Risk Management for Radiation-Induced Cardiovascular Disease (RICVD): The 2022 Consensus Statement of the Taiwan Society for Therapeutic Radiology and Oncology (TASTRO) and Taiwan Society of Cardiology (TSOC).

Advances in cancer management have significantly improved survival in patients with cancers. Cardiovascular complications of cancer treatment are becoming significant competing causes of death in these patients. Radiotherapy is an indispensable component of cancer treatment, and irradiation of the heart and vasculature during cancer radiotherapy is now recognized as a new risk factor for cardiovascular diseases. It is important to involve multidisciplinary expertise and provide practical recommendations to promote awareness, recognize risks, and provide adequate interventions without jeopardizing cancer control. In this consensus paper, experts from the Taiwan Society for Therapeutic Radiology and Oncology and Taiwan Society of Cardiology provide a focused update on the clinical practice for risk stratification and management of radiation-induced cardiovascular disease (RICVD). We believe that implementing RICVD care under a collaborative cardio-oncology program will significantly improve cancer treatment outcomes and will facilitate high quality clinical investigations.

Association of a multiple-step action with cervical lymph node yield of oral cancer patients in an Asian country.

BACKGROUND: High quality lymph node (LN) yield could increase survival, however strategies to improve LN yield have been seldom reported. This study aimed to assess the multiple-step action to promote quality of neck dissection in oral cancer. METHODS: A total of 400 patients with oral cancer who underwent primary tumor resection and neck dissection, including elective and radical neck dissection, were recruited after propensity score matching by clinical T and N categories between January 2009 and September 2018. Patients were treated by two independent departments in our institute. A multiple-step action was initiated in October 2015 in one department, and another department was as a control group. The impact of multiple-step action on LN yield and regional recurrence were analyzed using multivariate analysis and difference-in-differences (DID) linear regression analysis. RESULTS: The mean patient age was 55.2 + 11.1 years, and 92% were male. A total of 180 (45%) patients had T3-4 disease, and 129 (32%) patients had N2-3 disease. The multivariate linear regression and DID analyses revealed that multiple-step action had a positive effect on LN yield. A net improvement of LN yield with a coefficient of 13.78 (p < 0.001) after launching multiple-step action (since October 2015) was observed. A borderline protective effect of multiple-step action for cN0 patients with a reduced regional recurrence rate of 11.6% (p = 0.072) through DID analysis was noted. CONCLUSIONS: Multiple-step action was associated with increased LN yield and decreased regional recurrence in patients with oral cancer. The observed activity may promote surgeons to improve the quality of neck dissections, is feasible, and could be applied to a widespread patient population.

Design, synthesis and biological evaluation of pyridine derivatives as selective SHP2 inhibitors.

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers. Therefore, the development of SHP2 inhibitors has attracted extensive attention. In this study, based on the known inhibitor 1 (SHP099), novel SHP2 inhibitors were designed by means of scaffold hopping, and 35 pyridine derivatives as SHP2 inhibitors were found. The in vitro enzyme activity assay was performed on these compounds, and multiple selective SHP2 inhibitors with activity potency similar to that of SHP099 were obtained. Among them, compound (2-(4-(aminomethyl)piperidin-1-yl)-5-(2,3-dichlorophenyl)pyridin-3-yl)methanol (11a) was the most potent and highly selective SHP2 inhibitor with an in vitro enzyme activity IC50 value of 1.36 µM. Fluorescence titration assay verified that 11a bound directly to SHP2 protein. Subsequently, cell assay of representative compounds showed that these compounds could effectively inhibit the proliferation of Ba/F3 cells. In addition, the pharmacokinetic characteristics of the designed compounds were analyzed by the in silico ADMET prediction. Molecular docking study provided more detailed information on the binding mode of compounds and SHP2 protein. In brief, this study reported for the first time that pyridine derivatives as novel SHP2 inhibitors had good inhibitory activity and selectivity, providing new clues for the development of small molecule SHP2 inhibitors.

Exploring the effect of inhibitor AKB-9778 on VE-PTP by molecular docking and molecular dynamics simulation.

Diabetic macular edema, also known as diabetic eye disease, is mainly caused by the overexpression of vascular endothelial protein tyrosine phosphatase (VE-PTP) at hypoxia/ischemic. AKB-9778 is a known VE-PTP inhibitor that can effectively interact with the active site of VE-PTP to inhibit the activity of VE-PTP. However, the binding pattern of VE-PTP with AKB-9778 and the dynamic implications of AKB-9778 on VE-PTP system at the molecular level are poorly understood. Through molecular docking, it was found that the AKB-9778 was docked well in the binding pocket of VE-PTP by the interactions of hydrogen bond and Van der Waals. Furthermore, after molecular dynamic simulations on VE-PTP system and VE-PTP AKB-9778 system, a series of postdynamic analyses found that the flexibility and conformation of the active site undergone an obvious transition after VE-PTP binding with AKB-9778. Moreover, by constructing the RIN, it was found that the different interactions in the active site were the detailed reasons for the conformational differences between these two systems. Thus, the finding here might provide a deeper understanding of AKB-9778 as VE-PTP Inhibitor.

Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation.

SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migration and apoptosis. Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer. Hence, SHP2 has become a promising target for cancer immunotherapy. In this paper, we reported the identification of compound 1 as SHP2 inhibitor. Fragment-based ligand design, De novo design, ADMET and Molecular docking were performed to explore potential selective SHP2 allosteric inhibitors based on SHP836. The results of docking studies indicated that the selected compounds had higher selective SHP2 inhibition than existing inhibitors. Compound 1 was found to have a novel selectivity against SHP2 with an in vitro enzyme activity IC50 value of 9.97 µM. Fluorescence titration experiment confirmed that compound 1 directly bound to SHP2. Furthermore, the results of binding free energies demonstrated that electrostatic energy was the primary factor in elucidating the mechanism of SHP2 inhibition. Dynamic cross correlation studies also supported the results of docking and molecular dynamics simulation. This series of analyses provided important structural features for designing new selective SHP2 inhibitors as potential drugs and promising candidates for pre-clinical pharmacological investigations.

Isocitrate dehydrogenase 1-snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability.

BACKGROUND: The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown. METHODS: In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion. RESULTS: The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage (p = 0.012), lymph node metastasis (p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08-2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32-4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39-4.50; p = 0.002) in patients with breast cancer. CONCLUSION: Our findings revealed that a IDH1low/Snailhigh molecular signature could serve as an independent biomarker for poor prognosis in breast cancer.

Which nasopharyngeal cancer patients need adaptive radiotherapy?

BACKGROUND: Adaptive radiotherapy (ART) has potential benefits in patients with nasopharyngeal cancer (NPC). This retrospective study aimed to identify the factors favoring ART. MATERIALS AND METHODS: Forty NPC patients were retrospectively included in this study. All patients received two-phase, volumetric modulated arc radiotherapy (VMAT) and underwent a second computed tomography (CT) for the phase II ART. We generated phantom, non-ART plans by a hybrid method for comparison with ART plans. A paired t-test was used to evaluate the dose differences between these two plans. A subgroup analysis through a paired t-test was used to evaluate the factors favoring ART. RESULTS: The second CT images were captured at the median 22 fractions. The median total dose of the planning target volume-one (PTV-1) was 72 Gy, and the phase II dose was 16 Gy. The volumes of the ipsilateral parotid gland (23.2 vs. 19.2 ml, p <  0.000), contralateral parotid gland (23.0 vs. 18.4 ml, p <  0.000), clinical target volume-1 (CTV-1, 32.2 vs. 20.9 ml, p <  0.000), and PTV-1 (125.8 vs. 107.3 ml, p <  0.000) all shrunk significantly between these two CT simulation procedures. Among the nearby critical organs, only the ipsilateral parotid gland displayed significant dose reduction by the ART plan (5.3 vs. 6.0 Gy, p = 0.004). Compared to the phantom plan, the ART could significantly improve the PTV-1 target volume coverage of D98 (15.4 vs. 12.3 Gy, p < 0.000). Based on the D98 of PTV-1, the factors of a large initial weight (> 60 kg, p < 0.000), large body mass index (BMI) (> 21.5, p < 0.000), obvious weight loss (> 2.8 kg, p < 0.000), concurrent chemoradiotherapy (p < 0.000), and stages III-IV (p < 0.000) favored the use of ART. CONCLUSIONS: ART could significantly reduce the mean dose to the ipsilateral parotid gland. ART has dosimetrical benefit for patients with a heavy initial weight, large BMI, obvious weight loss, concurrent chemoradiotherapy, and cancer in stages III-IV.

Manzamine A Exerts Anticancer Activity against Human Colorectal Cancer Cells.

Marine sponges are known to produce numerous bioactive secondary metabolites as defense strategies to avoid predation. Manzamine A is a sponge-derived ß-carboline-fused pentacyclic alkaloid with various bioactivities, including recently reported anticancer activity on pancreatic cancer. However, its cytotoxicity and mode of action against other tumors remain unclear. In this study, we exhibit that manzamine A reduced cell proliferation in several colorectal cancer (CRC) cell lines. To further investigate the manzamine A triggered molecular regulation, we analyzed the gene expression with microarray and revealed that pathways including cell cycle, DNA repair, mRNA metabolism, and apoptosis were dysregulated. We verified that manzamine A induced cell cycle arrest at G0/G1 phase via inhibition of cyclin-dependent kinases by p53/p21/p27 and triggered a caspase-dependent apoptotic cell death through mitochondrial membrane potential depletion. Additionally, we performed bioinformatics analysis and demonstrated that manzamine A abolished epithelial⁻mesenchymal transition process. Several mesenchymal transcriptional factors, such as Snail, Slug, and Twist were suppressed and epithelial marker E-cadherin was induced simultaneously in HCT116 cells by manzamine A, leading to the epithelial-like phenotype and suppression of migration. These findings suggest that manzamine A may serve as a starting point for the development of an anticancer drug for the treatment of metastatic CRC.

An Approach to Optically Pure Bridging Chiral p-tert-Butylcalix[4]arenes through a Homologous Anionic Ortho-Fries Rearrangement.

A novel efficient approach to optically pure bridging chiral calix[4]arenes through a homologous anionic ortho-Fries rearrangement of inherently chiral calix[4]arenes was presented for the first time. As a result, two pairs of N,N'-dimethylformamidyl-substituted bridging chiral p-tert-butylcalix[4]arene enantiomers were facilely obtained. Their absolute configurations were determined through ROESY analysis, ECD comparison, and X-ray crystallographic analysis.

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database.

BACKGROUND: Bevacizumab is used for the treatment of advanced malignant tumors; it acts by inhibiting angiogenesis. This study aimed to examine adverse events (AEs) of bevacizumab, especially hemorrhage, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. RESEARCH DESIGN AND METHODS: The reporting odds ratio (ROR) and proportional reporting ratio (PRR) were used to analyze the AEs of bevacizumab using FAERS registration data from January 2004 to September 2022. Clinical information regarding hemorrhagic signals was further analyzed. RESULTS: The number of bevacizumab-associated AE reports was 96,477. Our study found that 892 significant preferred terms (PTs) were spread throughout 25 organ systems. The system organ classes (SOCs) focus on general disorders, administration site conditions, blood and lymphatic system disorders, injury, poisoning, and procedural complications. A total of 2,847 bevacizumab-related hemorrhage cases were reported, and 37 hemorrhagic signals were identified. Hemorrhagic signals were focused on SOC levels in vascular, gastrointestinal, and nervous system disorders. Colorectal, lung, and breast cancers are the three most common malignancies associated with BV-induced hemorrhage. CONCLUSION: The AE report from the present study confirms the majority of label information for bevacizumab, while also identifying new AEs. In addition, this was a large descriptive study of bevacizumab-induced hemorrhage.

Discovery of 1H-pyrazolo[3,4-b]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRASG12C-mutant non-small cell lung cancer.

The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1H-pyrazolo[3,4-b]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC50 value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRASG12C-mutant non-small cell lung cancer NCI-H358 cells, with an IC50 value of 0.58 µM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRASG12C inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRASG12C mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma.

Discovery of ellagic acid as a competitive inhibitor of Src homology phosphotyrosyl phosphatase 2 (SHP2) for cancer treatment: In vitro and in silico study.

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 µM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 µM and 0.39 ± 0.05 µM, respectively. Besides, the IC50 values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 µM, 2.04 ± 0.28 µM, and 11.79 ± 0.83 µM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRASG12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.

Oxidative stress mediates the inhibitory effects of Manzamine A on uterine leiomyoma cell proliferation and extracellular matrix deposition via SOAT inhibition.

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the ß-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids.

Design, synthesis, activity and molecular dynamics studies of 1,3,4-thiadiazole derivatives as selective allosteric inhibitors of SHP2 for the treatment of cancer.

Overexpression or gene mutation of SHP2 is closely linked with a variety of cancers and has been identified as a crucial anticancer target. In the study, we took SHP2 allosteric inhibitor SHP099 as the lead compound, and 32 1,3,4-thiadiazole derivatives were identified as selective allosteric inhibitors of SHP2. In vitro enzyme activity test showed that some compounds had high inhibition on full length SHP2, and almost no activity on homologous protein SHP1, exhibiting high selectivity. Compound YF704 (4w) had the best inhibition activity, with IC50 value of 0.25 ± 0.02 µM, and also showed strong inhibitory activity on SHP2-E76K and SHP2-E76A, with IC50 values of 6.88 ± 0.69 µM and 1.38 ± 0.12 µM, respectively. CCK8 proliferation test found that multiple compounds would effectively inhibit the proliferation of a variety of cancer cells. Among them, the IC50 values of compound YF704 on MV4-11 and NCI-H358 cells were 3.85 ± 0.34 µM and 12.01 ± 0.62 µM, respectively. Specially, these compounds were sensitive to NCI-H358 cells containing KRASG12C mutation, thus overcoming the problem that SHP099 was insensitive to such cells. Apoptosis experiment showed that compound YF704 would effectively induce apoptosis of MV4-11 cells. Western blot showed that compound YF704 would downregulate the phosphorylation levels of Erk1/2 and Akt in MV4-11 and NCI-H358 cells. Molecular docking study show that compound YF704 would effectively bind to the allosteric region of SHP2 and form hydrogen bond interactions with key residues Thr108, Arg111 and Phe113. Molecular dynamics study further revealed the binding mechanism of SHP2 and compound YF704. In conclusion, we hope to provide potential SHP2 selective inhibitors and provide valuable clues for cancer treatment.

Identification of natural product inhibitors of PTP1B based on high-throughput virtual screening strategy: In silico, in vitro and in vivo studies.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which is a potential therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). In this study, we identified several PTP1B inhibitors with high activity by using high-throughput virtual screening and in vitro enzyme inhibition activity verification strategies. Among them, baicalin was first reported as a selective mixed inhibitor of PTP1B, with IC50 value of 3.87 ± 0.45 µM, and its inhibitory activity against homologous proteins TCPTP, SHP2, and SHP1 exceeded 50 µM. Molecular docking study found that baicalin and PTP1B could bind stably, and revealed that baicalin had a dual inhibitory effect. Cell experiments showed that baicalin was almost non-toxic and could significantly enhance the phosphorylation of IRS-1 in C2C12 myotube cells. Animal experiments showed that baicalin could significantly reduce the blood sugar of STZ-induced diabetic mice models, and had a liver protective effect. In conclusion, this study can provide new ideas for the development of PTP1B selective inhibitors.

Identification of potential target endoribonuclease NSP15 inhibitors of SARS-COV-2 from natural products through high-throughput virtual screening and molecular dynamics simulation.

SARS-CoV-2 wreaks havoc around the world, triggering the COVID-19 pandemic. It has been confirmed that the endoribonuclease NSP15 is crucial to the viral replication, and thus identified as a potential drug target against COVID-19. The NSP15 protein was used as the target to conduct high-throughput virtual screening on 30,926 natural products from the NPASS database to identify potential NSP15 inhibitors. And 100 ns molecular dynamics simulations were performed on the NSP15 and NSP15-NPC198199 system. In all, 10 natural products with high docking scores with NSP15 protein were obtained, among which compound NPC198199 scored the highest. The analysis of the binding mode between NPC198199 and NSP15 found that NPC198199 would form H-bond interactions with multiple key residues at the catalytic site. Subsequently, a series of post-dynamics simulation analyses (including RMSD, RMSF, PCA, DCCM, RIN, binding free energy, and H-bond occupancy) were performed to further explore inhibitory mechanism of compound NPC198199 on NSP15 protein at the molecular level. The research strongly indicates that the 10 natural compounds screened can be used as potential inhibitors of NSP15, and provides valuable information for the subsequent drug discovery of anti-SARS-CoV-2. PRACTICAL APPLICATIONS: Natural products play an important role in the treatment of many difficult diseases. In this study, high-throughput virtual screening technology was used to screen the natural product database to obtain potential inhibitors against endoribonuclease NSP15. The binding mechanism between natural products and NSP15 was investigated at the molecular level by molecular dynamics technology so that it is expected to become candidate drugs for the treatment of SARS-CoV-2. We hope that our research can provide new clue to combat COVID-19 and overcome the epidemic situation as soon as possible.

Identification of the novel natural product inhibitors of SHP2 from the plant Toona sinensis: In vitro and in silico study.

In this study, we tested the inhibitory activity of 45 natural products extracted from the plant Toona sinensis on SHP2 protein, and identified four natural product inhibitors. The natural product 1,2,3,6-Tetragalloylglucose (A-1) was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.20 ± 0.029 µM and the selectivity of 1.8-fold and 4.35-fold to high homologous proteins SHP1 and PTP1B, respectively. Compound A-1 also showed high inhibitory activity on SHP2-E76K and SHP2-E76A mutants, with IC50 values of 0.95 ± 0.21 µM and 0.29 ± 0.045 µM, respectively. Cell viability assay showed that compound A-1 could inhibit the proliferation of a variety of cancer cells. Apoptosis assay showed that compound A-1 could effectively induce apoptosis of KRASG12C-mut NCI-H23 and KRASG12S-mut A549 cells. Western blot assay showed that compound A-1 could down regulate the phosphorylation levels of Erk1/2 and Akt in NCI-H23 and A549 cells. Molecular docking showed that compound A-1 could effectively dock to the catalytic active region of SHP2. Molecular dynamics simulation explored the effect of compound A-1 on SHP2, revealing the deep-seated binding mechanism. This study would provide valuable clues for the development of SHP2 and its mutant inhibitors.

Local treatment options for young women with ductal carcinoma in situ: A systematic review and meta-analysis comparing breast conserving surgery with or without adjuvant radiotherapy, and mastectomy.

PURPOSE: Young age is associated with poor prognosis in ductal carcinoma in situ (DCIS) of female breast and controversy exists regarding the optimal treatment modality for young patients. We aimed to compare treatment outcomes among breast conserving surgery (BCS), BCS with adjuvant radiotherapy (BCS + RT), and total mastectomy (MT) for young DCIS women. METHODS: PubMed, Cochrane, and Embase were searched for studies reporting comparative results among BCS, BCS + RT, or MT in ≤50 years old (y/o) DCIS females. Study quality was assessed and meta-analysis with subgroup analysis was performed to pool the effect sizes of the outcomes-of-interest. RESULTS: We included 3 randomized control trials and 18 observational studies. For DCIS women ≤50 y/o, RT following BCS significantly reduced the risk for ipsilateral breast tumor recurrence (IBTR) (HR = 0.66, 95% CI 0.50-0.87). However, the benefit was less robust in extremely young patients and with long follow-ups. RT revealed no statistically significant preventive effect on ipsilateral invasive recurrence (HR = 1.38, 95% CI 0.98-1.94). On the other hand, MT yielded the lowest IBTR (BCS + RT vs MT: HR = 4.4, 95% CI 2.06-9.40), both in ipsilateral DCIS recurrence and ipsilateral invasive recurrence. There was great heterogeneity and could not reach an evident conclusion concerning survival outcomes. CONCLUSION: This study highlighted the varying effect of RT for young DCIS females. The local control benefit of MT was definite without survival differences observed. Our study provided a moderate certainty of evidence to guide the treatment for young DCIS women. Further age-specific prospective trial is warranted.

High Superior-Middle Pharyngeal Constrictor Muscle Mean Dose Correlates with Severe Late Lung Infection and Survival in Nasopharyngeal Cancer Patients.

Purpose: The study aimed to evaluate 1) the correlation of doses of swallowing-related organs at risk (OAR) with severe swallowing-related late adverse effects (AE) in nasopharyngeal carcinoma (NPC) patients and 2) the effect of high mean doses of OARs on overall survival (OS). Patients and Methods: This retrospective cohort study enrolled non-metastatic Stage I-IV NPC patients from January 2012 to June 2017. OAR mean doses and severe (≥G3) swallowing-related late AE (xerostomia, dysphagia, and lung infection) were evaluated by t-test and validated using receiver operating characteristic curves. The risk factors of OS were calculated by Cox regression methods. Results: This study enrolled 185 (43 female, 142 male) NPC patients, mean age 52.4 years, primarily with Stage III (93, 50.3%) or Stage IV (67, 36.2%) disease. The mean doses of pharyngeal constrictor muscle (PCM), superior-middle PCM (SMPCM), and superior PCM (SPCM) were significantly higher in those with severe (≥G3) lung infection than in those without (65.7 vs 62.2 Gy, p = 0.036; 68.1 vs 64.2 Gy, p = 0.015; and 70.0 vs 65.9 Gy, p = 0.012, respectively). Patients with severe (≥G3) dysphagia had significant higher mean doses of base of tongue (56.2 vs 50.2 Gy, p = 0.008), laryngeal box (50.6 vs 46.4 Gy, p = 0.036), PCM (65.4 vs 62.1 Gy, p = 0.008), SMPCM (67.1 vs 64.2 Gy, p = 0.014), and SPCM (69.3 vs 65.8 Gy, p = 0.004). Mean SMPCM dose >64.9 Gy (adjusted hazard ratio [aHR] = 3.2, 95% confidence interval [CI] 1.2-8.8, p = 0.021), age >62 years (aHR = 2.7, 95% CI 1.1-6.9, p = 0.032), N3 status (aHR = 4.0, 95% CI 1.8-9.0, p = 001), and severe late AE of lung infection (aHR = 4.6, 95% CI 1.5-14.0, p = 0.007) significantly affected OS. Conclusion: Severe lung infection and dysphagia were associated with significantly higher mean doses of PCM, SMPCM, and SPCM. Among these OARs, only a high SMPCM mean dose was a risk factor for OS in NPC patients.

Impact of intracranial extension on survival in stage IV nasopharyngeal carcinoma: identification of a subset of patients with better prognosis.

OBJECTIVE: T-stage is an imperfect prognostic indicator for patients with nasopharyngeal carcinoma. We evaluated the effect of extent of intracranial involvement on survival after conventional radiotherapy in patients with Stage T4 nasopharyngeal carcinoma. METHODS: We conducted a retrospective analysis of the results of computed tomography, magnetic resonance imaging and treatment outcomes in 84 consecutive patients with Stage T4 nasopharyngeal carcinoma during the period September 1993 to December 2002 in Taiwan. The patients were subcategorized into those who had limited intracranial involvement (primary nasopharyngeal tumors with involvement of the unilateral cavernous sinus or the parasellar region only) or extensive involvement (extension of the tumors to the bilateral cavernous sinus or the parasellar region, into the orbit and the ethmoid sinus anteriorly, or to the prepontine region and the posterior cranial fossa). RESULTS: Extensive intracranial involvement was found in 51.2% of the patients. Among these patients, the 5-year rate of overall survival after conventional radiotherapy was only 3.4%. In contrast, the 5-year survival among patients with limited intracranial involvement was 42.9%. This difference was significant (P < 0.001). In the multivariate analysis, extensive intracranial involvement, advanced age and a nodal status of N3 correlated with poor overall survival (all P < 0.05). CONCLUSIONS: Among patients with T4 nasopharyngeal carcinoma, better treatment outcomes were associated with limited intracranial involvement. We conclude that a subdivision of Stage T4 nasopharyngeal carcinoma disease based on the extent of intracranial involvement would provide better prognostic information.