Suppression of Glioblastoma Stem Cell Potency and Tumor Growth via LRRK2 Inhibition.

Leucine-rich repeat kinase 2 (LRRK2), a large GTP-regulated serine/threonine kinase, is well-known for its mutations causing late-onset Parkinson's disease. However, the role of LRRK2 in glioblastoma (GBM) carcinogenesis has not yet been fully elucidated. Here, we discovered that LRRK2 was overexpressed in 40% of GBM patients, according to tissue microarray analysis, and high LRRK2 expression correlated with poor prognosis in GBM patients. LRRK2 and stemness factors were highly expressed in various patient-derived GBM stem cells, which are responsible for GBM initiation. Canonical serum-induced differentiation decreased the expression of both LRRK2 and stemness factors. Given that LRRK2 is a key regulator of glioma stem cell (GSC) stemness, we developed DNK72, a novel LRRK2 kinase inhibitor that penetrates the blood-brain barrier. DNK72 binds to the phosphorylation sites of active LRRK2 and dramatically reduced cell proliferation and stemness factors expression in in vitro studies. Orthotopic patient-derived xenograft mouse models demonstrated that LRRK2 inhibition with DNK72 effectively reduced tumor growth and increased survival time. We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.

Integrated proteogenomic characterization of glioblastoma evolution.

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

Antiamoebic activities of flavonoids against pathogenic free-living amoebae, Naegleria fowleri and Acanthamoeba species.

Free-living amoebae (FLA) rarely cause human infections but can invoke fatal infections in the central nervous system (CNS). No consensus treatment has been established for FLA infections of the CNS, emphasizing the urgent need to discover or develop safe and effective drugs. Flavonoids, natural compounds from plants and plant-derived products, are known to have antiprotozoan activities against several pathogenic protozoa parasites. The anti-FLA activity of flavonoids has also been proposed, while their antiamoebic activity for FLA needs to be emperically determined. We herein evaluated the antiamoebic activities of 18 flavonoids against Naegleria fowleri and Acanthamoeba species which included A. castellanii and A. polyphaga. These flavonoids showed different profiles of antiamoebic activity against N. fowleri and Acanthamoeba species. Demethoxycurcumin, kaempferol, resveratrol, and silybin (A+B) showed in vitro antiamoebic activity against both N. fowleri and Acanthamoeba species. Apigenin, costunolide, (‒)-epicatechin, (‒)-epigallocatechin, rosmarinic acid, and (‒)-trans-caryophyllene showed selective antiamoebic activity for Acanthamoeba species. Luteolin was more effective for N. fowleri. However, afzelin, berberine, (±)-catechin, chelerythrine, genistein, (+)-pinostrobin, and quercetin did not exhibit antiamoebic activity against the amoeba species. They neither showed selective antiamoebic activity with significant cytotoxicity to C6 glial cells. Our results provide a basis for the anti-FLA activity of flavonoids, which can be applied to develope alternative or supplemental therapeutic agents for FLA infections of the CNS.

Anti-Inflammatory and Antiatopic Effects of Rorippa cantoniensis (Lour.) Ohwi in RAW 264.7 and HaCaT Cells.

This study evaluated the effects of Rorippa cantoniensis (Lour.) ohwi extract (RCE) on factors associated with inflammation-related skin lesions in RAW 264.7 and HaCaT cells. RCE inhibited the levels of proinflammatory mediators and cytokines such as nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In addition, RCE significantly inhibited the expression of chemokines and cytokines such as MDC/CCL22, TARC/CCL17, RANTES/CCL5, CTSS, IL-6, IL-1ß, and TNF-α in HaCaT cells costimulated by TNF-α and interferon (IFN)-γ in a concentration-dependent manner. These results suggest that RCE attenuated the TNF-α- and IFN-γ-induced release of proinflammatory chemokines and cytokines probably by suppressing the activation of MAPK (JNK and p38), NF-κB, and STAT1 signaling. Moreover, RCE significantly increased the expression of skin components such as hyaluronic acid and aquaporin, which play important roles in the physical and chemical barriers of the skin. These results suggest that RCE has significant anti-inflammatory and antiatopic activities, which may be beneficial for the topical treatment of inflammatory skin disorders.

Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling.

Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated ß-galactosidase (SA-ßGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-ßGal+ GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.

Feasibility of partial-orbit irradiation as a treatment strategy for patients with orbital mucosa-associated lymphoid tissue lymphoma.

OBJECTIVE: For early-stage orbital mucosa-associated lymphoid tissue lymphoma (MALToma), radiotherapy (RT) is known to be the treatment of choice. The classical recommended treatment field is the entire ipsilateral orbit, exposing normal orbital structures such as the lacrimal gland and lens, which are sensitive to moderate doses of radiation, to the full treatment dose. Herein we aimed to evaluate the clinical outcomes and dosimetric values in patients with orbital MALToma who received RT. DESIGN: This study was a retrospective study. PARTICIPANTS: Forty patients with orbital MALToma treated with curative RT. METHODS: The patients were classified into the conjunctival RT (n = 23), partial-orbit RT (n = 10), and whole-orbit RT (n = 7) groups. The treatment outcomes and dosimetric values of the orbital structures were reviewed. RESULTS: We found the 5-year local, contralateral orbit, and overall relapse rates to be 5.0%, 5.9%, and 16.0%, respectively. Local relapse events occurred in 2 patients in the conjunctival RT group. No relapse was observed in the partial-orbit RT group. Whole-orbit RT caused significantly higher rates of dry eyes during treatment. The partial-orbit RT group showed a significantly lower ipsilateral eyeball mean dose and ipsilateral eyelid mean dose than the other groups. CONCLUSION: Partial-orbit RT showed encouraging clinical, toxicity, and dosimetric outcomes in patients with orbital MALToma and has the potential to be a treatment option for such patients.

Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5.

Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options. Using the human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists, we identified the proteins that interact with DRD2. DRD2 signaling promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces DRD2-TRAIL receptor interaction and subsequent cell death. Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy.

Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy.

Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.

LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL.

LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1- and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer. SIGNIFICANCE: EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer. This article is highlighted in the In This Issue feature, p. 517.

Phragmites australis (Cav.) Trin. ex Steud. Extract Induces Apoptosis-like Programmed Cell Death in Acanthamoeba castellanii Trophozoites.

Acanthamoeba keratitis (AK) is an infectious ocular disease which is difficult to diagnose correctly and cure. Development of an effective and safe therapeutic drug for AK is needed. Our preliminary screening of more than 200 extracts from wild plants collected in Korea suggested the potential amoebicidal activity of Phragmites australis (Cav.) Trin. ex Steud. extract (PAE) against Acanthamoeba species. Here, we aimed to analyze the amoebicidal activity of PAE on Acanthamoeba and its underlying amoebicidal mechanism. PAE induced amoebicidal activity against both A. castellanii and A. polyphaga trophozoites, while it showed low cytotoxicity in human corneal epithelial cells (HCE-2) and human retinal pigment epithelial cells (ARPE-19). Transmission electron microscopy analysis showed subcellular morphological changes, such as increased granules, abnormal mitochondria, and atypical cyst wall formation, in the PAE-treated A. castellanii. Fluorometric apoptosis assay and TUNEL assay revealed apoptosis-like programmed cell death (PCD) in the PAE-treated A. castellanii. The PAE treatment increased reactive oxygen species production and reduced mitochondrial membrane potential in the amoeba. The enhanced expression of autophagy-associated genes was also detected. These results suggested that PAE exerted a promising amoebicidal effect on A. castellanii trophozoites via the PCD pathway. PAE could be a potential candidate for developing a therapeutic drug for AK.

Analysis of thromboembolic events in head and neck cancer patients who underwent concurrent chemoradiotherapy with cisplatin.

BACKGROUND/AIMS: The study investigated the incidence of thromboembolic events (TEE) in head and neck (H&N) cancer patients who received concurrent chemoradiotherapy (CCRT) with cisplatin, and analyzed the factors affecting TEE occurrence. METHODS: Two hundred and fifty-seven patients who started CCRT with cisplatin for H&N cancer from January 2005 to December 2019 were analyzed. RESULTS: TEE occurred in five patients, an incidence rate of 1.9%. The 2-, 4-, and 6-month cumulative incidences of TEE were 0.8%, 1.6%, and 1.9%, respectively. Khorana score was the only factor associated with TEE occurrence (p = 0.010). CONCLUSION: The incidence of TEE in H&N cancer patients who underwent CCRT with cisplatin was relatively low when compared to other types of cancer. However, patients with a high Khorana score require more careful surveillance for possible TEE occurrence.

The efficacy of EGFR-tyrosine kinase inhibitor in non-small cell lung cancer patients with synchronous brain metastasis: a real-world study.

BACKGROUND/AIMS: The optimal treatment (Tx) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) remains to be determined. METHODS: A retrospective review was conducted on 77 NSCLC patients with synchronous BM who underwent first-line EGFR-tyrosine kinase inhibitor (TKI) Tx. The outcomes of patients were analyzed according to the clinicopathological characteristics including local Tx modalities. RESULTS: Fifty-nine patients underwent local Tx for BM (gamma knife surgery [GKS], 37; whole brain radiotherapy [WBRT], 18; others, four) concurrently or sequentially with EGFR-TKI. Patients treated with TKI alone showed significantly lower incidence of central nervous system (CNS) symptoms. The median progression-free survival (PFS) and overall survival (OS) after the initiation of EGFR-TKI for all patients were 9 and 19 months, respectively. In 60 patients with follow-up brain imaging, the median time to CNS progression was 15 months. Patients with EGFR exon 19 deletion had a significantly longer median OS than those with other mutations including L858R (23 months vs. 17 months). Other clinical characteristics, including CNS symptoms, number of BM, and the use of local Tx were not associated with OS, as well as PFS. In terms of the local optimal Tx modality, no difference was found between GKS and WBRT in the OS and PFS. CONCLUSION: This study suggests that EGFR-TKI may result in a favorable outcome in NSCLC patients with synchronous BM, especially in deletion 19 mutant, regardless of the extent of BM lesions or local Tx modalities. Patients with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.

Survey of radiation field and dose in human papillomavirus-positive oropharyngeal cancer: is de-escalation actually applied in clinical practice?

PURPOSE: Studies on de-escalation in radiation therapy (RT) for human papillomavirus-related (HPV(+)) oropharyngeal cancer (OPC) are currently ongoing. This study investigated the current practice regarding the radiation dose and field in the treatment of HPV(+) OPC. MATERIALS AND METHODS: The Korean Society for Head and Neck Oncology conducted a questionnaire on the primary treatment policy. Among them, for HPV(+) OPC scenarios, radiation oncologists were questioned regarding the field and dose of RT. RESULTS: Forty-two radiation oncologists responded to the survey. In definitive concurrent chemoradiotherapy (CCRT) treatment for stage T2N1M0 OPC, most respondents prescribed a dose of >60 Gy to the primary tonsil and involved ipsilateral lymph nodes. However, eight of the respondents prescribed a relatively low dose of ≤54 Gy. For stage T2N1M0 OPC, postoperative adjuvant RT was prescribed by eight and nine respondents with a lower dose of ≤50 Gy for the ipsilateral tonsil and involved neck, respectively. In definitive CCRT in complete remission after induction chemotherapy for initial stage T2N3M0 OPC, de-escalation of the tonsil and involved neck were performed by eight and seven respondents, respectively. Regarding whether de-escalation is applied in radiotherapy for HPV(+) OPC, 27 (64.3%) did not do it at present, and 15 (35.7%) were doing or considering it. CONCLUSION: The field and dose of prescribed treatment varied between institutions in Korea. Among them, dose de-escalation of RT in HPV(+) OPC was observed in approximately 20% of the respondents. Consensus guidelines will be set in the near future after the completion of ongoing prospective trials.

Effective Organs-at-Risk Dose Sparing in Volumetric Modulated Arc Therapy Using a Half-Beam Technique in Whole Pelvic Irradiation.

BACKGROUND: Although there are some controversies regarding whole pelvic radiation therapy (WPRT) due to its gastrointestinal and hematologic toxicities, it is considered for patients with gynecological, rectal, and prostate cancer. To effectively spare organs-at-risk (OAR) doses using multi-leaf collimator (MLC)'s optimal segments, potential dosimetric benefits in volumetric modulated arc therapy (VMAT) using a half-beam technique (HF) were investigated for WPRT. METHODS: While the size of a fully opened field (FF) was decided to entirely include a planning target volume in all beam's eye view across arc angles, the HF was designed to use half the FF from the isocenter for dose optimization. The left or the right half of the FF was alternatively opened in VMAT-HF using a pair of arcs rotating clockwise and counterclockwise. Dosimetric benefits of VMAT-HF, presented with dose conformity, homogeneity, and dose-volume parameters in terms of modulation complex score, were compared to VMAT optimized using the FF (VMAT-FF). Consequent normal tissue complication probability (NTCP) by reducing the irradiated volumes was evaluated as well as dose-volume parameters with statistical analysis for OAR. Moreover, beam-on time and MLC position precision were analyzed with log files to assess plan deliverability and clinical applicability of VMAT-HF as compared to VMAT-FF. RESULTS: While VMAT-HF used 60%-70% less intensity modulation complexity than VMAT-FF, it showed superior dose conformity. The small intestine and colon in VMAT-HF showed a noticeable reduction in the irradiated volumes of up to 35% and 15%, respectively, at an intermediate dose of 20-45 Gy. The small intestine showed statistically significant dose sparing at the volumes that received a dose from 15 to 45 Gy. Such a dose reduction for the small intestine and colon in VMAT-HF presented a significant NTCP reduction from that in VMAT-FF. Without sacrificing the beam delivery efficiency, VMAT-HF achieved effective OAR dose reduction in dose-volume histograms. CONCLUSIONS: VMAT-HF led to deliver conformal doses with effective gastrointestinal-OAR dose sparing despite using less modulation complexity. The dose of VMAT-HF was delivered with the same beam-on time with VMAT-FF but precise MLC leaf motions. The VMAT-HF potentially can play a valuable role in reducing OAR toxicities associated with WPRT.

Analysis of electric cigarette liquid effect on mouse brain tumor growth through EGFR and ERK activation.

INTRODUCTION: Recently, electric cigarettes with liquid (e-liquid) were introduced as an alternative to tobacco smoking. They were promoted as possible cessation aids and were considered to be potentially less harmful than traditional tobacco-based cigarettes. However, there is little information on the toxicants present in e-liquids and their possible carcinogenic effects. METHODS: Western blot analysis was performed to identify the protein levels of cancer progression related signal transducers. Patient-derived brain tumor cells (CSC2) were injected into mouse brains and tumor growth was then observed by performing magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining of the whole brain. Immunohistochemistry (IHC) staining and Immunofluorescence staining were performed to study the expression of pEGFR and pERK. RESULTS: Western blotting revealed that e-liquids increased pEGFR and pERK expression in a dose dependent manner. Animal experiments revealed that the e-liquid treated group had accelerated tumor growth and poor prognosis compared to the vehicle group. Histological staining showed activation of pEGFR and pERK in the e-liquid treated group. CONCLUSION: Our study revealed that e-liquid activates pEGFR and pERK, leading to accelerated brain tumor growth and poor prognosis.

Whole-Brain Radiotherapy vs. Localized Radiotherapy after Resection of Brain Metastases in the Era of Targeted Therapy: A Retrospective Study.

Whether targeted therapy (TT) and radiotherapy impact survival after resection of brain metastases (BM) is unknown. The purpose of this study was to analyze the factors affecting overall survival (OS), local control (LC), distant control (DC), and leptomeningeal metastases (LMM) in patients who had undergone resection of BM. We retrospectively analyzed 124 consecutive patients who had undergone resection of BM between 2004 and 2020. Patient information about age, sex, Karnofsky Performance Scale (KPS), origin of cancer, synchronicity, tumor size, status of primary cancer, use of TT, extent of resection, and postoperative radiotherapy was collected. Radiation therapy was categorized into whole-brain radiotherapy (WBRT), localized radiotherapy (local brain radiotherapy or stereotactic radiosurgery (LBRT/SRS)), and no radiation. We identified factors that affect OS, LC, DC, and LMM. In multivariable analysis, significant factors for OS were higher KPS score (≥90) (HR 0.53, p = 0.011), use of TT (HR 0.43, p = 0.001), controlled primary disease (HR 0.63, p = 0.047), and single BM (HR 0.55, p = 0.016). Significant factors for LC were gross total resection (HR 0.29, p = 0.014) and origin of cancer (p = 0.041). Both WBRT and LBRT/SRS showed superior LC than no radiation (HR 0.32, p = 0.034 and HR 0.38, p = 0.018, respectively). Significant factors for DC were use of TT (HR 0.54, p = 0.022) and single BM (HR 0.47, p = 0.004). Reduced incidence of LMM was associated with use of TT (HR 0.42, p = 0.038), synchronicity (HR 0.25, p = 0.028), and controlled primary cancer (HR 0.44, p = 0.047). TT was associated with prolonged OS, improved DC, and reduced LMM in resected BM patients. WBRT and LBRT/SRS showed similar benefits on LC. Considering the extended survival of cancer patients and the long-term effect of WBRT on cognitive function, LBRT/SRS appears to be a good option after resection of BM.

Impact of Body Mass Index on Local Recurrence according to Intrinsic Subtype Approximation in Korean Women with Early Stage Invasive Breast Cancer Receiving Contemporary Treatments.

Purpose: We investigated the prognostic impact of body mass index (BMI) on local recurrence (LR) according to intrinsic subtype in Korean women with early stage, invasive breast cancer. Materials and methods: We included 907 patients with pathological stage T1-2 and N0-1 breast cancer who underwent curative surgery between 2007 and 2012. Systemic treatments were administered in 876 patients (96.6%). In total, 701 patients (77.3%) received radiotherapy. Intrinsic subtypes were determined using immunohistochemical staining results. Results: During the median follow-up period of 72 months, LR as the first failure occurred in 29 patients, including 24 patients with isolated LR. The 5-year cumulative incidence rate of LR was 3.2% among all patients. In the luminal A subtype, a BMI of <18.5 kg/m2 was an independent risk factor for LR, as determined by a competing-risk regression model (relative risk, 3.33; p = 0.041). Severely obese patients (BMI >30 kg/m2) with the triple negative subtype had an increased risk of LR (relative risk, 3.81; p = 0.048). Conclusion: The present study identified traditionally underestimated risk groups for LR. BMI may diversely influence the rate of LR across intrinsic subtypes in Korean patients with breast cancer.

Local Recurrence in Young Women with Breast Cancer: Breast Conserving Therapy vs. Mastectomy Alone.

We compared the cumulative incidence of local recurrence in young patients (≤40 years) with breast cancer between breast conserving therapy (BCT) and mastectomy alone. Among 428 women with early-stage breast cancer who were treated between 2001 and 2012, 311 underwent BCT and 117 underwent mastectomy alone. Adjuvant systemic treatments were administered to 409 patients (95.6%). We compared the cumulative incidence of LR and survival rates between two groups. During a median follow-up period of 91 months, the 10-year cumulative incidence of LR was 9.3% (median interval of 36.5 months from surgery). Patients treated with BCT tended to have a higher risk for local recurrence (11.1% for BCT vs. 4.1% for mastectomy alone, p = 0.078). All patients with isolated LR after BCT (n = 23) underwent salvage mastectomy followed by systemic treatments. The 5-year distant metastasis-free survival and overall survival of patients with isolated LR after BCT were 44.2% and 82.2%, respectively. The BCT group exhibited an approximately 2.5-fold higher risk of LR than mastectomy alone group. Patients with isolated LR after BCT showed poor prognosis despite undergoing aggressive salvage treatments. The development of novel treatments should be investigated to reduce LR for improving prognosis and preserving cosmetic outcomes in young women.

Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities.

The transcriptomic classification of glioblastoma (GBM) has failed to predict survival and therapeutic vulnerabilities. A computational approach for unbiased identification of core biological traits of single cells and bulk tumors uncovered four tumor cell states and GBM subtypes distributed along neurodevelopmental and metabolic axes, classified as proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic. Each subtype was enriched with biologically coherent multiomic features. Mitochondrial GBM was associated with the most favorable clinical outcome. It relied exclusively on oxidative phosphorylation for energy production, whereas the glycolytic/plurimetabolic subtype was sustained by aerobic glycolysis and amino acid and lipid metabolism. Deletion of the glucose-proton symporter SLC45A1 was the truncal alteration most significantly associated with mitochondrial GBM, and the reintroduction of SLC45A1 in mitochondrial glioma cells induced acidification and loss of fitness. Mitochondrial, but not glycolytic/plurimetabolic, GBM exhibited marked vulnerability to inhibitors of oxidative phosphorylation. The pathway-based classification of GBM informs survival and enables precision targeting of cancer metabolism.