Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma.

BACKGROUND: A substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown. METHODS: Transcriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation. RESULTS: Members of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2. An immunosuppressive microenvironment featured by high infiltrates of Tregs and cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed. CONCLUSIONS: Our study revealed that elevated PHLDA2 expression regulated by DNA hypomethylation was correlated with poor prognosis and immunosuppressive microenvironment, and highlighted the role of PHLDA2 as a robust biomarker for predicting therapeutic efficacy of ICI plus anti-angiogenic agent combination therapy in ccRCC, which expand the dimension of precision medicine.

Analysis of the immune-inflammatory indices for patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.

The incidence of immune-related adverse events (irAEs) and their association with clinical outcomes in advanced renal cell carcinoma and urothelial carcinoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: This study aimed to summarize the occurrence of immune-related adverse events (irAEs) and further evaluate their association with clinical outcomes in patients with advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs). METHODS: A comprehensive search of PubMed, Embase, and the Cochrane Library up to December 2023 was conducted to identify eligible studies. The details of irAEs and data regarding their correlation with clinical outcomes were extracted. R software was used for meta-analysis. RESULTS: A total of 27 studies involving 6148 patients with RCC or UC were included. The pooled overall incidence for any-grade and grade ≥ 3 irAEs was 44.2 % (95 % CI: 38.1 %-50.5 %) and 15.7 % (95 % CI: 11.4 %-21.1 %), respectively. Compared to those without any irAEs, patients with irAEs showed improved PFS (HR = 0.44, 95 % CI: 0.35-0.56, p < 0.01) and OS (HR = 0.47, 95 % CI: 0.42-0.51, p < 0.01), as well as higher ORR (OR = 3.59, 95 % CI: 3.01-4.29, p < 0.01) and DCR (OR = 4.23, 95 % CI: 3.06-5.84, p < 0.01). Subgroup analysis indicated that clinical outcome improvements were associated with the occurrence of irAEs, regardless of tumor type or ICI agent. Notably, patients with cutaneous irAEs, thyroid dysfunction, and grade ≤ 2 irAEs had a higher probability to achieve better survival benefits from ICI-based therapy, while pulmonary irAEs and grade ≥ 3 irAEs seemed to have a negative impact on OS. Additionally, systemic glucocorticoids administration did not affect survival outcomes. CONCLUSION: Our findings suggest that the occurrence of irAEs could be considered as a potential prognostic factor for predicting the efficacy of ICIs in patients with advanced RCC and UC.

14-3-3σ downregulation sensitizes pancreatic cancer to carbon ions by suppressing the homologous recombination repair pathway.

This study explored the role of 14-3-3σ in carbon ion-irradiated pancreatic adenocarcinoma (PAAD) cells and xenografts and clarified the underlying mechanism. The clinical significance of 14-3-3σ in patients with PAAD was explored using publicly available databases. 14-3-3σ was silenced or overexpressed and combined with carbon ions to measure cell proliferation, cell cycle, and DNA damage repair. Immunoblotting and immunofluorescence (IF) assays were used to determine the underlying mechanisms of 14-3-3σ toward carbon ion radioresistance. We used the BALB/c mice to evaluate the biological behavior of 14-3-3σ in combination with carbon ions. Bioinformatic analysis revealed that PAAD expressed higher 14-3-3σ than normal pancreatic tissues; its overexpression was related to invasive clinicopathological features and a worse prognosis. Knockdown or overexpression of 14-3-3σ demonstrated that 14-3-3σ promoted the survival of PAAD cells after carbon ion irradiation. And 14-3-3σ was upregulated in PAAD cells during DNA damage (carbon ion irradiation, DNA damaging agent) and promotes cell recovery. We found that 14-3-3σ resulted in carbon ion radioresistance by promoting RPA2 and RAD51 accumulation in the nucleus in PAAD cells, thereby increasing homologous recombination repair (HRR) efficiency. Blocking the HR pathway consistently reduced 14-3-3σ overexpression-induced carbon ion radioresistance in PAAD cells. The enhanced radiosensitivity of 14-3-3σ depletion on carbon ion irradiation was also demonstrated in vivo. Altogether, 14-3-3σ functions in tumor progression and can be a potential target for developing biomarkers and treatment strategies for PAAD along with incorporating carbon ion irradiation.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.

BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism.

BACKGROUND: Toxoplasmosis affects a quarter of the world's population. Toxoplasma gondii (T.gondii) is an intracellular parasitic protozoa. Macrophages are necessary for proliferation and spread of T.gondii by regulating immunity and metabolism. Family with sequence similarity 96A (Fam96a; formally named Ciao2a) is an evolutionarily conserved protein that is highly expressed in macrophages, but whether it play a role in control of T. gondii infection is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we utilized myeloid cell-specific knockout mice to test its role in anti-T. gondii immunity. The results showed that myeloid cell-specific deletion of Fam96a led to exacerbate both acute and chronic toxoplasmosis after exposure to T. gondii. This was related to a defectively reprogrammed polarization in Fam96a-deficient macrophages inhibited the induction of immune effector molecules, including iNOS, by suppressing interferon/STAT1 signaling. Fam96a regulated macrophage polarization process was in part dependent on its ability to fine-tuning intracellular iron (Fe) homeostasis in response to inflammatory stimuli. In addition, Fam96a regulated the mitochondrial oxidative phosphorylation or related events that involved in control of T. gondii. CONCLUSIONS/SIGNIFICANCE: All these findings suggest that Fam96a ablation in macrophages disrupts iron homeostasis and inhibits immune effector molecules, which may aggravate both acute and chronic toxoplasmosis. It highlights that Fam96a may autonomously act as a critical gatekeeper of T. gondii control in macrophages.

Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki67.

BACKGROUND: KI67 is a well-known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa). METHODS: Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan-Meier curve and Cox regression analysis. The endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%-30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67-positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA-PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA-PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035). CONCLUSIONS: This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.

Prognostic significance of circulating tumor DNA in urothelial carcinoma: a systematic review and meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a noninvasive technique that provides valuable insights into molecular profiles and tumor disease management. This study aimed to evaluate the prognostic significance of circulating tumor DNA (ctDNA) in urothelial carcinoma (UC) through a systematic review and meta-analysis. METHODS: A comprehensive search was conducted in MEDLINE, EMBASE, and the Cochrane Library from the inception to December 2023. Studies investigating the prognostic value of ctDNA in UC were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted. Overall meta-analysis and subgroup exploration stratified by metastatic status, ctDNA sampling time, treatment type, and detection method was performed using the R software (version 4.2.2). RESULTS: A total of 16 studies with 1725 patients were included. Fourteen studies assessed the association between baseline ctDNA status and patient outcomes. Patients with elevated ctDNA levels exhibited significantly worse DFS (HR=6.26; 95% CI: 3.71-10.58, P <0.001) and OS (HR=4.23; 95% CI: 2.72-6.57, P <0.001) regardless of metastatic status, ctDNA sampling time, treatment type, and detection methods. Six studies evaluated the prognostic value of ctDNA dynamics in UC. Patients who showed a decrease or clearance in ctDNA levels during treatment or observation demonstrated more favorable DFS (HR=0.26, 95% CI: 0.17-0.41, P <0.001) and OS (HR=0.21, 95% CI: 0.11-0.38, P <0.001) compared to those who did not. The association remained consistent across the subgroup analysis based on metastatic status and detection methods. In the immune checkpoint inhibitor-treated setting, both lower baseline ctDNA level and ctDNA decrease during the treatment were significantly associated with more favorable oncologic outcomes. Furthermore, specific gene mutations such as FGFR3 identified in ctDNA also demonstrated predictive value in UC patients. CONCLUSION: This meta-analysis demonstrates a strong association of ctDNA status and its dynamic change with survival outcomes in UC, suggesting substantial clinical utility of ctDNA testing in prognosis prediction and decision making in this setting.

UBA2 as a Prognostic Biomarker and Potential Therapeutic Target in Glioma.

BACKGROUND: Gliomas are characterized by aggressive behavior, leading to severe disability and high mortality. Ubiquitin-like modifier activating enzyme 2 (UBA2) is a subunit of the E1-activating enzyme involved in the SUMOylation (SUMO, small ubiquitin-related modifier) of numerous proteins. Although the abnormality of UBA2 is linked to the progression of various tumor types, the role of UBA2 in glioma is still unknown. METHODS: A bioinformatic analysis using several public databases was conducted to examine the expression level, clinicopathological correlations, and prognostic significance of UBA2 in glioma. The correlation between UBA2 expression and drug sensitivity in cancers was also explored. Multiple cellular experiments were conducted to validate the role of UBA2 in glioma. RESULTS: Analysis of multiple databases and cellular experiments revealed that UBA2 was overexpressed in glioma tissues and cell lines, respectively. UBA2 expression in gliomas correlated with World Health Organization (WHO) grade, IDH gene status, 1p19q deletion, histological type, and immune cell infiltration in glioma. UBA2 expression in carcinomas also correlated with drug sensitivity. Kaplan-Meier analysis revealed that high expression of UBA2 predicted poorer survival in glioma patients. A nomogram model containing UBA2 expression was constructed for clinical practice. Knockdown of UBA2 was observed to suppress glioma cell progression and sensitize glioma cells to irradiation in vitro. CONCLUSION: Overall, this research showed that UBA2 might be involved not only in the development of glioma but also in the regulation of immunity, drug sensitivity, and radiosensitivity. Therefore, UBA2 may be a potential target for therapy and a candidate biomarker for glioma diagnosis and prognosis.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

Simultaneous type III congenital esophageal atresia and patent ductus arteriosus in a low-weight patient: A case report.

BACKGROUND: We report a low-birth-weight child (1.8 kg) with neonatal type III congenital esophageal atresia (CEA) combined with symptomatic patent ductus arteriosus (PDA). After comprehensive evaluation, esophageal anastomosis was performed on postnatal day 11 after excluding surgical contraindications, and arterial catheter ligation was performed at the same time. Concurrent surgery for CEA combined with PDA has not been clearly reported in the literature. CASE SUMMARY: We report a 6-day-old female child with type III CEA and PDA. The patient presented with foam at the mouth after birth, cough and shortness of breath after feeding. At another hospital, she was considered to have neonatal pneumonia, neonatal jaundice and congenital heart disease and transferred to our hospital. After iodine oil radiography of the esophagus and echocardiography we confirmed diagnosis of CEA and PDA. The diameter of the PDA was 8 mm, with obvious left to right shunting. We performed right rear extrapleural orificium fistula ligation and esophageal anastomosis, and ligation of PDA via left axilla straight incision after 5 d of hospitalization. The operations were successful, and the incision healed after 12 d, and the patient was discharged. We re-examined the patient 1 mo after surgery. She did not vomit when she ate rice flour. Esophageal angiography showed no stricture of the anastomotic stoma. The patient weighed 3.2 kg. CONCLUSION: For CEA patients with multiple risk factors, comprehensive, timely and accurate diagnosis and evaluation, and early treatment may improve prognosis.

Radiosensitization of Osteosarcoma Cells Using the PARP Inhibitor Olaparib Combined with X-rays or Carbon Ions.

Objective: Osteosarcomas are derived from bone-forming mesenchymal cells that are insensitive to radiation. This study aimed to investigate the radiosensitization of osteosarcoma cells (U2OS and K7M2) using the PARP inhibitor olaparib combined with X-rays or carbon ions (C-ions). Methods: The effect of olaparib on the proliferation of osteosarcoma cells after irradiation was assessed using CCK-8 and clone formation assays. Cells were treated with olaparib and/or radiation and the effects of olaparib on the cell cycle and apoptosis were analysed by flow cytometry after 48h. Immunofluorescence was used to stain the nuclei, γ-H2AX, 53BP1, and Rad51 proteins, and the number of γ-H2AX, 53BP1, and Rad51 foci was observed under a fluorescence microscope. The effect of olaparib combined with radiation on double-stranded DNA breaks in osteosarcoma cells was evaluated. Results: At the same radiation dose, olaparib reduced the proliferation and colony formation ability of irradiated osteosarcoma cells (P < 0.05). Olaparib monotherapy induced minimal apoptotic effects and G2/M phase arrest in osteosarcoma cells and irradiation alone induced moderate apoptosis and G2/M phase arrest. However, radiation combined with olaparib significantly increased the percentage of apoptotic cells and G2/M phase arrest in osteosarcoma cells (P < 0.05). Immunofluorescence experiments showed that compared to the radiation group, the formation of γ-H2AX and 53BP1 foci was significantly increased in the combined group (P < 0.05). The expression levels of Rad51 foci in the irradiated group were higher than those in the control group (P < 0.05). However, the number of Rad51 foci in the combined group was significantly decreased (P < 0.05). Conclusion: The PARP inhibitor olaparib combined with irradiation (X-rays or C-ions) enhanced the radiosensitivity of osteosarcoma cell lines (U2OS and K7M2). Our findings provide a potential theoretical basis for the clinical application of olaparib in overcoming radiation resistance in osteosarcoma.

Genomic and Evolutionary Characterization of Concurrent Intraductal Carcinoma and Adenocarcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. SIGNIFICANCE: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response.

BACKGROUND: The mutational pattern of homologous recombination repair (HRR)-associated gene alterations in Chinese urothelial carcinoma (UC) necessitates comprehensive sequencing efforts, and the clinical implications of HRR gene mutations in UC remain to be elucidated. MATERIALS AND METHODS: We delineated the mutational landscape of 343 Chinese UC patients from West China Hospital and 822 patients from The Cancer Genome Atlas (TCGA) using next-generation sequencing (NGS). Data from 182 metastatic UC patients from MSK-IMPACT cohort were used to assess the association between HRR mutations and immunotherapy efficacy. Comprehensive transcriptomic analysis was performed to explore the impact of HRR mutations on tumor immune microenvironment. RESULTS: Among Chinese UC patients, 34% harbored HRR gene mutations, with BRCA2, ATM, BRCA1, CDK12, and RAD51C being the most prevalently mutated genes. Mutational signatures contributing to UC differed between patients with and without HRR mutations. Signature 22 for exposure to aristolochic acid was only observed in Chinese UC patients. The presence of HRR mutations was correlated with higher tumor mutational burden, neoantigen burden, and PD-L1 expression. Importantly, patients with HRR mutations exhibited significantly improved prognosis following immunotherapy compared to those without HRR mutations. CONCLUSIONS: Our findings provide valuable insights into the genomic landscape of Chinese UC patients and underscore the molecular rationale for utilizing immunotherapy in UC patients with HRR mutations.

Efficacy and safety of carbon ion radiotherapy for chordomas: a systematic review and meta-analysis.

OBJECTIVE: Carbon ion radiotherapy (C-ion RT) for chordomas has been gradually performed in several research centres. This study aimed to systematically review the results of clinical reports from these institutions and to evaluate the safety and efficacy of C-ion RT. METHODS: In accordance with the PRISMA guidelines and set search strategies, we searched four databases for articles from their inception to February 11, 2023. These articles were screened, and data were extracted independently by two researchers. STATA 14.0 was used for statistical analysis of survival results. RESULTS: A total of 942 related articles were retrieved, 11 of which were included. Regarding lesion location, 57% (n = 552) originated in the sacral region, 41% (n = 398) in the skull base, and 2% (n = 19) in the spine (upper cervical). The local control (LC) rates at 1, 2, 3, 5, 9, and 10 years in these studies were 96%, 93%, 83%, 76%, 71%, and 54%, respectively. The overall survival (OS) rates at 1, 2, 3, 5, 9, and 10 years in these studies were 99%, 100%, 93%, 85%, 76%, and 69%, respectively. Acute and late toxicities were acceptable, acute toxicities were mainly grade 1 to grade 2 and late toxicities were mainly grade 1 to grade 3. CONCLUSION: C-ion RT has attractive clinical application prospects and is an important local treatment strategy for chordomas. Encouraging results were observed in terms of LC and OS. Meanwhile, the acute and late toxicities were acceptable. PROSPERO registration number: CRD42023398792.

A pilot study of stereotactic body radiotherapy combined with pelvic radiotherapy and GTVp boost based on multiparameter magnetic resonance image in patients with high-risk prostate cancer.

This pilot study aimed to explore the preliminary effects and safety of stereotactic body radiotherapy (SBRT) combined with preventive pelvic radiotherapy and primary gross tumor volumes (GTVp) boost in patients with high-risk prostate cancer based on multiparameter magnetic resonance image (mpMRI). Tumors were contoured as GTVp based on mpMRI. The prostate and proximal seminal vesicles were considered as the clinical target volume1. The pelvic lymphatic drainage area constituted clinical target volume 2. Radiation doses were 40Gy or 45Gy/5fractions to planning target volume of primary tumor, 37.5Gy/5f to prostate, seminal vesicle, and positive pelvic lymph nodes, and 25Gy/5f to pelvic synchronously. The treatment was delivered 3 times per week. Volumetric modulated arc radiotherapy and intensity-modulated radiotherapy were used to complete SBRT. The genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated. Quality of life data was also captured. A total of 15 patients were enrolled in this study with a median age of 78 (56-87) from 2017 to 2020. All patients received SBRT. At 3 months after radiotherapy, the proportion of PSA < 0.006 ng/mL was 66.7% (10/15). The 2-year biochemical relapse-free survival was 93.3%. The incidence of grade 1 acute GU side effects was 80% (12/15); the incidence of acute grade 1 GI toxicity was 66.7% (10/15); and no grade 2 or higher acute GU and GI side effects was observed. Two patients presented with temporary late grade 2 GI toxicity. International Prostatic System Score increased rapidly after a transient increase at 1 week (P = .001). There were no significant differences in EORTC quality of life scores in all domains except global health status. In this pilot study, it was revealed that SBRT combined with preventive pelvic radiotherapy and GTVp boost based on mpMRI image was effective and well tolerated for patients with high-risk prostate cancer.