Publications by authors named "Maurice Barcos"

30 Publications

  • Page 1 of 1

Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia.

Cancer 2014 Feb 25;120(4):521-9. Epub 2013 Oct 25.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York.

Background: Several studies have suggested that low 25(OH) vitamin D3 levels may be prognostic in some malignancies, but no studies have evaluated their impact on treatment outcome in patients with acute myeloid leukemia (AML).

Methods: Vitamin D levels were evaluated in 97 consecutive, newly diagnosed, intensively treated patients with AML. MicroRNA expression profiles and single nucleotide polymorphisms (SNPs) in the 25(OH) vitamin D3 pathway genes were evaluated and correlated with 25(OH) vitamin D3 levels and treatment outcome.

Results: Thirty-four patients (35%) had normal 25(OH) vitamin D3 levels (32-100 ng/mL), 34 patients (35%) had insufficient levels (20-31.9 ng/mL), and 29 patients (30%) had deficient levels (<20 ng/mL). Insufficient/deficient 25(OH) vitamin D3 levels were associated with worse relapse-free survival (RFS) compared with normal vitamin D3 levels. In multivariate analyses, deficient 25(OH) vitamin D3 , smoking, European Leukemia Network genetic group, and white blood cell count retained their statistical significance for RFS. Several microRNAs and SNPs were associated with 25(OH) vitamin D3 levels, although none remained significant after multiple test corrections; one 25(OH) vitamin D3 receptor SNP, rs10783219, was associated with a lower complete remission rate (P = .0442) and with shorter RFS (P = .0058) and overall survival (P = .0011).

Conclusions: It remains to be determined what role microRNA and SNP profiles play in contributing to low 25(OH) vitamin D3 level and/or outcome and whether supplementation will improve outcomes for patients with AML.
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http://dx.doi.org/10.1002/cncr.28368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948325PMC
February 2014

Myelodysplastic syndromes and autoimmune diseases--case series and review of literature.

Leuk Res 2013 Aug 18;37(8):894-9. Epub 2013 May 18.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, USA.

Our objective was to recognize the association of autoimmune diseases (AD) in patients with myelodysplastic syndromes (MDS) and understand how this association could affect prognosis and management of both diseases. We describe our cohort of 10 patients and 34 patients reported in the English literature in addition to ten cohort studies. Interestingly, four cases showed improvement in AD after 5-azacitidine treatment. The mechanism(s) of the association between AD and MDS are discussed. Treatment could be targeted against AD, MDS or both, though based on recent reports, treating MDS with hypomethylating agents alone could improve the associated AD.
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http://dx.doi.org/10.1016/j.leukres.2013.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699612PMC
August 2013

Is obesity a prognostic factor for acute myeloid leukemia outcome?

Ann Hematol 2012 Mar 21;91(3):359-65. Epub 2011 Sep 21.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Obesity adversely affects outcome in pediatric acute lymphocytic leukemia and acute myeloid leukemia (AML). We asked if obesity, measured by body mass index (BMI), affected outcome in 329 adult AML patients treated with high-dose cytarabine and idarubicin-containing regimens administered according to actual body weight. Age ≥ 60, unfavorable karyotype, secondary AML, and positive smoking status had adverse impact on overall survival in a multivariate analysis, while BMI did not. We conclude that high BMI should not be a barrier to administer high-dose cytarabine-containing regimens for AML induction.
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http://dx.doi.org/10.1007/s00277-011-1319-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469945PMC
March 2012

Smoking adversely affects survival in acute myeloid leukemia patients.

Int J Cancer 2012 Mar 2;130(6):1451-8. Epub 2011 Aug 2.

Department of Medicine, Leukemia Section, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Smoking adversely affects hematopoietic stem cell transplantation outcome. We asked whether smoking affected outcome of newly diagnosed acute myeloid leukemia (AML) patients treated with chemotherapy. Data were collected on 280 AML patients treated with high-dose cytarabine and idarubicin-containing regimens at Roswell Park Cancer Institute who had smoking status data at diagnosis. Patients' gender, age, AML presentation (de novo vs. secondary), white blood cell (WBC) count at diagnosis, karyotype and smoking status (never vs. ever) were analyzed. Among the 161 males and 119 females with a median follow-up of 12.9 months, 101 (36.1%) had never smoked and 179 (63.9%) were ever smokers. The proportion of patients between never and ever smokers was similar to respect to age, AML presentation, WBC count at diagnosis or karyotype based on univariate analysis of these categorical variables. Never smokers had a significantly longer overall survival (OS) (60.32 months) compared to ever smokers (30.89; p = 0.005). In multivariate analysis incorporating gender, age, AML presentation, WBC count, karyotype and smoking status as covariates, age, karyotype and smoking status retained prognostic value for OS. In summary, cigarette smoking has a deleterious effect on OS in AML.
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http://dx.doi.org/10.1002/ijc.26151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202035PMC
March 2012

Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia.

Cancer 2011 Nov 31;117(21):4861-8. Epub 2011 Mar 31.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Background: Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of patients with acute myeloid leukemia (AML) and was correlated with an adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulated STAT3 activity within 6 hours associated with a reduced viability within 48 hours.

Methods: A phase 1 clinical trial to evaluate the biologically effective dose and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in patients with AML aged <60 years was conducted. Data were compared with 117 historic AML patients who had received treatment with Hidac/Ida.

Results: In total, 61 patients were enrolled onto 11 different dose levels (from 0.01 to 0.65 mg/kg ideal body weight). The MTD was 0.5 mg/kg. Compared with historic controls, patients who received ATO/Hidac/Ida, although they had similar pretreatment characteristics, had better overall survival (P = .039).

Conclusions: ATO priming may have improved the outcome of patients aged <60 years with AML who received Hidac/Ida. The current data suggested that ATO may enhance the effect of chemotherapy. The authors concluded that further studies of this novel combination are warranted.
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http://dx.doi.org/10.1002/cncr.26097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129468PMC
November 2011

Myeloid blastic transformation of myeloproliferative neoplasms--a review of 112 cases.

Leuk Res 2011 May 19;35(5):608-13. Epub 2010 Aug 19.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Blastic transformation of myeloproliferative neoplasms (MPN) is still poorly understood. We describe a cohort of 23 Roswell Park Cancer Institute (RPCI) patients and 89 additional cases from the English literature for whom biologic features were described. We initially compared our 23 patients to the 89 cases from the literature. Our population had significantly less patients with prior history of polycythemia vera (PV), shorter time from MPN diagnosis to blastic transformation, <3 prior therapies, more frequent use of hydroxyurea and erythropoietin and less frequent use of alkylating agents. Interestingly, the overall survival of the two cohorts from the time of blastic transformation was similar. We therefore looked at the outcome of the entire cohort (n=112). Patients with prior history of essential thrombocythemia survived longer than patients with prior history of myelofibrosis or PV. Further, patients with <3 prior therapies, those who lacked complex karyotype and those <60 year old at MPN diagnosis had significantly longer survival. Among the PRCI population, 20/23 patients underwent induction treatment with cytarabine and an anthracycline containing regimens; 12 achieved remission and their overall survival was significantly longer than those who did not. Three patients underwent an allogeneic transplantation and their survival was significantly longer than those who did not. Patients with <3 prior therapies, those who lack complex karyotype and those <60 at MPN diagnosis have longer survival following blastic transformation. Finally, allogeneic transplantation represents the only chance for long-term survival in these patients.
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http://dx.doi.org/10.1016/j.leukres.2010.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017628PMC
May 2011

Bortezomib in combination with pegylated liposomal doxorubicin and thalidomide is an effective steroid independent salvage regimen for patients with relapsed or refractory multiple myeloma: results of a phase II clinical trial.

Leuk Lymphoma 2009 Jul;50(7):1096-101

Department of Medicine, Roswell Park Cancer Institute, State University of New York, Buffalo, NY 14051, USA.

Novel agents have demonstrated enhanced efficacy when combined with other antimyeloma agents especially dexamethasone. The steroid doses employed in myeloma regimens are often poorly tolerated. Therefore, in a phase II clinical trial we investigated the efficacy of a steroid-free combination including bortezomib, pegylated liposomal doxorubicin and thalidomide (VDT regimen). Twenty-three patients with relapsed or refractory myeloma or other plasma cell cancers were treated with the VDT regimen. Patient had a median of five prior therapies and 65.2% were refractory to their last regimen. The overall response rates were 55.5% and 22%, respectively. The median progression free survival was 10.9 months (95% CI: 7.3-15.8) and the median overall survival was 15.7 months (95% CI: 9.1-not reached). Fatigue and sensory neuropathy were the most common side effects noted. We observe that VDT is an effective steroid-free regimen with ability to induce durable remission even in patients with refractory myeloma.
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http://dx.doi.org/10.1080/10428190902912460DOI Listing
July 2009

Treating octogenarian and nonagenarian acute myeloid leukemia patients--predictive prognostic models.

Cancer 2009 Jun;115(11):2472-81

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Background: Treating the octogenarian and nonagenarian patients who have acute myeloid leukemia (AML) with intensive chemotherapy is controversial. Several models to predict outcome were proposed, including the use of a comorbidity index. However, it is unclear whether the Charlson comorbidity index (CCI) or the hematopoietic cell transplant comorbidity index (HCTCI) is more sensitive.

Methods: The authors analyzed their experience with 92 patients aged >or=80 years who had AML. Patients' pretreatment characteristics and their treatment outcomes were recorded.

Results: All patients were offered intensive treatment; 59 patients (64%) were treated intensively with a variety of regimens, whereas 33 patients (36%) elected to receive supportive care. The CCI and the HCTCI had similar predictive ability for outcome in both groups. A multivariate analyses of prognostic factors identified near-normal albumin (48% of patients; 1-year survival rate, >27%) as a favorable factor for the whole cohort, age <83 years (47% of patients; 1-year survival rate, >25%) and nonmonocytic morphology (75% of patients; 1-year survival rate, >26%) as favorable factors for the intensively treated cohort, and bone marrow blasts <46% (50% of patients; 1-year survival rate, >19%) as a favorable factor for patients who received supportive care.

Conclusions: This retrospective analysis was developed to assist in treatment decisions for octogenarian and nonagenarian patients with AML. The findings will need validation in a prospective study.
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http://dx.doi.org/10.1002/cncr.24285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688783PMC
June 2009

Metachronous and synchronous presentation of acute myeloid leukemia and lung cancer.

Leuk Res 2009 Sep 31;33(9):1208-11. Epub 2009 Jan 31.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Smoking is associated with both acute myeloid leukemia (AML) and lung cancer. We therefore searched our database for concomitant presentation of AML and lung cancer. Among 775 AML cases and 5225 lung cancer cases presenting to Roswell Park Cancer Institute between the years January 1992 and May 2008 we found 12 (1.5% of AML cases; 0.23% of lung cancer cases) cases (seven metachronous and five synchronous) with AML and lung cancer. All but one patient were smokers. There were no unique characteristic of either AML or lung cancer in these patients. Nine patients succumbed to AML, one died from an unrelated cause while undergoing treatment for AML, one died of lung cancer and one patient is alive after allogeneic transplantation for AML. In summary, this study supports the need for effective smoking cessation programs.
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http://dx.doi.org/10.1016/j.leukres.2008.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749654PMC
September 2009

Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice.

J Immunol 2008 May;180(10):7009-18

State University of New York, Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, Buffalo, NY 14214, USA.

Non-disrupted pieces of primary human lung tumor implanted into NOD-scid IL2Rgamma(null) mice consistently result in successful xenografts in which tissue architecture, including tumor-associated leukocytes, stromal fibroblasts, and tumor cells are preserved for prolonged periods with limited host-vs-graft interference. Human CD45(+) tumor-associated leukocytes within the xenograft are predominantly CD3(+) T cells with fewer CD138(+) plasma cells. The effector memory T cells that had been shown to be quiescent in human lung tumor microenvironments can be activated in situ as determined by the production of human IFN-gamma in response to exogenous IL-12. Plasma cells remain functional as evidenced by production of human Ig. Significant levels of human IFN-gamma and Ig were detected in sera from xenograft-bearing mice for up to 9 wk postengraftment. Tumor-associated T cells were found to migrate from the microenvironment of the xenograft to the lung, liver, and primarily the spleen. At 8 wk postengraftment, a significant portion of cells isolated from the mouse spleens were found to be human CD45(+) cells. The majority of CD45(+) cells were CD3(+) and expressed a phenotype consistent with an effector memory T cell, consisting of CD4(+) or CD8(+) T cells that were CD45RO(+), CD44(+), CD62L(-), and CD25(-). Following adoptive transfer into non-tumor bearing NOD-scid IL2Rgamma(null) mice, these human T cells were found to expand in the spleen, produce IFN-gamma, and maintain an effector memory phenotype. We conclude that the NOD-scid IL2Rgamma(null) tumor xenograft model provides an opportunity to study tumor and tumor-stromal cell interactions in situ for prolonged periods.
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http://dx.doi.org/10.4049/jimmunol.180.10.7009DOI Listing
May 2008

Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis.

Cancer Genet Cytogenet 2008 Apr;182(2):126-9

Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA.

Mitoxantrone is a DNA-topoisomerase 2 inhibitor used as a single agent for treatment of relapsing-remitting or progressive multiple sclerosis (MS). We present here two patients treated with mitoxantrone for MS who subsequently developed acute promyelocytic leukemia (APL). These constitute, to our knowledge, the eighth and ninth reports of APL in patients treated with mitoxantrone for MS. Topoisomerase 2 inhibitors are associated with therapy-related acute myeloid leukemia (t-AML) with 11q23 abnormalities, but therapy-related APL (t-APL) is less common, and documentation of nine cases of t-APL after mitoxantrone therapy for MS suggests a specific association.
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http://dx.doi.org/10.1016/j.cancergencyto.2008.01.004DOI Listing
April 2008

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following treatment of acute myeloid leukemia: possible role of cytarabine.

Leuk Res 2008 Jul 21;32(7):1043-8. Epub 2008 Feb 21.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, United States.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) have been reported only rarely following treatment of AML. We report five patients treated for de novo AML who developed t-MDS/t-AML, all with chromosome 7 abnormalities, including -7, del(7)(q22q36) and del(7)(p11.22p22). All had been treated with cytarabine, topoisomerase 2 inhibitors and granulocyte or granulocyte-monocyte colony-stimulating factor and three with alkylating agents as part of autologous transplant regimens. These cases further document t-MDS/t-AML as a complication of therapy for AML. Presence of chromosome 7 abnormalities in patients with and without prior alkylating agent therapy suggests possible association with the antimetabolite cytarabine.
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http://dx.doi.org/10.1016/j.leukres.2007.11.006DOI Listing
July 2008

Translocation (4;11)(p12;q23) with rearrangement of FRYL and MLL in therapy-related acute myeloid leukemia.

Cancer Genet Cytogenet 2007 Sep;177(2):143-6

Clinical Cytogenetics Laboratory, DNA Microarray and Genomics Facility, Departments of Pathology and Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Reciprocal chromosomal translocations involving the MLL gene at chromosome region 11q23 are recurring cytogenetic abnormalities in both de novo and therapy-related acute myeloid leukemia (AML) and in acute lymphoblastic leukemia. We report a t(4;11)(p12;q23) with rearrangement of MLL and FRYL (also known as AF4p12), a human homolog to the furry gene of Drosophila, in an adult patient with therapy-related AML after fludarabine and rituximab therapy for small lymphocytic lymphoma and radiation therapy for breast carcinoma. To our knowledge, t(4;11)(p12;q23) has been reported in two previous patients, and MLL and FRYL rearrangement was demonstrated in one of them. Both of the previous patients had therapy-related leukemias after exposure to topoisomerase II inhibitors, whereas our patient had received cytotoxic therapy that did not include a topoisomerase II inhibitor. Thus, t(4;11)(p12;q23) with MLL and FRYL involvement represents a new recurring 11q23 translocation, to date seen only in therapy-related acute leukemias.
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http://dx.doi.org/10.1016/j.cancergencyto.2007.05.021DOI Listing
September 2007

High dose CHOP: a phase II study of initial treatment in aggressive non-Hodgkin lymphoma. Cancer and Leukemia Group B 9351.

Leuk Lymphoma 2007 May;48(5):870-80

University of Minnesota, Minneapolis, MN 55455, USA.

Cyclophosphamide and doxorubicin, two important drugs in the treatment of lymphoma, exhibit a relationship between dose and fractional cell kill, and because of their toxicity profiles, they are candidates for significant dose escalation. We performed a phase II trial to determine the response rate, toxicity, and feasibility of escalated doses of both drugs as part of high dose CHOP in diffuse aggressive lymphoma. Patients who had advanced, previously untreated diffuse aggressive lymphomas (IWF E-H) and an International Prognostic Index of intermediate to high risk were eligible. Treatment was cyclophosphamide 2 gm/m(2)/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m(2)), doxorubicin 35 mg/m(2)/day as a continuous infusion on Days 1 and 2 (total 70 mg/m(2)), vincristine 1.4 mg/m(2) (maximum 2 mg) on Day 1 and prednisone 100 mg/day orally on Days 1 - 5 repeated every 3 weeks for a total of four cycles. G-CSF, prophylactic antibiotics, and mesna were provided. A total of 99 patients were enrolled; 98 received therapy. Major toxicities were Grade 4 neutropenia and thrombocytopenia occurring in 97% and 92%, respectively. Serious infections occurred in 53%. Treatment-related mortality was 2%. The overall response rate is 85%, and two-year failure free and overall survival are 39% and 64%, respectively. Persistent or relapsed lymphoma was the overwhelming cause of death. Six patients have developed AML or MDS. In view of the substantial toxicity accompanying high dose CHOP, the observed outcome suggests that its efficacy is not sufficient to make further study feasible.
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http://dx.doi.org/10.1080/10428190701259758DOI Listing
May 2007

Acute myeloid leukemia developing during imatinib mesylate therapy for chronic myeloid leukemia in the absence of new cytogenetic abnormalities.

Leuk Res 2007 Nov 27;31(11):1589-92. Epub 2007 Mar 27.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate produces a high rate of cytogenetic responses in patients with Philadelphia (Ph)-positive chronic myeloid leukemia (CML), but secondary clonal chromosome abnormalities may develop in Ph-negative cells, and acute myeloid leukemia (AML) has been reported in patients with secondary chromosome abnormalities. We report a patient who developed AML during imatinib treatment of Ph-positive CML despite a cytogenetic response and absence of secondary chromosome abnormalities. Thus, development of AML as a rare event in CML patients with cytogenetic responses to imatinib therapy does not depend on the development of secondary cytogenetic abnormalities.
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http://dx.doi.org/10.1016/j.leukres.2007.01.022DOI Listing
November 2007

Routine immunophenotyping in acute leukemia: Role in lineage assignment and reassignment.

Cytometry B Clin Cytom 2006 Sep;70(5):329-34

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Diagnostic evaluation of acute leukemia at Roswell Park Cancer Institute has routinely included immunophenotyping by multiparameter flow cytometry. In a retrospective analysis of 646 cases, morphology and cytochemistry established lineage in 612, but not in 34 (5%), of which 26, 5, and 3 were myeloid, undifferentiated, and lymphoid, respectively, based on immunophenotyping. In addition, immunophenotyping changed the lineage assigned based on morphology and cytochemistry in 11 cases (2%); 8 changed from lymphoid to myeloid, and 3 from myeloid to lymphoid. The data support routine inclusion of at least limited immunophenotyping in the diagnostic evaluation of acute leukemia.
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http://dx.doi.org/10.1002/cyto.b.20112DOI Listing
September 2006

Isochromosome 1q in a myelodysplastic syndrome after treatment for acute promyelocytic leukemia.

Cancer Genet Cytogenet 2006 Jun;167(2):155-60

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

A growing body of literature reports therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) in patients treated successfully for acute promyelocytic leukemia (APL). We report a t-MDS with an isochromosome 1q as a sole abnormality, 47,XY,+1,i(1)(q10), in a 46-year-old man with APL 14 years after he was treated with cytosine arabinosine and daunorubicin. The literature on t-MDS/t-AML after APL therapy and on isochromosome 1q is reviewed.
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http://dx.doi.org/10.1016/j.cancergencyto.2005.11.013DOI Listing
June 2006

Genomic profiling of myeloid sarcoma by array comparative genomic hybridization.

Genes Chromosomes Cancer 2005 Dec;44(4):373-83

Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Myeloid sarcoma (MS) is a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site. In this study, seven cases of MS [stomach (1), testis (1), skin (2), and lymph node (3)] and 3 synchronous and 1 follow-up bone marrow (BM) samples were studied for genomic abnormalities using array comparative genomic hybridization (array-CGH). Array-CGH construction used approximately 5,400 bacterial artificial chromosome clones from the RPCI-11 library, spanning the human genome. Data were analyzed using the DNAcopy software and custom heuristics. All MS cases had genomic abnormalities detected by array-CGH. Unbalanced genomic abnormalities in five MS cases were confirmed by conventional cytogenetics (CC) and/or fluorescence in situ hybridization (FISH); these abnormalities included loss of 4q32.1-q35.2, 6q16.1-q21, and 12p12.2-p13.2 and gain of 8q21.2-q24.3, 8, 11q21-q25, 13q21.32-q34, 19, and 21. Array-CGH was also invaluable in identifying possible deletions, partner translocations, and breakpoints that were questionable by CC. The remaining two MS cases had genomic aberrations detected by array-CGH, but were not studied further by CC/FISH. Chromosome 8 was most commonly abnormal (3/7 cases). Identical genomic abnormalities were demonstrated in MS and in synchronous BM in two cases. These results demonstrate that array-CGH is a powerful tool to screen MS tissue for unbalanced genomic abnormalities, allowing identification of chromosome abnormalities when concurrent BM is nonanalyzable or nonleukemic.
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http://dx.doi.org/10.1002/gcc.20239DOI Listing
December 2005

Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients.

J Clin Oncol 2005 Jul;23(19):4287-97

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, Mason Farm Rd, Chapel Hill, NC 27599-7295, USA.

Purpose: HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients.

Methods: This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology.

Results: Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (kappa = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy.

Conclusion: FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.
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http://dx.doi.org/10.1200/JCO.2005.11.012DOI Listing
July 2005

Human CD4+ effector memory T cells persisting in the microenvironment of lung cancer xenografts are activated by local delivery of IL-12 to proliferate, produce IFN-gamma, and eradicate tumor cells.

J Immunol 2005 Jan;174(2):898-906

Department of Microbiology and Immunology, State University of New York, Buffalo, NY 14214, USA.

The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-gamma. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45(+) leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-alpha. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4(+) effector memory T cell. We conclude that quiescent CD4(+) effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-gamma, leading to tumor cell eradication.
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http://dx.doi.org/10.4049/jimmunol.174.2.898DOI Listing
January 2005

Extra copies of chromosome 2 are a recurring aberration in ALK-negative lymphomas with anaplastic morphology.

Mod Pathol 2005 Feb;18(2):235-43

Department of Pathology, Buffalo General Hospital, The State University of New York, Buffalo, NY, USA.

The purpose of this study was to evaluate fluorescence in situ hybridization abnormalities of the 2p23 anaplastic lymphoma kinase (ALK) gene loci in lymphomas with anaplastic morphology. We studied 24 anaplastic large cell lymphomas (ALCL) classified by World Health Organization criteria [17 primary nodal/systemic (10 ALK+, 7 ALK-), seven primary cutaneous], and 17 additional non-Hodgkin's lymphomas [one ALK+ B-lineage lymphoma, 14 ALK- diffuse large B-cell lymphomas (seven anaplastic variants, five nonanaplastic, two secondary CD30+), two follicular lymphomas]. ALK- lymphomas with anaplastic morphology showed extra nonrearranged anaplastic lymphoma kinase gene loci (P=0.004) due to trisomy 2 irrespective of the following factors: B or T/null phenotype (P=0.315), diagnostic categories of systemic or cutaneous ALCL or the above-mentioned B-cell lymphomas (P=0.131), and CD30 positivity by immunohistochemistry (P=1.000). Trisomy 2 was absent in all ALK+ lymphomas (P=0.009), which showed rearranged ALK gene loci (P<0.001). Whether trisomy 2 is a primary or secondary event that leads to ALK- lymphomas cannot be determined from this study. Its presence in secondary B-cell lymphomas suggests that trisomy 2 may be a secondary cytogenetic aberration in lymphomas in general. Further investigation of this finding is necessary to further our understanding of the heterogeneous group of ALK- lymphomas.
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http://dx.doi.org/10.1038/modpathol.3800299DOI Listing
February 2005

Long-term survival with allogeneic stem cell transplant and donor lymphocyte infusion following salvage therapy with anti-CD52 monoclonal antibody (Campath) in a patient with alpha/beta hepatosplenic T-cell non-Hodgkin's lymphoma.

Leuk Lymphoma 2004 Aug;45(8):1673-5

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Hepatosplenic T-cell non-Hodgkin's lymphoma (HSTCL) is a rare, aggressive form of NHL, with a median survival of approximately 8 months. We were able to successfully induce complete remission in a patient with alpha/beta HSTCL who was refractory to multiple prior chemotherapy regimens, using the humanized anti-CD52 monoclonal antibody alemtuzumab (Campath). Once disease was controlled, the patient was able to undergo allogeneic stem cell transplantation (SCT), which resulted in complete remission. Furthermore, upon relapse, we were able to re-induce complete clinical and molecular remission with donor lymphocyte infusions. At Day 655 (post-SCT), the patient remains in complete remission. These data suggest a potential role for alemtuzumab and allogeneic SCT in the treatment of T-cell NHL.
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http://dx.doi.org/10.1080/10428190310001609924DOI Listing
August 2004

Precursor B lymphoblastic leukemia with surface light chain immunoglobulin restriction: a report of 15 patients.

Am J Clin Pathol 2004 Apr;121(4):512-25

Department of Pathology, Buffalo General Hospital, the State University of New York at Buffalo, USA.

We describe 15 patients (9 children) with precursor B-cell (pB) acute lymphoblastic leukemia (ALL) with surface immunoglobulin (sIg) light chain restriction revealed by flow cytometric immunophenotyping (FCI). The same sIg+ immunophenotype was present at diagnosis and in 3 relapses in 1 patient. In 15 patients, blasts were CD19+ CD10+ (bright coexpression) in 14, CD34+ in 12, surface kappa+ in 12, surface lambda+ in 3; in 8 of 8, terminal deoxyribonucleotidyl transferase (TdT)+; and in 4, surface IgD+ in 2 and surface IgM+ in 1. The 3 CD34- cases included 1 TdT+ case, 1 with t(1;19)(q23;p13), and 1 infant with 70% marrow blasts. One adult had CD10- CD19+ CD20- CD22+ CD34+ TdT+ sIg+ blasts with t(2;11)(p21;q23). Blasts were L1 or L2 in all cases (French-American-British classification). Karyotypic analysis in 12 of 12 analyzable cases was negative for 8q24 (myc) translocation. Karyotypic abnormalities, confirmed by fluorescence in situ hybridization in 6 cases, included hyperdiploidy, t(1;19)(q23;p13), t(12;21)(p13;q22), t(9;22)(q34;q11), t(2;11)(p21;q23), and trisomy 12. The sIg light chain restriction in pB ALL might be present in neoplasms arising from the early, intermediate, and late stages of precursor B-cell maturation; sIg light chain restriction revealed by FCI does not necessarily indicate a mature B-cell phenotype, further emphasizing the importance of a multidisciplinary approach to diagnosing B-lymphoid neoplasms.
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http://dx.doi.org/10.1309/WTXC-Q5NR-ACVX-TYBYDOI Listing
April 2004

Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251.

Cancer 2004 Apr;100(7):1438-48

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

Background: The objective of the current study was to evaluate the efficacy of intensive chemotherapy with and without cranial radiation for central nervous system (CNS) prophylaxis in adults with Burkitt leukemia or lymphoma.

Methods: Patients received 18 weeks of therapy. Prophylactic cranial radiation (2400 centigrays) and 12 doses of triple intrathecal chemotherapy were administered to the first cohort of patients. A subsequent cohort received the same therapy, with the exceptions that intrathecal therapy was reduced to six doses and radiotherapy was administered only to high-risk individuals.

Results: The median follow-up durations were 6.8 years in Cohort 1 and 4.1 years in Cohort 2. Three occurrences of transverse myelitis, 2 severe neuropathies, 3 cases of aphasia, and 1 case of blindness were documented in the first cohort of 52 patients (Cohort 1). In the subsequent cohort of 40 patients (Cohort 2), none of these occurrences were observed, and patients experienced less neurologic toxicity overall (61% vs. 26%; P=0.001). Responses were similar, and the 3-year event-free survival rate was 0.52 (95% confidence interval, 0.38-0.65) for Cohort 1 and 0.45 (0.29-0.60) for Cohort 2.

Conclusions: Intensive, short-duration chemotherapy with less intensive CNS prophylaxis led to control at this sanctuary site with little neurotoxicity and may be curative for adults with Burkitt leukemia or lymphoma.
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http://dx.doi.org/10.1002/cncr.20143DOI Listing
April 2004

Massive hyperdiploidy and tetraploidy in acute myelocytic leukemia and myelodysplastic syndrome.

Cancer Genet Cytogenet 2004 Jan;148(1):29-34

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Massive hyperdiploidy (>50 chromosomes) and tetraploidy (4n) are rare cytogenetic abnormalities in myelocytic malignancies, and their significance is unknown. We report on 11 patients with acute myelocytic leukemia (AML) and two patients with a myelodysplastic syndrome (MDS) with massive hyperdiploidy (10 patients) or tetraploidy (3 patients) seen at our institution over a 12-year period. Eleven patients were male and two were female. Age range was 44-84 years (median, 70 years). Only one AML patient had a previous MDS, and no patient had therapy-related disease. One or more copies of chromosomes 8 and 19 were gained in eight patients each; other frequently gained chromosomes included 13, 15, and 21. Eight patients had structural abnormalities in addition to chromosome gain; del(5q) was most common (five patients). Eleven patients received induction chemotherapy, but only four achieved complete remission. Survival ranged from 1 to 22 months, with a median of 6 months. We conclude that massive hyperdiploidy and tetraploidy are infrequent abnormalities in AML and MDS, are seen primarily in de novo disease in older male patients and are associated with a low remission rate and short survival. Massive hyperdiploidy and tetraploidy define a prognostically unfavorable cytogenetic group in de novo AML.
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http://dx.doi.org/10.1016/s0165-4608(03)00214-0DOI Listing
January 2004

Phenotypic heterogeneity of B cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Am J Clin Pathol 2003 Jun;119(6):824-32

Dept of Pathology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226, USA.

Although some studies have examined the expression of aberrant markers such as CD2, CD7, CD10, CD13, CD33, and CD34 on B cells in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a uniform multiparametric analysis of the frequency of expression of these markers using stringent criteria is lacking. By using 3-color flow cytometry, we analyzed 117 cases (bone marrow, 71; blood, 31; lymph nodes, 15) for coexpression of aberrant markers with CD19. Marker expression was considered positive when present on at least 20% of CD19+ cells. Of 117 cases, 40 (34.2%) showed expression of 1 or more aberrant markers. Expression of 4 aberrant markers was seen in 1 case, 3 in 4 cases, 2 in 15 cases, and 1 in 20 cases. Kaplan-Meier survival curves and the log-rank test revealed that the group with aberrant markers showed significantly shortened overall survival compared with the group without aberrant markers (P < .001). There is considerable phenotypic heterogeneity in CLL/SLL, and expression of aberrant markers indicates aggressiveness.
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http://dx.doi.org/10.1309/4AGU-T3LK-EURD-7T7KDOI Listing
June 2003

Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B.

J Clin Oncol 2003 Jan;21(1):5-15

University of Minnesota Medical School, Division of Hematology, Oncology and Transplantation, Minneapolis, MN 55455, USA.

Purpose: The array of options for the initial management of follicular small cleaved lymphoma (FSCL) and follicular mixed lymphoma (FML) ranges from little or no therapy to the use of intensive combinations of drugs. The Cancer and Leukemia Group B (CALGB) compared two contrasting approaches: a single agent, and combination chemotherapy capable of curing diffuse aggressive lymphomas.

Patients And Methods: A total of 228 patients with stage III or IV FSCL or FML were randomized to cyclophosphamide or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Treatment was continued in responders for 2 years beyond maximal response. The primary end point was survival in the most common subtype, FSCL.

Results: Ninety-one percent of all patients responded; complete responses were seen in 66% of those treated with cyclophosphamide and in 60% treated with CHOP-B (P =.36). At 10 years with either cyclophosphamide or CHOP-B, respectively, overall time to failure (25% failure free v 33%; P =.107) and survival (44% alive v 46%; P =.79) were similar by treatment. Outcomes in FSCL also were similar. In 46 patients with FML, at 10 years the combination was associated with better failure-free (9% v 48%; P =.005) and overall (25% v 61%; P =.024) survival. Acute toxic effects were more common with combination chemotherapy. Second malignancies, which might be attributed to treatment, were seen with both approaches.

Conclusion: There is no advantage to the initial use of the relatively intensive combination, CHOP-B, for patients with FSCL compared with the less toxic single agent, cyclophosphamide. However, in an unplanned subgroup analysis, patients with FML who received the combination experienced improved disease control and survival.
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http://dx.doi.org/10.1200/jco.2003.05.128DOI Listing
January 2003