NEJM This Week — July 9, 2026

This week's headline is pulmonary: the two companion TETON trials show inhaled treprostinil slows FVC decline and delays clinical worsening in idiopathic pulmonary fibrosis — a new option on top of nintedanib/pirfenidone, though cough and high discontinuation temper the enthusiasm. The most useful general-IM read is the critical-care nutrition review: a clean "less is more" acute-phase strategy (restrictive calories, standard-dose protein, no routine gastric-residual checks). TRANSCEND (setmelanotide for the rare acquired hypothalamic obesity) and ELEVATE (adjuvant ensartinib in ALK+ NSCLC) are summarized for awareness and flagged lower-yield. A superb histoplasmosis lung-transplant teaching case rounds out the issue.

PulmonaryTETON-1 & TETON-2 · RCTHigh yield · IM

Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis (TETON-1 & TETON-2)

In patients with IPF — most already on nintedanib or pirfenidone — does inhaled treprostinil vs placebo slow the decline in forced vital capacity (FVC)?

Population: Two 52-week, double-blind, placebo-controlled phase 3 trials: TETON-1 (598 patients, US/Canada) and TETON-2 (593 patients, Asia–Pacific/Europe/South America). Adults ≥40 yr with IPF, FVC ≥45% predicted; ~75–78% on background nintedanib or pirfenidone.
Intervention: Inhaled treprostinil, titrated to 12 breaths (72 µg) four times daily.
Comparison: Inhaled placebo.
Outcome: Median 52-wk FVC change favored treprostinil in both: TETON-1 +130.1 mL (95% CI 82.2–178.1; P<0.001), TETON-2 +95.6 mL (95% CI 52.2–139.0; P<0.001). Fewer clinical-worsening events (HR 0.67 and 0.71); combined-dataset acute-exacerbation HR 0.52 (0.30–0.91). Cough was the top adverse event (48–55% vs 24–33%) and leading cause of the high (~34–41%) drug-discontinuation rate.

Clinical takeaway. Two concordant phase 3 trials make inhaled treprostinil a new option that slows FVC decline and delays clinical worsening in IPF, including added onto nintedanib or pirfenidone. Per the editorial (Taichman), this is real progress after years of failures — but neither treprostinil nor the recently approved nerandomilast stops decline, tolerability is a genuine problem (cough, ~37% discontinuation), and because the trials were agnostic to pulmonary hypertension, we still can't identify who benefits most. What this changes: extends the IPF armamentarium; likely to support approval, but patient selection stays unresolved.

EndocrinologyTRANSCEND · RCTLower yield · IM

Setmelanotide for the Treatment of Acquired Hypothalamic Obesity

In acquired hypothalamic obesity (mostly post-craniopharyngioma), does the MC4R agonist setmelanotide vs placebo reduce BMI and hunger?

Population: 120 patients (81 setmelanotide, 39 placebo; 2:1), ages 4–66 (mean ~20 yr) with a hypothalamic tumor/lesion/injury and obesity; 78% craniopharyngioma.
Intervention: Setmelanotide 1.5–3.0 mg subcutaneously once daily for 52 weeks.
Comparison: Placebo.
Outcome: 52-wk BMI change −16.5% vs +3.3% (difference −19.8 pp; 95% CI −24.6 to −15.1; P<0.001); ≥5% BMI reduction 80% vs 10%. Hunger score −2.73 vs −1.45 (P=0.009). Serious AEs 28% vs 8%; skin hyperpigmentation (56%), nausea, vomiting most common.

Clinical takeaway. The first clearly effective drug for a disease with no approved therapies; per the editorial (Farooqi), the response shows residual MC4R/α-MSH signaling can be re-engaged even after hypothalamic injury. Watch for hyponatremia and adrenal crises in these panhypopituitary patients (many on desmopressin) as hunger and intake fall. What this changes: a new option for a rare condition — not a general-internist decision.

Heme / OncologyELEVATE · RCTLower yield · IM/ID

Ensartinib in Resected ALK-Positive Non–Small-Cell Lung Cancer

After complete resection of ALK+ NSCLC and adjuvant chemo, does 2 years of ensartinib vs placebo improve disease-free survival?

Population: 274 patients (137/137) with completely resected stage IB–IIIB ALK+ NSCLC after adjuvant chemo; all enrolled in China; prespecified interim analysis.
Intervention: Ensartinib 225 mg once daily for up to 24 months.
Comparison: Placebo.
Outcome: 24-mo disease-free survival (stage II–IIIB) 86.4% vs 53.5% (HR 0.20; 95% CI 0.11–0.38; P<0.001); overall population HR 0.20; CNS DFS HR 0.22. Overall survival immature (3 deaths). Grade ≥3 AEs 35.8% vs 18.2%.

Clinical takeaway. A large DFS benefit mirroring ALINA (adjuvant alectinib), adding ensartinib as another adjuvant ALK-inhibitor option — but OS is immature, 87% of placebo patients received an ALK inhibitor at recurrence, and the all-Chinese population limits generalizability. What this changes: incremental subspecialty thoracic-oncology option, not an internist/ID decision.

Critical CareReview · High yield · IM

Nutrition Therapy in Critically Ill Adults

How should you feed a critically ill adult in the acute phase — route, calories, protein, and monitoring?

•Prefer early enteral nutrition, but early short-term parenteral nutrition is a safe alternative when EN is contraindicated (CALORIES, NUTRIREA-2). •Restrictive / trophic energy delivery is as good as full-dose in the acute phase and causes fewer GI and metabolic complications — feed low early, especially in shock or refeeding risk. •High-dose protein (>2 g/kg/day) gives no benefit and may harm patients with AKI (EFFORT Protein, PRECISe, TARGET Protein) — target ~1.3 g/kg/day. •Keep glucose <180 mg/dL, ramp calories slowly with thiamine if refeeding risk (REFEEDING: caloric restriction improved 60-day survival 91% vs 78%), and stop routinely monitoring gastric residual volumes (no reduction in aspiration/pneumonia).

Teaching Case · Case Records of the MGH

Case 19-2026: A 68-Year-Old Man with Fatigue, Fever, and Hypoxemia · Infectious Disease / Transplant

High yield · ID

Key learning point. Final diagnosis: histoplasmosis (reactivation) 14 months after bilateral lung transplant, presenting as subacute fever, hypoxemia, pulmonary nodules, and mediastinal lymphadenopathy. Histoplasma capsulatum is a thermally dimorphic fungus — on tissue a narrow-based budding yeast 2–4 µm, and in culture (2–8 wk) showing pathognomonic tuberculate macroconidia (confirmed vs Sepedonium by MALDI-TOF). The small yeast forms are easily mistaken for candida on methenamine silver stain — the "candida" on this patient's earlier biopsy was likely Histoplasma. Serum/urine antigen assays cross-react between histoplasma and blastomyces, so they support but don't confirm the diagnosis. Treat severe/disseminated disease with liposomal amphotericin B → step-down oral azole (itraconazole standard; posaconazole chosen here for absorption/interactions), reduce immunosuppression (watch for IRIS), and manage the triazole–tacrolimus CYP3A4 interaction.

Also in this issue (out of scope or not summarized as trials): Perspectives — nursing-home supply and the aging Baby Boom; the long-term-care workforce crisis; state surveillance of assisted reproductive technology; "For Those Left Behind"; Interactive Medical Case — "A Rash and Red Urine"; Images in Clinical Medicine — Condyloma Acuminata of the Urethra; Sparganosis; Editorial — "The OMB and the Politicization of Science"; Medicine and Society — the dead-donor rule in an era of voluntary euthanasia; plus Correspondence (US CKD trends; measles inclusion-body encephalitis after allo-SCT; immediate vs deferred nonculprit-lesion PCI; one pivotal trial for FDA approval).

Summaries are original paraphrases prepared for educational use; figures are drawn from the published full text. Read the full articles at NEJM.org (subscription required). Trial registrations: TETON-1 (NCT04708782), TETON-2 (NCT05255991), TRANSCEND (NCT05774756), ELEVATE (NCT05341583). Citations: N Engl J Med 2026; Vol. 395, No. 2. DOIs: 10.1056/NEJMoa2501488, 10.1056/NEJMoa2512911 (editorial 10.1056/NEJMe2606821), 10.1056/NEJMoa2512275 (editorial 10.1056/NEJMe2606217), 10.1056/NEJMoa2518990, 10.1056/NEJMra2506111, 10.1056/NEJMcpc2517856.