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1.
Ann Oncol ; 28(11): 2866-2873, 2017 Nov 01.
Article in English | MEDLINE | ID: mdl-28945887

ABSTRACT

BACKGROUND: Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative. PATIENTS AND METHODS: Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer. RESULTS: At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%). CONCLUSIONS: GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.


Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Circulating Tumor DNA/genetics , Clinical Decision-Making , High-Throughput Nucleotide Sequencing/methods , Mutation , Receptors, Estrogen/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Follow-Up Studies , Genomics/methods , Humans , Middle Aged , Neoplasm Metastasis , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/genetics
3.
Blood Cancer J ; 7(2): e535, 2017 02 24.
Article in English | MEDLINE | ID: mdl-28234347

ABSTRACT

The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.


Subject(s)
Multiple Myeloma/genetics , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Humans , Multiple Myeloma/pathology , Neoplasm Recurrence, Local , Prognosis , Retinoblastoma Protein/genetics
4.
Leukemia ; 30(5): 1018-24, 2016 05.
Article in English | MEDLINE | ID: mdl-26854026

ABSTRACT

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal disorders involving hematopoietic stem and progenitor cells and are associated with myeloproliferation, splenomegaly and constitutional symptoms. Similar signs and symptoms can also be found in patients with chronic inflammatory diseases, and inflammatory processes have been found to play an important role in the pathogenesis and progression of MPNs. Signal transduction pathways involving JAK1, JAK2, STAT3 and STAT5 are causally involved in driving both the malignant cells and the inflammatory process. Moreover, anti-inflammatory and immune-modulating drugs have been used successfully in the treatment of MPNs. However, to date, many unresoved issues remain. These include the role of somatic mutations that are present in addition to JAK2V617F, CALR and MPL W515 mutations, the interdependency of malignant and nonmalignant cells and the means to eradicate MPN-initiating and -maintaining cells. It is imperative for successful therapeutic approaches to define whether the malignant clone or the inflammatory cells or both should be targeted. The present review will cover three aspects of the role of inflammation in MPNs: inflammatory states as important differential diagnoses in cases of suspected MPN (that is, in the absence of a clonal marker), the role of inflammation in MPN pathogenesis and progression and the use of anti-inflammatory drugs for MPNs. The findings emphasize the need to separate the inflammatory processes from the malignancy in order to improve our understanding of the pathogenesis, diagnosis and treatment of patients with Philadelphia-negative MPNs.


Subject(s)
Inflammation/drug therapy , Myeloproliferative Disorders/drug therapy , Neoplasms/pathology , Anti-Inflammatory Agents/therapeutic use , Clone Cells/pathology , Humans , Myeloproliferative Disorders/pathology
5.
Bone Marrow Transplant ; 50(5): 628-36, 2015 May.
Article in English | MEDLINE | ID: mdl-25665047

ABSTRACT

At present, allo-SCT is the only curative treatment for patients with myelofibrosis (MF). Unfortunately, a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at the time of diagnosis. The approval of the first JAK inhibitor, ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support for assessing the drug's candidacy in the peritransplant period. The drug's precise impact on clinical outcome following allo-SCT is currently not known; nor are the drug's long-term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who undergo allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology Annual Meeting in New Orleans, USA on 6 December 2013, and the European Hematology Association's Annual Meeting in Milan, Italy on 13 June 2014. This document summarizes the results of these efforts.


Subject(s)
Janus Kinases/antagonists & inhibitors , Primary Myelofibrosis/therapy , Pyrazoles/therapeutic use , Stem Cell Transplantation , Allografts , Humans , Nitriles , Primary Myelofibrosis/enzymology , Pyrimidines
6.
Curr Med Chem ; 19(26): 4399-413, 2012.
Article in English | MEDLINE | ID: mdl-22830345

ABSTRACT

Myeloproliferative neoplasms (MPN) are debilitating stem cell-derived clonal myeloid malignancies. Conventional treatments for the BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have, so far, been unsatisfactory. Following the discovery of dysregulated JAK-STAT signaling in patients with MPN, many efforts have been directed toward the development of molecularly targeted therapies, including inhibitors of JAK1 and JAK2. Ruxolitinib (previously known as INCB018424; Incyte Corporation, Wilmington, Delaware, USA) is a rationally designed potent oral JAK1 and JAK2 inhibitor that has undergone clinical trials in patients with PV, ET, and PMF. Ruxolitinib was approved on November 16, 2011 by the United States Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis (MF), including patients with PMF, post-PV MF, and post-ET MF. In randomized phase III studies, ruxolitinib treatment resulted in significant and durable reductions in splenomegaly and improvements in disease-related symptoms in patients with MF compared with placebo or best available therapy. The most common adverse events were anemia and thrombocytopenia, which were manageable and rarely led to discontinuation. This review addresses the cellular and molecular biology, and the clinical management of MPN.


Subject(s)
Myeloproliferative Disorders/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Humans , Myeloproliferative Disorders/metabolism , Nitriles , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyrimidines , Signal Transduction
7.
J Clin Oncol ; 21(1): 20-7, 2003 Jan 01.
Article in English | MEDLINE | ID: mdl-12506165

ABSTRACT

PURPOSE: To determine clinical features and patterns of outcome of primary testicular diffuse large B-cell lymphomas (DLCL). PATIENTS AND METHODS: A retrospective international survey of 373 patients with primary testicular DLCL. RESULTS: Most patients presented with localized disease (stage I to II), and the median age at diagnosis was 66 years (range, 19 to 91 years). Anthracycline-based chemotherapy was administered to 255 patients (68%), and prophylactic intrathecal chemotherapy was given to 68 patients (18%); 133 patients (36%) received prophylactic scrotal radiotherapy. Median overall survival was 4.8 years, and median progression-free survival was 4 years. The survival curves showed no clear evidence of a substantial proportion of cured patients. A favorable international prognostic index score (IPI), no B-symptoms, the use of anthracyclines, and prophylactic scrotal radiotherapy were significantly associated with longer survival at multivariate analysis. However, even for patients with stage I disease and good-risk IPI, the outcome seems worse than what was reported for DLCL at other sites. At a median follow-up of 7.6 years, 195 patients (52%) had relapsed. Extranodal recurrence was reported in 140 cases. Relapses in CNS were detected in 56 patients (15%) up to 10 years after presentation. A continuous risk of recurrence in the contralateral testis was seen in patients not receiving scrotal radiotherapy. CONCLUSION: Testicular DLCL is characterized by a particularly high risk of extranodal relapse even in cases with localized disease at diagnosis. Anthracycline-based chemotherapy, CNS prophylaxis, and contralateral testicular irradiation seem to improve the outcome. Their efficacy is under evaluation in a prospective clinical trial.


Subject(s)
Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/therapy , Testicular Neoplasms/diagnosis , Testicular Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Analysis of Variance , Disease-Free Survival , Humans , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Middle Aged , Prognosis , Recurrence , Retrospective Studies , Survival Rate , Testicular Neoplasms/mortality , Treatment Outcome
8.
Br J Haematol ; 115(3): 569-74, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11736937

ABSTRACT

We identified 103 consecutive patients who, 5 years after allogeneic transplantation for chronic myeloid leukaemia (CML), were in molecular remission (MR). The 103 patients were divided into three groups on the basis of reverse transcription-polymerase chain reaction (RT-PCR) studies for BCR-ABL transcripts in the first 5 years post transplant: Group A comprised 63 patients who had been continuously PCR negative; Group B comprised 20 patients with one or more positive PCR result but only at a low level; and Group C comprised 20 patients who had fulfilled the criteria for molecular relapse, been treated with donor lymphocyte infusions (DLI) and had thereafter regained complete MR within the 5-year post-transplant period. The median follow-up for all 103 patients was 8.4 years from transplant (range 5-17.6 years). In group A only one patient relapsed at 9.2 years. In group B eight patients (40%) relapsed: six at molecular, one at cytogenetic and one haematological levels. The actuarial probabilities of survival at 10 years for patients in Groups A, B and C were 97.4%, 92.9% and 100% respectively; the probabilities of relapse were 3%, 54% and 0% respectively. We conclude that molecular studies during the first 5 years post transplant can help to predict long-term leukaemia-free survival and, possibly, cure of CML.


Subject(s)
Fusion Proteins, bcr-abl/genetics , Hematopoietic Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adolescent , Adult , Blood Transfusion, Autologous , Child , Female , Follow-Up Studies , Genetic Markers , Humans , Lymphocyte Transfusion , Male , Middle Aged , Prognosis , Recurrence , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Survival Analysis , Time Factors , Transplantation, Homologous
10.
11.
Ann Saudi Med ; 16(1): 53-5, 1996.
Article in English | MEDLINE | ID: mdl-17372409

ABSTRACT

Saudi Arabia appears to have an usually high incidence of hepatocellular carcinoma, which has been causally associated with a high prevalence of hepatitis B virus (HBV). Other risk factors, including hepatitis C virus (HCV) infection are currently not known. A study was undertaken to establish the risk factors and clinicopathological features of hepatocellular carcinoma in Saudi Arabia. The profiles of 140 patients with a biopsy-proven hepatocellular carcinoma were analyzed. Demographic data revealed a strong male preponderance (male:female = 5.7:1) and 114 patients (81.4%) were found to have or have had HBV infection. The data concerning HCV infection were incomplete, but suggest a causal association (nine of 33 patients). An absence of alcohol as a risk factor was noteworthy. Clinical jaundice and right upper quadrant abdominal pain were the most frequent presenting features. Abnormal liver function tests were present in 125 patients 989.3%) at diagnosis and serum alpha fetoprotein was elevated in 112 patients (80%). The majority of patients had locally advanced, inoperable disease and the prognosis was uniformly dismal. The median survical was 61 days.

14.
Stem Cells ; 13(4): 355-9, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7549894

ABSTRACT

The relationships among thrombocytosis, abnormal platelet aggregation and altered hemostasis in primary thrombocythemia remain poorly understood. Consequently, the appropriate management of asymptomatic patients is controversial and needs to be individualized. For symptomatic patients, conventional therapy, usually hydroxyurea, is directed primarily at lowering the platelet count by suppression of megakaryocyte activity. Recombinant interferon alpha can selectively lower platelet counts and may offer a reasonable alternative. Recent experience with anagrelide is also most promising in both symptomatic and asymptomatic patients. Current thoughts on the pathogenesis and management guidelines are presented here.


Subject(s)
Thrombocytosis/etiology , Aspirin/therapeutic use , Diagnosis, Differential , Humans , Hydroxyurea/therapeutic use , Interferon Type I/therapeutic use , Myeloproliferative Disorders/diagnosis , Platelet Aggregation Inhibitors/therapeutic use , Plateletpheresis , Quinazolines/therapeutic use , Recombinant Proteins , Thrombocytosis/diagnosis , Thrombocytosis/therapy
15.
Leuk Lymphoma ; 14(3-4): 331-4, 1994 Jul.
Article in English | MEDLINE | ID: mdl-7950923

ABSTRACT

Myelosuppression is often the major limiting factor that prevents timely administration of cytotoxic chemotherapeutic agents, particularly in chemoresponsive malignancies. A study was designed to assess the role of GM-CSF in preventing myelosuppression in patients with intermediate-grade non-Hodgkin's lymphoma receiving combination chemotherapy (Cyclophosphamide, Vincristine, Prednisone and Epirubicin or Mitozantrone, +/- Bleomycin). A total of 24 patients were entered and data collated from 20 of them are amenable to analysis. All patients received the first chemotherapy cycle without GM-CSF and the second with GM-CSF (250 mg/m2 subcutaneously twice daily for 5 days commencing on the 5th day following chemotherapy). By entering only those patients who had suffered myelosuppression following chemotherapy, an internal control was established. GM-CSF administration significantly reduced the degree of neutropenia and leucopenia. The mean nadir white blood cell (WBC) and absolute neutrophil counts (ANC) were 2.88 x 10(9)/L and 0.97 x 10(9)/L in cycle 1 as compared to 5.95 x 10(9)/L and 2.92 x 10(9)/L respectively, in cycle 2 (p = 0.05 and 0.02, respectively). Eight patients (40%) had febrile neutropenias and 13 patients (65%) experienced a treatment delay by a median of 8 days during cycle 1. Six patients (30%) had febrile neutropenias and 2 patients (10%) had a treatment delay of 3 days during cycle 2. Reversible toxicity was seen in the majority of patients: bone pains (60%), skin rashes (35%), arthralgias (25%), and altered taste sensation (10%). No patient developed the capillary leak syndrome. This study demonstrates the efficacy of GM-CSF in preventing chemotherapy-induced myelosuppression.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Hematologic Diseases/prevention & control , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Hematologic Diseases/chemically induced , Humans , Leukocyte Count/drug effects , Lymphoma, Non-Hodgkin/blood , Male , Recombinant Proteins/therapeutic use
16.
Acta Oncol ; 33(5): 537-9, 1994.
Article in English | MEDLINE | ID: mdl-7917368

ABSTRACT

A phase II study using a combination of Ondansetron and Lorazepam to treat patients receiving either highly or moderately emetogenic chemotherapy regimens has recently been completed. A total of 56 patients were enrolled and data from 53 is amenable to analysis. The overall response rates were 100% and 91% for the highly and moderately emetogenic regimens respectively, with 16 out of 20 patients (80%) and 18 out of 33 patients (54.5%) achieving a complete or major response respectively. Toxicity was mild and no dose modifications were necessary.


Subject(s)
Antineoplastic Agents/adverse effects , Lorazepam/administration & dosage , Ondansetron/administration & dosage , Vomiting/prevention & control , Adolescent , Adult , Aged , Drug Therapy, Combination , Female , Humans , Lorazepam/adverse effects , Male , Middle Aged , Ondansetron/adverse effects
17.
18.
Oncology ; 48(5): 365-8, 1991.
Article in English | MEDLINE | ID: mdl-1745482

ABSTRACT

A total of 65 patients with advanced cutaneous malignant melanoma (MM) have now been treated with interferon alpha-2b (Intron A) at a dose of 10 million IU/m2 administered subcutaneously thrice weekly. Fifty-one patients were evaluable for response, and 4 of these (7.8%) achieved complete remission; 2 of these 4 remain so at 37 + and 54 + months. Six additional patients achieved a partial remission. All responders had subcutaneous, lymph node and/or pulmonary metastases only. In all responders, therapy was continued for a total of 12 months. The vast majority of patients experienced side effects, largely flu-like symptoms, mild leukopenia and mild hepatocellular dysfunction. No evidence of cumulative toxicity was observed. Our experience indicates that interferon alpha-2b is active in patients with advanced cutaneous MM.


Subject(s)
Interferon-alpha/therapeutic use , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adult , Aged , Drug Evaluation , Female , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Middle Aged , Recombinant Proteins
20.
Br J Clin Pract ; 43(10): 353-6, 1989 Oct.
Article in English | MEDLINE | ID: mdl-2698240

ABSTRACT

Despite improved understanding of the chronic lymphoid leukaemias, the long-term outcome for the majority of patients remains dismal. An alkylating agent, usually chlorambucil, with or without prednisone, remains the standard palliative treatment for chronic lymphocytic leukaemia. More recently, two new drugs have emerged, 2'deoxycoformycin and alpha-interferon, which appear to offer substantial benefit to patients with hairy cell leukaemia.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Adult , Combined Modality Therapy , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/classification , Prognosis
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