Decreased risk of radiation pneumonitis with concurrent use of renin-angiotensin system inhibitors in thoracic radiation therapy of lung cancer.

Background: Radiation pneumonitis (RP) is the primary dose-limiting toxicity associated with radiotherapy. This study aimed to observe the effects of renin-angiotensin system inhibitors in Chinese patients with lung cancer who received thoracic radiation. Methods: Patients with lung cancer who received thoracic radiation at a total dose of ≥45 Gray between October 2017 and December 2022 were enrolled in this study. We retrospectively evaluated the factors influencing grade 2 or higher RP. Results: A total of 320 patients were enrolled in this study; 62 patients were identified as angiotensin receptor blockers or angiotensin-converting enzyme inhibitor users. Additionally, 99 patients (30.9%) had grade 2 or higher RP, and the incidence in the renin-angiotensin system inhibitor group was 17.7% (11 out of 62 patients). Patients in the renin-angiotensin system inhibitors (RASi) group were older and had a higher percentage of males, lower percentage of ECOG score 0, higher percentage of hypertension, and higher percentage of adenocarcinoma than those in the non-RASi group. ECOG score [hazard ratio (HR) = 1.69, p = 0.009], history of smoking (HR = 1.76, p = 0.049), mean dose (HR = 3.63, p = 0.01), and RASi (HR = 0.3, p = 0.003) were independent predictive factors for RP. All subgroups benefited from RASi. Conclusion: This study showed that oral RASi administration has the potential to mitigate the incidence of grade 2 or higher RP in patients with lung cancer undergoing thoracic radiotherapy. To validate and further substantiate these findings, additional prospective research is warranted.

Renin-angiotensin system inhibitors mitigate radiation pneumonitis by activating ACE2-angiotensin-(1-7) axis via NF-κB/MAPK pathway.

Radiation pneumonitis (RP) affects both patients and physicians during radiation therapy for lung cancer. To date, there are no effective drugs for improving the clinical outcomes of RP. The activation of angiotensin-converting enzyme 2 (ACE2) improves experimental acute lung injury caused by severe acute respiratory syndrome coronavirus, acid inhalation, and sepsis. However, the effects and underlying mechanisms of ACE2 in RP remain unclear. Therefore, this study aimed to investigate the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on RP and ACE2/angiotensin-(1-7)/Mas receptor pathway activation. We found that radiotherapy decreased the expression of ACE2 and that overexpression of ACE2 alleviated lung injury in an RP mouse model. Moreover, captopril and valsartan restored ACE2 activation; attenuated P38, ERK, and p65 phosphorylation; and effectively mitigated RP in the mouse model. Further systematic retrospective analysis illustrated that the incidence of RP in patients using renin-angiotensin system inhibitors (RASis) was lower than that in patients not using RASis (18.2% vs. 35.8% at 3 months, p = 0.0497). In conclusion, the current findings demonstrate that ACE2 plays a critical role in RP and suggest that RASis may be useful potential therapeutic drugs for RP.

Comparative Study of Radiation-induced Lung Injury Model in Two Strains of Mice.

ABSTRACT: Radiation-induced lung injury (RILI) is a common complication of radiotherapy for thoracic tumor. Its incidence rate is as high as 20%. At present, there is no effective treatment in clinical practice. However, to study the mechanism of radiation-induced lung injury, we should first establish an appropriate animal model. In a series of scientific studies on RILI, mice are the animals most often chosen by researchers. However, there are few reports on which strain of mice is more suitable as a model of RILI. In this study, Kunming (KM) and C57BL/6 strains of mice were used as research objects to find the most suitable mice to replicate the RILI model. C57BL/6 mice and KM mice were exposed to irradiation at a dose of 20 Gy. The lung tissue of C57BL/6 mice exposed to radiation showed dilation and hyperemia of capillaries, infiltration of inflammatory cells, and thickening of alveolar septum, while the lung tissue of KM mice exposed to radiation was not as obvious as that of C57BL/6 mice. After irradiation, the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the lung tissue of C57BL/6 mice was significantly increased, while the expression of IL-6 and TNF-α in KM mice was almost unchanged. These studies showed that C57BL/6 mice are more suitable for the model of radiation-induced lung injury because of sensitive inflammatory reaction and the pathological changes of lung tissue.

Junctional Adhesion Molecule-Like Protein Promotes Tumor Progression and Metastasis via p38 Signaling Pathway in Gastric Cancer.

Junctional adhesion molecule-like protein (JAML), a newly discovered junctional adhesion molecule (JAM), mediates the adhesion and migration processes of various immune cells and endothelial/epithelial cells, ultimately regulating inflammation reaction. However, its role in tumors remains to be determined. The expression of JAML was examined in gastric cancer (GC) and peritumoral tissues from 63 patients. The relationship between JAML expression and clinical characteristics was also observed. In vitro, GC cell migration and proliferation were assessed by wound healing assay, transwell migration assay and EdU incorporation assay. Immunohistochemical staining results showed that JAML expression level was higher in GC tissues than in peritumoral tissues. High expression of JAML in cancer tissues was associated with worse cell differentiation, local lymph node involvement, deep infiltration, and advanced stage. In vitro, we found that JAML silencing inhibited GC cell migration and proliferation, while JAML overexpression promoted GC cell migration and proliferation, partially via p38 signaling. Taken together, our study revealed a critical role for JAML to promote GC cell migration and proliferation. JAML might be a novel diagnostic biomarker and therapeutic target for GC.

Epidemiology and survival outcomes of primary gastrointestinal melanoma: a SEER-based population study.

PURPOSE: Primary melanoma arising in the gastrointestinal (GI) tract is rare and poorly characterized. We sought to describe the epidemiology and survival outcomes of primary GI melanoma. PATIENTS AND METHODS: GI melanoma cases were extracted from the Surveillance, Epidemiology, and End Results (SEER) database by tumor site and histology codes. We calculated age-adjusted incidence, and analyzed demographics, clinical characteristics, as well as overall survival (OS) and cancer-specific survival (CSS) of GI melanoma. RESULTS: A total of 1080 histologically confirmed cases of primary GI melanoma were identified, with a median age of 71 years (IQR: 59-80). 49.9% of the cases originated from anus, 30.8% had distant disease at diagnosis, and 61.5% received cancer-directed surgery. The distribution of gender and age was varied in GI melanoma subtypes. The incidence of GI melanoma was 0.58 cases per million, and increased remarkably over age, especially in patients aged 60 years or older. The median OS and CSS of the whole cohort was 14 months (95% CI 12.7-15.3) and 22 months (95% CI 18.8-25.2), respectively. Anal melanoma patients had prolonged survival, while those with gastric melanoma had the poorest OS (18 and 4 months, respectively). Multivariate analysis showed that decreased survival was associated with age older than 80 years, gastric and esophageal origin, advanced-stage disease, lymph node metastasis, and without surgery of primary site. CONCLUSION: Patients with primary GI melanoma trended to present with advanced-stage disease. Overall, GI melanoma had a poor prognosis, but the outcome differed according to the primary sites.

Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer.

The immunity is dual host-protective and tumor-promoting in cancer development and progression. Many immune suppressive cells and cytokines in microenvironment can prevent cytotoxic T lymphocytes (CTL) and natural killer cells (NK) from killing tumor cells. Chemotherapy drugs and irradiation have been reported helpful in breaking immune tolerance and creating microenvironment for adoptive cell therapy. Low-dose cyclophosphamide or gemcitabine therapy can selectively deplete T regulatory cells (Treg). Paclitaxel can alter cytokine network at the tumor site, and 5-fluorouracil shows a pronounced effect on myeloid-derived suppressor cells (MDSC) depletion. Local tumor irradiation and total body irradiation (TBI) can also affect tumor microenvironment and facilitate immunotherapy. In this review, we summarize the particular effects of these agents and methods on immunomodulation, as well as their potential values in immunotherapy. The combination with immunotherapy represents a novel therapeutic strategy.

[Application of standardized uptake value for FDG PET-CT in predicting radiation pneumonitis].

OBJECTIVE: To investigate the correlation of radiation pneumonitis (RP) with standardized uptake value (SUV) for fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET-CT) in lung cancer patients treated with radiation therapy. METHODS: Fourty patients with unresectable non-small cell lung cancer (NSCLC) received FDG PET-CT before and after radiotherapy. The average SUV of the lung tissue irradiated with a dose of < or = 5 Gy, 5.1 approximately 15 Gy, 15.1 approximately 35 Gy, 35.1 approximately 60 Gy, >60 Gy were measured. The correlation between SUV and RP was analyzed by comparing the SUV in the patients with RP and without. The SUV ratio of the irradiated lung tissue to that of the non-irradiated lung tissue (L/B) was also calculated. RESULTS: Of the 40 patients, 8 developed RP, including 6 cases of grade 2 and 2 cases of grade 3. The SUV of irradiated lung tissues with a dose of 35.1 approximately 60 Gy was significantly correlated with RP. When SUV > or =1, the RP incidence rate was 41.7% versus 20.0% in the whole group, with a statistically significant difference. (chi2 = 3.96, P < 0.05). The sensitivity and specificity of SUV in predicting RP was 62.5% and 78.1%, respectively. When the value of L/B > or = 2.5, the RP incidence rate was 40.7% in this group versus 20.0% in the whole group, with a statistical significance (chi(2) = 4.92, P < 0.05). If taking L/B > or = 2.5 as a threshold value, the sensitivity and specificity in predicting RP was 72.7% and 90.9%, respectively. No statistically significant difference was found in predicting radiation pneumonitis between SUV > or =1 and L/B > or = 2.5 (chi2 = 0.002, P > 0.05). CONCLUSION: The standardized uptake value (SUV) and the SUV ratio of the irradiated lung tissue to that of the non-irradiated lung tissue (L/B) for FDG PET-CT are positively correlated with radiation pneumonitis, and clinicians may use it to predict the occurrence of radiation pneumonitis.