Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by bilateral radial aplasia with preserved thumbs and early-onset thrombocytopenia. While hematologic and skeletal abnormalities define the condition, its association with hematologic malignancies is extremely rare, with only a few reported cases of leukemia. Juvenile myelomonocytic leukemia (JMML) is an uncommon pediatric myelodysplastic/myeloproliferative neoplasm frequently linked to RAS pathway mutations. To our knowledge, JMML has not previously been reported in association with TAR syndrome.

The Hippo/YAP signaling pathway is a key regulatory network that governs organ size, tissue homeostasis, cell proliferation, and cell polarity. Aberrant Hippo/YAP signaling contributes to the initiation and progression of multiple cancers, making this pathway an attractive therapeutic target. Although several agents targeting Hippo/YAP have shown promise in preclinical models, clinical translation has been limited. These challenges likely stem from an incomplete understanding of the upstream regulators, downstream effectors, pathway crosstalk, and context-dependent roles of Hippo/YAP across different tumor types. Continued mechanistic investigation is required to clarify these complexities and reveal new therapeutic vulnerabilities. In this review, we summarize the current knowledge of the core components of the Hippo/YAP pathway, its regulatory mechanisms and interactions with other signaling cascades, its dysregulation in cancer, the involvement of microRNAs and lncRNAs in pathway modulation, and emerging therapeutic strategies targeting Hippo/YAP.

Background: From 2019 July 15 to 2022 February 14, the REZOR study enrolled 369 treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R mutation). Patients were randomly assigned 1:1 to receive either rezivertinib (180 mg/d) plus gefitinib placebo or gefitinib (250 mg/d) plus rezivertinib placebo. Previous results demonstrated significantly improved progression-free survival (PFS) with rezivertinib versus gefitinib and a favorable safety profile. Here, we update the analyses of central nervous system (CNS) outcomes in patients with baseline CNS metastases. Methods: All patients underwent brain magnetic resonance imaging at baseline and each subsequent efficacy evaluation until radiological disease progression or any other treatment discontinuation criteria were met. EGFR mutation status was determined by testing using tissue or plasma samples during screening. Patients with stable, asymptomatic CNS metastasis were eligible for enrollment. The CNS full analysis set (cFAS) comprised patients with baseline CNS metastasis identified on magnetic resonance imaging and evaluated by blinded independent central review according to the Response Assessment in Neuro-Oncology Brain Metastases criteria. Patients with measurable CNS target lesions formed the CNS evaluable-for-response set (cEFR). Results: As of the 2023 November 30 data cutoff, 159 patients had baseline CNS metastasis in the cFAS (rezivertinib: n = 81; gefitinib: n = 78) and 25 in the cEFR (rezivertinib: n = 12; gefitinib: n = 13) per blinded independent central review. In the cFAS, 59 CNS PFS events occurred (rezivertinib: n = 30; gefitinib: n = 29). Median CNS PFS was significantly longer with rezivertinib (24.9 months; 95% confidence interval [CI], 16.5 months-not estimable [NE]) than with gefitinib (15.2 months; 95% CI, 10.5 months-NE), with a hazard ratio of 0.58 (95% CI, 0.34 to 0.99; P = 0.047). In the cEFR, the CNS objective response rate was 83.3% (95% CI, 51.6% to 97.9%) with rezivertinib and 76.9% (95% CI, 46.2% to 95.0%) with gefitinib (odds ratio = 1.50; 95% CI, 0.20 to 11.0; P = 0.690). No new safety findings were observed. Conclusions: Rezivertinib demonstrated a statistically significant superior CNS efficacy over gefitinib as first-line treatment in advanced EGFR-mutated non-small cell lung cancer patients with baseline CNS metastases. The safety profile was consistent with previous analyses. Trial registration: NCT03866499 (ClinicalTrials.gov).

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal solid malignancies, characterized by aggressive biology and a paucity of effective treatments. Activating mutations in KRAS occur in more than 90% of cases and are fundamental to tumor initiation, progression, therapeutic resistance, and immune exclusion, establishing KRAS as the dominant oncogenic driver in PDAC. Long considered undruggable, KRAS has recently become a viable therapeutic target with the development of allele-specific inhibitors as well as pan-RAS(ON) agents capable of broadly suppressing mutant RAS signaling. Preclinical models and early-phase clinical trials demonstrate meaningful antitumor activity, with emerging evidence of tumor microenvironment remodeling and delayed resistance. Combination strategies integrating KRAS-directed therapies with chemotherapy, vertical pathway inhibition, immunotherapy, and emerging approaches such as KRAS degradation and RNA-targeted approaches are being explored to improve the depth and durability of response. Together, these advances signal a paradigm shift toward molecularly guided treatment strategies in PDAC and offer a promising path forward in a disease with substantial unmet clinical need.

Natural ferritin Fn) is a cage-like protein with a central cavity, making it a promising vehicle for drug delivery. However, its non-specific accumulation in iron-metabolizing organs impairs targeting precision and therapeutic efficacy. To overcome this challenge, we aimed to develop a novel biomimetic nanoplatform based on manganese-mineralized ferritin loaded with dihydroartemisinin (DHA@MFn) for precise ovarian cancer treatment, enabling controlled drug release and amplified therapeutic effects within the tumor microenvironment.

Cantharidin (CTD) is a natural anticancer compound whose clinical application is limited by poor water solubility, low bioavailability, and significant toxicity. To develop a more effective and safer therapeutic strategy, we proposed a synergistic combination therapy by integrating CTD with staurosporine (STS), a protein kinase inhibitor that shares complementary mechanisms of action targeting the mTOR/HIF-1α/VEGF pathway. We further developed an aptamer-guided liposomal nanosystem for the co-delivery of CTD and STS (Apt/CTD-STS/NL), aiming to enhance tumor targeting, improve bioavailability, and reduce the systemic toxicity of both drugs.

Muscle-invasive bladder cancer (MIBC) is an aggressive disease that typically requires multimodal treatment. Recently, immunotherapy strategies targeting the tumor microenvironment (TME) have reshaped the therapeutic approach for MIBC. Our study explores the expression of immune checkpoint biomarkers TIGIT, LAG-3, and PD-L1 across molecular subtypes of MIBC.

'Cutaneous T-cell lymphoma (CTCL), particularly tumor stage mycosis fungoides (MF), presents significant therapeutic challenges due to limited treatment efficacy. This study addresses the unmet need for novel targeted therapies targeting the constitutively hyperactive STAT3/5 pathway.

Diffuse Midline Glioma (DMG), often formerly called Diffuse Intrinsic Pontine Glioma (DIPG) when in the brainstem, DMG/DIPG is a lethal pediatric brain tumor defined by infiltrative growth, resistance to conventional therapies, and a profound immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), including resident microglia and infiltrating monocyte-derived macrophages, are the predominant immune population in DMG/DIPG. These cells adopt an immunosuppressive, pro-tumor state, promoting immune evasion and limiting the efficacy of therapies such as chimeric antigen receptor (CAR) T cells. Reprogramming TAMs toward a pro-inflammatory, anti-tumor phenotype offers a promising strategy to remodel the DMG/DIPG microenvironment. This review is the first to provide a comprehensive, integrative perspective on TAM-directed strategies in DMG/DIPG, spanning molecular, epigenetic, and biophysical approaches. We summarize TAM-mediated tumor progression and therapy resistance, and discuss molecular reprogramming strategies, including colony-stimulating factor 1 receptor (CSF1R) inhibition, microRNA-based circuits, and epigenetic modulators such as histone deacetylase (HDAC) and bromodomain and extra-terminal domain (BET) inhibitors. Nanoparticle-mediated delivery systems allow selective TAM targeting and enhanced blood-brain barrier (BBB) penetration. Additional strategies, including oncolytic viruses and macrophage-specific checkpoint blockade (e.g., CD47/SIRPα axis inhibitors), simultaneously promote tumor clearance and immune activation. We also highlight emerging biophysical approaches to modulate TAM function in situ. Photodynamic therapy (PDT) induces immunogenic cell death and pro-inflammatory macrophage activity, while focused ultrasound (FUS) transiently disrupts the BBB to enhance drug delivery and immune infiltration. Photobiomodulation and low-level light therapy (LLLT) may influence macrophage metabolism and phenotype, though their application in DMG/DIPG remains largely unexplored. Finally, we discuss combinatorial strategies integrating TAM reprogramming with CAR T cell therapy or chemotherapy to overcome the immunologically "cold" nature of DMG/DIPG. By uniting mechanistic insights with translational opportunities, this review establishes TAM reprogramming as a critical, underexplored frontier in DMG/DIPG immunotherapy, offering the potential to render an otherwise intractable tumor immunologically targetable.

Hsa-miR-99a has been linked to the advancement of several malignancies, including colorectal cancer (CRC). This investigation seeks to elucidate its function and regulatory network in CRC.

Undifferentiated small round cell sarcoma (USRCS) are a rare, aggressive group of tumors associated with rapid progression, metastasis, and poor prognosis. Preoperative diagnosis remains elusive, particularly for extraosseous variants, and effective treatments are lacking. This case reports the use of pembrolizumab, bevacizumab, and conventional chemotherapy (gemcitabine plus paclitaxel) as a first-line treatment for a patient with primary USRCS in the gallbladder neck; the patient achieved remarkable partial remission for more than 9 months. This case represents the second documented instance of gallbladder USRCS and the first managed with this specific combination regimen. These findings suggest that integrating immunotherapy and targeted agents with conventional chemotherapy may offer a promising therapeutic strategy for USRCS.

This study aimed to evaluate the diagnostic yield and complications associated with computed tomography (CT)-guided transthoracic core-needle biopsy (CNB) of lung lesions and to identify factors influencing biopsy outcomes.

Gastric carcinoma poses a significant global health challenge, often diagnosed late due to its similarity to chronic gastric conditions. Helicobacter pylori (Hp) infection plays a crucial role in gastric carcinogenesis through inflammation and the release of virulent products.

Ovarian cancer remains the most lethal gynecologic cancer and has the worst prognosis among all female reproductive malignancies worldwide. In Ethiopia, ovarian cancer is the third most prevalent malignancy among women, following breast and cervical cancers. Despite extensive research on the topic, evidence regarding the determinants of mortality among ovarian cancer patients remains limited. Therefore, the primary aim of this study was to identify predictors of ovarian cancer mortality among patients receiving care at oncology centers in Addis Ababa, Ethiopia.

Pulmonary metastasectomy is an established part of the multimodal treatment of various malignant diseases. While the procedure typically focuses on complete removal of metastatic lesions, the role of mediastinal lymph node involvement remains unclear. We aimed to analyze the prevalence of lymph node involvement and its impact on prognosis in patients undergoing pulmonary metastasectomy.

T cell dysfunction (TCD) plays a critical role in cancer progression and significantly impacts patient outcomes. Despite its importance, the exact molecular mechanisms underlying TCD remain poorly understood. To address this, we constructed a comprehensive pan-cancer landscape of TCD, with a particular focus on identifying miRNA biomarkers that define and predict TCD severity. Our analysis revealed six key miRNAs (miR-203b, miR-214, miR-4772, miR-141, miR-200a, and miR-200b) that were closely associated with varying degrees of TCD. These prognostic miRNAs not only exhibited distinct expression patterns across four identified TCD subtypes (from low to high TCD severity) but also demonstrated strong predictive performance in classifying patients with different levels of TCD. The identified miRNA signatures serve as reliable biomarkers for stratifying patients into high-risk and low-risk groups, with higher TCD levels correlating to poorer overall survival. In addition to miRNA biomarkers, we observed that patients with severe TCD exhibited increased infiltration of immune cells and macrophages and dysregulation of DNA methylation patterns. Patients with higher degrees of TCD displayed low methylation levels, which further contributed to the progression of T cell dysfunction. In summary, our study highlights the pivotal role of miRNA biomarkers in shaping the landscape of T cell dysfunction across cancers. These miRNAs serve as both prognostic indicators and predictive tools, enabling accurate classification of TCD severity and offering new avenues for therapeutic exploration and patient stratification in cancer immunotherapy.

Breast cancer treatment depends on tumour subtypes. In particular, patients with oestrogen receptor-positive (ER+) tumours are treated with hormonal therapy. In Sweden, the recommended treatment duration is five years, with current guidelines advising an additional five years for women at high risk of disease recurrence. However, the impact of extended therapy on metastatic progression has not been thoroughly quantified at the population level. In this article, we use a modelling approach to estimate the time-varying effect of hormonal treatment on time to metastasis. The model is then used to compare 5- and 10-year treatment durations at different tumour sizes. Rather than using a common statistical modelling approach, we incorporate the effect of endocrine therapy within a biologically inspired natural history model of breast cancer to accommodate key features of the expected treatment-outcome relationship. We fitted the model using maximum likelihood and data from a cohort of 9,716 incident cases diagnosed with invasive ER+ breast cancer between 2005 and 2020. Based on our main model estimates, the 10-year metastasis-free survival would improve from 92.8% to 96.1% for a symptomatic patient with a 20 mm tumour with ten years (instead of five) of hormonal treatment. Our natural history model quantifies the impact of prolonged hormonal treatment on metastatic events in ER+ breast cancer patients, including features that are not captured by traditional statistical approaches. Results suggest a significant reduction in metastatic tumour growth rates during treatment, supporting the extension of endocrine therapy to 10 years for people with large tumours.

Although some patients with cervical cancer respond well to therapy, others show minimal response and develop recurrence after treatment. A better understanding of the molecular features that distinguish and drive the variable responses to therapy is needed to improve patient stratification and treatment. In this issue of Cancer Research, Sandoval and colleagues conduct integrated multiomic analyses of longitudinal patient cohorts to characterize the molecular and cellular reprogramming induced by chemoradiation therapy (CRT). The analyses show that treatment fundamentally reshapes the tumor microenvironment, inducing a shift from lymphoid-dominant to myeloid-dominant immune infiltration. The authors also identify the induction of MDM2-dependent DNA damage response specifically in tumor cells. Leveraging both treatment-naïve and CRT-exposed patient-derived xenografts, they demonstrate that MDM2 inhibition enhances radiation response, with the greatest efficacy in therapy-resistant tumors. These findings identify MDM2 as a rational, therapy-induced target emerging from unbiased analysis. As the field moves toward integrating targeted therapies and immunotherapy with standard chemoradiation, this study underscores the importance of understanding when, where, and in whom to intervene. See related article by Sandoval et al., p. 1639.

Serous tubal intraepithelial carcinomas (STIC) are precursors of high-grade serous carcinoma (HGSC), the deadliest subtype of ovarian carcinoma. To establish clinically actionable strategies against these lesions, a better understanding of the mutational, transcriptional, and genetic/epigenetic alterations, as well as interactions among epithelial, immune, and stromal cells, is essential. In this issue of Cancer Research, Shih and colleagues conducted the first integrated spatial multiomics analysis of ovarian precancerous lesions, revealing substantial heterogeneity within the fallopian tube epithelium that may influence cancer susceptibility. They described four molecular subclasses of STICs according to their epithelial transcriptomic profiles: proliferative, immunoreactive, mixed, and dormant (PIMD) subtypes. Molecular links of this "PIMD" STIC subclassification to tumor progression were proposed, uncovering early events in ovarian tumorigenesis and potential genetic drivers of STIC heterogeneity. Furthermore, the STIC subtypes showed distinct histologic and molecular characteristics that warrant further investigation to develop a deeper understanding of the molecular and cellular processes driving the evolution of STIC heterogeneity, which may facilitate the development of early diagnostic approaches for HGSC. Collectively, the findings that not all STICs are equal open new avenues for further clinicopathologic, translational, and basic research to improve risk classification and early intervention in HGSC. See related article by Chang et al., p. 1739.

Tensins are a family of adhesion proteins that play a role in constructing the cytoskeleton, as well as in intracellular and extracellular communication. Their expression was evaluated in 22 pancreatic cancer patients using the immunohistochemistry method. TNS1 expression occurred more frequently among patients with tumor diameter ≥ 2 cm, which may suggest an association with the development of pancreatic cancer. Intraductal TNS1 was observed less often with presence of necrosis and hemorrhages in tumor. The fact that cancer cells secrete TNS1 suggests that it could be investigated as a potential target for liquid biopsies. TNS4 expression occurred more frequently among females and was observed when necrosis in tumor was strong. TNS2 and TNS3 are not involved in the development of ductal pancreatic adenocarcinoma.