Drug repurposing of cyclin-dependent kinase inhibitors for neutrophilic acute respiratory distress syndrome and psoriasis.

BACKGROUND: Neutrophilic inflammation, characterized by dysregulated neutrophil activation, triggers a variety of inflammatory responses such as chemotactic infiltration, oxidative bursts, degranulation, neutrophil extracellular traps (NETs) formation, and delayed turnover. This type of inflammation is pivotal in the pathogenesis of acute respiratory distress syndrome (ARDS) and psoriasis. Despite current treatments, managing neutrophil-associated inflammatory symptoms remains a significant challenge. AIM OF REVIEW: This review emphasizes the role of cyclin-dependent kinases (CDKs) in neutrophil activation and inflammation. It aims to highlight the therapeutic potential of repurposing CDK inhibitors to manage neutrophilic inflammation, particularly in ARDS and psoriasis. Additionally, it discusses the necessary precautions for the clinical application of these inhibitors due to potential off-target effects and the need for dose optimization. KEY SCIENTIFIC CONCEPTS OF REVIEW: CDKs regulate key neutrophilic functions, including chemotactic responses, degranulation, NET formation, and apoptosis. Repurposing CDK inhibitors, originally developed for cancer treatment, shows promise in controlling neutrophilic inflammation. Clinical anticancer drugs, palbociclib and ribociclib, have demonstrated efficacy in treating neutrophilic ARDS and psoriasis by targeting off-label pathways, phosphoinositide 3-kinase (PI3K) and phosphodiesterase 4 (PDE4), respectively. While CDK inhibitors offer promising therapeutic benefits, their clinical repurposing requires careful consideration of off-target effects and dose optimization. Further exploration and clinical trials are necessary to ensure their safety and efficacy in treating inflammatory conditions.

Utilizing radiomics and dosiomics with AI for precision prediction of radiation dermatitis in breast cancer patients.

PURPOSE: This study explores integrating clinical features with radiomic and dosiomic characteristics into AI models to enhance the prediction accuracy of radiation dermatitis (RD) in breast cancer patients undergoing volumetric modulated arc therapy (VMAT). MATERIALS AND METHODS: This study involved a retrospective analysis of 120 breast cancer patients treated with VMAT at Kaohsiung Veterans General Hospital from 2018 to 2023. Patient data included CT images, radiation doses, Dose-Volume Histogram (DVH) data, and clinical information. Using a Treatment Planning System (TPS), we segmented CT images into Regions of Interest (ROIs) to extract radiomic and dosiomic features, focusing on intensity, shape, texture, and dose distribution characteristics. Features significantly associated with the development of RD were identified using ANOVA and LASSO regression (p-value < 0.05). These features were then employed to train and evaluate Logistic Regression (LR) and Random Forest (RF) models, using tenfold cross-validation to ensure robust assessment of model efficacy. RESULTS: In this study, 102 out of 120 VMAT-treated breast cancer patients were included in the detailed analysis. Thirty-two percent of these patients developed Grade 2+ RD. Age and BMI were identified as significant clinical predictors. Through feature selection, we narrowed down the vast pool of radiomic and dosiomic data to 689 features, distributed across 10 feature subsets for model construction. In the LR model, the J subset, comprising DVH, Radiomics, and Dosiomics features, demonstrated the highest predictive performance with an AUC of 0.82. The RF model showed that subset I, which includes clinical, radiomic, and dosiomic features, achieved the best predictive accuracy with an AUC of 0.83. These results emphasize that integrating radiomic and dosiomic features significantly enhances the prediction of Grade 2+ RD. CONCLUSION: Integrating clinical, radiomic, and dosiomic characteristics into AI models significantly improves the prediction of Grade 2+ RD risk in breast cancer patients post-VMAT. The RF model analysis demonstrates that a comprehensive feature set maximizes predictive efficacy, marking a promising step towards utilizing AI in radiation therapy risk assessment and enhancing patient care outcomes.

Programmed Death Ligand-1 and Tumor Burden Score Dictate Treatment Responses in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The significance of tumor burden for survival is unknown for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The purpose of our study was to evaluate the prognostic impact of programmed death ligand-1 (PD-L1) and tumor burden score (TBS) in patients with R/M HNSCC. PATIENTS AND METHODS: R/M HNSCC patients who were treated with cisplatin, 5-fluorouracil plus cetuximab (EPF) or pembrolizumab (PPF) as first-line treatment were included in our study. PD-L1 and TBS were estimated and correlated with treatment responses. Kaplan-Meier curves were plotted for outcomes estimation. RESULTS: A total of 252 R/M HNSCC patients were included, with 126 high tumor burden (HTB) and 126 low tumor burden (LTB) patients. Median progression-free survival (PFS) was 7.1 months in LTB and 3.9 months in HTB (p < 0.001) and median overall survival (OS) was 14.2 months in LTB and 9.2 months in HTB (p = 0.001). Patients with LTB had better PFS and OS than those with HTB independent of PD-L1 status. Subgroup analysis showed HTB patients treated with EPF had better survival than those treated with PPF, regardless of PD-L1 expression. For LTB PD-L1 positive patients, there was a longer survival with PPF than EPF, while for LTB PD-L1 negative patients, survival was similar between PPF and EPF. Multivariate analysis exhibited that tumor burden was significantly correlated with OS. CONCLUSIONS: Tumor burden is significantly correlated with survival in patients with R/M HNSCC. PD-L1 and TBS should be taken into consideration to determine first-line treatment.

A Novel Prognostic Model Using Pan-Immune-Inflammation Value and Programmed Death Ligand 1 in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitors: A Retrospective Multicenter Analysis.

BACKGROUND: Little is known regarding the prognostication of the Pan-Immune-Inflammation Value (PIV) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). OBJECTIVES: This study aimed to investigate the prognostic role of PIV in patients with R/M HNSCC receiving immune checkpoint inhibitors (ICI). PATIENTS AND METHODS: Patients who were diagnosed to have R/M HNSCC and treated with ICI were reviewed retrospectively. The cutoff value of PIV was set at the median. Patients were stratified into high PIV and low PIV. Kaplan-Meier curves were estimated for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 192 patients were included in our study for oncologic outcomes evaluation. For the total population, the median PFS was 5.5 months and OS was 18.2 months. After stratification by PIV, median PFS was 11.7 months in the low PIV and 2.8 months in the high PIV groups (p < 0.001). The median OS was 21.8 months in the low PIV and 11.5 months in the high PIV groups (p < 0.001). Multivariate analysis demonstrated that PIV and PD-L1 were independent predictors associated with survival. A prognostic model using both PIV and PD-L1 was constructed. The median PFS was 12.2, 6.4, and 3.0 months for patients with risk scores of 0, 1, and 2, respectively (p < 0.001). The median OS was 23.7, 18.1, and 11.4 months for patients with risk scores of 0, 1, and 2, respectively (p < 0.001). CONCLUSIONS: PIV is a prognostic biomarker in patients with R/M HNSCC treated with ICI. A prognostic model using PIV and PD-L1 could provide outcome prediction and risk stratification.

Prognostic impact of cortactin in patients with hypopharyngeal cancer and its role for tegafur-uracil maintenance after adjuvant chemoradiotherapy.

The prognosis of patients with hypopharyngeal cancer (HPC) remains poor. Our study aims to investigate the prognostic impact of cortactin in patients with HPC and its role for tegafur-uracil (UFUR) maintenance after adjuvant chemoradiotherapy (CRT). Patients who were diagnosed to have HPC and underwent laryngopharyngectomy followed by adjuvant CRT were enrolled into our study. Immunohistochemical staining was performed for cortactin evaluation. Kaplan-Meier curves were depicted for recurrence-free survival (RFS) and overall survival (OS). A total of 157 patients were enrolled into our study. After stratified by cortactin, 53 patients were cortactin (+) and 104 patients were cortactin (-). The median RFS was 86.7 months in cortactin (-) and 10.2 months in cortactin (+) (P < 0.001). The median OS was 93.4 months in cortactin (-) and 16.9 months in cortactin (+) (P < 0.001). Patients were further classified according to UFUR maintenance or not after adjuvant CRT. In cortactin (+) patients, the median RFS and OS were 13.6 months versus 7.0 months (P = 0.006) and 24.0 months versus 10.0 months (P < 0.001) in UFUR (+) and UFUR (-), respectively. In cortactin (-) patients, the median RFS and OS were 96.0 months versus 72.2 months (P = 0.262) and 98.5 months versus 105.0 months (P = 0.665) in UFUR (+) and UFUR (-), respectively. Cortactin has a significantly impact in HPC patients. UFUR maintenance provided survival benefits in patients with cortactin (+) after adjuvant CRT.

Using machine learning algorithm to analyse the hypothyroidism complications caused by radiotherapy in patients with head and neck cancer.

Machine learning algorithms were used to analyze the odds and predictors of complications of thyroid damage after radiation therapy in patients with head and neck cancer. This study used decision tree (DT), random forest (RF), and support vector machine (SVM) algorithms to evaluate predictors for the data of 137 head and neck cancer patients. Candidate factors included gender, age, thyroid volume, minimum dose, average dose, maximum dose, number of treatments, and relative volume of the organ receiving X dose (X: 10, 20, 30, 40, 50, 60 Gy). The algorithm was optimized according to these factors and tenfold cross-validation to analyze the state of thyroid damage and select the predictors of thyroid dysfunction. The importance of the predictors identified by the three machine learning algorithms was ranked: the top five predictors were age, thyroid volume, average dose, V50 and V60. Of these, age and volume were negatively correlated with thyroid damage, indicating that the greater the age and thyroid volume, the lower the risk of thyroid damage; the average dose, V50 and V60 were positively correlated with thyroid damage, indicating that the larger the average dose, V50 and V60, the higher the risk of thyroid damage. The RF algorithm was most accurate in predicting the probability of thyroid damage among the three algorithms optimized using the above factors. The Area under the receiver operating characteristic curve (AUC) was 0.827 and the accuracy (ACC) was 0.824. This study found that five predictors (age, thyroid volume, mean dose, V50 and V60) are important factors affecting the chance that patients with head and neck cancer who received radiation therapy will develop hypothyroidism. Using these factors as the prediction basis of the algorithm and using RF to predict the occurrence of hypothyroidism had the highest ACC, which was 82.4%. This algorithm is quite helpful in predicting the probability of radiotherapy complications. It also provides references for assisting medical decision-making in the future.

Targeting PI3K/AKT/mTOR Signaling Pathway as a Radiosensitization in Head and Neck Squamous Cell Carcinomas.

Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway.

Platinum Plus Tegafur-Uracil versus Platinum Alone during Concurrent Chemoradiotherapy in Patients with Nonmetastatic Nasopharyngeal Carcinoma: A Propensity-Score-Matching Analysis.

Concurrent chemoradiotherapy (CCRT) with a cisplatin-based regimen is the standard treatment for patients with nasopharyngeal carcinoma (NPC). Our study was a propensity-score-matching analysis and it aimed to investigate the oncologic outcomes of platinum plus tegafur−uracil versus platinum alone during CCRT in patient with nonmetastatic NPC. Patients with pathologic confirmed NPC in 2018−2022 were reviewed. Patients treated with platinum plus tegafur−uracil (CCRT-UP) or platinum alone (CCRT-P) during CCRT were recruited into this study. A propensity-score-matching analysis was conducted to diminish the selection bias. The recurrence-free survival (RFS) and overall survival (OS) were presented with Kaplan−Meier curves. The treatment-related adverse effects (AEs) were recorded according to the National Cancer Institute's Common Terminology Criteria V3.0. A total of 44 patients with CCRT-UP and 44 patients with CCRT-P were identified after propensity score matching. The median RFS was not reached (NR) in the CCRT-UP group, and it was 12.5 months in the CCRT-P group (p < 0.001). The median OS was NR in the CCRT-UP group, and it was 15.9 months in the CCRT-P group (p < 0.001). The overall response rate and disease-control rate were insignificant between the CCRT-UP and CCRT-P groups. A subgroup analysis showed that the median OS was significantly longer in the CCRT-UP group than in the CCRT-P group, regardless of the clinical stage. A multivariate analysis exhibited that CCRT-UP was independently correlated with survival. The grade 3−4 AEs were insignificant between the CCRT-UP and CCRT-P arms. CCRT-UP had better RFS and OS in nonmetastatic NPC patients with similar toxic profiles. Further larger-scaled prospective randomized control trials are warranted to validate our conclusions.

5-Methoxytryptophan Sensitizing Head and Neck Squamous Carcinoma Cell to Cisplatitn Through Inhibiting Signal Transducer and Activator of Transcription 3 (STAT3).

Head and neck squamous cell carcinoma (HNSCC) is a common cancer of the oral cavity. Cisplatin (CDDP) is the ideal chemo-radiotherapy used for several tumor types, but resistance to the drug has become a major obstacle in treating patients with HNSCC. 5-methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, reduces inflammation-mediated proliferation and metastasis. This study aimed to assess the anti-oral cancer activity of 5-MTP when used alone or in combination with CDDP. Results showed that CDDP dose dependently reduced the growth of SSC25 cells but not 5-MTP. The combination of CDDP and 5-MTP exerted additional inhibitory effect on the growth of SSC25 cells by attenuating the phosphorylation of STAT3. In the 4-nitroquinoline-1-oxide-induced oral cancer mouse model, 5-MTP sensitized the reduction effect of CDDP on tumorigenesis, which restricted the tongue tissue in hyperkeratotic lesion rather than squamous cell carcinoma. The combination of CDDP and 5-MTP may be a potent therapeutic strategy for HNSCC patients with radiotherapy.

Treatment Sequences in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Cetuximab Followed by Immunotherapy or Vice Versa.

BACKGROUND: The prognosis was poor when patients had recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Herein, we conducted an observational study of cetuximab followed by immunotherapy (Cet-IO) versus immunotherapy followed by cetuximab (IO-Cet) in patients with R/M HNSCC. METHODS: Patients who were diagnosed with R/M HNSCC and treated with a sequential cetuximab-containing regimen and immunotherapy-containing regimen were enrolled in our study. Kaplan-Meier curves were estimated for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 75 patients were enrolled in our study for oncologic outcomes evaluation, with 40 patients in Cet-IO and 35 patients in IO-Cet. The median PFS1 was 5.1 months in Cet-IO and 4.5 months in IO-Cet (p = 0.777) and the median PFS2 was 16.5 months in Cet-IO and 11.4 months in IO-Cet (p = 0.566). The median OS was 23.7 months versus 22.8 months in Cet-IO and IO-Cet, respectively (p = 0.484). The overall response rate (ORR) were 73% in Cet-IO versus 37% in IO-Cet (p = 0.002). Multivariate analysis demonstrated that the treatment sequences, Cet-IO or IO-Cet, were insignificantly different with survival. CONCLUSION: Both Cet-IO and IO-Cet are effective in R/M HNSCC patients with insignificant survival differences. The higher ORR of Cet-IO might render it to be considered in patients with large tumor burdens and urgent needs for treatment responses. Further prospective studies are merited to validate our conclusions.

The role of induction chemotherapy in patients with locally advanced head and neck squamous cell carcinoma: A nationwide population-based matched study.

INTRODUCTION: Induction chemotherapy (IC) has a proven role in organ preservation and reducing distant failure. However, its ability to prolong survival remains controversy. Herein, our study aimed to investigate the impact of primary tumor location on survival in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with IC. METHODS: Patients who were older than 18 years and diagnosed with LA-HNSCC between 2007 and 2016 were retrospectively identified from Taiwan National Health Insurance Research Database and Taiwan Cancer Registry. Patients were categorized into two group: IC group and CCRT group. In order to reduce the selection bias, IC patients were individually matched with the CCRT patients. The oncologic outcomes were presented with overall survival (OS). RESULTS: A total of 5547 patients were identified. After matching, 2208 patients were analyzed for outcomes comparison, including 1104 patients in each group. In general, median OS were 27.3 months versus 28.5 months in IC and CCRT group, respectively (p = 0.6151). Patients were stratified by primary tumor location. For patients with oral cavity cancers, the median OS was significantly inferior in IC group than those in CCRT group, while for patients with non-oral cavity cancer, the median OS was superior in IC group than those in CCRT group. CONCLUSIONS: Primary tumor location has a significant impact on survival in patients with LA-HNSCC treated with IC. Our study provides a strong evidence that primary tumor location should be taken into consideration during multidisciplinary approach.

Impact of Parenteral Glutamine Supplement on Oncologic Outcomes in Patients with Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy.

Background: Oral mucositis (OM) is a common toxic side effect in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) that has a negative impact on treatment outcomes and patients' survival. Our study aimed to evaluate the impact of parenteral glutamine supplement (dipeptiven) on oncologic outcomes in patients with NPC treated with CCRT. Methods: Patients who were diagnosed with pathologically proved NPC and treated with CCRT were enrolled into our study. Patients were classified as dipeptiven (+) and dipeptiven (−). Oncologic outcomes were measured, and multivariate regression analysis was performed. Grade 3−4 treatment related toxicities were also documented. Results: A total of 144 patients with NPC were recruited in this study to evaluate oncologic outcomes, with 41 dipeptiven (+) and 103 dipeptiven (−). CCRT interruption rate and severe adverse effect (SAE) rate were significant lower in the dipeptiven (+) group than in the dipeptiven (−) group. The median overall survival (OS) was not mature yet in the dipeptiven (+) group and 30 months in the dipeptiven (−) group (p < 0.01). Multivariate analysis demonstrated that dipeptiven supplementation and CCRT interruption were independent predictors associated with better survival. The OS was longest in patients with a dipeptiven supplement and patients who had CCRT interruption had significantly worst OS. As for safety profiles, grade 3 to 4 adverse effects were fewer in dipeptiven (+) than in dipeptiven (−). Conclusion: Dipeptiven supplementation is crucial in NPC patients treated with CCRT, which can ameliorate treatment-related toxicity and augment treatment efficacy. Further prospective clinical trials are warranted to validate our results.

Tegafur-Uracil versus 5-Fluorouracil in Combination with Cisplatin and Cetuximab in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Propensity Score Matching Analysis.

There are increasing incidences of elderly patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, the treatment is not yet established. We conducted a propensity score matching analysis to evaluate the efficacy and safety of tegafur-uracil versus 5-fluorouracil in combination with cisplatin plus cetuximab in elderly patients with R/M HNSCC. Elderly patients with R/M HNSCC treated with cetuximab-containing chemotherapy were recruited into this study. In order to reduce the selection bias, propensity score matching was performed. Kaplan-Meier curves were plotted for progression-free survival (PFS) and overall survival (OS). Toxicities were graded according to the National Cancer Institute's Common Terminology Criteria V3.0. After propensity sore matching, 54 patients with tegafur-uracil, cisplatin plus cetuximab (UPEx), and 54 patients with 5-fluorouracil, cisplatin plus cetuximab (EXTREME) were identified. The median PFS was 5.4 months in UPEx and 5.8 months in EXTREME (p = 0.451). The median OS was 10.8 months in UPEx and 10.2 months in EXTREME (p = 0.807). The overall response rate (ORR) and disease control rate (DCR) were insignificant in both arms, accounting for 61% versus 59% (p = 0.680) and 72% versus 70% (p = 0.732) in the UPEx arm and the EXTREME arm, respectively. A multivariate analysis showed that age and ECOG PS were, independently, predictors. Grade 3/4 adverse events were much fewer in UPEx than in EXTREME (p < 0.001). Both cetuximab-containing chemotherapies are effective in elderly patients with R/M HNSCC. Safety profiles are improved when tegafur-uracil is substituted for 5-fluorouracil. Further prospective studies are warranted to validate our conclusions.

Outcomes of patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

Nasopharyngeal cancer shows a good response to intensity-modulated radiotherapy. However, there is no clear evidence for the benefits of routine use of image-guided radiotherapy. The purpose of this study was to perform a retrospective investigation of the treatment outcomes, treatment-related complications and prognostic factors for nasopharyngeal cancer treated with intensity-modulated radiotherapy and image-guided radiotherapy techniques. Retrospective analysis was performed on 326 consecutive nasopharyngeal cancer patients treated between 2004 and 2015. Potentially significant patient-related and treatment-related variables were analyzed. Radiation-related complications were recorded. The 5-year overall survival and disease-free survival rates of these patients were 77.9% and 70.5%, respectively. Age, AJCC (American Joint Committee on Cancer) stage, retropharyngeal lymphadenopathy, treatment interruption and body mass index were independent prognostic factors for overall survival. Age, AJCC stage, retropharyngeal lymphadenopathy, image-guided radiotherapy and body mass index were independent prognostic factors for disease-free survival. In conclusion, intensity-modulated radiotherapy significantly improves the treatment outcomes of nasopharyngeal cancer. With the aid of image-guided radiotherapy, the advantage of intensity-modulated radiotherapy might be further amplified.

Calibration of the EBT3 Gafchromic Film Using HNN Deep Learning.

To achieve a dose distribution conformal to the target volume while sparing normal tissues, intensity modulation with steep dose gradient is used for treatment planning. To successfully deliver such treatment, high spatial and dosimetric accuracy are crucial and need to be verified. With high 2D dosimetry resolution and a self-development property, the Ashland Inc. product EBT3 Gafchromic film is a widely used quality assurance tool designed especially for this. However, the film should be recalibrated each quarter due to the "aging effect," and calibration uncertainties always exist between individual films even in the same lot. Recently, artificial neural networks (ANN) are applied to many fields. If a physicist can collect the calibration data, it could be accumulated to be a substantial ANN data input used for film calibration. We therefore use the Keras functional Application Program Interface to build a hierarchical neural network (HNN), with the inputs of net optical densities, pixel values, and inverse transmittances to reveal the delivered dose and train the neural network with deep learning. For comparison, the film dose calculated using red-channel net optical density with power function fitting was performed and taken as a conventional method. The results show that the percentage error of the film dose using the HNN method is less than 4% for the aging effect verification test and less than 4.5% for the intralot variation test; in contrast, the conventional method could yield errors higher than 10% and 7%, respectively. This HNN method to calibrate the EBT film could be further improved by adding training data or adjusting the HNN structure. The model could help physicists spend less calibration time and reduce film usage.

PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy.

Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC.

Haemorrhage rates of ruptured and unruptured brain arteriovenous malformation after radiosurgery: a nationwide population-based cohort study.

OBJECTIVES: The present nationwide population-based cohort study aims to assess the effectiveness of gamma knife radiosurgery (GKS) on ruptured and unruptured brain arteriovenous malformations (AVMs) by evaluating the haemorrhage rates. DESIGN: A nationwide, retrospective cohort study. SETTING: Taiwan National Health Insurance Research Database (NHIRD). PARTICIPANTS: An observational study of 1515 patients who were diagnosed with brain AVMs between 1997 and 2013 from the Taiwan NHIRD. PRIMARY OUTCOME AND SECONDARY OUTCOME MEASURES: We performed a survival analysis using the Kaplan-Meier method. Multivariate Cox proportional hazards regression models were used to explore the relationship between treatment modalities (GKS vs non-GKS) and haemorrhage, adjusted for age and sex. RESULTS: The GKS and non-GKS groups included 317 and 1198 patients, respectively. Patients in the GKS group (mean±SD, 33.08±15.48 years of age) tended to be younger than those in the non-GKS group (37.40±17.62) (p<0.001). The 15-year follow-up revealed that the rate of bleeding risk was lower in the GKS group than in the non-GKRS group (adjusted HR (aHR) 0.61; 95% CI 0.40 to 0.92). The bleeding risk of ruptured AVMs was significantly lower in GKS group than in the non-GKS group (aHR 0.34; 95% CI 0.19 to 0.62). On the other hand, the bleeding risk of unruptured AVMs was higher in the GKS group than in the non-GKS group (aHR 1.95; 95% CI 1.04 to 3.65). In the unruptured AVM group, the incidence of bleeding was significantly higher among patients in the GKS group that were of >40 years of age (aHR 3.21; 95% CI 1.12 to 9.14). CONCLUSIONS: GKS is safe and it reduces the risk of haemorrhage in patients with ruptured AVMs. The administration of GKS to patients with unruptured AVMs who are above the age of 40 years old male might increase the risk of haemorrhage.

The Impact of Insurance and Marital Status on Survival in Patients with Nasopharyngeal Carcinoma.

OBJECTIVE: This study aimed to explore the influence of social support on the survival outcomes of patients with nasopharyngeal carcinoma (NPC). We examined whether the combined proxy influenced whether patients were more likely to receive radiotherapy. METHODOLOGY: data were collected from the 18 registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results database. The association between both insurance status and marital status and disease-specific survival rates were evaluated with a multivariate Cox proportional-hazards regression model to calculate the hazard ratios and associated confidence intervals. Odds ratio (OR) computed by logistic regression was also used to examine the relationship between the receipt of radiotherapy and insurance and marital status. RESULTS: insured and uninsured patients differed significantly in T-stage, N-stage, M-stage, radiotherapy use, race, and marital status. The uninsured-non-married patients showed the lowest 5-year disease-specific survival rates. We further found unmarried patients with either Medicaid (OR, 0.40), or no insurance (OR, 0.24) had lower odds of receiving radiotherapy than those with insurance at diagnosis. CONCLUSIONS: uninsured-unmarried NPC patients had a significantly higher risk of distant metastasis at diagnosis, poorer 5-year disease-specific survival, and were less likely to receive radiotherapy than insured-married patients.

Calibration of Gafchromic EBT Film Using the Microtek ScanMaker 9800XL Plus Flatbed Scanner with a Modified One Red-Channel after Three-Channel Method.

PURPOSE: Using the Microtek ScanMaker 9800XL Plus (9800XL+) flatbed scanner, a method is presented to accurately calibrate EBT film, which cannot be calibrated simply using a general three-channel method because of the nonhomogeneous scanning. MATERIALS AND METHODS: Through the percentage-depth-dose method, 6-MV photon beams with two different monitor units were delivered to eight EBT2 films, each of which was tightly sandwiched in a 30-cm cubic polystyrene phantom and positioned parallel to the central axis of the beam. Before and after irradiation, all films were scanned using the Microtek 9800XL+ scanner and the pixel values (PVs) were measured along the central axis of the beam on the film and fitted to the corresponding depth doses. Before calibration, the irradiated film image was first modified using a template matrix, which was generated using the prescanned background images. Then, a modified one red-channel after three-channel method was used to calibrate the film. RESULTS: Without a template matrix, the three-channel method cannot be used because the PVs do not correspond to a rational fitting form. Using the proposed method, the difference between the fitted dose and the delivered dose is <2%. The green channel, and not the red, is found to have the largest dynamic range. CONCLUSION: The proposed technique allows the use of the three-channel method to calibrate film using a Microtek 9800XL+ scanner.

Cortactin as a potential predictor of second esophageal neoplasia in hypopharyngeal carcinoma.

OBJECTIVE: Hypopharyngeal carcinoma has a very poor prognosis. The high incidence of second esophageal neoplasia is one of the major causes. To establish an efficient follow-up scheme for increasing the diagnostic yield and reducing the adverse impact of second esophageal neoplasia on survival, the purpose of this study was to explore a biomarker to predict second esophageal neoplasia. METHODS: In this retrospective cohort study, consecutive tissue specimens from those patients who underwent tumor resection between September 2007 and October 2015 were collected. Gene amplification was performed by real-time PCR. The expression of cortactin was evaluated by immunohistochemistry. The predictive risk factors of developing second esophageal neoplasia and prognostic factors related to survival were analyzed. RESULTS: A total of 187 patients were included with a mean follow-up of 48months (12-118months). Second esophageal tumors were found in 53 (28.3%), including 41 (21.9%) esophageal squamous cell carcinoma and 12 severe dysplasia. The results of multivariate analyses revealed that age (OR 2.81, 95% CI 1.16-6.78), cortactin overexpression (OR 2.49, 95% CI 1.17-5.33), and stage IV versus I (OR 6.49, 95% CI 1.68-25.18) were independent predictors of second esophageal neoplasia, and second esophageal neoplasia (HR 1.78, 95% CI 1.05-3.01) was an independent predictor of overall survival. CONCLUSION: This is the first report to identify a potential biomarker for predicting second esophageal neoplasia in patients with hypopharyngeal carcinoma. In those patients with cortactin overexpression and younger age (≤60years old), close surveillance for second esophageal neoplasia is required. In addition, the real effect of cortactin overexpression on development of primary esophageal carcinoma is required to be validated in a large cohort study.