NEJM Group

Hairy-cell leukemia, a rare B-cell cancer driven by a BRAF mutation and manifesting with cytopenias and splenomegaly, is responsive to purine analogue chemotherapy and to BRAF inhibitors combined with anti-CD20 antibodies.    Figure 2 from the review illustrates the pathogenesis of hairy-cell leukemia (HCL).    The V600E missense mutation in the cytosolic serine–threonine kinase BRAF leads to its constitutive activation (independently of upstream regulation by RAS at the plasma membrane, as shown in Inset A) and, hence, to downstream phosphorylation of the MEK kinases (pMEK), which in turn phosphorylate the ERK kinases (pERK); Inset B shows pERK expression by HCL cells in a bone marrow–biopsy section (immunoperoxidase stain). Subsequent pERK-mediated phosphorylation of numerous targets in the nucleus and the cytoplasm generally promotes survival, proliferation, growth, and motility. At the molecular level, among the genes transcriptionally upregulated by the RAF–MEK–ERK signaling pathway in HCL, there are not only those commonly up-regulated in most cell types but also some that are characteristic markers of HCL (i.e., CD25 and TRAP), as well as the whole expression signature that distinguishes HCL from normal mature B-cell subsets and mature B-cell neoplasms. At the cellular level, aberrant pathway activity in HCL induces the characteristic hairy projections of the leukemic cells and inhibits apoptosis; Inset C shows a confocal immunofluorescence image of a primary HCL cell exposed in vitro to the BRAF inhibitor vemurafenib, which first trims the hairy projections (rich in F-actin and thus labeled in green by the cytoskeleton marker phalloidin) and then induces apoptosis, as indicated by the red staining for the apoptotic marker annexin V. (The blue stain is nuclear dye DRAQ5.) Read the Review Article “Hairy-Cell Leukemia” by Brunangelo Falini, MD, and Enrico Tiacci, MD, from the University and Hospital of Perugia: https://nej.md/3NkpIgR 

To limit the detection of clinically unimportant prostate cancer, magnetic resonance imaging (MRI) was introduced as a screening tool because life-threatening prostate cancer is more likely to cause abnormalities that are visible on MRI.     Whether delaying diagnosis is safe when an elevated prostate-specific antigen (PSA) level is found but no abnormalities are seen on MRI is uncertain.    In the GÖTEBORG-2 trial, researchers assessed whether performing biopsy of the prostate only in men with an elevated PSA level and visible lesions on MRI could reduce prostate cancer overdiagnosis.    13,153 men underwent PSA screening, and those with a PSA level of 3 ng per milliliter or higher underwent MRI of the prostate. Participants were randomly assigned to either the systematic biopsy group, in which they underwent systematic biopsy and, if suspicious lesions were found on MRI, targeted biopsy, or the MRI-targeted biopsy group, in which they underwent MRI-targeted biopsy only.     Participants repeated screening every 2, 4, or 8 years, depending on PSA levels. The primary outcome was detection of clinically insignificant prostate cancer.    In this trial, omitting biopsy in patients with negative MRI results eliminated more than half of diagnoses of clinically insignificant prostate cancer, and the associated risk of having incurable cancer diagnosed at repeat screening or as interval cancer was very low.    Read the full GÖTEBORG-2 trial results and Plain Language Summary: https://nej.md/4ewOjKT    #ClinicalTrials #MedicalResearch 

A 𝗵𝗲𝗺𝗮𝘁𝗼𝗽𝗼𝗶𝗲𝘁𝗶𝗰 𝘀𝘁𝗲𝗺 𝗰𝗲𝗹𝗹 is a type of stem cell that differentiates into the cellular components of the blood, including red cells, granulocytes, lymphocytes, monocytes, and platelets. To learn more about this NEJM Illustrated Glossary term, read the editorial “CSF1R Blockade for Refractory Chronic Graft-versus-Host Disease” by Mohamad Mohty, MD, PhD, from Sorbonne Université, INSERM, CRSA PARIS, and Greater Paris University Hospitals - AP-HP: https://nej.md/3MOORQs        Explore more terms: https://nej.md/glossary   

Still’s disease is an uncommon, systemic, autoinflammatory disease of uncertain cause. It is often misdiagnosed because of heterogeneous symptoms, including fever, rash, leukocytosis, and arthralgia. Learn more in “Avoiding Rash Decisions,” the latest Interactive Medical Case, by Dylan Eiger, MD, PhD, Anand Vaidya, MD, Jennifer Hanberg, MD, Roger Clark, DO, and Staci Eisenberg, MD: https://nej.md/3zmYR0n 

A recent study suggests that reexpression of a protein found during fetal development plays a role in the suppression of immunity in early colorectal adenomas and cancers.    Figure 1 from the article shows SOX17 and immune evasion in early colorectal cancer development.    SRY-box transcription factor 17 (SOX17) plays a crucial role in fetal development (Panel A), including formation of the gut endoderm and the vascular system, but also endometrial embryo receptivity acting mainly by ensuring an immune-tolerant environment. In adults, SOX17 is usually epigenetically silenced, which enables immune surveillance through up-regulation of major histocompatibility complex (MHC) class I expression and the interferon-γ receptor. During the initial phases of colorectal cancer development (Panel B), LGR5-negative epithelial cells can reactivate the fetal SOX17 program and thus reduce the susceptibility of tumor cells to interferon-γ, down-regulate MHC class I expression, and suppress T-cell infiltration. Thus, an immune-suppressive environment is established, enabling tumor outgrowth.    Learn more in the Clinical Implications of Basic Research article “Reactivation of SOX17 Program as Immune-Evasion Mechanism in Early Colorectal Cancer Development” by Aysel Ahadova, PhD, and Matthias Kloor, MD, PhD, from Heidelberg University and the DKFZ German Cancer Research Center: https://nej.md/3ZzbEHH 

The 𝘋𝘪𝘢𝘨𝘯𝘰𝘴𝘵𝘪𝘤 𝘢𝘯𝘥 𝘚𝘵𝘢𝘵𝘪𝘴𝘵𝘪𝘤𝘢𝘭 𝘔𝘢𝘯𝘶𝘢𝘭 𝘰𝘧 𝘔𝘦𝘯𝘵𝘢𝘭 𝘋𝘪𝘴𝘰𝘳𝘥𝘦𝘳𝘴, fifth edition, criteria for the diagnosis of neuroleptic malignant syndrome include exposure to a dopamine-blocking drug, severe muscular rigidity, fever, and at least two of the following features: diaphoresis, dysphagia, tremor, incontinence, an altered level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, or an elevated serum creatine kinase level. In practice, the syndrome is easier to identify than this list of items suggests.     The history, medication list, and context usually make it apparent that the patient has been exposed to a drug implicated in neuroleptic malignant syndrome, but this is not always evident, particularly with medications that are not used primarily for the treatment of psychosis or delirium.    To learn more, read the Review Article “Neuroleptic Malignant Syndrome” by Eelco F.M. Wijdicks, MD, PhD, and Allan H. Ropper, MD, from Mayo Clinic: https://nej.md/3N31DL6 

Data from nonrandomized comparisons have suggested that survival might be better with long-term oxygen therapy used for 24 hours per day than with the typically recommended 15 hours per day.     Data from randomized trials directly comparing these two durations of oxygen therapy are lacking.    In the REDOX trial, researchers assessed hospitalization and mortality among patients with chronic severe hypoxemia who received long-term oxygen therapy for either 24 or 15 hours per day.    241 adults who were starting oxygen therapy for chronic severe hypoxemia at rest were randomly assigned to receive long-term oxygen therapy (LTOT) for either 24 or 15 hours per day. The primary outcome was a composite of hospitalization or death from any cause within 1 year.    Among patients with severe hypoxemia, long-term oxygen therapy used for 24 hours per day, as compared with 15 hours per day, did not reduce the risk of hospitalization or death within 1 year.    Read the full REDOX trial results and Plain Language Summary: https://nej.md/4cR3pK4    #ClinicalTrials #MedicalResearch 

The 2024 Albert Lasker Award for Basic Medical Research recognizes Dr. Zhijian (James) Chen for his elucidation of how DNA stimulates immune responses.    Figure 1 from the article illustrates the cGAS–STING DNA sensing pathway.    The cyclic GMP–AMP synthase (cGAS) enzyme binds to viral DNA, tumor DNA, or our own aberrant DNA. DNA binding activates cGAS to synthesize cyclic GMP–AMP (cGAMP) from ATP and GTP nucleotides. Bacteria also produce cyclic dinucleotides (CDNs). Bacterial cyclic dinucleotides and cGAMP bind to STING, a protein of the endoplasmic reticulum, which results in activation of a signaling pathway that stimulates the production of type I interferons. IRF3 denotes interferon regulatory factor 3, IκBα nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor alpha, NF-κB nuclear factor κB, and TBK1 TANK binding kinase 1.    Read the Clinical Implications of Basic Research article “How DNA Sensing Drives Inflammation” by Russell E. Vance, PhD, from the Howard Hughes Medical Institute (HHMI) and the University of California, Berkeley: https://nej.md/4e9pCEt 

𝗖𝗼𝗻𝗱𝗶𝘁𝗶𝗼𝗻𝗶𝗻𝗴 is a term used to describe a course of treatment comprising one or more medications administered to patients before transplantation of allogeneic or autologous hematopoietic stem cells. Typically, radiation and alkylating agents such as busulfan that eliminate the recipient’s hematopoietic cells are given to “make space” for the transplanted cells. For most allogeneic transplant recipients, additional agents are given to eliminate immune cells and prevent immunologic rejection of the graft. To learn more about this NEJM Illustrated Glossary term, read the editorial “CSF1R Blockade for Refractory Chronic Graft-versus-Host Disease” by Mohamad Mohty, MD, PhD, from Sorbonne Université, INSERM, CRSA PARIS, and Greater Paris University Hospitals - AP-HP: https://nej.md/3MOORQs      Explore more terms: https://nej.md/glossary    

Case Record of the Massachusetts General Hospital: A 47-year-old man was admitted to the hospital because of confusion, pneumonia involving the right lower lobe, and acute kidney failure. The creatine kinase level was 28,581 U per liter. A diagnosis was made.    Figure 2 from the case shows environmental sources, clinical manifestations, laboratory findings, and radiologic findings of legionella pneumonia.    Transmission typically occurs through aerosolization from an environmental source. Inhalation and inoculation result in prodromal symptoms, including fever, malaise, and headache. Over the course of several days, a cough develops that may or may not be productive of purulent sputum. Altered mental status is frequently described with severe cases. Nonpulmonary symptoms, such as headache and gastrointestinal symptoms, may be severe and lead to misdiagnosis. Laboratory findings are consistent with severe community-acquired pneumonia and may show leukocytosis or leukopenia, elevated levels of liver enzymes, lactate dehydrogenase, and creatine kinase, and hyponatremia; however, these findings lack specificity. Radiologic findings nearly always include a consolidating pneumonia at the time of presentation. Extrapulmonary infection is rare and occurs almost exclusively in immunocompromised patients.    Read more about this real-life case in “A 47-Year-Old Man with Confusion and Kidney Failure” by Sachin J. Shah, MD, MPH, Melissa C. Price, MD, and Sanjat Kanjilal, MD, MPH, from Massachusetts General Hospital, Harvard Medical School, Harvard Pilgrim Health Care Institute, and Brigham and Women's Hospital: https://nej.md/3B9Fx7e