T-cells while preventing graft-versus-host disease using regulatory T-cells or genetically modified T-cells with suicide switches. Ongoing clinical trials
Lenalidomide inhibits the proliferation of chronic lymphocytic leukemia (CLL) cells through a mechanism dependent on cereblon and p21, but independent of p53. Treatment with lenalidomide upregulates the expression of the cyclin-dependent kinase inhibitor p21 in CLL cells, leading to inhibition of proliferation. Silencing of either cereblon or p21 impairs the ability of lenalidomide to inhibit CLL cell proliferation. Lenalidomide also induces p21 expression in CLL cells isolated from patients, indicating it can directly inhibit CLL cell proliferation through cereblon and p21 in vivo.
Antibody mediated rejection of solid organ allograftstashagarwal
Objectives:
Introduction of Antibody mediated rejection AMR
Role of C4d in transplant rejection
Donor specific antibodies DSA
Presentation of AMR in kidney, liver, lung and heart.
- LDOC1 mRNA expression is associated with markers of poor prognosis in chronic lymphocytic leukemia (CLL) and predicts overall survival better than other markers.
- A novel LDOC1 splice variant, LDOC1S, was identified that encodes only the leucine zipper domain. LDOC1S and LDOC1 are differentially expressed in normal and malignant B-cells.
- Knockdown of LDOC1 in HeLa cells using siRNA identified 122 differentially expressed genes involved in cancer pathways, suggesting LDOC1 may regulate genes important for proliferation and survival.
Gene therapy aims to cure β-thalassemias by using lentiviral vectors to insert functional β-globin genes into hematopoietic stem cells. The first patient treated achieved long-term transfusion independence with stable multi-year expression of the corrected globin. Analysis found most genetically modified cells contained the vector integrated near the HMGA2 gene, though the majority of cells remained unmodified. Ongoing work continues to optimize the therapy.
The document discusses minimal residual disease (MRD), which refers to small amounts of malignant cells that remain undetectable by conventional methods but can be detected using highly sensitive techniques like PCR. It provides an overview of techniques used for MRD detection in various hematologic malignancies, including morphology, immunophenotyping, cytogenetics, FISH, and PCR. The sensitivity and limitations of each technique is reviewed. Common genomic targets for MRD detection are discussed for several leukemias and lymphomas. The significance of accurately measuring MRD levels for prognosis, monitoring relapse risk, and guiding treatment is also summarized.
Dr. Stephen Mulligan is a leading researcher in chronic lymphocytic leukemia (CLL) based in Australia. He is the founding chair of the CLL Global Consortium and director of hematology programs at the University of Sydney. His research interests include mechanisms of drug resistance in CLL and signaling pathways. Recent breakthroughs in CLL described by Dr. Mulligan include trials showing improved progression-free survival for frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) compared to bendamustine and rituximab (BR). Oral FCR was also found to be safe and effective in elderly CLL patients with overall response rates over 95%.
This document discusses antibody-mediated rejection (ABMR) in kidney transplant recipients. It provides information on:
- The role of HLA and non-HLA antibodies in ABMR, including donor-specific antibodies (DSAs)
- Methods for detecting sensitization and antibodies pre-transplant, including complement-dependent cytotoxicity, flow cytometry, and Luminex single-antigen beads
- Studies showing an association between preformed DSA strength/level and risk of ABMR, graft survival
- Trials of desensitization protocols using IVIG, with or without plasmapheresis, to reduce DSA levels and risk of ABMR
This document summarizes causes of eosinophilia, including:
1) It classifies causes of eosinophilia as primary (clonal, idiopathic) or secondary. Secondary causes include infections, tissue invasion by parasites, drugs, allergies, autoimmune diseases, and malignancies.
2) Common primary causes include hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), and myeloproliferative neoplasms associated with eosinophilia such as those involving FIP1L1-PDGFRA, PDGFRB, FGFR1, and KIT mutations.
3) Secondary causes discussed include parasitic infections, fungal infections, HIV, drugs
Minimal Residual Disease in Acute lymphoblastic leukemiaDr. Liza Bulsara
This document discusses minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). It provides information on several key points:
1. MRD refers to small amounts of leukemia cells that can be detected through sensitive laboratory techniques like flow cytometry and PCR, but not through standard morphology.
2. Various methods for detecting MRD are discussed, including immunophenotyping, PCR, FISH, and cytogenetics. PCR can detect a single malignant cell among 100,000 normal cells and is the most sensitive method.
3. MRD levels determined at different time points during treatment have prognostic significance and can be used for risk stratification and determining the need for treatment intensification or reduction. Monitoring
This document discusses aplastic anemia and infections in patients undergoing stem cell transplantation (SCT) or immunosuppressive therapy (IST) for aplastic anemia in India. It notes that true incidence of aplastic anemia in India is unknown but it is more common in Asia than the West. For patients under 40, SCT from a HLA-matched sibling donor is the treatment of choice. However, late referrals and financial constraints can increase morbidity and mortality during SCT and IST in India due to less effective first-line treatments, recurrent transfusions, and infections. The document provides data on outcomes of various transplantation approaches and immunosuppressive therapies for aplastic anemia at Christian Medical College, Vello
This document discusses phenotypic heterogeneity in multiple myeloma and identifies distinct subclones within patient samples that have different genomic profiles, clonogenic potential, and drug sensitivity. FACS-sorted subclones from patient samples are often associated with different cytogenetic profiles. After drug exposure, minimal residual disease is a reservoir of chemoresistant cells that can lead to relapse. Achieving a complete response and eliminating minimal residual disease is associated with longer survival times.
The document describes a restaurant management software called Smartetouch Omni. It offers features to simplify online ordering, table booking, marketing and business management. Some key features mentioned include no commission or monthly fees, branded mobile apps, embedded marketing services, SMS/email notifications, loyalty programs and more. The software aims to help restaurants upgrade their business and take it to the next level.
Transplantation of organs and tissues has become common for treating diseases. Complications include graft-versus-host disease (GVHD) and increased risk of infection and cancer due to lifelong immunosuppression. GVHD occurs when transplanted immune cells attack the recipient's body, commonly affecting the skin, bowel and liver. Opportunistic infections are frequent due to weakened immunity, including viruses like CMV and fungi such as Candida. Cancer risk is elevated 100-fold, with lymphoproliferative disorders, Kaposi's sarcoma and skin cancers being most common.
Successful Treatment of Severe Aplastic Anemia with Autologous Cord Blood Tra...lifextechnologies
1) A 20-month-old boy developed severe aplastic anemia after receiving a liver transplant for unknown fulminant hepatic failure.
2) He was treated with an autologous cord blood transplant using the cord blood that had been stored at his birth.
3) He had a successful engraftment and remains in remission 3 years later, demonstrating autologous cord blood transplantation can treat severe aplastic anemia in rare cases.
This document summarizes research on the immunobiology of chronic lymphocytic leukemia (CLL). Key points include:
1) CLL results from the transformation of B lymphocytes expressing antigen receptors (BCRs) of restricted structure that can be polyreactive and autoreactive.
2) These BCRs bind both natural antigens and novel autoantigens generated during apoptosis.
3) CLL subgroups differ in retention of polyreactivity, with retention associated with worse clinical outcomes.
This document summarizes research on the immunobiology of chronic lymphocytic leukemia (CLL). Key points include:
1. CLL results from the selection and transformation of B cells expressing B-cell receptors (BCRs) of restricted structure that can be polyreactive and autoreactive.
2. These BCRs bind to natural antigens as well as novel autoantigens generated during apoptosis.
3. CLL subgroups differ in retention of polyreactivity, with retention associated with worse clinical outcomes. Binding to autoantigens on apoptotic cells correlates with poor survival.
Cellular Immune Therapy with Allogeneic Stem Cell Transplantationspa718
This document discusses cellular immune therapy approaches using hematopoietic stem cell transplantation. It notes that high-dose chemotherapy alone does not fully eradicate malignancies and relapse remains a major treatment failure. The graft-versus-malignancy effect provided by allogeneic transplantation is responsible for residual disease eradication but is associated with graft-versus-host disease. The document reviews approaches to enhance the graft-versus-malignancy effect through donor lymphocyte infusions, antigen-specific cytotoxic T-cells, and chimeric antigen receptor T-cells while preventing graft-versus-host disease using regulatory T-cells or genetically modified T-cells with suicide switches. Ongoing clinical trials
Lenalidomide inhibits the proliferation of chronic lymphocytic leukemia (CLL) cells through a mechanism dependent on cereblon and p21, but independent of p53. Treatment with lenalidomide upregulates the expression of the cyclin-dependent kinase inhibitor p21 in CLL cells, leading to inhibition of proliferation. Silencing of either cereblon or p21 impairs the ability of lenalidomide to inhibit CLL cell proliferation. Lenalidomide also induces p21 expression in CLL cells isolated from patients, indicating it can directly inhibit CLL cell proliferation through cereblon and p21 in vivo.
Antibody mediated rejection of solid organ allograftstashagarwal
Objectives:
Introduction of Antibody mediated rejection AMR
Role of C4d in transplant rejection
Donor specific antibodies DSA
Presentation of AMR in kidney, liver, lung and heart.
- LDOC1 mRNA expression is associated with markers of poor prognosis in chronic lymphocytic leukemia (CLL) and predicts overall survival better than other markers.
- A novel LDOC1 splice variant, LDOC1S, was identified that encodes only the leucine zipper domain. LDOC1S and LDOC1 are differentially expressed in normal and malignant B-cells.
- Knockdown of LDOC1 in HeLa cells using siRNA identified 122 differentially expressed genes involved in cancer pathways, suggesting LDOC1 may regulate genes important for proliferation and survival.
Gene therapy aims to cure β-thalassemias by using lentiviral vectors to insert functional β-globin genes into hematopoietic stem cells. The first patient treated achieved long-term transfusion independence with stable multi-year expression of the corrected globin. Analysis found most genetically modified cells contained the vector integrated near the HMGA2 gene, though the majority of cells remained unmodified. Ongoing work continues to optimize the therapy.
The document discusses minimal residual disease (MRD), which refers to small amounts of malignant cells that remain undetectable by conventional methods but can be detected using highly sensitive techniques like PCR. It provides an overview of techniques used for MRD detection in various hematologic malignancies, including morphology, immunophenotyping, cytogenetics, FISH, and PCR. The sensitivity and limitations of each technique is reviewed. Common genomic targets for MRD detection are discussed for several leukemias and lymphomas. The significance of accurately measuring MRD levels for prognosis, monitoring relapse risk, and guiding treatment is also summarized.
Dr. Stephen Mulligan is a leading researcher in chronic lymphocytic leukemia (CLL) based in Australia. He is the founding chair of the CLL Global Consortium and director of hematology programs at the University of Sydney. His research interests include mechanisms of drug resistance in CLL and signaling pathways. Recent breakthroughs in CLL described by Dr. Mulligan include trials showing improved progression-free survival for frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) compared to bendamustine and rituximab (BR). Oral FCR was also found to be safe and effective in elderly CLL patients with overall response rates over 95%.
This document discusses antibody-mediated rejection (ABMR) in kidney transplant recipients. It provides information on:
- The role of HLA and non-HLA antibodies in ABMR, including donor-specific antibodies (DSAs)
- Methods for detecting sensitization and antibodies pre-transplant, including complement-dependent cytotoxicity, flow cytometry, and Luminex single-antigen beads
- Studies showing an association between preformed DSA strength/level and risk of ABMR, graft survival
- Trials of desensitization protocols using IVIG, with or without plasmapheresis, to reduce DSA levels and risk of ABMR
This document summarizes causes of eosinophilia, including:
1) It classifies causes of eosinophilia as primary (clonal, idiopathic) or secondary. Secondary causes include infections, tissue invasion by parasites, drugs, allergies, autoimmune diseases, and malignancies.
2) Common primary causes include hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), and myeloproliferative neoplasms associated with eosinophilia such as those involving FIP1L1-PDGFRA, PDGFRB, FGFR1, and KIT mutations.
3) Secondary causes discussed include parasitic infections, fungal infections, HIV, drugs
Minimal Residual Disease in Acute lymphoblastic leukemiaDr. Liza Bulsara
This document discusses minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). It provides information on several key points:
1. MRD refers to small amounts of leukemia cells that can be detected through sensitive laboratory techniques like flow cytometry and PCR, but not through standard morphology.
2. Various methods for detecting MRD are discussed, including immunophenotyping, PCR, FISH, and cytogenetics. PCR can detect a single malignant cell among 100,000 normal cells and is the most sensitive method.
3. MRD levels determined at different time points during treatment have prognostic significance and can be used for risk stratification and determining the need for treatment intensification or reduction. Monitoring
This document discusses aplastic anemia and infections in patients undergoing stem cell transplantation (SCT) or immunosuppressive therapy (IST) for aplastic anemia in India. It notes that true incidence of aplastic anemia in India is unknown but it is more common in Asia than the West. For patients under 40, SCT from a HLA-matched sibling donor is the treatment of choice. However, late referrals and financial constraints can increase morbidity and mortality during SCT and IST in India due to less effective first-line treatments, recurrent transfusions, and infections. The document provides data on outcomes of various transplantation approaches and immunosuppressive therapies for aplastic anemia at Christian Medical College, Vello
This document discusses phenotypic heterogeneity in multiple myeloma and identifies distinct subclones within patient samples that have different genomic profiles, clonogenic potential, and drug sensitivity. FACS-sorted subclones from patient samples are often associated with different cytogenetic profiles. After drug exposure, minimal residual disease is a reservoir of chemoresistant cells that can lead to relapse. Achieving a complete response and eliminating minimal residual disease is associated with longer survival times.
The document describes a restaurant management software called Smartetouch Omni. It offers features to simplify online ordering, table booking, marketing and business management. Some key features mentioned include no commission or monthly fees, branded mobile apps, embedded marketing services, SMS/email notifications, loyalty programs and more. The software aims to help restaurants upgrade their business and take it to the next level.
Dokumen tersebut merangkum tentang internet, termasuk definisi, manfaat, fasilitas, layanan, perangkat keras dan perangkat pendukung yang digunakan untuk mengakses internet. Secara singkat, internet adalah jaringan global yang menghubungkan komputer dari seluruh dunia untuk berkomunikasi dan bertukar informasi.
Nanoparticles that communicate in vivo to amplify tumour targetingEdwin Alvarado
This document describes a new approach for targeted cancer therapy using communicating nanoparticles. Signaling nanoparticles are designed to first target tumors and then activate the body's coagulation cascade locally. This amplification broadcasts the location of the tumor to receiving nanoparticles circulating in the blood that can then deliver diagnostic or therapeutic agents to the tumor in much higher doses than non-communicating nanoparticles. The system takes advantage of the body's natural coagulation pathway to transmit signals between nanoparticles. In experiments, signaling gold nanorods were able to precisely induce coagulation when heated in tumors, demonstrating the ability of the system to activate coagulation specifically at tumor sites.
This document outlines the training modules, bonuses, and resources available in the Auction Profit School dashboard. The training modules cover topics like eBay and Amazon selling strategies, sourcing products, setting up product listings, and product duplication. Bonus items include 100 free digital products to sell and examples of additional products. The "Grow Your Business" section provides books and videos on social media tactics, customer follow-up, eBay listing secrets, and using different social networks. Users must view video content within the member area.
This document discusses using an extract from the plant Petiveria alliacea L. to treat gastroesophageal reflux disease (GERD). It reports on a study with 20 patients who had symptoms of GERD and were given capsules containing P. alliacea extract or a placebo over 4 weeks. The results showed that the patients taking the P. alliacea extract had a reduction in GERD symptoms and episodes compared to the placebo group, suggesting this plant extract may be an effective natural treatment for GERD.
The document compares and contrasts the biodiversity of two ecosystems in Puerto Rico: the Caribbean National Forest and the Guánica State Forest. It finds that the Guánica State Forest has greater biodiversity due to its location near the coast, resulting in more diverse temperatures, precipitation, and flora and fauna. In particular, the forest's proximity to the shoreline and exposure to harsher conditions have led to a higher degree of variation in plant and animal species than is found in the Caribbean National Forest.
The document proposes extracting Petiveria alliacea L. to test its ability to treat gastroesophageal reflux disease (GERD). It outlines experiments to determine if the extract can increase stomach pH levels and reduce acid irrigation over time. Mice will receive diets with or without the extract, with and without acid promoters, to analyze pH and acid levels in the stomach over 4 weeks. The goal is to provide an alternative GERD treatment that relieves pain and controls the disease through neutralizing stomach acid.
This document describes a new method for site-specifically labeling proteins using genetically encoded norbornene and tetrazine probes. Specifically:
- A norbornene-containing amino acid was genetically encoded in E. coli and mammalian cells using the pyrrolysyl tRNA synthetase system.
- A series of tetrazine probes were developed that react rapidly and specifically with norbornenes via a Diels-Alder reaction.
- The labeling of encoded norbornene was shown to be specific and much faster than other bioorthogonal reactions, demonstrating advantages for protein labeling in vitro and on cells.
- Rapid and site-specific labeling of a cell surface protein was demonstrated,
This document summarizes a research article from Blood about targeting Kaposi's sarcoma-associated herpesvirus (KSHV) in multicentric Castleman disease (MCD) with antiviral drugs. It discusses how:
1) Uldrick et al conducted a pilot study using valganciclovir and zidovudine to target two KSHV enzymes involved in viral DNA synthesis, representing the first antiviral chemotherapy targeting KSHV.
2) MCD has an unusual pathoetiology that allows antiviral drugs to work by targeting KSHV-infected cells amid uninfected cells driven to multiply by viral cytokines.
3) The study provides hope that targeting latent viral proteins
This document compares and contrasts the Guánica State Forest and Caribbean National Forest in Puerto Rico. It discusses how the biodiversity, flora, fauna, and climate differ between the two ecosystems. The Guánica State Forest has higher biodiversity and is more diverse overall due to its location near the coast and exposure to varying temperatures and precipitation, while the Caribbean National Forest has adapted to harsher and more arid conditions inland. The conclusion is that the Guánica State Forest is the more diverse of the two forests compared.
Gm1 gangliosidosis and morquio b disease an update on genetic alterations and...Edwin Alvarado
This document reports on genetic alterations and clinical findings related to GM1 gangliosidosis and Morquio B disease, which are rare lysosomal storage disorders caused by beta-galactosidase deficiency. Molecular analysis identified 27 mutations in 25 GM1 gangliosidosis patients, including 9 new mutations. Three remarkable cases were described, including a patient with GM1 gangliosidosis and triple X syndrome. Clinical features of patients were collected and compared. Homology modeling was used to analyze the structural effects of new missense mutations. The findings provide insights into classifying late-onset GM1 gangliosidosis and Morquio B disease.
Student Alert App is a dedicated school mobile application for Student, Parent & Management. The student alert app enables Parent - School interaction in an instant manner bridging all the possible communication gaps. This software is hosted on google app engine ensuring Scalability and Ruberstness.
Dokumen tersebut merangkum tentang internet, termasuk definisi, manfaat, fasilitas, layanan, perangkat keras dan perangkat pendukung yang digunakan untuk mengakses internet. Secara singkat, internet adalah jaringan global yang menghubungkan komputer dari seluruh dunia untuk berkomunikasi dan bertukar informasi.
Carlos López Fernández de Castillejo is applying for a PhD fellowship to further his research on dissecting the leukaemic stem cell niche. His research aims to 1) validate a novel therapy for myeloproliferative neoplasms that preserves the bone marrow microenvironment rather than targeting mutated cells, and 2) investigate how the microenvironment contributes to acute myeloid leukemia development and mutant stem cell support. His previous work demonstrated that damage to mesenchymal stem cells in the bone marrow niche is required for myeloproliferative neoplasm progression in mice and humans. Preserving the niche through drug therapies blocked disease progression in mice. This fellowship could increase understanding of acute myeloid leukemia biology
Successful clearance of human parainfluenza virus type 2 viraemia with intrav...Yan'an Hou
This case report describes a 47-year-old man who presented with fulminant myocarditis caused by human parainfluenza virus type 2 (HPIV-2) infection. He had persistent HPIV-2 viraemia that was successfully cleared after treatment with intravenous ribavirin and intravenous immunoglobulin. This is the first reported case of documented HPIV-2 viraemia clearance following antiviral therapy in a patient with myocarditis. The patient's clinical condition and cardiac enzyme levels improved after starting ribavirin, and histological examination confirmed lymphocytic myocarditis.
The document discusses antiphospholipid antibodies in pediatric lupus nephritis. It defines antiphospholipid antibody syndrome as an autoimmune disorder that can manifest as recurrent thrombosis. It also defines systemic lupus erythematosus as an autoimmune disease that can damage organs like the kidneys, skin, blood cells, and nervous system. Antiphospholipid antibodies are found to be associated with clinical symptoms like thrombosis and pregnancy complications in pediatric lupus nephritis patients.
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This document summarizes a review article on the current state and future directions of hematopoietic stem cell engineering. The review discusses how early clinical trials using first-generation gamma-retroviral vectors showed successes in treating immune deficiencies but also safety issues like leukemia. This prompted improvements in vector design, targeted gene delivery methods, and use of pluripotent stem cells. The review evaluates these new approaches and highlights the remaining challenges to developing safer and more effective hematopoietic stem cell therapies.
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CRISPR is genome editing technique mainly based on a natural immune process used by bacteria to defend themselves against invading viruses. Genome editing is the use of various technologies to make a permanent changes in the genomic DNA sequence of a cell or organism.
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aplastic anemia power point presentationmitalipatter
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This document discusses flow cytometry and its application in cancer diagnosis and molecular testing. It provides details on several tests performed using flow cytometry, including immunophenotyping for different types of leukemia and lymphoma. It also discusses the classification of acute leukemias according to the FAB and WHO systems and provides information on different FAB subtypes of acute myeloid leukemia such as M0, M1, M2, M3, M4, and M5. The document aims to inform clinicians on the diagnostic and clinical utility of various flow cytometry tests.
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2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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High dose zidovudine plus valganciclovir for kaposi sarcoma
1. From bloodjournal.hematologylibrary.org by guest on August 8, 2012. For personal use only.
2011 117: 6977-6986
Prepublished online April 12, 2011;
doi:10.1182/blood-2010-11-317610
High-dose zidovudine plus valganciclovir for Kaposi sarcoma
herpesvirus-associated multicentric Castleman disease: a pilot study of
virus-activated cytotoxic therapy
Thomas S. Uldrick, Mark N. Polizzotto, Karen Aleman, Deirdre O'Mahony, Kathleen M. Wyvill,
Victoria Wang, Vickie Marshall, Stefania Pittaluga, Seth M. Steinberg, Giovanna Tosato, Denise
Whitby, Richard F. Little and Robert Yarchoan
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Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.
2. From bloodjournal.hematologylibrary.org by guest on August 8, 2012. For personal use only.
Plenary paper
High-dose zidovudine plus valganciclovir for Kaposi sarcoma
herpesvirus-associated multicentric Castleman disease: a pilot study of
virus-activated cytotoxic therapy
Thomas S. Uldrick,1 Mark N. Polizzotto,1 Karen Aleman,1 Deirdre O’Mahony,1 Kathleen M. Wyvill,1 Victoria Wang,1
Vickie Marshall,2 Stefania Pittaluga,3 Seth M. Steinberg,4 Giovanna Tosato,5 Denise Whitby,2 Richard F. Little,1 and
Robert Yarchoan1
1HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD; 2Viral Oncology Section, AIDS and Cancer
Virus Program, SAIC-Frederick, NCI-Frederick, Frederick, MD; 3Laboratory of Pathology, 4Biostatistics and Data Management Section, and 5Laboratory of
Cellular Oncology, Center for Cancer Research, NCI, Bethesda, MD
Kaposi sarcoma herpesvirus (KSHV)– respectively, phosphorylate ganciclovir 12 months and beyond. At the time of
associated multicentric Castleman dis- and zidovudine to toxic moieties. In a best response, the patients showed sig-
ease (MCD) is a lymphoproliferative disor- pilot study, 14 HIV-infected patients with nificant improvements in C-reactive pro-
der most commonly observed in HIV- symptomatic KSHV-MCD received high- tein, albumin, platelets, human IL-6, IL-10,
infected patients. It is characterized by dose zidovudine (600 mg orally every and KSHV viral load. The most common
KSHV-infected plasmablasts that fre- 6 hours) and the oral prodrug, valganci- toxicities were hematologic. These obser-
quently express lytic genes. Patients clovir (900 mg orally every 12 hours). Re- vations provide evidence that therapy de-
manifest inflammatory symptoms attrib- sponses were evaluated using new re- signed to target cells with lytic KSHV
uted to overproduction of KSHV viral IL-6, sponse criteria. A total of 86% of patients replication has activity in KSHV-MCD. This
human IL-6, and human IL-6. There is no attained major clinical responses and 50% trial was registered at www.clinicaltrials.gov
standard therapy and no established re- attained major biochemical responses. as #NCT00099073. (Blood. 2011;117(26):
sponse criteria. We investigated an ap- Median progression-free survival was 6977-6986)
proach targeting 2 KSHV lytic genes, 6 months. With 43 months of median fol-
ORF36 and ORF21, the protein of which, low-up, overall survival was 86% at
Introduction
Multicentric Castleman disease (MCD) is a rare disorder character- In addition, KSHV-MCD is unusual in that a substantial proportion
ized by inflammatory symptoms that include fever, splenomegaly, of the KSHV-infected plasmablasts have lytic KSHV gene
lymphadenopathy, respiratory symptoms, edema, effusions, cytope- expression.9
nias, hypoalbuminemia, and elevated inflammatory markers.1,2 Clinically, KSHV-MCD often waxes and wanes, but without
Kaposi sarcoma-herpesvirus (KSHV), also called human herpesvi- treatment, it is generally fatal within 2 years.1 Causes of death
rus-8,3 is the cause of a sizable subset of MCD,4,5 especially MCD include multiorgan failure, progressive KS, immunoblastic lympho-
arising in immunosuppressed patients, such as those infected with mas, or intercurrent infections. A pooled evaluation of 86 published
HIV. KSHV is also the etiologic agent of Kaposi sarcoma (KS) and cases between 1985 and 2006 reported median survival of approxi-
primary effusion lymphoma (PEL); not uncommonly, patients mately 12 months, although fatality rate was less in patients who
manifest more than 1 of these disorders. received highly active antiretroviral therapy (HAART).15 There is
KSHV-associated MCD (KSHV-MCD) is diagnosed pathologi- evidence that KSHV-MCD incidence is increasing with widespread
cally, usually through a lymph node biopsy demonstrating hypocel- use of HAART.16
lular germinal centers with vascularized core and proliferation of There is no standard treatment for KSHV-MCD. Furthermore,
perifollicular monotypic plasmablastic cells that usually express there are currently no standardized response criteria for MCD,
IgM and .6 A number of these plasmablastic cells are KSHV- making it difficult to compare results of different therapeutic
infected, expressing KSHV latency associated nuclear antigen.7,8 A approaches. Successful treatment has been reported with various
sizable subset of these cells express a KSHV-encoded viral chemotherapeutic agents, including vincristine, vinblastine, etopo-
interleukin-6 (vIL-6),5 a gene whose mRNA is sometimes detect- side, cyclophosphamide, and doxorubicin, alone or in combina-
able in latently infected cells, and is significantly up-regulated with tion1,15; as well as with ganciclovir,17 IFN-␣,18,19 and thalido-
lytic activation.5,9-12 KSHV-MCD patients often have detectable mide.20,21 Steroids have been described to reduce inflammatory
serum vIL-6, and inflammatory symptoms in this condition are symptoms in MCD not associated with KSHV.22 With all of these
attributed in part to vIL-6.13 Elevated serum human IL-6 (hIL-6) modalities, relapse is common. The best-studied agent in KSHV-
and IL-10 may also contribute to KSHV-MCD symptomatology.14 MCD is the monoclonal anti-CD20 antibody rituximab, either as
Submitted November 5, 2010; accepted March 31, 2011. Prepublished online as The online version of this article contains a data supplement.
Blood First Edition paper, April 12, 2011; DOI 10.1182/blood-2010-11-317610.
An Inside Blood analysis of this article appears at the front of this issue.
BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26 6977
3. From bloodjournal.hematologylibrary.org by guest on August 8, 2012. For personal use only.
6978 ULDRICK et al BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26
first-line monotherapy23 or after chemotherapy.24 Whereas ritux- Table 1. Baseline patient characteristics
imab was often effective in the management of symptoms and Characteristic Value
correction of biochemical abnormalities, KS flared in 35% to 67% Sex
of patients. Disease-free survival at 1 to 2 years was 77% to 79%. Men 13
Thus, more effective therapies for KSHV-MCD are needed. Women 1
Our group is exploring selectively targeting KSHV-MCD Race/ethnicity
plasmablasts based on their expression of KSHV lytic genes.25 One African 3
KSHV lytic gene, ORF36, encodes a phosphotransferase that Black 3
White 7
activates ganciclovir to a toxic triphosphate moiety, and another,
Hispanic (Puerto Rican) 1
ORF21, encodes a thymidine kinase that phosphorylates zidovu-
Median age, y (range) 41 (28-56)
dine (AZT).25-27 We previously showed that PEL cells in which
Median ECOG Performance Status (range) 2 (1-3)
KSHV was lytically activated produced increased amounts of AZT Median time since HIV diagnosis, y (range) 6.5 (0.3-18)
and ganciclovir triphosphate moieties. AZT and ganciclovir had Median time on antiretroviral therapy, y (range) 3.5 (2 wk to 13 y)
synergistic toxicity at doses attainable in patients, in these PEL HIV viral load Ͻ 50 copies/mL, no. (%) of patients 9 (64)
lines.25 We hypothesized that the combination of AZT and Median CD4, cells/mL (range) 270 (67-1319)
ganciclovir would selectively target the KSHV-infected plasma- Median time since MCD diagnosis, mo (range) 1.5 (0.5-45)
blasts in KSHV-MCD and have utility in the treatment of History of KS, no. (%) of patients 8 (57)
symptomatic disease. To translate these findings, we conducted History of KSHV-associated lymphoma, no. (%) of patients 1 (7)
Prior therapies*
a pilot study of high-dose AZT and valganciclovir (VGC), an
Median no. (range) 1 (0-7)
orally available prodrug of ganciclovir, in patients with symptom-
Prior therapy, no. (%) of patients 8 (57)
atic KSHV-MCD. In conducting this study, we also prospectively
Clinical symptoms, no. (%) of patients
defined clinical, biochemical, and radiographic criteria to assess Fever/night sweats 13 (93)
responses to KSHV-MCD, and piloted the use of these criteria in Fatigue 13 (93)
assessing responses. Weight loss 12 (86)
Respiratory symptoms 12 (86)
Gastrointestinal symptoms 11 (79)
Neuropathy 5 (36)
Methods Headache 5 (36)
Edema 3 (21)
Study population
Rash 3 (21)
Starting in 2004, patients with pathologically confirmed KSHV-associated Myalgia 2 (14)
MCD were enrolled in a clinical research protocol to investigate the natural Median biochemical parameters (range)
history of the disease and assess virus-activated cytotoxic therapy with CRP, mg/dL 7.5 (1-35.9)†
AZT/VGC. Patients with symptomatic MCD, defined as at least 1 clinical Albumin, g/dL 2.8 (1.5-3.5)
symptom (Table 1) and at least 1 laboratory abnormality (elevated Sodium, mEq/L 134 (127-142)
C-reactive protein [CRP], hyponatremia, hypoalbuminemia, thrombocyto- Platelets, ϫ 103/L 115 (16-347)
penia, or anemia) attributed to KSHV-MCD, were eligible for treatment Hemoglobin, g/dL 10.1 (7.7-12.7)
with AZT/VGC. There was no limitation on number of prior therapies. Per Radiographic parameters
protocol, AZT/VGC was used as initial therapy in symptomatic patients, Median spleen size, cm (range) 18.5 (10-26.5)
except those for whom this approach did not appear appropriate; patients Enlarged lymph nodes, no. of patients 12
with advanced KS, diffuse large B-cell lymphoma, or with life-threatening
*Number of different regimens, including steroids, used to treat MCD.
disease (ie, Eastern Cooperative Oncology Group performance status of †CRP was assayed using Siemens Dimension Vista platform (Siemens AG);
4 or end-organ damage) received alternate biochemotherapy regimens from study inception until May 2009 a standard sensitivity assay (sCRP) was used,
instead of AZT/VGC. The protocol (#NCT00099073) was approved by the which was subsequently replaced by a high sensitivity (hsCRP) assay. Correction of
National Cancer Institute Institutional Review Board. All patients gave CRP for values obtained after May 2009 was performed using a formula:
written informed consent in accordance with the Declaration of Helsinki. ͓sCRP ϭ (hsCRP Ϫ 0.56)/0.93͔, which was validated by the National Institutes of Health
Clinical Center Department of Laboratory Medicine. Normal CRP Ͻ 0.04 mg/dL.
Treatment regimen
evidence of substantial HIV resistance to AZT. Patients continued on
Treatment consisted of AZT 600 mg orally every 6 hours combined with AZT/VGC therapy as long as there was evidence of clinical benefit.
VGC 900 mg orally every 12 hours. Substitution with AZT 300 mg Therapy was continued several cycles beyond initial improvement of
intravenously every 6 hours combined with ganciclovir 5 mg/kg intrave- clinical symptoms with the aim of treating residual subclinical disease. The
nous every 12 hours was allowed for inpatients not able to tolerate or absorb ultimate goal of therapy was complete resolution of clinical, biochemical,
oral medications. Patients initially received AZT/VGC for 7 days, with the and radiographic abnormalities attributed to MCD with long-term remis-
option of continuing for up to 21 days during the first cycle if patients had sion of disease. AZT/VGC was discontinued in patients with progressive
substantial symptoms after the first 7 days. Patients with severe MCD symptoms or dose-limiting toxicities, and alternative therapeutic ap-
symptoms and laboratory abnormalities could receive corticosteroids proaches were used.
during initial therapy, generally consisting of a single dose or a short steroid
taper at the beginning of the first cycle. Response evaluations
Given the risk of hematotoxicity with prolonged dosing high-dose
AZT/VGC, subsequent 21-day cycles generally consisted of 7 days of Patients were monitored for clinical, biochemical, and radiographic re-
therapy followed by 14 days off therapy, although the protocol allowed for a sponses (Table 2). Evaluation included structured review of symptoms,
longer durations of treatment at investigator discretion. Concurrent antiret- physical examination, and laboratory studies day 1 of each cycle, or at the
roviral therapy was generally adjusted during the periods of treatment with time progression. Symptoms were graded using the National Cancer
AZT/VGC to avoid administration of 4 antiretroviral agents, including Institute Common Terminology Criteria for Adverse Events, Version 3.
3 nucleoside reverse-transcriptase inhibitors, as long as there was no Clinical decisions were based on patient performance status, and review of
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BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26 ZIDOVUDINE ϩ VALGANCICLOVIR FOR CASTLEMAN DISEASE 6979
Table 2. KSHV-associated MCD response criteria
Response category Response and criteria
Clinical response CR
Full resolution of all signs and symptoms attributable to MCD, lasting 1 cycle (3-4 wk depending on regimen); requires normalization of
involved nodal areas on physical examination
SFD
Full resolution of all symptoms attributable to MCD
PR
Improvement in at least 50% of signs and symptoms by at least 1 grade (NCI-CTCAE, Version 3), with no increased MCD-related
increases, lasting 1 cycle (3-4 wk depending on regimen)
SD
No change in signs and symptoms of MCD meeting criteria for CR, PR, or PD
PD
Worsening of 2 or more symptoms by at least 1 grade
Biochemical response* CR
Normalization of abnormalities attributed to MCD in the following laboratory values: hemoglobin, platelets, albumin, sodium, and CRP,
lasting 1 cycle (3-4 wk depending on regimen)
PR
At least 50% improvement in all laboratory value abnormalities attributable to MCD, lasting 1 cycle (3-4 wk depending on regimen)
SD
No change in biochemical parameters that meet criteria for CR, PR, or PD
PD
Ն 25% and 1 grade worsening of at least 2 biochemical parameters attributable to MCD OR clear deterioration in one parameter with
negative impact on physiologic or health status
Radiographic response CR
Normalization of all lymph nodes to Ͻ 1.5 cm in greatest transverse dimension, with decrease to Ͻ 1 cm of lymph nodes that measure
1.1-1.5 cm at baseline, or 75% decrease in SPD of measured lymph nodes; spleen Ͻ 12 cm greatest dimension, no pleural effusions
Cru
Residual lymph node mass Ͼ 1.5 cm or spleen Ͼ 12 cm that has decrease by Ն 75% and does not change over 1 y
PR
For lymph nodes, Ն 50% decrease in SPD of 6 dominant nodes; for spleen, Ն 50% decrease in longest transverse dimension
SD
Not meeting criteria for CR, CRu, PR, or PD
PD
For lymph nodes, Ն 25% increase in the SPD; for spleen, increase Ն 25% in longest dimension
Overall response CR
CR in all categories
PR
PR or better in all categories
SD
SD or better in all categories
PD
Progression in any 1 category
Data are based on signs and symptoms probably or definitely attributed to KSHV-MCD.
CR indicates complete response; SFD, symptom-free disease; PR, partial response; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse
Events; SD, stable disease; PD, progressive disease; SPD, sum products of the diameters; and Cru, complete response, unconfirmed.
*Determination of partial or complete biochemical responses was not based on improvements in hemoglobin or platelet counts that occurred within 3 weeks (one cycle) of
transfusions or growth factor support.
symptoms probably or definitely attributed to KSHV-MCD (Table 1), as Biochemical responses were based on resolution of laboratory
well as clinical laboratory parameters, including complete blood counts, abnormalities generally attributable to MCD. Biochemical responses as
blood chemistries, and CRP. Patient samples were obtained for correlative defined in the original protocol required 50% or greater relative
studies, including cell-associated KSHV-viral load, serum vIL-6, and serum improvement (normalization toward the lower or upper limit of normal)
multiplex cytokine analyses. These correlative biomarkers did not guide in each of 12 laboratory parameters. However, as we gained experience
clinical decision-making. in KSHV-MCD, it became evident that these criteria were frequently
There are no standard MCD response criteria. One aim of this affected by conditions other than the MCD and thus did not provide a
protocol was to develop MCD response criteria and gain experience with good assessment of the disease status. Before performing formal
and assess the feasibility and utility of these criteria. Criteria were evaluation of biochemical response in any patient, criteria were revised
defined for responses in 3 categories: clinical, biochemical, and with a study amendment to include only the 5 most commonly abnormal
radiographic (Table 2), incorporating abnormalities commonly seen in biochemical parameters: CRP, hemoglobin, platelets, albumin, and
KSHV-MCD.1 Clinical responses were considered primary. A clinical sodium (Table 2). In evaluating biochemical response, improvements in
complete response required full resolution of the clinical signs and hemoglobin and platelets were considered only if they occurred or were
symptoms probably or definitely attributable to MCD lasting 1 cycle sustained independent of transfusion or erythroid growth factors. All
(3-4 weeks). Table 1 shows categories of symptoms noted at baseline patients were assessed uniformly using revised criteria.
and used in response evaluations. A category of “symptom-free disease” Radiographic responses were evaluated by computed tomography scans
was defined as full resolution of all clinical symptoms attributed to obtained at baseline, every 2 cycles until clinical stabilization, and then
MCD but did not require resolution of asymptomatic lymph nodes noted on every 3 months. Radiographic response criteria were based on response
physical examination or maintenance of a full cycle. criteria for malignant lymphoma established by the International Working
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6980 ULDRICK et al BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26
Group.28 Modifications of radiographic criteria for KSHV-MCD included
use of computed tomography imaging alone, with [18F]-fluorodeoxyglucose-
positron emission tomography explored only for research purposes, specific
Results
criteria for resolution of splenomegaly, and specific requirement for Patient characteristics
resolution of pleural effusions. Overall response integrated the clinical,
biochemical, and radiographic responses. Importantly, complete overall Of 22 patients enrolled on the KSHV-MCD protocol between 2004 and
response using these criteria required resolution of all abnormalities 2009, 14 patients were treated with AZT/VGC. Of the other 8 patients,
attributed to MCD. 4 were clinically asymptomatic and felt not to require therapy, 2 had
advanced KS requiring chemotherapy, 1 had diffuse large B-cell
vIL-6 assay lymphoma, and 1 had life-threatening MCD treated with a more
aggressive regimen. Baseline characteristics of patients treated with
KSHV-encoded vIL-6 was measured using a previously described sandwich
enzyme-linked immunosorbent assay that used clone v6m 31.2.4 murine AZT/VGC are outlined in Table 1. All had HIV infection and were on
monoclonal anti–vIL-6 antibody,29 and which had been modified from an HAART, although several patients, including 4 of 5 with detectable
earlier vIL-6 assay.13,30,31 The lower limit of detection for serum vIL-6 was viral loads at entry, reporting missing some doses of their
1560 pg/mL and 95% upper limit of reactivity in serum from health blood antiretroviral drugs when they were ill with their MCD flare.
donors was 2850 pg/mL. The assay did not cross-react with hIL-6.29 In Eight had received previous therapy for their MCD, and had
evaluating patients with known KSHV-MCD at different time points, vIL-6 received up to 7 different prior regimens. Prior therapies
values are presented down to 1560 pg/mL. included cyclophosphamide, doxorubicin, vincristine and pred-
nisone; rituximab; VGC monotherapy; and intravenous
KSHV quantitative real-time PCR immunoglobulin.
Four patients were on glucocorticoids before starting AZT/
KSHV-viral load was measured using previously described methods.29,32,33
VGC; in such cases, steroids were continued during the initial
Briefly, DNA was extracted from peripheral blood mononuclear cells
(PBMCs) and KSHV DNA was detected using primers for the K6 gene therapy and then tapered when possible. Four additional patients
region.32 The number of cellular equivalents was determined using a received at least a single dose of glucocorticoids during the first
quantitative assay for human endogenous retrovirus 3,34 and KSHV viral cycle (2 for thrombocytopenia, 2 for clinical symptoms). Glucocor-
load was reported as viral DNA copies per million PBMCs.33 ticoids were discontinued during the first cycle in 5 of these
8 patients, whereas 3 patients remained steroid-dependent through-
Other assays out therapy. Two of these 3 patients were switched to an alternate
therapy for MCD during cycle 2, and 1 was maintained on
Serum hIL-6, IL-10, and 5 other cytokines (IL-1, IL-8, IL-12 p70, IFN ␥, physiologic dosing of hydrocortisone because of adrenal insuffi-
and TNF-␣) were evaluated using the MSD 96-Well Multiarray Proinflam- ciency. One additional patient who discontinued glucocorticoids
matory 7-plex Assay (Meso-Scale Discovery) and the Sector Imager. As
during cycle 1 received methylprednisolone for sinus inflammation
previously described, the Meso-Scale hIL-6 assay did cross-react with
vIL-6.29 CD4 counts were assessed by FACS. Plasma HIV-1 mRNA was
during cycle 7. In addition, patients sometimes required transfu-
measured by quantitative RNA polymerase chain reaction using Roche sions because of cytopenias attributed to MCD activity; red blood
Amplicor HIV-1 Monitoring Kits (Roche Diagnostic Systems). cell transfusions were required in 9 patients and platelet transfu-
sions in 7 patients. Two patients received erythropoietin.
Statistical methods Clinical responses
As a pilot study evaluating AZT/VGC efficacy in the treatment of Patients received a median of 8.5 cycles of therapy (range, 1-29 cycles).
symptomatic KSHV-MCD, we evaluated the best clinical, biochemical,
Five (36%) were symptom-free after the first cycle. With additional
radiographic, and overall responses. The protocol used a 2-stage Simon
therapy, 12 of 14 (86%) had a major response (partial response or better)
optimal design to evaluate AZT/VGC, with ␣ ϭ 0.15,  ϭ 0.15, and a
targeted 25% response rate. If 1 or more of the first 8 patients had at least a as a best clinical response (Table 3). Seven (50%) achieved a clinical
partial response in 1 response parameter (clinical, biochemical, or radio- complete response and 2 achieved a partial response. Three achieved
graphic), 14 patients were to be treated with AZT/VGC. In addition, symptom-free disease not classified as a complete clinical response
progression-free survival (time from starting therapy to time of disease because of either symptom-free duration of Ͼ 1 cycle (2 patients) or
progression requiring a change in therapy or death) and overall survival persistent adenopathy on physical examination with recurrence of
were determined using Kaplan-Meier methodology. For survival analysis, clinical symptoms after 5 cycles (one patient). The 2 patients who did
patient status was assessed from the start of therapy until September 7, not have a clinical partial response or better had clinical stable disease at
2010. Clinical and research laboratory correlatives of MCD disease activity the end of cycle 1; given lack of improvement in clinical symptoms,
were evaluated as follows: paired nonparametric analysis was performed
each received an alternate regimen after 19 to 28 days of AZT/VGC.
using an exact Wilcoxon signed-rank test comparing changes from baseline
laboratories to those at a time of best clinical response for: platelets,
One of these patients was found to have intercurrent bacterial endocardi-
hemoglobin, albumin, CRP, vIL-6, hIL-6, IL-10, and KSHV viral load. tis. Notably, the 6 patients who never received glucocorticoids during
hIL-6, IL-10, and KSHV viral load were log10 transformed for analyses; AZT/VGC treatment all had a clinical major response; 4 had a complete
undetectable KSHV viral loads were converted to 1 to permit valid log10 response and 2 had a partial response. In 8 patients who received at least
transformation. Because vIL-6 was often below the threshold of detection, 1 dose of glucocorticoids, 3 achieved a complete response, 3 symptom-
vIL-6 was considered detectable or not, with changes evaluated using the free disease, and 2 had stable disease.
McNemar test for paired categorical data. Statistical analyses of correlative
parameters were exploratory, with no formal correction for multiple Biochemical and radiographic responses
comparisons. However, because multiple parameters were examined, P
values Յ .01 are interpreted as statistically significant, values between .01 Seven patients (50%) had biochemical major response (partial
and Յ .05 indicate strong trends, and values Ͼ .05 are considered not response or better), with 3 (21%) achieving complete responses and
significant. All P values are 2-sided. Toxicities across all cycles possibly, 4 (29%) achieving partial responses. Six of the remaining patients
probably, or definitively attributed to therapy were tabulated. met criteria for stable disease and 1 had worsening biochemical
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BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26 ZIDOVUDINE ϩ VALGANCICLOVIR FOR CASTLEMAN DISEASE 6981
Table 3. Best response to treatment with AZT/VGC in 14 patients the lowest of the 3 categories. Overall response categorization was
with symptomatic KSHV-MCD affected by the fact that clinical responses generally preceded
Response category Best response No. (%) biochemical and radiographic responses (supplemental Table 1,
Clinical response Complete response 7 (50) available on the Blood Web site; see the Supplemental Materials
Symptom-free disease 3 (21) link at the top of the online article). Based on stringent
Partial response 2 (14) protocol-defined criteria, 4 of 14 patients (29%) achieved an
Major clinical response 12 (86)
overall partial response or better, including 3 overall complete
Stable disease 2 (14)
responses and 1 overall partial response. Two of these 4 patients
Biochemical response Complete response 3 (21)
Partial response 4 (29)
received limited glucocorticoids during the first cycle of therapy,
Major biochemical response 7 (50) but otherwise none received glucocorticoids during their treat-
Stable disease 6 (43) ment for up to 20 cycles. In 9 of the remaining 10 patients, best
Progressive disease 1 (7) overall response was stable disease, and in 1 patient, best overall
Radiographic response* Complete response 4 (29) response was progressive disease. It should be noted, that of
Complete response, unconfirmed 1 (7) 9 patients with overall stable disease, only 1 had stable disease in
Major radiographic response 5 (36) all 3 categories; 8 had a partial response or better clinically, and
Stable disease 8 (67)
4 had a major response in other categories.
Overall response Complete response 3 (21)
Partial response 1 (7) Progression-free and overall survival
Stable disease 9 (64)
Progressive disease 1 (7) With a median potential 42.8-month follow-up, median progression-
Major clinical response ϭ complete response ϩ symptom-free disease ϩ partial
free survival was 6 months (Figure 2A) and the estimated propor-
response; major biochemical response ϭ complete response ϩ partial response; tion of patients who had not progressed at month 12 is 23%. Three
and major radiographic response ϭ complete response ϩ complete response uncon- patients who obtained a lasting overall complete response were
firmed ϩ partial response.
treated for 13, 20, and 29 cycles, which was 9, 10, and 22 cycles
*One patient was not evaluable radiographically.
beyond resolution of clinical and biochemical abnormalities attrib-
uted to KSHV-MCD. They remain symptom-free for 10, 29, and
parameters when his course was complicated by bacterial endocar- 33 months after stopping AZT/VGC. One patient with an overall
ditis with cerebral emboli. Among 3 patients receiving steroids at partial response when last evaluated died of untreated systemic
the time of determination of best biochemical response, 2 were Streptococcus pneumoniae infection with possible progressive
classified as stable disease and 1 as progressive disease. Thirteen MCD as well. In the remaining 10 patients, AZT/VGC therapy was
patients completed the required radiographic studies and were changed for overall disease recurrence or progression (8 patients),
evaluable for radiographic response. Four patients (29%) achieved worsening KSHV-associated extracavitary PEL (one patient), or
a radiographic complete response as best response, which required investigator preference because of inadequate clinical improve-
normalization of both lymphadenopathy and splenomegaly, and ment (one patient with overall stable disease at last evaluation).
1 patient had a response unconfirmed based on residual spleno- Patients who recurred or progressed went on to receive 1 or more
megaly (spleen 12.5 cm) that was unchanged over 12 months. additional therapies; subsequent therapies included a combination
Eight patients had radiographic stable disease, although decreases of rituximab and liposomal doxorubicin (7), EPOCH [infusional
in spleen and lymph node size were common (Figure 1). etoposide, vincristine, doxorubicin, with oral prednisone, and bolus
Overall responses
cyclophosphamide] (2), IFN-␣ (7), subsequent additional AZT/
VGC (2), and rituximab monotherapy (1).
Patients were evaluated individually in each of the 3 categories at Median overall survival has not been reached (Figure 2B).
each cycle, and overall responses were conservatively defined as Twelve of 14 patients remain alive, and overall survival at
Figure 1. Best radiographic responses. (A) Percentage change in sum of the products of 6 representational lymph nodes at time of best radiographic response compared
with baseline, in the 11 patients with pathologic lymphadenopathy at baseline evaluable. Patients can have a radiographic complete response with Ͻ 100% decrease in sum of
the products of representational lymph nodes as long as there is no pathologic adenopathy at time of evaluation. (B) Percentage change in longest dimension of spleen size
(normalized to spleen upper limit of normal ϭ 12 cm) at time of best radiographic response compared with baseline, 10 patients with splenomegaly at baseline evaluable,
maximum normalization ϭ 100%.
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6982 ULDRICK et al BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26
A 100 Progression!Free Survival B Overall Survival
100
75
75
Percent Progression!Free
Percent Alive
50
50
25
25
0
0
0 12 24 36 48 60 0 12 24 36 48 60
Months Months
Figure 2. Kaplan-Meier survival function. (A) Progression-free survival. (B) Overall survival. Hatch marks represent time subjects censored.
12 months and beyond is 86% (95% confidence interval, 60%- vIL-6, hIL-6, IL-10, and KSHV viral load. For each patient,
96%). In addition to the patient described in the preceding baseline values were compared with values from the first time
paragraph who died of pneumococcal infection, an additional the tests were obtained after the best clinical response. Thirteen
patient died at home with febrile neutropenia while being treated patients were evaluable for changes in cytokines and KSHV
with combination chemotherapy for progressive extracavitary PEL. viral load. Relatively large decreases that were either statisti-
Changes in biochemical laboratory parameters cally significant or exhibiting strong trends were observed for
IL-10 (P ϭ .0002), hIL-6 (P ϭ .027), and KSHV viral load
Changes in the 5 individual laboratory parameters used in the (P ϭ .021). Excluding the patient with bacterial endocarditis,
response criteria were assessed in each patient from the start of observed differences were statistically significant for IL-10
therapy to the time of best clinical response. Analyses were (P ϭ .0005), hIL-6 (P ϭ .001), and KSHV viral load (P ϭ .0049).
performed first in all 14 patients (Table 4), then repeated excluding
Each of 5 patients with elevated vIL-6 at entry had a decrease
the patient whose clinical course was complicated by bacterial
during therapy; however, with this small number, this decrease was
endocarditis with cerebral emboli. Statistically significant changes
not statistically significant (Figure 3B).
or strong trends were observed for decreases in CRP (P ϭ .0085;
Six of 12 patients who initially achieved partial clinical response or
Figure 3A), increases in albumin (P ϭ .0033), and increases in
better subsequently had clinical progression of MCD. In all cases,
platelet counts (P ϭ .02), whereas changes in sodium (P ϭ .44)
and hemoglobin (P ϭ .31) were not statistically significant. Exclud- clinical deterioration was accompanied by rising CRP; compared with a
ing the patient with bacterial endocarditis, changes in CRP median CRP at the time of best clinical response of 0.49 mg/dL (range,
(P ϭ .0002), albumin (P ϭ .0007), and platelets (P ϭ .0081) were Ͻ 0.4-0.95 mg/dL), median CRP at time of clinical progression was
all statistically significant, whereas changes in sodium and hemo- 9.8 mg/dL, (range, 5.3-14.2 mg/dL). vIL-6 was detectable in 3 of these
globin were not. In addition, median CRP decreased across patients 6 patients at the time of relapse (range, 2771-12 335 pg/mL) and in all
over the first 4 cycles (supplemental Figure 1). cases was increased compared with the level at time of best clinical
response (range, Ͻ 1560-3693 pg/mL). The other 3 patients had unde-
Immunologic and virologic studies
tectable serum vIL-6 at both time points. Patients who relapsed all had
We evaluated immunologic and virologic parameters previously increasing hIL-6 (median increase, 33.2 pg/mL; range, 7.3-192.2 pg/
demonstrated to be associated with MCD activity, including nL), IL-10 (median increase, 9324 pg/mL; range, 839-15 549 pg/mL),
Table 4. Changes in biochemical parameters from baseline to time of best clinical response in patients with KSHV-MCD treated with
AZT/VGC
Median baseline Median best clinical Median change
Parameter n (range) response (range) (range) P
CRP, mg/dL 14 7.5 (1, 35.9) 0.5 (Ͻ 0.4, 23.2) Ϫ7 (22.2, Ϫ29) .0085
Albumin, g/dL 14 2.8 (1.5, 3.5) 3.4 (1.4, 4.3) 0.6 (Ϫ0.6, 2.4) .0033
Sodium, mEq/L 14 134 (127, 142) 136 (131, 141) 0 (Ϫ6, 8) .46
Hemoglobin, g/dL 14 10.1 (7.7, 12.7) 11.2 (7, 14.1) 0.85 (Ϫ2.2, 5.1) .31
Platelets, ϫ 1000/L 14 115 (16, 347) 206 (21, 477) 71 (Ϫ103, 244) .02
hIL-6, pg/mL* 13 17.9 (2.1, 171.5) 5.8 (1.8, 192.2) Ϫ5.4 (84.2, Ϫ123.7) .027
IL-10, pg/mL 13 617 (5.6, 573 925) 22.8 (1.7, 38 875) Ϫ283 (33 000, Ϫ573,872) .0002
KSHV viral load, copies/106 PBMCs 13 17 637 (0, 3.9 million) 231 (0, 2.4 million) Ϫ9787 (2.3 million, Ϫ2.8 million) .021
Matched comparisons were performed using an exact Wilcoxon signed-rank test, using log10 transformation for hIL-6, IL-10, and KSHV viral load. Values for hIL-6, IL10,
and KSHV viral load include only the 13 patients evaluable at both baseline and time of best clinical response.
*Using this assay, the mean serum hIL-6 level in healthy donors is 2.3 pg/mL (SD 1.1 pg/mL).35
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BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26 ZIDOVUDINE ϩ VALGANCICLOVIR FOR CASTLEMAN DISEASE 6983
Figure 3. Changes in C-reactive protein and viral IL-6 in patients with symptomatic KSHV-MCD from baseline to time of best clinical response. Wilcoxon
matched-pair signed-rank test comparing changes from baseline laboratories to a time point of best clinical response is performed on all evaluable patients (14 patients
evaluable for CRP, 12 patients evaluable for vIL-6) and then repeated with exclusion of 1 patient whose assessment was confounded by development endocarditis *(f----f) in
(A) C-reactive protein (mg/dL), (P ϭ .0085, *P ϭ .0002) and (B) vIL-6 (pg/mL; not significant). In 6 patients, vIL-6 was undetectable both at baseline and time of best clinical response.
and KSHV viral load (median increase, 91 043 copies/106 PBMCs; through their activation of AZT and ganciclovir to toxic moieties.
range, 1600-297 830 copies/106 PBMCs). However, these drugs may have other effects on the KSHV life
cycle contributing to clinical activity. In particular, ganciclovir can
Toxicities
inhibit KSHV replication,36,37 and VGC alone has been reported to
Principal toxicities possibly, probably, or definitely attributable to reduce the frequency of flares or induce a remission in 3 patients
AZT/VGC are outlined in Table 5 and were mainly hematologic. with KSHV-MCD.17 This raises the possibility that the results seen
Anemia, thrombocytopenia, and neutropenia were observed, al- are in part related to the ability of VGC to block KSHV replication.
though the contribution of drugs to these abnormalities was often Through its antiviral effect, ganciclovir can reduce KSHV spread to
difficult to separate from underlying MCD. In total, 4 major new cells, and this may contribute to its clinical activity in
infections were noted: 1 patient developed both a catheter-related KSHV-MCD. However, for cells already infected with KSHV,
urinary tract infection and Clostridium difficile colitis, 1 developed ganciclovir blocks a relatively late step in the KSHV lytic cycle and
group G Streptococcus endocarditis while neutropenic and receiv- thus would not be expected to suppress expression of vIL-6.38,39 In
ing high-dose dexamethasone, and 1 patient developed pneumococ- addition, cidofovir, another antiviral drug with activity against
cal sepsis. This latter patient refused therapy for his sepsis and died KSHV, has not been found to have utility in KSHV-MCD,40
of this complication, which was considered unlikely to be the result suggesting that targeting anti-KSHV replicative activity alone may
of AZT/VGC. In addition, 1 patient had neutropenic fever. No not be sufficient to yield anti-MCD activity. Additional studies are
adverse effect on HIV control was noted, and HIV viral load was needed to sort out these possibilities.
undetectable at the end of therapy in all patients. Fluctuations in Our interest in the cytotoxic use of high-dose AZT in KSHV-
CD4 counts were common in the setting of symptomatic MCD and associated malignancies arose after experience from the initial
were considered unlikely to be the result of AZT/VGC. phase 1 trial of study of AZT raised the possibility that very
high-dose AZT may have activity in KS. In this study of patients
with AIDS or symptomatic HIV infection, 4 of 9 patients with KS
Discussion had major responses (3 partial, 1 complete).41,42 KS patients who
responded all received very high doses of AZT, 30 mg/kg per day
This study provides evidence that high-dose AZT/VGC has or more. After the discovery of KSHV,3 a virally encoded
activity in patients with symptomatic KSHV-MCD. Twelve of thymidine kinase that efficiently phosphorylates AZT, ORF21, was
14 patients had a substantial clinical improvement meeting described.27 AZT at a dose of 10 m/L induces cell toxicity in PEL
criteria for major clinical response, and 7 met criteria for a cells induced to lytic KSHV activation; such AZT levels are
major biochemical response. Patients had improvement in attained with an intravenous dose of 5 mg/kg.25,43 One hypothesis
circulating levels of hIL-6, vIL-6, KSHV viral load, and other is that the KS responses that the original AZT trial were at least
parameters related to MCD pathogenesis. It is worth noting that partially the result of KSHV ORF21-induced accumulation of toxic
this pilot study was not randomized and that KSHV-MCD AZT triphosphate, and associated cytotoxic activity in a subset of
symptoms may wax and wane spontaneously. Controlled trials KS tumor cells with lytic KSHV replication. However, we cannot
would be needed to further define the efficacy of AZT/VGC and exclude the possibility that the KS responses in that study were
compare it with other approaches. Nonetheless, comparison related to control of HIV viremia and resulting enhanced immune
with studies of the natural history of KSHV-MCD1,2,15 as well as function, as is currently observed in some patients receiving
the temporal relationship between AZT/VGC administration and HAART.44,45
symptom improvement provides evidence that responses ob- The finding that decreases in hIL-6 and KSHV viral load
served in the patients in this study were largely a result of paralleled clinical improvement in patients treated with AZT/
administered therapy. VGC is consistent with the current understanding that KSHV
The rationale for this regimen is to selectively target MCD- activation, and KSHV-induced cytokine dysregulation, contrib-
KSHV cells expressing KSHV lytic genes (ORF21 and ORF36) uted to the pathogenesis of KSHV-MCD.14,31,46,47 Only a subset
9. From bloodjournal.hematologylibrary.org by guest on August 8, 2012. For personal use only.
6984 ULDRICK et al BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26
Table 5. Select event-based toxicities possibly, probably, or definitely attributed to AZT combined with VCG, over a total of 137 cycles
Toxicity Grade 1 Grade 2 Grade 3 Grade 4
Hematologic
Anemia 35 (26) 10 (7) 11 (8) 5 (4)
Thrombocytopenia 14 (10) 4 (3) 4 (3)
Neutropenia 7 (5) 17 (12) 17 (12) 4 (3)
Bleeding 1 (Ͻ 1) — — —
Gastrointestinal
Abdominal pain 7 (5) 1 (Ͻ 1) — —
Anorexia 11 (8) 7 (5) — —
Constipation 4 (3) — — —
Diarrhea 9 (7) — — —
Dysguesia 10 (7) — — —
Mucositis 1 (Ͻ 1) — —
Nausea 15 (11) 4 (3) 1 (Ͻ 1) —
Vomit 5 (4) 3 (2) — —
Major infection/neutropenic fever — 1 (Ͻ 1) 3 (2) —
Metabolic
Elevated alkaline phosphatase 7 (5) — — —
Elevated amylase 5 (4) — — —
Elevated transaminases 8 (6) 1 (Ͻ 1) — —
Elevated bilirubin — 1 (Ͻ 1) — —
Elevated CPK 2 (1) — — —
Neurologic
Headache 5 (4) 2 (1) — —
Neuropathy 5 (4) 2 (1) — —
Insomnia 2 (1) — 1 (Ͻ 1) —
Values are no. (%).
— indicates none observed.
of patients had elevated vIL-6 at entry (most probably because follow-up will be important to establish whether additional KSHV-
of the relative insensitivity of the assay). Despite the inability to MCD directed therapy is needed.
monitor trends in serum vIL-6 Ͻ 1560 pg/mL, in cases where Although this regimen of AZT/VGC appeared to have
serum vIL-6 was detectable, levels decreased in parallel with the activity in KSHV-MCD, there were limitations. Patients with
improvement in clinical symptoms and increased with worsen- severe KSHV-MCD symptoms, advanced KS, or concurrent
ing inflammatory symptoms, consistent with an important role lymphoma were treated with alternative approaches, and the
for vIL-6 in KSHV-MCD. Serum IL-10, which can be up- response rates observed cannot be extrapolated to these groups.
regulated by KSHV miR-K12-7,48 also paralleled symptomatol- In patients treated with AZT/VGC, median progression-free
ogy in patients receiving AZT/VGC. survival was 6 months, and 8 patients who initially responded
Estimated overall survival of study subjects was 86% at the had subsequent relapses. Higher doses of AZT, up to 90 mg/kg
end of 4 years. As noted, a number of patients received per day orally, were administered on the initial phase 1 trial of
additional therapies. Nonetheless, these results demonstrate AZT,41,42,49 and regimens using higher drug doses could have
that, with available therapies for KSHV-MCD, overall survival greater activity. In addition, latently infected cells that do not
can be substantially better than the 2-year survival reported express ORF21 and ORF36 would not be expected to respond to
previously.1 Furthermore, in 3 of 14 patients, we attained an virus-activated cytoxic therapy, and continuous AZT/VGC
overall complete response with AZT/VGC, and patients subse- might possibly have a greater cytotoxic effect by targeting
quently remained symptom-free for up to 33 months after KSHV-infected cells as they become lytically active. However,
stopping therapy. In these 3 patients, there were incremental either of these changes in AZT/VGC administration would have
decreases in biochemical disease parameters over time. Interest- to be balanced against toxicity. Alternatively, intermittent
ingly, PBMC-associated KSHV was often still detectable in AZT/VGC could be combined with other therapies, such as
patients when they first attained their best clinical response, and rituximab, in KSHV-MCD, or used to consolidate responses
in patients who went on to durable remission, this only became after other therapies have been used in the acute flares.
undetectable after approximately 1 year of cyclic therapy. These Presently, there are no accepted response criteria for MCD. We
observations suggest that AZT/VGC, in the dose schedule used developed specific response criteria both to more precisely define
here, can diminish the burden of KSHV-infected MCD plasma- the responses to therapy and evaluate the utility of the proposed
blasts but that this process occurs at a relatively slow rate. criteria. Initially proposed biochemical criteria were unwieldy, and
AZT/VGC would only be anticipated to have direct cytotoxic based on preliminary experience, were revised to simplify the
effects in cells expressing KSHV lytic genes ORF21 and/or biochemical criteria (Table 2). The revised criteria could be easily
ORF36; and because many MCD plasmablastic cells that implemented, rely on commonly used laboratory and imaging
express vIL-6 do not have full lytic KSHV gene expression, we studies, and were consistent with our general clinical impressions.
thought it unlikely to be curative for MCD when we initiated the Interestingly, the radiographic responses using these criteria often
study. Nonetheless, our results indicate that certain patients with lagged behind the biochemical and clinical responses. Moreover,
KSHV-MCD may be able to attain lasting remissions after several the 3 patients who attained complete overall responses (including
months of AZT/VCG therapy and continued cART. Long-term radiographic responses) remained relapse-free off KSHV-MCD
10. From bloodjournal.hematologylibrary.org by guest on August 8, 2012. For personal use only.
BLOOD, 30 JUNE 2011 ⅐ VOLUME 117, NUMBER 26 ZIDOVUDINE ϩ VALGANCICLOVIR FOR CASTLEMAN DISEASE 6985
therapy during up to 33 months of observation. Harmonization of the Medical Oncology Branch, the Metabolism Branch, the
KSHV-MCD response criteria across studies is desirable, and our National Institutes of Health Clinical Center, and the AIDS
observations suggest that a modified version of the proposed Monitoring Laboratory.
criteria that emphasizes clinical symptoms and select widely This work was supported in part by the Intramural Research
available biochemical measures (ie, CRP, platelets, hemoglobin, Program of the National Institutes of Health, National Cancer
and albumin) may be useful in the assessment of KSHV-MCD in Institute as well as the National Cancer Institute, National Institutes
both clinical and research settings. It is not clear if persistent of Health (contract HHSN261200800001E).
lympadenopathy and/or splenomegaly after clinical and biochemi-
cal responses represent residual KSHV-MCD or persistent reactive
lymphoid hyperplasia, and novel imaging techniques that use
radiopharmaceutical agents specific to herpesvirus-infected cells Authorship
are of interest in this regard.50
In conclusion, this study provides evidence that AZT/VGC has Contribution: T.S.U., R.F.L., and R.Y. designed the study; T.S.U.,
activity in the treatment of KSHV-MCD. It supports the paradigm M.N.P., K.A., D.O., K.M.W., R.F.L., and R.Y. cared for the
that lytically active KSHV-infected cells are important in disease patients; T.S.U., M.N.P., D.O., K.A., K.M.W., S.P., R.F.L., and R.Y.
pathophysiology and that KSHV lytic genes can be used to collected data; V.W., G.T., and R.Y. developed and performed
selectively target KSHV-infected plasmablasts in this rare lym- vIL-6 assay; V.M. and D.W. developed and performed KSHV viral
phoproliferative disorder. Nonetheless, AZT/VGC has limitations, load assays; T.S.U., S.M.S., and R.Y. analyzed data; and T.S.U. and
and it will be important to consider strategies to optimize this R.Y. wrote the manuscript.
approach or its use in combination with other therapies for Conflict-of-interest disclosure: G.T. is a coinventor on a
KSHV-MCD. Evaluation of additional cytotoxic approaches specifi- patent describing the measurement of KSHV vIL-6. This
cally targeting cells expressing KSHV lytic genes appears war- invention was made when G.T. was an employee of the US
ranted in KSHV-MCD.51 As our understanding of this rare disease Government under 45 Code of Federal Regulations Part 7. All
continues to improve, durable remissions for the majority of rights, title, and interest to this patent have been assigned to the
HIV-infected patients with KSHV-MCD obtained through the use US Department of Health and Human Services. The government
of targeted therapy appear to be an attainable goal. conveys a portion of the royalties it receives to its employee
inventors under the Federal Technology Transfer Act of 1986
(PL 99-502). R.Y. is the spouse of G.T. The remaining authors
Acknowledgments declare no competing financial interests.
Correspondence: RobertYarchoan, HIV &AIDS Malignancy Branch,
The authors thank the patients who participated in this study as Center for Cancer Research, NCI, 10 Center Dr, Rm 6N106, MSC 1868,
well as clinical staff of the HIV and AIDS Malignancy Branch, Bethesda, MD 20892-1868; e-mail: yarchoan@helix.nih.gov.
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