Emmanuel Berchmans - Academia.edu (original) (raw)
Papers by Emmanuel Berchmans
Blood, Nov 20, 2009
Abstract 4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive a... more Abstract 4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive accretion of long-lived mature B-lymphocytes. Although the classical Rai and Binet staging is still commonly used, a new molecular understanding has identified specific signatures which could help predict disease progression and survival. Given the recent success of immunotherapeutic strategies and immunomodulatory drugs in the treatment of CLL we sought to identify potentially immunologically relevant targets and their relation to well known disease criterion. Methods Our study characterized the mRNA expression of 29 known cancer-testis antigens (CTAs) in 66 patients with CLL at varying stages of disease using a RT-PCR based expression panel. Relevant clinical criterion such as RAI stage, B2m, ZAP-70, IGVH mutational status, CD38, cytogenetics by FISH analysis, WBC count, age, gender, and treatment among others were then taken into account. The binary RNA expression data associated with the clinical and demographic factors were evaluated using chi-square or Wilcoxon rank sum analysis. Results Of the cancer-testis antigens tested, the MAGE family of CTAs revealed statistically significant correlations with multiple clinical criteria. Our analysis reveals a correlation between previous chemo-immunotherapy treatment and MAGE-A1, B2, E1, MAD-CT-2, SPA-17, and PAGE-5 expression. Beyond treatment, total white blood cell count was shown to have a significant association with MAGE family members A1, A3, and B2 expression. In addition, MAD-CT-2 and MAGE-B2 were significantly correlated with the expression of FMC-7 and SSX-4 and LAGE-1 correlated with the presence of B-cell symptomatology. Conclusions Preliminary RT-PCR based CTA phenotyping has unveiled interesting correlations to clinical criteria, opening multiple avenues for future immunotherapeutic interventions as well as possible prognostic value in CLL. Further investigation to better understand the biological value of this information in warranted. Disclosures: Pinilla: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; exelixis: Research Funding.
Blood, Nov 16, 2012
Abstract 3828 Background: The identification of appropriate target antigens is critical to the su... more Abstract 3828 Background: The identification of appropriate target antigens is critical to the success of cancer immunotherapies. Cancer-testis antigens (CTAs) are ectopically expressed immunoprivileged antigens transcriptionally controlled by DNA methylation which have utility as immunotherapeutic targets. 5-azacytidine (AZA), an analogue of cytidine, has been shown to induce expression of CTAs in cancer. We analyzed matched samples from 42 myelodysplastic syndrome patients receiving an oral AZA to determine if an anti-CTA immune response was generated. Methods: Immunoglobulin G (IgG) responses to CTAs were analyzed by High Throughput Immunoblot assay (HTI), 29 CTAs were bound in a concise pattern to nitrocellulose filters and developed in the following methodology. Patient sera were incubated with the HTI filters and any CTA specific antibodies bound to respective antigens and reactive antibodies were detected by secondary anti-human antibodies in a colorimetric assay. Filters were read by 5 blinded individuals, spots were scored positive or negative against control antigens. These results were compared to the paired post-therapy sample, a score of 5 was maximal change of pre to post. Those CTAs with strong antibody presence post-therapy were then confirmed via ELISA resulting in an antibody titer reflected as ug/mL. A standardization of human IgG, as well as a healthy donor control was used to determine the validity of identified responses. Results: When HTI was examined thoroughly several CTAs, MAGEs, SSX2, NY-ESO1 and MAD-CTs were of particular interest. All patients regardless of pre- or post- therapy exhibited SSX2 expression at high levels this was further confirmed with ELISA exhibiting little to no change from pre- to post-therapy. HTI examination of MAD-CT antigens revealed that pre-treatment, MAD-CT-1 and MAD-CT-2 antibody presence, responses were nearly identical, and thirty-four had the exact same response levels. PRAME, a CTA absent from our HTI filter, was evaluated only through ELISA. We determined that eighteen patients presented with an increased anti-PRAME antibody titers at post-treatment when compared to pre-treatment. Of the cancer testis antigens analyzed patients had the highest average changes in antibody titer to PRAME at post-treatment, with a 0.128 ug/mL average increases. Conclusions: Our findings suggest that CTAs could be further pursued as an immunotherapeutic target in myelodysplastic syndrome and that treatment with AZA could be exploited to modulate antigen expression in combination with immunotherapeutic approaches. Although responses were variable throughout the patients in total, some patients had robust responses at post-treatment. The CTAs, MAGEs, SSX2, NY-ESO1 and PRAME, are of particular interest, due to prior and new findings, as well as, on-going clinical trials. Five patients had a robust antibody response according to HTI to at least six antigens. Eight patients were of further interest according to ELISA examination. Further data on the relation with clinical response and possible prognostic factors of response to therapy will be presented. Disclosures: Skikne: Celgene: Employment, Equity Ownership. MacBeth:Celgene: Employment.
Leukemia Research, Mar 1, 2011
Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endo... more Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosupression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2′deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer testis antigens (CTAs) and co-stimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.
Journal of Clinical Oncology, May 20, 2012
6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosi... more 6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosis. Clinical staging systems and the use of biomarkers such as cytogenetics and the IGVH mutational status remain the gold standard for stratification. Cancer testis antigens (CTAs) expression analyses have shown prognostic impact in other hematological malignancies such as acute leukemias and multiple myeloma. With the analysis of CTAs we aim to discover additional molecular markers that can help us predict the clinical course and outcome in CLL patients. Methods: We analyzed the expression by RT-PCR of 39 known CTAs including members of the MAGE, GAGE, MAD-CT and SSX CTAs families in a group of 59 CLL patients seen at our institution. The Moffitt Cancer Center Total Cancer Care (TCC) database was used to correlated these findings with relevant clinical and molecular markers such as Rai stage, demographic data, initial WBC count, IGVH mutational status, CD38 expression, cytogenetics by FISH analysis and treatment outcomes. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan Meier curves with a SPSS statistical software Results: Deletion 13q was the most common gene abnormality in 35/59 (59.3%). 29/59 (49.1%) required at least one line of treatment. MAGE family CTAs were present in 53/59 (83.9%), MAD-CT in 24/59 (40.7%), SSX in 14/59 (23.7%) and GAGE in 12/59(20.3%). 35/59 (59.3%) CLL patients expressed 2 or more MAGE family CTAs. No differences were noted in the Rai staging, initial white blood cell count, B symptoms, extranodal disease, presence of CD38, or unmutated IVGH. The OS was not significantly different among all CTAs families with a tendency towards a better OS those expressing the SSX family (p=0.63). Additionally, CLL patients with single expression of MAD-CT1 (p=0.05) and MAGE-B2 (p=0.038) antigens correlated with improved survival. Conclusions: Patients with SSX family have a trend towards improved survival. When analyzed by individual antigen, MAD-CT1 and MAGE-B2 expression was associated with improved survival. Further studies with a larger number of patients are needed to assess the real value of the expression of CTAs in CLL.
Journal of Clinical Oncology, 2012
6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosi... more 6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosis. Clinical staging systems and the use of biomarkers such as cytogenetics and the IGVH mutational status remain the gold standard for stratification. Cancer testis antigens (CTAs) expression analyses have shown prognostic impact in other hematological malignancies such as acute leukemias and multiple myeloma. With the analysis of CTAs we aim to discover additional molecular markers that can help us predict the clinical course and outcome in CLL patients. Methods: We analyzed the expression by RT-PCR of 39 known CTAs including members of the MAGE, GAGE, MAD-CT and SSX CTAs families in a group of 59 CLL patients seen at our institution. The Moffitt Cancer Center Total Cancer Care (TCC) database was used to correlated these findings with relevant clinical and molecular markers such as Rai stage, demographic data, initial WBC count, IGVH mutational status, CD38 expression, cytogenetics by F...
Blood, 2011
1725 Introduction: Immunotherapeutic strategies have been limited by the lack of known tumor rest... more 1725 Introduction: Immunotherapeutic strategies have been limited by the lack of known tumor restricted antigens and inadequate immune responses. In our Institution, an ongoing Phase I dose escalation study in 11 high risk MDS patients, who failed hypo-methylating agents, were enrolled in a K562-GMCSF-CD40 ligand transfected “bystander” vaccine, in combination with lenalidomide, and have shown promising responses.…
Blood, 2009
4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive accretion ... more 4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive accretion of long-lived mature B-lymphocytes. Although the classical Rai and Binet staging is still commonly used, a new molecular understanding has identified specific signatures which could help predict disease progression and survival. Given the recent success of immunotherapeutic strategies and immunomodulatory drugs in the treatment of CLL we sought to identify potentially immunologically relevant targets and their relation to well known disease criterion. Methods Our study characterized the mRNA expression of 29 known cancer-testis antigens (CTAs) in 66 patients with CLL at varying stages of disease using a RT-PCR based expression panel. Relevant clinical criterion such as RAI stage, B2m, ZAP-70, IGVH mutational status, CD38, cytogenetics by FISH analysis, WBC count, age, gender, and treatment among others were then taken into account. The binary RNA expression data associated with the clini...
Oncotarget, 2016
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumo... more Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumorrestricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2′-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors.
Neurosurgical review, Jan 16, 2016
Brachytherapy (BT) for glioblastoma multiforme (GBM) involves the use of radioactive isotopes to ... more Brachytherapy (BT) for glioblastoma multiforme (GBM) involves the use of radioactive isotopes to deliver ionizing radiation directly into the tumor bed. Its application as a means to prolong survival in GBM patients over the past few decades has come with variable success. The objective of this review is to describe the utility of BT in GBM, and to report the outcomes and adverse events associated with its use in different multimodal treatment approaches. A search of the literature was conducted using the PubMed database. The most recent search was performed in September 2015. Thirty-two series involving 1571 patients were included in our review. The longest median overall survival (MOS) following BT for newly diagnosed GBM reached 28.5 months. Overall, 1-, 2-, and 3-year survival rates were 46-89 %, 20-57 %, and 14-27 %. For recurrent GBM, the longest reported MOS after BT was 15.9 months. One-, 2- and 3-year survival rates for recurrent GBM were 10-66 %, 3-23 %, and 9-15 %. Advers...
Neurosurgical review, Jan 27, 2016
Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resectio... more Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resection of primary brain tumors and metastases. We conducted a systematic review of the literature to further understand the role of 5-ALA in neurosurgery. Our goal was to identify the utility of 5-ALA during resection by evaluating its sensitivity and specificity for different tumor types, as well as the extent of tumor resection achieved while using 5-ALA. A search of the literature was conducted using the PubMed database for the period January 1990 through May 2014. Surgical series in which 5-ALA was used for brain neoplasm resections were evaluated for tumor histology, sensitivity, specificity, extent of resection, complications, and outcomes. Twenty-two series, involving 1163 patients, were included in our review. 5-ALA sensitivity was highest in high-grade gliomas (85 %) and meningiomas (81 %). 5-ALA specificity was high in meningiomas (100 %), as well as metastases (84 %) and high-grade...
Leukemia Research, 2011
Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endo... more Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosupression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2′deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer testis antigens (CTAs) and co-stimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.
Abdominal Radiology, 2019
Objectives Gender dysphoria is defined as a conflict between the biological gender and the gender... more Objectives Gender dysphoria is defined as a conflict between the biological gender and the gender with which the person identifies. Gender reassignment therapy can alter external sexual features to resemble those of the desired gender and are broadly classified into two types, female to male (FTM) and male to female (MTF). In this paper we describe expected findings and complications of gender reassignment therapy. Methods Collaborative multi-institutional project supported by Ovarian and Uterine Cancer Disease Focused panel of Society of Abdominal Radiology. Results Gender dysphoria is defined as a conflict between the biological gender and the gender with which the person identifies. Gender reassignment therapy can alter external sexual features to resemble those of the desired gender and are broadly classified into two types, female to male (FTM) and male to female (MTF). These therapies include hormonal treatment as well as surgical procedures. FTM genital reconstructive therapy includes creation of a neophallus, which can be achieved by metoidioplasty or phalloplasty with mastectomy, along with testosterone administration. MTF gender reassignment surgery includes complete removal of external genitalia with penectomy and orchiectomy, with vaginoplasty, clitoroplasty, labiaplasty, and breast augmentation along with estrogen supplements. Conclusion Surgical techniques alter the standard anatomy and make imaging interpretation challenging if radiologists are unfamiliar with expected post-operative appearances. It is important to recognize the complications related to surgical and non-surgical treatment of gender dysphoria to avoid interpretation errors. Furthermore, increasing the prevalence of transgender patients requires increased sensitivity when interpreting imaging studies to reduce the potential for misdiagnoses in reporting due to frequently incomplete available clinical history.
Blood, Nov 20, 2009
Abstract 4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive a... more Abstract 4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive accretion of long-lived mature B-lymphocytes. Although the classical Rai and Binet staging is still commonly used, a new molecular understanding has identified specific signatures which could help predict disease progression and survival. Given the recent success of immunotherapeutic strategies and immunomodulatory drugs in the treatment of CLL we sought to identify potentially immunologically relevant targets and their relation to well known disease criterion. Methods Our study characterized the mRNA expression of 29 known cancer-testis antigens (CTAs) in 66 patients with CLL at varying stages of disease using a RT-PCR based expression panel. Relevant clinical criterion such as RAI stage, B2m, ZAP-70, IGVH mutational status, CD38, cytogenetics by FISH analysis, WBC count, age, gender, and treatment among others were then taken into account. The binary RNA expression data associated with the clinical and demographic factors were evaluated using chi-square or Wilcoxon rank sum analysis. Results Of the cancer-testis antigens tested, the MAGE family of CTAs revealed statistically significant correlations with multiple clinical criteria. Our analysis reveals a correlation between previous chemo-immunotherapy treatment and MAGE-A1, B2, E1, MAD-CT-2, SPA-17, and PAGE-5 expression. Beyond treatment, total white blood cell count was shown to have a significant association with MAGE family members A1, A3, and B2 expression. In addition, MAD-CT-2 and MAGE-B2 were significantly correlated with the expression of FMC-7 and SSX-4 and LAGE-1 correlated with the presence of B-cell symptomatology. Conclusions Preliminary RT-PCR based CTA phenotyping has unveiled interesting correlations to clinical criteria, opening multiple avenues for future immunotherapeutic interventions as well as possible prognostic value in CLL. Further investigation to better understand the biological value of this information in warranted. Disclosures: Pinilla: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; exelixis: Research Funding.
Blood, Nov 16, 2012
Abstract 3828 Background: The identification of appropriate target antigens is critical to the su... more Abstract 3828 Background: The identification of appropriate target antigens is critical to the success of cancer immunotherapies. Cancer-testis antigens (CTAs) are ectopically expressed immunoprivileged antigens transcriptionally controlled by DNA methylation which have utility as immunotherapeutic targets. 5-azacytidine (AZA), an analogue of cytidine, has been shown to induce expression of CTAs in cancer. We analyzed matched samples from 42 myelodysplastic syndrome patients receiving an oral AZA to determine if an anti-CTA immune response was generated. Methods: Immunoglobulin G (IgG) responses to CTAs were analyzed by High Throughput Immunoblot assay (HTI), 29 CTAs were bound in a concise pattern to nitrocellulose filters and developed in the following methodology. Patient sera were incubated with the HTI filters and any CTA specific antibodies bound to respective antigens and reactive antibodies were detected by secondary anti-human antibodies in a colorimetric assay. Filters were read by 5 blinded individuals, spots were scored positive or negative against control antigens. These results were compared to the paired post-therapy sample, a score of 5 was maximal change of pre to post. Those CTAs with strong antibody presence post-therapy were then confirmed via ELISA resulting in an antibody titer reflected as ug/mL. A standardization of human IgG, as well as a healthy donor control was used to determine the validity of identified responses. Results: When HTI was examined thoroughly several CTAs, MAGEs, SSX2, NY-ESO1 and MAD-CTs were of particular interest. All patients regardless of pre- or post- therapy exhibited SSX2 expression at high levels this was further confirmed with ELISA exhibiting little to no change from pre- to post-therapy. HTI examination of MAD-CT antigens revealed that pre-treatment, MAD-CT-1 and MAD-CT-2 antibody presence, responses were nearly identical, and thirty-four had the exact same response levels. PRAME, a CTA absent from our HTI filter, was evaluated only through ELISA. We determined that eighteen patients presented with an increased anti-PRAME antibody titers at post-treatment when compared to pre-treatment. Of the cancer testis antigens analyzed patients had the highest average changes in antibody titer to PRAME at post-treatment, with a 0.128 ug/mL average increases. Conclusions: Our findings suggest that CTAs could be further pursued as an immunotherapeutic target in myelodysplastic syndrome and that treatment with AZA could be exploited to modulate antigen expression in combination with immunotherapeutic approaches. Although responses were variable throughout the patients in total, some patients had robust responses at post-treatment. The CTAs, MAGEs, SSX2, NY-ESO1 and PRAME, are of particular interest, due to prior and new findings, as well as, on-going clinical trials. Five patients had a robust antibody response according to HTI to at least six antigens. Eight patients were of further interest according to ELISA examination. Further data on the relation with clinical response and possible prognostic factors of response to therapy will be presented. Disclosures: Skikne: Celgene: Employment, Equity Ownership. MacBeth:Celgene: Employment.
Leukemia Research, Mar 1, 2011
Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endo... more Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosupression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2′deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer testis antigens (CTAs) and co-stimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.
Journal of Clinical Oncology, May 20, 2012
6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosi... more 6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosis. Clinical staging systems and the use of biomarkers such as cytogenetics and the IGVH mutational status remain the gold standard for stratification. Cancer testis antigens (CTAs) expression analyses have shown prognostic impact in other hematological malignancies such as acute leukemias and multiple myeloma. With the analysis of CTAs we aim to discover additional molecular markers that can help us predict the clinical course and outcome in CLL patients. Methods: We analyzed the expression by RT-PCR of 39 known CTAs including members of the MAGE, GAGE, MAD-CT and SSX CTAs families in a group of 59 CLL patients seen at our institution. The Moffitt Cancer Center Total Cancer Care (TCC) database was used to correlated these findings with relevant clinical and molecular markers such as Rai stage, demographic data, initial WBC count, IGVH mutational status, CD38 expression, cytogenetics by FISH analysis and treatment outcomes. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan Meier curves with a SPSS statistical software Results: Deletion 13q was the most common gene abnormality in 35/59 (59.3%). 29/59 (49.1%) required at least one line of treatment. MAGE family CTAs were present in 53/59 (83.9%), MAD-CT in 24/59 (40.7%), SSX in 14/59 (23.7%) and GAGE in 12/59(20.3%). 35/59 (59.3%) CLL patients expressed 2 or more MAGE family CTAs. No differences were noted in the Rai staging, initial white blood cell count, B symptoms, extranodal disease, presence of CD38, or unmutated IVGH. The OS was not significantly different among all CTAs families with a tendency towards a better OS those expressing the SSX family (p=0.63). Additionally, CLL patients with single expression of MAD-CT1 (p=0.05) and MAGE-B2 (p=0.038) antigens correlated with improved survival. Conclusions: Patients with SSX family have a trend towards improved survival. When analyzed by individual antigen, MAD-CT1 and MAGE-B2 expression was associated with improved survival. Further studies with a larger number of patients are needed to assess the real value of the expression of CTAs in CLL.
Journal of Clinical Oncology, 2012
6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosi... more 6575 Background: CLL is the most common leukemia in adults and has a variable course and prognosis. Clinical staging systems and the use of biomarkers such as cytogenetics and the IGVH mutational status remain the gold standard for stratification. Cancer testis antigens (CTAs) expression analyses have shown prognostic impact in other hematological malignancies such as acute leukemias and multiple myeloma. With the analysis of CTAs we aim to discover additional molecular markers that can help us predict the clinical course and outcome in CLL patients. Methods: We analyzed the expression by RT-PCR of 39 known CTAs including members of the MAGE, GAGE, MAD-CT and SSX CTAs families in a group of 59 CLL patients seen at our institution. The Moffitt Cancer Center Total Cancer Care (TCC) database was used to correlated these findings with relevant clinical and molecular markers such as Rai stage, demographic data, initial WBC count, IGVH mutational status, CD38 expression, cytogenetics by F...
Blood, 2011
1725 Introduction: Immunotherapeutic strategies have been limited by the lack of known tumor rest... more 1725 Introduction: Immunotherapeutic strategies have been limited by the lack of known tumor restricted antigens and inadequate immune responses. In our Institution, an ongoing Phase I dose escalation study in 11 high risk MDS patients, who failed hypo-methylating agents, were enrolled in a K562-GMCSF-CD40 ligand transfected “bystander” vaccine, in combination with lenalidomide, and have shown promising responses.…
Blood, 2009
4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive accretion ... more 4701 Background Chronic Lymphocytic Leukemia (CLL) is characterized by the progressive accretion of long-lived mature B-lymphocytes. Although the classical Rai and Binet staging is still commonly used, a new molecular understanding has identified specific signatures which could help predict disease progression and survival. Given the recent success of immunotherapeutic strategies and immunomodulatory drugs in the treatment of CLL we sought to identify potentially immunologically relevant targets and their relation to well known disease criterion. Methods Our study characterized the mRNA expression of 29 known cancer-testis antigens (CTAs) in 66 patients with CLL at varying stages of disease using a RT-PCR based expression panel. Relevant clinical criterion such as RAI stage, B2m, ZAP-70, IGVH mutational status, CD38, cytogenetics by FISH analysis, WBC count, age, gender, and treatment among others were then taken into account. The binary RNA expression data associated with the clini...
Oncotarget, 2016
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumo... more Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumorrestricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2′-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors.
Neurosurgical review, Jan 16, 2016
Brachytherapy (BT) for glioblastoma multiforme (GBM) involves the use of radioactive isotopes to ... more Brachytherapy (BT) for glioblastoma multiforme (GBM) involves the use of radioactive isotopes to deliver ionizing radiation directly into the tumor bed. Its application as a means to prolong survival in GBM patients over the past few decades has come with variable success. The objective of this review is to describe the utility of BT in GBM, and to report the outcomes and adverse events associated with its use in different multimodal treatment approaches. A search of the literature was conducted using the PubMed database. The most recent search was performed in September 2015. Thirty-two series involving 1571 patients were included in our review. The longest median overall survival (MOS) following BT for newly diagnosed GBM reached 28.5 months. Overall, 1-, 2-, and 3-year survival rates were 46-89 %, 20-57 %, and 14-27 %. For recurrent GBM, the longest reported MOS after BT was 15.9 months. One-, 2- and 3-year survival rates for recurrent GBM were 10-66 %, 3-23 %, and 9-15 %. Advers...
Neurosurgical review, Jan 27, 2016
Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resectio... more Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resection of primary brain tumors and metastases. We conducted a systematic review of the literature to further understand the role of 5-ALA in neurosurgery. Our goal was to identify the utility of 5-ALA during resection by evaluating its sensitivity and specificity for different tumor types, as well as the extent of tumor resection achieved while using 5-ALA. A search of the literature was conducted using the PubMed database for the period January 1990 through May 2014. Surgical series in which 5-ALA was used for brain neoplasm resections were evaluated for tumor histology, sensitivity, specificity, extent of resection, complications, and outcomes. Twenty-two series, involving 1163 patients, were included in our review. 5-ALA sensitivity was highest in high-grade gliomas (85 %) and meningiomas (81 %). 5-ALA specificity was high in meningiomas (100 %), as well as metastases (84 %) and high-grade...
Leukemia Research, 2011
Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endo... more Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosupression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2′deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer testis antigens (CTAs) and co-stimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.
Abdominal Radiology, 2019
Objectives Gender dysphoria is defined as a conflict between the biological gender and the gender... more Objectives Gender dysphoria is defined as a conflict between the biological gender and the gender with which the person identifies. Gender reassignment therapy can alter external sexual features to resemble those of the desired gender and are broadly classified into two types, female to male (FTM) and male to female (MTF). In this paper we describe expected findings and complications of gender reassignment therapy. Methods Collaborative multi-institutional project supported by Ovarian and Uterine Cancer Disease Focused panel of Society of Abdominal Radiology. Results Gender dysphoria is defined as a conflict between the biological gender and the gender with which the person identifies. Gender reassignment therapy can alter external sexual features to resemble those of the desired gender and are broadly classified into two types, female to male (FTM) and male to female (MTF). These therapies include hormonal treatment as well as surgical procedures. FTM genital reconstructive therapy includes creation of a neophallus, which can be achieved by metoidioplasty or phalloplasty with mastectomy, along with testosterone administration. MTF gender reassignment surgery includes complete removal of external genitalia with penectomy and orchiectomy, with vaginoplasty, clitoroplasty, labiaplasty, and breast augmentation along with estrogen supplements. Conclusion Surgical techniques alter the standard anatomy and make imaging interpretation challenging if radiologists are unfamiliar with expected post-operative appearances. It is important to recognize the complications related to surgical and non-surgical treatment of gender dysphoria to avoid interpretation errors. Furthermore, increasing the prevalence of transgender patients requires increased sensitivity when interpreting imaging studies to reduce the potential for misdiagnoses in reporting due to frequently incomplete available clinical history.