Precious Gene: The Application of RET-Altered Inhibitors.

The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy.

Role of primary tumor volume and metastatic lymph node volume in response to curative effect of definitive radiotherapy for locally advanced head and neck cancer.

BACKGROUND: Studies have shown mixed results concerning the role of primary tumor volume (TV) and metastatic lymph node (NV) volume in response to the curative effect of definitive radiotherapy for locally advanced head and neck squamous cell carcinoma (LAHNSCC). OBJECTIVE: We aimed to evaluate the impact of TV and NV on the efficacy of radical radiotherapy in LAHNSCC patients, with the goal of guiding individualized therapy. PATIENTS AND METHODS: Patients with LAHNSCC who received radical radiation therapy and were reexamined within 6 months post-therapy from January 2012 to December 2021 were selected. The volumes of the primary tumors and metastatic lymph nodes were calculated by software and then were divided into a large TV group vs small TV group and a large NV group vs small NV group according to the relationship with the median. Additionally, patients who received concurrent chemoradiotherapy (CCRT) or not were divided into the CCRT group and the radiotherapy (RT) group. Patients with lymph node metastasis were divided into node concurrent chemotherapy (N-CCRT) group and a node metastatic chemotherapy (N-RT) group according to whether they received concurrent chemotherapy or not. The volume shrinkage rate (VSR), objective response rate (ORR), local control rate (LCR) and overall survival (OS) were recorded and analyzed. RESULTS: 96 patients were included in the primary tumor volume group, and 73 patients were included in the metastatic lymph node group. Receiver operating characteristic (ROC) curves were constructed for objective remission (OR) endpoints, and a volume threshold was defined for TV and NV patients. The threshold primary tumor volume was 32.45 cm3, and the threshold metastatic lymph node volume was 6.05 cm3.The primary TV shrinkage rates of the small TV and the large TV groups were basically the same, P = 0.801. Similarly, the ORR and LCR were not significantly different between the small TV group and the large TV group (PORR = 0.118, PLCR = 0.315). Additionally, the TV shrinkage rate did not significantly differ between the CCRT group and the RT group, P = 0.133. Additionally, there was no significant difference in ORR or LCR in CCRT group (PORR = 0.057, PLCR = 0.088). However, the metastatic lymph node volume shrinkage rate in the small NV group was significantly greater than that in the large NV group (P = 0.001). The ORR and LCR of the small NV subgroup were significantly greater than those of the large NV subgroup (PORR = 0.002, PLCR = 0.037). Moreover, compared with that of the N-RT group, the NV shrinkage rate of the N-CCRT group was 84.10 ± s3.11%, and the shrinkage rate was 70.76 ± s5.77% (P = 0.047). For the ORR and LCR, the N-CCRT group and N-RT group were significantly different (PORR = 0.030, PLCR = 0.037). The median OS of the whole group was 26 months. However, neither TV/NV nor concurrent chemotherapy seemed to influence OS. CONCLUSION: Primary tumor volume is not a prognostic factor for the response to curative effect radiotherapy in LAHNSCC patients. Nevertheless, metastatic lymph nodes are a prognostic factor for the response to curative effect radiotherapy in LAHNSCC patients. Patients with smaller lymph nodes have better local control.

Soft sensing modeling of penicillin fermentation process based on local selection ensemble learning.

In the process of penicillin fermentation, there is a strong nonlinear relationship between the input eigenvector and multiple output vectors, which makes the prediction accuracy of the existing model difficult to meet the requirements of chemical production. Therefore, a local selective ensemble learning multi-objective soft sensing modeling strategy is proposed in this study. Firstly, a localization method based on transfer entropy and k-means is proposed to reconstruct the sample set. Then, based on the reconstructed local samples, the local soft sensing model is established by the multi-objective support vector regression method, and the selective ensemble of sub-models and the adaptive calculation of prediction weights are realized. At the same time, to reduce the adverse effects caused by improper selection of model parameters, the sparrow search algorithm is used to realize the tuning of the mentioned model parameters. Finally, the proposed modeling strategy is simulated. The results show that, compared with other methods, the proposed local selective ensemble learning multi-objective soft sensing modeling strategy has better prediction performance.

Gas-Solid Flow Characteristics of Airflow and Dust Particles in Blasting Excavation of Underground Metal Mine Tunnels.

Effective dust removal has long been a challenge in the blasting mining of underground metal mine tunnels, and uncontrolled dust diffusion seriously endangers workers' respiratory systems and the underground space safety environment. However, the vast majority of existing numerical studies on dust diffusion are focused on coal mine fully mechanized mining, which is different from metal mine blasting excavation in terms of stope structure and dust properties. Furthermore, the mechanism by which the forced and exhaust ventilation modes affect the diffusion characteristics of inhalable particles is unclear. In this work, gas-solid flow characteristics for dust diffusion in a typical metal mine blasting tunnel were numerically investigated based on the Euler-Lagrange method, where the blasting face instantly released 6.37 × 107 particles with 100 different sizes, ranging from 0.8 to 200 µm. The interphase forces between airflow and dust particles are comprehensively modeled, and the particle diffusion effect caused by fluid turbulence is described by a discrete random walk model. Detailed information for airflow turbulence and particle migration was revealed, and dust removal efficiencies for inhalable particulate matter (PM10) by forced, exhaust, and hybrid ventilation were analyzed. Numerical results predict a complex airflow pattern in the working roadway, including the jet-flow region, return airflow core region, airflow disorder region, and secondary flow region. Dust diffusion temporal characteristics can be divided into three stages, namely, the initial stage of dust generation, the efficient ventilation and dust removal stage, and the later stage of dust diffusion. Dust diffusion spatial characteristics indicate that under the Coanda wall attachment effect, the dust concentration exhibits nonuniform distribution in both vertical and horizontal directions of the return air roadway. The dust removal efficiency of hybrid ventilation on inhalable particles above respiratory height is better than that of forced ventilation, especially in the return air roadway. The additional exhaust air duct based on forced ventilation can discharge more inhalable particles from the tunnel.

Advanced navigation technology enables endobronchial brachytherapy for peripheral lung cancer: An old technique plays a new role.

PURPOSE: To investigate the feasibility of super-selectively endobronchial brachytherapy in the treatment of peripheral lung cancer guided by advanced navigation technology. METHODS AND MATERIALS: Six patients with peripheral lung tumors successfully underwent treatment with super-selectively endobronchial brachytherapy guided by advanced navigation technology following pathway planning and were subsequently followed up to assess survival and treatment-related toxicities. RESULTS: The endobronchial applicators were successfully placed inside the tumors of all patients using advanced navigation techniques according to the pretreatment plan, and brachytherapy was delivered at curative doses after evaluation using radiotherapy planning software. None of the patients showed local progression of the treated lesions during the follow-up for a duration ranging from 11 months to 35 months, with a median follow-up time of 23 months. The patient with the longest follow-up, nearly 3 years, exhibited a stable condition. After undergoing endobronchial brachytherapy, patients predominantly experienced localized fibrosis as indicated. No significant alterations in cardiopulmonary function were detected during the follow-up, and no other adverse effects were found. CONCLUSIONS: The use of endobronchial brachytherapy for the curative treatment of peripheral lung cancers is feasible. Furthermore, the development of novel bronchial navigation techniques has the potential to broaden the application of endobronchial brachytherapy.

Elucidating the impact of oxygen functional groups on the catalytic activity of M-N4-C catalysts for the oxygen reduction reaction: a density functional theory and machine learning approach.

Efforts to enhance the efficiency of electrocatalysts for the oxygen reduction reaction (ORR) in energy conversion and storage devices present formidable challenges. In this endeavor, M-N4-C single-atom catalysts (MN4) have emerged as promising candidates due to their precise atomic structure and adaptable electronic properties. However, MN4 catalysts inherently introduce oxygen functional groups (OGs), intricately influencing the catalytic process and complicating the identification of active sites. This study employs advanced density functional theory (DFT) calculations to investigate the profound influence of OGs on ORR catalysis within MN4 catalysts (referred to as OGs@MN4, where M represents Fe or Co). We established the following activity order for the 2eORR: for OGs@CoN4: OH@CoN4 > CoN4 > CHO@CoN4 > C-O-C@CoN4 > COC@CoN4 > COOH@CoN4 > CO@CoN4; for OGs@FeN4: COC@FeN4 > CO@FeN4 > OH@FeN4 > FeN4 > COOH@FeN4 > CHO@FeN4 > C-O-C@FeN4. Multiple oxygen combinations were constructed and found to be the true origin of MN4 activity (for instance, the overpotential of 2OH@CoN4 as low as 0.07 V). Furthermore, we explored the performance of the OGs@MN4 system through charge and d-band center analysis, revealing the limitations of previous electron-withdrawing/donating strategies. Machine learning analysis, including GBR, GPR, and LINER models, effectively guides the prediction of catalyst performance (with an R2 value of 0.93 for predicting ΔG*OOH_vac in the GBR model). The Eg descriptor was identified as the primary factor characterizing ΔG*OOH_vac (accounting for 62.8%; OGs@CoN4: R2 = 0.9077, OGs@FeN4: R2 = 0.7781). This study unveils the significant impact of OGs on MN4 catalysts and pioneers design and synthesis criteria rooted in Eg. These innovative findings provide valuable insights into understanding the origins of catalytic activity and guiding the design of carbon-based single-atom catalysts, appealing to a broad audience interested in energy conversion technologies and materials science.

Reuterin promotes pyroptosis in hepatocellular cancer cells through mtDNA-mediated STING activation and caspase 8 expression.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.

Cathepsin B as a potential prognostic and therapeutic marker for human lung squamous cell carcinoma.

BACKGROUND: The lung squamous cell carcinoma survival rate is very poor despite multimodal treatment. It is urgent to discover novel candidate biomarkers for prognostic assessment and therapeutic targets to lung squamous cell carcinoma (SCC). RESULTS: Herein a two-dimensional gel electrophoresis and ESI-Q-TOF MS/MS-based proteomic approach was used to identify differentially expressed proteins between lung SCC and adjacent normal tissues. 31 proteins with significant alteration were identified. These proteins were mainly involved in metabolism, calcium ion binding, signal transduction and so on. Cathepsin B (CTSB) was one of the most significantly altered proteins and was confirmed by western blotting. Immunohistochemistry showed the correlation between higher CTSB expression and lower survival rate. No statistically significant difference between CTSB-shRNA treated group and the controls was observed in tumor volume, tumor weight, proliferation and apoptosis. However, the CTSB-shRNA significantly inhibited tumor metastases and prolonged survival in LL/2 metastatic model. Moreover, CTSB, Shh and Ptch were up-regulated in patients with metastatic lung SCC, suggesting that hedgehog signaling might be activated in metastatic lung SCC which could affect the expression of CTSB that influence the invasive activity of lung SCC. CONCLUSIONS: These data suggested that CTSB might serve as a prognostic and therapeutic marker for lung SCC.

Clinical characteristics of patients with solitary pulmonary mass after radical treatment for primary cancers: pulmonary metastasis or second primary lung cancer?

We identified clinical characteristics of 30 pulmonary metastasis (PM) patients and 29 second primary lung cancer (SPLC) patients with feature of solitary pulmonary mass (SPM) after radical treatment of prior cancers. 6.7% and 44.8% patients presented with centrally located SPM and the median event-free durations were 33 and 72 months in PM and SPLC groups, respectively. PM was more likely to be found in prior cancers with stage III. In conclusion, the location of SPM, the event-free duration and the prior tumor staging were important features for differentiating SPLC from PM among patients with SPM after prior cancers.

[Expression of thymidylate synthase and dihydropyrimidine dehydrogenase in penile cancer].

OBJECTIVE: To investigate the expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in penile cancer. METHODS: A total of 96 patients with penile cancer were included, the expression of TS and DPD in tumor tissues were examined by immunohistochemistry method, the relationship of TS and DPD expressions with the clinical characters were also analyzed. RESULTS: The expression of TS and DPD in penile cancer tissue were 41. 67% (40/96) and 33. 33% (32/96) respectively. There was a positive correlation between TS and DPD expression (Pearson C= 0. 362, P<0. 01). DPD was found to be more expressed in non-smoking patients (P = 0. 040). CONCLUSION: TS and DPD were moderately expressed in penile cancer and their expressions were positively correlated. This could be helpful for the application of fluorouracil in chemotherapy for the patients with penile cancer.

Pact-Net: Parallel CNNs and Transformers for medical image segmentation.

BACKGROUND AND OBJECTIVE: The image segmentation of diseases can help clinical diagnosis and treatment in medical image analysis. Because medical images usually have low contrast and large changes in the size and shape of some structures, this will lead to over-segmentation and under-segmentation. These problems are particularly evident in the segmentation of skin damage. The blurring of the boundary in skin images and the specificity of patients will further increase the difficulty of skin lesion segmentation. Currently, most researchers use deep learning networks to solve these skin segmentation problems. However, traditional convolution methods often fail to obtain satisfactory segmentation performance due to their shortcomings in obtaining global features. Recently, Transformers with good global information extraction ability has achieved satisfactory results in computer vision, which brings new solutions to optimize the model of medical image segmentation further. METHODS: To extract more features related to medical image segmentation and effectively use features to further optimize the skin image segmentation model, we designed a network that combines CNNs and Transformers to improve local and global features, called Parallel CNNs and Transformers for Medical Image Segmentation (Pact-Net). Specifically, due to the advantages of Transformers in extracting global information, we create a novel fusion module CSMF, which uses channel and spatial attention mechanism and multi-scale mechanism to effectively fuse the global information extracted by Transformers into the local features extracted by CNNs. Therefore, our Pact-Net dual-branch runs in parallel to effectively capture global and local information. RESULTS: Our Pact-Net exceeds the models submitted on the three datasets ISIC 2016, ISIC 2017 and ISIC 2018, and the indicators required for the datasets reach 86.95%, 79.31% and 84.14%, respectively. We also conducted medical image segmentation experiments on cell and polyp datasets to evaluate the robustness, learning and generalization ability of the network. The ablation study of each part of Pact-Net proves the validity of each component, and the comparison with state-of-the-art methods on different indicators proves the predominance of the network. CONCLUSIONS: This paper uses the advantages of CNNs and Transformers in extracting local and global features, and further integrates features for skin lesion segmentation. Compared with the state-of-the-art methods, Pact-Net can achieve the most advanced segmentation ability on the skin lesion segmentation dataset, which can help doctors diagnose and treat diseases.

Betamethasone-loaded dissolvable microneedle patch for oral ulcer treatment.

Oral inflammatory disease (OID) is among the most common oral lesions, affecting people's quality of life and even leading to oral cancer. Oral ulcers are the most common OID. However, the pain and fear caused by the localized injection of hormones hinder the clinical treatment of oral ulcers. To address this problem, soluble hyaluronic acid (HA) microneedle patches (BSP-BDP@HAMN) containing betamethasone 21-phosphate sodium (BSP) and betamethasone 17,21-dipropionate (BDP) were fabricated for potential application in oral ulcers. BSP-BDP@HAMNs had the sufficient mechanical strength to penetrate the rat tongue abdomen mucosa with an insertion depth of approximately 207 ± 3 µm. The rapidly solubilized HA microneedle carrier released BSP and BDP into the ulcer base within 3 min of entering the mucosa. Cellular assays have shown that BDP@HAMNs have wound healing-promoting and anti-inflammatory effects. Compared with topical injections and creams, BSP-BDP@HAMNs not only penetrated the ulcer surface painlessly but also worked deep in the ulcer for a long time. In conclusion, the proposed BSP-BDP@HAMN patch can improve the comfort and efficacy of oral ulcer treatment, thus providing a new prospect for oral ulcer treatment.

Lidocaine-Loaded Hyaluronic Acid Adhesive Microneedle Patch for Oral Mucosal Topical Anesthesia.

The pain and fear caused by direct local injection of anesthetic or the poor experience with surface anesthetic cream increase the difficulty of clinical treatment for oral diseases. To address this problem, a hyaluronic acid microneedle patch (Li-HAMNs) that consists of fast-dissolving lidocaine hydrochloride (LDC)-loaded tips and a wet-adhesive backing layer made of polyvinyl alcohol (PVA)/carboxymethylcellulose sodium (CMC-Na) was fabricated to explore its potential use in dental topical anesthesia. Li-HAMNs could puncture the stratum corneum with an insertion depth of about 279 µm in the isolated porcine oral mucosal. The fast-dissolving tips could release LDC to improve the patients' convenience and compliance. Importantly, the backing layer, which has good adhesion ability and water-absorbing properties, could surmount the contraction and extension of oral masticatory muscles and the saliva scour. In the tail flick test, the topical anesthesia efficacy of the Li-HAMNs group was much better than clinical lidocaine cream (EMLA cream, LDC, 1.2 mg) in spite of a relatively lower LDC dose with Li-HAMNs (LDC, 0.5 mg). It is believed that the proposed adhesive microneedle patch could enhance transmucosal delivery of anesthetics and thus open a new chapter in the painless treatment of oral diseases.

Microneedle Array Patch Made of Kangfuxin/Chitosan/Fucoidan Complex Enables Full-Thickness Wound Healing.

Skin wound caused by external injury is usually difficult to be cured by conventional topical administration because of its poor drug diffusion across the stratum corneum. It has been recognized that stratum corneum is the major obstacle for transdermal drug delivery. To address this issue, microneedles (MNs) have been developed to penetrate the stratum corneum of the skin and then form micron-sized pores between the epidermis and the dermis layers. As such, biomacromolecule drugs and/or insoluble drug molecules can be allowed for effective transdermal penetration. A multifunctional microneedle array patch that can avoid wound infection and promote tissue remolding has important value for wound healing. Among others, marine polysaccharides have attracted much attention in multifarious biomedical applications due to their excellent (bio)physical and chemical properties. Herein, we developed a microneedle array patch using a blend of kangfuxin (KFX), chitosan (CS), and fucoidan (FD), named KCFMN, for accelerating full-thickness wound healing. The traditional Chinese medicine KFX extracted from Periplaneta americana (PA) has effective bio-functions in promoting wound healing. The macro-/micro-morphology and (bio)physicochemical properties of such composite microneedles were also studied. We showed that the KCFMN patch displayed noticeable antibacterial properties and good cytocompatibility. In particular, the KCFMN patch significantly accelerated the wound healing development in a full-thickness wound in rats by improving the epithelial thickness and collagen deposition. Thus, this versatile KCFMN patch has great prospects as a dressing for full-thickness wound healing.

Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes.

BACKGROUND: It has been reported that antidiabetic drugs affect the risk of cancer and the prognosis of patients with diabetes, but few studies have demonstrated the influence of different antidiabetic agents on outcomes after anticancer therapy among patients with cancer. The objective of this study was to evaluate the influence of the antidiabetic drugs metformin and insulin on the prognosis of patients with advanced nonsmall cell lung cancer (NSCLC) plus type 2 diabetes who received first-line chemotherapy. METHODS: Data on patients with NSCLC who had diabetes from 5 hospitals in China during January 2004 to March 2009 were reviewed retrospectively. Ninety-nine patients were included in the final analysis. The influence of metformin and insulin on chemotherapy response rates and survival in these patients was evaluated. RESULTS: Chemotherapy with metformin (Group A) produced superior results compared with insulin (Group B) and compared with drugs other than metformin and insulin (Group C) in terms of both progression-free survival (PFS) (8.4 months vs 4.7 months vs 6.4 months, respectively; P = .002) and overall survival (OS) (20.0 months vs 13.1 months vs 13.0 months, respectively; P = .007). Although no significant differences in the response rate (RR) were observed between these 3 groups, when groups B and C (ie, the nonmetformin group) were combined, there was a tendency for better disease control in Group A than that in nonmetformin group. No significant difference in survival was observed between chemotherapy with insulin (Group B) versus other drugs (Group C). CONCLUSIONS: The current data suggested that metformin may improve chemotherapy outcomes and survival for patients who have NSCLC with diabetes.

The Prognostic Value of Preoperative Systemic Inflammatory Response Index (SIRI) in Patients With High-Grade Glioma and the Establishment of a Nomogram.

BACKGROUND: The predictive value of systemic inflammatory response index (SIRI) was confirmed in some malignant tumors. However, few studies investigated the prognostic value of SIRI in high-grade gliomas. This study aimed to evaluate the prognostic relationship of preoperative SIRI in high-grade gliomas and established a nomogram accordingly. METHODS: Data of operable high-grade glioma patients were analyzed. Kaplan-Meier, log-rank test, cox regression and propensity score matching (PSM) analysis were used to analyze survival. ROC curve and area under the curve (AUC) were used to compare the ability of preoperative SIRI, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and monocyte-lymphocyte ratio (MLR) to predict prognosis. A nomogram based on the results was established. The consistency index (C-index) was calculated and a calibration curve was drawn.The prediction effect of the nomogram and WHO grade was compared by AUC. RESULTS: A total of 105 patients were included. Kaplan-Meier survival analysis showed that the overall survival (OS) of grade III gliomas patients with lower preoperative SIRI (SIRI<1.26) was significantly prolonged (p=0.037), and grade IV gliomas patients with lower preoperative SIRI had a tendency to obtain longer OS (p = 0.107). Cox regression showed preoperative SIRI was an independent prognostic factor for grade IV and grade III glioma, however, in IDH mutant-type IV gliomas, patients with lower SIRI only showed a tendency to obtain better OS. Similar results were obtained in PSM. The prognostic value of SIRI were better than PLR and MLR by ROC analysis. And in grade IV gliomas, the predictive value of SIRI was better than NLR. The nomogram established based on preoperative SIRI, age, extent of resection, number of gliomas, MGMT methylation status and histological types (only in grade III gliomas) could predict the prognosis more accurately. CONCLUSION: SIRI was valuable for prognosis prediction in high-grade glioma. The nomogram covering SIRI could more accurately predict the survival rate in operable high-grade glioma patients.

Reirradiation of Whole Brain for Recurrent Brain Metastases: A Case Report of Lung Cancer With 12-Year Survival.

Whole brain radiotherapy (WBRT) for brain metastases (BMs) was considered to be dose limited. Reirradiation of WBRT for recurrent BM has always been challenged. Here, we report a patient with multiple BMs of non-small-cell lung cancer (NSCLC), who received two courses of WBRT at the interval of 5 years with the cumulative administration dose for whole brain as 70 Gy and a boost for the local site as 30 Gy. Furthermore, after experiencing relapse in the brain, he underwent extra gamma knife (GK) radiotherapy for local brain metastasis for the third time after 5 years. The overall survival was 12 years since he was initially diagnosed with NSCLC with multiple brain metastases. Meanwhile, each time of radiotherapy brought a good tumor response to brain metastasis. Outstandingly, during the whole survival, he had a good quality of life (QoL) with Karnofsky Performance Score (KPS) above 80. Even after the last GK was executed, he had just a mild neurocognitive defect. In conclusion, with the cautious evaluation of a patient, we suggest that reirradiation of WBRT could be a choice, and the cumulative radiation dose of the brain may be individually modified.

Patterns of Treatment Failure after Concurrent Chemoradiotherapy or Adjuvant Radiotherapy in Patients with Locally Advanced Cervical Cancer.

OBJECTIVE: To identify patterns of therapy failure after radiotherapy in Chinese patients with locally advanced cervical cancer (LACC). METHODS: A retrospective study was conducted at a Chinese hospital from June 2012 to July 2018. All analyses were done using SPSS 26. RESULTS: 105 patients with treatment failure were included. After a median follow-up of 27 months (range 10-82), the 3-year survival rate after therapy failure was 19.4%. In multivariate analysis, squamous cell carcinoma antigen (SCC-Ag) <4 ng/mL (p < 0.001) and disease-free interval >12 months (p = 0.013) showed significant survival benefits. We identified 3 types of failure: distant lymph node metastasis (n = 50), hematogenous metastasis (n = 53) and pelvic failure (n = 48). Most metastatic para-aortic lymph nodes (PALN) were inferior to the level of left renal hilum (84.8%, n = 28). A total of 80% of patients with supraclavicular lymph nodes (SCLN) metastasis ignored imaging on supraclavicular region. For solitary SCLN or lung metastasis, the prognosis was better than that combined with other sites failure, respectively (p = 0.005; p = 0.001). Many patients with central sites recurrence received insufficient doses of intracavitary brachytherapy (IBT) for low tolerance to pain. CONCLUSION: The distribution of metastatic PALN is asymmetrical and optimizing clinical target volume to minimize toxicity of para-aortic radiation is necessary. The effect of ultrasonography as preliminary screening and follow-up means on SCLN metastasis can be expected. Pain management and psychological interventions are essential for patients receiving IBT.

DJ-1 promotes epithelial-to-mesenchymal transition via enhancing FGF9 expression in colorectal cancer.

Tumor metastasis is the main contributor to high recurrence and mortality in colorectal cancer (CRC). In a previous study, we found that DJ-1 plays an important role in CRC metastasis, and is the main target in Ciclopirox olamine (CPX)-treated CRC. However, the mechanism underlying DJ-1-induced CRC metastasis remains elusive. In the present study, our results showed that DJ-1 could activate Wnt signaling resulting in enhanced invasive potential and epithelial-to-mesenchymal transition (EMT) in CRC cells. RNA-seq and bioinformatics analysis reveals that the DJ-1/Wnt signaling pathway may promote CRC cells' EMT by regulating fibroblast growth factor 9 (FGF9) expression. Molecular validation showed that expression of FGF9 was upregulated by the DJ-1/Wnt signaling pathway and decreasing FGF9-expression impeded DJ-1-induced CRC invasive ability and EMT, suggesting that FGF9 is involved in DJ-1-enhanced CRC metastasis. In addition, we show that FGF9 was overexpressed in CRC human specimens and was significantly associated with tumor differentiation. High FGF9 expression was correlated with worse overall survival, and a correlation exhibited between FGF9 and EMT markers (E-cadherin and Vimentin) in CRC samples. Together, our results determined that FGF9 was involved in DJ-1-induced invasion and EMT in CRC cells, and may represent a promising therapeutic candidate for CRC anti-metastatic strategies.

Simultaneous Integrated Boost Intensity-Modulated Radiotherapy for Locally Advanced Drug-Resistant Gastrointestinal Stromal Tumors: A Feasibility Study.

BACKGROUND: As an emerging clinical problem, locally advanced drug-resistant gastrointestinal stromal tumors (LADRGISTs) has relatively few therapeutic schemes. Although radiotherapy is not often considered for GISTs, it could be a valuable contributing modality. The aim of our study is to explore a safe and effective radiation regimen for LADR-GISTs. METHODS: Three patients with LADR-GISTs were treated with simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) plans. In the SIB-IMRT plans, gross target volume (GTV) was divided into GTV-outer, GTV-mid, and GTV-center. And the prescribed dose of planning gross target volume (PGTV) and GTV-outer were both set to 50.4 Gy in 28 fractions. GTV-mid and GTV-center were simultaneously boosted to 60-62 Gy and 62-64 Gy respectively. For comparison purposes, conventional IMRT (Con-IMRT) plans with uniform dose distribution were generated for same optimization objectives without a dose boost to GTV-mid and GTV-center. All plans were optimized to make sure that deliver at least 95% of the prescription dose was delivered to PGTV. Isodose distribution, dose profiles, conformity indexes (CIs), monitor units (MUs), and dose volume histogram (DVH) was evaluated for each individual patient. After the three patients were treated with SIB-IMRT plans, the relative changes in the tumor size and CT values by CT scanning were also tracked. RESULTS: Compared with Con-IMRT plans, SIB-IMRT plans saw a significant increase from D95 to D2 of the GTV. With steeper dose gradients in the dose profiles, SIB-IMRT plans had GTV-mid and GTV-center accumulated with higher dose mainly by delivering extra 93 MUs in average. However, there was no significant difference in CIs and organs at risks (OARs) DVH. The relative changes in tumor size and CT values of the three patients in follow up were up to the Choi criteria and the three patients were all assessed as partial response. CONCLUSIONS: The proposed SIB-IMRT may be a potential technique for achieving objective response and prolonging survival of selected GISTs patients.