Showing papers by "Memorial Sloan Kettering Cancer Center published in 2003"
TL;DR: Current understanding on the mechanisms of TGF-β signaling from cell membrane to the nucleus is presented and the transcriptional regulation of target gene expression is reviewed.
5,340 citations
TL;DR: A novel graph theoretic clustering algorithm, "Molecular Complex Detection" (MCODE), that detects densely connected regions in large protein-protein interaction networks that may represent molecular complexes is described.
Abstract: Recent advances in proteomics technologies such as two-hybrid, phage display and mass spectrometry have enabled us to create a detailed map of biomolecular interaction networks. Initial mapping efforts have already produced a wealth of data. As the size of the interaction set increases, databases and computational methods will be required to store, visualize and analyze the information in order to effectively aid in knowledge discovery. This paper describes a novel graph theoretic clustering algorithm, "Molecular Complex Detection" (MCODE), that detects densely connected regions in large protein-protein interaction networks that may represent molecular complexes. The method is based on vertex weighting by local neighborhood density and outward traversal from a locally dense seed protein to isolate the dense regions according to given parameters. The algorithm has the advantage over other graph clustering methods of having a directed mode that allows fine-tuning of clusters of interest without considering the rest of the network and allows examination of cluster interconnectivity, which is relevant for protein networks. Protein interaction and complex information from the yeast Saccharomyces cerevisiae was used for evaluation. Dense regions of protein interaction networks can be found, based solely on connectivity data, many of which correspond to known protein complexes. The algorithm is not affected by a known high rate of false positives in data from high-throughput interaction techniques. The program is available from ftp://ftp.mshri.on.ca/pub/BIND/Tools/MCODE
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4,599 citations
TL;DR: The results reaffirm the thesis that miRNAs have an important role in establishing the complex spatial and temporal patterns of gene activity necessary for the orderly progression of development and suggest additional roles in the function of the mature organism.
Abstract: Background: The recent discoveries of microRNA (miRNA) genes and characterization of the first few target genes regulated by miRNAs in Caenorhabditis elegans and Drosophila melanogaster have set the stage for elucidation of a novel network of regulatory control. We present a computational method for wholegenome prediction of miRNA target genes. The method is validated using known examples. For each miRNA, target genes are selected on the basis of three properties: sequence complementarity using a position-weighted local alignment algorithm, free energies of RNA-RNA duplexes, and conservation of target sites in related genomes. Application to the D. melanogaster, Drosophila pseudoobscura and Anopheles gambiae genomes identifies several hundred target genes potentially regulated by one or more known miRNAs.
2,997 citations
TL;DR: Overexpression of this bone metastasis gene set is superimposed on a poor-prognosis gene expression signature already present in the parental breast cancer population, suggesting that metastasis requires a set of functions beyond those underlying the emergence of the primary tumor.
2,493 citations
TL;DR: Recent progress in the evolution of adverse effects grading systems is updated and the development of CTCAE v3.0 is reviewed, which represents an international collaboration and consensus of the oncology research community.
2,321 citations
TL;DR: Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression, suggesting KIT and PDGFra mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
Abstract: Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
2,249 citations
Memorial Sloan Kettering Cancer Center1, Harvard University2, Indiana University3, University of Minnesota4, University of Utah5, Boston University6, University of California, San Diego7, Kaiser Permanente8, Virginia Commonwealth University9, Eastern Virginia Medical School10, University of Texas Southwestern Medical Center11, Mayo Clinic12
TL;DR: These guidelines differ from those published in 1997 in several ways: the screening interval for double contrast barium enema has been shortened to 5 years, and colonoscopy is the preferred test for the diagnostic investigation of patients with findings on screening and for screening patients with a family history of hereditary nonpolyposis colorectal cancer.
2,196 citations
TL;DR: The prevalence of self-reactive antibody formation and its regulation in human B cells is determined and a majority (55 to 75%) of all antibodies expressed by early immature B cells displayedSelf-reactivity, including polyreactive and anti-nuclear specificities.
Abstract: During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation in human B cells. A majority (55 to 75%) of all antibodies expressed by early immature B cells displayed self-reactivity, including polyreactive and anti-nuclear specificities. Most of these autoantibodies were removed from the population at two discrete checkpoints during B cell development. Inefficient checkpoint regulation would lead to substantial increases in circulating autoantibodies.
1,863 citations
TL;DR: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.
Abstract: background In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy — but not tamoxifen therapy of longer duration — prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. methods We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. results A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast — 75 in the letrozole group and 132 in the placebo group — with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P ≤ 0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. conclusions As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.
1,538 citations
TL;DR: The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer.
Abstract: The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer. However, tumour cells that are relieved from TGF-β growth constraints might then overproduce this cytokine to create a local immunosuppressive environment that fosters tumour growth and exacerbates the invasive and metastatic behaviour of the tumour cells themselves. For these reasons, there is a growing interest in understanding and therapeutically targeting TGF-β-mediated processes in cancer progression.
1,537 citations
TL;DR: Microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range, indicating that endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth.
Abstract: About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.
TL;DR: Two crystal structures of the glucocorticoid receptor DNA-binding domain complexed with DNA are reported, which have a globular fold which contains two Zn-nucleated substructures of distinct conformation and function.
Abstract: Two crystal structures of the glucocorticoid receptor DNA-binding domain complexed with DNA are reported. The domain has a globular fold which contains two Zn-nucleated substructures of distinct conformation and function. When it binds DNA, the domain dimerizes, placing the subunits in adjacent major grooves. In one complex, the DNA has the symmetrical consensus target sequence; in the second, the central spacing between the target's half-sites is larger by one base pair. This results in one subunit interacting specifically with the consensus target half-site and the other nonspecifically with a noncognate element. The DNA-induced dimer fixes the separation of the subunits' recognition surfaces so that the spacing between the half-sites becomes a critical feature of the target sequence's identity.
TL;DR: Recent progress in understanding the biochemical mechanisms and regulation of the caspase activation pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values are focused on.
Abstract: Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
TL;DR: A TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice is identified, indicating that Tip-DCs are not essential for T cell priming.
Research Triangle Park1, Harvard University2, Yale University3, Robert Wood Johnson Foundation4, University of Pennsylvania5, Columbia University6, University of North Carolina at Chapel Hill7, Memorial Sloan Kettering Cancer Center8, University of Arkansas for Medical Sciences9, University of Southern California10, Janssen Pharmaceutica11, Johnson & Johnson12, Cedars-Sinai Medical Center13
TL;DR: The goal of this article is to articulate the 4 central challenges facing clinical research at present--public participation, information systems, workforce training, and funding; to make recommendations about how they might be addressed by particular stakeholders; and to invite a broader, participatory dialogue with a view to improving the overall performance of the US clinical research enterprise.
Abstract: Medical scientists and public health policy makers are increasingly concerned that the scientific discoveries of the past generation are failing to be translated efficiently into tangible human benefit. This concern has generated several initiatives, including the Clinical Research Roundtable at the Institute of Medicine, which first convened in June 2000. Representatives from a diverse group of stakeholders in the nation’s clinical research enterprise have collaborated to address the issues it faces. The context of clinical research is increasingly encumbered by high costs, slow results, lack of funding, regulatory burdens, fragmented infrastructure, incompatible databases, and a shortage of qualified investigators and willing participants. These factors have contributed to 2 major obstacles, or translational blocks: impeding the translation of basic science discoveries into clinical studies and of clinical studies into medical practice and health decision making in systems of care. Considering data from across the entire health care system, it has become clear that these 2 translational blocks can be removed only by the collaborative efforts of multiple system stakeholders. The goal of this article is to articulate the 4 central challenges facing clinical research at present—public participation, information systems, workforce training, and funding; to make recommendations about how they might be addressed by particular stakeholders; and to invite a broader, participatory dialogue with a viewtoimprovingtheoverallperformanceoftheUSclinicalresearchenterprise.
TL;DR: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcomeFor patients with nonmetastatic Ewing's Sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.
Abstract: Background Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. Methods Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. Results A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were random...
Seconda Università degli Studi di Napoli1, University of Graz2, University of Rome Tor Vergata3, University of Vienna4, University of Naples Federico II5, University of Regensburg6, University of Sydney7, University of L'Aquila8, University of Miami9, University of Ljubljana10, University of Tübingen11, University of Geneva12, University of Buenos Aires13, University of Florence14, Medical College of Wisconsin15, University of Connecticut16, Memorial Sloan Kettering Cancer Center17, Cornell University18, University of Lübeck19, University of Barcelona20, University of Siena21, Rutgers University22, Shinshu University23, University of Modena and Reggio Emilia24, Keio University25, Ludwig Maximilian University of Munich26, New York University27
TL;DR: The virtual Consensus Net Meeting on Dermoscopy represents a valid tool for better standardization of the dermoscopic terminology and, moreover, opens up a new territory for diagnosing and managing pigmented skin lesions.
Abstract: Background: There is a need for better standardization of the dermoscopic terminology in assessing pigmented skin lesions. Objective: The virtual Consensus Net Meeting on Dermoscopy was organized to investigate reproducibility and validity of the various features and diagnostic algorithms. Methods: Dermoscopic images of 108 lesions were evaluated via the Internet by 40 experienced dermoscopists using a 2-step diagnostic procedure. The first-step algorithm distinguished melanocytic versus nonmelanocytic lesions. The second step in the diagnostic procedure used 4 algorithms (pattern analysis, ABCD rule, Menzies method, and 7-point checklist) to distinguish melanoma versus benign melanocytic lesions. κ Values, log odds ratios, sensitivity, specificity, and positive likelihood ratios were estimated for all diagnostic algorithms and dermoscopic features. Results: Interobserver agreement was fair to good for all diagnostic methods, but it was poor for the majority of dermoscopic criteria. Intraobserver agreement was good to excellent for all algorithms and features considered. Pattern analysis allowed the best diagnostic performance (positive likelihood ratio: 5.1), whereas alternative algorithms revealed comparable sensitivity but less specificity. Interobserver agreement on management decisions made by dermoscopy was fairly good (mean κ value: 0.53). Conclusion: The virtual Consensus Net Meeting on Dermoscopy represents a valid tool for better standardization of the dermoscopic terminology and, moreover, opens up a new territory for diagnosing and managing pigmented skin lesions. (J Am Acad Dermatol 2003;48:679-93.) J Am Acad Dermatol 2003;48:679-93.
TL;DR: It is reported herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF, and it is identified as a natural ligand forCD74, which has been implicated previously in signaling and accessory functions for immune cell activation.
Abstract: Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 K d, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.
TL;DR: It is proposed that the opposing effects on mTOR activity of the GbetaL- and raptor-mediated interactions regulate the mTOR pathway.
TL;DR: Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.
Abstract: Ribosome biogenesis and translation control are essential cellular processes that are governed at numerous levels. Several tumour suppressors and proto-oncogenes have been found either to affect the formation of the mature ribosome or to regulate the activity of proteins known as translation factors. Disruption in one or more of the steps that control protein biosynthesis has been associated with alterations in the cell cycle and regulation of cell growth. Therefore, certain tumour suppressors and proto-oncogenes might regulate malignant progression by altering the protein synthesis machinery. Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.
TL;DR: Crystal structures of c-Abl show that the N-terminal myristoyl modification of c -Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it.
TL;DR: A user-friendly nomogram is developed that uses information commonly available to the surgeon to easily and accurately calculate the likelihood of having additional, non-SLN metastases for an individual patient.
Abstract: Background:The standard of care for breast cancer patients with sentinel lymph node (SLN) metastases includes complete axillary lymph node dissection (ALND). However, many question the need for complete ALND in every patient with detectable SLN metastases, particularly those perceived to have a low risk of non-SLN metastases. Accurate estimates of the likelihood of additional disease in the axilla could assist greatly in decision-making regarding further treatment.
TL;DR: Spiritual well-being offers some protection against end-of-life despair in those for whom death is imminent, and these findings have important implications for palliative care practice.
TL;DR: In this population, a few known risk factors account for a majority of esophageal and gastric cancers, and results suggest that the incidence of these cancers may be decreased by reducing the prevalence of smoking, gastric reflux, and being overweight and by increasing the consumption of fruits and vegetables.
Abstract: Background Several risk factors have been identified for esophageal adenocarcinoma, gastric cardia adenocarcinoma, esophageal squamous cell carcinoma, and noncardia gastric adenocarcinoma, but no study has comprehensively examined their contributions to the cancer burden in the general population. Herein, we estimate the population attributable risks (PARs) for various risk factors observed in a multicenter population-based case-control study. Methods We calculated PARs by using 293 patients with esophageal adenocarcinoma, 261 with gastric cardia adenocarcinoma, 221 with esophageal squamous cell carcinoma, 368 with noncardia gastric adenocarcinoma, and 695 control subjects. We included smoking for all four tumor types and Helicobacter pylori infection for noncardia gastric adenocarcinoma as established causal risk factors as well as several other factors for which causality is under evaluation. Results Ever smoking, body mass index above the lowest quartile, history of gastroesophageal reflux, and low fruit and vegetable consumption accounted for 39.7% (95% confidence interval [CI] = 25.6% to 55.8%), 41.1% (95% CI = 23.8% to 60.9%), 29.7% (95% CI = 19.5% to 42.3%), and 15.3% (95% CI = 5.8% to 34.6%) of esophageal adenocarcinomas, respectively, with a combined PAR of 78.7% (95% CI = 66.5% to 87.3%). Ever smoking and body mass index above the lowest quartile were responsible for 45.2% (95% CI = 31.3% to 59.9%) and 19.2% (95% CI = 4.9% to 52.0%) of gastric cardia adenocarcinomas, respectively, with a combined PAR of 56.2% (95% CI = 38.1% to 72.8%). Ever smoking, alcohol consumption, and low fruit and vegetable consumption accounted for 56.9% (95% CI = 36.6% to 75.1%), 72.4% (95% CI = 53.3% to 85.8%), and 28.7% (95% CI = 11.1% to 56.5%) of esophageal squamous cell carcinomas, respectively, with a combined PAR of 89.4% (95% CI = 79.1% to 95.0%). Ever smoking, history of gastric ulcers, nitrite intake above the lowest quartile, and H. pylori infection were responsible for 18.3% (95% CI = 6.5% to 41.8%), 9.7% (95% CI = 5.4% to 16.8%), 40.7% (95% CI = 23.4% to 60.7%), and 10.4% (95% CI = 0.3% to 79.6%) of noncardia gastric adenocarcinomas, respectively, with a combined PAR of 59.0% (95% CI = 16.2% to 91.4%). Conclusion In this population, a few known risk factors account for a majority of esophageal and gastric cancers. These results suggest that the incidence of these cancers may be decreased by reducing the prevalence of smoking, gastroesophageal reflux, and being overweight and by increasing the consumption of fruits and vegetables.
TL;DR: The results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.
Abstract: Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/− > Ptenhy/− (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Ptenpc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.
TL;DR: The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of outcome and aid clinicians with decisions regarding major therapeutic modalities.
TL;DR: This work has identified different types of epithelial-plasticity changes in tumour cells towards fibroblastoid phenotypes as crucial events that occur during metastasis, and many molecules and signalling pathways cooperate to trigger these processes.
Abstract: In contrast to the aberrant control of proliferation, apoptosis, angiogenesis and lifespan, the cellular mechanisms that cause local invasion and metastasis of tumour cells are still poorly understood. New experimental approaches have identified different types of epithelial-plasticity changes in tumour cells towards fibroblastoid phenotypes as crucial events that occur during metastasis, and many molecules and signalling pathways cooperate to trigger these processes.
Journal Article•
TL;DR: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.
Abstract: Purpose: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer. Experimental Design: SAHA was administered for 3 days every 21 days in part A and 5 days for 1–3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues. Results: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m 2 /day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m 2 /day), therapy was delayed ≥1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m 2 /day × 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m 2 /day × 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m 2 /day × 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms. Conclusions: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo , and has antitumor activity in solid and hematological tumors.
TL;DR: In this paper, the authors show that T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15) uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors.
Abstract: The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.
University of Florida1, Memorial Sloan Kettering Cancer Center2, University of Southern California3, Boston University4, University of Siena5, MedStar Washington Hospital Center6, Anschutz Medical Campus7, University of Texas MD Anderson Cancer Center8, Cedars-Sinai Medical Center9, Icahn School of Medicine at Mount Sinai10, Case Western Reserve University11, Johns Hopkins University12, University of Pisa13
TL;DR: A surveillance guideline is proposed using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.
Abstract: Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.