Scott J Rodig

Harvard Medical School, Boston, Massachusetts, United States

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Publications (170)1677.59 Total impact

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    ABSTRACT: Esophageal adenocarcinoma (EAC) is an increasingly common disease with a dismal 5-year survival of 10-15%. In the first systematic evaluation of the PD-1 pathway in EAC, we identify expression of PD-L2 in cancer cells in 51.7% of EACs. Epithelial PD-L1 was expressed on only 2% of cases, though PD-L1 positive immune cells were observed in 18% of EACs. We also evaluated expression in the precursor lesion of EAC, Barrett's Esophagus (BE), which emerges following gastric reflux-induced esophageal inflammation, and found PD-L2 expression in BE but not in non-BE esophagitis. As the progression from squamous esophagitis to BE is accompanied by a transition from a Th1 to Th2 immune response, we hypothesized that the Th2 cytokines IL-4/IL-13 could contribute to PD-L2 induction. We confirmed these cytokines can augment PD-L2 expression in EAC cell lines. These results suggest that the inflammatory environment in BE and EAC may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in EACs with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials. Copyright © 2015, American Association for Cancer Research.
    06/2015; DOI:10.1158/2326-6066.CIR-15-0046
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    ABSTRACT: PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. Copyright © 2015, American Association for Cancer Research.
    05/2015; DOI:10.1158/2326-6066.CIR-15-0024
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    ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.059 · 7.21 Impact Factor
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    ABSTRACT: MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib. We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects. After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%). Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; number, NCT01614821.).
    New England Journal of Medicine 04/2015; 372(15):1430-1440. DOI:10.1056/NEJMoa1501548 · 54.42 Impact Factor
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    ABSTRACT: Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo "CDS" or "3' UTR" develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 04/2015; DOI:10.1016/j.cell.2015.02.043 · 33.12 Impact Factor
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    ABSTRACT: Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell- and natural killer cell-dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 03/2015; 7(277):277ra30. DOI:10.1126/scitranslmed.aaa1260 · 14.41 Impact Factor
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    ABSTRACT: Purpose: LKB1 loss is common in lung cancer but no assay exists to efficiently evaluate presence or absence of LKB1. We validated an immunohistochemistry (IHC) assay for LKB1 loss and determined the impact of LKB1 loss in KRAS-mutant NSCLC. Experimental Design: We optimized and validated an IHC assay for LKB1 (clone Ley37D/G6) using a panel of lung cancer cell lines and tumors with known LKB1 mutations, including 2 patients with Peutz-Jeghers syndrome (PJS) who developed lung adenocarcinoma. We retrospectively analyzed tumors for LKB1 using IHC from 154 KRAS-mutant NSCLC patients, including 123 smokers and 31 never-smokers, and correlated the findings with patient and tumor characteristics and clinical outcome. Results: LKB1 expression was lost by IHC in 30% of KRAS mutant NSCLC (smokers 35% vs. never-smokers 13%, P=0.017). LKB1 loss did not correlate with a specific KRAS mutation but was more frequent in tumors with KRAS transversion mutations (P=0.029). KRAS mutant NSCLC patients with concurrent LKB1 loss had a higher number of metastatic sites at the time of diagnosis (median 2.5 vs. 2, P=0.01), higher incidence of extra-thoracic metastases (P=0.01), and developed brain metastasis more frequently (48% vs. 25%, P=0.02). There was a non-significant trend to worse survival in stage IV KRAS-mutant NSCLC patients with LKB1 loss. Conclusions: LKB1 IHC is a reliable and efficient assay to evaluate for loss of LKB1 in clinical samples of NSCLC. LKB1 loss is more common in smokers, and is associated with a more aggressive clinical phenotype in KRAS-mutant NSCLC patients, accordingly to preclinical models. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(12). DOI:10.1158/1078-0432.CCR-14-3112 · 8.19 Impact Factor
  • Caleb Ho M.D., Ph.D Scott J. Rodig M.D.
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    ABSTRACT: Histomorphology, immunohistochemistry (IHC), and genetics are essential tools for the evaluation and classification of lymphoid malignancies. Advances in diagnostic techniques include the development of immunohistochemical assays that can serve as surrogates for genetic tests. We review the performance of a select subset of assays that detect the aberrant expression of onco-proteins secondary to chromosomal translocations (MYC; BCL2), somatic mutations (BRAF V600E; NOTCH1), and gene copy number gains (CD274 (encoding PD-L1); PDCD1LG2 (encoding PD-L2)) in fixed tissue biopsy sections. We discuss the limitations of IHC, but also its primary advantage over genetics; specifically, its ability to assess the final, common phenotypic consequences of a multitude of genetic and non-genetic events that influence protein expression. The information provided by IHC and genetic testing are thus intimately related; surgical pathologists will increasingly need to interpret and integrate the results of both to provide a comprehensive assessment of tumor biology and guide therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Seminars in Diagnostic Pathology 02/2015; DOI:10.1053/j.semdp.2015.02.016 · 1.80 Impact Factor
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    ABSTRACT: There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma - both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors.
    Oncotarget 12/2014; 6(7). · 6.63 Impact Factor
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    ABSTRACT: The Ten-ElevenTranslocation-2 (TET2) gene encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors leading to ineffective hematopoiesis. We used genome editing technology to disrupt the zebrafish Tet2 catalytic domain. tet2 m/m zebrafish exhibited normal embryonic and larval hematopoiesis, but developed progressive clonal myelodysplasia as they aged, culminating in MDS at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultant tet2 m/m mutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow, but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in non-hematopoietic tissues but not in hematopoietic cells. tet2 m/m are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and for small molecule screens in embryos to identify compounds with specific activity against tet2 mutant cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Molecular and Cellular Biology 12/2014; 35(5). DOI:10.1128/MCB.00971-14 · 5.04 Impact Factor
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    ABSTRACT: Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
    Nature Medicine 12/2014; 21(1). DOI:10.1038/nm.3751 · 28.05 Impact Factor
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    ABSTRACT: Background Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. Methods In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. Results Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. Conclusions Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; number, NCT01592370 .).
    New England Journal of Medicine 12/2014; 372(4). DOI:10.1056/NEJMoa1411087 · 54.42 Impact Factor
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    ABSTRACT: Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that are distinguished by a combination of histomorphological, phenotypic, and genetic features. A subset of B-cell lymphomas, however, has one or more characteristics that overlap BL and DLBCL, and are categorized as B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U). Molecular analyses support the concept that there is a biological continuum between BL and DLBCL that includes variable activity of MYC, an oncoprotein once thought to be only associated with BL, but now recognized as a major predictor of survival among patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We tested whether a targeted expression profiling panel could be used to categorize tumors as BL and DLBCL, resolve the molecular heterogeneity of BCL-U, and capture MYC activity using RNA from formalin-fixed, paraffin-embedded biopsy specimens. A diagnostic molecular classifier accurately predicted pathological diagnoses of BL and DLBCL, and provided more objective subclassification for a subset of BCL-U and genetic double-hit lymphomas as molecular BL or DLBCL. A molecular classifier of MYC activity correlated with MYC IHC and stratified patients with primary DLBCL treated with R-CHOP into high- and low-risk groups. These results establish a framework for classifying and stratifying MYC-driven, aggressive, B-cell lymphomas on the basis of quantitative molecular profiling that is applicable to fixed biopsy specimens. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
    The Journal of molecular diagnostics: JMD 11/2014; 17(1). DOI:10.1016/j.jmoldx.2014.08.006 · 3.96 Impact Factor
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    ABSTRACT: Background Myc family members are important contributors to oncogenesis in a variety of tumors. Identification of therapeutic targets are needed in small cell lung carcinoma (SCLC), an aggressive disease with limited treatment options. Sequencing studies have identified MYC amplification in 2-7% of SCLC. We hypothesized that immunohistochemistry (IHC) will detect Myc protein overexpression in SCLC and will correlate with gene amplification.Design103 cases of formalin-fixed, paraffin-embedded SCLC were examined. Myc protein expression was scored based on extent of IHC staining. MYC copy number (CN) was evalutated using dual color chromogenic in situ hybridization (CISH) for the MYC locus and chromosome 8 (Chr8) centromeric control. Amplification was defined as a MYC/Chr8 ratio of 2 or greater.Results38% of SCLC had some degree of Myc protein expression and 9% of cases were MYC amplified. MYC CN was significantly correlated with extent of Myc protein expression (Spearman's ρ=0.57, p<0.01). There was no significant association between MYC expression or copy number and clinicopathologic features.ConclusionsMYC amplification by CISH was identified in 9% of SCLC and correlated with protein expression. As novel Myc-targeted therapies develop, CISH and IHC should be considered as biomarkers of Myc pathway dysregulation in SCLC.This article is protected by copyright. All rights reserved.
    Histopathology 11/2014; 67(1). DOI:10.1111/his.12622 · 3.30 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):5582-5582. DOI:10.1158/1538-7445.AM2014-5582 · 9.28 Impact Factor
  • Leukemia 09/2014; 29(1). DOI:10.1038/leu.2014.262 · 9.38 Impact Factor
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    ABSTRACT: Activating mutations of the interleukin-7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T-ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand-independent activation of STAT5. We hypothesized that the reducing agent N-acetylcysteine (NAC), a well-tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R-mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R-mutant DND-41 cells as assessed by non-reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND-41 cells, and Ba/F3 cells transformed by an IL7R-mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND-41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T-ALL.
    British Journal of Haematology 09/2014; 168(2). DOI:10.1111/bjh.13115 · 4.96 Impact Factor
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    ABSTRACT: Intratumoral hypoxia and hypoxia inducible factor-1α (HIF-1-α)-dependent CD39/CD73 ectoenzymes may govern the accumulation of tumor-protecting extracellular adenosine and signaling through A2A adenosine receptors (A2AR) in tumor microenvironments (TME). Here, we explored the conceptually novel motivation to use supplemental oxygen as a treatment to inhibit the hypoxia/HIF-1α-CD39/CD73-driven accumulation of extracellular adenosine in the TME in order to weaken the tumor protection. We report that hyperoxic breathing (60 % O2) decreased the TME hypoxia, as well as levels of HIF-1α and downstream target proteins of HIF-1α in the TME according to proteomic studies in mice. Importantly, oxygenation also downregulated the expression of adenosine-generating ectoenzymes and significantly lowered levels of tumor-protecting extracellular adenosine in the TME. Using supplemental oxygen as a tool in studies of the TME, we also identified FHL-1 as a potentially useful marker for the conversion of hypoxic into normoxic TME. Hyperoxic breathing resulted in the upregulation of antigen-presenting MHC class I molecules on tumor cells and in the better recognition and increased susceptibility to killing by tumor-reactive cytotoxic T cells. Therapeutic breathing of 60 % oxygen resulted in the significant inhibition of growth of established B16.F10 melanoma tumors and prolonged survival of mice. Taken together, the data presented here provide proof-of principle for the therapeutic potential of systemic oxygenation to convert the hypoxic, adenosine-rich and tumor-protecting TME into a normoxic and extracellular adenosine-poor TME that, in turn, may facilitate tumor regression. We propose to explore the combination of supplemental oxygen with existing immunotherapies of cancer.
    Journal of Molecular Medicine 08/2014; DOI:10.1007/s00109-014-1189-3 · 4.74 Impact Factor
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    ABSTRACT: Background Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome. Methods Samples from patients with advanced UC and correlative clinical data were collected. Genomic imbalances were investigated by array comparative genomic hybridization (aCGH). ALK gene status was evaluated by fluorescence in situ hybridization (FISH). ALK expression was assessed by immunohistochemistry (IHC) and high-throughput mutation analysis with Oncomap 3 platform. Next generation sequencing was performed using Illumina Genome Analyzer IIx, and Illumina HiSeq 2000 in the FISH positive case. Results 70 of 96 patients had tissue available for all the tests performed. Arm level copy number gains at chromosome 2 were identified in 17 (24%) patients. Minor copy number alterations (CNAs) in the proximity of ALK locus were found in 3 patients by aCGH. By FISH analysis, one of these samples had a deletion of the 5′ALK. Whole genome next generation sequencing was inconclusive to confirm the deletion at the level of the ALK gene at the coverage level used. We did not observe an association between ALK CNA and overall survival, ECOG PS, or development of visceral disease. Conclusions ALK genomic alterations are rare and probably without prognostic implications in UC. The potential for testing ALK inhibitors in UC merits further investigation but might be restricted to the identification of an enriched population.
    PLoS ONE 08/2014; 9(8):e103325. DOI:10.1371/journal.pone.0103325 · 3.53 Impact Factor

Publication Stats

5k Citations
1,677.59 Total Impact Points


  • 2005–2015
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Neurology
      Boston, Massachusetts, United States
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2003–2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2010–2014
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2012
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2011–2012
    • Boston Children's Hospital
      Boston, Massachusetts, United States
    • The University of Manchester
      • Faculty of Medical and Human Sciences
      Manchester, ENG, United Kingdom