Marasmius androsaceus mitigates depression-exacerbated intestinal radiation injuries through reprogramming hippocampal miRNA expression.

INTRODUCTION: Cancer patients commonly experience high levels of psychological stress, which poses significant risks to their well-being. Radiotherapy is a primary treatment modality for cancer; however, it often leads to intestinal injuries in these patients. Nevertheless, the impact of mental stress on radiotherapy-intertwined complications remains unclear. METHODS: To induce intestinal injury, we employed total abdominal irradiation in our experimental model. We conducted high-throughput sequencing to analyze the expression profile of miRNAs in the hippocampus. RESULTS: We observed that mice with depression exhibited more severe intestinal injuries following total abdominal irradiation. Remarkably, oral administration of Marasmius androsaceus not only alleviated the depressive phenotype but also mitigated radiation-induced intestinal toxicity. Notably, this radioprotective effect was not observed in mice without depression. Depression disrupted the hippocampal miRNA expression profile in mice subjected to local irradiation of the abdomen, leading to the accumulation of miR-139-5p and miR-184-3p in the hippocampus, serum, and small intestine tissues. However, treatment with Marasmius androsaceus reprogrammed the miRNA expression signature in mice with depression. Furthermore, intravenous injection of antagomirs targeting miR-139-5p and miR-184-3p ameliorated depression, up-regulated Spn expression, reduced radiation enteritis, and improved the integrity of the small intestine in irradiated mice. CONCLUSION: Our findings demonstrate the efficacy of Marasmius androsaceus, a small mushroom, in alleviating depression-aggravated intestinal toxicity following radiotherapy by reprogramming hippocampal miRNA expression.

Metabolomics and Transcriptomics Analyses Reveals the Molecular Regulatory Mechanisms of Walnut (Juglans regia L.) Embryos in Response to Shade Treatment.

The walnut is an important nut that has numerous uses worldwide. However, due to dwarf and close plantation methods as well as continuous cloudy or rainy days that occur during periods of walnut oil accumulation, the walnut fruit exhibits varying degrees of stress under low-light conditions. However, the effects of shade on metabolites and genes in walnut embryos remain unclear in the literature. The purpose of this study is to investigate the lipid biosynthesis process that occurs in walnut embryos under shade treatment via the use of metabolomics and transcriptomics analyses. The results indicate that the oil content decreases significantly under shaded conditions, while the protein content increases significantly. The expression levels of fatty acid desaturase 2 (FAD2) and stearoyl-ACP-desaturase (SAD) involved in the lipid biosynthesis mechanism were significantly reduced in the shaded group, which resulted in reductions in oleic (C18:1), linoleic (C18:2), and α-linolenic (C18:3) acids. The reduced oil content was consistent with the downregulation of genes associated with the lipid biosynthesis mechanism. In the amino acid biosynthesis process, the upregulated cysteine synthase (cscK) and anthranilate synthase beta subunit 2 (trpG) genes promoted the accumulation of L-aspartic acid and L-citrulline. The increase in protein content was consistent with the upregulation of genes related to amino acid biosynthesis. Thus, our study provides new insights into the regulatory mechanisms of shade underlying overall walnut fruit quality.

Selenium application during fruit development can effectively inhibit browning of fresh-cut apples by enhancing antioxidant capacity and suppressing polyphenol oxidase activity.

Browning is a crucial factor affecting the quality of fresh-cut apples. A safe, simple, and effective method to inhibit browning is urgently needed in fresh-cut apple production. We carried out this study to explore the effect mechanism of exogenous selenium (Se) fertilizer on fresh-cut apple browning. During the development of apples, 0.75 kg/plant Se fertilizer was exerted on the 'Fuji' apple tree at the critical stage of the young fruit stage (late May), early fruit expansion stage (late June), and fruit expansion stage (late July), an equal amount of Se-free organic fertilizer was used as control. Polyphenol oxidase (PPO), peroxidase (POD), and phenylalanine ammonia-lyase (PAL) activities, phenolic and malondialdehyde (MDA) content, antioxidant enzymes activity, and DPPH free radical scavenging rate of the apple at different development stages were investigated. The highest Se accumulation efficiency was observed in apple fruit one month after applying Se fertilizer, which was 41.1%. Se-rich apples exhibited a more remarkable ability to resist browning than control after fresh-cut. The anti-browning effect of the fertilization group (M7) was the best, the PPO activity decreased to 0.5 × 103 U kg-1, and the browning index was 28.6. The total Se content (TSC) of 331.4 µg kg-1 DW and organic Se content (OSC) of 292.0 µg kg-1 DW were the highest in the apple samples, reached the classification standard of Se content in Se-rich food. The correlation analysis found that fresh-cut apple browning was closely related to antioxidant capacity and PPO activity. The stronger the antioxidant capacity of fresh-cut apples treated with Se fertilizer, the lower their browning degree. Therefore, exogenous Se can alleviate fresh-cut apples browning by improving antioxidant capacity and reducing PPO activity. Se-rich apples could increase the Se content of the human essential trace element and inhibit the browning of fresh-cut apples, which would become a new, safe and effective way to solve the fresh-cut apples browning.

Efficacy and cost-effectiveness analysis of pretreatment percutaneous endoscopic gastrostomy in unresectable locally advanced esophageal cancer patients treated with concurrent chemoradiotherapy (GASTO 1059).

BACKGROUND: We launched a single-arm phase II study to determine the efficacy and cost-effectiveness of percutaneous endoscopic gastrostomy (PEG) before concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients received pretreatment PEG and enteral nutrition during CCRT. The primary outcome was the change of weight during CCRT. The secondary outcome included nutrition status, loco-regional objective response rate (ORR), loco-regional progression-free survival (LRFS), overall survival (OS), and toxicities. A 3-state Markov model was applied for cost-effectiveness analysis. Eligible patients were matched and compared with those who had nasogastric tube feeding (NTF) or oral nutritional supplements (ONS). RESULTS: Sixty-three eligible patients received pretreatment PEG-based CCRT. The mean change of weight during CCRT was -1.4% (standard deviation, 4.4%), and after CCRT, 28.6% of patients gained weight and 98.4% had normal albumin levels. The loco-regional ORR and 1-year LRFS were 98.4% and 88.3%. The incidence of grade ≥3 esophagitis was 14.3%. After matching, another 63 patients were included in the NTF group and 63 in the ONS group. More patients gained weight after CCRT in the PEG group (p = 0.001). The PEG group showed higher loco-regional ORR (p = 0.036) and longer 1-year LRFS (p = 0.030). In cost analysis, the PEG group showed an incremental cost-effectiveness ratio of $3457.65 per quality-adjusted life-years (QALY) compared with the ONS group with a probability of cost-effectiveness of 77.7% at the $10,000 per QALY willingness-to-pay threshold. CONCLUSION: Pretreatment PEG is associated with better nutritional status and treatment outcome in ESCC patients treated with CCRT compared with ONS and NTF. Pretreatment of PEG can be cost-effective because of its significant clinical benefits.

Multiregional radiomic model for breast cancer diagnosis: value of ultrasound-based peritumoral and parenchymal radiomics.

Background: Breast cancer consists not only of neoplastic cells but also of significant changes in the surrounding and parenchymal stroma, which can be reflected in radiomics. This study aimed to perform breast lesion classification through an ultrasound-based multiregional (intratumoral, peritumoral, and parenchymal) radiomic model. Methods: We retrospectively reviewed ultrasound images of breast lesions from institution #1 (n=485) and institution #2 (n=106). Radiomic features were extracted from different regions (intratumoral, peritumoral, and ipsilateral breast parenchymal) and selected to train the random forest classifier with the training cohort (n=339, a subset of the institution #1 dataset). Then, the intratumoral, peritumoral, and parenchymal, intratumoral & peritumoral (In&Peri), intratumoral & parenchymal (In&P), and intratumoral & peritumoral & parenchymal (In&Peri&P) models were developed and validated on the internal (n=146, another subset of institution 1) and external (n=106, institution #2 dataset) test cohorts. Discrimination was evaluated using the area under the curve (AUC). Calibration curve and Hosmer-Lemeshow test assessed calibration. Integrated discrimination improvement (IDI) was used to assess performance improvement. Results: The performance of the In&Peri (AUC values 0.892 and 0.866), In&P (0.866 and 0.863), and In&Peri&P (0.929 and 0.911) models was significantly better than that of the intratumoral model (0.849 and 0.838) in the internal and external test cohorts (IDI test, all P<0.05). The intratumoral, In&Peri and In&Peri&P models showed good calibration (Hosmer-Lemeshow test, all P>0.05). The multiregional (In&Peri&P) model had the highest discrimination among the 6 radiomic models in the test cohorts, respectively. Conclusions: The multiregional model combining radiomic information of intratumoral, peritumoral, and ipsilateral parenchymal regions yielded better performance than the intratumoral model in distinguishing malignant breast lesions from benign lesions.

The BELL1-like homeobox gene MdBLH14 from apple controls flowering and plant height via repression of MdGA20ox3.

Apple growth and yield are largely dependent on plant height and flowering characteristics. The BELL1-like homeobox (BLH) transcription factors regulate extensive plant biological processes. However, the BLH-mediated regulation of plant height and flowering in apple remains elusive. In the current study, 19 members of the MdBLH family were identified in the apple genome. Segmental duplication and purifying selection are the main reasons for the evolution of the MdBLH genes. A BLH1-like gene, MdBLH14, was isolated and functionally characterized. The MdBLH14 was preferentially expressed in flower buds, and downregulated during the floral induction period. The subcellular localization in tobacco leaves indicated that MdBLH14 is a nuclear protein. Overexpression of MdBLH14 in Arabidopsis led to a significant dwarfing and late-flowering phenotype by hindering active GA accumulation. Additionally, MdKNOX19, another member of the TALE superfamily, physically interacts with MdBLH14 and synergistically inhibits the expression of MdGA20ox3. This is the first report on the function of the MdBLH14 from apple, and its mechanism involving plant flower induction and growth. The data presented here provide a theoretical basis for genetically breeding new apple varieties.

Transcriptomics and metabolomics provide insight into the anti-browning mechanism of selenium in freshly cut apples.

Enzymatic browning has a considerable negative impact on the acceptability and marketability of freshly cut apples. However, the molecular mechanism by which selenium (Se) positively affects freshly cut apples in this regard is not yet clear. In this study, 0.75 kg/plant of Se-enriched organic fertilizer was applied to "Fuji" apple trees during the young fruit stage (M5, May 25), the early fruit enlargement stage (M6, June 25), and the fruit enlargement stage (M7, July 25), respectively. The same amount of Se-free organic fertilizer was applied as a control. Herein, the regulatory mechanism by which exogenous Se exerts its anti-browning effect in freshly cut apples was investigated. The results showed that the M7 treatment applied in Se-reinforced apples could remarkably inhibit their browning at 1 h after being freshly cut. Additionally, the expression of polyphenol oxidase (PPO) and peroxidase (POD) genes treated with exogenous Se was significantly reduced compared to controls. Moreover, the lipoxygenase (LOX) and phospholipase D (PLD) genes, which are involved in membrane lipid oxidation, were expressed at higher levels in the control. The gene expression levels of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and ascorbate peroxidase (APX) were upregulated in the different exogenous Se treatment groups. Similarly, the main metabolites measured during the browning process were phenols and lipids; thus, it could be speculated that the mechanism by which exogenous Se produces its anti-browning effect may be by reducing phenolase activity, improving the antioxidant capacity of the fruits, and alleviating membrane lipid peroxidation. In summary, this study provides evidence regarding and insight into the response mechanism employed by exogenous Se to inhibit browning in freshly cut apples.

Association of lymphopenia and RDW elevation with risk of mortality in acute aortic dissection.

OBJECTIVE: The study aimed to investigate whether lymphopenia and red blood cell distribution width (RDW) elevation are associated with an increased risk of mortality in acute aortic dissection (AAD). METHODS: This multicenter retrospective cohort study enrolled patients diagnosed with AAD by aortic computed tomographic angiography (CTA) from 2010 to 2021 in five teaching hospitals in central-western China. Cox proportional hazards regression and Kaplan-Meier curves were used in univariable and multivariable models. Clinical outcomes were defined as all-cause in-hospital mortality, while associations were evaluated between lymphopenia, accompanied by an elevated RDW, and risk of mortality. RESULTS: Of 1903 participants, the median age was 53 (interquartile range [IQR], 46-62) years, and females accounted for 21.9%. Adjusted increased risk of mortality was linearly related to the decreasing lymphocyte percentage (P-non-linearity = 0.942) and increasing RDW (P-non-linearity = 0.612), and per standard deviation (SD) of increment lymphocyte percentage and RDW was associated with the 26% (0.74, 0.64-0.84) decrement and 5% (1.05, 0.95-1.15) increment in hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality, respectively. Importantly, lymphopenia and elevation of RDW exhibited a significant interaction with increasing the risk of AAD mortality (P-value for interaction = 0.037). CONCLUSIONS: Lymphopenia accompanied by the elevation of RDW, which may reflect the immune dysregulation of AAD patients, is associated with an increased risk of mortality. Assessment of immunological biomarkers derived from routine tests may provide novel perspectives for identifying the risk of mortality.

Moderately hypo-fractionated radiotherapy combined with S-1 in inoperable locally advanced esophageal squamous cell carcinoma: A prospective, single-arm phase II study (GASTO-1045).

Purpose: We launched this prospective phase II single-arm trial on the combination of moderately hypo-fractionated radiotherapy and S-1, to explore the safety and efficacy of the new potent regimen in inoperable locally advanced esophageal squamous carcinoma (LA-ESCC) patients. Methods: Patients with unresectable stage II-IVB LA-ESCC (UICC 2002, IVB only with metastatic celiac or supraclavicular lymph nodes) were included. Moderately hypofractionated radiotherapy (60Gy in 24 fractions) concurrent with S-1 was delivered. Meanwhile, gastrostomy tube placement by percutaneous endoscopic gastrostomy (PEG) was performed to provide nutritional support. Nutritional supplements were prescribed to meet requirements. The study outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), failure pattern, toxicities, nutritional status and treatment compliance. Endoscopy was routinely performed during post-treatment follow-up. Results: Fifty-eight patients were included with a median follow-up of 24.4 months. The median age was 63 years (range 49-83 years) and 42 patients (72.4%) had stage III or IV diseases. The ORR was 91.3% and the CR rate was 60.3%. The estimated 2-year PFS rate and 2-year OS rate was 44.2% (95% confidence interval (CI), 31.3-57.1%) and 71.4% (95% CI, 59.4-83.4%), respectively. Radiation-induced esophagitis was the most common non-hematologic toxicity and 5 patients (8.6%) developed grade≥3 esophagitis. While, with PEG nutrition support, the nutrition-related indicators presented a clear trend toward a gradual improvement. Treatment-related death was not observed. Conclusions: The moderately hypo-fractionated radiotherapy combined with S-1 showed promising loco-regional disease control and survival benefit in inoperable LA-ESCC patients. Meanwhile, favorable nutritional status and low incidence of severe radiation-induced esophagitis were observed with PEG nutritional support. Moreover, endoscopy examination contributed to the early detection of recurrent esophageal lesions and timely salvage treatment. The efficacy and toxicity of the combined regimen deserved further evaluation. Trial registration: Clinicaltrials.gov, identifier NCT03660449.

Safety profile of 0.0015% tafluprost eye drops in China: a post-marketing observational study.

AIM: To investigate the treatment pattern and safety of tafluprost for glaucoma and ocular hypertension (OH) in clinical practice in China. METHODS: This post-marketing observational study included patients who received tafluprost to lower intraocular pressure (IOP) within 30d between September 2017 and March 2020 in 20 hospitals in China. Adverse drug reactions (ADRs) during tafluprost treatment and within 30d after the treatment were collected. RESULTS: A total of 2544 patients were included in this study, of them 58.5% (1488/2544) had primary open angle glaucoma (POAG), 21.9% (556/2544) had OH and 19.7% (500/2544) used tafluprost for other reasons. Of 359 ADRs occurred in 10.1% (258/2544) patients, and no serious adverse event occurred. The most common ADR was conjunctival hyperemia (128 ADRs in 124 patients, 4.9%). Totally 1670 participants (65.6%) combined tafluprost with carbonic anhydrase inhibitors (CAIs; 37.1%, 620/1670), sympathomimetics (33.5%, 559/1670), ß-blockers (33.2%, 555/1670), other prostaglandin analogs (PGAs; 15.6%, 260/1670) and other eye drops (15.1%, 253/1670). The highest incidence of conjunctival hyperemia was noted in patients who received tafluprost in combination with other PGAs (23 ADRs in 23 patients, 8.8%, 23/260) and the lowest was in combination with CAIs (16 ADRs in 16 patients, 2.6%, 16/620). Tafluprost was applied in primary angle-closure glaucoma (41.6%, 208/500), after glaucoma surgery (17.8%, 89/500) and after non-glaucoma surgery (15.8%, 79/500). CONCLUSION: Tafluprost is safe for POAG and OH, and tolerable when combined with other eye drops and under various clinical circumstances.

Gut Microbiome Is Associated With the Response to Chemoradiotherapy in Patients With Non-small Cell Lung Cancer.

PURPOSE: To explore the dynamic change of gut microbiota and its predictive role in progression-free survival (PFS) in non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). METHODS AND MATERIALS: Forty-one patients with NSCLC in 2 phase 2 trials (NCT02573506 and NCT03006575) were analyzed. A total of 102 fecal samples were collected at 3 time points (T0, before CCRT; T1, 2 weeks after the initiation of CCRT; and T2, the end of CCRT). Gut microbiota composition and functionality were analyzed by 16S rRNA gene sequencing and shotgun metagenomics, respectively. Alpha diversity, taxonomic composition, and KEGG functional pathways were compared between patients in the long-PFS group (PFS ≥11.0 months) and short-PFS group (PFS <11.0 months). A random forest classifier was constructed to identify microbial signature related to PFS. Clinical and microbial factors potentially predictive of PFS were assessed in the univariate and multivariate Cox regression analysis. RESULTS: The abundance of Bacteroidota and Proteobacteria increased, while the abundance of Firmicutes decreased after CCRT. Shannon index (P = .006) and PD index (P = .022) were significantly higher in the long-PFS group than for those in the short-PFS group at T1. The PFS-prediction microbial signature at T1 included unclassified members of the Lanchospiraceae spp., such as NK4A136 and UCG-003 groups, Dorea sp., various strains from within the Eubacterium hallii and E. siraeum groups, and an unclassified member of the Muribaculaceae, which yielded an area under the ROC curve of 0.87. These discriminatory genera mostly belong to phylum Firmicutes/family Clostridia. Multivariate analysis indicated PD index (HR = 8.036, P = .016) and the abundance of Dorea sp. at T1 (HR = 4.186, P = .043) were independent predictors of PFS. The KEGG pathways at T1 overrepresented in the long-PFS group included fatty acid metabolism, fatty acid biosynthesis, and arginine biosynthesis. Those overrepresented in the short-PFS group included lipopolysaccharide biosynthesis, ascorbate and aldarate metabolism, and biosynthesis of vancomycin group antibiotics. CONCLUSIONS: Gut microbiota composition and functionality at 2 weeks after the initiation of CCRT were associated with PFS in NSCLC. Further research is needed to confirm these results.

Hypofractionated concurrent chemoradiotherapy related lymphopenia and its association with survival in locally advanced non-small cell lung cancer patients.

Background: To evaluate longitudinal changes of concurrent chemoradiotherapy (CCRT) related lymphopenia and its association with survival in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Methods: Total lymphocyte count (TLC) at baseline, weekly intervals during CCRT and monthly intervals up to 12 months after CCRT were documented. The Common Terminology Criteria for Adverse Events version 5.0 was used to grade the severity of lymphopenia. Cox regression analysis was performed to evaluate the association between overall survival (OS) and CCRT related lymphopenia at different timepoints. Logistic regression model was used to determine the clinical factors associated with TLC level. Results: 381 LA-NSCLC patients treated with definitive CCRT without consolidation therapy (NCT02573506/NCT02577341) between 2011 to 2020 were analyzed. With a median follow-up of 45.8 months, the median OS was 41.0 months for all patients. Univariable analysis demonstrated that the 3 weeks during CCRT Grade (G) 4 lymphopenia (P=0.018), 2 months after CCRT G1-4 lymphopenia (P=0.004), 6 months after CCRT (6m-post-CCRT) G1-4 lymphopenia (P=0.001), and TLC nadir (P=0.020) were significantly associated with poorer OS. Multivariable analysis suggested that 6m-post-CCRT G1-4 lymphopenia (HR 2.614; P=0.041) were one of the independent predictors of OS. Further analysis inferred that radiation dose (OR: 1.328; P=0.005), GTV volume (OR: 1.004; P=0.036), and baseline TLC (OR: 0.288; P=0.001) were associated with 6m-post-CCRT lymphopenia. Conclusion: The persistent lymphopenia at 6 months after CCRT was an independent prognostic factor of OS in LA-NSCLC patients. Higher radiation dose, larger gross tumor volume and lower baseline TLC were significantly related to 6m-post-CCRT lymphopenia.

Effects of ultrasound-guided alveolar recruitment manoeuvres compared with sustained inflation or no recruitment manoeuvres on atelectasis in laparoscopic gynaecological surgery as assessed by ultrasonography: a randomized clinical trial.

BACKGROUND: The majority of patients may experience atelectasis under general anesthesia, and the Trendelenburg position and pneumoperitoneum can aggravate atelectasis during laparoscopic surgery, which promotes postoperative pulmonary complications. Lung recruitment manoeuvres have been proven to reduce perioperative atelectasis, but it remains controversial which method is optimal. Ultrasonic imaging can be conducive to confirming the effect of lung recruitment manoeuvres. The purpose of our study was to assess the effects of ultrasound-guided alveolar recruitment manoeuvres by ultrasonography on reducing perioperative atelectasis and to check whether the effects of recruitment manoeuvres under ultrasound guidance (visual and semiquantitative) on atelectasis are superior to sustained inflation recruitment manoeuvres (classical and widely used) in laparoscopic gynaecological surgery. METHODS: In this randomized, controlled, double-blinded study, women undergoing laparoscopic gynecological surgery were enrolled. Patients were randomly assigned to receive either lung ultrasound-guided alveolar recruitment manoeuvres (UD group), sustained inflation alveolar recruitment manoeuvres (SI group), or no RMs (C group) using a computer-generated table of random numbers. Lung ultrasonography was performed at four predefined time points. The primary outcome was the difference in lung ultrasound score (LUS) among groups at the end of surgery. RESULTS: Lung ultrasound scores in the UD group were significantly lower than those in both the SI group and the C group immediately after the end of surgery (7.67 ± 1.15 versus 9.70 ± 102, difference, -2.03 [95% confidence interval, -2.77 to -1.29], P < 0.001; 7.67 ± 1.15 versus 11.73 ± 1.96, difference, -4.07 [95% confidence interval, -4.81 to -3.33], P < 0.001;, respectively). The intergroup differences were sustained until 30 min after tracheal extubation (9.33 ± 0.96 versus 11.13 ± 0.97, difference, -1.80 [95% confidence interval, -2.42 to -1.18], P < 0.001; 9.33 ± 0.96 versus 10.77 ± 1.57, difference, -1.43 [95% confidence interval, -2.05 to -0.82], P < 0.001;, respectively). The SI group had a significantly lower LUS than the C group at the end of surgery (9.70 ± 1.02 versus 11.73 ± 1.96, difference, -2.03 [95% confidence interval, -2.77 to -1.29] P < 0.001), but the benefit did not persist 30 min after tracheal extubation. CONCLUSIONS: During general anesthesia, ultrasound-guided recruitment manoeuvres can reduce perioperative aeration loss and improve oxygenation. Furthermore, these effects of ultrasound-guided recruitment manoeuvres on atelectasis are superior to sustained inflation recruitment manoeuvres. TRIAL REGISTRATION: Chictr.org.cn, ChiCTR2100042731, Registered 27 January 2021, www.chictr.org.cn .

A Prospective Phase II Study of Simultaneous Modulated Accelerated Radiotherapy Concurrently With CDDP/S1 for Esophageal Squamous Cell Carcinoma in the Elderly.

BACKGROUND: To explore the efficacy and toxicity of simultaneous modulated accelerated radiotherapy (SMART) concurrently with cisplatin (CDDP) and S1 (tegafur/gimeracil/oteracil) in elderly patients with esophageal squamous cell carcinoma (ESCC). METHODS: This single-arm, phase II study enrolled pathologically confirmed, stage II-IVa ESCC of 70-80 years old and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients received SMART (64 Gy to gross tumor volume and 48 Gy to clinical target volume in 30 fractions) with concurrent CDDP (day 1 of each week) and S1 (days 1-14, 22-35). The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicities. RESULTS: Thirty-seven eligible patients were analyzed with median follow-up of 25.7 months for all and 46.1 months for survivors. The ORR was 88.9%. Patients with baseline weight loss <5% (p=0.050) and nutritional risk index (NRI) ≥105.2 (p=0.023) had better tumor response. Median PFS was 13.8 months with 2-year PFS of 37.5%. Median OS was 27.7 months with 2-year OS of 57.5%. OS was significantly associated with ECOG PS (p=0.005), stage (p=0.014), gross tumor volume (p=0.004), baseline NRI (p=0.036), baseline C-reactive protein (CRP) level (p=0.003) and tumor response (p=0.000). CRP level (p=0.016) and tumor response (p=0.021) were independently prognostic of OS. ≥grade 3 anemia, neutropenia and thrombocytopenia occurred in 2.7%, 10.8% and 13.5% of patients; ≥grade 3 esophagitis and pneumonitis occurred in 18.9% and 2.7% of patient, respectively. CONCLUSION: SMART concurrently with CDDP/S1 yielded satisfactory response rate, survival outcome and tolerable treatment-related toxicities in elderly patients with ESCC. Further studies are warranted to validate the results.

Explore the Diagnostic Efficiency of Chinese Thyroid Imaging Reporting and Data Systems by Comparing With the Other Four Systems (ACR TI-RADS, Kwak-TIRADS, KSThR-TIRADS, and EU-TIRADS): A Single-Center Study.

Purpose: To explore the characteristics of C-TIRADS by comparing it with ACR-TIRADS, Kwak-TIRADS, KSThR-TIRADS and EU-TIRADS. Methods: A total of 1096 nodules were collected from 884 patients undergoing thyroidectomy in our center between May 2018 and December 2020. Divided the nodules into two groups: ">10mm" and "≤10mm". Ultrasound characteristics of each nodule were observed and recorded by 2 doctors, then classified based on ACR-TIRADS, Kwak-TIRADS, KSThR-TIRADS, EU-TIRADS, and C-TIRADS. Results: A total of 682 benign nodules cases (62.23%) and 414 malignant nodules cases (37.77%) were identified. The ICC value of each guideline was:0.937(ACR-TIRADS), 0.858(EU-IRADS), 0.811(Kwak-TIRADS), 0.835(KTA/KSThR-TIRADS) and 0.854(C-TIRADS). The nodule malignancy rates in the groups(Kwak-TIRADS 4B, C-TIRADS 4B、4C) of two sizes were significantly different (all p<0.05). There was no statistical difference in the other grades of two sizes (all p>0.05). Unnecessary biopsy rates were the lowest in C-TIRADS (49.02% p<0.001). Furthermore, Kwak-TIRADS had the highest sensitivity and NPV (89.9%, 91.0%, all p<0.05), while C-TIRADS had the highest specificity and PPV (82.3%, 69.2%, all p<0.05). C-TIRADS and Kwak-TIRADS had the highest accuracy (76.0%, 72.5%, P=0.071). The AUCs of the 5 guidelines were C-TIRADS(0.816, P<0.05), Kwak-TIRADS(0.789, P<0.05) KTA/KSThR-TIRADS and ACR-TIRADS(0.773, 0.763, P=0.305), EU-TIRADS(0.734, P<0.05). The AUCs of the five guidelines were not statistically different between "nodules>10mm" and "nodules ≤ 10mm" (all P>0.05). Conclusions: All five guides showed excellent interobserver agreement. C-TIRADS was slightly efficient than Kwak-IRADS, KTA/KSThR-TIRADS and ACR-TIRADS, and had greater advantages than EU-TIRADS. The diagnostic abilities of the five guidelines for "nodules ≤ 10mm" were not inferior to that of "nodules> 10mm". C-TIRADS is simple and easy to implement and can provide effective thyroid tumor risk stratification for thyroid nodule diagnosis, especially in China.

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.

Hypofractionated Intensity Modulated Radiation Therapy With Concurrent Chemotherapy in Locally Advanced Non-Small Cell Lung Cancer: A Phase II Prospective Clinical Trial (GASTO1011).

PURPOSE: We aimed to explore the efficacy and toxicity of split-course hypofractionated radiation therapy with concurrent chemotherapy (HRT-CHT) in patients with locally advanced non-small cell lung cancer (LANSCLC) in this single-arm, phase II study. METHODS AND MATERIALS: Patients with LANSCLC were considered eligible if their forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC%) and carbon monoxide diffusing capacity (DLCO%) were ≥40% and ≥45%, respectively. HRT-CHT using the intensity modulated radiation therapy technique was administered with 51 Gy in 17 fractions as the first course followed by a break. Patients without disease progression or persistent ≥grade 2 toxicities had an HRT-CHT of 15 to 18 Gy in 5 to 6 fractions as a boost. The primary endpoint was progression-free survival, and the secondary endpoint was overall survival (OS). RESULTS: Eighty-nine patients were enrolled and analyzed. The median follow-up was 29.5 months for all patients and 35.3 months for the survivors. The objective response rate was 97.8%; the median progression-free survival and OS were 11.0 and 27.0 months, respectively. Grade 3 acute esophagitis/pneumonitis occurred in 15 (16.9%)/7 (7.9%) patients. Grade 3/5 late pneumonitis occurred in 2 (2.2%)/1 (1.1%) patients. Of the 78 (87.6%) who completed the split-course HRT-CHT per protocol, patients with better FEV1/FVC% and DLCO% after the break had significantly better OS (for the FEV/FVC1% ≥ 80% vs 60%-79% vs 41%-59% groups, 2-year OS values were 57.2% vs 56.9% vs 0%, respectively, P = .024; for the DLCO% ≥ 80% vs 60%-79% vs 45%-59% groups, 2-year OS values were 70.4% vs 48.4% vs 37.5%, respectively, P = .049). CONCLUSIONS: Split-course HRT-CHT achieved a promising response rate and survival with tolerable toxicity in LANSCLC. Pulmonary function tests are necessary indicators for radiation treatment planning and dose escalation.

Modeling the risk of radiation pneumonitis in esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

BACKGROUND: To develop and validate a nomogram for the prediction of symptomatic radiation pneumonitis (RP) in patients with esophageal squamous cell carcinoma (ESCC) who received definitive concurrent chemoradiotherapy. METHODS: Clinical factors, dose-volume histogram parameters, and pulmonary function parameters were collected from 402 ESCC patients between 2010 and 2017, including 321 patients in the primary cohort and 81 in the validation cohort. The end-point was the occurrence of symptomatic RP (grade ≥ 2) within the first 12 months after radiotherapy. Univariate and multivariate logistic regression analyses were applied to evaluate the predictive value of each factor for RP. A prediction model was generated in the primary cohort, which was internally validated to assess its performance. RESULTS: In the primary cohort, 31 patients (9.7%) experienced symptomatic RP. Based on logistic regression model, patients with larger planning target volumes (PTVs) or higher lung V20 had a higher predictive risk of RP, whereas the overall risk was substantially higher for three-dimensional conformal radiotherapy (3DCRT) than intensity-modulated radiotherapy. On multivariate analysis, independent predictive factors for RP were smoking history (P = 0.035), radiotherapy modality (P < 0.001), PTV (P = 0.039), and lung V20 (P < 0.001), which were incorporated into the nomogram. The areas under the receiver operating characteristic curve of the nomogram in the primary and validation cohorts were 0.772 and 0.900, respectively, which were superior to each predictor alone. CONCLUSIONS: Non-smoking status, 3DCRT, lung V20 (> 27.5%), and PTV (≥ 713.0 cc) were significantly associated with a higher risk of RP. A nomogram was built with satisfactory prediction ability.

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.