N Engl J Med
· 2026 Jun · PMID 42308485
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Modern risk-adapted management of thyroid cancer involves risk stratification as an active, dynamic process that begins with the detection of a thyroid nodule and continues throughout the clinical course of diagnosis, ac...Modern risk-adapted management of thyroid cancer involves risk stratification as an active, dynamic process that begins with the detection of a thyroid nodule and continues throughout the clinical course of diagnosis, active surveillance or treatment, and follow-up. Rooted in clinicopathological staging, which can be further refined with the molecular risk characterization of the tumor, initial management plans are developed and modified over time on the basis of the natural history of the disease and the response to therapy. We present a clinical framework for therapeutic decision making that can be used to compare, contrast, and illustrate the relative risks, benefits, and patient preferences that are integral to the development of a personalized management plan. We examine examples of therapeutic decision making in active surveillance of low-risk papillary thyroid cancer, minimalist therapeutic management options for low- and intermediate-risk thyroid cancer, and systemic therapies for advanced thyroid cancer, showing how the therapeutic decision-making framework can be used to achieve informed consensus and management recommendations.
Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group, Lee TC, Barina LA
… +236 more, Walls G, Goodman AL, Yahav D, Cheng MP, Bonten M, Bowen AC, Boyles T, Daneman N, Ekkelenkamp MB, Ghanem-Zoubi N, Hensgens MPM, Jager NGL, Kaasch AJ, Kouijzer IJE, Lewis RJ, Lumley T, Lye DC, McDonald EG, McKew G, McLean ARD, McMullan BJ, McQuilten ZK, Morpeth SC, Paterson DL, Roberts JA, Robinson JO, Saito H, Scarborough M, Ten Oever J, Turner RM, Tverring J, van Hal SJ, Webb SA, Whiteway LM, Arias CA, Henderson A, Heriot GS, Snelling TL, Afra K, Ali SS, Amit S, Anagnostou NA, Archuleta S, Aston SJ, Athan E, Baharav N, Bai AD, Barber BE, Baskaran A, Berkeley MMA, Best EJ, Bhilave NR, Bloomfield MG, Bond KA, Bostock J, Botheras CL, Boyd MA, Bradshaw SME, Briggs EJ, Britton PN, Campbell AJ, Carr BZ, Chancellor JA, Chen K, Cheong EY, Chew KL, Chia PY, Chomba R, Chong BSW, Clews CJN, Cohen JM, Commons RJ, Cutfield T, Daley P, Daniel DS, Davies J, De P, Denholm JT, Di Virgilio M, Dishon-Benattar Y, Dotel R, Duan EH, Easom N, Eliakim-Raz N, England MM, Fahmy M, Findlater AR, Flanagan KL, Foo EZJ, Foo H, Forster DP, Fralick M, Frazer JL, Gador-Whyte AP, Garnham K, German GJ, Ghosh N, Gisolf EH, Giulieri SG, Goulding SR, Grant JM, Gregson D, Grimwade KC, Grupper M, Guy SD, Gwee A, Hall VG, Hardy EJ, Harris DJ, Hatcher J, Hobbs MR, Holmes NE, Howden BP, Huggan PJ, Jennings ZA, Johnstone J, Juniper T, Kalimuddin S, Kamfose M, Kandel C, Kelly MJ, Kozak RA, Kümin M, Lamontagne F, Lau JSY, Lee IR, Lin RJ, Lindsay D, Llewelyn MJ, Longtin Y, Lother SA, Luey CE, MacFadden DR, Mahony AA, Malden C, Malhamé I, Manning LA, Marks M, Martin LJ, Matthews GV, McGann PH, McMahon JH, Melon A, Menon V, Mertz D, Meyer MP, Molton JS, Mora JM, Moran E, Mortimer LM, Motaganahalli S, Muller MP, Munro APS, Murray FA, Murthy S, Nagendra V, Nel H, New DWJ, Nguyen V, Norton G, Norton KM, Nourse CB, Nye CJS, O'Callaghan K, O'Sullivan MVN, Ong SWX, Otu AA, Owen M, Papenburg J, Parkes LO, Paul M, Perez-Patrigeon S, Petersiel N, Petrella L, Pett SL, Pham D, Piazzese CJ, Poulin S, Rehak R, Rennert-May E, Richards AJ, Rogers BA, Sahng E, Salada B, Scheuerman O, Schneider K, Schulz TR, Schwartz KL, Simos PA, Singh H, Sinkeler FS, Smith S, Smith BJ, Smith SW, Somayaji R, Sommerville C, Song RXJ, Sowden DC, Stark MJ, Stone NRH, Strunk T, Sud A, Swe KP, Symons CR, Tan YE, Ten Doesschate T, Thien SY, Thomas A, Trad MA, Tramontana AR, Tsang JLY, Ulett K, Underwood J, van Welzen BJ, Vazquez-Grande G, Velasquez Reyes DC, Verberk JDM, Voss LM, Ward D, Webb RH, Whitmore TJ, Wieder-Finesod A, Wilson HL, Wilson EW, Wong HM, Wong She K, Wuerz T, Yamamura DL, Yeoh A, Yow BLH, Dymock M, Mahar RK, McGlothlin A, Marsh JA, Davis JS, Tong SYC
N Engl J Med
· 2026 Jun · PMID 42308484
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BACKGROUND: bacteremia is associated with high mortality. Whether cefazolin or an antistaphylococcal penicillin should be preferred for the treatment of methicillin-susceptible bacteremia is unclear. METHODS: In an ong...BACKGROUND: bacteremia is associated with high mortality. Whether cefazolin or an antistaphylococcal penicillin should be preferred for the treatment of methicillin-susceptible bacteremia is unclear. METHODS: In an ongoing international Bayesian adaptive platform trial, we conducted an open-label, randomized comparison of cefazolin with an antistaphylococcal penicillin (flucloxacillin or cloxacillin) in adult patients with penicillin-resistant, methicillin-susceptible bacteremia. The primary outcome, which was evaluated with a hierarchical Bayesian logistic-regression model, was death from any cause within 90 days after enrollment in the platform. We assessed the posterior probability of the noninferiority of cefazolin to flucloxacillin or cloxacillin (with the criterion for noninferiority prespecified as an adjusted odds ratio of <1.2, which approximates an absolute difference in mortality of <2.5 percentage points if mortality in the antistaphylococcal-penicillin group is 15%), as well as the posterior probability of superiority (with the criterion of an adjusted odds ratio of <1.0). Secondary safety outcomes included the development of acute kidney injury within 14 days. RESULTS: This domain of the ongoing trial was conducted between February 17, 2022, and August 7, 2024, by which time the criterion for noninferiority had been met. Mortality at 90 days among adults who could be evaluated was 15.0% (97 deaths among 645 patients) in the cefazolin group and 17.0% (109 deaths among 642 patients) in the antistaphylococcal-penicillin group (adjusted odds ratio, 0.81; 95% credible interval, 0.59 to 1.12; probability of noninferiority, 99.2%; probability of superiority, 89.8%). Acute kidney injury occurred in 92 of 660 patients (13.9%) in the cefazolin group, as compared with 127 of 648 (19.6%) in the antistaphylococcal-penicillin group (adjusted odds ratio, 0.67; 95% credible interval, 0.50 to 0.89; probability of superiority, 99.7%). CONCLUSIONS: In patients with methicillin-susceptible bacteremia, cefazolin was noninferior to flucloxacillin or cloxacillin with respect to 90-day mortality and was associated with a lower incidence of acute kidney injury. (Funded by the National Health and Medical Research Council and others; SNAP ClinicalTrials.gov number, NCT05137119.).
de Bitter TJJ, van der Sanden B, Sagath L
… +34 more, Höps W, Arts P, de Groot M, Weiss MM, Derks R, den Ouden A, van den Heuvel S, Timmermans RGJ, van Leeuwen T, Corominas Galbany J, Smits JGA, Snijders Blok L, Hofste T, Steehouwer M, Zomer N, Sabbagh Q, Kamsteeg EJ, Lugtenberg D, Bosgoed EA, Rodenburg RJ, Ming Sun S, Mensenkamp AR, Ligtenberg MJL, de Leeuw N, Hellebrekers DMEI, Stegmann APA, Paulussen ADC, Blok MJ, van Zelst-Stams WAG, van den Wijngaard A, Yntema HG, Gilissen C, Hoischen A, Vissers LELM
N Engl J Med
· 2026 Jun · PMID 42294850
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Cohn DM, Gurugama P, Longhurst HJ
… +20 more, Aygören-Pürsün E, Craig TJ, Farkas H, Jacobs J, Lumry WR, Magerl M, Peter J, Riedl MA, Maag D, Golden A, Shah MY, Sutherland A, Miller CR, Abdelhady AM, Xu Y, Butler JS, Lebwohl D, Leonard J, Banerji A, HAELO Investigators
N Engl J Med
· 2026 Jun · PMID 42294842
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BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic condition characterized by recurrent and debilitating swelling attacks. Lonvoguran ziclumeran (lonvo-z) - an investigational, in vivo g...BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic condition characterized by recurrent and debilitating swelling attacks. Lonvoguran ziclumeran (lonvo-z) - an investigational, in vivo gene-editing treatment based on clustered regularly interspaced short palindromic repeats (CRISPR) - is being developed as a single-dose treatment for hereditary angioedema. METHODS: In a phase 3, double-blind trial, we randomly assigned, in a 2:1 ratio, patients who were 16 years of age or older and had hereditary angioedema with C1 inhibitor deficiency to receive a single intravenous infusion of lonvo-z (at a dose of 50 mg) or placebo. The primary end point was the number of investigator-confirmed hereditary angioedema attacks per month (the monthly attack rate) from week 5 through week 28 after infusion. RESULTS: A total of 80 patients underwent randomization; 52 were assigned to receive lonvo-z and 28 to receive placebo. As of February 10, 2026, the median duration of follow-up was 7.5 months (range, 4.9 to 12.8). The least-squares mean monthly attack rate from weeks 5 through 28 was 0.26 (95% confidence interval [CI], 0.15 to 0.45) in the lonvo-z group and 2.10 (95% CI, 1.55 to 2.86) in the placebo group (relative difference, -87%; 95% CI, -93 to -78; P<0.001). Adverse events that occurred during or after infusion of lonvo-z or placebo were reported in 92% and 86% of the patients in the lonvo-z and placebo groups, respectively, from day 1 through week 28. Among the adverse events that occurred during or after infusion and more often in the lonvo-z group than in the placebo group, the most common (occurring in >10% of the patients in the lonvo-z group) included infusion-related reaction, headache, fatigue, back pain, and upper respiratory tract infection. No serious or grade 3 or higher adverse events were reported in the lonvo-z group. CONCLUSIONS: Among patients with hereditary angioedema, a single intravenous infusion of lonvo-z resulted in a significantly lower rate of hereditary angioedema attacks than placebo. (Funded by Intellia Therapeutics; HAELO ClinicalTrials.gov number, NCT06634420.).
Mina R, Beksac M, Rodríguez-Otero P
… +56 more, Chen W, Mateos MV, Li J, Moreau P, Cohen YC, Min CK, Jelinek T, Ye JC, Magen H, Rubinstein SM, Fu W, Hungria V, Cengiz Seval G, Farias JS, Radocha J, Maral S, Turgut M, Koh Y, O'Leary D, Schmidt Filho J, Thertulien R, An G, Huang SY, Grosicki S, Tyczyńska A, Banerjee R, Pianko MJ, Martínez-López J, Steckiewicz P, Maruyama D, Fukushima K, Oriol A, Lopez Pardo J, Goldschmidt H, Pawlyn C, Perrot A, Zamagni E, Dimopoulos MA, Rasche L, Tolbert J, Terry W, Courtoux C, Liu X, Vasey SY, Connors K, Festa M, Heuck C, Langlois A, O'Rourke L, Zhou J, Qin X, Lu J, Gong J, Vieyra D, Voorhees PM, MonumenTAL-3 Investigators
N Engl J Med
· 2026 Jun · PMID 42294841
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BACKGROUND: Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1-2 trials, with a limited effect...BACKGROUND: Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1-2 trials, with a limited effect on normal B cells. METHODS: In a phase 3 trial, we randomly assigned patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy to receive talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The primary end point was progression-free survival as assessed by an independent review committee. Key secondary end points were overall response, complete response or better (complete or stringent complete response), measurable residual disease-negative complete response, and overall survival. RESULTS: A total of 287, 287, and 290 patients were assigned to the Tal-DP, Tal-D, and DPd groups, respectively. At the interim analysis (median follow-up, 24.6 months), progression-free survival was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio for disease progression or death, Tal-DP vs. DPd, 0.28 [95% confidence interval {CI}, 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P<0.001 for both comparisons). The overall response was higher with Tal-DP and Tal-D than with DPd (88.2% and 88.5% vs. 77.6%), as was complete response or better (71.1% and 69.0% vs. 34.5%) and measurable residual disease-negative complete response (52.3% and 46.3% vs. 15.9%) (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (hazard ratio for death, Tal-DP vs. DPd, 0.47 [95% CI, 0.30 to 0.73], and Tal-D vs. DPd, 0.51 [95% CI, 0.33 to 0.78]). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively; fatal adverse events occurred in 1.8%, 4.0%, and 4.6%. CONCLUSIONS: Among patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy, both Tal-DP and Tal-D led to significantly longer progression-free survival than DPd. (Funded by Johnson & Johnson; MonumenTAL-3 ClinicalTrials.gov number, NCT05455320.).
SODa-BIC Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Serpa Neto A, McNamara M
… +26 more, White K, Cooper DJ, Fujii T, Higgins AM, Hodgson CL, Navarra L, Nichol A, Peake S, Réa-Neto A, Secombe P, Osborne F, Burrill H, See E, Young M, Zampieri FG, Plummer M, Christie C, Nunnink L, Mackay J, McGuinness S, Marmol J, Tiruvoipati R, Bailey M, Young PJ, Bellomo R, Udy A
N Engl J Med
· 2026 Jun · PMID 42283370
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BACKGROUND: Metabolic acidosis is common in critically ill patients and is associated with organ dysfunction and death. Sodium bicarbonate is used to correct acidemia, but its benefit in patients with metabolic acidosis...BACKGROUND: Metabolic acidosis is common in critically ill patients and is associated with organ dysfunction and death. Sodium bicarbonate is used to correct acidemia, but its benefit in patients with metabolic acidosis who are receiving vasopressors remains uncertain. METHODS: In this pragmatic, adaptive, double-blind, randomized trial, we assigned adults with metabolic acidosis (pH, <7.30; base excess, no more than -4 mmol per liter; and partial pressure of arterial carbon dioxide, ≤45 mm Hg without intubation or ≤50 mm Hg with intubation) who were receiving vasopressors in the intensive care unit (ICU) to receive either sodium bicarbonate or placebo (5% dextrose). Sodium bicarbonate or placebo was infused for up to 5 hours, with the infusion rate adjusted for a target pH of at least 7.30 and base excess of at least 0 mmol per liter. The primary outcome was a major adverse kidney event, defined as death, use of renal-replacement therapy, or persistent renal dysfunction, within 30 days. RESULTS: A total of 500 patients were enrolled in 55 ICUs across seven countries; 245 patients were assigned to receive sodium bicarbonate and 255 to receive placebo. A major adverse kidney event within 30 days occurred in 98 of 244 patients (40.2%) in the sodium bicarbonate group and in 100 of 254 patients (39.4%) in the placebo group (adjusted difference, 1.2 percentage points; 95% confidence interval [CI], -7.1 to 9.4; P = 0.78). Renal-replacement therapy was used within 30 days in 16.8% of the patients in the sodium bicarbonate group and in 20.9% of those in the placebo group (adjusted difference, -3.9 percentage points; 95% CI, -10.6 to 2.7). In-hospital mortality by day 30 was 25.4% in the sodium bicarbonate group and 24.0% in the placebo group (adjusted difference, 1.8 percentage points; 95% CI, -5.6 to 9.2). Four patients (1.6%) in the sodium bicarbonate group had an adverse effect, as compared with none in the placebo group (P = 0.06). CONCLUSIONS: The use of sodium bicarbonate in critically ill patients with metabolic acidosis receiving vasopressors did not lead to a lower risk of major adverse kidney events within 30 days than placebo. (Funded by the National Health and Medical Research Council of Australia; SODa-BIC ClinicalTrials.gov number, NCT05697770.).
Frangoul H, de la Fuente J, Chopra Y
… +20 more, Meisel R, Amrolia PJ, Algeri M, Sharma A, Cappellini MD, Corbacioglu S, Kattamis A, Lobitz S, de Montalembert M, Rondelli D, Sheth S, Steinberg MH, Walters MC, Boerner K, Liu T, Zairis S, Hobbs W, Grupp SA, Locatelli F, CLIMB THAL-141 and CLIMB SCD-151 Study Groups
N Engl J Med
· 2026 Jun · PMID 42274009
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BACKGROUND: Exagamglogene autotemcel (exa-cel) is a cell therapy in which autologous CD34+ hematopoietic cells are engineered through ex vivo clustered regularly interspaced short palindromic repeats-Cas9 editing of the...BACKGROUND: Exagamglogene autotemcel (exa-cel) is a cell therapy in which autologous CD34+ hematopoietic cells are engineered through ex vivo clustered regularly interspaced short palindromic repeats-Cas9 editing of the erythroid-specific enhancer region of to express fetal hemoglobin. In phase 3 studies involving participants 12 to 35 years of age with sickle cell disease or transfusion-dependent β-thalassemia, exa-cel eliminated vaso-occlusive crises and the need for red-cell transfusions. METHODS: In two ongoing, phase 3, open-label, single-group studies, we evaluated exa-cel in children 5 to 11 years of age with transfusion-dependent β-thalassemia or sickle cell disease. Before exa-cel infusion, participants underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end points were transfusion independence for at least 12 consecutive months in children with transfusion-dependent β-thalassemia and freedom from severe vaso-occlusive crises for at least 12 consecutive months in children with sickle cell disease. RESULTS: A total of 15 children with transfusion-dependent β-thalassemia and 11 with sickle cell disease received exa-cel; median follow-up was 16.0 months (range, 2.2 to 32.1) and 16.9 months (range, 7.6 to 33.1), respectively. Of 8 children with transfusion-dependent β-thalassemia who were followed to at least 16 months, 8 were transfusion independent; the status of the remaining 7 was not yet evaluable. Of 8 children with sickle cell disease who were followed to at least 16 months, 8 were free of vaso-occlusive crises; the status of the remaining 3 was not yet evaluable. All the children had at least one grade 3 or 4 adverse event; 2 children with transfusion-dependent β-thalassemia had severe veno-occlusive liver disease that was assessed as being related to busulfan conditioning, 1 of whom died. CONCLUSIONS: Exa-cel therapy resulted in transfusion independence or freedom from severe vaso-occlusive crises in participants with transfusion-dependent β-thalassemia or sickle cell disease, respectively, who were followed for at least 16 months. All the participants had grade 3 or 4 adverse events. (Funded by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-141 ClinicalTrials.gov number, NCT05356195; CLIMB SCD-151 ClinicalTrials.gov number, NCT05329649.).
ARISE FLUIDS Investigators, the ANZICS Clinical Trials Group, and the ACEM Clinical Trials Network, Peake SL, Macdonald SPJ
… +16 more, Howe BD, Milford E, Jones P, Arendts G, Bailey M, Burcham J, Delaney A, Egerton-Warburton D, Fatovich D, Fraser JF, Higgins AM, Keijzers G, Udy AA, Williams P, Young PJ, Bellomo R
N Engl J Med
· 2026 Jun · PMID 42274006
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BACKGROUND: The optimal approach to early resuscitation in septic shock is unknown. Equipoise exists between the use of larger volumes of intravenous fluids to restore perfusion and the use of early vasopressor therapy a...BACKGROUND: The optimal approach to early resuscitation in septic shock is unknown. Equipoise exists between the use of larger volumes of intravenous fluids to restore perfusion and the use of early vasopressor therapy along with smaller volumes of fluids to minimize potential harm from excess fluid. METHODS: We randomly assigned adult patients who presented to the emergency department with septic shock to receive either fluids at restricted volumes and early vasopressor therapy (vasopressor group) or higher volumes of fluids and later vasopressor therapy (fluids group) for at least 6 hours and up to 24 hours. The primary outcome was days alive and out of the hospital from randomization to day 90. RESULTS: A total of 1000 patients underwent randomization, with 499 assigned to the vasopressor group and 501 to the fluids group. Informed consent was not obtained for 37 patients, which left 963 patients in the intention-to-treat population (481 in the vasopressor group and 482 in the fluids group). Three patients in the fluids group were lost to follow-up for the primary outcome. In the first 24 hours after randomization, patients in the vasopressor group received less intravenous fluid than those in the fluids group (median difference, -1108 ml; 95% confidence interval [CI], -1395 to -850). The percentage of patients who received vasopressors was higher by 18.9 percentage points (95% CI, 13.3 to 24.5) in the vasopressor group. The median number of days alive and out of the hospital at day 90 was 76 (interquartile range, 55 to 83) in the vasopressor group and 76 (interquartile range, 55 to 82) in the fluids group (difference, 0.0 days; 95% CI, -2.7 to 2.7; P = 1.00). Adverse events occurred in similar percentages of patients in the two groups, except for pulmonary edema (0.6% in the vasopressor group vs. 5.0% in the fluids group; P<0.001). CONCLUSIONS: Among adult patients who presented to the emergency department with septic shock, an approach that involved restricted fluid volume and early vasopressors did not result in a greater number of days alive and out of the hospital at day 90 than an approach involving greater fluid volume and later administration of vasopressors. (Funded by the Australian National Health and Medical Council Medical Research Future Fund and the New Zealand Health Research Council; ARISE FLUIDS ClinicalTrials.gov number, NCT04569942.).