Palbociclib is an excellent CDK4/6 inhibitor, but its clinical application is mainly limited to the treatment of advanced ER+/HR+ and HER2- breast cancer. Its efficacy in colorectal cancer (CRC) is evaluated in multiple trials and so far remains undetermined. We found that the PIK3CA-mutant CRC cells were insensitive to palbociclib treatment compared with the PIK3CA wild-type counterparts, and they were in an OIS (oncogene-induced senescence) state which was predisposed to a strong senescence-associated secretory phenotype (SASP) upon treatment. These senescent cells excessively secreted various SASP factors LCN2, and ultimately caused palbociclib-resistance via upregulation of EGFR in the non-senescent CRC cells. Importantly, a drug combination screen identified that erlotinib could synergize with palbociclib to overcome the SASP-induced resistance. Overall, we found that PIK3CA mutation-induced senescence compromised the efficacy of palbociclib treatment in CRC but co-targeting EGFR could minimize the OIS-associated side effects while preserving the beneficial effects. ### Competing Interest Statement The authors have declared no competing interest.

Aim: To investigate radiotherapy efficacy and prognostic factors in patients with hepatocellular carcinoma (HCC) with cardiophrenic angle or superior diaphragmatic lymph node metastasis (LNM). Methods: We retrospectively analyzed 72 patients with HCC presenting with cardiophrenic angle or superior diaphragmatic LNM at Zhongshan Hospital of Fudan University from 2010 to 2023. Response rates, survival rates, local control rates, prognostic risk factors, and side effects of external beam radiation therapy (EBRT) were compared between patients with EBRT (EBRT group) and those without EBRT (non-EBRT group). Results: The overall response rates in the EBRT group and the non-EBRT group were 68.8% (22/32) and 7.5% (3/40), while median survival was 16.1 (95%CI: 8.09-24.12) and 5.9 months (95%CI: 3.05-7.76) respectively (HR = 2.87, P < 0.001). The survival was significantly prolonged with a daily dose > 4 Gy (P = 0.014). EBRT (P < 0.001) was identified as a factor correlated with the local control rate. Multivariate analysis revealed that tumor thrombosis, multiple intrahepatic tumors, a maximal intrahepatic tumor diameter ≥ 5 cm, abdominal LNM, and lack of EBRT were poor prognostic factors. Gastrointestinal (GI) bleeding in patients with bioequivalent dose 10 (BED10) ≤ 70 and > 70 were 0% (0/22) and 30.0% (3/10), respectively (P = 0.024). Conclusion: EBRT was a safe and effective treatment for HCC patients with cardiophrenic angle or superior diaphragmatic LNM and might prolong overall survival. Dose > 4 Gy per day and BED10 ≤ 70 would be recommended for LNM. Patients with tumor thrombosis, multiple intrahepatic tumors, a maximal intrahepatic tumor diameter ≥ 5 cm, abdominal LNM, and lack of EBRT had a poor prognosis.

PURPOSE:To investigate the feasibility of constructing new geometric parameters that correlate well with dosimetric parameters.METHODS:100 rectal cancer patients were enrolled. The targets were identified manually, while the organs at risk (bladder, small bowel, left and right femoral heads) were segmented both manually and automatically. The radiotherapy plans were optimized according to the automatically contoured organs at risk. Forty cases were randomly selected to establish the relationship between dose and distance for each organ at risk, termed "dose-distance curves," which were then applied to the new geometric parameters. The correlation between these new geometric parameters and dosimetric parameters was analyzed in the remaining 60 test cases.RESULTS:The "dose-distance curves" were similar across the four organs at risk, exhibiting an inverse function shape with a rapid decrease initially and a slower rate at a later stage. The Pearson correlation coefficients of new geometric parameters and dosimetric parameters in the bladder, small intestine, and left and right femur heads were 0.96, 0.97, 0.88, and 0.70, respectively.CONCLUSIONS:The new geometric parameters predicated on "distance from the target" showed a high correlation with corresponding dosimetric parameters in rectal cancer cases. It is feasible to utilize the new geometric parameters to evaluate the dose deviation attributable to automatic segmentation.

Background: To screen and confirm microRNAs(miRs) relating to TLR4-dependent immune, which may promote radiation-induced liver diseases (RILDs) by changing cytokines in liver microenvironments.Methods: Eighteen HCC patients, underwent surgical resection post-RT, were enrolled in this study. MiRs (has- let-7e, miR-9, miR-21, miR-34a, miR-122, miR-125, miR-146a, miR-155, and miR-200) were detected by qRT-PCR. MiR-146a was screened to inhibit TLR4-dependent immune and RILDs. Furthermore, Hepatic cells (HL-7702), cocultured with/without hepatic stellate cells (HSCs) (LX-2), were irradiated with 6 Gy. And, LX2 cells were overexpressed miR-146a-5p or not to evaluate that whether overexpressing miR-146a in LX-2 cells could reduce RILDs. Flow cytometry and AO/EB methods were used to detect mortality of HL-7702 cells 48h-post-RT. Expression levels of α-SMA/TLR4/miR-146a in LX2 cells and cytokines in cell supernatants were also detected.Results: Among the miRNAs, miR-146a and miR-200 were significantly related to TLR4 expression level in liver tissues (P=0.043 and 0.014). But, only miR-146a up-regulation was significantly correlated mild RILDs (P=0.025). In vitro, irradiation could significantly inhibit the expression level of miR-146a, but up-regulate that of TLR4 and α-SMA in LX-2 (P=0.016 and 0.0003), and up-regulate IL-1β, IL6, IL-8 and IL-12 expression in cell supernatants (P=0.002, 0.012, 0.018 and 0.049, respectively). The mortality proportion of HL-7702 cells co-cultured with LX-2 significantly increased than HL-7702 cells cultured alone 48h post-RT(P=0.003), but significantly decreased post-RT when HL-7702 cells co-cultured with LX-2 overexpressed miR-146a-5p and significantly down-regulated TLR4 expression.Conclusions: miR-146a was screened and confirmed to inhibit TLR4 dependent immune of HSCs and release RILDs.

The effect of αCD47-G1 or αCD47-G4 on the expression of NK cell markers.

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.

All supplementary data: supplementary figures s1-s13 and table s1

OV-αmCD47-G2b is efficacious to treat ovarian cancer in an ID8 immunocompetent metastasis mouse model.

Supplementary Tables S1-S2 and Supplementary Figures S1-S5

Supplementary methods, tables and figures.

Schematic map of OV-αCD47 used in this study.

OV treatments increase NK cell and T cell infiltration in the ID8-hCD47 immunocompetent ovarian cancer metastasis mouse model.

Interventional therapy is very important in current clinical applications. However, the lack of quantifiable embolic agents to affect the therapeutic effects negatively. In the present study, we sought to prepare a novel embolic agent, 99mTc-Konjac glucoman/Poly(lactide-co-glycolide)@Polyethyleneimine@Diethylenetriaminepentaacetic acid (KGM/PLGA@PEI@DTPA)microspheres, which can be located and quantified noninvasively to further evaluate its biological effects in animal models. The KGM/PLGA microspheres were prepared with water/oil/water double emulsion-solvent evaporation. Subsequently, the surface modification was performed with PEI and DTPA as a bifunctional chelator to label the microspheres with 99mTc. The in vitro stability of 99mTc-KGM/PLGA@PEI@DTPA was determined through instant thin layer chromatography, and the in vitro cytotoxicity of KGM/PLGA@-PEI@DTPA was evaluated with CCK-8 assays. The location and quantitative calculation of 99mTc-KGM/PLGA@-PEI@DTPA in vivo were evaluated in rabbits through SPECT/CT, and the in vivo toxicity was assayed in rabbits.The microspheres showed no toxicity in vitro and in vivo, andthe diameter of microsphere was about 82.5 +/- 14.5 mu m (range 60-120 mu m). The 99mTc-KGM/PLGA@PEI@DTPA was stable in phosphate-buffered saline and 50% fetal bovine serum within 6 h. The Single-photon emission computed tomography/computed tomography(SPECT/CT) imaging and biodistribution results showed that microspheres were mainly distributed in the liver, kidney, and bladder, and excreted through the urinary system. And the dose of microspheres embolizing in the liver was approximately 2.54 mg, 50.79% of the total injection, an estimate calculated according to the gamma ray emission from 99mTc in SPECT/CT.Hence, the 99mTc-KGM/PLGA@PEI@DTPA may be as a quantitative embolic agent and provide potential clinical value for interventional therapy.

OV-αCD47-G1 improves the therapeutic efficacy against ovarian cancer in a xenograft model.

The effect of αCD47-G1 on the expression of the genes markering macrophage polarization in vitro.

Supplementary data Fig.1 Study design Supplementary data Fig.2 Flow chart of patient receiving FDG-PET and FLT-PET

Estrogen receptor (ER) is overexpressed in approximately 2/3 of breast cancer patients’ lesions. Noninvasive detection of ER in vivo and dynamic monitoring of ER are crucial for individualized treatment decision-making. 16α-18F-17β-fluoroestradiol (18F-FES) positron emission tomography (PET) has been used in a variety of preclinical and clinical studies to detect ER expression. However, there is still a lack of technical specifications in China. This technical specification was jointly written by domestic experts who had experience of 18F-FES PET imaging and was formed through consultation based on their own experience and research progress in this field both domestically and internationally. This technical specification introduced the synthesis method and quality control requirements of 18F-FES, recommended its clinical application scenarios, and classified them. In addition, experts’ suggestions were provided throughout the entire process systemically and detailly, including pre-imaging preparation, imaging process, image analysis (normal biological distribution, determination of ER positive and negative, lesion detection, influencing factors, false negative and false positive, report requirements), and the limitations of this imaging technique were proposed. The future application prospects were also discussed. This specification aimed to promote the standardized application of 18F-FES PET in China, achieve repeatability and comparability, and provide important molecular imaging technical support for accurate diagnosis and treatment of breast cancer.

OV-αCD47-G1 treatments promote macrophage M1 polarization and NK cell activation in ID8-hCD47 immunocompetent ovarian cancer metastasis mouse model.

Purpose of the Report: Accurate clinical axillary evaluation plays an important role in the diagnosis and treatment planning for early-stage breast cancer (BC). This study aimed to develop a scalable, non-invasive and robust machine learning model for predicting of the pathological node status using dedicated-PET integrating the clinical characteristics in early-stage BC. Materials and Methods: A total of 420 BC patients confirmed by postoperative pathology were retrospectively analyzed. 18F-fluorodeoxyglucose (18F-FDG) Mammi-PET, ultrasound, physical examination, Lymph-PET, and clinical characteristics were analyzed. The least absolute shrinkage and selection operator (LASSO) regression analysis were used in developing prediction models. The characteristic curve (ROC) of the area under receiver-operator (AUC) and DeLong test were used to evaluate and compare the performance of the models. The clinical utility of the models was determined via decision curve analysis (DCA). Then, a nomogram was developed based on the model with the best predictive efficiency and clinical utility and was validated using the calibration plots. Results: A total of 290 patients were enrolled in this study. The AUC of the integrated model diagnosed performance was 0.94 (95% confidence interval (CI), 0.91–0.97) in the training set (n = 203) and 0.93 (95% CI, 0.88–0.99) in the validation set (n = 87) (both p < 0.05). In clinical N0 subgroup, the negative predictive value reached 96.88%, and in clinical N1 subgroup, the positive predictive value reached 92.73%. Conclusions: The use of a machine learning integrated model can greatly improve the true positive and true negative rate of identifying clinical axillary lymph node status in early-stage BC.

OBJECTIVE:To design a series of geometric indexes, which can improve the correlation between geometric parameters and dosimetric parameters.METHODS:48 cases of upper abdomen were selected. Manual and automatic segmentation were performed for two organs at risk, which were stomach and duodenum. Three overlapping structures, which were the overlaps with target expanded by 5 mm, 10 mm and 20 mm, were generated for each organ at risk. The geometric parameters of overlapping structures were calculated. The relationship between these geometric parameters and the dosimetric parameters of organs was investigated.RESULTS:When the geometric parameters of overlapping structures related to the target expand 5 mm, 10 mm and 20 mm were larger than 0.4, 0.6 and 0.8 respectively, the maximum dose differences of manual and automatic segmentation were less than 3 Gy. For the case with no overlaps between the organs and the target expansions, the overlap structure corresponding to target expanding 20 mm were recommended for safety considerations.CONCLUSIONS:For organs at risk in the upper abdomen, the overlapping geometric parameters were closely related to the maximum dose of organs. Overlapping geometric parameters could predict whether the difference of maximum dose caused by automaticsegmentation was clinically acceptable or not.