Long-Term Analysis of Patients With Ewing Sarcoma Included in the Euro-EWING99 Study

Abstract: Euro-EWING99 study was a large, international, prospective study recruiting patients with Ewing sarcoma (EWS) between 1999 and 2015. It assessed three different clinical questions through randomized trials. We report here the characteristics and outcomes of all patients. Patients younger than 50 years with EWS were included in the study. They received induction chemotherapy (six courses of vincristine [day 1], ifosfamide [day 1-3], doxorubicin [day 1-3], and etoposide [day 1-3; VIDE], administered every 3 weeks), local therapy (surgery/radiotherapy), and different consolidation treatments according to clinical risk group and trial.The objectives of the study were to describe the entire cohort according to the initial staging group, to describe the survival outcomes (overall survival [OS]; progression-free survival [PFS]; and local control), and to evaluate prognostic factors associated with OS and PFS. Three thousand three hundred ninety-five patients were included in the study, including 2,267 with a localized disease, 614 with pleuropulmonary metastases, and 514 with extrapulmonary metastases. Ninety-eight percent of patients received ≥4 neoadjuvant VIDE courses. The modalities of local treatment and consolidation therapy differed among the three staging groups. With a median follow-up of 7.2 years, PFS of the entire cohort was 60.2% and 55.4% at 3 and 5 years, respectively. OS was 72.6% and 64.6% at 3 and 5 years, respectively. In addition to metastatic status at diagnosis, main prognostic factors included patient age, tumor volume, and histologic response both for PFS and OS, independent of metastatic status. To our knowledge, this study is the largest published series of patients with EWS and may serve as a landmark paper for EWS. It confirms the major prognostic value of the complete histologic response after neoadjuvant therapy.

Valentin T
Winter S
Dirksen U
Hawkins DS
Gelderblom H
Risbourg S
Berlanga P
Gaspar N
Janeway KA
Juergens H
Kirchberg IE
Ladenstein R
Laurence V
Le Deley MC
McCabe MG
Merks H
Ranft A
Strauss S
Van De Sande MAJ
Whelan J
Marec-Berard P
Brennan B


Statistical and Methodological Considerations in the Evaluation of Ultra-Low-Dose Nivolumab

Journal of clinical oncology : official journal of the American Society of Clinical Oncology


Radiographic Progression With and Without Prostate-Specific Antigen Rise in Patients With Advanced Prostate Cancer Treated With Enzalutamide


Reply to: Statistical and Methodological Considerations in the Evaluation of Ultra-Low-Dose Nivolumab

Prabhash K
Noronha V
Pawar A
Shetake A
Badwe R


Dexamethasone-Free Antiemetic Prophylaxis for Children and Adolescents Receiving Highly Emetogenic Chemotherapy: A Multicenter, Phase III, Noninferiority Trial (CIVIC POD)

Abstract: Dexamethasone combined with a 5-hydroxytryptamine-3 receptor antagonist and a neurokinin-1 receptor antagonist is the guideline-recommended prophylaxis for chemotherapy-induced nausea and vomiting (CINV) in children receiving highly emetogenic chemotherapy (HEC), but it is associated with clinically relevant toxicities. The role of olanzapine as a dexamethasone-sparing agent for pediatric CINV prophylaxis remains uncertain. The Chemotherapy Induced Vomiting in Children-Prophylaxis Omitting Dexamethasone (CIVIC POD) was an investigator-initiated, multicenter, open-label, phase III, randomized noninferiority (NI) trial (INPHOG-SUPP-22-03) that enrolled patients age 4-18 years scheduled to receive single- or multiday HEC. Patients were randomly assigned 1:1 to dexamethasone, palonosetron, and fosaprepitant (DEX) or olanzapine, palonosetron, and fosaprepitant (OLANZ) for one chemotherapy cycle. The primary end point was complete response (CR) to vomiting (no vomiting and no rescue antiemetics) during the overall period (0-120 h after last chemotherapy). The prespecified NI margin was -15%. A total of 310 patients were randomly assigned (DEX, n = 156; OLANZ, n = 154). The median age was 13 years, 62.3% were male, and 51.9% received multiday chemotherapy. The per-protocol population included 299 patients (DEX, n = 151; OLANZ, n = 148). The overall-period CR to vomiting was 56.9% with DEX and 63.5% with OLANZ (absolute difference, 6.6% [95% CI, -4.5 to 17.7]), meeting NI criteria. Acute-period CR to vomiting was 64.2% versus 68.9%, and delayed-period CR was 78.8% versus 79.1% (DEX v OLANZ). CR to nausea during the overall, acute, and delayed periods was 54.3% versus 53.4%, 59.6% versus 59.5%, and 69.5% versus 68.9%, respectively. Any-grade somnolence was more frequent with OLANZ (50.7% v 17.2%). A dexamethasone-free regimen using olanzapine demonstrated noninferior control of vomiting compared with standard prophylaxis in children and adolescents receiving HEC, supporting olanzapine as a potential corticosteroid-sparing alternative for pediatric CINV prophylaxis.

Radhakrishnan V
Srinivasan P
Das G
Bakhshi S
Mahajan A
Ganesan P
Thiruvengadam Kothandan B
Arora RS
Parmpalli Manjunath S
Ganguly S
Pushpam D
Bansal M
Keerthivasagam S
Sharma A
Goel A
Begum M
Khan A
Rajaraman S


High-Risk Smoldering Multiple Myeloma: A Review of Controversies in Early Treatment Versus Observation

Abstract: Smoldering multiple myeloma (SMM) is an asymptomatic but biologically heterogeneous plasma cell disorder with a variable risk of progression to multiple myeloma (MM). Accurate risk stratification is essential as only a subset of patients-defined as high-risk SMM -faces a ≥50% risk of progression within 2 years. Contemporary approaches integrating clinical variables, dynamic biomarkers, genomic alterations, and immune profiling have improved risk assessment although some limitations remain. The therapeutic paradigm of SMM is evolving. Randomized phase III trials have consistently shown that early treatment delays progression to MM. Most recently, daratumumab monotherapy became the first approved treatment for high-risk-SMM following the AQUILA trial, which demonstrated a significant progression-free survival benefit (hazard ratio [HR], 0.49 [95% CI, 0.36 to 0.67], P < .001) and a trend toward improved overall survival (OS; HR, 0.52 [95% CI, 0.27 to 0.98]) versus observation. This approval challenges the traditional watch-and-wait approach and establishes early intervention as a validated option for selected patients. However, important uncertainties persist. With modern surveillance and advanced imaging, most progression events are asymptomatic and irreversible end-organ damage is uncommon. OS benefit from early treatment remains inconclusive, particularly in the era of quadruplet regimens available at MM progression. In addition, difficulties in precisely identifying truly high-risk patients raise concerns about overtreatment. Emerging data from intensive regimens, bispecific antibodies, and chimeric antigen receptor -T cell therapies suggest that deep and durable responses-and possibly cure-may be achievable in selected patients with high-risk-SMM, but long-term benefit and safety require further study. In conclusion, following the approval of daratumumab, SMM management should be risk-adapted and patient-centered: observation remains appropriate for some patients, while early treatment should be considered for carefully selected high- and ultrahigh-risk individuals.


Limiting Dexamethasone Exposure With Highly Emetogenic Chemotherapy Regimens: Is the Verdict In?


Erratum: Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor-Naïve Myelofibrosis: Phase III SENTRY Trial

Bose P
Ali H
Al-Ali HK
Garcia-Gutierrez V
Grosicki S
Grudeva-Popova Z
Harrison C
Hong J
Hou HA
Kwiatek M
Loschi M
Passamonti F
Podoltsev N
Rampal R
Tantravahi S
Urian LG
Chai Y
Taverna P
Mark T
Sadiq A
Rangwala R
Vachhani P
Mascarenhas J
SENTRY Trial Investigators


Rethinking Regulatory Protections for Accelerated Approvals With Supplementary Indications


COMMIT: A Randomized Study of mFOLFOX6/Bevacizumab/Atezolizumab or Atezolizumab Alone as First-Line Treatment of Deficient DNA Mismatch Repair Metastatic Colorectal Cancer

Abstract: Immunotherapy for frontline mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) is effective; however, nearly half of the patients treated with single-agent PD-1 therapy will progress within 12 months. Preclinical studies in CRC and clinical data from other cancers suggest that vascular endothelial growth factor inhibition and chemotherapy can synergize with PD-L1 inhibition. The NRG-GI004/SWOG-S1610 (COMMIT) three-arm prospective phase III open-label trial randomly assigned first-line dMMR/MSI-H mCRC patients (1:1:1) to either: mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU bolus 400 mg/m², and 46-hour infusional 5-FU 2,400 mg/m²)/bevacizumab (FFX/bev), or atezolizumab (atezo) monotherapy (840 mg IV once every 2 weeks), or the combination of FFX/bev/atezo. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Because of KEYNOTE 177 results, the FFX/bev arm was closed after 20 patients were enrolled. The study continued with atezo alone versus FFX/bev/atezo, with a revised sample size of 100 patients in the two remaining arms (120 patients across all three arms). From November 2017 to March 2025, a total of 102 patients were enrolled in the three arms: FFX/bev: n = 20, atezo: n = 41, and FFX/bev/atezo: n = 41. At a median follow-up of 46 months for the two arms (median age: 63.3 years; 47.6% female; 23.2% BRAF V600E mutated), PFS of FFX/bev/atezo was superior to that of atezo (hazard ratio [HR], 0.439 [95% CI, 0.23 to 0.84]; P = .0103) and below the critical value of 0.0152. The objective response rate was 86.1% versus 46%, and the disease control rate at 12 months was 64.7% versus 32.4% in the FFX/bev/atezo arm compared with the atezo-only arm, respectively. Grade 3 or higher adverse events of any attribution occurred in 52 patients (atezo: 18; combination arm: 34). The combination of FFX/bev plus atezo led to significantly longer PFS compared with atezo monotherapy in the first-line treatment of dMMR/MSI-H mCRC.

Rocha Lima CMSP
Yothers G
George TJ
Hochster HS
Sanoff HK
Cohen DJ
Guthrie KA
Jacobs SA
Saeed A
Kopetz S
Colangelo LH
Freeman TJ
Cole SW
Khalil M
Devanna S
Zuckerman DS
Hong TS
Henry NL
Ganz PA
Blanke CD
Wolmark N
Overman MJ


Long-Term Clinical Outcomes of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory ALL

Abstract: We report the 5-year analysis of tisagenlecleucel in 79 pediatric and young adult patients with relapsed or refractory (r/r) B-cell ALL (B-ALL) from the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), with a median follow-up of 79.4 months. Tisagenlecleucel was administered as a single infusion with dosing normalized by weight in patients ≤50 kg. Key long-term end points included relapse-free survival (RFS), overall survival (OS), and safety. Censoring included loss to follow-up, withdrawal of consent, new anticancer therapy (± stem cell transplantation [SCT]), and death. The estimated 5-year RFS among responders (n = 70) with and without inclusion of SCT in censoring for new anticancer therapies was 47.3% and 51.0%, respectively. The median time to B-cell recovery was not reached with censoring for all further anticancer therapies, including SCT. The median OS was not reached. The estimated OS at 5 years was 55.0% and 62.4% with and without inclusion of SCT in censoring for new anticancer therapies, respectively. In total, 17 responders received a postinfusion SCT, 14 while still in complete remission. No new or unexpected adverse events were reported. These findings continue to support the potential of tisagenlecleucel as definitive therapy for many heavily pretreated pediatric and young adult patients with r/r B-ALL.

Grupp SA
Maude SL
Rives S
Hiramatsu H
Baruchel A
Bader P
Bittencourt H
Buechner J
Laetsch TW
De Moerloose B
Qayed M
Stefanski HE
Davis KL
Driscoll TA
Nemecek E
Peters C
Yanik G
Balduzzi A
Boissel N
Khaw SL
Krueger J
Levine JE
Myers GD
Tiwari R
O'Donovan D
Awasthi R
Ramos R
Willert J
Pulsipher MA


Dynamic Circulating Tumor DNA Methylation Monitoring Guiding Postoperative Surveillance in Nonmetastatic Colorectal Cancer: A Prospective, Randomized, Phase III FIND Trial

Abstract: We hypothesized that a dynamic surveillance strategy guided by circulating tumor DNA (ctDNA) methylation would increase the rate of curative-intent therapy for recurrence in patients with nonmetastatic colorectal cancer (CRC) after curative resection. The FIND trial (ClinicalTrials.gov identifier: NCT05904665) is a prospective, multicenter, randomized, phase III study. Patients with nonmetastatic CRC were randomly assigned to ctDNA-guided surveillance or standard computed tomography (CT)-based monitoring. In the ctDNA-guided group, a positive ctDNA result triggered immediate CT imaging; if negative, bimonthly CT continued alongside quarterly ctDNA testing. After two consecutive ctDNA-negative results, imaging reverted to standard frequency. The primary end point was the proportion of patients with recurrence receiving curative-intent metastasis-directed therapy. Among 584 eligible patients (289 ctDNA-guided, 295 control) in the modified intention-to-treat population, with a median follow-up of 23.3 months, recurrence rates were similar (18.0% v 18.6%, P = .919). The ctDNA-guided group had a significantly higher rate of curative-intent treatment (48.1% v 23.6%, relative risk 2.03, P = .008). The median time to clinical recurrence was significantly shorter in the ctDNA-guided group than in the control group (9.5 v 13.4 months; P < .001), representing a lead time of 3.9 months. Among recurrences confined to the liver and/or lungs, the ctDNA-guided group showed higher curative resection rates (42.3% v 18.2%, P = .002). These patients had more favorable hepatic metastatic features: fewer lesions (≤3: 75.0% v 28.6%, P = .005), smaller tumor size (≤3 cm: 90.0% v 57.1%, P = .033), and more unilobar disease (80.0% v 28.6%, P = .002). ctDNA methylation-guided dynamic surveillance improves the rate of curative-intent therapy for recurrence in patients with initially nonmetastatic CRC through earlier detection of resectable metastases, pending validation of long-term survival benefit in future analyses with mature data.

Mo S
Zhou C
Ma M
Luo W
Li Y
Lu P
Tang P
Li Y
Ma X
Hu X
Cheng C
Yang J
Zhuo C
Jian J
Yu C
Ding J
Xiong C
Jiang F
Mu R
Lu Z
Yu J
Jin S
Luan J
Li X
Cai S
Zou H
Li Y
Li Q
Liu F
Ding C
Peng J


He Was Always There

Abstract: Not every patient is on the chart-this essay is about learning to see the one who was always there.


Anti-TIGIT in PD-L1-High Advanced Non-Small Cell Lung Cancer: Insights From SKYSCRAPER-01 and the Path Forward


Five-Year Outcomes of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy for Locally Advanced Rectal Cancer: Updated Results of the STELLAR Trial

Abstract: This updated analysis of the STELLAR trial reports 5-year outcomes comparing short-course radiotherapy followed by chemotherapy (SCRT-based total neoadjuvant therapy [TNT]) with standard long-course chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients with distal or middle-third LARC were randomly assigned to receive either SCRT-based TNT or CRT. At a median follow-up of 68.7 months, the 5-year disease-free survival (DFS) was 62.0% in the TNT group and 58.7% in the CRT group, with a hazard ratio (HR) for DFS of 0.849 (95% CI, 0.662 to 1.089). Five-year overall survival (OS) was significantly higher with TNT (78.1% v 69.7%; HR, 0.739 [95% CI, 0.550 to 0.993]). Distant metastasis (DM) and locoregional recurrence (LRR) rates were similar between the two groups. In high-risk patients (per European Society for Medical Oncology criteria), TNT was associated with improved OS (HR, 0.663 [95% CI, 0.469 to 0.937]) and showed a nonsignificant trend toward improved DFS (HR, 0.765 [95% CI, 0.568 to 1.032]). In patients with DM or LRR, TNT was associated with both improved postrecurrence progression-free survival (HR, 0.691 [95% CI, 0.497 to 0.961]) and postrecurrence survival (HR, 0.698 [95% CI, 0.490 to 0.994]). These results suggest that SCRT-based TNT provides a durable survival advantage and is a viable alternative to CRT, especially in patients with high-risk disease.

Tang Y
Zhou HT
Xu TZ
Li N
Jiang LM
Jiang J
Lu NN
Li S
Chen SL
Ma HY
Cai Y
Li YH
Zhu Y
He MY
Wang X
Liu K
Zhang HY
Wang J
Zhao T
Li GF
Yang JL
Zhang K
Wang WL
Xiao WW
Chi Y
Yang L
Zhou AP
Zou SM
Fang H
Wang SL
Zhang HZ
Wang XS
Wei LC
Liu SX
Gao YH
Li YX
Hu C
Jin J


Erratum: High-Dose Methotrexate as CNS Prophylaxis in Ultra High-Risk Large B-Cell Lymphoma: An International Multicenter Analysis

Wilson MR
Lewis KL
Kirkwood AA
Cwynarski K
Cheah CY
El-Galaly TC
Villa D
Savage KJ
Ghione P
Bobillo S
Smedby KE
Harrysson S
Trneny M
Klanova M
Puckrin R
Fox CP
Bishton M
Thanarajasingam G
Doo NW
Hapgood G
Soussain C
Choquet S
Dickinson M
Talaulikar D
de Mel S
Preston G
Ahearne M
Hawkes EA
Schorb E
Clavert A
Ku M
Guidetti A
Narkhede M
Calimeri T
Durot E
Smith J
Renaud L
McKay P
Eyre TA


Time-Varying Effects of Copy Number Alteration Clustering: Methodologic Concerns in Survival Analysis of Relapsed/Refractory Germ Cell Tumors


Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Renal Cell Carcinoma With Bone Metastases: RADICAL (Alliance A031801)

Abstract: Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223) evaluated cabozantinib ± radium-223 in mRCC with BM. This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% (P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

McKay RR
Ballman KV
Atherton PJ
Ajmera A
Al Baghdadi T
Baumann BC
Beltran H
Berg S
Chen RC
Choudhury AD
Cole S
Jacene HA
Lang JM
Kilari D
Kwok Y
McGregor B
Morris MJ
Parikh M
Swami U
Tan A
Yang YA
Zhang T
Galsky M
Rosenberg J
George D
Choueiri TK


SKYSCRAPER-01: Tiragolumab in Combination With Atezolizumab in Previously Untreated PD-L1-High, Locally Advanced, Unresectable or Metastatic Non-Small Cell Lung Cancer

Abstract: Tiragolumab plus atezolizumab has shown encouraging survival outcomes in metastatic non-small cell lung cancer (NSCLC), primarily in patients with PD-L1-high tumors. We further evaluated the combination of tiragolumab plus atezolizumab in the phase III SKYSCRAPER-01 study. Patients with untreated, locally advanced unresectable/metastatic PD-L1-high (by central laboratory testing) NSCLC were randomly assigned 1:1 to receive either tiragolumab (600 mg) plus atezolizumab (1,200 mg) or placebo plus atezolizumab (1,200 mg) intravenously in 21-day cycles until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PD-L1-high per 22C3 assay). Five hundred twenty-one patients were randomly assigned to either the tiragolumab plus atezolizumab group (n = 262) or the placebo plus atezolizumab group (n = 259). At the primary PFS analysis (Mar 12, 2022; median follow-up 9.9 months [IQR, 6.2-13.8]), median INV-PFS was 7.0 months (95% CI, 5.6 to 9.8) with tiragolumab plus atezolizumab and 5.6 months (95% CI, 4.4 to 7.0) with placebo plus atezolizumab (hazard ratio [HR], 0.78 [95% CI, 0.63 to 0.97]; P = .02 [nonsignificant]). At the final OS analysis (Sept 24, 2024; median follow-up 17.9 months [IQR, 6.7-39.0]), median OS was 23.1 months (95% CI, 17.7 to 28.8) with tiragolumab plus atezolizumab and 16.9 months (95% CI, 14.6 to 21.3) with placebo plus atezolizumab (HR, 0.87 [95% CI, 0.7 to 1.1]; P = .22 [nonsignificant]). Overall, 41.2% (n = 110/267) and 33.8% (n = 89/263) of patients experienced grade 3-4 adverse events with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively. Four and two treatment-related deaths occurred in each group, respectively. Tiragolumab plus atezolizumab did not demonstrate a statistically significant INV-PFS or OS benefit over atezolizumab in patients with previously untreated PD-L1-high NSCLC.

Peters S
Herbst R
Horinouchi H
Paz-Ares L
Johnson M
Solomon BJ
Gumus M
Erman M
Bondarenko I
Kim DW
Felip E
Morabito A
Bryl M
Urban L
Nosaki K
Reck M
Meng R
Stroud C
Kundu P
Wen X
Patil NS
Huang M
Troutman S
Matheny C
Cho BC


Erratum: Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in AML: The PRISM Risk Model

Lachowiez CA
Zeidner JF
Othman J
Kaempf A
Yun S
Heiblig M
Heuser M
Shahswar R
Marroquin RM
Cannova JM
Žučenka A
Marvin-Peek J
Senapati J
Abaza Y
Swaroop A
Zacheo I
Monaco F
Belhabri A
Tauveron-Jalenques U
Tavernier E
Carré M
Requena GA
Cook RJ
Traer E
Saultz JN
O'Nions J
Basheer F
Laurie J
Handa S
Stein EM
Baer MR
Olin R
Blum W
Schiller G
Lin T
Curran E
Yocum A
Madarang E
Daver N
Kadia TM
Marconi G
Madanat Y
Dillon R
DiNardo CD
Swords R
Arango Ossa JE
Watts J
Loghavi S
Pollyea DA
Bernard E
PRISM-AML Investigators


Reply to: Time-Varying Effects of Copy Number Alteration Clustering: Methodologic Concerns in Survival Analysis of Relapsed/Refractory Germ Cell Tumors

Urbini M
Eleveld TF
Polano M
Scarpi E
Menna C
Gianni C
Janssen FW
Schepisi G
Gurioli G
Kucerova L
Gillis AJM
Virga A
Bleve S
Rosti G
Ulivi P
Mego M
Looijenga LHJ
De Giorgi U


Developing a Histology-Based Artificial Intelligence Biomarker to Predict Adjuvant Chemotherapy Benefit in Pancreatic Cancer

Abstract: The choice of adjuvant chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is mainly guided by patients' general condition. We hypothesized that tumor morphology may predict differential treatment benefit and tested whether deep learning applied to histology images could derive a biomarker of relative benefit from gemcitabine (GEM) versus modified FOLFIRINOX (mFOLFIRINOX) in resected PDAC. Standard whole-slide images from a retrospective multicentric series of 231 patients who underwent curative-intent pancreatectomy and received adjuvant mFOLFIRINOX (n = 54) or GEM (n = 177) were used to train regimen-specific histology models on disease-free survival (DFS), which were then combined into PANCprAId, a biomarker estimating personalized relative benefit from adjuvant GEM versus mFOLFIRINOX. External validation was performed in the randomized PRODIGE-24/CCTG PA6 trial (n = 313). In PRODIGE-24/CCTG PA6, the treatment-specific histology scores used to construct PANCprAId stratified outcomes among patients treated with GEM (hazard ratio [HR], 1.69 [95% CI, 1.04 to 2.73]; P = .03) and mFOLFIRINOX (HR, 2.02 [95% CI, 1.4 to 3.0]; P < .001). When combined into PANCprAId, the biomarker identified subgroups with differential relative benefit from adjuvant GEM versus mFOLFIRINOX, with significant treatment interactions for DFS (interaction P = .003) and cancer-specific survival (interaction P = .001). Predicted sensitivity to each regimen was associated with distinct epithelial and stromal features. Histology-based deep learning can derive a predictive biomarker of relative benefit from adjuvant GEM versus mFOLFIRINOX in resected PDAC.

Beaufils A
De Martino J
Jiang X
Blanchard T
Fraunhoffer N
Mendes D
Pignolet C
Bourega T
Meneghetti AR
Sainath S
Albuquerque M
Colnot N
Tihy M
Turpin A
Ben Abdelghani M
Wei A
Mitry E
Lecomte T
Biagi J
Artru P
Evesque L
Lambert A
Renouf DJ
Mauduit M
Dusetti NJ
Hammel P
Conroy T
Bachet JB
de Mestier L
Rebours V
Cros J
Kather JN
Nicolle R


Izalontamab Brengitecan (Iza-Bren), a First-in-Class EGFR-HER3 Bispecific Antibody-Drug Conjugate in Extensive-Stage Small Cell Lung Cancer: Results From a Phase Ib Study

Abstract: Small cell lung cancer (SCLC) remains one of the most aggressive malignancies, with limited treatment options beyond frontline chemo-immunotherapy. Izalontamab brengitecan (iza-bren, BL-B01D1) is a first-in-class bispecific antibody-drug conjugate cotargeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). We expanded the SCLC cohort to further evaluate the efficacy and safety of iza-bren in patients with extensive-stage SCLC (ES-SCLC). This open-label, multicenter, dose-expansion phase Ib study (ClinicalTrials.gov identifier: NCT05194982) enrolled patients with ES-SCLC who had progressed on prior systemic therapies. Patients received iza-bren 2.5 mg/kg once daily on days 1 and 8 of each 3-week cycle. The primary end points were objective response rate (ORR) and safety/tolerability. Secondary end points included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory end point included the assessment of potential associations between EGFR/HER3 expression and clinical outcomes. As of December 5, 2024, 52 patients were enrolled. The ORR was 48.1% (95% CI, 34.0 to 62.4), with a median PFS of 4.1 months (95% CI, 3.0 to 5.5) and a median OS of 12.2 months (95% CI, 9.1 to 13.2). In patients who received iza-bren as second-line treatment (n = 22), the ORR was 72.7% (95% CI, 49.8 to 89.3), median PFS 6.2 months (95% CI, 3.7 to 8.2), and median OS 15.0 months (95% CI, 8.7 to not reached). The most common treatment-related adverse events were hematologic toxicities (neutropenia, thrombocytopenia, anemia, and leukopenia). Exploratory biomarker analysis suggested that positive HER3 expression may be associated with better treatment response. Iza-bren showed encouraging antitumor activity in relapsed ES-SCLC, particularly in the second-line setting. A phase III randomized controlled trial of iza-bren compared with topotecan (ClinicalTrials.gov identifier: NCT06500026) is ongoing.

Zhao Y
Zhao H
Wang Q
Yang K
Li Y
Fu Z
Yang W
He Z
Wang Y
Ma Y
Yang Y
Fang W
Xiao S
Zhu H
Zhu Y
Zhang L
Huang Y


Reply to: "Is Dual-Checkpoint Blockade Beneficial Beyond Prolonging Chemoradiotherapy-to-Surgery Interval in Rectal Cancer?" and "Dual Immunotherapy in the Neoadjuvant Interval for Locally Advanced Rectal Cancer: A New Hope?"


Dual Immunotherapy in the Neoadjuvant Interval for Locally Advanced Rectal Cancer: A New Hope?


Moderate Hypofractionation for Regional Node Irradiation Is Safe and Effective


Is Dual-Checkpoint Blockade Beneficial Beyond Prolonging Chemoradiotherapy-to-Surgery Interval in Rectal Cancer?


AAML1831: A Phase III Trial Comparing Standard Induction Therapy With CPX-351 in De Novo Pediatric AML: A Report From the Children's Oncology Group

Abstract: The Children's Oncology Group phase III clinical trial AAML1831 (ClinicalTrials.gov identifier: NCT04293562) evaluated liposomal daunorubicin and cytarabine (CPX-351) versus standard daunorubicin/cytarabine (DA) induction therapy in children and young adults with newly diagnosed AML. We hypothesized that CPX-351 given during induction 1 and 2 would improve outcomes compared with DA. Patients (21 years and younger) were randomly assigned to two cycles of DA induction (arm A = DA) or CPX-351 (arm B = CPX-351). All patients also received gemtuzumab ozogamicin in induction 1. Postinduction chemotherapy was according to risk assignment made at the end of induction 1 (EOI1). Those with high-risk (HR) AML received consolidation with allogeneic hematopoietic stem-cell transplantation (HSCT), whereas low-risk (LR) patients received chemotherapy alone. Protocol-specified interim analysis monitored efficacy and futility of CPX-351 induction with respect to the primary end point, event-free survival (EFS) from study entry. Disease-free survival (DFS) was calculated to determine the impact of EOI1 risk assignment. Seven hundred twenty-one eligible patients with FLT3 wild-type AML were randomly assigned to DA (n = 358) or CPX-351 (n = 363). Interim analysis determined that the futility monitoring rule was crossed because of inferior EFS in the CPX-351 arm and the random assignment was stopped. The two-year EFS from study entry was 62.2% for DA versus 51.2% for CPX-351 (P = .011). DFS for patients with HR AML was comparable for both arms. However, DFS was significantly lower and cumulative incidence of relapse (CIR) was higher for LR patients assigned to CPX-351 versus DA (2-year DFS from EOI1: DA: 73.8% v CPX-351 57.5% [P = .001]; 2-year CIR Arm DA: 23.6% v CPX-351: 39.9% [P = .001]). CPX-351 was inferior to DA induction in the AAML1831 trial with differential EFS largely driven by events in LR patients.

Pollard JA
Alonzo TA
Gerbing RB
Kutny M
Hirsch B
Raca G
Leger K
Wilkes J
Pabari R
Wadhwa A
Graff Z
Kahwash S
Chisholm K
Chewning J
Horan J
Aplenc R
Place A
Tasian SK
Tarlock K
Menig S
Militano O
Ky B
Hudson C
Loken MR
Menssen A
Brodersen LE
Meshinchi S
Kolb EA
Cooper TM


Reply to: Post-Recurrence Therapy After Hepatectomy: Clarifying Overall Survival in JCOG0603


Hypo- Versus Standard Fractionated Locoregional Radiotherapy of Patients With High-Risk Breast Cancer in the Randomized Phase III Trial: The Danish Breast Cancer Group Skagen Trial 1

Abstract: Adjuvant radiotherapy for node-positive breast cancer (BC) using 50Gy/25fx has been Danish Breast Cancer Group (DBCG) standard. Hypofractionated radiotherapy based on 40Gy/15fx has been increasingly used; however, it is less frequently for locoregional therapy because of concern over more morbidity. DBCG Skagen trial 1 hypothesized that 40Gy/15fx did not cause more lymphedema than 50Gy/25fx 3 years after radiotherapy without compromising the pattern of failure. Skagen trial 1 is a phase III, noninferiority trial randomly assigning high-risk BC patients with an indication for locoregional radiotherapy to standard 50Gy/25fx versus experimental 40Gy/15fx. The primary end point was arm lymphedema; assuming a 3-year incidence with 50Gy/25fx of 10%, noninferiority was predefined to maximum 5% excess incidence with 40Gy/15fx. Accrual continued until 3-year estimates were reported in 1,012 patients. Between 2015 and 2021, 2,963 patients consented from 17 centers; the intention-to-treat cohort comprised 2,908 patients: 1,444 had 50Gy (50%), and 1,464 had 40Gy (50%). The median age was 57 years (range, 23-86). At a median follow-up of 4.1 years (IQR, 3.0-5.0), the 3-year rates of lymphedema were 9.4% (50Gy) versus 8.0% (40Gy), odds ratio 0.84 (95% CI, 0.62 to 1.14), and P = .27, thus within the +5-percentage-point noninferiority margin. The median follow-up for cancer outcomes was 5.25 years (IQR, 4.26 to 6.96). Within 8 years, the hazard ratio for locoregional recurrence was 0.96 (95% CI, 0.62 to 1.51), that for distant recurrence was 1.10 (95% CI, 0.89 to 1.37), that for BC mortality was 1.25 (95% CI, 0.93 to 1.66), and that for all-cause mortality was 1.08 (95% CI, 0.85 to 1.36), thus all with no differences by random assignment. 40Gy/15fx for locoregional radiotherapy of BC did not result in more lymphedema compared with 50Gy/25fx. There were no differences in locoregional or distant recurrences, breast cancer mortality, nor all-cause mortality between the random assignment arms.

Offersen BV
Alsner J
Høgsbjerg K
Nielsen HM
Maae E
Nielsen MH
Mjaaland I
Maraldo MV
Kirkove C
Lörincz T
Al-Rawi S
Blix ES
Schreiber A
Krause M
Kasti UM
Matthiessen LW
Kronborg C
Tramm T
Jensen MB
Overgaard J
DBCG RT Committee


Into the Unknown: Regulatory Perspective on Identifying Optimized Dosages of Oncology Radiopharmaceutical Therapies

Maguire WF
Plyku D
Agrawal S
Fotenos A
John CS
Saber H
Shord SS
Cheuk AV
Hofling A
Suzman DL


Post-Recurrence Therapy After Hepatectomy: Clarifying Overall Survival in JCOG0603


Total Neoadjuvant Therapy With Long-Course Radiotherapy Versus Chemoradiotherapy in High-Risk Locally Advanced Rectal Cancer (TNTCRT): A Multicenter, Randomized, Phase III Trial

Abstract: High-risk locally advanced rectal cancer (LARC) carries a substantial risk of distant recurrence, which limits disease-free survival (DFS). We compared total neoadjuvant therapy (TNT) integrating long-course radiotherapy (LCRT) with uninterrupted doublet chemotherapy (doublet-LC TNT) versus conventional neoadjuvant chemoradiotherapy (nCRT). In this multicenter, randomized, phase III trial, patients with stage II/III LARC and at least 1 high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with extramural vascular invasion) were enrolled. Patients were assigned to doublet-LC TNT (induction, concurrent, and consolidation capecitabine plus oxaliplatin with LCRT) before surgery or nCRT (capecitabine with LCRT) followed by surgery and adjuvant chemotherapy. The primary end point was DFS (ClinicalTrials.gov identifier: NCT03177382). Between June 6, 2017, and December 27, 2023, 458 patients were randomly assigned to doublet-LC TNT (n = 232) or nCRT (n = 226). At a median follow-up of 51 months, doublet-LC TNT improved 3-year DFS (74.8% v 66.0%; hazard ratio [HR], 0.674 [95% CI, 0.489 to 0.929]; P = .016). Metastasis-free survival (MFS; 77.7% v 67.6%; HR, 0.655 [95% CI, 0.469 to 0.915]) and pathologic complete response rates (pCR; 26.37% v 9.80%; P < .001) were higher with doublet-LC TNT, whereas locoregional failure remained low and comparable (6.03% v 6.19%; P = .943). Although grade ≥3 adverse events during the neoadjuvant phase were more frequent with doublet-LC TNT (27.59% v 8.56%; P < .001), severe toxicities during the entire treatment course (28.02% v 24.32%; P = .371) and major postoperative complications (3.98% v 2.94%; P = .567) were comparable. Compared with conventional nCRT, doublet-LC TNT improved DFS, MFS, and pCR rates with manageable toxicity. These findings support this intensified, doublet-based regimen as a standard option within the modern TNT paradigm. Further comparative studies are warranted to evaluate these results against other short-course radiotherapy‑based or nondoublet-concurrent TNT regimens.

Wang X
Tang Y
Lu J
Meng W
Liu P
Zhou J
Wen F
Ding P
Li J
Wang B
Guo Q
Qiu J
Sun H
Deng X
Shen Y
Zeng H
Jiang D
Wang D
Li Y
Xiao Y
Wang Z


Erratum: All-Oral Combination of Revumenib, Decitabine, and Venetoclax for Relapsed or Refractory AML (SAVE)

Issa GC
Cuglievan B
El Hajjar G
Jen WY
Bataller A
Short NJ
DiNardo CD
Alvarado Y
Loghavi S
Duose DY
Zhang B
Furudate K
Ning J
Xiao L
Mouhayar E
Pinto A
Bidikian A
Thompson E
Daver N
Garcia-Manero G
Farhat A
McCall D
Kadia TM
Abbas HA
Tan S
Bazinet A
Jabbour E
Montalban-Bravo G
Ravandi F
Takahashi K
Andreeff M
Kantarjian HM


Thrombopoietin Receptor Agonists for Chemotherapy-Induced Thrombocytopenia in GI Cancers-A Big Solution for a Small Problem or a Solution at All?


Corticosteroids in Glioblastoma Management: A Reconsideration of a 65-Year Practice


Precision in Proximity: The Radiation Oncologist's Perspective on Tailoring Total Neoadjuvant Therapy by Rectal Tumor Location


Reply to: Precision in Proximity: The Radiation Oncologist's Perspective on Tailoring Total Neoadjuvant Therapy by Rectal Tumor Location


International Myeloma Working Group Recommendations for the Diagnosis and Management of Solitary Plasmacytomas

Abstract: Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

Kastritis E
Kumar SK
Rajkumar VS
Chng WJ
Costa L
Engelhardt M
Gonsalves W
Hungria V
Hillengass J
Jevremovic D
Katodritou E
Kristinsson SY
Lonial S
Ludwig H
McCarthy P
Mai E
Manier S
Martin T
Mateos MV
Mian H
Mikhael J
Moreau P
Munshi NC
Paiva B
Pawlyn C
Rasche L
Richter J
San Miguel J
Sborov DW
Usmani SZ
Dimopoulos MA
Zamagni E


Optimizing Outcomes After Pediatric Haploidentical Donor Transplant: Role of Graft-Versus-Host Disease Prophylaxis?


Are Radiopharmaceutical Therapy Trials Designed to Undertreat?


Reply to: Optimizing Outcomes After Pediatric Haploidentical Donor Transplant: Role of Graft-Versus-Host Disease Prophylaxis?


Breast Cancer Follow-Up and Surveillance After Primary Treatment: ASCO Guideline Update

Abstract: To offer clinicians recommendations concerning breast cancer follow-up and surveillance after primary treatment. ASCO convened an Expert Panel to develop recommendations based on a systematic review and a formal consensus process. One randomized controlled trial (RCT) was identified and formed the evidentiary basis for the surveillance mammography guideline recommendation. No RCTs were identified that evaluated different follow-up approaches by risk of relapse in patients treated for early-stage breast cancer. Given the dearth of evidence identified in the systematic review of the literature, formal modified Delphi consensus-based recommendations were generated. The guideline offers recommendations on the role of a risk-based approach to the frequency and intensity of follow-up among patients with breast cancer in the adjuvant setting. Regular history, physical examination, and mammography are recommended for breast cancer follow-up. Either virtual or in-person visits can be offered. Certain patients at high risk of cancer recurrence warrant closer surveillance, such as those patients with locally advanced disease or residual disease following neoadjuvant chemotherapy. Recommendations on the use of blood-based biomarkers and supplemental imaging are provided. Guideline recommendations will be updated once additional evidence-based tools become available to better individualize surveillance.Additional information is available at www.ascopubs.org/topics/asco-guidelines/breast-cancer.

Nahleh Z
Alfano CM
Somerfield MR
Lee JM
Hieken TJ
Magnuson A
Rao RD
Chew HK
Chia SKL
Harvey BE
Landsberger E
Lim B
Mwanzi SA
Parsons HA
Patt D
Sukumar JS
Sung H
Werutsky G
Lustberg M


Durvalumab With Radiation Therapy in Patients With Inoperable Locally Advanced Non-Small Cell Lung Cancer Ineligible for Concurrent Chemoradiotherapy (DART)

Abstract: Concurrent platinum-based chemotherapy and radiation therapy (cCRT) followed by consolidative durvalumab is the standard of care (SoC) for fit patients with inoperable, locally advanced non-small cell lung cancer (LA-NSCLC). However, no SoC exists for patients who are cCRT-ineligible because of age, comorbidities, or frailty. Here, we investigated the efficacy and adverse events (AEs) of concurrent and consolidative durvalumab with definitive radiation therapy (RT) without chemotherapy. In this multicenter, single-arm, prospective phase II study, patients received conventionally fractionated RT plus concurrent and consolidative durvalumab (1,500 mg fixed dose once every 4 weeks) for up to 12 months. The primary end point was 2-year progression-free survival (PFS) of 36% compared with historical results of 20% with sequential CRT (86% power). Additional end points included overall survival (OS) and cancer-specific survival (CSS). Fifty-eight patients (median age 82 years [IQR, 76-86]; 16 [28%] PD-L1-negative; eight [14%] Eastern Cooperative Oncology Group [ECOG] score 2; 46 [79%] ECOG score 1; four [7%] ECOG score 0) were treated per protocol. The study met its primary end point with a 2-year PFS of 39% (one-sided CI, 29 to 100) and a 2-year OS of 54%. Better performance status and PD-L1 positivity were associated with improved PFS; better ECOG was associated with improved OS; PD-L1 positivity was associated with better CSS. Grade 3/4 treatment-related AEs occurred in 12 (21%) patients. Grade 5 AEs occurred in four (7%) patients (radiation pneumonitis (n = 2) and cardiac arrest (n = 2)). Durvalumab was discontinued early because of AEs in 18 (31%) patients. Thoracic RT with concurrent and consolidative durvalumab is a promising treatment option for cCRT-ineligible patients with LA-NSCLC, demonstrating better PFS with a favorable safety profile compared with historical controls.

Rimner A
Lebow ES
Fitzgerald KJ
Kratochvil L
Toumbacaris N
Gelblum DY
Kotecha R
Gomez DR
Wu AJ
Shepherd AF
Yorke ED
Eng J
Ng K
Riely GJ
Iqbal A
Rudin CM
Jones DR
Isbell JM
Rocco G
Rusch VW
Ginsberg MS
Zhang Z
Simone CB 2nd
Kris MG
Shaverdian N
Chaft JE


Adjuvant Chemotherapy ± Chemoradiotherapy for Adenocarcinoma of the Pancreatic Head: Results of the Radiotherapy Random Assignment of NRG Oncology/RTOG 0848

Abstract: To assess whether adding fluoropyrimidine sensitized radiotherapy (CXRT) to adjuvant chemotherapy improves overall survival (OS) after curative intent resection of the pancreatic head. This was a multicenter, randomized phase III, two step trial. Step 1: gemcitabine versus gemcitabine + erlotinib (previously reported). Step 2: random assignment to sixth chemotherapy cycle ± CXRT after five cycles of step 1 chemotherapy without progression. Outcomes of step 2 random assignment are reported here. Assuming 17 months median OS (chemotherapy alone), the sample size was 354 patients (hazard ratio [HR], 0.76, 80% power, one-sided α = .05, 316 OS events). OS/disease-free survival (DFS) were estimated by Kaplan-Meier and arms compared using the log-rank test. A total of 354 patients (median age 63, 55% male, 56% performance status, 1) were randomly assigned to chemotherapy (174) or chemotherapy + CXRT (180). Univariable median and 5-year OS (90% CIs) were 2.6 years (2.1-3.1) and 23.1% (17.7-28.6) for chemotherapy alone, and 2.3 years (2.0-2.6) and 27.9% (22.2-33.6) for chemotherapy + CXRT. The OS primary end point was not met (HR, 0.96 [90% CI, 0.79 to 1.18]; one-sided P = .38, two-sided P = .77). Chemotherapy + CXRT was associated with a trend for improved DFS (univariably; HR, 0.82 [95% CI, 0.65 to 1.03]; P = .089), without increase in grade 4/5 toxicities. However, grade 3 toxicity increased (38% v 19%, P < .001). Significantly, treatment by nodal status interactions showed that CXRT improved OS (P = .0063) and DFS (P = .014) in node-negative patients. Overall, the addition of adjuvant CXRT to adjuvant gemcitabine did not statistically significantly improve OS, DFS, or increase grade 4/5 toxicity. For node-negative patients, CXRT improved OS and DFS. These results, if confirmed in studies with current or future systemic therapies, would support the use of adjuvant/neoadjuvant CXRT for node-negative patients.

Abrams RA
Winter KA
Goodman KA
Regine WF
Safran HP
Guha CS
Kachnic LA
Gillin MT
Philip PA
Lowy AM
O'Reilly E
Van Laethem JL
Seaward SA
Wu AJ
Wu JJ
Aljumaily RM
DiPetrillo TA
Geva R
Anne PR
Liles DK
Ling DC
Conlin A
Moughan J
Crane CH


Smoking in Patients With Cancer: Guidance for Delivering Effective Tobacco Treatment in Cancer Care


A Shopping List

Abstract: A story of nourishment, serendipity, and the unexpected bonds that connect us with patients.


Development and External Validation of a Transcriptome-Based Multivariable Prediction Model for Treatment-Free Remission in Chronic Myeloid Leukemia

Abstract: Treatment-free remission (TFR) is a major therapeutic objective in chronic myeloid leukemia (CML). However, nearly 50% of patients relapse after tyrosine kinase inhibitor (TKI) discontinuation, and no robust predictive biomarker is currently available. We profiled peripheral blood cell transcriptomes at imatinib (IMA) discontinuation in patients from the multicenter STIM2 trial (n = 96) to develop a transcriptome-based model predicting TFR by 2 years. A DESEQ2-based machine learning approach was compared with classical machine learning algorithms. The signature was then externally validated in an independent real-world cohort of patients attempting IMA or nilotinib cessation (n = 70). The biologic processes associated with the signature were further explored. We identified a 50-gene signature discriminating patients with sustained 2-year TFR from those experiencing molecular relapse (area under the receiver operating characteristic curve [AUROC], 0.83 [95% CI, 0.73 to 0.93] and 0.75 [95% CI, 0.55 to 1.00] in the training and internal validation cohorts, respectively). The discriminative performance was confirmed in the external test cohort, both as a binary predictor of 2-year TFR (AUROC, 0.71 [95% CI, 0.58 to 0.83] overall; 0.77 [95% CI, 0.61 to 0.92] in IMA-treated patients) and as a time-to-event predictor (log-rank P = .0042). The high TFR-signature group showed a higher proportion of myeloid immune cells and natural killer T cells, with an enrichment in Hedgehog signaling, whereas the low TFR-signature group demonstrated a higher proportion of lymphoid cells with an enrichment in mTOR signaling and a trend for oxidative phosphorylation activation. T-cell receptor and immunoglobulin heavy-chain repertoire analyses showed significantly greater polyclonality in the high TFR-signature group. These findings demonstrate that transcriptomic profiling at TKI discontinuation can predict TFR outcomes in patients with CML and provide biologic insights into the mechanisms underlying sustained TFR.

Alcazer V
Dulucq S
Mosnier I
Chabane K
Bertin-Mourot P
Derruau S
Balsat M
Labussiere-Wallet H
Sujobert P
Mahon FX
Etienne G
Nicolini F
Hayette S

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Journal Article
Multicenter Study
Validation Study


Taking Responsibility

Abstract: This essay is about how caring for my complicated father with amyotrophic lateral sclerosis (ALS) unexpectedly shaped how I approached my work as a gynecologic oncologist.


Epstein: Bill Gates's foundation vows to change after failing to act on warnings


Ebola: DRC outbreak is now "fastest growing in history," as strikes hinder response


Digitisation of primary care excludes those in greatest need


Daily pill for serious heart condition approved for NHS use


Ectopic pregnancy: Rise in admissions may be linked to deprivation, study suggests


Private equity involvement in UK healthcare


Cyclosporiasis: "Explosive diarrhoea" spreads to UK in outbreak linked to Mexico


England records nearly 2900 excess deaths in recent heatwaves, as GPs are told to consider closing if indoor temperatures reach 30°C


Massive surge in doctors facing fitness-to-practise complaints, GMC data show


Emergency department: Over 80s most likely to face waits longer than 12 hours, analysis shows


Lyme disease should be notifiable


Social care reform: 23(rd) time lucky?


Fauci's Senate hearing: Why he refused to answer questions, and whether his Biden pardon could shield him from legal threats


Cryptocurrency based trading and gambling harms require a public health approach

Parsonage J
Newall P
Hickman M
Ioannidis K
Bowden-Jones H


Antihistamines for atopic dermatitis (eczema): systematic review and network meta-analysis of randomised trials

Abstract: To systematically synthesise the benefits and harms of add-on oral antihistamines for managing atopic dermatitis (eczema). Systematic review and network meta-analysis of randomised trials. Medline, Embase, CENTRAL, the United States Food and Drug Administration, and the European Medicines Agency databases from database inception to 5 May 2025. Randomised trials assessing add-on oral H1 antihistamines, H2 blockers, mast cell stabilisers (nedocromil sodium and sodium cromoglycate), or their combinations. Paired reviewers independently screened records, extracted data, and assessed risk of bias using a modified Cochrane Risk of Bias tool version 2. Random effects bayesian meta-analyses synthesised atopic dermatitis severity (oSCORAD-objective scoring atopic dermatitis, 0-83; minimal important difference 8.2; lower better), itch severity (numerical rating scale, 0-10; minimal important difference 3; lower better), sleep disturbance, atopic dermatitis related quality of life, and harms. The network meta-analysis GRADE (Grading of Recommendations Assessment, Development and Evaluation) and Core GRADE approaches informed certainty of evidence ratings. 47 trials enrolled 6230 children and adults with primarily moderate to severe atopic dermatitis. With moderate certainty, compared with placebo, adding a first generation or second generation H1 antihistamine likely resulted in a small reduction in atopic dermatitis severity (mean difference -1.87, 95% credible interval -3.47 to -0.27) and itch severity (-0.89, -1.41 to -0.37). Although statistically detectable, these effects are well below established minimal important differences (smallest change in an outcome that a patient would identify as important). With low certainty, all studied interventions may not improve sleep disturbance or reduce atopic dermatitis exacerbations. First generation agents probably increase cognitive impairment and may increase treatment discontinuation because of adverse events (risk difference 66 more per 1000, 95% credible interval 0 to 231 more; moderate certainty). Second generation agents differ in their risk of cognitive impairment (range of mean effects 0 more per 1000 for loratadine, 16 more per 1000 for levocetirizine, and 17 more per 1000 for cetirizine). Among patients with atopic dermatitis, adding H1 antihistamines probably results in a clinically unimportant reduction in atopic dermatitis severity and itch severity, and may not reduce sleep disturbance or atopic dermatitis exacerbations. First generation agents increase cognitive impairment and may increase treatment discontinuation because of adverse events. Cognitive impairment risk differs among second generation agents. These findings provide evidence against routine antihistamine use in atopic dermatitis management and will inform updated clinical guidelines. PROSPERO CRD42022345643.

Chu AWL
Wen A
Guyatt GH
Rao M
Bakaa L
Zhao IX
Roldan Y
Spergel JM
LeBovidge J
Boguniewicz M
Martin SA
Lind ML
Silverberg JI
Lio PA
Asiniwasis RN
Wang J
De Benedetto A
Greenhawt M
Wheeler KE
Ong PY
Frazier WT
Nelson H
O'Brien M
Capozza K
Begolka WS
Gardner DD
Schneider LC
Chu DK

Humans
Dermatitis, Atopic
Randomized Controlled Trials as Topic
Histamine Antagonists
Cromolyn Sodium
Severity of Illness Index
Histamine H1 Antagonists
Pruritus
Drug Therapy, Combination

Journal Article
Systematic Review
Network Meta-Analysis


Exam failure: Doctors sue royal colleges over marking mistake


Prevention of migraine with antithrombotic agents in people with patent foramen ovale


Antithrombotic treatment for migraine in patients with patent foramen ovale: multicentre, randomised, active controlled, open label trial

Abstract: To evaluate the efficacy and safety of antithrombotic treatment for migraine prevention in participants with patent foramen ovale (PFO). Investigator initiated, multicentre, prospective, randomised, active controlled, open label clinical trial with blinded outcome assessment and hierarchical hypothesis testing. Secondary and tertiary care hospitals across 39 centres in China. 1000 adults aged 18-64 years with a diagnosis of migraine for more than one year, experiencing at least four migraine days per month, and with PFO confirmed by echocardiography. All participants completed a 12 week screening period before randomisation during which eligibility was confirmed and baseline headache data were prospectively recorded. Participants with previous stroke, transient ischaemic attack, intracranial haemorrhage, non-PFO right-to-left shunt, or contraindications to study drugs were excluded. Of the randomised participants, 984 (75.1% female) were included in the full analysis set. After the screening phase, participants were randomised in a 1:1:1:1 ratio to receive aspirin (300 mg once daily), clopidogrel (75 mg once daily), rivaroxaban (20 mg once daily), or metoprolol (25 mg twice daily) for 12 weeks. No additional preventive migraine treatments were permitted during the intervention period. The primary outcome was the proportion of participants achieving a ≥50% reduction in monthly migraine days or attacks from baseline to weeks 9-12. Safety outcomes included bleeding and other adverse events. For the primary endpoint, aspirin, clopidogrel, and rivaroxaban were all non-inferior to metoprolol. Responder rates were 61.7% (148/240) with aspirin, 66.8% (157/235) with clopidogrel, 78.4% (185/236) with rivaroxaban, and 61.8% (144/233) with metoprolol. Rivaroxaban further showed a statistically higher responder rate than metoprolol, with an absolute difference of 16.2% (98.33% confidence interval 6.0 to 26.4; P<0.001). Among secondary endpoints, rivaroxaban was associated with greater reductions in migraine days and attacks, higher rates of complete migraine cessation, and greater improvements in migraine specific quality-of-life scores than metoprolol. No major bleeding events occurred. The antithrombotic agents evaluated in this trial (aspirin, clopidogrel, and rivaroxaban) were all non-inferior to metoprolol for responder rate in participants with PFO and migraine. Rivaroxaban also showed superior responder rates over metoprolol without an increase in major bleeding events. ClinicalTrials.gov NCT05546320.

Li Z
Wang C
Tang Y
Dong J
Dong J
Ouyang W
Zhang F
Pan J
Wan J
Han Y
Yang K
Liu Y
Wang Q
Li B
Tursun I
Shen Q
Li S
Lai H
Che H
Wang G
Ma Q
Hang Y
Huang K
Li Y
Wang P
Gao F
Liu W
Zhang H
Hu H
You T
Liu H
Chen L
Cheng Y
Zhang C
Wang R
Chen Z
Gong M
Fu Q
He C
Wang P
Shen C
Tan H
Zhang X
Zhang X
Zhang R
Wang Y
Pan X

Humans
Female
Adult
Migraine Disorders
Foramen Ovale, Patent
Middle Aged
Male
Clopidogrel
Fibrinolytic Agents
Aspirin
Prospective Studies
Rivaroxaban
Metoprolol
Treatment Outcome
Young Adult
Adolescent
China
Platelet Aggregation Inhibitors

Journal Article
Randomized Controlled Trial
Multicenter Study
Review


Fossil fuel industry has no place at climate COP

Dobson J
Cook S
Frumkin H
Haines A
Rao M
Abbasi K


US measles: Cases now surpass last year's total as vaccination rates decline


Social care: Burnham vows to fast track Casey review


Does Mounjaro cause hair loss?


Johnson & Johnson offers $5.5bn to settle talcum powder cancer claims


Endometriosis: biomarker testing offers hope for earlier diagnosis


Man died from sepsis after emergency department discharged him owing to overcrowding


Reforming global health architecture requires confronting its political economy

Torres Valencia OG
Rahmayanti NM
Bernal-Serrano D


Hussam Abu Safiya: The medical community cannot remain passive as a senior paediatrician is left to die in an Israeli prison

Nimerawi A
Abdel Mannan O
Zuberi SM
Wilkinson A
Maynard N


Peptides: US advisory committee recommends six for FDA "compounding list"


ADHD benefits claims rise: As Burnham mulls reforms, can the NHS and welfare system survive the strain?


UK maternity inquiries: 25 years of the same diagnosis


Medical tourism erodes Africa's health sovereignty


West Nile virus: Cases rise in parts of Europe


ADHD prescriptions rise to record levels in England


Russia's healthcare crumbles amid Putin's war with Ukraine


No-touch versus conventional vein in coronary artery bypass grafting: three year follow-up of multicentre randomised PATENCY trial


How to keep medicines safe during a heatwave


Recognising and managing polymyalgia rheumatica


Investigation and management of breakthrough ischemic stroke in anticoagulated patients with atrial fibrillation

Abstract: Ischemic stroke is a serious complication of atrial fibrillation that is associated with substantial morbidity and mortality. For patients with non-valvular atrial fibrillation, treatment with a direct oral anticoagulant (DOAC) is first line treatment for stroke prevention. Ischemic strokes can still occur, however, despite appropriate anticoagulation-an event known as a breakthrough stroke. In this review, we provide an examination of breakthrough stroke through its epidemiology, mechanisms by which breakthrough strokes happen, and a framework for classification. We then propose a systematic, stepwise algorithm to investigate breakthrough stroke, including standardized criteria to identify an ideal population for future clinical trials using the AF-BREACH criteria (Atrial Fibrillation related BReakthrough Embolic Stroke despite appropriate anticoagulation without alternative Cause identified). Lastly, we discuss the emerging evidence for pharmacological and non-pharmacological management strategies.

Lun R
Pensato U
Shaw JR
Pivato CA
Sposato LA
Field TS
Demchuk AM

Humans
Atrial Fibrillation
Anticoagulants
Ischemic Stroke
Algorithms
Stroke


Undiagnosed coeliac disease presenting with oral ulcers: a missed opportunity


How can I make time for training?


Burnham warns that NHS "will collapse" without social care reform


Social media ban: France becomes first European country to introduce restrictions for under 15s


Workplace support for women through menopause


Devolution can create new opportunities for better health


Medical students hit with punitive "unprofessional" sanctions to keep them in line, report warns


When I use a word . . . The Edinburgh Medical School 1726-2026


AI might help the NHS-but we need to build the evidence


Wildfires and health: With the US and Canada blanketed by smoke, what are the risks?


Nottingham attacks: Trust that treated killer faces manslaughter probe


China has banned an unproven Alzheimer's operation and detained its inventor, but international clinical trials of dcLVA are still going ahead-why?


Why the X chromosome is rich in L1 mobile elements

Abstract: Preferential insertion into the late-replicating inactive X explains L1 accumulation in this chromosome.

Humans
Chromosomes, Human, X
Long Interspersed Nucleotide Elements
X Chromosome Inactivation
Female


Signatures of aging and disease in a single organelle

Abstract: Changes in lysosomal metabolites are associated with both aging organs and lysosomal storage diseases.

Animals
Humans
Aging
Lysosomal Storage Diseases
Lysosomes
Mice


Erratum for the Research Article "Elastic ice microfibers"


When mammals crossed between continents

Abstract: The Great American Biotic Interchange informs the dynamics of modern species invasions.

Animals
Biota
Introduced Species
Mammals
North America
South America
Animal Migration


Witness to ocean acidification

Abstract: Calcareous marine plankton can indicate past and present ocean acidification.


An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease

Abstract: Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.

Cottle T
Joh L
Posner C
DeCosta A
Campagna DR
Fleming MD
Ducamp S
Kardon JR

Animals
Humans
5-Aminolevulinate Synthetase
Endopeptidase Clp
Erythropoiesis
Feedback, Physiological
Heme
Mitochondria
Mitochondrial Proteins
Proteolysis
Nuclear Proteins
HEK293 Cells


In Other Journals

Abstract: Editors' selections from the current scientific literature.

Szuromi P
Maroso M
Sirois C
Smith KT
McCartney M
Osório J
Nusinovich Y


Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders

Abstract: Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

Puszynska AM
Nguyen TP
Cangelosi AL
Armani A
Roberts JM
Singh KA
Cameron JC
Tseyang T
Liu GY
Lai S
Sprenger HG
Yang J
Colgan WN
Kedir JF
Kajderowicz KM
Esantsi TK
Lu YR
Waite M
Kunchok T
Lewis CA
Schulte F
Bell GW
Sabatini DM
Weissman JS

Animals
Humans
Mice
Adipose Tissue, White
Aging
Brain
Caloric Restriction
Cystine
Lysosomal Storage Diseases
Lysosomes
Metabolome
Myocardium
Atlases as Topic
Rats
Male
Female
Mice, Inbred C57BL
Rats, Inbred F344


Toward an exact quantum many-body treatment of Kondo correlation in magnetic impurities

Abstract: The Kondo effect is a prototypical quantum phenomenon arising from the interaction between localized electrons in a magnetic impurity and itinerant electrons in a metallic host. Although this phenomenon has served as the testing ground for quantum many-body methods for decades, the precise description of Kondo physics with material specificity remains challenging. Here, we present a systematic ab initio approach to converge toward an exact zero-temperature electronic treatment of Kondo correlations. Across a series of 3d transition metals, we extracted Kondo temperatures matching subtle experimental trends, with accuracy exceeding that of standard models. We further obtained microscopic insight into the origin of these trends. More broadly, we demonstrate the possibility to start from fully ab initio many-body simulations and push toward the realm of converged predictions.

Zhu T
Peng L
Zhai H
Cui ZH
Chi R
Chan GK


Catalytic Appel fluorination of alcohols with potassium fluoride

Abstract: Appel halogenation reactions are widely used to convert alcohols to alkyl halides but are not suitable to prepare alkyl fluorides because fluoride is sequestered as a difluorophosphorane. In this work, we introduce bench-stable neopentoxyphosphonium salts to solve this enduring challenge. With these reagents, various alcohols undergo fluorination with potassium fluoride under hydrogen bonding phase-transfer catalysis, a manifold offering a pathway to enantioselective fluorination of alcohols. Mechanistically, a neopentoxyfluorophosphorane is formed, which undergoes reversible exchange with the alcohol substrate in preference to difluorophosphorane formation. The catalyst assists with potassium fluoride solubilization and with phosphorus-fluorine bond dissociation, leading to the alkoxyphosphonium fluoride ion pair undergoing stereoinvertive fluorination. Turnover results from stronger binding of the catalyst to fluoride than phosphine oxide, the by-product of the reaction, which is recyclable as starting material for the synthesis of the phosphonium reagents.

Mondal A
Struijs JJC
Doyle CJN
Chen Z
Wang Z
Tangamornchaipattana W
Allais C
Richardson PF
Piper J
Paton RS
Aldridge S
Gouverneur V


Rigor is not readiness: The PERL framework for evidence-based policy

Abstract: Policy Evidence Readiness Levels help decision-makers assess evidence maturity and uncertainty.


Ancient DNA shows how smallpox got to the Americas

Abstract: " Landmark" paper finds European contact introduced the disease.

Animals
Humans
Americas
DNA, Ancient
DNA, Viral
Europe
Smallpox
Variola virus


The molecular architecture of mammalian vitreous body collagen fibrils

Abstract: Collagen, a fundamental constituent of the extracellular matrix, has long remained elusive to high-resolution structural characterization. Using a tailored system and optimized cryo-electron microscopy processing for long-period filaments, we determined the structure of native collagen fibrils from the porcine vitreous body, with local resolutions extending from 2.6 to 7 angstroms. Each 67-nanometer periodic unit contains type II, V/XI, and IX collagen triple helices together with opticin, at a stoichiometry of 8:4:4:4, which reveals their detailed higher-order molecular packing. Abundant galactose-glucose disaccharides modify hydroxylysine residues in conserved -glycine-X-hydroxylysine- motifs, mediating fibril packing and structural stability. Our structure uncovers the glycan-mediated assembly principle of collagen fibrils and clarifies the structure-function basis of collagens in the vitreous body.

Animals
Amino Acid Motifs
Cryoelectron Microscopy
Fibrillar Collagens
Hydroxylysine
Swine
Vitreous Body


AI's top startups are barely publishing their research

Abstract: More than half of AI "unicorns" have never published a paper or preprint.


n-Type polymer layers enable efficient, scalable, and thermally stable perovskite solar modules

Abstract: Fullerene-based electron transport layers (ETLs) used in inverted (p-i-n) perovskite solar cells face issues regarding cost, scalability, and instability, whereas highly stable inorganic oxides feature unfavorable energy alignment and enhance hysteresis, which reduce power conversion efficiency (PCE). We report a nonfullerene conjugated polymer, 2PB-T, that incorporates coplanar and electron-withdrawing perylene bisimide (PBI) units into its backbone. The PBI polymeric backbone and side-chain engineering address the instability of small-molecule ETLs by optimizing electron transport properties, film uniformity, and interfacial binding. Small-area devices achieved a champion PCE of 27.8%, with a certified maximum power point tracking (MPPT) efficiency of 27.3%. Perovskite modules with areas of 20.6 and 625 square centimeters reached PCEs of 24.4 and 22.5%, respectively. Small-area devices retained more than 98.6% of their initial PCE after 1752 hours of continuous MPPT at 85°C in air, and the 625-square-centimeter module maintained 96.9% of its initial PCE after 5900 hours of outdoor operation.

Gao D
Gong J
Yang L
Wang N
Chang B
Qian L
Vanin F
Zhang C
Yu Z
Li S
Gong J
Zhu Z


Golden Age report is a missed opportunity, critics say

Abstract: They worry attempt to shake up a "calcified system" could do more harm than good.


Rewiring the paralyzed body's false alarm

Abstract: Autonomic dysreflexia can be reversed using epidural electrical neuromodulation.

Humans
Epidural Space
Paralysis
Autonomic Dysreflexia
Electric Stimulation Therapy


U.S. unveils first Genesis Mission grants for AI in research

Abstract: The 278 winners now face a 9-month race to prove they deserve additional funding.


Surfacing brain stimulation

Abstract: Brain functional circuits can guide precision surface brain stimulation.

Animals
Humans
Cerebral Cortex
Deep Brain Stimulation
Nerve Net
Parkinson Disease
Precision Medicine
Functional Neuroimaging


The perils of fluency


NIH is again terminating politically sensitive grants

Abstract: With cancellation of health disparities project, agency may be testing new way to legally kill grants disliked by White House.

Humans
Financing, Government
National Institutes of Health (U.S.)
Politics
Research Support as Topic
United States
Health Inequities


The genomic identity of early smallpox in South America

Abstract: Smallpox was a major driver of population collapse in the Americas after European contact, yet the genetic identity of the causal strains remains unknown. Here, we report the first ancient smallpox genomes in the Americas, dating to approximately 1492-1631 common era (CE), recovered from two Inca-Colonial individuals in northern Chile. These genomes form a now-extinct lineage that diverged around 1296 CE, after the splitting of early medieval European strains but before the emergence of modern variola lineages, providing direct molecular evidence for smallpox introduction through European colonization. We further identify a constant tempo of gene inactivation until the late 16th century, followed by a phase of constraint and a subsequent rebound in substitution rates, linking variola virus evolution to major shifts in human demography and epidemiology.

Romero González B
Reyes-Madrid M
Arriaza B
Cassidy LM
Moraga M
la Fuente Castro C
Nakagome S

Humans
Smallpox
Genome, Viral
Variola virus
Chile
Phylogeny
Evolution, Molecular
History, Medieval
History, 16th Century
DNA, Ancient


Spatiotemporal multiomics uncover tumor ecosystem dynamics during metastatic colonization

Abstract: The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

Sun Y
Zhong Y
Liu S
Zhang Z
Wang C
Liu Y
Chen J
Guo W
Gu X
Rao K
Wang Z
Cao M
Wang Y
Huang W
Zou X
Chen X
Qiu S
Shi Y
Sun H
Huang X
Wang Y
Wang J
Wu Z
Tian R
Zhang Y
Gu J
Jiang M
Bai Y
Li G
Xie M
Xi F
Peng L
Liu S
Yang S
Zhang Y
Esteban MA
Jin X
Chen A
Wang J
Cang Y
Peng DH
Xu X
Zhou J
Wu L
Fan J

Animals
Humans
Mice
CX3C Chemokine Receptor 1
Epigenesis, Genetic
Histones
Liver Neoplasms
Lung Neoplasms
Macrophages
Multiomics
Neoplasm Micrometastasis
Single-Cell Analysis
Spatial Transcriptomics
Tumor Microenvironment
Carcinoma, Hepatocellular
Liver Neoplasms, Experimental
Male
Mice, Inbred C57BL


Editor's Note for the Report "Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance"


Plasma surface engineering for efficient and stable perovskite solar cells and modules

Abstract: The instability of perovskite solar cells (PSCs) stems largely from the formation and evolution of interfacial defects associated with the soft, multicomponent perovskite lattice. We report a scalable, plasma-based passivation strategy that forms conformal, uniform, and strong-bonded heterostructure through in situ chemical reactions on large-area perovskite films. This approach also mitigates defect accumulation within the laser-scribed interconnection regions, where localized damage often dominates module-level performance losses. We achieved a power conversion efficiency (PCE) of 27.2% in small-area devices (active area 8.313 square millimeters) and 24.0% (certified efficiency of 23.5%) in 100-square-centimeter (cm2) modules (aperture area 65.05 cm2). The small-area device retained 98.1% of its initial PCE after 2000 hours of maximum power point tracking at 85°C under 1-sun illumination, and the 100-cm2 module retained 99.3% of its initial PCE after 1600 hours at 65°C under 1-sun illumination.

Fan R
Ma Y
Xu S
Cheng L
Zhang Z
Li Y
Liu H
Bao Z
Liu G
Wu Y
Zhuang X
Li K
Chen Y
Tze Fung Ng J
Huang B
Zhou W
Zhang Y
Han Y
Yin R
Liu S
Xia T
Xiao M
Zhan X
Zhao X
Chen Q
Zhou H


Supergene control of chiral development in mirror-image flowers

Abstract: How genes determine the development of chiral structures is a fascinating question. The reciprocal placement of female and male organs on opposite sides of mirror-image flowers promotes efficient cross-pollination. Here, we identified that in butterfly lilies, female and male organs deflect by a combination of genetically controlled chirality and gravitropism, orienting left and right with respect to an external rather than internal reference axis. We found coordinated organ placement to be controlled by a hemizygous supergene containing two candidate causal loci, MIR156-R and YUCCA-R, that are responsible for opposite female and male organ orientation, respectively. The resulting differential placement of pollen carrying the two supergene alleles on pollinators' bodies leads to their transfer to the stigmas of flowers with opposite handedness and maintenance of the reproductive polymorphism.

Xue H
Saltini M
Illing N
Shepherd K
Page-Macdonald O
Marketos O
Robertson C
Shankar A
Süß S
Kappel C
Alseekh S
Deinum EE
Ingle RA
Lenhard M

Gene Expression Regulation, Developmental


X-chromosome inactivation draws L1 mutagenesis to the human X chromosome

Abstract: X-chromosome inactivation (XCI) enables gene dosage compensation in XX eutherians. Long interspersed element-1 (LINE-1 or L1) retrotransposons are unusually abundant on the human X chromosome and are hypothesized to facilitate XCI. Here, we used long-read DNA sequencing to conduct a haplotype-aware analysis of engineered L1 integration preferences in the PA-1 human embryonic carcinoma cell line. Crucially, clonal XCI in PA-1 cells enabled derivation of active (Xa) and inactive (Xi) X-chromosome haplotypes. L1 integration strongly favored the Xi and other genomic regions that undergo DNA replication late in S-phase. These results suggest that the X chromosome is L1 rich because of XCI and imply that L1 integration preference for the Xi in XX individuals could potentially double the frequency of X-linked pathogenic L1 mutations in their XY descendants.

de Los Rios Barreda J
Ferreiro ME
Jansz N
Bell CC
Botto JM
Nguyen TV
Pradhan B
Chen M
Colomer-Boronat A
Da Costa Guevara DJ
Flasch DA
Gericke S
Wilson TE
Ewing AD
Heras SR
Sanchez-Luque FJ
Lister R
Moran JV
Faulkner GJ

Humans
Cell Line, Tumor
Chromosomes, Human, X
DNA Replication
Haplotypes
Long Interspersed Nucleotide Elements
Mutagenesis
X Chromosome Inactivation
HeLa Cells


China's cordgrass removal increases erosion


Churn, not crisis, for UK science

Abstract: When Andy Burnham became the United Kingdom's prime minister last week, among his first acts was to abolish the Department for Science, Innovation and Technology (DSIT), folding it into a new superministry for Business, Innovation, Science and Trade. The science minister, Patrick Vallance, stepped down the same day. Viewed from the United States, where the federal research system is under pressure, it may be tempting to see Britain's reshuffle as kindred turmoil and proof that political instability is corroding science on both sides of the Atlantic. That reading would be wrong. Britain has rearranged the machinery of its science policy, not undermined its foundations. The change could sharpen the contribution of UK research to the economic renewal that Burnham has made his defining mission.

Journal Article
Historical Article
Editorial


How black holes get hitched

Abstract: Analyses of hundreds of collisions find black holes pair up in at least three ways.


Enabling sustainable supply of the essential cancer medicines etoposide and teniposide in yeast

Abstract: Lignans constitute a diverse family of plant metabolites with therapeutic potential. Among them, podophyllotoxin-type aryltetralin lignans serve as precursors for etoposide and teniposide. Etoposide is an essential anticancer medicine approved for first-line treatment of small cell lung cancer, whereas teniposide is used for treatment of leukemia and some brain tumors. Currently, these drugs depend on extraction of precursors from the endangered plant Sinopodophyllum hexandrum, followed by chemical transformations. By identifying key glycosyltransferases and executing more than 60 genetic edits involving 45 heterologous enzymes, the complex biosynthetic pathway of podophyllotoxin-type lignans was reconstructed in yeast. In this study, we established a chemoenzymatic route that streamlines the synthesis of etoposide and teniposide through a single chemical step from biosynthetic precursor 4'-demethyl-epipodophyllotoxin-4-O-glucoside, which enables a secure supply chain of these essential medicines.

Shen S
Hu X
Li D
Tong Y
Lv Y
Tian Z
Wang J
Tang H
Wang Y
Kang L
Nielsen J
Huang L
Hu Y

Antineoplastic Agents, Phytogenic
Biosynthetic Pathways
Etoposide
Glycosyltransferases
Podophyllotoxin
Saccharomyces cerevisiae
Teniposide
Berberidaceae
Protein Engineering
Metabolic Engineering
Genes, Plant


Privacy-preserving tools banned in census

Abstract: Critics say goal is to reduce immigration and add Republican seats in Congress.


A rocky rollout

Abstract: A powerful new prevention drug could help end the HIV epidemic-but supply is falling far short.

Humans
Anti-HIV Agents
HIV Infections
HIV-1
Acetamides
Indazoles
Pre-Exposure Prophylaxis


Making antimicrobial knowledge contagious


Crick: A Mind in Motion


When the future loses its voice


A 10-million-year biogeographic holding pen primed the Great American Biotic Interchange

Abstract: The movement of taxa between North and South America across the Panamanian land bridge, known as the Great American Biotic Interchange (GABI), established modern-day mammal assemblages in the Americas, heralding the decisive end of what has been called the "splendid isolation" of the South American fauna. Lacking substantive low-latitude records, previous work on this pattern relied on South American and temperate North American fossils to conclude that pulsed interchanges began about 2.8 million years ago (mya). Based on new low-latitude fossil data from México, we found evidence for a prolonged, triphasic interchange. Phase 1 consisted of the initial accumulation of northern higher-latitude mammals in a Mexican "holding pen" beginning 10 mya. Dispersal began in phase 2, with a strong north-south gradient and increasing biogeographic connections (7 to 3 mya). The final phase consisted of the already well-described taxonomic pulses (from ~2.8 mya).

Tseng ZJ
Kahn LX
Pacheco-Castro A
Carranza-Castañeda O
Aranda-Gomez JJ
Wang Y
Chávez-Ambriz JC
Hannold C
McDonald HG
Wang X

Animals
Animal Distribution
Fossils
Mammals
Mexico
North America
South America
Biota


Calcium isotopes link ocean acidification to Aptian-Albian foraminiferal extinctions

Abstract: The second-largest extinction event in the evolutionary history of planktic foraminifera occurred at the Aptian-Albian boundary. This extinction may reflect ocean acidification (OA) associated with Oceanic Anoxic Event 1b. As calcium isotope ratios (δ44/40Ca) can track how biocalcification rates respond to OA, we measured δ44/40Ca records for planktic and benthic foraminifera, bulk carbonates, and authigenic calcite across the Aptian-Albian boundary in the South Atlantic. Benthic and bulk δ44/40Ca data display a distinct sequence of negative and positive excursions, similar to δ44/40Ca variations across other OA events. Planktic δ44/40Ca values increase markedly, tracking a reduction in calcification rates coincident with decreases in the size, diversity, and shell thickness of planktic foraminifera. These results suggest that OA drove extinctions of planktic foraminifera at the Aptian-Albian boundary.

Chen J
Jacobson AD
Huber BT
MacLeod KG
Wan C
Waldeck AR
Balestra B
Sageman BB

Atlantic Ocean
Calcification, Physiologic
Calcium Carbonate
Calcium Isotopes
Extinction, Biological
Foraminifera
Ocean Acidification
Seawater
Zooplankton


Beyond the scales: Marine archaeogenomics for the conservation and restoration of fisheries

Abstract: Protection and restoration of marine environments are essential for food security and climate change mitigation. Yet historical and archaeological research have shown that conservation and management often rely on arbitrary ecological baselines in ecosystems already shaped by long-term human impacts. Archaeogenomics, the combination of ancient DNA (aDNA) and whole-genome sequencing, provides invaluable insights into these impacts. Recent improvements in laboratory and computational techniques enable the assessment of past fish population dynamics, migration patterns, historical trade routes, long-term anthropogenic pressures, and responses to environmental change. This Review compiles aDNA research on archaeological fish remains, emphasizing studies from 2020 to 2025 that used whole-genome analysis to investigate historical fisheries and marine ecosystem change. We highlight the growing potential of archaeogenomics to inform restoration, conservation, sustainable fisheries management, and climate adaptation strategies worldwide.

Animals
Fisheries
Conservation of Natural Resources
Fishes
DNA, Ancient
Genomics
Climate Change
Archaeology
Ecosystem
Whole Genome Sequencing
Population Dynamics


In Science Journals

Abstract: Highlights from the Science family of journals.

Sonawala U
Seale M
Szuromi P
Simonti C
Funk MA
Stajic J
Yin Y
VanHook A
Yeston JS
Vignieri S
Ray LB
Jiang D
Kelly PN
Hurtley SM
Smith J
Hallberg D
Fogg CN


Recovering signatures of archaic hominin introgression using ancestral recombination graphs

Abstract: Admixture between modern humans and extinct hominins has shaped the genomes of present-day individuals, but reconstructing this history has been constrained by the scarcity of archaic samples and unadmixed outgroup populations. We introduce TRACE, a reference- and outgroup-free approach that uses features of ancestral recombination graphs to identify archaic ancestry. Simulations show TRACE has high precision and low false discovery rates. Applied to 1000 Genomes, TRACE recovers known Neanderthal and Denisovan introgression and uncovers ghost admixture from uncharacterized hominins in both Africans and non-Africans. Ghost ancestry persists in Neanderthal and Denisovan ancestry deserts, challenging their interpretation as Homo sapiens-specific regions. In Oceanians, TRACE finds deep lineages are enriched in Denisovan compared to Neanderthal regions, supporting super-archaic introgression. TRACE enables mapping archaic introgression without archaic genomes.

Zhang Y
Biddanda A
Johnson SA
O'Dushlaine C
Moorjani P


A tiny cone of reactivity

Abstract: Colliding molecules react only when their orientations and point of impact fall within a narrow range.


Birdsong diversity across the world

Abstract: Birdsong motifs are shaped by evolutionary history, biological traits, and environmental constraints.

Animals
Biological Evolution
Songbirds
Vocalization, Animal
Phylogeny


Ballooning under water

Abstract: Insect larval buoyancy is controlled by material properties of their air sacs.


No strain, no gain

Abstract: A modular approach could expand the repertoire of spring-loaded covalent drugs.


A 3D genome atlas of human tonsil and the role of loop extrusion in B cell somatic hypermutation

Abstract: B cell maturation within the germinal center tissue microenvironment involves immunoglobulin gene diversification by somatic hypermutation (SHM). How three-dimensional (3D) genome architecture influences SHM is not fully understood. We leveraged sequencing-based and image-based 3D genomics and transcriptomics to map single-cell 3D genome organization and gene expression across cell types and states in human tonsils and in B cell lymphoma cell lines. These analyses revealed trajectories of compartment, looping, and nuclear position changes during the B cell immune response and activation of SHM. Targeted protein degradation of cohesin component RAD21 revealed its contribution to enabling SHM. Our results provide a single-cell 3D genome atlas of human tonsil cells and outline the links between the chromatin loop extrusion machinery and SHM.

Cheng Y
Wang J
Zhang Y
Yadavalli AD
Liu M
Jin S
Buddle G
Haberman A
Schatz DG
Wang S

Humans
B-Lymphocytes
Cell Cycle Proteins
Cell Line, Tumor
Chromatin
Cohesins
DNA-Binding Proteins
Genome, Human
Germinal Center
Nuclear Proteins
Palatine Tonsil
Single-Cell Gene Expression Analysis
Somatic Hypermutation, Immunoglobulin
Atlases as Topic


Crush-resistant air sacs allow insect larvae to exploit aquatic habitats at extreme depth

Abstract: The absence of aquatic insects from pelagic marine habitats has been attributed to their air-filled tracheal respiratory system, which could implode at depth while undertaking diel vertical migrations to escape predatory fish. However, we found that the aquatic larvae of the lake fly Chaoborus edulis in Lake Malawi have modified their tracheal system into reinforced buoyancy-regulating air-filled sacs, allowing them to escape predatory fish by undertaking these migrations well over 200 meters deep into the lake's anoxic hypolimnion during the day. The crush depth of their air sacs increases with each instar, with final instars resisting implosion at depths greater than half a kilometer. Contrary to expectations, these insects adapt to the extreme hydrostatic pressures of deep-water habitats, allowing them to coexist with pelagic fish.

McKenzie EKG
Ngochera MJR
Chombo J
McLennan H
Proud R
Ames T
Matthews PGD

Animals
Larva
Ecosystem
Lakes
Air Sacs
Hydrostatic Pressure
Fishes
Predatory Behavior
Animal Migration
Calliphoridae


Invasive species' environmental impacts are more severe in the Global South

Abstract: Invasive alien species (IAS) are a major threat to biodiversity, yet their impact distribution remains poorly understood. Global biodiversity assessments suggest the highest impacts in wealthy countries of the Global North, but this is only inferred from IAS numbers, reflecting research bias. Using a new global database of standardized impact measures, we calculated average impact severity per country and found that it is higher in the Global South despite more than twice as many reports in the Global North. Weak governance and limited management capacity are the main drivers of high impact severity. Emerging economies with rapid economic growth but poor governance are particularly vulnerable. Failure to recognize the Global South as facing the highest IAS impacts diverts attention away from the most threatened regions.

Animals
Biodiversity
Conservation of Natural Resources
Environment
Introduced Species
Developing Countries


The rise and fall of language diversity through the Holocene

Abstract: Characterizing the factors that have shaped linguistic diversity is fundamental for understanding human history, culture, and cognition. In this study, we combined statistical and social computational modeling, ethnographic data, and paleodemographic inference to model trajectories of global linguistic diversity. Before the onset of plant and animal domestication, the number of languages was smaller than it is today (4500 to 6000 compared with 7500). Subsequent increases in global population precipitated increased linguistic diversity. We uncovered a linguistic "golden age" with tens of thousands of languages 3000 to 1000 years ago. Great loss of linguistic diversity did not begin with recent colonial expansion but as multinational empires first spread along with their languages, pathogens, and cultures. Thus, extinction has likely played a much greater role in shaping linguistic and cultural diversity than previously thought.

Animals
Humans
Cultural Diversity
Extinction, Biological
History, Ancient
Language
Linguistics


Brazil's environmental governance at risk

Cianciaruso MV
Bini LM
Diniz-Filho JA
Loyola R


Crystal structure of a closed ternary complex of a HNA Reverse Transcriptase in complex with a HNA/DNA duplex

Abstract: 1,5-Anhydrohexitol nucleic acid (HNA) is a promising xeno nucleic acid (XNA) for applications such as aptamers and catalysts, due to its favourable physico-chemical properties. Realizing this potential requires efficient and high-fidelity polymerases capable of processing HNA. A key component are HNA reverse transcriptases that convert HNA into DNA, an essential step in standard SELEX workflows. Although HNA reverse transcriptases have been generated by directed evolution, structural insight is essential to guide further enzyme engineering. Here, we report the 2.8 Å crystal structure of the engineered HNA reverse transcriptase KOD-H4, derived from the B-family DNA polymerase of Thermococcus kodakarensis, captured in a closed ternary complex with dATP, a 3'-terminated primer and a mixed HNA/DNA template. Compared to a previously reported open ternary KOD-H4 structure, the presented structure adopts a more closed conformation with increased finger and thumb domain closure and formation of a canonical Watson-Crick-Franklin base pair at the insertion site. Direct downstream nucleotides show more distorted base pairing and one HNA residue transits from the unusual 1C4 conformation it adopted in the open complex to the 4C1 hexitol sugar conformation. These findings demonstrate that KOD-H4 can form a closed, pre-catalytic complex resembling that of the wildtype enzyme with natural substrates, and reveal state-dependent conformational flexibility of HNA. Such flexibility should be considered in the design and optimization of enzymes that process HNA.

Gutfreund C
Abramov M
Coosemans F
Holliger P
Herdewijn P
Betz K
Marx A

RNA-Directed DNA Polymerase
Crystallography, X-Ray
DNA
Models, Molecular
Thermococcus
Nucleic Acids
Sugar Alcohols


Entering the new normal - psychosocial work environment and health during the transition from full remote to a hybrid work arrangement in a higher education context

Abstract: This longitudinal study explored the perceptions of psychosocial work factors, work-related health, and job satisfaction of 745 professional service staff, working in a higher education setting in Sweden, during the transition from full remote work to a hybrid work arrangement over 12-months. The study also explored whether these perceptions differed due to gender and household composition. The questionnaire data were analyzed using linear mixed-effects models with estimated marginal means and Bonferroni-adjusted pairwise comparisons. The results showed that while overall perceptions of psychosocial work factors showed modest changes during the transition, except for social support from colleagues, which significantly increased over time. Professional service staff reported higher levels of stress and exhaustion during the transition, while job satisfaction remained unchanged. The results also highlighted significant gender differences during the transition, as women reported less favourable perceptions of psychosocial work factors and higher levels of stress, while men's perceptions remained largely stable across these outcomes. Significant overall differences in household composition were also observed, as individuals living in single-person households and in single-parent households reported less favourable perceptions of psychosocial work factors and their work-related health compared to cohabitants and cohabitants with children, though all household groups followed similar trajectories during the transition. The findings suggest that higher education institutions should implement action plans for gender equality and family-supportive practices in hybrid work arrangements to ensure that the benefits of hybrid work are accessible to all employees.

Casely-Hayford J
Tinnerholm Ljungberg H
Aboagye E
Björklund C
Kwak L
Toivanen S
Bergström G
Jensen I

Humans
Male
Female
Sweden
Job Satisfaction
Working Conditions
Workplace
Adult
Surveys and Questionnaires
Longitudinal Studies
Social Support
Stress, Psychological
Middle Aged


Testing standards for AI-based scores in automated essay scoring

Abstract: Recent developments in the field of artificial intelligence and machine learning allow the wide application of large language models for the evaluation of written text and other non-numerical data. When applied in the context of psychological and educational assessments, such models can be used for assigning scores to essays and other types of responses. In contrast to classical tests, essays do not consist of test items, which leads to specific challenges in the evaluation of testing standards for scores obtained from AI models that differ from those observed for classical ability tests and personality questionnaires. To address these challenges, we discuss the evaluation of validity, fairness, and reliability for scores obtained from models of artificial intelligence in the context of automated essay scoring. We review existing methods, propose new methods, and further illustrate the reviewed methods with an empirical example based on the Hewlett Foundation data set on automated essay scoring. By applying the proposed framework to an evaluation based on a DistilBERT model, we find the model to be robust with sufficiently high internal consistency (Spearman-Brown coefficients in the range from .77 to .92). We further found empirical evidence for the validity of the evaluation model, but also indications for violations of fairness when comparing the human and AI scores across different topics. This study provides a standardized, replicable toolkit for researchers and practitioners to evaluate the psychometric quality of AI-based assessments.

Humans
Artificial Intelligence
Reproducibility of Results
Large Language Models
Machine Learning
Educational Measurement


Promote or prevent? A regulatory focus perspective on managerial risk taking

Abstract: This study examines the heterogeneity of CEOs' risk attitudes and how fixed versus variable compensation components shape their strategic risk-taking, as part of corporate governance policy. Building on psychological Regulatory Focus Theory (RFT) and established management frameworks, we developed a conceptual model with six hypotheses. We applied a validated Polish Linguistic Inquiry and Word Count (LIWC) dictionary to measure CEOs' promotion and prevention focus through content analysis of their shareholder letters. Our dataset covers 82 companies listed on the Warsaw Stock Exchange (WSE) from 2011 to 2020, analyzed using longitudinal panel data. The results confirmed that a CEO's regulatory focus is a significant motivational factor in strategic risk-taking. Promotion-focused CEOs tend to pursue bolder, riskier decisions, increasing the firm's strategic risk, whereas prevention-focused CEOs are more cautious and inclined to mitigate risk, aligning with prior findings in the literature. Moreover, these relationships are moderated by compensation structure. Higher fixed salaries are associated with reduced strategic risk, reinforcing risk aversion, while larger annual bonuses are associated with greater risk-taking. In particular, fixed compensation strengthened the natural risk-avoidant tendencies of prevention-focused CEOs, suggesting that higher guaranteed income reinforces a cautious strategy. Unexpectedly, large annual bonuses did not temper the risk appetite of promotion-focused CEOs; instead, bonuses amplified their risk-taking, indicating that intrinsic motivation can outweigh extrinsic incentives for risk moderation. These findings underscore the need for tailoring executive compensation policies to individual CEOs' risk preferences. Fixed salaries may temper excessive risk-taking in promotion-focused CEOs, while performance-based bonuses may motivate otherwise cautious, prevention-focused CEOs to undertake strategic risks. Such insights are valuable for refining corporate governance strategies in European public firms, especially in Poland, to better align CEO behavior with shareholder interests.

Humans
Risk-Taking
Motivation
Salaries and Fringe Benefits