The Role of Thoracic Vertebral Body Dosimetry in Minimizing Acute Hematologic Toxicities of Patients With Non-Small Cell Lung Cancer Receiving Lung Radiation Therapy and Immunotherapy.

PURPOSE: Hematologic toxicities (HTs) are among the most common toxicities of combined immunotherapy and radiation therapy (RT). It remains essential to prevent RT-induced HTs because they can cause treatment discontinuation (influencing antitumoral effects) and because lymphopenia might dampen the effects of immunotherapy. To date, there are no studies examining the effect of thoracic vertebral body (TVB) RT dose on HTs in patients with non-small cell lung cancer receiving combined lung RT and programmed cell death (ligand) 1 immunotherapy. METHODS AND MATERIALS: For standardization, all doses were reported as 2-Gy equivalents (EQD2). Mirroring publications before the immunotherapy era, TVB volumes referred to T1-T10, and specific dosimetric parameters (DmeanEQD2, V5EQD2-V60EQD2) were analyzed. Logistic regression estimated associations between grade ≥3 HTs (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability (NTCP) models were constructed by logistic regression analysis modeling for HT3+. Receiver operating characteristic (ROC) analysis delineated TVB dosimetric thresholds, the stratification of which was able to evaluate post-RT absolute lymphocyte count and immunotherapy responses. Areas under the curve (AUCs) for NTCP models were corroborated by bootstrapping (optimism-corrected) methodology. RESULTS: In 132 patients, there were 26 (19.7%) instances of HT3+. On multivariate analysis, DmeanEQD2 and V5EQD2 to V20EQD2 were associated with HT3+ (P < .05 for all). The NTCP models illustrated a 50% probability of HT3+ at a DmeanEQD2 = 39.8 Gy, V5EQD2 = 87.4%, V10EQD2 = 77.0%, and V20EQD2 = 68.4%. ROC analysis delineated optimal thresholds of HT3+ with DmeanEQD2 ± 30.2 Gy, V5EQD2 ± 69.1%, V10EQD2 ± 64.6%, and V20EQD2 ± 53.5%. Patients treated with values above those cutoffs had over double the risk of HT3+, with significant differences in post-RT absolute lymphocyte count and immunotherapy responses (P < .05 for all). AUCs for each individual parameter ranged from 0.743 to 0.798, and combining all 4 aforementioned cutoffs into a ROC curve resulted in a qualitatively higher AUC (0.836). CONCLUSIONS: This hypothesis-generating work suggests that TVB dosimetry may equate with HT3+ in patients with non-small cell lung cancer undergoing combined lung RT/immunotherapy. Applying TVB dose constraints in this population could reduce HT3+ and avoid dampening of immunotherapy responses, but prospective validation is required.

Gustave Roussy immune score is a prognostic marker in patients with small cell lung cancer undergoing immunotherapy: a real-world retrospective study.

Background: The utilization of the Gustave Roussy Immune Score (GRIm-Score) in patient selection for immunotherapy was initially reported. The objective of this retrospective study is to assess the potential of the GRIm-Score, a novel prognostic score based on nutritional and inflammatory markers, as a prognostic predictor in patients with small cell lung cancer (SCLC) undergoing immunotherapy. Methods: This retrospective study conducted at a single center included 159 patients with SCLC who received immunotherapy. The objective of the study was to investigate potential differences in overall survival (OS) and progression-free survival (PFS) among patients stratified by their GRIm-Score, utilizing the Kaplan-Meier survival analysis and the log-rank test. The final independent prognostic factors were identified through both propensity score matching (PSM) analysis and multivariable Cox proportional hazards regression analysis. Results: Our analysis of the 159 patients revealed that there was a significant decrease in both OS and PFS with each increase in the GRIm-Score group, displaying a stepwise pattern. Moreover, even after conducting PSM analysis, the significant associations between the modified three-category risk scale-based GRIm-Score and survival outcomes remained significant. Both the total cohort and PSM cohort were subjected to multivariable analysis, which demonstrated that the three-category risk assessment-based GRIm-Score was a valuable predictor of both OS and PFS. Conclusions: In addition, the GRIm-Score may serve as a valuable and non-invasive prognostic predictor for SCLC patients undergoing PD1/PD-L1 immunotherapy.

Asymptomatic adult Wilms' tumor: A case report.

Wilms' tumor, also called nephroblastoma, is an extremely uncommon kidney tumor of adulthood. We reported a adult man with a left kidney mass diagnosed as Wilms' tumor. Case presentation: A 25-year-old man was hospitalized due to injury of the anterior cruciate ligament of the right knee. Preoperative imaging accidentally revealed a mass measuring 53 × 46 mm involving the middle and lower segments of the left kidney without evidence supporting the invasion of the surrounding structures or metastasis. The patient didn't show any symptom commonly occurred in Wilms' tumor, such as flank pain or hematuria. After nephrectomy, the diagnosis of adult Wilms' tumor was confirmed based on the tumor morphology and immunohistochemical findings. Conclusion: In adult patients without any clinical manifestations or favorable imaging findings for low-stage renal cell carcinoma, the diagnosis of Wilms' tumor should be taken into consideration.

Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aß1­42­induced degeneration.

Alzheimer's disease (AD), one of the most common types of chronic neurodegenerative diseases, is pathologically characterized by the formation of amyloid ß (Aß) peptide­containing plaques and neurofibrillary tangles. Among Aß peptides, Aß1­42 induces neuronal toxicity and neurodegeneration. In our previous studies, Cdk5 was found to regulate Aß1­42­induced mitochondrial fission via the phosphorylation of dynamin­related protein 1 (Drp1) at Ser579. However, whether blockage of Drp1 phosphorylation at Ser579 protects neurons against Aß1­42­induced degeneration remains to be elucidated. Thus, the aim the present study was to examine the effect of mutant Drp1­S579A on neurodegeneration and its underlying mechanism. First, the phosphorylation­defect (phospho­defect) mutant, Lenti­Drp1­S579A was constructed. Phospho­defect Drp1­S579A expression was detected in primary cultures of mouse cortical neurons infected with Lenti­Drp1­S579A using western blotting and it was found to successfully attenuate the phosphorylation of endogenous Drp1 at Ser579. In primary neuronal cultures, the neuronal processes were evaluated under microscopy. Treatment with 10 µM Aß1­42 significantly decreased dendritic density and length, spine outgrowth and synapse number. As expected, infection of neurons with Lenti­Drp1­S579A efficiently alleviated the inhibitory effect of Aß1­42 on neurite outgrowth and synapse density. In addition, infection with Lenti­Drp1­S579A abolished the cleavage of caspase­3 and apoptosis in neurons exposed to Aß1­42. Thus, the current data demonstrated that blockage of Drp1 phosphorylation at Ser579 may be an effective strategy to protect neurons against Aß1­42­induced degeneration and apoptosis. These findings underline the therapeutic potential of targeting Drp1 in the treatment of AD.

Downregulation of astrocyte elevated gene-1 expression inhibits the development of vasculogenic mimicry in gliomas.

Vasculogenic mimicry (VM) contributes to the resistance of anti-angiogenic therapies in glioma. Certain genes, including MMP-2 and VEGF may be associated with the development of VM. Astrocyte elevated gene-1 (AEG-1) is considered to be an oncogene that promotes autophagy, invasion, metastasis, angiogenesis and drug resistance; however, the association between AEG-1 and VM formation is still unknown. The present study investigated the effects of AEG-1 downregulation on VM formation in the U87 glioma cell line in vitro and in xenograft models of glioma, and the potential underlying mechanisms of action. In the present study, U87 glioma cells were infected with the AEG-1 short hairpin RNA lentivirus. A Matrigel-based tube formation assay was performed to evaluate VM formation in vitro. Reverse transcription-quantitative PCR and western blot analysis were conducted to investigate the mRNA and protein expression levels of MMP-2 and VEGF. Glioma xenograft models were generated through the intracerebral implantation of U87 glioma cells into nude rats; CD34/Periodic Acid-Schiff double-staining was performed to detect VM channels in vivo. Following AEG-1 downregulation in U87 cells, the development of VM was significantly decreased in vitro and in vivo. In addition, the expression levels of MMP-2 and VEGF in glioma cells were decreased compared with the control group. These results suggested that downregulation of AEG-1 expression could significantly inhibit the development of VM in gliomas, both in vitro and in vivo, and may be partially related to the regulation of VEGF and MMP-2 expression.

[Effects and mechanism of decorin on the proliferation of HuH7 hepatoma carcinoma cells in vitro].

AIM: To investigate the effects and mechanism of decorin( DCN) on the proliferation of HuH7 hepatoma carcinoma cell line in vitro. METHODS: Hepatoma carcinoma cells was cultured with DCN in different concentration (0, 25, 50, 75, 100, 125, 150, 200 microg/L) for different time(12, 24, 48, 72 h and 2 weeks). Cell activities were studied by MTT and clone test. The changes of cell cycle and apoptosis were analyzed by Flow cytometry. RESULTS: The proliferation of HuH7 cells could be inhibited by DCN in vitro and the inhibition effect was the time and dose dependent relationship. DCN could block cell cycle at G(1); phase. Apoptosis of hepatocarcinoma cells could be efficiently induced by DCN in a time/dose-dependent manner. CONCLUSION: DCN may be a negative regulatory protein inhibiting hepatoma carcinoma cell proliferation through inhibiting cell cycle and inducing apoptosis of cell in vitro.