This clinical article examines whether treatment-induced changes in bone marrow, as measured by changes in peripheral blood cell counts, can serve as a potential biomarker for outcomes in glioblastoma patients treated with radiation therapy and temozolomide (TMZ). The study retrospectively analyzed complete blood counts and clinical/imaging data from 86 glioblastoma patients who completed radiation therapy and at least 6 cycles of TMZ chemotherapy. The results showed that decreases in white blood cell counts over 6 months of TMZ treatment were associated with improved overall survival. Specifically, the 2-year survival rate was 25% for patients with increased white blood cell counts versus 58% for patients with decreased counts. Additionally, consistent with previous literature, IDH mutation
The document discusses the EGFR pathway in colorectal cancer. It notes that EGFR is overexpressed in 25-82% of colorectal cancers and is involved in cell proliferation pathways. While EGFR overexpression is sometimes associated with worse outcomes, the significance is unclear due to inconsistent measurement methods. Anti-EGFR therapies like cetuximab show promise for colorectal cancer, but EGFR expression levels alone do not predict response to treatment. EGFR gene amplification analysis is also an uncertain prognostic indicator due to varying definitions and guidelines. Overall the role of EGFR in colorectal cancer requires further standardized research.
Chemoprevention seeks to use natural, synthetic, or biological agents to prevent cancer development and progression. It can involve blocking cancer initiation through agents that prevent DNA damage from carcinogens. It can also suppress promotion and progression of initiated cells through inhibition of signal transduction pathways. The FDA has approved selective estrogen receptor modulators like tamoxifen and raloxifene for breast cancer chemoprevention and aspirin use has been associated with reduced colorectal cancer risk. However, some agents like beta-carotene and retinoids have been found to increase cancer risk in smokers.
The document discusses treatment options for patients with relapsed myeloma. It provides details on current treatment goals, classes of drugs used to treat relapsed myeloma, and clinical trial data on combinations of these drugs. Specifically, it summarizes clinical trial results showing improved progression-free and overall survival for combinations of bortezomib, lenalidomide, and dexamethasone compared to dexamethasone alone in relapsed patients. It also discusses factors to consider when selecting a salvage therapy for relapsed myeloma, including disease characteristics, prior treatments, and toxicity risks.
This document summarizes key findings from several studies related to acute myeloid leukemia (AML) in elderly patients:
1) A phase 3 trial found that azacitidine extended overall survival compared to conventional care regimens in older patients with newly diagnosed AML, with median OS of 10.4 months for azacitidine vs 6.5 months for conventional care.
2) Subanalyses found azacitidine provided particularly long OS benefits vs conventional care for patients with poor-risk cytogenetics (median OS 6.4 vs 3.2 months) or myelodysplasia-related changes (1-year OS 55.1% vs 31.3% for LDAC preselected
This document discusses the toxicities of targeted cancer therapies. It begins by defining targeted therapy and describing the ideal features of an anticancer target. It then outlines several common toxicities of targeted therapies including cardiovascular issues like hypertension and ventricular dysfunction, QTc prolongation, thromboembolic complications, and various skin toxicities. Specific mechanisms, risk factors, management strategies, and monitoring approaches are described for each toxicity.
Pharmacogenomics uses a patient's genetic profile to select optimal drug therapies and dosages. Gene polymorphisms like substitutions, deletions and insertions can affect drug efficacy and toxicity. Biomarkers can help predict cancer prognosis and treatment response. For example, EGFR mutations predict response to EGFR inhibitors in NSCLC, while BRAF mutations indicate response to BRAF inhibitors in melanoma. Resistance often develops from additional mutations that prevent drug binding. Combination therapies can overcome resistance by targeting alternate pathways.
The document discusses the EGFR pathway in colorectal cancer. It notes that EGFR is overexpressed in 25-82% of colorectal cancers and is involved in cell proliferation pathways. While EGFR overexpression is sometimes associated with worse outcomes, the significance is unclear due to inconsistent measurement methods. Anti-EGFR therapies like cetuximab show promise for colorectal cancer, but EGFR expression levels alone do not predict response to treatment. EGFR gene amplification analysis is also an uncertain prognostic indicator due to varying definitions and guidelines. Overall the role of EGFR in colorectal cancer requires further standardized research.
Chemoprevention seeks to use natural, synthetic, or biological agents to prevent cancer development and progression. It can involve blocking cancer initiation through agents that prevent DNA damage from carcinogens. It can also suppress promotion and progression of initiated cells through inhibition of signal transduction pathways. The FDA has approved selective estrogen receptor modulators like tamoxifen and raloxifene for breast cancer chemoprevention and aspirin use has been associated with reduced colorectal cancer risk. However, some agents like beta-carotene and retinoids have been found to increase cancer risk in smokers.
The document discusses treatment options for patients with relapsed myeloma. It provides details on current treatment goals, classes of drugs used to treat relapsed myeloma, and clinical trial data on combinations of these drugs. Specifically, it summarizes clinical trial results showing improved progression-free and overall survival for combinations of bortezomib, lenalidomide, and dexamethasone compared to dexamethasone alone in relapsed patients. It also discusses factors to consider when selecting a salvage therapy for relapsed myeloma, including disease characteristics, prior treatments, and toxicity risks.
This document summarizes key findings from several studies related to acute myeloid leukemia (AML) in elderly patients:
1) A phase 3 trial found that azacitidine extended overall survival compared to conventional care regimens in older patients with newly diagnosed AML, with median OS of 10.4 months for azacitidine vs 6.5 months for conventional care.
2) Subanalyses found azacitidine provided particularly long OS benefits vs conventional care for patients with poor-risk cytogenetics (median OS 6.4 vs 3.2 months) or myelodysplasia-related changes (1-year OS 55.1% vs 31.3% for LDAC preselected
This document discusses the toxicities of targeted cancer therapies. It begins by defining targeted therapy and describing the ideal features of an anticancer target. It then outlines several common toxicities of targeted therapies including cardiovascular issues like hypertension and ventricular dysfunction, QTc prolongation, thromboembolic complications, and various skin toxicities. Specific mechanisms, risk factors, management strategies, and monitoring approaches are described for each toxicity.
Pharmacogenomics uses a patient's genetic profile to select optimal drug therapies and dosages. Gene polymorphisms like substitutions, deletions and insertions can affect drug efficacy and toxicity. Biomarkers can help predict cancer prognosis and treatment response. For example, EGFR mutations predict response to EGFR inhibitors in NSCLC, while BRAF mutations indicate response to BRAF inhibitors in melanoma. Resistance often develops from additional mutations that prevent drug binding. Combination therapies can overcome resistance by targeting alternate pathways.
This document discusses whether patients with refractory anemia with excess blasts (RAEB) or oligoblastic acute myeloid leukemia (AML) should receive induction chemotherapy prior to allogeneic stem cell transplantation. While historically it was believed that less disease is better for transplantation, recent retrospective studies have found no benefit and potential harms to giving chemotherapy induction prior to transplant. Hypomethylating agents are a less toxic alternative to reduce disease burden before transplant. The conclusion is that for MDS and oligoblastic AML, allogeneic transplant is the most curative option and induction chemotherapy before transplant has not been shown to improve outcomes, so patients should proceed directly to transplantation.
Multidisciplinary approach to the management of leukemias amlmadurai
The document discusses the multidisciplinary approach to managing leukemias like AML and MDS. It presents the case of a 68-year old male patient presenting with fever and fatigue, and details the diagnostic workup showing features consistent with acute myeloid leukemia. The document then reviews classification, prognostic factors, recent treatment trials, and the role of allogeneic stem cell transplantation for AML patients.
1) Current chemotherapy combinations for relapsed AML such as MEC (mitoxantrone, etoposide, cytarabine) and FLAG (fludarabine, cytarabine, G-CSF) produce overall response rates of 40-60% but have not been shown to be clearly superior to one another.
2) Single agent therapies approved for relapsed AML include hypomethylating agents, immunomodulatory drugs, and targeted therapies but have shown limited and disappointing efficacy as single agents.
3) Clofarabine has shown efficacy in combinations with cytarabine for relapsed AML, with complete response rates as high as 50% in some studies
Jubair, a 12-year-old boy, was admitted with fever, pallor, blackish spots on the body, gum bleeding, and blood in stool. Examination found pallor, gum swelling, and enlarged liver and spleen. Tests showed low blood cell counts, elevated D-dimer and fibrinogen levels. Bone marrow biopsy found 60% promyelocytes. Immunophenotyping and genetic testing confirmed the diagnosis of acute promyelocytic leukemia (APL). APL is a type of acute myeloid leukemia characterized by a genetic mutation and abnormal promyelocytes. It requires emergent treatment including all-trans retinoic acid (ATRA) to induce differentiation and prevent potentially fatal
Carlos E. Bueso-Ramos, MD, PhD, and Naval Daver, MD, prepared useful practice aids pertaining to AML for this CME/MOC/CC activity titled Pathology Insights on Innovation in AML: The Rapid Emergence of Precision Diagnostics & Novel Therapy Across the Spectrum of Care. For the full presentation, monograph, complete CME/MOC/CC information, and to apply for credit, please visit us at http://bit.ly/2mhXbz6. CME/MOC/CC credit will be available until October 27, 2020.
This document provides information about Dr. Jason Westin, an assistant professor at MD Anderson Cancer Center whose research focuses on improving therapy and outcomes for patients with lymphoma. His specific research interests include diffuse large B-cell lymphoma, developing systems to identify optimal therapeutic combinations for individual patients, drug synergy and antagonism, scale free networks in cancer therapy, and developing sensitive disease monitoring methods. The document also summarizes several of Dr. Westin's presentations on novel targeted therapies in T-cell lymphoma from 2014, including studies on drugs such as brentuximab, mogamulizumab, lenalidomide, alisertib, selinexor, romidepsin, panobinostat, and inhibitors of the
Should patients with refractory anemia with excess blasts or those with oligoblastic AML receive induction therapy prior to allogeneic transplantation?
Yes: Suporn Chancharunee, MD
No: Nina Shah, MD
Mechanism of resistance to target therapyVito Lorusso
1. The document discusses resistance mechanisms to targeted kinase inhibitors (TKI) in metastatic renal cell carcinoma (mRCC).
2. Primary resistance is defined as a lack of response from the start of TKI therapy, while secondary resistance arises after an initial response followed by disease progression. Mechanisms of primary resistance include alternative pro-angiogenic pathways and non-angiogenic tumor growth.
3. Secondary resistance mechanisms include a new angiogenic wave induced by hypoxia, epithelial-to-mesenchymal transition, intratumoral heterogeneity, and gene mutations. Overcoming resistance may involve using non cross-resistant drugs that target pathways driving resistance.
Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer that has spread to other organs and continues to progress despite hormone therapy. Current treatments aim to reduce testosterone levels, disrupt microtubules during cell division, activate the immune system, or use radiopharmaceuticals, but all have limitations like toxicity or development of resistance. Researchers are exploring new targets and combinations of drugs to block cancer progression and prolong survival for men with mCRPC, which remains largely incurable.
Effects and outcome of a policy of intermittent Imatinib treatment in elderly...Mohsin Maqbool
This study evaluated a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. 76 patients in complete cytogenetic response on stable imatinib therapy for over 2 years were given intermittent imatinib treatment, with 1 month on and 1 month off initially, extending to longer periods off over time. The majority maintained cytogenetic and molecular responses on this intermittent schedule, with 13% losing responses and resuming daily imatinib to regain responses. No patients progressed to advanced phases of disease. Intermittent imatinib treatment appeared to maintain responses in the majority without affecting long term outcomes.
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTSspa718
This document summarizes treatment approaches for non-Hodgkin's lymphoma in elderly patients. It discusses palliative options for refractory/relapsed diffuse large B-cell lymphoma such as gemcitabine-based chemotherapy, low-dose oral chemotherapy, and hyperfractionated cyclophosphamide. It also reviews novel anti-CD20 monoclonal antibodies showing efficacy against relapsed/refractory indolent lymphoma, and brentuximab vedotin's mechanism of action and responses seen in relapsed/refractory systemic anaplastic large cell lymphoma. Finally, it provides a high-level overview of the MD Anderson Cancer Center's Department of Lymphoma/Myeloma and its disease-specific
This document summarizes a systematic review and meta-analysis that evaluated the prognostic impact of microRNAs (miRNAs) in patients with T cell acute lymphoblastic leukemia (T-ALL). Seventeen studies were included in the systematic review and sixteen were included in the meta-analysis. The meta-analysis found that overall miRNA expression was associated with a decreased risk of death by 7.1% in T-ALL patients. Upregulated miRNA expressions were associated with lower risk of death while downregulated expressions were associated with higher risk of death. The findings suggest that miRNA expression may help prognostic evaluation in T-ALL patients, although results were inconclusive.
This document discusses the importance of cancer biomarkers for selecting effective targeted drug therapies. It provides examples of predictive biomarkers such as BCR-ABL for CML treated with tyrosine kinase inhibitors, EGFR mutations for NSCLC treated with EGFR inhibitors, and HER2 overexpression for breast cancer treated with trastuzumab. The use of predictive biomarkers can help personalize cancer treatment by identifying patients most likely to respond to a specific drug and avoid unnecessary toxicity for those who will not benefit.
1) Hematopoietic stem cell transplantation (HSCT) can cure thalassemia patients by replacing defective bone marrow with healthy donor marrow.
2) A study of 98 thalassemia patients who received HSCT found that 94% survived with a novel reduced toxicity conditioning regimen having similar outcomes as standard regimens.
3) HSCT can cure thalassemia patients of all ages, including those over 10 years old, with survival rates over 90% found in the study. Gene therapy may also provide a cure in the future without requiring donors.
Recent trends in genomic biomarkers pepgra healthcarePEPGRA Healthcare
Cardiovascular disease is a significant health concern worldwide despite having many genomics developments providing valuable new candidates for better biomarkers and novel therapeutic targets. The main integration of new technologies promises the discovery and validation of better biomarkers of the presence of cardio disease, its progression, and the response to treatment in this blog. Some of the features are:
1. Analyzing the Gene expression
2. Genome-wide association studies
3. Linkage analysis
4. Wrapping up...
Continue Reading: http://bit.ly/3bqq3Np
Contact us:
UK: +44-1143520021
US/Canada: +1-972-502-9262
India: +91-9884350006
Email id: sales.cro@pepgra.com
Website: www.pepgra.com
Acquired Resistance to Targeted Therapy in EGFR and ALK-Positive Lung Cancer:...H. Jack West
This is a presentation I did for a meeting on new general management of acquired resistance in 2014, including the concept of local therapy for limited progression, and new treatment approaches and new agents for this setting. It features discussion of several of the most important trials.
Metronomic chemotherapy involves the chronic administration of chemotherapy drugs at low, minimally toxic doses on a frequent schedule with no prolonged breaks. This strategy aims to control cancer by targeting tumor vasculature and is an attractive option in resource-limited areas due to its low cost, oral administration, and minimal side effects compared to conventional chemotherapy. Combining metronomic chemotherapy with drug repositioning and targeted therapies may lead to improved cancer control through multi-pronged effects on cancer cells, vasculature, and the immune system. However, determining the optimal biological dose and identifying surrogate markers pose challenges to realizing the full potential of this approach.
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...JohnJulie1
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...EditorSara
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
This document discusses whether patients with refractory anemia with excess blasts (RAEB) or oligoblastic acute myeloid leukemia (AML) should receive induction chemotherapy prior to allogeneic stem cell transplantation. While historically it was believed that less disease is better for transplantation, recent retrospective studies have found no benefit and potential harms to giving chemotherapy induction prior to transplant. Hypomethylating agents are a less toxic alternative to reduce disease burden before transplant. The conclusion is that for MDS and oligoblastic AML, allogeneic transplant is the most curative option and induction chemotherapy before transplant has not been shown to improve outcomes, so patients should proceed directly to transplantation.
Multidisciplinary approach to the management of leukemias amlmadurai
The document discusses the multidisciplinary approach to managing leukemias like AML and MDS. It presents the case of a 68-year old male patient presenting with fever and fatigue, and details the diagnostic workup showing features consistent with acute myeloid leukemia. The document then reviews classification, prognostic factors, recent treatment trials, and the role of allogeneic stem cell transplantation for AML patients.
1) Current chemotherapy combinations for relapsed AML such as MEC (mitoxantrone, etoposide, cytarabine) and FLAG (fludarabine, cytarabine, G-CSF) produce overall response rates of 40-60% but have not been shown to be clearly superior to one another.
2) Single agent therapies approved for relapsed AML include hypomethylating agents, immunomodulatory drugs, and targeted therapies but have shown limited and disappointing efficacy as single agents.
3) Clofarabine has shown efficacy in combinations with cytarabine for relapsed AML, with complete response rates as high as 50% in some studies
Jubair, a 12-year-old boy, was admitted with fever, pallor, blackish spots on the body, gum bleeding, and blood in stool. Examination found pallor, gum swelling, and enlarged liver and spleen. Tests showed low blood cell counts, elevated D-dimer and fibrinogen levels. Bone marrow biopsy found 60% promyelocytes. Immunophenotyping and genetic testing confirmed the diagnosis of acute promyelocytic leukemia (APL). APL is a type of acute myeloid leukemia characterized by a genetic mutation and abnormal promyelocytes. It requires emergent treatment including all-trans retinoic acid (ATRA) to induce differentiation and prevent potentially fatal
Carlos E. Bueso-Ramos, MD, PhD, and Naval Daver, MD, prepared useful practice aids pertaining to AML for this CME/MOC/CC activity titled Pathology Insights on Innovation in AML: The Rapid Emergence of Precision Diagnostics & Novel Therapy Across the Spectrum of Care. For the full presentation, monograph, complete CME/MOC/CC information, and to apply for credit, please visit us at http://bit.ly/2mhXbz6. CME/MOC/CC credit will be available until October 27, 2020.
This document provides information about Dr. Jason Westin, an assistant professor at MD Anderson Cancer Center whose research focuses on improving therapy and outcomes for patients with lymphoma. His specific research interests include diffuse large B-cell lymphoma, developing systems to identify optimal therapeutic combinations for individual patients, drug synergy and antagonism, scale free networks in cancer therapy, and developing sensitive disease monitoring methods. The document also summarizes several of Dr. Westin's presentations on novel targeted therapies in T-cell lymphoma from 2014, including studies on drugs such as brentuximab, mogamulizumab, lenalidomide, alisertib, selinexor, romidepsin, panobinostat, and inhibitors of the
Should patients with refractory anemia with excess blasts or those with oligoblastic AML receive induction therapy prior to allogeneic transplantation?
Yes: Suporn Chancharunee, MD
No: Nina Shah, MD
Mechanism of resistance to target therapyVito Lorusso
1. The document discusses resistance mechanisms to targeted kinase inhibitors (TKI) in metastatic renal cell carcinoma (mRCC).
2. Primary resistance is defined as a lack of response from the start of TKI therapy, while secondary resistance arises after an initial response followed by disease progression. Mechanisms of primary resistance include alternative pro-angiogenic pathways and non-angiogenic tumor growth.
3. Secondary resistance mechanisms include a new angiogenic wave induced by hypoxia, epithelial-to-mesenchymal transition, intratumoral heterogeneity, and gene mutations. Overcoming resistance may involve using non cross-resistant drugs that target pathways driving resistance.
Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer that has spread to other organs and continues to progress despite hormone therapy. Current treatments aim to reduce testosterone levels, disrupt microtubules during cell division, activate the immune system, or use radiopharmaceuticals, but all have limitations like toxicity or development of resistance. Researchers are exploring new targets and combinations of drugs to block cancer progression and prolong survival for men with mCRPC, which remains largely incurable.
Effects and outcome of a policy of intermittent Imatinib treatment in elderly...Mohsin Maqbool
This study evaluated a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. 76 patients in complete cytogenetic response on stable imatinib therapy for over 2 years were given intermittent imatinib treatment, with 1 month on and 1 month off initially, extending to longer periods off over time. The majority maintained cytogenetic and molecular responses on this intermittent schedule, with 13% losing responses and resuming daily imatinib to regain responses. No patients progressed to advanced phases of disease. Intermittent imatinib treatment appeared to maintain responses in the majority without affecting long term outcomes.
TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTSspa718
This document summarizes treatment approaches for non-Hodgkin's lymphoma in elderly patients. It discusses palliative options for refractory/relapsed diffuse large B-cell lymphoma such as gemcitabine-based chemotherapy, low-dose oral chemotherapy, and hyperfractionated cyclophosphamide. It also reviews novel anti-CD20 monoclonal antibodies showing efficacy against relapsed/refractory indolent lymphoma, and brentuximab vedotin's mechanism of action and responses seen in relapsed/refractory systemic anaplastic large cell lymphoma. Finally, it provides a high-level overview of the MD Anderson Cancer Center's Department of Lymphoma/Myeloma and its disease-specific
This document summarizes a systematic review and meta-analysis that evaluated the prognostic impact of microRNAs (miRNAs) in patients with T cell acute lymphoblastic leukemia (T-ALL). Seventeen studies were included in the systematic review and sixteen were included in the meta-analysis. The meta-analysis found that overall miRNA expression was associated with a decreased risk of death by 7.1% in T-ALL patients. Upregulated miRNA expressions were associated with lower risk of death while downregulated expressions were associated with higher risk of death. The findings suggest that miRNA expression may help prognostic evaluation in T-ALL patients, although results were inconclusive.
This document discusses the importance of cancer biomarkers for selecting effective targeted drug therapies. It provides examples of predictive biomarkers such as BCR-ABL for CML treated with tyrosine kinase inhibitors, EGFR mutations for NSCLC treated with EGFR inhibitors, and HER2 overexpression for breast cancer treated with trastuzumab. The use of predictive biomarkers can help personalize cancer treatment by identifying patients most likely to respond to a specific drug and avoid unnecessary toxicity for those who will not benefit.
1) Hematopoietic stem cell transplantation (HSCT) can cure thalassemia patients by replacing defective bone marrow with healthy donor marrow.
2) A study of 98 thalassemia patients who received HSCT found that 94% survived with a novel reduced toxicity conditioning regimen having similar outcomes as standard regimens.
3) HSCT can cure thalassemia patients of all ages, including those over 10 years old, with survival rates over 90% found in the study. Gene therapy may also provide a cure in the future without requiring donors.
Recent trends in genomic biomarkers pepgra healthcarePEPGRA Healthcare
Cardiovascular disease is a significant health concern worldwide despite having many genomics developments providing valuable new candidates for better biomarkers and novel therapeutic targets. The main integration of new technologies promises the discovery and validation of better biomarkers of the presence of cardio disease, its progression, and the response to treatment in this blog. Some of the features are:
1. Analyzing the Gene expression
2. Genome-wide association studies
3. Linkage analysis
4. Wrapping up...
Continue Reading: http://bit.ly/3bqq3Np
Contact us:
UK: +44-1143520021
US/Canada: +1-972-502-9262
India: +91-9884350006
Email id: sales.cro@pepgra.com
Website: www.pepgra.com
Acquired Resistance to Targeted Therapy in EGFR and ALK-Positive Lung Cancer:...H. Jack West
This is a presentation I did for a meeting on new general management of acquired resistance in 2014, including the concept of local therapy for limited progression, and new treatment approaches and new agents for this setting. It features discussion of several of the most important trials.
Metronomic chemotherapy involves the chronic administration of chemotherapy drugs at low, minimally toxic doses on a frequent schedule with no prolonged breaks. This strategy aims to control cancer by targeting tumor vasculature and is an attractive option in resource-limited areas due to its low cost, oral administration, and minimal side effects compared to conventional chemotherapy. Combining metronomic chemotherapy with drug repositioning and targeted therapies may lead to improved cancer control through multi-pronged effects on cancer cells, vasculature, and the immune system. However, determining the optimal biological dose and identifying surrogate markers pose challenges to realizing the full potential of this approach.
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...JohnJulie1
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...EditorSara
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...EditorSara
This study aimed to investigate the correlation between the expression of P4HB and GRP78 proteins and their prognostic value in gastric cancer. The study found that P4HB protein expression was positively correlated with GRP78 protein expression in gastric cancer tissue samples. High expression of either P4HB or GRP78 alone, or co-expression of both, was associated with poorer overall survival in patients. When considering postoperative adjuvant chemotherapy, high co-expression of P4HB and GRP78 only represented an unfavorable prognosis in patients who received chemotherapy. A prognostic nomogram incorporating P4HB and GRP78 expression and other factors was developed and found to have better predictive performance than the TNM staging system.
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...NainaAnon
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
It is important to note that standard cancer treatments (surgery, chemo/radiation) can always be optimized and improved and many examples exist of life enhancing advancements for almost every type of cancer.
This document summarizes a presentation on the management of metastatic colorectal cancer (mCRC) in 2017. It discusses several key points:
1) Patient stratification is important in determining treatment approach for mCRC, taking into account factors like disease extent and symptoms.
2) A multidisciplinary team approach is mandatory for developing optimal treatment plans.
3) Assessment of predictive biomarkers like RAS mutations helps determine which first-line treatments may be most effective.
4) Tumor location (right vs left-sided colon cancer) can impact treatment outcomes and response to certain drugs like anti-EGFR therapies.
5) Multiple clinical trials over time have led to improved survival outcomes and more
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...daranisaha
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...eshaasini
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...semualkaira
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...semualkaira
: Prolyl 4-hydroxylase, beta polypeptide (P4HB)
and Glucose‑regulated protein 78 (GRP78) represent for poor
prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer
This document discusses tumor cell proliferation and immunotherapy for cancers. It provides details on the cell cycle phases (M, G1, S, G2, G0) and how they relate to tumor growth and response to treatment. It also discusses cell kinetics, the growth fraction, and cancer stem cells. Targeted therapies discussed include those that inhibit angiogenesis by targeting VEGF, as well as EGFR inhibitors. Bevacizumab is highlighted as an anti-angiogenic therapy shown to improve outcomes for ovarian cancer both as a single agent and in combination with other drugs.
Precision medicine is a rapidly growing field of medicine that proposes individually customized diagnostics and therapeutics based upon molecular and genetic profile of individual patients. The main goal of precision medicine is to minimize harmful side effects and maximize benefits. In particular, hematological malignancies were seen as the most direct candidates of the most promising applications of precision medicine. However, Precision medicine approaches face multiple challenges. Despite these challenges and limitations, continuous effort is carried out to use these molecular findings as disease biomarkers and targets for therapeutic intervention. In the last decade the hemato-oncology witnessed a major revolution in the understanding of the molecular pathogenesis of hematological malignancies. While the therapeutic research for hematologic malignancies is continuously expanding, some medicines have been approved in hematological malignancies patients’ therapeutic algorithm and many are still under investigation.
Bridging the Gap in Personalized Oncology using Omics Data and Epidemiology_C...CrimsonpublishersCancer
This document discusses advances in personalized oncology and challenges in implementing personalized medicine. It reviews how personalized oncology has been applied to several cancers including leukemia, melanoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer using biomarkers and high-throughput technologies. However, challenges remain in integrating omics data with epidemiology to fully realize personalized healthcare. Barriers include the need to analyze large datasets from different sources and effectively translate genomic findings into clinical practice.
The document discusses controversies in the management of low grade gliomas (LGGs). LGGs are the most common primary brain tumors in adults and have better prognosis than high grade gliomas. There is no consensus on the optimal treatment approach due to the lack of well-designed clinical trials. Controversies exist regarding the extent of surgery, use and timing of radiation therapy, and role of chemotherapy. Molecular markers such as IDH1 mutations and 1p/19q codeletions can help stratify patients, but do not definitively guide treatment decisions. Symptom control, observation, surgery, radiation, and chemotherapy are all discussed as potential management strategies, but there is disagreement on their appropriate use.
This document summarizes recent developments in molecular targeted therapies for head and neck cancer. It discusses two primary strategies - blocking EGFR signaling and angiogenesis pathways. Epidermal growth factor receptor (EGFR) is overexpressed in many head and neck cancers and associated with poorer outcomes. Cetuximab, an anti-EGFR monoclonal antibody, has shown efficacy in combination with radiation for locally advanced disease and in extending survival when added to chemotherapy for metastatic disease. Other targeted agents discussed include tyrosine kinase inhibitors and anti-angiogenic drugs.
The survey analyzed treatment patterns for multiple myeloma in Germany between 2008-2011 based on data from 478 patients. Key findings include:
- Bortezomib-chemotherapy regimens are now preferred for first-line treatment regardless of planned autologous stem cell transplantation (ASCT), which was performed in around 30% of eligible patients.
- Thalidomide- and lenalidomide-based therapies are commonly used in the second-line setting in 31% of patients.
- Cytogenetic testing increased from 23% in 2008 to 53% in 2011 and influences treatment decisions, though age and comorbidities remain major factors.
- Supportive care needs decreased
This document reviews current understanding of cellular receptor signaling pathways that interact with estrogen receptors and their role in resistance to endocrine therapy for breast cancer. It discusses how growth factor pathways like HER2, IGF1R, and FGFR interact with and modify estrogen receptor activity through various mechanisms. This crosstalk can lead to downregulation of estrogen receptors, decreased response to estrogen, and development of resistance. The document also reviews clinical trials examining combination therapies that target these pathways in addition to endocrine therapy, with the aim of reducing or reversing resistance.
Sequencing in management of Multiple sclerosisAmr Hassan
Sequencing of DMTs for individual multiple sclerosis patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.
Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multi...CristinaGeorgianaZah
authors:
Christina Peters, MD1; Jean-Hugues Dalle, MD, PhD2; Franco Locatelli, MD, PhD3; Ulrike Poetschger, PhD4; Petr Sedlacek, MD5;
Jochen Buechner, MD, PhD6; Peter J. Shaw, MD7; Raquel Staciuk, MD8; Marianne Ifversen, MD, PhD9; Herbert Pichler, MD1;
Kim Vettenranta, MD, PhD10; Peter Svec, MD, PhD11; Olga Aleinikova, MD, PhD12; Jerry Stein, MD13; Tayfun Gu¨ngo¨ r, MD14;
Jacek Toporski, MD15; Tony H. Truong, MD, MPH16; Cristina Diaz-de-Heredia, MD17; Marc Bierings, MD, PhD18; Hany Ariffin, MD, PhD19;
Mohammed Essa, MD20; Birgit Burkhardt, MD, PhD21; Kirk Schultz, MD22; Roland Meisel, MD23; Arjan Lankester, MD, PhD24;
Marc Ansari, MD25; and Martin Schrappe, MD, PhD,26 on behalf of the IBFM Study Group; Arend von Stackelberg, MD,27 on behalf of the
IntReALL Study Group; Adriana Balduzzi, MD,28 on behalf of the I-BFM SCT Study Group; Selim Corbacioglu, MD,29 on behalf of the
EBMT Paediatric Diseases Working Party; and Peter Bader, MD30
Methotrexate in treatment of rheumatoid arthritisNusrat Fatemee
Methotrexate is considered the first-line treatment for rheumatoid arthritis and has been used to treat the disease since the 1980s. It works by reducing inflammation and immune system activity. While its exact mechanism is unknown, it likely involves effects on T cells, B cells, and cytokines like TNF-α, IL-6, and IL-1. Common side effects include liver and kidney toxicity. Future research seeks to develop targeted drug delivery methods to increase effectiveness and reduce side effects. Methotrexate remains a cornerstone therapy for rheumatoid arthritis treatment.
2. E. J. Vaios et al.
J Neurosurg October 14, 20162
treatment, GBM remains incurable, with a median sur-
vival of less than 19 months and only a 30% probability
of survival 2 years after diagnosis.1,19
The genetic heterogeneity of GBM and the emergence
of various resistance mechanisms are proposed limita-
tions of standardized therapies.1,18
However, MGMT pro-
moter methylation and IDH1 mutation have been identi-
fied in genome-wide association studies as robust genetic
markers for improved clinical outcomes in patients treated
with standard chemoradiation.1,18
While IDH status is con-
sidered an independent biomarker for clinical outcomes,
MGMT promoter methylation is associated with improved
response to TMZ and radiation and thus serves as a pre-
dictive biomarker of more favorable treatment outcomes.
This observed relationship between the molecular-genetic
tumor signature and treatment response has elevated the
importance of noninvasive biomarkers that enable real-
time selection and adjustment of personalized therapies.
The unique role of the local and systemic tumor environ-
ment is increasingly recognized in overall tumor biology
and treatment outcome.18,23
The identification of a periph-
eral biomarker for treatment response and overall survival
(OS) would improve patient management and perhaps
alter chemotherapy (e.g., TMZ) dosing protocols, which
currently do not account for individual pharmacogenetics,
pharmacokinetics, or pharmacodynamics.2
The use of circulating blood counts as a marker of
drug activity and clinical outcomes is an emerging area
of investigation. The current understanding of the effect
of chemotherapeutic agents suggests that greater toxicity
to various organ systems, such as the bone marrow, might
reflect increased potency and, conversely, be associated
with a more favorable antitumor profile.11,12
For instance,
in patients with renal cell carcinoma, leukopenia induced
by the tyrosine kinase inhibitor sunitinib was identified
as an independent and prognostic marker for improved
response rate and progression-free survival (PFS).4
This
finding was further supported by work from Zhu et al.,24
suggesting that sunitinib-induced decreases in neutro-
phils, monocytes, and platelets were associated with im-
proved progression and survival outcomes in patients with
hepatocellular carcinoma.
TMZ therapy, in combination with radiotherapy, sig-
nificantly improves OS in GBM patients.15
However, dos-
ing is based solely on patient body surface area and does
not account for variability in resistance mechanisms and
drug metabolism, raising the possibility that some patients
may be dosed subtherapeutically. Inadequate dosing may
partially contribute to the observed resistance to cyto-
toxic treatment and ultimately tumor recurrence. One of
the most common adverse effects of chemotherapy with
TMZ is myelosuppression, including thrombocytopenia
and leukopenia. It remains unclear whether patients who
do not show a notable decrease in blood counts in re-
sponse to TMZ are treated subtherapeutically. Therefore,
we hypothesized that changes in circulating blood counts
may be predictive of clinical outcomes, with alterations in
blood counts indicative of myelosuppression being associ-
ated with improved OS and PFS.
Methods
We conducted a retrospective, chart-review analysis of
clinical and demographic data from patients who previ-
ously underwent surgery and treatment for primary GBM
at the Massachusetts General Hospital between 2007 and
2014. Patient data were obtained from a Massachusetts
General Hospital institutional database. This time interval
allowed enough time for diagnosis and to follow a com-
plete blood count throughout the patient’s disease course.
This study received institutional review board approval
from Massachusetts General Hospital for all activities.
Eligibility
All patients were treated at the Massachusetts General
Hospital and met the following eligibility criteria: newly
diagnosed with GBM (WHO Grade IV) between Janu-
ary 1, 2007, and July 30, 2014; 18 years of age or older at
the time of diagnosis; surgical biopsy/resection after ini-
tial presentation; and treatment with at least 6 cycles of
monthly TMZ. Patients who did not complete 6 months
of TMZ therapy for any reason were excluded from the
study.
Variables
Descriptive information, including age, sex, and steroid
use, was collected. Steroid use was defined as exposure to
steroids (e.g., dexamethasone) at any given time during the
course of chemotherapy. Genetic information including
chromosomal abnormalities, point mutations, and gene
methylation was recorded. This included known prognos-
tic markers for gliomas such as epidermal growth factor
receptor (EGFR) amplification, MGMT promoter methyl-
ation, IDH mutation, and 1p/19q co-deletion. The genetic
characteristics of the sample are reported as the percent-
age of those patients for whom that genetic variable was
tested. Absolute peripheral blood platelet, red blood cell,
white blood cell, eosinophil, basophil, lymphocyte, neu-
trophil, and monocyte count measurements were recorded
at a maximum of 15 discrete time points during the course
of treatment. Time points included before surgery, after
surgery, before chemoradiation, and before each monthly
TMZ treatment cycle. PFS and OS were also assessed.
Statistics
The primary outcome measure was OS, which was de-
fined as the length of time from the date of initial diagno-
sis to time of death or last date known to be alive for those
who were censored. The secondary outcome measure was
PFS, which was defined as the length of time from initial
diagnosis to the time of first progression based on radiol-
ogy report and clinician notes indicating a switch in ther-
apy or last date known to be progression free for censored
patients. The effect of changes in peripheral blood counts
on clinical outcomes was assessed during the interval
between baseline measurement (before chemoradiation)
and Cycle 6 of monthly TMZ, as this time interval had
the greatest sample size and was controlled for the im-
munosuppressive effect of steroid use during surgery and
chemoradiation. Baseline and 6-month blood counts were
3. Bone marrow response as a potential biomarker
J Neurosurg October 14, 2016 3
performed closest to the time of chemoradiation or TMZ
initiation, but no earlier than 2 weeks prior. Changes in
blood counts are reported as the percentage change from
baseline to Cycle 6 of monthly TMZ.
Genetic variables known to be strong prognostic mark-
ers were compared with clinical outcomes using logistic
regression or Pearson’s chi-square test. Spearman or Pear-
son correlation coefficients were estimated to measure
the relation between baseline demographic variables and
clinical outcome measures. Wilcoxon rank-sum tests and
Kruskal-Wallis tests by ranks were used to examine dif-
ferences in mean blood count changes between groups
of patients stratified by IDH mutation and MGMT pro-
moter methylation. Univariate and multivariate Cox pro-
portional hazards models were used to evaluate variables
for association with PFS and OS. Variables were cho-
sen for multivariate analysis using the backward selec-
tion method based on statistical significance in univari-
ate analysis. Percentage changes from baseline in white
blood cell and red blood cell counts were included in the
multivariate model as dichotomized variables, indicating
either an increase or a decrease in that blood count from
baseline. IDH mutation was excluded from the multivari-
ate analysis due to a sample size less than 10. A Wilcoxon
rank-sum test was performed to assess the association be-
tween changes in neutrophils and steroid use. Neutrophil
counts at Cycle 6 of TMZ were compared between pa-
tients with and without steroid treatment using a 2-sample
t-test. Changes in neutrophil counts were excluded from
the multivariate analysis as they were confounded by ste-
roid use. Survival probabilities were compared between
patient groups, stratified by the dichotomous white blood
cell variable, using the log-rank test. In subgroup analy-
sis, patients with a decreased peripheral white blood cell
count from baseline were subdivided into groups based on
the degree of change, using either quartiles or the median
decrease. Here too the log-rank test was used to compare
survival curves between these patient subgroups. All re-
ported p values were 2-sided, and statistical significance
was considered as p < 0.05.
Results
Descriptive Data Analysis
In total, 86 patients diagnosed with GBM were in-
cluded in this study. Their median age at diagnosis was 55
years; 32 patients (37%) were women and 54 (63%) were
men. Nineteen patients (22%) were still alive at the time
of data cutoff for analysis. The median OS for the entire
group was 800 days, and the median PFS was 453 days.
Baseline and 6-month peripheral blood counts are listed
in Table 1. Mutation frequencies in the patient cohort are
reported in Table 2.
Univariate and Multivariate Analysis of Biomarker Impact
on OS
By univariate analysis, MGMT promoter methylation
and IDH mutation were associated with better OS and
PFS, consistent with the literature (Table 3 and Supple-
mental Table 1A). EGFR amplification, changes in neutro-
phil counts, changes in peripheral red and white blood cell
parameters, steroid use, and patient age at diagnosis were
also associated with OS (Table 3). As predicted, patients
receiving steroids during TMZ therapy had worse OS, with
a 2-year survival rate of 51% compared with 71% in pa-
tients who were not treated with steroids (p = 0.0051). Ad-
ditionally, changes in neutrophil counts differed between
patients with and without steroid use (p = 0.0032), and
patients receiving steroids had significantly greater neutro-
phil counts at 6 months of TMZ compared with those who
never received steroids (p = 0.0031). Changes in neutrophil
counts were not associated with OS in patients who never
received steroids (p = 0.300). On multivariate analysis,
MGMT promoter methylation, a decreased white blood
cell count from baseline, and wild-type EGFR status (i.e.,
EGFR not amplified) were significantly associated with
improved OS (Table 4). These associations remained sig-
nificant on multivariate analysis that incorporated patient
age and steroid use, despite our observation that steroid use
was associated with increased white blood cells counts (p
= 0.0585). On subgroup analysis, decreases in white blood
cell counts remained associated with improved OS with
hazard ratios of 0.410 (p = 0.053) and 0.109 (p = 0.066) in
patients with and without steroid use.
Association of MGMT and IDH With Alterations in
Circulating Blood Cell Counts
MGMT promoter methylation and IDH1 mutation are
known to be robust prognostic markers for OS in GBM pa-
tients.1,18
Regarding the association of these genetic mark-
ers with alterations in circulating biomarkers that were
significant on univariate analysis, we report that MGMT
promoter methylation was not correlated with changes in
peripheral red blood cell or white blood cell (p = 0.4492)
counts. Similarly, IDH mutation was not correlated with
changes in peripheral red blood cell (p = 0.2198) or white
blood cell (p = 0.3447) counts during the course of treat-
ment.
Association of Changes in White Blood Cell Counts
With OS
The Kaplan-Meier estimated 2-year survival rate for
patients with a decrease in white blood cell counts from
baseline was 58% and that for patients with an increase
relative to baseline was 25% (p = 0.0019; Fig. 1). Patients
with decreases in white blood cell counts had a median
OS of 850 days (95% CI 691–1097 days) compared with
627 days (95% CI 454–745 days) for those with increases
in white blood cell counts from baseline. We found no sig-
nificant differences in OS between subgroups of patients
with decreased white blood cell counts during treatment,
when the data were stratified by quartile or median de-
crease.
Discussion
We here demonstrate that treatment-associated my-
elosuppression, as manifested by a decrease in circulat-
ing white blood cell counts from baseline during adjuvant
4. E. J. Vaios et al.
J Neurosurg October 14, 20164
TMZ therapy, might serve as a potential prognostic mark-
er for clinical outcomes in patients with GBM. Our se-
rial assessment of peripheral blood counts and additional
laboratory and radiographic data found that a decrease
in white blood cells from baseline during adjuvant TMZ
therapy predicts significantly improved OS.
Our institutional survival data for patients with de-
creases in white blood cells compares favorably with data
from the original EORTC/NCIC trial, which reported a
median survival of 14.6 months and a 2-year survival rate
of 26.5% for patients receiving radiotherapy plus TMZ.16
The present findings are consistent with findings of pre-
vious studies demonstrating an association of MGMT
promoter methylation and IDH1 mutation with improved
clinical outcomes.3,5,6,17,21
Interestingly, we found that
MGMT promoter methylation and IDH mutation did not
correlate with changes in white blood cell counts, suggest-
ing that these changes may serve as an independent prog-
nostic factor.
Despite these robust findings, our study is limited by
its modest sample size and retrospective nature. Neverthe-
less, our exploratory analysis of hematological parameters
identified that treatment-related changes in white blood
cell counts are associated with OS, with decreases in white
blood cell counts from baseline serving as a biomarker for
improved OS. This association was maintained on mul-
tivariate analysis, even after controlling for other known
prognostic variables, including age at the time of diagno-
sis, steroid use, EGFR amplification status, and MGMT
promoter methylation status. On subgroup analysis, de-
creases in white blood cell counts from baseline main-
tained a strong association with improved OS regardless of
whether a patient used steroids during TMZ therapy. No-
tably, an increase in white blood cell counts from baseline
was also considered an important biomarker for worse OS,
suggesting that changes in white blood cell counts play an
TABLE 2. Summary of patient characteristics
Characteristic Value
Sex
Male
Female
54 (63%)
32 (37%)
Age at diagnosis, yrs
Mean (SD)
Range
55.37 (12.55)
18.00–80.00
OS, days
Mean (SD)
Range
915.09 (476.37)
324.00–2660.00
PFS, days
Mean (SD)
Range
622.10 (487.02)
12.00–2660.00
Genetic mutation
EGFR
MGMT
IDH
37 (50.00%)
39 (54.17%)
6 (8.96%)
Steroid use
Deceased
62 (72.09%)
67 (77.91%)
Values represent n (%) unless otherwise indicated.
TABLE 1. Patient blood counts
Hematology Value
Baseline
Platelets (×109
/L)
Mean (SD)
Range
279.28 (97.59)
95.00–589.00
Red blood cells (×1012
/L)
Mean (SD)
Range
4.28 (0.43)
3.27–5.16
White blood cells (×109
/L)
Mean (SD)
Range
8.69 (3.29)
3.27–20.00
Eosinophils (×109
/L)
Mean (SD)
Range
0.11 (0.11)
0.00–0.58
Basophils (×109
/L)
Mean (SD)
Range
0.03 (0.03)
0.00–0.20
Lymphocytes (×109
/L)
Mean (SD)
Range
1.67 (0.73)
0.52–3.93
Neutrophils (×109
/L)
Mean (SD)
Range
6.21 (2.90)
2.16–15.43
Monocytes (×109
/L)
Mean (SD)
Range
0.46 (0.24)
0.14–1.51
6-mo adjuvant TMZ*
Platelets (×109
/L)
Mean (SD)
Range
188.74 (65.76)
80.00–400.00
Red blood cells (×1012
/L)
Mean (SD)
Range
4.13 (0.45)
3.24–5.29
White blood cells (×109
/L)
Mean (SD)
Range
5.68 (2.50)
3.00–14.10
Eosinophils (×109
/L)
Mean (SD)
Range
0.12 (0.10)
0.00–0.45
Basophils (×109
/L)
Mean (SD)
Range
0.02 (0.02)
0.00–0.15
Lymphocytes (×109
/L)
Mean (SD)
Range
0.99 (0.41)
0.35–2.10
Neutrophils (×109
/L)
Mean (SD)
Range
3.97 (2.21)
0.02–11.30
Monocytes (×109
/L)
Mean (SD)
Range
0.40 (0.18)
0.02–1.02
* Blood counts obtained at the time of the 6th monthly cycle of TMZ treatment.
5. Bone marrow response as a potential biomarker
J Neurosurg October 14, 2016 5
important biological role in the tumor microenvironment
independent of chemotherapy.
We were unable to identify an association between
changes in the peripheral platelet count and clinical out-
comes, as described by Williams et al.22
This finding sug-
gests that decreases in white blood cell counts, rather than
general “bone marrow suppression,” might be a predictor
of improved OS. However, we did not observe a statis-
tically significant association between white blood cell
changes and PFS in our multivariate model, when con-
trolling for steroid use and other markers that were sig-
nificant on univariate analysis (Supplemental Data). Our
findings, however, indicate that patient age and MGMT
promoter methylation are important predictors of PFS.
Changes in neutrophils were also significantly associ-
ated with OS and PFS, with neutrophil increases from
baseline predicting worse outcomes. However, given the
association of neutrophil counts with medications (e.g.,
steroid use), infections, and environmental factors, these
findings remain more challenging to interpret. Neutrophil
counts were likely confounded by steroid use, perhaps in-
dicative of more aggressive tumor growth necessitating
steroid administration for the management of edema. Con-
sistent with the literature, our study found that steroid use
was associated with elevated neutrophil counts and worse
outcomes. In patients who did not receive steroids, we did
not observe an association between neutrophil counts and
OS. Therefore, this hematological parameter was excluded
from our multivariate analysis.
The observed relationship between a decrease in white
blood cell counts and clinical outcomes is possibly due to
higher in vivo drug concentrations of TMZ, resulting from
differences in drug metabolism. TMZ activity is dose and
schedule dependent and induces cytotoxicity primarily by
causing O6
-meG lesions, which deplete the repair enzyme
MGMT, leading to double-strand DNA breaks and tumor
cell apoptosis.7,13,14,25
TMZ is administered orally and has
a half-life of 1.8 hours, reaching concentrations in the CSF
that are 30%–40% of plasma concentrations. The clini-
cal efficacy of TMZ and its active metabolite depends on
MGMT activity; the integrity of the mismatch repair sys-
tem, which recognizes O6
-meG lesions in template DNA
strands; and function of the base excision repair system,
which corrects highly lethal N3
-meA lesions via poly
(ADP-ribose) polymerase.9,10,20
There are no guidelines for
dose adjustment based on the tumor genetic signature or
in the context of severe renal or hepatic impairment. Since
TABLE 3. Univariate analysis for OS
Covariate HR 95% CI p Value*
Sex
Male
Female
0.685
—
0.418–1.124
—
0.1346
—
Age 1.021 1.000–1.042 0.0470
Genetic mutations
EGFR
MGMT
IDH
1.818
0.353
0.100
1.074–3.078
0.203–0.615
0.014–0.726
0.0261
0.0002
0.0228
Percent change in
Platelets
Red blood cells
White blood cells
Eosinophils
Basophils
Lymphocytes
Neutrophils
Monocytes
1.163
0.074
3.133
0.979
0.938
1.330
1.856
1.407
0.443–3.051
0.007–0.787
1.489–6.591
0.895–1.070
0.678–1.296
0.675–2.621
1.218–2.828
0.873–2.270
0.7588
0.0308
0.0026
0.6340
0.6973
0.4102
0.0040
0.1610
Steroids
Used
Not used
2.286
—
1.262–4.142 0.0064
—
* Based on log-rank test.
TABLE 4. Multivariate analysis for OS
Covariate HR 95% CI p Value*
Age 1.064 1.033–1.096 <0.0001
MGMT 0.106 0.043–0.259 <0.0001
EGFR 1.779 0.978–3.247 0.0594
White blood cells
Increase
Decrease
3.040
—
1.245–7.407
—
0.0147
—
Red blood cells
Increase
Decrease
1.065
—
0.578–1.961
—
0.8390
—
Steroids
Used
Not used
1.196
—
0.575–2.494
—
0.6317
—
IDH was excluded due to inadequate sample size.
* Based on log-rank test.
Fig. 1. Kaplan-Meier analysis of OS in patients stratified by increase
(dotted line) or decrease (solid line) in white blood cell counts from base-
line. A significant survival benefit is noted for patients with a decrease in
white blood cells relative to baseline (log-rank p = 0.0019).
6. E. J. Vaios et al.
J Neurosurg October 14, 20166
current dosing guidelines do not factor interpatient differ-
ences in resistance mechanisms or patient-specific drug
metabolism, it is possible that some patients are treated
subtherapeutically.
Given the routine and reliable assessment of periph-
eral blood counts in GBM patients receiving conventional
therapies, white blood cell counts could serve as a valuable
biomarker of treatment response and for predicting clini-
cal outcomes. Future prospective studies should address
whether blood cell counts could serve as a correlate bio-
marker for in vivo TMZ levels and drug activity as well as
a predictor of clinical outcomes, which in turn could help
to optimize dosing and scheduling of chemotherapy by ac-
counting for variability in drug metabolism.
Conclusions
We report a temporal relationship between changes in
peripheral white blood cell counts during adjuvant TMZ
treatment and clinical outcomes. Specifically, depression
of white blood cell counts appears to be an independent
prognostic factor and was associated with improved OS.
This relationship may be a reflection of plasma TMZ levels
and, in time, may serve as a surrogate marker of therapeu-
tic efficacy. These findings warrant further investigation in
prospective studies, including correlations with the degree
of change in white blood cell counts and pharmacokinet-
ics of TMZ in individual patients. It also remains unclear
whether treatment-associated changes in white blood cell
counts correlate with drug-induced antitumor activity or
represent an independent factor of the altered local and
systemic tumor environment.
Acknowledgments
This work was supported by the 2015 Neurosurgical Research
and Education Foundation (NREF) Medical Student Summer
Research Fellowship (Eugene J. Vaios) and the Harvard Medical
School Scholars in Medicine Office (Eugene J. Vaios).
Jorg Dietrich received support from the American Academy of
Neurology, the American Cancer Society, and generous gifts from
the family foundations of Bryan Lockwood, Ronald Tawil, and
Sheila McPhee.
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Disclosures
The authors report no conflict of interest concerning the materi-
als or methods used in this study or the findings specified in this
paper.
Author Contributions
Conception and design: Vaios, Nahed, Dietrich. Acquisition of
data: Vaios. Analysis and interpretation of data: Vaios, Nahed,
Muzikansky, Dietrich. Drafting the article: Vaios. Critically revis-
ing the article: Vaios, Nahed, Fathi, Dietrich. Reviewed submitted
version of manuscript: all authors. Approved the final version of
the manuscript on behalf of all authors: Vaios. Statistical analysis:
Vaios, Muzikansky. Administrative/technical/material support:
Nahed, Dietrich. Study supervision: Nahed, Dietrich.
Supplemental Information
Online-Only Content
Supplemental material is available with the online version of the
article.
Supplemental Tables 1A and B. http://thejns.org/doi/
suppl/0.3171/2016.7.JNS16609.
Correspondence
Eugene John Vaios, Vanderbilt Hall Box 099, 107 Ave. Louis
Pasteur, Boston, MA 02115. email: eugene_vaios@hms.harvard.
edu.