High-grade serous tubo-ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single-cell RNA and single-cell T-cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRβ+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1-expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRβ+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti-CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA-4/LAG-3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF-1/CSF-1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi-resistant HRD and refractory HRP tumors.

PURPOSE:The standard treatment schedule for unresectable stage III non-small cell lung cancer (NSCLC) is chemotherapy with concurrent radiation therapy (60 Gy delivered in 30 fractions), although moderately hypofractionated radiation therapy (Hypo-RT) has also been considered as an alternative strategy. This study aimed to compare the efficacy and toxicity of moderately Hypo-RT with helical TomoTherapy versus conventionally fractionated radiation therapy (Con-RT) in patients with unresectable stage III NSCLC receiving concurrent chemotherapy. METHODS AND MATERIALS:In this randomized, multicenter, nonblinded phase 3 clinical trial, eligible patients were randomised at a 1:1 ratio to either the Hypo-RT group (60 Gy in 20 fractions) or Con-RT group (60 Gy in 30 fractions). All patients received 2 cycles of concurrent platinum-based chemotherapy plus 2 cycles of consolidation therapy. The primary endpoint was 3-year overall survival (OS) in the intention-to-treat population. The secondary endpoints were progression-free survival and treatment-related adverse events. RESULTS:A total of 146 patients were enrolled from July 27, 2018, to November 1, 2021. The median follow-up was 46 months. The 3-year OS rates in the Hypo-RT and Con-RT groups were 58.4% and 38.4%, respectively (P = .02). The median OS from randomisation was 41 months in the Hypo-RT group and 30 months in the Con-RT group (hazard ratio, 0.61; 95% confidence interval, 0.40-0.94; P = .02). There was no significant difference in the rates of grade ≥2 treatment-related adverse events between the 2 groups. CONCLUSIONS:Moderately Hypo-RT using helical TomoTherapy may improve OS in patients with unresectable stage III NSCLC, while maintaining toxicity rates.

OBJECTIVE:To study the feasibility and potential benefits of beam angle optimization (BAO) to automated planning in liver cancer.METHODS:An approach of beam angle sampling is proposed to implement BAO along with the module Auto-planning in treatment planning system (TPS) Pinnacle. An in-house developed plan quality metric (PQM) is taken as the preferred evaluating method during the sampling. The process is driven automatically by in-house made Pinnacle scripts both in sampling and scoring. In addition, dosimetry analysis and physician's opinion are also performed as the supplementary and compared with the result of PQM.RESULTS:It is revealed by the numerical analysis of PQM scores that only 15% patients whose superior trials evaluated by PQM are also the initial trials. Gantry optimization can bring benefit to plan quality along with auto-planning in liver cancer. Similar results are provided by both dose comparison and physician's opinion.CONCLUSIONS:It is possible to introduce a full automated approach of beam angle optimization to automated planning process. The advantages of this procedure can be observed both in numerical analysis and physician's opinion.

Background Stereotactic body radio therapy (SBRT) has emerged as a standard treatment option for nonsurgical candidates with early-stage non-small cell lung cancer (NSCLC). Pathological proof is sometimes difficult to obtain in patients with solitary pulmonary nodules (SPNs). We aimed to compare the clinical outcomes of stereotactic body radiotherapy via helical tomotherapy (HT-SBRT) for early-stage lung cancer patients with or without a pathological diagnosis. Methods Between June 2011 and December 2016, we treated 119 lung cancer patients with HT-SBRT, including 55 with a clinical diagnosis and 64 with a pathological diagnosis. Survival outcomes, including local control (LC), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were compared between two cohorts with and without a pathological diagnosis. Results The median follow-up for the whole group was 69 months. Patients with a clinical diagnosis were significantly older ( p = 0.002). No significant differences were observed between the clinical and pathological diagnosis cohorts in terms of the long-term outcome, with 5-year LC, PFS, CSS, and OS of 87% versus 83% ( p = 0.58), 48% versus 45% ( p = 0.82), 87% versus 84% ( p = 0.65), and 60% versus 63% ( p = 0.79), respectively. Recurrence patterns and toxicity were also similar. Conclusions Empiric SBRT appears to be a safe and effective treatment option in a multidisciplinary setting when patients with SPNs highly suggestive of malignancy are unable/refuse to obtain a definitive pathological diagnosis.

Homologous recombination deficiency (HRD) causes faulty double-strand break repair and is a prevalent cause of tumorigenesis. However, the incidence of HRD and its clinical significance in pan-cancer patients remain unknown. Using computational analysis of Single-nucleotide polymorphism array data from 10,619 cancer patients, we demonstrate that HRD frequently occurs across multiple cancer types. Analysis of the pan-cancer cohort revealed that HRD is not only a biomarker for ovarian cancer and triple-negative breast cancer, but also has clinical prognostic value in numerous cancer types, including adrenocortical cancer and thymoma. We discovered that homologous recombination-related genes have a high mutation or deletion frequency. Pathway analysis shows HRD is positively correlated with the DNA damage response and the immune-related signaling pathways. Single cell RNA sequencing of tumor-infiltrating lymphocytes reveals a significantly higher proportion of exhausted T cells in HRD patients, indicating pre-existing immunity. Finally, HRD could be utilized to predict pan-cancer patients' responses to Programmed cell death protein 1 immunotherapy. In summary, our work establishes a comprehensive map of HRD in pan-cancer. The findings have significant implications for expanding the scope of Poly ADP-ribose polymerase inhibitor therapy and, possibly, immunotherapy.

Background: Radiation pneumonitis (RP) is a type of toxicity commonly associated with thoracic radiation therapy. We sought to establish a random forest (RF) model and evaluate its ability to predict RP in patients with non-small cell lung cancer (NSCLC) receiving moderately hypofractionated radiotherapy (hypo-RT). Methods: A total of 106 patients with stage II–IVa NSCLC who received moderately hypofractionated helical tomotherapy (2.3–3.0 Gy/fraction) at Zhongshan Hospital were included. All enrolled patients were divided chronologically into the training (67 patients) and validation (39 patients) groups. Higher than or equal to grade 2 RP was defined as the end point. Logistic regression and RF models were established and compared using the receiver operating characteristic (ROC) and a confusion matrix in the training and validation groups. Results: The cumulative incidence of the end point was 25.4% and 17.9% in the training and validation groups, respectively. Logistic regression models were constructed by dosage parameters of total lungs, ipsilateral or contralateral lungs, respectively. ROC analysis revealed that the dosimetric factors of total lungs yielded a superior classification performance than did that of the ipsilateral or contralateral lungs [area under the curve (AUC) =0.920, AUC =0.701, and AUC =0.661, respectively]. Furthermore, the RF model yielded a better prediction capacity than did the traditional logistic model based on the dosimetric factors of the total lungs (accuracy: 88.06%; precision: 84.62%; sensitivity: 64.71%; specificity: 96.00%). Moreover, the RF identified mean lung dose [MLD; mean decrease gini (MDG) =5.74], V20 (MDG =4.62), and V35 (MDG =3.08) of total lungs as the most common primary differentiators of RP. Conclusions: Our RF model established based on the dosimetric parameters of the total lungs could accurately predict the RP risk in patients with NSCLC treated with moderately hypofractionated tomotherapy.

Objective To evaluate the efficacy and toxicity of hypofractionated radiotherapy (hypo-RT) for stage III non-small-cell lung cancer (NSCLC) in the Chinese population. Methods Eighty-six stage III NSCLC patients who received hypo-RT (60 Gy/20 fractions, BED = 78.00 Gy: 73 patients; 62.5 Gy/25 fractions, BED = 78.13 Gy: 13 patients) were recruited. Fifty-seven patients who received conventional radiotherapy (60 Gy/30 fractions, BED = 72.00 Gy) during the same period were enrolled as the control group. All hypo-RT treatments were conducted using image-guided technology. The efficacy and toxicity of the treatment were compared between the two groups. Results The median duration of follow-up was 23.0 months (range: 4.0–82.0 months). Univariate and multivariate analyses of all 143 stage III NSCLC patients revealed that hypo-RT was an independent factor for progression-free survival (PFS) and overall survival (OS). The median PFS and OS of hypo-RT were significantly higher than in the conventional RT group (PFS: 14.30, 11.00 months, p=0.035; OS: 43.30, 31.50 months, p=0.045). The incidence rates of symptomatic radiation pneumonitis and radiation esophagitis (≥grade 2) were 17.77% and 27.91%, respectively, in the hypo-RT group. Compared to the conventional radiation therapy group (22.81% and 19.30%, respectively), no significant differences were found between the two common side effects (p=0.662 and p=0.241, respectively). Conclusion For Chinese stage III NSCLC patients, image-guided hypo-RT offers favorable prognosis, and the treatment toxicity was totally acceptable. This radiation modality deserves further prospective clinical trials.

Background: Try to re-optimize the results of pinnacle Auto-planning (AP) and explore the feasibility of obtaining more dosiologically advantageous AP plans by reducing "experience-based optimization parameters". Methods: 35 rectal cancer cases with preoperative radiotherapy were selected and all plans are designed retrospectively with Pinnacle9.1 AP. Firstly we take the doctor's clinical prescription as a universal optimization parameters, get the first reference group CP; secondly we set the results of manual plans (MP) which were already used for clinical treatments as the optimization parameters, replacing the physicist's initial experience, get the second reference group IE; at last we reduce the results of MP by 15% as the optimization parameters , get the control group T. By keeping the other optimization conditions unchanged, we designed AP plans for all three groups. Wilcoxon rank sum tests were performed for CP-T and IE-T based on the dosiological parameters of the planning target volume(PTV) and organs at risk(OARs). Results: Dose distribution of all three groups was in a clinically acceptable range. The dose of OARs in T group was significantly lower than CP and IE,the differences were statistically significant. Conclusion: Experience-based AP plan has a space for re-optimization, and appropriately reducing the results of MP as optimization parameters is a simple and feasible way.

Abstract Ovarian cancer patients with homologous recombination deficiency (HRD) tumors would benefit from PARP inhibitor (PARPi) therapy. However, patients with HRD tumors account for less than 50% of the whole cohort, so new biomarkers still need to be developed. Based on the data from the SNP array and somatic mutation profiles in the ovarian cancer genome, we found that high frequency of actionable mutations existed in patients with non‐HRD tumors. Through transcriptome analysis, we identified that a downstream target of the cGAS‐STING pathway, CXCL11, was upregulated in HRD tumors and could be used as a predictor of survival outcome. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL11 expression signature was closely correlated with cytotoxic cells, neoantigen load and immune checkpoint blockade (ICB). Clinical trial data confirmed that the expression of CXCL11 could be used as a biomarker for anti‐PD‐1/PD‐L1 therapy. Finally, in vivo and in vitro experiments showed that cancer cells with PARPi treatment increased the expression of CXCL11. Collectively, our study not only provides biomarkers of ovarian cancer complementary to the HRD score but also introduces a potential new perspective for identifying prognostic biomarkers of immunotherapy.

Background: Ovarian cancer patients with tumors positive for homologous recombination deficiency (HRD) would benefit from PAPR inhibitor (PAPRi)therapy. However, patients with HRD-positive tumors account for less than 50% of the whole cohort. So new biomarkers still need to be developed. The aim of this study was to identify biomarkers complementary to HRD for improving the clinical outcome of ovarian serous cystadenocarcinoma (OSC). Methods: The HRD score was established from SNP array data of OSC cohort from TCGA. The genomic landscape and transcriptome data of patients with different HRD scores were analyzed in order to identify biomarkers complementary to HRD. The candidate biomarker was validated in vivo and in vitro experiments. Results: Based on the data from the SNP array and somatic mutation profiles in the OSC patients’ genome, we found that high frequency of actionable mutations existed in NF1 and CDK12 in patients with HRD-negative tumors. We then leveraged the gene expression profiles to screen out CXCL11 expression that was associated with the HRD score and could be used as a predictor of survival outcome. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL11 expression was closely correlated with cytotoxic cells, neoantigen load and immune checkpoint blockade (ICB). Finally, in vivo and in vitro experiments showed that PAPRi increased the expression of CXCL11 . Conclusions: Collectively, our study not only provides biomarkers of ovarian cancer complementary to the HRD score but also introduced a potential new perspective for identifying cancer biomarkers associated with genomic instability.

AIMS:The aim of this study is to investigate patients with unresectable Stage III non-small-cell lung cancer (NSCLC) receiving radiotherapy with induction and concurrent pemetrexed or docetaxel plus cisplatin (PP/DP) chemotherapy and to identify the subgroup most likely to benefit from induction chemotherapy (IC).SUBJECTS AND METHODS:Patients with unresectable measurable Stage III NSCLC received two cycles of PP/DP IC followed by concurrent chemoradiotherapy at a dose of 60-66 Gy.STATISTICAL ANALYSIS USED:Cox regression analysis was performed to evaluate the prognostic factors for survival; logistic regression analysis was used to evaluate the predictors for response to IC, and the receiver operating characteristic curves were used to evaluate the independent factors predicting response.RESULTS:Eighty patients were included; the median survival time (MST) was 22.1 months. Partial response (PR) to IC was an independent prognostic factor for overall survival. For patients in the PR and stable disease groups, the MST was 36.7 and 19.5 months, respectively. The independent predictors of PR to IC included classification as stage N3 cancer, baseline carcinoembryonic antigen (CEA) levels >10 ng/ml, and cytokeratin fragment 19 (CYFRA21-1) levels >6 ng/ml. With each additional independent predictor, the likelihood of having have PR to IC increased.CONCLUSIONS:Radiotherapy with induction and concurrent PP/DP chemotherapy is feasible for patients with unresectable Stage III NSCLC. IC may improve the survival of IC responders, as predicted by elevated CEA and CYFRA21-1 levels and classification as stage N3 cancer. Additional randomized trials on IC may consider these predictors to tailor individualized treatments.

BACKGROUND:Tight control of endosome trafficking is essential for the generation of a normally patterned embryo. Recent studies have found that VPS50 is a key ingredient in EARP which is required for recycling of internalized TfRs to the cell surface and dense-core vesicle maturation. However, the role of VPS50 in embryogenesis and human physiology are poorly understood.RESULTS:We identified a rare missense heterozygous VPS50 mutation (p. Gly169Val) in NTDs by high-throughput sequencing. In vitro functional analysis demonstrated that the p. Gly169Val was a loss-of-function mutation, delaying transferrin recycling and altering its interaction with VPS53. Using WISH during zebrafish embryogenesis, we demonstrated that vps50 gene was expressed throughout the early embryo, especially in the head. Abnormal body axis phenotypes were observed in those vps50 knock-down zebrafishes. Further rescue study in zebrafish suggested that the mutation displayed loss-of-function effects comparing with wild-type VPS50.CONCLUSIONS:These findings thus demonstrated that the functional mutations in VPS50 might contribute to neurodevelopmental disorder and highlighted the critical importance of VPS50 function in cellular and organismal physiology.

Background: For patients with locally advanced gastric cancer (LAGC) after D2 gastrectomy, the survival benefits of receiving adjuvant chemoradiotherapy versus adjuvant chemotherapy are unclear. This study aimed to compare the 5- and 7-year overall survival (OS) in the two groups and to identify which patients can benefit more from adjuvant chemoradiotherapy. Methods: Retrospective data were collected from January 2009 to December 2014. The 5- and 7-year OS and disease-free survival (DFS) were compared between the two groups using the Chi-square test. The association of OS with prognostic factors was identified using the Cox's proportional hazard model, which was then adjusted for survival coparison using propensity score-matching (PSM) analysis. The association of OS with each clinical/demographic factor was compared between the two groups using the Kaplan-Meier analysis. Results: A total of 415 eligible patients were identified (135 adjuvant chemoradiotherapy, 280 adjuvant chemotherapy). Significant 5- and 7-year OS and DFS benefits were found in the adjuvant chemoradiotherapy group versus chemotherapy group. Multivariate analysis showed that age, TNM stage, lymph node (LN) ratio, tumor deposits, and total/subtotal gastrectomy were independent prognostic factors. When the PSM analysis was adjusting by these factors, 135 patients were matched with an improved survival benefit from adjuvant chemoradiotherapy. Patients in the adjuvant chemoradiotherapy group had a lower locoregional relapse. Subset analysis also identified significant OS benefits of adjuvant chemoradiotherapy in patients with LN ratio <50%, pIIIA, and pIIIB stage disease, while OS benefits were not observed in patients with tumor deposits, pN3b classification, or pIIIC stage disease. Conclusion: Adjuvant chemoradiotherapy was shown to be superior in improving the OS in a certain population of patients compared with adjuvant chemotherapy. This finding may help to better guide the individualized treatments of patients with stage III LAGC after D2 gastrectomy.

BACKGROUND AND PURPOSE:This study was aimed to identify the clinical and dosimetric parameters that predict symptomatic radiation pneumonitis (SRP, radiation pneumonitis≥2 grade) in patients with pulmonary metastasis from hepatocellular carcinoma (HCC) after helical tomotherapy (HT) hypofractionated simultaneous multitarget radiotherapy. MATERIALS AND METHODS:62 patients with 407 pulmonary metastases from HCC were consecutively treated with HT. The median radiation dose was a 49.7Gy in 4.0Gy/fraction to 95% of the planning target volume (PTV). The associations between the clinical and dosimetric data and incidences of SRP were analyzed. The dose-pneumonitis relationship was analyzed based on Biologically Effective Dose (BED). RESULTS:Univariate analysis showed that the gross tumor volume (GTV), PTV, median lung dose (MLD), the number of pulmonary metastatic lesions (NPML), and the percentage of non-target normal lung (NTNL) volume receiving more than a BED of 3-50Gy (VBED3-50) were associated with SRP. Multivariate logistic regression analysis showed that VBED20 and NPML were significant parameters (both P<0.001) CONCLUSIONS: Our findings indicated that SRP can be predicted with NPML>5 and VBED20≥30.4% with the α/β ratio of 3Gy.

AbstractPurposeTo build a knowledge‐based model of liver cancer for Auto‐Planning, a function in Pinnacle, which is used as an automated inverse intensity modulated radiation therapy (IMRT) planning system.Methods and MaterialsFifty Tomotherapy patients were enrolled to extract the dose–volume histograms (DVHs) information and construct the protocol for Auto‐Planning model. Twenty more patients were chosen additionally to test the model. Manual planning and automatic planning were performed blindly for all twenty test patients with the same machine and treatment planning system. The dose distributions of target and organs at risks (OARs), along with the working time for planning, were evaluated.ResultsStatistically significant results showed that automated plans performed better in target conformity index (CI) while mean target dose was 0.5 Gy higher than manual plans. The differences between target homogeneity indexes (HI) of the two methods were not statistically significant. Additionally, the doses of normal liver, left kidney, and small bowel were significantly reduced with automated plan. Particularly, mean dose and V15 of normal liver were 1.4 Gy and 40.5 cc lower with automated plans respectively. Mean doses of left kidney and small bowel were reduced with automated plans by 1.2 Gy and 2.1 Gy respectively. In contrast, working time was also significantly reduced with automated planning.ConclusionsAuto‐Planning shows availability and effectiveness in our knowledge‐based model for liver cancer.