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  • Original Article

    RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors

    The T→A transversion at position 1799 of BRAF (BRAF V600E) is present in approximately 50% of patients with metastatic melanoma. BRAF V600E induces constitutive signaling through the mitogen-activated protein kinase (MAPK) pathway, stimulating cancer-cell proliferation and survival. The clinical…

    • January 19, 2012
    • Su F., Viros A., Milagre C., et al.
    • N Engl J Med 2012; 366:207 - 215

      Patients with melanoma who are treated with a BRAF inhibitor have a high incidence of keratoacanthomas. Most of the tumors have oncogenic mutations in HRAS that probably preceded the use of the BRAF inhibitor. In animal models, second tumors are blocked when a MEK inhibitor is added to the BRAF inhibitor.

    • Original Article

      Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian Cancers

      Sex cord–stromal tumors and germ-cell tumors account for less than 10% of ovarian cancers. Unlike epithelial ovarian cancers, both sex cord–stromal tumors and germ-cell tumors can also occur in the testicle; testicular germ-cell tumors are the most common cancer in boys and men of European…

      • January 19, 2012
      • Heravi-Moussavi A., Anglesio M.S., Cheng S.-W.G., et al.
      • N Engl J Med 2012; 366:234 - 242

        Primitive cancers have so-called hot-spot mutations in DICER1 that alter the function of DICER1, an enzyme that processes microRNA. Some of these cancers harbor a loss-of-function mutation in the other DICER1 allele, suggesting a new mutational mechanism of oncogenesis.

      • Editorial

        RAF around the Edges — The Paradox of BRAF Inhibitors

        The recent success of BRAF inhibitors represents a great stride forward for melanoma research. When used to treat patients with melanoma who harbor the BRAF V600E mutation, these inhibitors lead to the remission of even advanced lesions. However, resistance to BRAF inhibitors emerges within months.…

        • January 19, 2012
        • Weeraratna A.T.
        • N Engl J Med 2012; 366:271 - 273

          The recent success of BRAF inhibitors represents a great stride forward for melanoma research. When used to treat patients with melanoma who harbor the BRAF V600E mutation, these inhibitors lead to the remission of even advanced lesions. However, ...

        • Original Article

          Germline Mutations in HOXB13 and Prostate-Cancer Risk

          Prostate cancer is the most common noncutaneous cancer diagnosed in men in the United States, with more than 240,000 new cases expected in 2011. Despite the demonstration of a strong familial component, identification of the genetic basis for hereditary prostate cancer has been challenging. Linkage…

          • January 12, 2012
          • Ewing C.M., Ray A.M., Lange E.M., et al.
          • N Engl J Med 2012; 366:141 - 149

            Prostate cancer runs in families. However, the genes that affect the incidence remain largely undefined. The authors have identified a rare germline variant of a homeobox gene, HOXB13, in four families with a history of prostate cancer.

          • Case Records of the Massachusetts General Hospital

            Case 1-2012 — An 82-Year-Old Man with Persistent Ulcers on the Hands

            Presentation of Case. Dr. Sarah Gee (Dermatology): An 82-year-old man was admitted to this hospital because of persistent skin lesions on the hands. The patient had a history of diabetes mellitus and recurrent hidradenitis suppurativa. Five weeks before admission, he was admitted to another…

            • January 12, 2012
            • Kroshinsky D., Hoang M.P., Hasserjian R.P.
            • N Engl J Med 2012; 366:166 - 174

              An 82-year-old man was admitted to this hospital because of a 4-month history of bullous and ulcerated skin lesions on the hands, which did not respond to antibiotic therapy and débridement. A diagnostic procedure was performed.

            • Original Article

              TFAP2E–DKK4 and Chemoresistance in Colorectal Cancer

              The treatment options and prognosis for patients with advanced colorectal cancer have improved through the development of novel drugs. However, studies of the molecular biology of cancer initiation and progression have so far provided scant knowledge of the molecular mechanisms contributing to…

              • January 5, 2012
              • Ebert M.P.A., Tänzer M., Balluff B., et al.
              • N Engl J Med 2012; 366:44 - 53

                Patients whose tumors showed methylation and decreased expression of the gene TFAP2E were more than five times as likely as patients with normal TFAP2E gene expression to have resistance to fluorouracil.

              • Correspondence

                TET2 and DNMT3A Mutations in Human T-Cell Lymphoma

                To the Editor: Despite the poor prognosis of T-cell lymphomas, the genetic basis of these cancers is poorly defined. We have found acquired TET2 mutations in both human myeloid cancers and T-cell lymphoma. TET proteins are involved in the epigenetic control of transcription, at least through the…

                • January 5, 2012
                • N Engl J Med 2012; 366:95 - 96
                • Free Full Text

                A substantial fraction of T-cell lymphomas carry mutations in two genes — TET2 and DNMT3A — that are involved in DNA methylation. The co-occurrence of these mutations suggests that inhibitors of DNA methylation could possibly have antitumor effects in such patients.

              • Original Article

                SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

                Chronic lymphocytic leukemia is an incurable disease characterized by extensive clinical heterogeneity despite a common diagnostic immunophenotype (surface expression of CD19+, CD20+dim, CD5+, CD23+, and sIgMdim). Whereas the course of disease is indolent in some patients, it is steadily…

                • December 29, 2011
                • Wang L., Lawrence M.S., Wan Y., et al.
                • N Engl J Med 2011; 365:2497 - 2506

                  CLL is a heterogeneous disease with a variable clinical course and response to therapy. New genetic lesions have been noted in subgroups of patients through whole-exome and whole-genome sequencing. An abnormality in RNA splicing has been found in 15% of patients.

                • Editorial

                  Mutations in RNA Splicing Machinery in Human Cancers

                  Massively parallel sequencing of cancer genomes is revealing a panoramic view of the genetic drivers of human neoplasms. In this issue of the Journal, Wang et al. describe an analysis of the coding sequences of samples from 91 patients with chronic lymphocytic leukemia. The disease is characterized…

                  • December 29, 2011
                  • Ebert B. and Bernard O.A.
                  • N Engl J Med 2011; 365:2534 - 2535

                    Massively parallel sequencing of cancer genomes is revealing a panoramic view of the genetic drivers of human neoplasms. In this issue of the Journal, Wang et al.1 describe an analysis of the coding sequences of samples from 91 patients with chronic ...

                  • Perspective

                    The Emperor of All Maladies — The Beginning of the Beginning

                    Richard Feynman, the eminent physicist, once said that "great ideas . . . do not last unless they are passed purposely and clearly from generation to generation." In 1979, Horace Freeland Judson, in his magnificent The Eighth Day of Creation, passed to his generation the great ideas of molecular…

                    • December 22, 2011
                    • Schwartz R.
                    • N Engl J Med 2011; 365:2353 - 2355
                    • Audio

                    In his Pulitzer Prize–winning book, Siddhartha Mukherjee explores the great ideas of oncology, up to the development of imatinib. But the research direction set by imatinib has yielded few useful drugs; its model seems to be the wrong roadmap for finding magic bullets.

                  • Images in Clinical Medicine

                    Neurofibromatosis

                    Figure 1.

                    • November 24, 2011
                    • Ibrahim A. and Asuku M.E.
                    • N Engl J Med 2011; 365:2020
                    • Free Full Text

                    A 26-year-old woman presented with painless nodular skin lesions that had first developed 7 years earlier. Skin nodules initially appeared on the anterior chest wall and progressed to involve the whole body. Her medical history and that of her family were unremarkable.

                  • Correspondence

                    HRAS Mutation Mosaicism Causing Urothelial Cancer and Epidermal Nevus

                    To the Editor: Mosaicism of an oncogenic AKT1 mutation causes Proteus syndrome, which is associated with epidermal nevi and an increased risk of cancer. The occurrence of oncogenic mutations in mosaicism may increase a person's risk for malignant conditions. Somatic RAS mutations occur in 30% of…

                    • November 17, 2011
                    • N Engl J Med 2011; 365:1940 - 1942
                    • Free Full Text

                    To the Editor: Mosaicism of an oncogenic AKT1 mutation causes Proteus syndrome, which is associated with epidermal nevi and an increased risk of cancer.1 The occurrence of oncogenic mutations in mosaicism may increase a person's risk for malignant ...

                  • Original Article

                    Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy

                    Although cellular therapies may be effective in cancer treatment, their potential for expansion, damage of normal organs,– and malignant transformation is a source of concern. In contrast, the toxic effects of small molecules usually diminish once the drugs are withdrawn. One approach to…

                    • November 3, 2011
                    • Di Stasi A., Tey S.-K., Dotti G., et al.
                    • N Engl J Med 2011; 365:1673 - 1683

                      The introduction of a transgene into human donor T cells that can kill the cells when dimerization is induced by a pharmacologic agent has improved prospects for the exploitation of T-cell graft-versus-tumor effects while controlling graft-versus-host disease.

                    • Editorial

                      Eliminating Cells Gone Astray

                      The therapeutic use of cells from healthy donors or patients is increasing. Decades ago, transfusion medicine and bone marrow transplantation provided the first successful cell therapeutics and established the foundations for cell delivery. Clinical investigation soon uncovered the double-edged…

                      • November 3, 2011
                      • Sadelain M.
                      • N Engl J Med 2011; 365:1735 - 1737

                        The therapeutic use of cells from healthy donors or patients is increasing. Decades ago, transfusion medicine and bone marrow transplantation provided the first successful cell therapeutics and established the foundations for cell delivery. Clinical ...

                      • Case Records of the Massachusetts General Hospital

                        Case 31-2011 — A 55-Year-Old Man with Oligometastatic Lung Cancer

                        Presentation of Case. A 55-year-old man was seen in the cancer center at this hospital because of stage IV non–small-cell lung cancer (NSCLC). The patient had been well until approximately 5 months earlier, when headaches developed, followed by left-sided weakness, leftward drift while walking,…

                        • October 13, 2011
                        • Lanuti M., Sequist L.V., Sharma A., Mino-Kenudson M.
                        • N Engl J Med 2011; 365:1426 - 1435
                        • CME

                        A 55-year-old man was seen at this hospital because of headaches, weakness of the left side of the body, and a mass in the brain. Chest CT showed a mass in the right lower lobe of the lung; biopsy revealed adenocarcinoma. Additional diagnostic testing was performed.

                      • Original Article

                        Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

                        The myelodysplastic syndromes are a heterogeneous group of hematologic cancers characterized by low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia. These disorders have increased in prevalence and are expected to continue to do so. Blood films and bone…

                        • October 13, 2011
                        • Papaemmanuil E., Cazzola M., Boultwood J., et al.
                        • N Engl J Med 2011; 365:1384 - 1395

                          Abnormalities in a gene encoding a messenger RNA splicing enzyme were found in nearly two thirds of patients with myelodysplastic syndromes characterized by ring sideroblasts. Patients with mutations had improved survival as compared with those without mutations.

                        • Original Article

                          Brief Report: Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia

                          With the use of gene-transfer techniques, T cells can be genetically modified to stably express antibodies on their surface, conferring new antigen specificity. Chimeric antigen receptors combine an antigen-recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain…

                          • August 25, 2011
                          • Porter D.L., Levine B.L., Kalos M., Bagg A., June C.H.
                          • N Engl J Med 2011; 365:725 - 733

                            A patient with refractory CLL had delayed development of the rapid tumor lysis syndrome and remission after an infusion of T cells engineered to express an antigen receptor capable of recognizing B cells (CD19) coupled to two signaling molecules.

                          • Editorial

                            Redirecting T Cells

                            The pursuit of tumor-reactive T cells as a cancer therapy has continued unabated since the discovery of the graft-versus-leukemia effect in patients undergoing allogeneic hematopoietic stem-cell transplantation. Some successes have been noted: the adoptive transfer of Epstein–Barr virus (EBV…

                            • August 25, 2011
                            • Urba W.J. and Longo D.L.
                            • N Engl J Med 2011; 365:754 - 757

                              The pursuit of tumor-reactive T cells as a cancer therapy has continued unabated since the discovery of the graft-versus-leukemia effect in patients undergoing allogeneic hematopoietic stem-cell transplantation.1 Some successes have been noted: the ...

                            • Correspondence

                              Drug-Induced Effects on Erlotinib Metabolism

                              To the Editor: A 78-year-old nonsmoking woman with a history of depression and dyslipidemia presented with a stage IV lung adenocarcinoma, harboring an activating mutation of the epidermal growth factor receptor (EGFR) (exon 19 deletion). Erlotinib was started at the recommended dose of 150 mg per…

                              • July 28, 2011
                              • N Engl J Med 2011; 365:379 - 380
                              • Free Full Text

                              A woman with lung cancer in whom the usual toxicities from erlotinib did not develop at the standard dose had a tumor response and side effects when the erlotinib dose was increased. Furthermore, the erlotinib dose had to be reduced when fenofibrate was stopped.

                            • Case Records of the Massachusetts General Hospital

                              Case 21-2011 — A 31-Year-Old Man with ALK-Positive Adenocarcinoma of the Lung

                              Presentation of Case. A 31-year-old man was seen in the outpatient cancer center at this hospital because of dysphagia and a mediastinal mass. The patient had been well until approximately 3 months before this evaluation, when progressive difficulty swallowing (solid foods but not liquids)…

                              • July 14, 2011
                              • Shaw A.T., Forcione D.G., Digumarthy S.R., Iafrate A.J.
                              • N Engl J Med 2011; 365:158 - 167
                              • CME

                              A 31-year-old man was seen at this hospital because of dysphagia and a mediastinal mass compressing the esophagus. CT images showed gastrohepatic and subcarinal lymphadenopathy and multiple lung nodules. A diagnostic procedure was performed, and management decisions were made.

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                            American Association for the Study of Liver Diseases

                            The following courses will be offered in Atlanta, unless otherwise indicated: "Hepatitis Single Topic Conference: HCV Direct Antiviral Agents (DAA): Concepts, Development and Optimal Use" (March 16 and 17); "The Henry M. and Lillian Stratton Basic Research Single Topic Conference: Mitochondria and Hepatotoxicity" (June 8 and 9); "Clinical Research Single Topic Conference: Acetaminophen Poisoning" (June 9 and 10); and "63rd Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2012" (Boston, Nov. 9-13).

                            Contact AASLD, 1001 North Fairfax St., Suite 400, Alexandria, VA 22314; or call (703) 299-9766; or see http://www.aasld.org .

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