Effect of miR-1297 on Kidney Injury in Rats with Diabetic Nephropathy through the PTEN/PI3K/AKT Pathway.

PURPOSE: This study aimed to determine the influence of miR-1297 on kidney injury in rats with diabetic nephropathy (DN) and its causal role. METHODS: A DN rat model was established through right kidney resection and intraperitoneal injection of streptozotocin (STZ). Sham rats did not undergo right kidney resection or STZ injection. The DN rats were divided into the DN model and antagomiR-1297 treatment groups. Kidney morphology was observed using hematoxylin and eosin staining. Renal function indices, including blood urea nitrogen (BUN), serum creatinine (SCr), and urinary protein, were measured using kits. Levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined through enzyme-linked immunosorbent assay (ELISA). Fibrin (FN), collagen type I (Col I), and α-smooth muscle actin (α-SMA) were assessed through western blotting and real-time reverse transcription-polymerase chain reaction. Apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. miR-1297 targets were predicted using bioinformatic software and verified through luciferase reporter assay. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway expression was analyzed through western blotting. RESULTS: AntagomiR-1297 reduced BUN (p = 0.005), SCr (p = 0.012), and urine protein (p < 0.001) levels and improved kidney tissue morphology. It prevented renal interstitial fibrosis by decreasing FN, Col I, and α-SMA protein levels (all p < 0.001). AntagomiR-1297 increased SOD (p = 0.001) and GSH-Px (p = 0.002) levels. Additionally, it reduced levels of cell inflammatory factors, including TNF-α, IL-6, and IL-1ß (all p < 0.001), and alleviated apoptosis (p < 0.001) in rat kidney tissue with DN. miR-1297 was pinpointed as a target for PTEN. AntagomiR-1297 increased PTEN expression and suppressed PI3K and AKT phosphorylation (all p < 0.001). CONCLUSIONS: AntagomiR-1297 can mitigate renal fibrosis, renal inflammation, apoptosis, and oxidative stress levels through the PTEN/PI3K/AKT pathway.

Anatomical changes and dosimetric analysis of the neck region based on FBCT for nasopharyngeal carcinoma patients during radiotherapy.

BACKGROUND: The study aimed to investigate anatomical changes in the neck region and evaluate their impact on dose distribution in patients with nasopharyngeal carcinoma (NPC) undergoing intensity modulated radiation therapy (IMRT). Additionally, the study sought to determine the optimal time for replanning during the course of treatment. METHODS: Twenty patients diagnosed with NPC underwent IMRT, with weekly pretreatment kV fan beam computed tomography (FBCT) scans in the treatment room. Metastasized lymph nodes in the neck region and organs at risk (OARs) were redelineation using the images from the FBCT scans. Subsequently, the original treatment plan (PLAN0) was replicated to each FBCT scan to generate new plans labeled as PLAN 1-6. The dose-volume histograms (DVH) of the new plans and the original plan were compared. One-way repeated measure ANOVA was utilized to establish threshold(s) at various time points. The presence of such threshold(s) would signify significant change(s), suggesting the need for replanning. RESULTS: Progressive volume reductions were observed over time in the neck region, the gross target volume for metastatic lymph nodes (GTVnd), as well as the submandibular glands and parotids. Compared to PLAN0, the mean dose (Dmean) of GTVnd-L significantly increased in PLAN5, while the minimum dose covering 95% of the volume (D95%) of PGTVnd-L showed a significant decrease from PLAN3 to PLAN6. Similarly, the Dmean of GTVnd-R significantly increased from PLAN4 to PLAN6, whereas the D95% of PGTVnd-R exhibited a significant decrease during the same period. Furthermore, the dose of bilateral parotid glands, bilateral submandibular glands, brainstem and spinal cord was gradually increased in the middle and late period of treatment. CONCLUSION: Significant anatomical and dosimetric changes were noted in both the target volumes and OARs. Considering the thresholds identified, it is imperative to undertake replanning at approximately 20 fractions. This measure ensures the delivery of adequate doses to target volumes while mitigating the risk of overdosing on OARs.

Analysis of Individualized Silicone Rubber Bolus Using Fan Beam Computed Tomography in Postmastectomy Radiotherapy: A Dosimetric Evaluation and Skin Acute Radiation Dermatitis Survey.

Objective: To investigate the dosimetric effects of using individualized silicone rubber (SR) bolus on the target area and organs at risk (OARs) during postmastectomy radiotherapy (PMRT), as well as evaluate skin acute radiation dermatitis (ARD). Methods: A retrospective study was performed on 30 patients with breast cancer. Each patient was prepared with an individualized SR bolus of 3 mm thickness. Fan-beam computed tomography (FBCT) was performed at the first and second fractions, and then once a week for a total of 5 times. Dosimetric metrics such as homogeneity index (HI), conformity index (CI), skin dose (SD), and OARs including the heart, lungs, and spinal cord were compared between the original plan and the FBCTs. The acute side effects were recorded. Results: In targets' dosimetric metrics, there were no significant differences in Dmean and V105% between planning computed tomography (CT) and actual treatments (P > .05), while the differences in D95%, V95%, HI, and CI were statistically significant (P < .05). In OARs, there were no significant differences between the Dmean, V5, and V20 of the affected lung, V5 of the heart and Dmax of the spinal cord (P > .05) except the V30 of affected lung, which was slightly lower than the planning CT (P < .05). In SD, both Dmax and Dmean in actual treatments were increased than plan A, and the difference was statistically significant (P < .05), while the skin-V20 and skin-V30 has no difference. Among the 30 patients, only one patient had no skin ARD, and 5 patients developed ARD of grade 2, while the remaining 24 patients were grade 1. Conclusion: The OR bolus showed good anastomoses and high interfraction reproducibility with the chest wall, and did not cause deformation during irradiation. It ensured accurate dose delivery of the target and OARs during the treatment, which may increase SD by over 101%. In this study, no cases of grade 3 skin ARD were observed. However, the potential of using OR bolus to reduce grade 1 and 2 skin ARD warrants further investigation with a larger sample size.

Surface guided radiation therapy with an innovative open-face mask and mouth bite: patient motion management in brain stereotactic radiotherapy.

INTRODUCTION: To guarantee treatment reproducibility and stability, immobilization devices are essential. Additionally, surface-guided radiation therapy (SGRT) serves as an accurate complement to frameless stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) by aiding patient positioning and real-time monitoring, especially when non-coplanar fields are in use. At our institute, we have developed a surface-guided SRS (SG-SRS) workflow that incorporates our innovative open-face mask (OM) and mouth bite (MB) to guarantee a precise and accurate dose delivery. METHODS: This study included 40 patients, and all patients were divided into closed mask (CM) and open-face mask (OM) groups according to different positioning flow. Cone beam computed tomography (CBCT) scans were performed, and the registration results were recorded before and after the treatment. Then Bland-Altman method was used to analyze the consistency of AlignRT-guided positioning errors and CBCT scanning results in the OM group. The error changes between 31 fractions in one patient were recorded to evaluate the feasibility of monitoring during treatment. RESULTS: The median of translation error between stages of the AlignRT positioning process was (0.03-0.07) cm, and the median of rotation error was (0.20-0.40)°, which were significantly better than those of the Fraxion positioning process (0.09-0.11) cm and (0.60-0.75)°. The mean bias values between the AlignRT guided positioning errors and CBCT were 0.01 cm, - 0.07 cm, 0.03 cm, - 0.30°, - 0.08° and 0.00°. The 31 inter-fractional errors of a single patient monitored by SGRT were within 0.10 cm and 0.50°. CONCLUSIONS: The application of the SGRT with an innovative open-face mask and mouth bite device could achieve precision positioning accuracy and stability, and the accuracy of the AlignRT system exhibits excellent constancy with the CBCT gold standard. The non-coplanar radiation field monitoring can provide reliable support for motion management in fractional treatment.

A pilot trial of consolidation bevacizumab after hypo-fractionated concurrent chemoradiotherapy in patients with unresectable locally advanced non-squamous non-small-cell lung cancer.

PURPOSE: To determine the feasibility of incorporating bevacizumab consolidation into hypo-fractionated concurrent chemoradiotherapy (hypo-CCRT) for patients with unresectable locally advanced non-squamous non-small-cell lung cancer (LA-NS-NSCLC). PATIENTS AND METHODS: Eligible patients were treated with hypo-RT (40Gy in 10 fractions) followed by hypo-boost (24-28Gy in 6-7 fractions), along with concurrent weekly chemotherapy. Patients who completed the hypo-CCRT without experiencing ≥G2 toxicities received consolidation bevacizumab every 3 weeks for up to 1 year, until disease progression or unacceptable treatment-related toxicities. The primary endpoint was the risk of G4 or higher hemorrhage. Secondary endpoints included progression-free survival (PFS), overall survival (OS), locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), and objective response rate (ORR). All time-to-event endpoints (OS, PFS, LRFS, and DMFS) were measured from the start of radiotherapy. RESULTS: Between December 2017 and July 2020, a total of 27 patients were included in the analysis, with a median follow-up duration of 28.0 months. One patient (3.7%) developed G5 hemorrhage during bevacizumab consolidation. Additionally, seven patients (25.9%) had G3 cough and three patients (11.1%) experienced G3 pneumonitis. The ORR for the entire cohort was 92.6%. The median OS was 37.0 months (95% confidence interval, 8.9-65.1 months), the median PFS was 16.0 months (95% confidence interval, 14.0-18.0 months), the median LRFS was not reached, and the median DMFS was 18.0 months. CONCLUSIONS: This pilot study met its goal of demonstrating the tolerability of consolidation bevacizumab after hypo-CCRT. Further investigation of antiangiogenic and immunotherapy combinations in LA-NSCLC is warranted, while the potential for grade 3 respiratory toxicities should be taken into consideration.

Mitophagy: A potential therapeutic target for insulin resistance.

Glucose and lipid metabolism disorders caused by insulin resistance (IR) can lead to metabolic disorders such as diabetes, obesity, and the metabolic syndrome. Early and targeted intervention of IR is beneficial for the treatment of various metabolic disorders. Although significant progress has been made in the development of IR drug therapies, the state of the condition has not improved significantly. There is a critical need to identify novel therapeutic targets. Mitophagy is a type of selective autophagy quality control system that is activated to clear damaged and dysfunctional mitochondria. Mitophagy is highly regulated by various signaling pathways, such as the AMPK/mTOR pathway which is involved in the initiation of mitophagy, and the PINK1/Parkin, BNIP3/Nix, and FUNDC1 pathways, which are involved in mitophagosome formation. Mitophagy is involved in numerous human diseases such as neurological disorders, cardiovascular diseases, cancer, and aging. However, recently, there has been an increasing interest in the role of mitophagy in metabolic disorders. There is emerging evidence that normal mitophagy can improve IR. Unfortunately, few studies have investigated the relationship between mitophagy and IR. Therefore, we set out to review the role of mitophagy in IR and explore whether mitophagy may be a potential new target for IR therapy. We hope that this effort serves to stimulate further research in this area.

Concurrent Chemoradiation Therapy With or Without Nimotuzumab in Locally Advanced Squamous Cell Lung Cancer: A Phase 2 Randomized Trial.

PURPOSE: The study aimed to evaluate the efficacy and safety of concurrent chemoradiation therapy (CCRT) combined with nimotuzumab in patients with unresectable stage III squamous cell lung cancer (SqCLC). METHODS AND MATERIALS: A prospective, single-center, open-label, randomized phase 2 trial was performed in patients with unresectable stage III SqCLC. Patients were randomized to receive 65 Gy thoracic radiation over 5 weeks concurrent with docetaxel and cisplatin or the same CCRT regimen combined with 200 mg of nimotuzumab (NIMO-CCRT), administered weekly by intravenous infusion. The primary endpoint was overall survival. The secondary endpoints were progression-free survival, objective response rate, failure patterns, and treatment-related toxicity. RESULTS: From August 2015 to June 2020, 126 patients with SqCLC were randomized. Four patients withdrew consent before the start of treatment, and 122 patients were included for analysis, including 57 in the NIMO-CCRT group and 65 in the CCRT group. The median OS was 24.9 months in the NIMO-CCRT group and 23.5 months in the CCRT group (P = .655). The median PFS was 12.1 months in the NIMO-CCRT group and 13.7 months in the CCRT group (P = .968). The NIMO-CCRT group had a significantly lower risk of brain metastasis, with adjusted subdistribution hazard ratio of 0.099 (95% confidence interval, 0.012-0.81; P = .031). The incidence of grade ≥3 pneumonitis (P = .894) and esophagitis (P = .974) was similar between the 2 arms. There was no grade 2 or higher skin toxicity in NIMO-CCRT group. CONCLUSIONS: The coincident application of nimotuzumab with CCRT was well tolerated for locally advanced SCCL. The NIMO-CCRT group had an OS and PFS similar to that in the CCRT group, but a lower risk of brain metastasis. Further investigations are warranted.

Hypo-fractionated radiotherapy with concurrent chemotherapy for locoregional recurrence of non-small cell lung cancer after complete resection: A prospective, single-arm, phase II study (GASTO-1017).

OBJECTIVES: To explore the efficacy and toxicities of split-course hypo-fractionated radiotherapy with concurrent chemotherapy (HFRT-CHT) with intensity modulated radiotherapy (IMRT) technique in non-small cell lung cancer (NSCLC) patients with postoperative locoregional recurrence (LRR). MATERIALS AND METHODS: NSCLC patients were eligible if confirmed as LRR disease without distant metastasis after complete resection. HFRT-CHT using IMRT technique was administered with 51 Gy in 17 fractions or 40 Gy in 10 fractions as the first course followed by a break. Patients with no disease progression and no persistent Grade ≥2 toxicities had the second course of 15 Gy in 5 fractions or 28 Gy in 7 fractions as a boost. The primary endpoint was progression-free survival (PFS). RESULTS: Fifty-eight patients were enrolled and analyzed. With a median follow-up of 23.9 months for all, the 2-year and 3-year PFS rate was 59.7 % and 46.4 %, the 2-year and 3-year OS rate was 72.5 % and 52.2 %, respectively, and a favorable objective response rate of 95.9 % was obtained after the whole courses protocol. Grade 3 acute pneumonitis and esophagitis occurred in 2 (3.4 %) and 7 (12.1 %) patients, and fatal pneumonitis was reported in one case (1.7 %). Exploratory subgroup analysis showed that performance status (PS) (PS 0 vs. 1: 2-year PFS, 88.1 % vs. 46.9 %,P = 0.001; 2-year OS, 100 % vs. 59.4 %, P < 0.001), recurrence site (single vs. multiple: 2-year PFS, 93.8 % vs. 47.4 %, P = 0.008; 2-year OS, 100 % vs. 63.0 %, P = 0.001), and gross tumor volume (GTV) (<50cm3 vs. ≥ 50cm3: 2-year PFS, 70.6 % vs. 46.2 %, P = 0.024; 2-year OS, 85.6 % vs. 57.4 %, P = 0.034) were significantly associated with PFS and OS. CONCLUSION: Split-course HFRT-CHT with IMRT technique achieved promising disease control and satisfactory survival with moderate toxicities in postoperative LRR of NSCLC. Good PS, a single recurrence site and GTV<50cm3 tended to have prolonged PFS and OS. Early detection of LRR may improve the efficacy of HFRT-CHT.

Moderately Hypofractionated Once-Daily Compared With Twice-Daily Thoracic Radiation Therapy Concurrently With Etoposide and Cisplatin in Limited-Stage Small Cell Lung Cancer: A Multicenter, Phase II, Randomized Trial.

PURPOSE: Chemotherapy and concurrent thoracic radiation therapy (CCTRT) followed by prophylactic cranial irradiation (PCI) is the standard of care for limited-stage small cell lung cancer (LS-SCLC). We aimed to compare the efficacy and toxicity of moderately hypofractionated once-daily CCTRT with that of a standard twice-daily regimen. METHODS AND MATERIALS: This multicenter, phase 2, randomized study enrolled patients aged 18 to 75 years old who had pathologically confirmed LS-SCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received 4 to 6 cycles of etoposide-cisplatin chemotherapy and were randomized to receive twice-daily CCTRT at 45 Gray (Gy) in 30 fractions or once-daily CCTRT at 65 Gy in 26 fractions, commencing with cycles 1 to 3 of chemotherapy. PCI was given to good responders. The primary endpoint was progression-free survival (PFS). RESULTS: The analyses included 182 patients, with 94 in the twice-daily group and 88 in the once-daily group. CCTRT started with cycle 3 of chemotherapy for most patients (80.2%). At a median follow-up of 24.3 months, the median PFS was 13.4 months (95% confidence interval [CI], 10.8-16.0) in the twice-daily group versus 17.2 months (95% CI, 11.8-22.6) in the once-daily group (P = .031), with 2-year PFS rates of 28.4% (95% CI, 18.2-38.6) and 42.3% (95% CI, 31.1-53.5), respectively. The estimated overall survival was 33.6 months in the twice-daily group versus 39.3 months in the once-daily group (P = .137). The median locoregional PFS was 23.9 months in the twice-daily group and was not reached in the once-daily group (P = .017). The incidences of most toxicities were similar in both groups, except for a higher incidence of ≥grade 3 acute lymphopenia in the once-daily group (71.7% vs 40.2% in the twice-daily group; P < .001). There was no difference in the incidences of ≥grade 3 esophagitis (17.4% vs 15.3%, respectively), pneumonitis (3.3% vs 2.4%, respectively) or treatment-related death (2.2% vs 1.2%, respectively) between the once-daily and twice-daily groups. CONCLUSIONS: Moderately hypofractionated, once-daily CCTRT showed improved PFS and similar toxicities compared with twice-daily CCTRT in LS-SCLC. This regimen should be evaluated for comparison in a phase 3 randomized trial.

Daphnetin Preconditioning Decreases Cardiac Injury and Susceptibility to Ventricular Arrhythmia following Ischaemia-Reperfusion through the TLR4/MyD88/NF-Κb Signalling Pathway.

BACKGROUND/AIMS: Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro. METHODS: Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique. RESULTS: DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R. CONCLUSIONS: DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway.

Survival Outcomes and Prognostic Analysis Following Greater Cytoreductive Radiotherapy in Patients With Metastatic Prostate Cancer.

Purpose: To assess the survival outcomes of patients with metastatic prostate cancer (mPCa) who undergo greater cytoreductive radiotherapy in a real-world clinical practice and determine their prognostic factors. Methods: We performed a retrospective study of 160 patients with mPCa who underwent cytoreductive radiotherapy between 2009 and 2018 at a single institution. The degree of the cytoreductive burden was calculated for each patient. Overall survival (OS) was calculated from the date of detection of metastases. Variables associated with prostate-specific antigen (PSA) response and OS were evaluated via univariate and multivariate analyses. Results: The median follow-up period was 47.2 months. The median OS was 42.3 months with a 5-year OS rate of 37.9%. The PSA levels of 90 patients (56.7%) decline by > 50% after radiotherapy. The 5-year OS rates of patients who underwent total, major, and minor cytoreductive radiotherapy were 53.4, 38.2, 17.6%, respectively; the corresponding median OS intervals were 62.5, 41.0, and 24.4 months, respectively (P < 0.001). A greater extent of cytoreduction (P < 0.05), lower PSA at radiotherapy initiation [hazard ratio 0.51, 95% confidence interval [CI] 0.33-0.78; P = 0.002] and better PSA response [hazard ratio 0.47, 95% CI 0.30-0.72; P < 0.001] were independent factors associated with superior OS. A high metastatic burden (as defined in the CHAARTED trial) was the only independent predictor of a poorer PSA response (odds ratio 0.36, 95% CI 0.19-0.69; P = 0.002). Grade 2 late gastrointestinal and genitourinary toxicities were observed in 3 and 2 patients, respectively, and only 1 patient had grade 3 late gastrointestinal toxicity. Conclusion: Cytoreductive radiotherapy is effective and safe in select patients with mPCa. Greater cytoreduction, together with lower PSA at radiotherapy initiation and improved PSA response are favorable prognostic factors. Further studies are needed to confirm our findings.

3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice.

Trimethylamine N-oxide (TMAO) is closely related to cardiovascular diseases, particularly heart failure (HF). Recent studies shows that 3,3-dimethyl-1-butanol (DMB) can reduce plasma TMAO levels. However, the role of DMB in overload-induced HF is not well understood. In this research study, we explored the effects and the underlying mechanisms of DMB in overload-induced HF. Aortic banding (AB) surgery was performed in C57BL6/J mice to induce HF, and a subset group of mice underwent a sham operation. After surgery, the mice were fed with a normal diet and given water supplemented with or without 1% DMB for 6 weeks. Cardiac function, plasma TMAO level, cardiac hypertrophy and fibrosis, expression of inflammatory, electrophysiological studies and signaling pathway were analyzed at the sixth week after AB surgery. DMB reduced TMAO levels in overload-induced HF mice. Adverse cardiac structural remodeling, such as cardiac hypertrophy, fibrosis and inflammation, was elevated in overload-induced HF mice. Susceptibility to ventricular arrhythmia also significantly increased in overload-induced HF mice. However, these changes were prevented by DMB treatment. DMB attenuated all of these changes by reducing plasma TMAO levels, hence negatively inhibiting the p65 NF-κB signaling pathway and TGF-ß1/Smad3 signaling pathway. DMB plays an important role in attenuating the development of cardiac structural remodeling and electrical remodeling in overload-induced HF mice. This may be attributed to the p65 NF-κB signaling pathway and TGF-ß1/Smad3 signaling pathway inhibition.

Survival Outcomes After Adding Stereotactic Body Radiotherapy to Metastatic Renal Cell Carcinoma Patients Treated With Tyrosine Kinase Inhibitors.

OBJECTIVE: Long-lasting control is rarely achieved with tyrosine kinase inhibitors (TKI) alone in metastatic renal cell carcinoma (mRCC). Our study aimed to investigate the survival outcomes of adding stereotactic body radiotherapy (SBRT) to TKI in mRCC. MATERIALS AND METHODS: From September 2015 to September 2018, 56 patients treated with TKI received SBRT for 103 unresectable lesions. A total of 24 and 32 patients were irradiated before and after TKI failure, respectively. Overall survival (OS) was calculated from metastases. Progression-free survival (PFS) was calculated from SBRT. RESULTS: Overall, 10, 32, and 12 patients had International Metastatic Renal Cell Carcinoma Database Consortium favorable, intermediate, and poor risk. Median follow-up was 21.7 months (range, 5.1 to 110.6 mo). Median OS was 61.2 months. The median PFS was 11.5 months, while the 2-year LC rate was 94%. Sixteen (34%) lesions achieved complete response (CR) in patients irradiated before TKI failure, whereas only 4 (7%) lesions yielded CR in those irradiated after TKI failure (P=0.001). The median PFS in CR group was significantly longer than that of non-CR group (18.9 vs. 7.1 mo; P=0.003). The 5-year OS in CR group was 86%, compared with 48% in non-CR group (P=0.010). Four (7%) patients experienced Grade 3 toxicity. CONCLUSIONS: Adding SBRT to TKI is safe and seems to improve survival in mRCC. Patients irradiated before TKI failure have higher CR rate, and the favorable local response might turn into survival benefit.

Dose-volume analysis of predictors for acute anal toxicity after radiotherapy in prostate cancer patients.

BACKGROUND: This study aimed to evaluate the clinical and dosimetric factors predictive of acute anal toxicity (AAT) after radiotherapy in prostate cancer (PCa) patients with or without hemorrhoids. METHODS: We analyzed data from 347 PCa patients (248 cases treated from July 2013 to November 2017 for training cohort and 99 cases treated in 2018 for validation cohort) treated with pelvic radiotherapy at a single institution. Anal canal dose-volume histogram was used to determine the prescribed dose. Univariate and multivariate analyses were used to evaluate the risk of AAT as a function of clinical and dosimetric factors. RESULTS: Totally, 39.5% (98/248) and 31.3% (31/99) of the PCa patients developed AAT in training and validation cohorts, respectively. The incidence of AAT was much higher in patients with hemorrhoids than in those without hemorrhoids in both training and validation cohorts. Hemorrhoids and volume received more than 20 Gy (V20) were valuated as independent factors for predicting AAT in training cohort. Similar results were also observed in our validation cohort. The combination of hemorrhoids and high anal canal V20 (> 74.93% as determined by ROC curves) showed the highest specificity and positive predictive values for predicting AAT in both training and validation cohorts. CONCLUSIONS: AAT occurs commonly in PCa patients with hemorrhoids during and after pelvic radiotherapy. Hemorrhoids and anal canal V20 are independent predictors of AAT. These factors should be carefully considered during treatment planning to minimize the incidence of AAT.

Myeloid differentiation protein 1 protected myocardial function against high-fat stimulation induced pathological remodelling.

Myeloid differentiation 1 (MD-1) is a secreted protein that regulates the immune response of B cell through interacting with radioprotective 105 (RP105). Disrupted immune response may contribute to the development of cardiac diseases, while the roles of MD-1 remain elusive. Our studies aimed to explore the functions and molecular mechanisms of MD-1 in obesity-induced cardiomyopathy. H9C2 myocardial cells were treated with free fatty acid (FFA) containing palmitic acid and oleic acid to challenge high-fat stimulation and adenoviruses harbouring human MD-1 coding sequences or shRNA for MD-1 overexpression or knockdown in vitro. MD-1 overexpression or knockdown transgenic mice were generated to assess the effects of MD-1 on high-fat diet (HD) induced cardiomyopathy in vivo. Our results showed that MD-1 was down-regulated in H9C2 cells exposed to FFA stimulation for 48 hours and in obesity mice induced by HD for 20 weeks. Both in vivo and in vitro, silencing of MD-1 accelerated myocardial function injury induced by HD stimulation through increased cardiac hypertrophy and fibrosis, while overexpression of MD-1 alleviated the effects of HD by inhibiting the process of cardiac remodelling. Moreover, the MAPK and NF-κB pathways were overactivated in MD-1 deficient mice and H9C2 cells after high-fat treatment. Inhibition of MAPK and NF-κB pathways played a cardioprotective role against the adverse effects of MD-1 silencing on high-fat stimulation induced pathological remodelling. In conclusion, MD-1 protected myocardial function against high-fat stimulation induced cardiac pathological remodelling through negative regulation for MAPK/NF-κB signalling pathways, providing feasible strategies for obesity cardiomyopathy.

Antibody drug conjugates of cleavable amino-alkyl and aryl maytansinoids.

Natural products have been used for many medicinal purposes for centuries. Antibody drug conjugates (ADCs) have utilized this rich source of small molecule therapeutics to produce several clinically useful treatments. ADCs based on the natural product maytansine have been successful clinically. The authors further the utility of the anti-cancer natural product maytansine by developing efficacious payloads and linker-payloads for conjugating to antibodies. The success of our approach was realized in the EGFRvIII targeting ADC EGFRvIII-16. The ADC was able to regress tumors in 2 tumor models (U251/EGFRvIII and MMT/EGFRvIII). When compared to a positive control ADC, the efficacy observed was similar or improved while the isotype control ADCs had no effect.

A longitudinal evaluation of early anatomical changes of parotid gland in intensity modulated radiotherapy of nasopharyngeal carcinoma patients with parapharyngeal space involvement.

INTRODUCTION: Radiotherapy of nasopharyngeal carcinoma patients with parapharyngeal space (PPS) involvement may deliver high dose to the parotid gland. This study evaluated parotid gland changes during and up to 3 months after radiotherapy. METHODS: Kilovoltage computed tomography (CT) scans of head and neck region of 39 nasopharyngeal carcinoma patients with PPS involvement were performed at pre-radiotherapy, 10th, 20th and 30th fractions and 3 months after treatment. The parotid glands were contoured in pre-radiotherapy planning CT scan and in subsequent scans. Dice similarity coefficient (DSC), percentage volume change and centroid movement between the planning CT and the subsequent CTs were obtained from the contouring software. In addition, the distance between medial and lateral borders of parotid glands from the mid-line at various time intervals were also measured. RESULTS: The ipsilateral parotid gland received a mean dose of about 5 Gy higher than the contralateral side. The mean DSC and parotid volume decreased by more than 30% at 20th fraction and reached the minimum at 30th fraction. Partial recovery was observed at 3 months after treatment. The centroid displacement followed a similar pattern, which moved medially and superiorly by an average of 0.30 cm and 0.18 cm, respectively, at 30th fraction. The changes in ipsilateral gland were slightly greater than the contralateral side. CONCLUSIONS: Substantial volume change and medial movement of parotid gland were observed with slightly greater magnitude in the ipsilateral side. Adaptive radiotherapy was suggested at around 15th to 20th fraction so as to optimise the original dose distribution of the plan.

A novel supine isocentric approach for craniospinal irradiation and its clinical outcome.

OBJECTIVE: To report a novel approach for craniospinal irradiation (CSI) using a supine isocentric technique. METHODS: Patients were treated in the supine position using CT simulation. Half-beam-blocked lateral cranial fields and superior spinal fields have the same isocentre, and their beam divergences match. Tangential irradiation provides a non-divergent junction for the other two full-beam spinal fields. Shielding for cranial fields was generated, and dose distribution was calculated using a three-dimensional planning system. When sacral spinal fields were required, two lateral opposite fields were designed to protect the urogenital organs. All treatment portals were filmed once per week. RESULTS: At a median follow-up of 49.8 months, 5 relapses and no cases of radiation myelitis developed in 26 consecutive patients. In the junctions of the brain-spine or spine-spine field, no failure occurred. Three failures occurred in the primary site alone, two in the spinal axis alone. CONCLUSION: The results of our study have shown that our novel approach for CSI was not associated with increased failures at the field junction and deaths. In addition, no radiation myelitis, pneumonia, severe damage to the heart and gastrointestinal tract, and second cancers occurred in our study. ADVANCES IN KNOWLEDGE: This new approach is an optimal alternative in cancer centre without tomotherapy because of its convenience for immobilization, repeatability, optimal dose distribution and satisfactory clinical outcome.