Hyaluronic acid-based injectable formulation developed to mitigate metastasis and radiation-induced skin fibrosis in breast cancer treatment.

The standard treatment for early-stage breast cancer involves breast-conserving surgery followed by adjuvant radiotherapy. However, approximately 20 % of patients experience distant metastasis, and adjuvant radiotherapy often leads to radiation-induced skin fibrosis (RISF). In this study, we develop an on-site injectable formulation composed of selenocystamine (SeCA) and hyaluronic acid (HyA), referred to as SeCA cross-linked HyA (SCH) agent, and investigate its potential to mitigate metastasis and prevent RISF associated with breast cancer therapy. SCH agents are synthesized using the nanoprecipitation method to modulate cell-cell tight junctions and tissue inflammation. The toxicity assessments reveal that SCH agents with a higher Se content (Se payload 17.4 µg/mL) are well tolerated by L929 cells compared to SeCA (Se payload 3.2 µg/mL). In vitro, SCH agents significantly enhance cell-cell tight junctions and effectively mitigate migration and invasion of breast cancer cells (4T1). In vivo, SCH agents mitigate distant lung metastasis. Furthermore, in animal models, SCH agents reduce RISF and promote wound repair. These findings highlight the potential of SCH agents as a novel therapeutic formulation for effectively mitigating metastasis and reducing RISF. This holds great promise for improving clinical outcomes in breast cancer patients undergoing adjuvant radiotherapy.

A predictive survival model for patients with stage IV oropharyngeal squamous cell carcinoma treated with chemoradiation.

PURPOSE: To evaluate the pre-treatment and post-treatment clinical factors associated with rate of survival at 1, 3, and 5 years in stage IV oropharyngeal cancer patients treated with concurrent chemoradiation with/without neoadjuvant chemotherapy. METHODS: This retrospective cohort study involved 128 Stage IV oropharyngeal cancer patients that were treated at our tertiary referral center between 2008 and 2020. The pre-treatment and post-treatment clinical parameters including nutritional status and inflammatory markers were retrospectively reviewed. RESULTS: The 5-year overall survival rate for all patients was 36.72%. The disease-specific survival (DSS) at 1-year and 3-year were 80% and 63%, whereas the disease-free survival (DFS) at 1-year and 3-year were 49% and 40%, respectively. In multivariate analyses, pretreatment hemoglobin (Hb) < 12 g/dL (hazard ratio [HR] 2.551, 95% confidence interval [CI] 1.366-4.762, p = 0.003), pretreatment systemic immune inflammation (SII) ≥ 1751 (HR 2.173, 95% CI 1.015-4.652, p = 0.046), and posttreatment systemic inflammation response index (SIRI) ≥ 261 (HR 2.074, 95% CI 1.045-4.115, p = 0.037) were independent indicators for worsened DSS. Pretreatment Hb < 12 g/dl (HR 1.692, 95% CI 1.019-2.809, p = 0.032), pretreatment SII ≥ 1751 (HR 1.968, 95% CI 1.061-3.650, p = 0.032), and posttreatment SII ≥ 1690 (HR 1.922, 95% CI 1.105-3.345, p = 0.021) were independent indicators for worsened DFS. A nomogram was developed using pretreatment Hb, pretreatment SII, and posttreatment SIRI to forecast DSS. CONCLUSIONS: The pretreatment Hb, pretreatment SII, posttreatment SII, and posttreatment SIRI are associated with survival in patients with stage IV oropharyngeal cancers. The developed nomogram aids in survival prediction and treatment adjustment.

Impact of Varying Chest Wall Target Volume Delineation on Postmastectomy Radiation Therapy Outcomes in Breast Cancer Patients with Implant-Based Reconstruction.

BACKGROUND: The target volume for post-mastectomy radiation therapy (PMRT) in breast cancer patients with reconstruction has been a subject of debate. Traditionally, the RT chest wall (CW) volume encompasses the entire implant. For patients with retropectoral implants, the deep lymphatic plexus dorsal part of the implant is no longer considered high risk and can be omitted. This study aimed to assess the radiation dose distribution and treatment outcomes associated with different CW delineation according to ESTRO ACROP guideline for patients who have undergone implant-based reconstruction. METHODS: We conducted a retrospective review of breast cancer patients who underwent a mastectomy followed by two-stage implant-based breast reconstruction and adjuvant radiation therapy (RT) between 2007 and 2022. The expanders/implants were positioned retropectorally. The chest wall target volumes were categorized into two groups: the prepectoral group, which excluded the deep lymphatic plexus, and the whole expander group. RESULTS: The study included 26 patients, with 15 in the prepectoral group and 11 in the whole expander group. No significant differences were observed in normal organ exposure between the two groups. There was a trend toward a lower ipsilateral lung mean dose in the prepectoral group (10.2 vs. 11.1 Gy, p = 0.06). Both groups exhibited limited instances of reconstruction failure and local recurrence. CONCLUSIONS: For patients undergoing two-stage expander/implant retropectoral breast reconstruction and PMRT, our data provided comparable outcomes and normal organ exposure for those omitting the deep lymphatic plexus.

Downregulation of TAZ elicits a mitochondrial redox imbalance and ferroptosis in lung epithelial cells exposed to diesel exhaust particles.

Mitochondrial dysfunction was reported to be involved in the development of lung diseases including chronic obstructive pulmonary disease (COPD). However, molecular regulation underlying metabolic disorders in the airway epithelia exposed to air pollution remains unclear. In the present study, lung bronchial epithelial BEAS-2B and alveolar epithelial A549 cells were treated with diesel exhaust particles (DEPs), the primary representative of ambient particle matter. This treatment elicited cell death accompanied by induction of lipid reactive oxygen species (ROS) production and ferroptosis. Lipidomics analyses revealed that DEPs increased glycerophospholipid contents. Accordingly, DEPs upregulated expression of the electron transport chain (ETC) complex and induced mitochondrial ROS production. Mechanistically, DEP exposure downregulated the Hippo transducer transcriptional co-activator with PDZ-binding motif (TAZ), which was further identified to be crucial for the ferroptosis-associated antioxidant system, including glutathione peroxidase 4 (GPX4), the glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione-disulfide reductase (GSR). Moreover, immunohistochemistry confirmed downregulation of GPX4 and upregulation of lipid peroxidation in the bronchial epithelium of COPD patients and Sprague-Dawley rats exposed to air pollution. Finally, proteomics analyses confirmed alterations of ETC-related proteins in bronchoalveolar lavage from COPD patients compared to healthy subjects. Together, our study discovered that involvement of mitochondrial redox dysregulation plays a vital role in pulmonary epithelial cell destruction after exposure to air pollution.

Integrating subvolume dose and myocardial perfusion imaging parameters to assess the impact of radiation therapy on heart function in breast cancer patients: A comparative analysis between left- and right-sided breast cancer.

BACKGROUND: This study aimed to utilize an innovative method of integrating the 20 subvolume dose of left ventricle and the Tl-201 single photon emission computed tomography (SPECT) with myocardial perfusion imaging (MPI) parameters in patients with left- and right-sided breast cancer after radiation therapy. METHODS: Female patients with breast cancer underwent SPECT MPI before commencing radiotherapy and 12 months later were enrolled from January 2014 to December 2018. The images of CT simulation and SPECT MPI were integrated into the treatment planning system. The differences of doses and parameters of MPI in all cardiac subvolumes between left- and right-sided breast cancer patients were analyzed. RESULTS: Patients with left-sided breast cancer (n = 61) received a higher radiation dose to the heart, left ventricular, and its territories and subvolumes, compared to patients with right-sided breast cancer (n = 19). The 20-segment analysis also showed statistically significant disparities in the average radiation doses received by the two groups. In different coronary artery territories, the end-diastolic perfusion and end-systolic perfusion showed a decrease in both sides, with no significant differences. However, the wall motion and wall thickening showed a significant decline in subregions within the left- and right-sided coronary artery territories. CONCLUSION: This study demonstrates an innovative integrated method combining the left ventricular 20 regional doses with SPECT MPI which shows that left-sided breast cancer patients receive a higher subvolume dose than right-sided breast cancer patients. Further research is needed to confirm the potential impact on heart function after radiotherapy on both sides.

Fucoidan/chitosan layered PLGA nanoparticles with melatonin loading for inducing intestinal absorption and addressing triple-negative breast cancer progression.

Melatonin and fucoidan are naturally active compounds that have been reported to have therapeutic benefits for patients receiving cancer treatment. However, both compounds face significant challenges, including physical, chemical, and biological metabolisms in the gastrointestinal tract, which limit their ability to achieve therapeutic concentrations at the tumor site. Furthermore, the effectiveness of melatonin and fucoidan as adjuvants in vivo is influenced by the route of administration through the digestive system and their accumulation at the endpoint of the tumor. In this study, we developed an oral administration of nanoparticle, MNPs@C@F, that consisted of PLGA nanoparticles modified with chitosan, to promote intestinal microfold cell transcytosis for the delivery of melatonin and fucoidan into tumors. The experimental results indicated that melatonin and fucoidan in the tumors could regulate the tumor microenvironment by decreasing P-gp, Twist, HIF-1α, and anti-inflammatory immune cell expression, and increasing cytotoxic T cell populations following doxorubicin treatment. This resulted in an increase in chemo-drug sensitivity, inhibition of distant organ metastasis, and promotion of immunogenic cell death. This study demonstrates a favorable co-delivery system of melatonin and fucoidan to directly reduce drug resistance and metastasis in TNBC.

Ultrasound Is Beneficial to Determine Lymphadenopathy in Oral Cancer Patients after Radiotherapy.

The present study aimed to investigate whether the addition of ultrasound (US) +/- fine needle aspiration (FNA) to magnetic resonance imaging (MRI) or computed tomography (CT) improves the diagnostic accuracy in assessing neck lymphadenopathy in oral cancer patients after neck irradiation. We retrospectively reviewed oral cancer patients who had neck lymphadenopathy after radiotherapy (RT) or chemoradiation therapy (CRT) from February 2008 to November 2019. The following diagnostic modalities were assessed: (1) MRI/CT, (2) MRI/CT with a post-RT US predictive model, and (3) MRI/CT with US + FNA. The receiver operating characteristic (ROC) curves were used to assess the diagnostic performance. A total of 104 irradiation-treated oral cancer patients who subsequently had neck lymphadenopathy were recruited and analyzed. Finally, there were 68 (65%) malignant and 36 (35%) benign lymphadenopathies. In terms of the diagnostic performance, the area under the ROC curves (C-statistics) was 0.983, 0.920, and 0.828 for MRI/CT with US + FNA, MRI/CT with a post-RT US predictive model, and MRI/CT, respectively. The addition of US to MRI/CT to evaluate cervical lymphadenopathy could achieve a better diagnostic accuracy than MRI/CT alone in oral cancer patients after neck irradiation.

Glucose Transporter 1-Mediated Transcytosis of Glucosamine-Labeled Liposomal Ceramide Targets Hypoxia Niches and Cancer Stem Cells to Enhance Therapeutic Efficacy.

Tumour hypoxia plays an important role in modulating tumorigenesis, angiogenesis, invasion, immunosuppression, resistance to treatment, and even maintenance of the stemness of cancer stem cells (CSCs). Moreover, the targeting and treatment of hypoxic cancer cells and CSCs to reduce the influence of tumor hypoxia on cancer therapy remains an imperative clinical problem that needs to be addressed. Since cancer cells upregulate the expression of glucose transporter 1 (GLUT1) through the Warburg effect, we considered the possibility of GLUT1-mediated transcytosis in cancer cells and developed a tumor hypoxia-targeting nanomedicine. Our experimental results indicate that glucosamine-labeled liposomal ceramide can be efficiently transported between cancer cells by GLUT1 transporters and substantially accumulated in the hypoxic area in in vitro CSC spheroids and in vivo tumor xenografts. We also verified the effects of exogenous ceramide on tumor hypoxia, including important bioactivities such as upregulation of p53 and retinoblastoma protein (RB), downregulation of hypoxia-inducible factor-1 alpha (HIF-1α) expression, disruption of the OCT4-SOX2 network of stemness, and inhibition of CD47 and PD-L1 expression. To achieve an ideal therapeutic outcome, we combined treatment of glucosamine-labeled liposomal ceramide with paclitaxel and carboplatin, and we found an excellent synergistic effect, with tumor clearance being noted in three-fourths of the mice. Overall, our findings provide a potential therapeutic strategy for the treatment of cancer.

Evaluation of the cardiac subvolume dose and myocardial perfusion in left breast cancer patients with postoperative radiotherapy: a prospective study.

Adjuvant breast radiotherapy could reduce the risk of local recurrence. However, the radiation dose received by the heart also increases the risk of cardiotoxicity and causes consequential heart diseases. This prospective study aimed to evaluate more precisely cardiac subvolume doses and corresponding myocardial perfusion defects according to the American Heart Association (AHA)'s 20-segment model for single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) interpretation for breast cancer after radiotherapy. The 61 female patients who underwent adjuvant radiotherapy following breast cancer surgery for left breast cancer were enrolled. SPECT MPI were performed before radiotherapy for baseline study, and 12 months after for follow-up. Enrolled patients were divided into two groups, new perfusion defect (NPD) and non new perfusion defect found (non-NPD) according to myocardial perfusion scale score. CT simulation data, radiation treatment planning, and SPECT MPI images were fused and registered. The left ventricle was divided into four rings, three territories, and 20 segments according to the AHA's 20-segment model of the LV. The doses between NPD and non-NPD groups were compared by the Mann-Whitney test. The patients were divided into two groups: NPD group (n = 28) and non-NPD group (n = 33). The mean heart dose was 3.14 Gy in the NPD group and 3.08 Gy in the non-NPD group. Mean LV doses were 4.84 Gy and 4.71 Gy, respectively. The radiation dose of the NPD group was higher than the non-NPD group in the 20 segments of LV. There was significant difference in segment 3 (p = 0.03). The study indicated that the radiation doses to 20 segments of LV in NPD were higher than those in non-NPD significantly at segment 3, and higher in other segments in general. In the bull's eye plot combining radiation dose and NPD area, we found that the new cardiac perfusion decline may exist even in the low radiation dose region.Trial registration: FEMH-IRB-101085-F. Registered 01/01/2013, https://clinicaltrials.gov/ct2/show/NCT01758419?cond=NCT01758419&draw=2&rank=1 .

Postchemoradiotherapy systemic inflammation response index predicts treatment response and overall survival for patients with locally advanced nasopharyngeal cancer.

BACKGROUND/PURPOSE: To explore the clinical utility of the systemic inflammation response index (SIRI) in the prediction of patients with poor treatment response to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal cancer (NPC). METHODS: A total of 167 stage III-IVB (AJCC 7th edition) nasopharyngeal cancer patients who received CCRT were retrospectively collected. The SIRI was calculated using the following formula: SIRI = neutrophil count × monocyte count/lymphocyte count (109/L). The optimal cutoff values of the SIRI for noncomplete response were determined by receiver operating characteristic curve analysis. Logistic regression analyses were performed to identify factors predictive of treatment response. We used Cox proportional hazards models to identify predictors of survival. RESULTS: Multivariate logistic regression showed that only the posttreatment SIRI was independently associated with treatment response in locally advanced NPC. A posttreatment SIRI≥1.15 was a risk factor for developing an incomplete response after CCRT (odds ratio 3.10, 95% confidence interval (CI): 1.22-9.08, p = 0.025). A posttreatment SIRI≥1.15 was also an independent negative predictor of progression-free survival (hazard ratio 2.38, 95% CI: 1.35-4.20, p = 0.003) and overall survival (hazard ratio 2.13, 95% CI: 1.15-3.96, p = 0.017). CONCLUSION: The posttreatment SIRI could be used to predict the treatment response and prognosis of locally advanced NPC.

Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer.

In this study, we determined the diagnostic performance of adding ultrasound (US) with/without fine-needle aspiration cytology (FNAC) to computed tomography (CT)/magnetic resonance imaging (MRI) in evaluating neck lymphadenopathy (LAP) in patients with head and neck cancer treated with irradiation. We included 269 patients who had neck LAP after radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) resulting from cancers of the head and neck region between October 2008 and September 2018. The diagnostic methods consisted of the following: 1) CT/MRI alone, 2) CT/MRI combined with a post-RT US predictive model, and 3) CT/MRI combined with US + FNAC. We compared their diagnostic performance using receiver operating characteristic (ROC) curves. In total, 141 (52%) malignant and 128 (48%) benign LAPs were observed. Regarding the diagnostic accuracy, the area under the ROC curves was highest for the combined CT/MRI and US + FNAC (0.965), followed by the combined CT/MRI and post-RT US predictive model (0.906) and CT/MRI alone (0.836). Our data suggest that the addition of a US examination to CT/MRI resulted in higher diagnostic performance than CT/MRI alone in terms of diagnosing recurrent or persistent nodal disease during the evaluation of LAP in patients with irradiation-treated head and neck cancer.

Total Skin Treatment with Helical Arc Radiotherapy.

For widespread cutaneous lymphoma, such as mycosis fungoides or leukemia cutis, in patients with acute myeloid leukemia (AML) and for chronic myeloproliferative diseases, total skin irradiation is an efficient treatment modality for disease control. Total skin irradiation aims to homogeneously irradiate the skin of the entire body. However, the natural geometric shape and skin folding of the human body pose challenges to treatment. This article introduces treatment techniques and the evolution of total skin irradiation. Articles on total skin irradiation by helical tomotherapy and the advantages of total skin irradiation by helical tomotherapy are reviewed. Differences among each treatment technique and treatment advantages are compared. Adverse treatment effects and clinical care during irradiation and possible dose regimens are mentioned for future prospects of total skin irradiation.

Obesity-mediated upregulation of the YAP/IL33 signaling axis promotes aggressiveness and induces an immunosuppressive tumor microenvironment in breast cancer.

Obesity is a well-known risk factor for breast cancer formation and is associated with elevated mortality and a poor prognosis. An obesity-mediated inflammatory microenvironment is conducive to the malignant progression of tumors. However, the detailed molecular mechanism is still needed to be clarified. Herein, we identified that breast cancer cells from mice with diet-induced obesity exhibited increased growth, invasiveness, and stemness capacities. A transcriptome analysis revealed that expressions of interleukin 33 (IL33) signaling pathway-related genes were elevated in obesity-associated breast cancer cells. Importantly, IL33 expression was significantly associated with the yes-associated protein (YAP) signature, and IL33 was transcriptionally regulated by YAP. Suppression of IL33 reduced tumor migration and invasion, while the addition of IL33 activated nuclear factor (NF)-κB signaling and revived tumor mobility in YAP-silenced cells. Furthermore, suppression of YAP attenuated IL33 expression which was accompanied by relief of obesity-mediated immunosuppression. Clinical analyses showed that IL33 expression was markedly associated with macrophage and regulatory T cell infiltration. These findings reveal a crucial role of the YAP/IL33 axis in promoting aggressiveness and immunosuppression of obesity-associated breast cancer progression.

Speech and Swallowing Rehabilitation Potentially Decreases Body Weight Loss and Improves Survival in Head and Neck Cancer Survivors.

This retrospective observational cohort study aims to assess the outcomes and associated factors in head and neck cancer (HNC) survivors with dysphagia, and to investigate the relationship between outcomes and speech and swallowing rehabilitation (SSR). We enrolled patients who were diagnosed with HNC between October 2016 and July 2018; we included 393 patients who developed dysphagia after definite treatment and were referred to speech-language pathologists (SLPs). We then classified patients into groups according to whether they received SSR. We used the clinical variables-including age, sex, site of malignancy, cancer stage, treatment modality, SSR, initial ECOG score, initial KPS, initial body weight (BW), and initial BMI-to evaluate the association between the percentage of BW change and overall survival (OS). There were 152 (39%) and 241 (61%) patients who received and did not receive SSR, respectively. In multivariate linear regression, SSR was significantly associated with percentage change in BW at 3 months post-treatment. Having SSR was positively associated with the percentage change in BW and decreased the BW loss [ß coefficient (95% CIs) = 2.53 (0.92 to 4.14)] compared to having no SSR. In the multivariate Cox regression, SSR was an independent factor for OS. Compared to no SSR, the hazard ratio (95% CIs) for patients who received SSR was 0.48 (0.31 to 0.74). SSR helps to avoid BW loss and increases overall survival. HNC patients who develop dysphagia after treatment should be encouraged to participate in SSR.