Chimeric antigen receptor (CAR) T cells represent an exciting therapeutic strategy with improved survival outcomes for patients with hematological malignancies. However, the efficacy of CAR T-cell therapy in the treatment of solid tumors remains suboptimal due to therapeutic barriers associated with the solid tumor microenvironment. We investigated whether ionizing radiation could improve vascular perfusion and CAR T-cell delivery in an EGFRvIII-expressing B16F10 melanoma model. Tumors received radiation doses of 2-12 Gy, and perfusion was evaluated at multiple time points using immunofluorescence detection of intravenously administered fluorescent dyes. We found that a single 8-Gy dose of ionizing radiation produced the most significant increase in B16F10 tumor perfusion 4 h after irradiation. Consistently, the irradiation of tumors 4 h prior to a systemic administration of EGFRvIII-targeting CAR T cells led to higher intratumoral CAR T-cell accumulation than in non-irradiated tumors. This approach also resulted in a significantly delayed tumor growth and improved survival relative to radiation or CAR T cells alone. Interestingly, the CD28ζ EGFRvIII-CAR T-cell levels substantially increased in irradiated tumors over time relative to 4-1BBζ EGFRvIII-CAR T cells and produced greater tumor growth delays and survival improvements in comparison to 4-1BBζ EGFRvIII-CAR T cells administered at a 10-fold higher concentration. Taken together, these data highlight the importance of co-stimulatory domains in CAR T-cell function in vivo and demonstrate that irradiating tumors prior to systemic CAR T-cell infusion can increase CAR T-cell infiltration and efficacy in solid tumors.
Clinical trials of adoptive cellular therapy demonstrate that a key characteristic associated with durable responses is in vivo expansion and persistence of transferred T cells. Strategies to develop a less differentiated, stem/memory population in the infusion product and peri-infusional regimens to promote the maintenance of desired T cell states following adoptive transfer would be desirable. Endogenous T cell therapy studies have routinely achieved memory T cells enriched for expression of interleukin (IL)-7 receptor; to eliminate the conventional requirement for immunosuppressive lymphodepletion and its attendant life-threatening toxicities, we performed the first-in-human use of IL-7 in combination with adoptively transferred antigen-specific memory CD8 T cells in a patient with refractory metastatic uveal melanoma. Single-cell immune repertoire profiling of serial peripheral blood sampling revealed substantial in vivo proliferation and expansion of a stem cell memory population in the endogenous T cell therapy product that achieved a >79% predominance of total circulating T cells by 3 weeks post-infusion in this non-lymphodepleted recipient. Although the patient's disease ultimately progressed, these findings demonstrate safety and proof of concept for an IL-7 treatment regimen for expansion of adoptively transferred T cells in vivo and induced memory differentiation in a heavily pretreated patient with refractory solid malignancy.
Spiral ganglion neurons (SGNs) relay auditory sensory information from the cochlea to the brain. Their loss results in permanent hearing impairment in humans due to their limited regenerative capacity. Progress in hearing restoration has been constrained by the inaccessibility of human inner ear tissue and challenges in generating functionally mature human SGN-like neurons from stem cells in vitro. To generate human SGN-like neurons from human induced pluripotent stem cells (hiPSCs), we recapitulated key signaling pathways involved in human inner ear development. On day (D) 11 of differentiation, nerve growth factor receptor-positive cells (precursors of pre-placodal ectoderm and neural crest) were isolated using magnetic sorting. From D18 to D25, cultures were treated with sonic hedgehogs to induce otic neural progenitors. Neuronal maturation was subsequently promoted by a cocktail of brain-derived neurotrophic factor, neurotrophin-3, and insulin-like growth factor-1, which supports SGN development. Cellular identity and functionality were assessed using single-cell RNA sequencing, immunocytochemistry, whole-cell patch-clamp electrophysiology, co-culture assays, and calcium ion (Ca²⁺) imaging. hiPSC-derived SGN-like neurons exhibited morphological, molecular, electrophysiological, and functional characteristics of SGNs in vivo. Neurons acquired bipolar morphology and were wrapped by glial cells. Transcriptomic analysis revealed that SGN-like neurons were distinct from other neuronal lineages and showed similarity to type I and type II SGNs based on expression of synaptic and intrinsic excitability-related genes. Electrophysiological recordings revealed progressive hyperpolarization of resting membrane potential and emergence of overshooting action potentials, consistent with neuronal maturation. In co-culture systems, human SGN-like neurons formed functional synaptic connections with mouse cochlear hair cells and cochlear nucleus neurons, evidenced by Ca2+ transients and induction of the immediate early gene c-Fos. This study reports a robust and reproducible protocol for generating human SGN-like neurons from hiPSCs, providing a versatile platform for studying human auditory development, disease modeling, drug screening, and cell-based therapies for hearing restoration.
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.
Several studies have shown functional cell behavior on cellulose-based scaffolds for tissue engineering; however, the link between the cellulose surface physicochemistry and these behaviors is not well identified, reported, or studied. This literature review compiled reports that measured cellulose-cell interaction studies and looked for the main surface properties aiming to link behavior with physicochemical properties. This search reveals key gaps, including missing baseline material characterization prior to composite generation or 3D assembly. It also shows that most studies rely on suspension and bulk analyses that fail to capture the cell-material interface. These omissions hinder mechanistic interpretation of protein adsorption, integrin engagement, and downstream signaling. Finally, we propose the use of interface sensitive techniques such as quartz microbalance and dissipation (QCM-D) and multiparametric surface plasmon resonance (MP-SPR) to establish rigorous characterization frameworks and enable the rational design of next generation cellulose biomaterials.
Can single-cell, mass spectrometry-based proteomics identify proteins associated with reduced developmental competence of Patl2-/- Metaphase II (MII) mouse oocytes and reveal therapeutic targets for Patl2-related infertility? Abnormal protein content is detected in Patl2-/- MII oocytes, which can be rescued by spindle transfer (ST). PATL2 is an RNA-binding protein that represses maternal mRNA translation during oocyte maturation. PATL2 mutations in humans often cause germinal vesicle (GV) arrest, although some affected patients produce MII oocytes with reduced fertilization and embryo developmental potential. Consequently, oocyte donation is required. The Patl2-/- knockout mouse model offers a unique opportunity to study Patl2-related infertility and evaluate potential treatments. Patl2 -/- mice (C57BL/6NTac-Patl2tm1a), with deletion of exon 7, were bred from April 2021 to October 2023, yielding 36 homozygous females from 271 pups. To investigate the role of Patl2 at the MII stage, in vivo MII oocytes from Patl2-/- and Patl2+/+ females were collected for analysis of key quality markers and single-cell proteomics. Based on these results, maternal ST was tested to rescue abnormal embryo development. At least three replicates were conducted per experiment. Four- to 12-week-old mice underwent superovulation and oocyte collection to assess in vitro and in vivo maturation. In vivo-matured MII oocytes were used to evaluate activation (AR) and blastocyst rates (BR) after PIEZO-ICSI, spindle configuration, and calcium oscillatory patterns following SrCl2 exposure. Vitrified-warmed oocytes were used for single-cell proteomics using a timsTOF ultra mass spectrometer operated in diaPASEF mode. ST involved transferring the Patl2-/- spindle to Patl2+/+ enucleated cytoplasm, followed by parthenogenetic activation (PA) via SrCl2 exposure. Patl2 -/- females exhibit lower in vivo MII rates (79.63%) than Patl2+/+ females (89.39%, P = 0.0123) but similar in vitro maturation rates (GV-MII = 48.74%) compared to Patl2+/+ females (52.85%, P = 0.5230). After PIEZO-ICSI with wild-type sperm, reduced AR (Patl2-/- = 31.71%, Patl2+/+ = 76.74%, P < 0.0001) and BR (Patl2-/- = 7.69%, Patl2+/+ = 42.42%, P = 0.0237) were observed in knockout oocytes. However, Patl2-/- oocytes exhibited normal spindle rates (78.57%) as seen in Patl2+/+ oocytes (86.00%, P = 0.3491), as well as a similar capacity to sustain long-lasting calcium oscillations (A×F = 6.15 ± 4.80) compared to Patl2+/+ oocytes (A×F = 4.59 ± 2.96, P = 0.1453). Single-cell proteomics identified 4882 proteins and confirmed the absence of Patl2 in knockout oocytes, from analyzing 25 Patl2+/+ and 27 Patl2-/- MII oocytes. After filtering, 3747 proteins were used for statistical analysis, revealing 1508 differentially expressed proteins (q-value < 0.05; 992 downregulated, 516 upregulated in Patl2-/- oocytes). The levels of multiple RNA-binding proteins, some of which are proposed Patl2 interactors (Cpeb1, Eif4e1b), were found to be significantly reduced in Patl2-/- oocytes. Additionally, the protein products of several maternal effect genes (MEGs) implicated in mRNA regulation (Zar1, Igf2bp2) and cell cycle division (Tcl1a, Cdk1, Mos) were downregulated, while MEGs participating in epigenetic modifications (Zfp57, Trim28) were upregulated in the knockout group. Consistent with these observations, ST-PA treatment significantly increased AR (100%) and BR (75%) in the Patl2-/- oocytes in comparison to PA alone (AR = 75.95%, P = 0.0078; BR = 45.00%, P = 0.0128), effectively rescuing development to wild-type levels. Lastly, ST-PA treatment did not alter embryonic development in Patl2+/+ oocytes and produced outcomes comparable to PA alone, supporting the technical safety and applicability of the technique. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE massIVE partner repository with the dataset identifier MSV000100606. Patl2 -/- mice exhibit a less severe phenotype compared to patients carrying PATL2 variants. Patl2-/- female mice display a high MII rate without significant spindle abnormalities, which contrasts with a previously published report. Additionally, ST treatment was conducted using parthenogenetically activated oocytes, rather than biparental embryos. ST represents a promising treatment for PATL2-related female infertility in patients with MII oocytes, as it appears to restore cytoplasmic defects linked to abnormal RNA-binding proteins and MEGs identified by single-cell proteomics. In contrast, other proposed treatments for poor embryo development, such as assisted oocyte activation, is unlikely to be effective since Patl2-/- oocytes show a normal calcium response. This study was supported by the Special Research Fund (BOF) (starting grant BOF.STG.2021.0042.01 awarded to B.H.) and the Research Foundation-Flanders (FWO) (fellowship 1177425 N awarded to E.A.). B.H. has been receiving unrestricted educational funding from Ferring Pharmaceuticals (Aalst, Belgium). A.C.B., E.A., A.C., M.F-I-A., J.G., A.R., M.B., A.B., C.A., K.C.P., D.S., K.G., and F.V.M. have nothing to disclose. B.H. reports being board member of the Belgian Ethical Committee on embryo research.
The TEM8 receptor (coded by ANTXR1) plays several roles in oncogenesis and novel oncolytic therapies, such as the SVV-01 virus, uniquely bind this protein in neuroendocrine tumor (NET) histologies, such as small-cell lung cancer (SCLC). Emerging pre-clinical data suggest that TEM8-targeting therapies may convert immunologically "cold" tumor microenvironments (TME) into "hot" milieu with greater responses to immune checkpoint inhibitors (ICIs). NextGen sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) was performed on SCLC (N = 1404) and other NET (N = 1668) samples submitted to Caris Life Sciences (Phoenix, AZ). Samples were stratified by ANTXR1 expression quartiles (Q1 low, Q4 high). TME cell fractions were estimated by RNA deconvolution using quanTIseq. Real-world overall survival (OS) was assessed from insurance claim data. The landscape of pathogenic gene mutations was similar among ANTXR1 Q1 vs Q4 tumors among SCLC and NET cohorts. The TME of SCLC and NET Q4 tumors comprised a greater fraction of B cells and M1/M2 macrophages and were more frequently classified as 'T cell-inflamed' based on a transcriptional signature predictive of response to ICI. However, OS from the start of ICI was similar between ANTXR1 Q1 and Q4 cohorts. Increased B cell and M1/M2 macrophage infiltrate, along with T-cell inflamed status, associated with ANTXR1 Q4 TMEs suggest these patients with SCLC and NET may respond preferentially to ICI. A Phase 1 trial incorporating SVV-01 along with ICI is underway. Prospective investigation of molecular associations and clinical outcomes related to ANTXR1 expression in SCLC is warranted.
The role of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) in endometrial cancer (EC) progression remains poorly understood, particularly its involvement in metabolic-epigenetic crosstalk via lactate-driven histone lactylation. This study aimed to investigate HPDL's mechanistic contribution to EC pathogenesis. Stable HPDL-overexpressing and knockdown EC cell lines (HEC-1-B and AN3CA) were generated using lentiviral vectors. Functional assays (proliferation, migration, invasion), subcutaneous xenograft models in BALB/c nude mice, and molecular analyses were conducted. Lactate levels, Pan-lysine lactylation (pan-kla), histone H3K18 lactylation (H3K18la), and effects of sodium oxamate (lactate modulator) were assessed. Lactate Dehydrogenase A/Lactate Dehydrogenase B (LDHA/LDHB) knockdown, promoter activity assays, and chromatin immunoprecipitation (ChIP) were performed to evaluate H3K18la occupancy at LDHA/LDHB promoters. HPDL knockdown reduced intracellular lactate, Pan-Kla, and H3K18la levels, while overexpression elevated these markers. Sodium oxamate amplified lactate and lactylation in HPDL-overexpressing cells but suppressed histone lactylation independently of HPDL. LDHA/LDHB knockdown diminished lactylation, repressed HPDL expression, and inhibited promoter activity. ChIP revealed H3K18la enrichment at LDHA/LDHB promoters in HPDL-overexpressing cells and reduced occupancy in knockdown models. HPDL enhanced EC cell proliferation, migration, and invasion in vitro. In vivo, HPDL-overexpressing xenografts exhibited accelerated tumor growth and larger volumes compared to controls. HPDL regulates histone lactylation via LDHA/LDHB and promotes the proliferation of EC cells.
Endothelial-to-mesenchymal transition (EndMT) is a phenotypic switch in which endothelial cells acquire mesenchymal characteristics, involving both functional and morphological changes. While EndMT is essential for cardiac development, its aberrant activation contributes to adult cardiovascular pathologies, including calcific aortic valve disease (CAVD). Dysregulation of ectonucleotidases-membrane-bound enzymes that regulate extracellular ATP and adenosine metabolism-has been implicated in such diseases. Altered extracellular nucleotide signaling influences valvular interstitial cell (VIC) degeneration and may interact with valvular endothelial cells (VECs) undergoing EndMT. The objective of this study was to investigate the role of the purinergic signaling system in regulating EndMT in human aortic VECs. Primary human VECs were cultured in vitro and treated with inhibitors of ectonucleoside triphosphate diphosphohydrolase 1 (CD39), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and 5'-nucleotidase (CD73), alongside adenosine and P2 purinergic receptor agonists. EndMT markers and signaling pathways were assessed via phosphorylation assays and mRNA expression analysis of key transcription factors, including SLUG, SNAIL, ZEB1, and ZEB2. Inhibition of ATP- and AMP-hydrolyzing enzymes (CD39, ENPP1, CD73) enhanced p38 phosphorylation and modulated SLUG expression. Activation of P2 and adenosine A2B receptors altered SNAIL levels, while A2A receptor signaling influenced ZEB1 and ZEB2 expression. These perturbations resulted in pronounced morphological changes consistent with EndMT. In conclusion, dysregulation of the purinergic signaling system induces EndMT in human aortic VECs, highlighting a potential mechanistic link between extracellular nucleotide metabolism and valvular pathology. Targeting purinergic pathways may represent a therapeutic avenue for CAVD and related vascular disorders.
Hepatosplenic T-cell lymphoma (HSTL) is a highly aggressive form of mature T-cell lymphoma, characterised by abnormal proliferation of cytotoxic T cells in the spleen, liver, and bone marrow. It accounts for <1.0% of all non-Hodgkin lymphomas. We present a case of HSTL in a 32-year-old male who came with pancytopenia, abdominal distension, constitutional symptoms, and splenomegaly. Initial bone marrow examination was misdiagnosed as Myelodysplastic Syndrome (MDS) or Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN). A repeated bone marrow examination showed CD3-positive neoplastic lymphoid cells in the bone marrow intrasinusoidally and immunophenotyping revealed predominance of gamma-delta (γδ) T-cells. This case highlights the importance of including HSTL in the differential diagnosis when a patient exhibits splenomegaly and pancytopenia even though background dyspoiesis is prominent. This will enable an early diagnosis of this aggressive cancer.
Extranodal marginal zone lymphoma (EMZL) is a type of low-grade B-cell lymphoma that most commonly occurs in gastric tissue. To our knowledge, only five cases have been documented noting primary EMZL of the fallopian tube and only one case involving the ovary. We describe a rare case of extranodal marginal zone B-cell lymphoma, involving the left fallopian tube, left ovary, uterus, and left pelvic sentinel lymph node. A 78-year-old female presented to her gynecologist due to worsening of vulvar pain. A transvaginal ultrasound revealed a left adnexal tubular mass. The patient had a total robotic hysterectomy and bilateral salpingo-oophorectomy. Intraoperative frozen section of the left fallopian tube mass showed a small blue cell tumor, favoring lymphoma. Histologic sections of the ovary revealed effacement of the architecture by a diffuse atypical lymphoid infiltrate composed predominately of small CD20(+) B-lymphocytes, including few with pale cytoplasm. Similar findings were noted in the endometrium, myometrium, serosa, left fallopian tube and ovary, and left pelvic sentinel lymph node. Molecular testing was positive for MYD88 mutation but negative for CXCR4 mutation. Differential diagnosis included EMZL and lymphoplasmacytic lymphoma; however, given the absence of IgM paraprotein/monoclonal protein, a diagnosis of EMZL was favored. The patient was managed with surveillance; positron emission tomography scan was negative for recurrence at one year. Although EMZL of the ovary and fallopian tube is rare, it should be maintained on the differential diagnosis if atypical lymphoid cells or dense lymphoid aggregates are observed in the surgical specimen.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, highly aggressive hematologic malignancy characterized by frequent involvement of the skin and bone marrow. Central nervous system (CNS) infiltration is uncommon and may be clinically occult, thereby posing diagnostic challenges. We report the case of a 74 year-old man who initially presented with progressively enlarging cutaneous masses on the trunk. Histopathological examination of skin biopsy demonstrated BPDCN with a characteristic immunophenotype, and subsequent bone marrow studies confirmed extensive marrow involvement. The patient was treated with a combination of azacitidine and low-dose cytarabine to achieve sustained hematologic remission with marked regression of skin lesions and splenomegaly, despite intermittent treatment-related myelosuppression. After several months of stable disease, he was readmitted with new-onset paroxysmal occipital headache and blurred vision. Peripheral blood counts, bone marrow evaluation, and systemic imaging were unremarkable, and brain and orbital magnetic resonance imaging showed no abnormalities. Cerebrospinal fluid (CSF) analysis revealed marked pleocytosis with abundant atypical cells. Flow cytometry identified BPDCN cells accounting for 97.6% of nucleated cells, establishing the diagnosis of CNS involvement. Intrathecal methotrexate combined with cytarabine led to the rapid resolution of neurologic and visual symptoms. This case study demonstrates that BPDCN may lead to isolated CNS involvement despite ongoing systemic remission, highlighting the importance of cerebrospinal fluid evaluation in patients with unexplained neurologic manifestations.
B7-H3 is a cell surface protein overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR) T cell therapy. The most clinically advanced B7-H3 CARs derive from murine monoclonal antibodies (mAbs) 376.96 and MGA271 and are now in phase 1/2 trials. However, non-human mAb sequences can provoke immune responses, leading to CAR T cell rejection and therapeutic failure. Although single-chain variable fragment (scFv) humanization reduces this risk, residual foreign residues within variable domains remain. To overcome this limitation, here we use in vitro phage display to generate fully human B7-H3-specific scFvs for CAR design. In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 are well tolerated and demonstrate superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induces complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors.
Prenylated hydroxychalcones (xanthohumols) are hop-derived flavonoids with promising anticancer activity; however, their membrane interactions and structure-activity relationships remain incompletely understood. Here, xanthohumol C (XHC) and its semi-synthetic derivatives, 1″,2″-dihydroxanthohumol C (DHXHC) and 1″,2″-dihydroxanthohumol K (DHXHK), were evaluated for cytotoxic, pro-apoptotic, and membrane-modulating effects in comparison with xanthohumol (XH). In vitro antiproliferative activity against eleven human and one murine cancer cell lines yielded IC50 values in the micromolar range, with XHC showing the highest activity toward epidermoid carcinoma, urinary bladder carcinoma, and glioblastoma cells. Apoptosis induction was confirmed in MCC-13 Merkel carcinoma cells. Hemolytic activity toward human erythrocytes was concentration-dependent in the range of 10-100 μM, with XHC classified as toxic at 100 μM, while DHXHC and DHXHK were only slightly toxic. Membrane interactions were studied using fluorescence spectroscopy in cancer cell-mimicking lipid membranes. At low micromolar concentrations (0.5-5 μM), XHC and DHXHC increased DPH anisotropy, indicating membrane stiffening, while Laurdan generalized polarization decreased, consistent with enhanced interfacial hydration. In contrast, DHXHK showed negligible membrane effects. These results suggest that differences in molecular structure, including planarity, may contribute to the observed variation in membrane interactions and cytotoxic effects among xanthohumol derivatives.
BACKGROUND Crossed fused renal ectopia (CFRE) is an uncommon congenital renal anomaly in which 1 kidney crosses the midline and fuses with the contralateral kidney. Although CFRE is often asymptomatic, its rare association with renal malignancy poses substantial diagnostic and surgical challenges due to abnormal anatomy and vascular supply. This report describes clear cell renal cell carcinoma (RCC) arising in CFRE with direct invasion into the contralateral, normally positioned kidney. CASE REPORT A 60-year-old man presented with a 2-month history of mild left loin pain without urinary or systemic symptoms. Initial laboratory findings were unremarkable. Imaging studies, including contrast-enhanced computed tomography, demonstrated a congenitally ectopic right kidney fused to the left kidney, consistent with CFRE, and a large heterogeneously enhancing mass replacing most of the ectopic kidney and extending into the lower pole of the normally located left kidney. Positron emission tomography showed no evidence of distant metastasis. The patient underwent radical nephrectomy of the ectopic right kidney combined with partial nephrectomy of the invaded segment of the left kidney, with preservation of renal perfusion. Histopathologic examination confirmed clear cell RCC, World Health Organization/International Society of Urological Pathology grade 3, staged as pT3a, with negative surgical margins. The postoperative course was uneventful, and renal function was preserved. CONCLUSIONS This is the first documented report of RCC arising in CFRE with invasion into the contralateral normal kidney. It emphasizes the importance of detailed preoperative imaging, individualized surgical planning, and nephron-sparing strategies in the management of complex renal anomalies with malignancy.
Primary cutaneous T-cell lymphoma (CTCL) comprises a group of rare, aggressive non-Hodgkin lymphomas, of which mycosis fungoides (MF) and Sézary syndrome are the most common subtypes. In the absence of a universally accepted standard of care for advanced stages, allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers curative potential; however, post-transplant relapses remains the principle cause of treatment failure, making effective maintenance strategies crucial. This report describes the case of a young woman with stage IVA MF who, following failure of multiple conventional therapies, underwent haploidentical allo-HSCT and initiated chidamide maintenance upon achieving complete remission. This approach successfully consolidated remission for 10 months; however, the patient relapsed at 11 months post-transplant and ultimately died of neutropenic septic shock. This case suggests that post-transplant chidamide maintenance may have value in delaying disease progression in advanced MF; however, treatment-related toxicities and the risk of relapse remain significant clinical challenges requiring further investigation.
Although evidence links ferroptosis to tumor immunity, the rationale and translational potential of ferroptosis-based therapy remain unresolved. Here, we show that inducing tumor-cell ferroptosis enhances anti-tumor immunity by potentiating major histocompatibility complex II (MHC-II)-dependent antigen presentation in tumor-infiltrating macrophages. Multi-omics analyses reveal that all-trans retinoic acid (ATRA) released from ferroptotic tumor cells directly targets CD38 through the transcriptional factor retinoic acid receptor alpha (RARα) and activates transcription factor EB (TFEB) to control MHC-II expression in macrophage by inducing autophagy. Clinically, a ferroptosis signature correlates with improved immunotherapy response. We also developed a drug-free nano-redox lever that selectively targets and disrupts glutathione metabolism in hypoxic tumor regions by accepting electrons, thereby potentiating ferroptosis-mediated immune stimulation. This creates a positive feedback loop wherein activated macrophages further promote immune-driven tumor ferroptosis, synergizing with anti-PD-1 (programmed cell death protein 1) therapy across preclinical models. Together, our study identifies an uncovered role for ferroptosis in tumor immunity and provides a clinically translatable approach to enhance immunotherapy efficacy.
Hypoxia is a common characteristic of solid tumors, especially in hepatocellular carcinoma (HCC). Hypoxia-inducible factors (HIFs), particularly HIF-1α, mediate metabolic adaptation, which is crucial for survival of hypoxic cells. Branched-chain amino transferase 1 (BCAT1) catalyzes the reversible transamination reaction between branched-chain amino acids (BCAAs) and branched-chain keto acids (BCKAs), involving the inter-conversion of α-ketoglutarate (α-KG) and glutamate. We investigate and delineate the mechanisms by which BCAT1 consumes α-KG and stabilizes HIF-1α, suppressing α-KG-dependent oxygen dehydrogenase, prolyl hydroxylase-domain protein (PHD), inducing HIF-1α-mediated metabolic reprogramming and promoting hypoxic survival of HCC. We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo. We further validate the over-expression and correlation of BCAT1 and HIF-1α downstream metabolic genes in HCC clinical samples. Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients.
Lung cancer resection is curative but associated with postoperative morbidity and mortality. This study evaluated whether elevated blood eosinophil count (BEC) was associated with postoperative outcomes in early-stage lung cancer. This was a retrospective cohort study of consecutive adult patients undergoing lung resection for stage I and II non-small cell lung cancer in a large tertiary referral center from September 2017 to June 2021. Data were drawn from the institution's Data Warehouse. The primary outcome was 90-day healthcare utilization defined as emergency department visit or hospital readmission. Secondary outcomes were postoperative complications, index hospitalization length of stay, and 1-year survival. Preoperative 90-day BEC was categorized by a threshold of 200 cells/µL. Covariates were age, sex, smoking status, Charlson Comorbidity Index, chronic obstructive pulmonary disease (COPD), asthma, tumor size, nodal status, surgical approach, and blood results (white blood cells, hemoglobin, and creatinine). The main analyses were validated by a second international cohort. Log-Poisson with robust variance estimation and Cox proportional hazards regression models were fit for primary and secondary outcomes. Analyses were replicated for BEC thresholds of 150 and 300 cells/µL. Among 715 patients undergoing lung resection (median age = 69 years, 42% male, 29% with COPD), 146 patients (20%) had high preoperative BEC ≥ 200 cells/µL. BEC ≥ 200 cells/µL was associated with a higher rate of 90-day healthcare utilization:19% vs. 14% for BEC < 200 cells/µL. This association remained after adjustment (Risk Ratio [RR], 1.52; 95% Confidence Interval [CI], 1.02-2.25) and the validation cohort (RR, 2.23; 95% CI, 1.06-4.69). BEC as a continuous measure was also associated with the primary outcome in both cohorts: RR, 2.15 (95% CI, 1.49-3.12) and RR, 1.42 (95% CI, 1.10-1.94), respectively. BEC ≥ 200 cells/µL was associated with higher probability of death 1 year post-surgery (adjusted Hazard Ratio, 2.41; 95% CI, 1.08-5.35). There was no difference in the risk of postoperative pulmonary complications between high and low BEC (RR, 0.86; 95% CI, 0.58-1.27). Elevated preoperative BEC was associated with higher risk of postoperative healthcare utilization and lower 1-year survival after lung cancer resection among patients with or without respiratory disease.
Despite efforts over the last decade by clinical investigators and organizations to enhance diversity in clinical trials, significant underrepresentation of Asian, Asian Pacific Islander, and Hispanic patients remains an issue. Our editorial highlights key barriers to achieving equity in clinical trial enrollment among patients with non-small cell lung cancer (NSCLC) along with strategies to improve diversity to ensure more generalized clinical outcomes. Adult Asian, Asian Pacific Islander, and Hispanic patients with non-small cell lung cancer (NSCLC) are enrolled at much lower rates compared with their white counterparts. Given the high mortality of NSCLC and mutations that drive cancer growth that are different among ethnic/racial groups, it is crucial to improve equity in clinical trial enrollment.