NEJM evidence最新文献

Background: A predictive model for early-stage classic Hodgkin's lymphoma (cHL) does not exist. Leveraging patient-level data from large clinical trials and registries, we developed and validated a model that we term the Early-Stage cHL International Prognostication Index (E-HIPI) to predict 2-year progression-free survival (PFS).

Methods: We developed the model using the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines in 3000 adults with newly diagnosed early-stage cHL from four international phase III clinical trials conducted from 1994 to 2011. External validation was performed in two cohorts, totaling 2360 treated patients from five international cHL registries (1996 to 2019). Two-year PFS was estimated using a Cox model with pretreatment variables selected using backward elimination. Internal validation corrected for overfitting. External validation assessed discrimination and calibration. The final model was also compared against European Organisation for Research and Treatment of Cancer (EORTC) favorable or unfavorable status.

Results: The median age in the development cohort was 31.2 years; 77.4% had stage II disease. The estimated 2-year PFS was 93.7%. Final variables retained in the model were sex and continuous values of maximum tumor diameter (MTD), and levels of hemoglobin and albumin. The optimism-corrected C statistic in the development cohort was 0.63 (95% confidence interval, 0.60 to 0.69). Two-year PFS was lower in the validation cohorts 1 (90.3%) and 2 (91.6%). In validation cohort 1, the C statistic was 0.63 and the calibration slope was near 1, but overall calibration indicated underprediction, which improved on updating the intercept. The performance was similar in validation cohort 2. In addition, higher-risk E-HIPI scores were associated with worse outcomes in both the EORTC unfavorable and favorable subgroups. When included altogether in one Cox model, the E-HIPI was associated with PFS, whereas EORTC favorable or unfavorable status was not. Online risk calculators were developed (https://rtools.mayo.edu/holistic_ehipi/).

Conclusions: Utilizing objective, continuous, and readily available variables, we developed and validated a new prediction model for early-stage cHL. Male sex, lower hemoglobin or albumin levels, and higher MTDs were associated with worse PFS. (Funded by the National Cancer Institute; grant number, NCI R01 CA 262265-04.).

AbstractMorning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient's presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of a 74-year-old woman who presents to the emergency department with a 3-month history of bilateral leg weakness and paresthesia. Using questions, physical examination, and testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is refined until a final diagnosis is made.

Background: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 rearrangements (MLN-FGFR1) are associated with poor prognosis. They are caused by chromosome 8p11 rearrangements that result in FGFR1 fusion genes and constitutive FGFR1 activation. We report on a phase 2 study, in which there were no concurrent control patients, termed FIGHT-203, in which we evaluated the FGFR1-3 inhibitor, pemigatinib, for the treatment of MLN-FGFR1.

Methods: We assigned eligible patients to receive oral pemigatinib 13.5 mg once daily (2 weeks on followed by 1 week off or continuously). End points included complete response rate (primary) and complete cytogenetic response rate. Responses were assessed locally by investigators per protocol-defined criteria and were retrospectively adjudicated by a central review committee using criteria defined by the committee.

Results: Of 47 treated patients (safety population), 45 had confirmed FGFR1 rearrangement and were analyzed for efficacy; of these patients, 24 (53%) were in the chronic phase of illness; 18 (40%) were in blast phase; and three previously treated patients (7%) exhibited the rearrangement without morphologic bone marrow or extramedullary involvement. The overall complete response rate, as determined by central review, was 74% (31 out of 42); this occurred in 96% (23 out of 24) of patients in chronic phase and 44% (8 out of 18) of patients in blast phase. A complete cytogenetic response was observed in 73% (33 out of 45) of patients overall, consisting of 88% (21 out of 24) of patients in chronic phase, 50% (9 out of 18) of patients in blast phase, and all three patients who had a rearrangement only. The median duration of complete response was not reached (95% confidence interval, 27.9 months to not reached). The most common any-grade treatment-emergent adverse event was hyperphosphatemia (76%); the most common grade-3-and-over event was stomatitis (19%). Pemigatinib discontinuation, interruption, and dose reduction occurred in 5 (11%), 30 (64%), and 28 (60%) patients, respectively.

Conclusions: In our study, pemigatinib manifested near complete efficacy in chronic-phase patients with MLN-FGFR1, while the complete response rate was close to 50% in blast-phase patients. Toxicities were manageable with dose modifications. (Funded by Incyte Corporation; FIGHT-203 ClinicalTrials.gov number, NCT03011372.).

AbstractMorning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of an 80-year-old man with progressively worsening left groin pain following a fall 1 week prior to presentation. Using questions, physical examination, and diagnostic testing, an illness script for the presentation emerges; the differential is refined until a final diagnosis is made.

Background: Intrauterine devices (IUDs) are highly effective, yet acceptability and continuation differ by user and device characteristics. We evaluated the efficacy of the NTCu380 Mini, a 380-mm² copper IUD available in Europe and Canada, and compared safety and continuation with the TCu380A IUD, the 380-mm² copper IUD available in the United States.

Methods: We randomly assigned participants between 16 and 40 years of age in a 4:1 ratio to the NTCu380 Mini or TCu380A and assessed over 37 months. The primary outcome was NTCu380 Mini efficacy measured by the Pearl Index (defined as the number of pregnancies per 100 woman-years) in participants 35 years of age and under. Additional outcomes included NTCu380 Mini time to pregnancy by survival analysis, and comparative adverse events (AEs) and continuation rates of NTCu380 Mini versus TCu380A.

Results: We randomly assigned 887 participants to NTCu380 Mini (744 [83.9%] nulliparous) and 218 to TCu380A (183 [83.9%] nulliparous), of whom 875 (98.6%) and 213 (97.7%), respectively, had successful placement. The NTCu380 Mini IUD 3-year cumulative Pearl Index was 1.86 (95% confidence interval [CI], 1.20 to 2.74) pregnancies per 100 women-years; the cumulative rate of pregnancy through year 3 was 4.8% (95% CI, 2.8 to 6.9%). Serious AEs occurred in 31 (3.5%) NTCu380 Mini and 4 (1.9%) TCu380A users (P=0.28). Discontinuation occurred in 449 (51.3%) NTCu380 Mini and 122 (57.3%) TCu380A users (P=0.07). AEs led to discontinuation less frequently among NTCu380 Mini (152 [20.8%]) than TCu380A users (57 [33.2%]) (P=0.001), particularly bleeding or pelvic pain AEs (103 [14.5%] vs. 46 [27.3%], respectively; P<0.001).

Conclusions: In this predominantly nulliparous population, the NTCu380 Mini IUD had an approximate 5% pregnancy rate over 3 years, with fewer side effects leading to discontinuation than observed among TCu380A users. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03124160.) The findings and conclusions in this article are those of the authors and do not necessarily reflect the views of the Planned Parenthood Federation of America, Inc.

Background: Revakinagene taroretcel (NT-501) is an encapsulated cell therapy producing ciliary neurotrophic factor that slowed retinal degeneration in patients with macular telangiectasia type 2 (MacTel) in phase 2 trials.

Methods: In NTMT-03-A and NTMT-03-B - identically designed phase 3, multicenter, randomized sham-controlled trials - we evaluated efficacy and safety of NT-501 in MacTel. The primary end point was rate of change in ellipsoid zone area (EZA) (photoreceptor) loss over 24 months (mm²/24 months). Secondary outcomes included changes in retinal sensitivity, reading speed, and National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) scores (range, 0 to 100; higher scores indicate better function). Safety end points included the proportion of participants experiencing one or more treatment-emergent serious adverse event(s) and loss of 15 or more letters in best-corrected visual acuity (BCVA). Delayed dark adaptation and miosis were among the monitored adverse events.

Results: In NTMT-03-A, adjusted rates of change of EZA loss were 0.075 mm²/24 months (95% confidence interval [CI], 0.051 to 0.099) and 0.166 mm²/24 months (95% CI, 0.141 to 0.191) in the NT-501 (n=58) and sham (n=57) groups, respectively, with a difference of -0.091 mm²/24 months (95% CI, -0.125 to -0.056; P<0.001) between groups. In NTMT-03-B, rates of EZA loss were 0.111 mm²/24 months (95% CI, 0.084 to 0.139) and 0.160 mm²/24 months (95% CI, 0.131 to 0.189) in the NT-501 (n=59) and sham (n=54) groups, respectively, with a difference of -0.049 mm²/24 months (95% CI, -0.089 to -0.008; P=0.02). Retinal sensitivity and reading-speed changes between groups were inconsistent in the trials. NEI VFQ-25 scores, BCVA loss, and treatment-emergent serious adverse events did not differ between treatment groups. Miosis was experienced by 17% and 14% of participants receiving NT-501 in NTMT-03-A and NTMT-03-B, respectively, and by none of the participants in sham groups. Delayed dark adaptation was experienced by 17% and 24% of participants receiving NT-501 in NTMT-03-A and NTMT-03-B, respectively, by none in the NTMT-03-A sham group, and by 2% in the NTMT-03-B sham group.

Conclusions: NT-501 for MacTel resulted in statistically significantly reduced EZA loss compared with sham procedures. (Funded by Neurotech Pharmaceuticals; ClinicalTrials.gov numbers, NCT03316300 and NCT03319849.).

Background: Once-weekly semaglutide is approved for the management of type 2 diabetes and obesity. The efficacy and safety of semaglutide in adults with type 1 diabetes are not established.

Methods: In this 26-week, double-blind trial, we randomly assigned 72 adults with type 1 diabetes using an automated insulin delivery (AID) system and with a body mass index of 30 or higher in a 1:1 ratio to receive once-weekly semaglutide up to 1 mg or placebo. The primary composite end point consisted of achieving all of the following elements: continuous glucose monitoring (CGM)-based time between 70 and 180 mg/dl of greater than 70% and time below 70 mg/dl of less than 4%; and weight reduction of at least 5%.

Results: A significantly greater percentage of patients in the semaglutide group than in the placebo group achieved the primary composite outcome (36% vs. 0%; between-group difference, 36 percentage points; 95% confidence interval [CI], 20.6 to 52.2; P<0.001). The difference in the least-squares mean change from baseline to week 26 for the semaglutide versus placebo group for glycated hemoglobin was -0.3 percentage points (95% CI, -0.6 to -0.05), for percentage of time with CGM glucose levels between 70 and 180 mg/dl it was 8.8 percentage points (95% CI, 3.9 to 13.7), and for body weight it was -8.8 kg (95% CI, -10.6 to -7.0). There were two severe hypoglycemia events in each group, and no diabetic ketoacidosis was reported.

Conclusions: In adults with type 1 diabetes and obesity, semaglutide treatment, compared with AID use alone, significantly improved achievement of a composite of time in range of greater than 70%, with time below range of less than 4%, and a 5% body weight reduction. (Funded by Breakthrough T1D [Type 1 Diabetes]; ADJUST-T1D trial ; Clinicaltrials.gov number, NCT05537233).