Second generation tyrosine kinase inhibitors (TKIs) have improved response rates in patients with chronic phase chronic myeloid leukaemia (CP-CML). Phase 2 trials demonstrated increased deep molecular response rates when combining second generation TKIs with pegylated interferon alfa (Peg-IFN). This trial aimed to evaluate the efficacy and the safety of combining nilotinib with Peg-IFN alfa-2a in patients with newly diagnosed CP-CML.

In PETALs, this open-label, randomised, multicentre phase 3 trial, we enrolled patients with newly diagnosed CP-CML from 27 French academic institutions via a centrally-generated electronic system in a 1:1 ratio to two groups: 300 mg oral nilotinib alone twice a day (the nilotinib only group) or 300 mg nilotinib twice a day combined with subcutaneous Peg-IFN (30 μg per week for the first month of treatment and 45 μg per week thereafter) for a maximum of 2 years. The randomly allocated patients were stratified by their Sokal index and European Treatment and Outcome Study long-term survival index. Eligible patients had major BCR::ABL1 transcripts, an Eastern Cooperative Oncology Group performance score of two or lower, who had never received TKIs, and were aged between 18 and 65 years. The primary endpoint was the cumulative rate of molecular response 4·5 (MR4·5; defined as BCR::ABL1 international scale [IS] of 0·0032% and lower), analysed in the intention-to-treat population (n=200). This trial is registered at ClinicalTrials.gov, NCT02201459, and is completed.

205 patients were enrolled between Aug 6, 2014, and Sept 29, 2016, after which five patients were declared ineligible and excluded, resulting in 200 patients being randomly allocated (99 to the nilotinib group and 101 to the combination group). The median age at diagnosis was 45 years (IQR 36-55); 130 patients (65%) were male and 70 (35%) were female. Median follow-up in this cohort was 67 months (IQR 32·6-70·6). The primary objective was met, with higher rates of MR4·5 in the combination group (24% [95% CI 16·0-34·1] vs 15% [8·6-24·2], p=0·048) at month 12. There were equivalent grade 3-4 haematological side effects in the both groups (14 vs 14) with a predominance for grade 3-4 thrombocytopenia without haemorrhages (six in the combination group vs five in the nilotinib group). Psychiatric grade 3-4 events occurred in six (6%) patients in the combination group (including three unsuccessful suicide attempts) compared with five (5%) in the nilotinib group (including one unsuccessful suicide attempt). Six vascular events also occurred in six patients in the combination group and seven vascular events in five patients in the nilotinib group (all grades 3-4).

In this setting, Peg-IFN combined with nilotinib induced higher initial rates of MR4·5 compared to TKI monotherapy, despite additional side effects. The onset of psychiatric events might promote immediate cease of Peg-IFN and psychiatrist advice Whether this early molecular response translates into sustained treatment-free survival should be studied in a randomised trial sufficiently powered for this outcome.

Novartis Pharma.

The treatment landscape for relapsed or refractory diffuse large B-cell lymphoma has changed profoundly with the introduction of novel drug classes, some approved solely on the basis of single-arm early-phase trials. We aimed to evaluate antitumour activity and safety outcomes across drug classes in early-phase trials in relapsed or refractory diffuse large B-cell lymphoma since 2000.

We did a systematic review and meta-analysis of phase 1-2 trials. We searched PubMed, Embase.com, Web of Science and Wiley/Cochrane Library from database inception to May 9, 2025. We included English-language studies published between Jan 1, 2000, and May 9, 2025, enrolling adults aged 18 years or older with relapsed or refractory diffuse large B-cell lymphoma treated with experimental agents alone or combined with CD20-antibodies; trials including other B-cell malignancies were eligible if diffuse large B-cell lymphoma-specific responses could be extracted. Trials restricted to highly-selected subgroups, supportive-care, administration-routes, country-specific approvals, and conference abstracts were excluded. Two investigators independently extracted summary data. The primary outcomes were objective response rate and complete response rate, and were pooled using random-effects generalised linear mixed models. Adverse events were secondary outcomes. Prespecified subgroup analyses evaluated drug class and publication period. The study was registered with PROSPERO, CRD42023394451.

We identified 2797 citations, of which 1824 unique records remained after removal of duplicates. 132 trials including 7786 patients were eligible for analysis. 3375 (43%) of 7786 patients were female and 4411 (57%) were male. Objective response rate was 30·5% (95% CI 26·0-35·5, I²=84·7%) and complete response rate 14·3% (11·5-17·7, I²=82·2%). Response rates varied across drug classes, with the highest objective response rate or complete response rate for cellular therapies (70·0%, 95% CI 61·0-77·0 and 51·0%, 95% CI 43·0-59·0), followed by bispecific antibodies (46·0%, 38·0-53·0 and 30·0%, 24·0-36·0) and antibody-drug conjugates (40·0%, 32·0-47·0 and 18·0%, 13·0-24·0). Objective response rate increased over time, from 16·6% (95% CI 9·0-29·0) in 2000-08 to 36·8% (30·0-45·0) in 2018-25. The overall rate of dose-limiting-toxicities or discontinuations was 6·0% (95% CI 4·7-7·6). The rate of grade 3-4 adverse events was 61·5% (95% CI 54·2-68·3), treatment-related-mortality was 0·6% (0·4-1·0), and non-relapse-mortality was 3·6% (2·9-4·5). Treatment-related mortality remained below 1% over time.

Since the year 2000, early-phase trials in relapsed or refractory diffuse large B-cell lymphoma have shown more than a doubling of response rates, driven primarily by cellular and bispecific antibody therapies, while maintaining low treatment-related mortality. These results provide risk-benefit trends in early-phase trials and define contemporary benchmarks for clinicians, investigators and regulators.

None.

Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial.

The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed).

BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%).

Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed.

Eli Lilly and Company.

This study aimed to identify a subset of patients with pN1 oral squamous cell carcinoma (OSCC) and no adverse pathological features who derive significant benefit from adjuvant radiotherapy (RT).

In this multicenter retrospective study, 232 eligible pN1 OSCC patients were analyzed. Patients were stratified by T-stage (T1-2 vs. T3-4) and lymph node yield (LNY; high: ≥20; low: <20). The impact of adjuvant RT on survival outcomes was evaluated.

A significant survival benefit from adjuvant RT was observed exclusively in the subgroup with advanced T-stage (T3-4) and low LNY (< 20), with improved disease-free survival (69.2% vs. 23.1%, p = 0.003), overall survival (76.9% vs. 38.5%, p = 0.012), and disease-specific survival (80.8% vs. 46.2%, p = 0.014). In contrast, no significant survival differences were found in the other T-stage/LNY subgroups. Furthermore, LNY alone did not independently predict prognosis or RT benefit in the overall cohort.

This retrospective study suggests that pN1 OSCC patients with T3-4a stage disease and a low LNY (LNY < 20, levels I-III) may represent a subgroup that derives benefit from adjuvant RT. These exploratory findings suggest a practical model that warrants prospective validation to guide personalized therapy.

This study provides clinical evidence to help refine the postoperative management of pN1 OSCC patients without high-risk features. It provides a practical stratification tool to guide personalized treatment decisions, aiming to optimize survival outcomes while reducing unnecessary radiotherapy.

This study investigates how Chinese breast cancer survivors reconstruct damaged identities and negotiate cultural norms to build resilience within a specific socio-cultural context.

Using narrative inquiry and a life-course perspective, in-depth interviews were conducted with 15 female breast cancer survivors in Beijing. The study employed thematic narrative analysis to identify cross-cutting patterns while preserving individual story integrity. Rigor was ensured through data saturation and member checking.

Resilience is manifested as a transformative narrative practice across three dimensions: (1) body narrative, survivors transition from chaos narratives to quest narratives, reclaiming identities by ascribing meaning to physical scars; (2) relational narrative, survivors negotiate the tension between Confucian gender expectations and self-care, shifting from stoic endurance to accepting vulnerability; and (3) social narrative, survivors bridge the gap between "silent island" of isolation and collective empowerment by establishing narrative communities that challenge social stigma.

These findings reveal a duality of resilience-constrained by cultural structures yet empowered with agency. This study proposes a tripartite social work interventions framework, recommending that social workers act as narrative witnesses, cultural mediators, and community architects. By integrating local cultural wisdom with narrative techniques, social workers can effectively facilitate identity reconstruction and the social integration of breast cancer survivors.

Demoralization is common among individuals with breast cancer, and both social support and resilience are recognized as protective factors. However, the way these two factors interact at the symptom level remains unclear. This study therefore sought to clarify how resilience modifies the association between social support and demoralization at both symptom and construct levels.

In this cross-sectional analysis, a total of 412 patients with breast cancer from the Be Resilient to Breast Cancer (BRBC) program completed the Perceived Social Support Scale (PSSS), the Cancer-Specific Resilience Scale (RS-SC-10), and the Demoralization Scale-II (DS-II). Moderated network analysis, Johnson-Neyman techniques, and response surface analysis were used to examine the moderating role of resilience from both symptom-level (micro) and scale-level (macro) perspectives.

The mean age of participants was 50.8 years, ranging from 28 to 85 years, and 43.2% of them were diagnosed with stage II cancer. Higher social support and resilience were each negatively associated with demoralization. Resilience significantly moderated the associations between social support and demoralization, including the edge between friends' actual assistance and feeling unsupported (β = -0.002, SE = 0.002, p = 0.024), and between others' emotional care and self-undervaluation (β = 0.013, SE = 0.004, p = 0.004). Demoralization was lowest when patients reported concurrently high social support and resilience, and remained relatively low even when patients reported low social support but high resilience (F = 29.18, P < 0.01).

Resilience appears to be associated with an enhanced protective effect of social support on demoralization and, when high, may be associated with lower demoralization even in the context of low external social support. Interventions that concurrently enhance internal resilience and external social support may be promising strategies to reduce demoralization and improve psychological well-being in patients with breast cancer.

Immune checkpoint inhibitors (ICI) have transformed the treatment of metastatic malignancies, yet only 20-40% of unselected patients benefit. Peripheral blood could offer a minimally invasive and dynamic source for predictive biomarkers of ICI therapy.This study evaluated circulating immune cell frequencies and phenotypes before and during ICI therapy to identify tumor-agnostic blood-based biomarkers. We analyzed routine blood immune cell counts in a retrospective cohort of 202 patients treated with ICIs. Next, we investigated the findings in a prospectively collected cohort of 45 patients using multiparametric flow cytometry for characterization of immune cell subsets. We considered early radiological response, progression-free survival (PFS), and overall survival (OS) as clinical outcomes.Higher pre-treatment monocyte and lower lymphocyte counts were consistently associated with inferior PFS and OS but not with early radiological response in the retrospective cohort. In the prospective cohort, detailed immunophenotyping identified elevated pre-treatment frequencies of intermediate (CD14⁺CD16⁺) monocytes as a marker of poorer PFS and OS. Within lymphocyte subsets, higher T cell frequencies were associated with better OS, and a higher pre-treatment frequency of CD226-expressing CD8⁺ memory T cells with better ICI response. ICI therapy induced increase in TIGIT⁺CD8⁺ and CD4⁺ memory T cell subsets, regardless of treatment response.In conclusion, elevated pre-treatment levels of blood monocytes, together with decreased levels lymphocytes, were associated with poor survival of ICI-treated patients. Although detailed immunophenotyping of pre-treatment blood immune cell populations showed limited predictive utility, specific subpopulations, such as intermediate monocytes and CD226⁺CD8⁺ memory T cells, may harbor potential as prognostic/predictive indicators.

Ropeginterferon alfa-2b is an interferon used in the treatment of myeloproliferative neoplasms, particularly polycythemia vera. Its efficacy in achieving hematologic and molecular responses has been demonstrated in clinical trials, but pooled data on long-term outcomes and sustained response remain limited. This systematic review and meta-analysis aimed to evaluate the hematologic and molecular response over 36 months. PubMed, Scopus, Science Direct, and Google Scholar databases were searched to identify studies reporting hematologic and molecular responses to ropeginterferon alfa-2b. Studies were included if they provided data on complete hematologic response (CHR) and JAK2V617F variant allele frequency (VAF) reduction. Pooled proportions and mean reductions were calculated using random-effects models. The pooled proportion of CHR increased progressively from 0.19 (95% CI: 0.04-0.57) at 3 months to 0.73 (95% CI: 0.17-0.97) at 36 months. Molecular response, measured by VAF reduction, deepened over time from - 7.33 (95% CI: -9.85 to -4.81) at 3 months to -54.90 (95% CI: -65.61 to -43.99) at 36 months. Subgroup analyses revealed significant variability in response rates, particularly in early follow-up periods. Ropeginterferon alfa-2b achieves significant and sustained hematologic and molecular responses over 36 months. This makes it a promising treatment for polycythemia vera. While variability in early responses needs further investigation, the sustained long-term efficacy compared to hydroxyurea supports its use in clinical practice. Future studies should focus on identifying predictors of response and optimizing treatment protocols to maximize patient outcomes.

The classification of mesenchymal neoplasms is undergoing a period of punctuated equilibrium thanks to the increasing availability and routine application of next-generation sequencing. This is especially true for the characterization of undifferentiated/ unclassified mesenchymal tumors, which have historically been grouped morphologically as spindle cell, epithelioid cell, round cell and pleomorphic neoplasms. Herein, we report four undifferentiated epithelioid mesenchymal neoplasms harboring a novel GLI2::CREBBP gene fusion. All patients were adult males who presented with a small superficial mass. Histologically, the tumors were composed of nests or sheets of bland epithelioid cells often embedded within prominent collagenous stroma. One case contained metaplastic bone, and dystrophic calcification in a region of prior ischemia. Immunohistochemistry showed variable keratin expression in three cases, but was otherwise non-contributory. Targeted next generation sequencing revealed a GLI2::CREBBP fusion in all cases. Clinically, three of the tumors followed an indolent clinical course; however, one patient ultimately died as a result of metastatic disease, suggesting GLI2::CREBBP-rearranged nested-hyalinizing epithelioid neoplasms may behave potentially aggressive. Further study is necessary to characterize the biological potential and molecular-pathologic spectrum of this potentially novel entity.

The purpose of this study was to examine whether Ki67-scores have a predictive significance for pathological complete response (pCR) and invasive disease-free survival (IDFS) in HER2-positive breast cancer.

This retrospective, bi-centric cohort study focused on HER2-positive early breast cancer patients undergoing neoadjuvant chemotherapy from 2015 to 2023. Multivariable logistic regression was used to find independent association between various clinical parameters, including Ki67, and pCR. Ki67-values were categorized into three groups (low ≤ 15%, intermediate 15-35%, high > 35%). Kaplan-Meier estimator calculated differences in IDFS.

The study included 244 patients with known Ki67-expression. 147 patients (60.3%) achieved pCR. When categorized, 18 (7.4%) were Ki67 low, 114 (46.7%) Ki67 intermediate and 112 (45.9%) Ki67 high. No correlation between Ki67-score as continuous variable and pCR was observed (p = 0.25). HER2 immunohistochemistry (IHC) score 3 + significantly increased pCR compared to IHC score 2 + (63.2% vs. 45%, p = 0.031). Hormone receptor (HR)-positive tumors had a lower pCR rate (53.1% vs. 74.4%, p = 0.001) compared to HR-negative tumors. 5-year IDFS showed no difference between low Ki67 (88.9%; 95% CI 75.5-100%), intermediate Ki67 (82.0%; 95% CI 72.6-92.7%), and high Ki67 (80.9%, 95% CI 70.1-92.3%) subgroups (p = 0.7).

In HER2-positive breast cancer, the Ki67-score showed no association with either pCR or IDFS, thereby questioning its clinical utility. Conversely the HER2 IHC-score and HR-status were predictive indicators for achieving pCR. Clinical decisions in patients with early HER2-positive breast cancer should not be influenced by Ki67-scores, especially not by using cut-offs.