Proposals for the delineation of neck clinical target volume for definitive Radiation therapy in patients with oral/ oropharyngeal squamous cell cancer based on lymph node distribution.

PURPOSE/OBJECTIVE(S): To establish the distribution pattern of cervical lymph node metastasis (LNM) and propose optimized clinical target volume (CTV) boundaries specific to oral/ oropharyngeal squamous cell cancer (OSCC/OPSCC). MATERIALS/METHODS: 531 patients with pathologically confirmed OSCC/OPSCC were enrolled from January 2013 to June 2022. Patients were stratified into two groups based on the minimal distance from the lesion's edge to the body's midline: ≤1 cm or > 1 cm. The geometric center of cervical metastatic LN was marked on a template CT. LN distribution probability maps were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to OSCC/OPSCC. RESULTS: A total of 1962 positive LNs were enrolled. Compared with the > 1 cm group, the ≤ 1 cm group has following feature tendencies: male smokers, younger, median organs, large gross lesion, infiltrative growth pattern, contralateral LNM. The most frequently involved level of LNM was ipsilateral II, but ipsilateral Ib had the highest involvement rate in the > 1 cm OSCC group. In addition, tongue cancer had a higher incidence of LN extranodal extension (ENE), which mainly distributes in ipsilateral level II. The skip metastasis was prone to from level III to Vb (3.5 %) in LN(+)/ENE (-), and level Ib to VIa (3.7 %) in LN(+)/ENE (+). Accordingly, we proposed the following modifications: 1. only including lateral and posterior margin of submandibular gland within 5 mm; 2. retracting posterior boundary of level II to front edge of levator scapula muscle, and descending the upper boundary to transverse process of C2 vertebra only for OSCC; 3. including posterior third of thyroglossal muscle or anterior edge of sternocleidomastoid muscle; 4. sparing level Va in case of only level II involvement; 5. including upper area of the thyroid cartilage plate in case of level Ib LN(+)/ENE (+); 6. sparing level VIIa is considered. CONCLUSION: This is the first description of LN topographic spread patterns for OSCC/OPSCC. Modified CTV for prophylactic irradiation was proposed to spare the organs at risk and minimize adverse effects.

The effectiveness of various treatment approaches for laryngeal contact granulomas.

OBJECTIVES: To assess and compare the effectiveness of various treatment approaches for laryngeal contact granulomas (LCG). METHODS: A retrospective analysis was conducted on a cohort of 45 patients diagnosed with LCG at the Second Affiliated Hospital of Xi'an Jiaotong University from October 2017 to May 2023. Based on the treatment modalities administered, patients were categorized into three groups: acid suppression alone, hormone injection combined with acid suppression, and surgery combined with acid suppression. Subsequently, the study compared differences in treatment efficacy and average healing time among these three groups, using various indicators. RESULTS: The findings indicate that the granuloma size in LCG patients with hoarseness (0.126, 95% CI 0.087-0.288) was significantly greater compared to LCG patients without hoarseness (0.047, 95% CI 0.014-0.083) (P = 0.001). However, there were no significant variations in age, morphology (unlobulated/lobulated), laterality ratio (left/right), sex ratio (male/female), history of tracheal intubation (non-intubation/intubation), and RFS score (RFS > 7/RFS ≤ 7) (P > 0.05), regardless of the presence of hoarseness symptoms. At the treatment observation endpoint of 3 months, the curative ratio in the group receiving hormone injection combined with acid suppression was found to be significantly higher compared to the group receiving acid suppression alone (P = 0.018). In addition, the average healing time of patients in the hormone injection combined with acid suppression group was notably shorter than that of the acid suppression alone group (P = 0.007). CONCLUSIONS: The combination of hormonal injections and acid suppression may enhance the curative ratio and expedite the healing time of LCG.

The subglottic involvement is an independent risk factor for recurrence of laryngeal amyloidosis.

OBJECTIVE: To analyze the risk factors for recurrence of laryngeal amyloidosis (LA). METHODS: The clinical data of patients with LA admitted in the Otolaryngology Head and Neck Surgery Department of the Second Affiliated Hospital of Xi'an Jiaotong University from August 2009 to June 2022 were analyzed retrospectively; then, the risk factors for recurrence and their impacts on the recurrence time were also analyzed. RESULTS: Of the 44 patients with LA, the majority (38 cases, 86.4%) only involved one anatomical region and the others (6 cases, 13.6%) involved two laryngeal regions concurrently. Overall, the glottic region was the most commonly affected area (28 cases, 63.6%), followed by the supraglottic region (16 cases, 36.4%) and subglottic region (6 cases, 13.6%). In addition, all the lesions were categorized as isolated nodule (31.8%), submucosal localized deposition (52.3%), and submucosal diffuse deposition (15.9%) according to their morphologies under electronic laryngoscope. Finally, six patients (13.6%) had recurrence after operation with a median recurrence time of 24.5 months, and subglottic involvement was confirmed to be an independent risk factor for recurrence of LA by univariate and multivariate logistic regression analyses (P < 0.05). Meanwhile, the patients with subglottic involvement presented as submucosal diffuse deposition had a considerable shorter recurrence time (t = 5.759, P = 0.005). CONCLUSION: The subglottic involvement is an independent risk factor for recurrence of LA.

[Effects of Decitabine Combined with Anlotinib on Proliferation and Apoptosis of Multiple Myeloma Cells].

OBJECTIVE: To investigate the biological effects and its relative mechanism of decitabine combined with anlotinib on multiple myeloma cells. METHODS: The human MM cell lines and primary cells were treated with different concentrations of decitabine, anlotinib, and decitabine+anlotinib, respectively. The cell viability was detected and combination effect was calculated by CCK-8 assay. The apoptosis rate was measured by flow cytometry and the level of c-Myc protein was determined by Western blot. RESULTS: Both decitabine and anlotinib could effectively inhibit the proliferation and induce the apoptosis of MM cell lines NCI-H929 and RPMI-8226. The effect of combined treatment on the inhibition of cell proliferation and induction of apoptosis was stronger than that of single-drug treatment. The combination of the two drugs also showed strong cytotoxicity in primary MM cells. Decitabine and anlotinib could down-regulate the level of c-Myc protein in MM cells and the c-Myc level in the combination group was the lowest. CONCLUSION: Decitabine combined with anlotinib can effectively inhibit the proliferation and induce apoptosis of MM cells, which provides a certain experimental basis for the treatment of human MM.

Radiation-induced eosinophil increase ratio predicts patient outcomes in non-small celllung cancer.

Background and purpose: Radiotherapy (RT) is a double-edged sword in regulating immune responses. This study aimed to investigate the impact of thoracic RT on circulating eosinophils and its association with patient outcomes in non-small cell lung cancer (NSCLC). Materials and methods: This retrospective study included 240 patients with advanced NSCLC treated with definitive thoracic RT from January 2012 to January 2020. Statistics included Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS), multivariate Cox analyses to identify significant variables, and Spearman's correlation to qualify the relationship between dose-volume histogram (DVH) parameters and EIR. Results: Absolute eosinophil counts (AECs) showed an increasing trend during RT and an obvious peak in the 1st month after RT. Thresholds of eosinophil increase ratio (EIR) at the 1st month after RT for both OS and PFS were 1.43. Patients with high EIR above 1.43 experienced particularly favorable clinical outcomes (five-year OS: 21% versus 10%, P<0.0001; five-year PFS: 10% versus 8%, P=0.014), but may not derive PFS benefit from the addition of chemotherapy to RT. The higher a patient's EIR, the larger the potential benefit in the absence of chemotherapy. DVH parameters including heart mean dose and heart V10 were negatively associated with EIR. None of these DVH parameters was correlated with the clinical outcomes. Conclusion: EIR may serve as a potential biomarker to predict OS and PFS in NSCLC patients treated with RT. These findings require prospective studies to evaluate the role of such prognostic marker to identify patients at risk to tailor interventions.

Synthesis and in vitro biological evaluation of novel dendrocandin analogue as potential anti-tumor agent.

Dendrocandins are characteristic chemical structures of D. officinale and have strong physiological bioactivities. In this study, a dendrocandin analogue (1) has been prepared by total synthesis (9 steps, 12.6% overall yield) in which coupling reaction and Wittig reaction as the key steps. Compound 1 was also evaluated for its anticancer activity in vitro against six human cancer cells (MCF-7, A549, A431, SW480, HepG-2 and HL-60) using MTT assays. Compound 1 showed potent cytotoxicity, with the IC50 value 16.27 ± 0.26 µM. The expression levels of apoptotic proteins indicated that compound 1 can up-regulate the expression of apoptotic proteins, leading to apoptosis. This compound suggested that it's potential as anticancer agent for further development.

Protein Phosphatase 2A-Dependent Mitotic hnRNPA1 Dephosphorylation and TERRA Formation Facilitate Telomere Capping.

The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2-M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ataxia telangiectasia and Rad3-related (ATR)-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance. IMPLICATIONS: This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.

Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review.

Background and Objective: Radiotherapy (RT) is one of the fundamental anti-cancer regimens by means of inducing in situ tumor vaccination and driving a systemic anti-tumor immune response. It can affect the tumor microenvironment (TME) components consisting of blood vessels, immunocytes, fibroblasts, and extracellular matrix (ECM), and might subsequently suppress anti-tumor immunity through expression of molecules such as programmed death ligand-1 (PD-L1). Immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD-1)/PD-L1 therapies, have been regarded as effective in the reinvigoration of the immune system and another major cancer treatment. Experimentally, combination of RT and ICIs therapy shows a greater synergistic effect than either therapy alone. Methods: We performed a narrative review of the literature in the PubMed database. The research string comprised various combinations of "radiotherapy", "programmed death-ligand 1", "microenvironment", "exosome", "myeloid cell", "tumor cell", "tumor immunity". The database was searched independently by two authors. A third reviewer mediated any discordance of the results of the two screeners. Key Content and Findings: RT upregulates PD-L1 expression in tumor cells, tumor-derived exosomes (TEXs), myeloid-derived suppressor cells (MDSCs), and macrophages. The signaling pathways correlated to PD-L1 expression in tumor cells include the DNA damage signaling pathway, epidermal growth factor receptor (EGFR) pathway, interferon gamma (IFN-γ) pathway, cGAS-STING pathway, and JAK/STATs pathway. Conclusions: PD-L1 upregulation post-RT is found not only in tumor cells but also in the TME and is one of the mechanisms of tumor evasion. Therefore, further studies are necessary to fully comprehend this biological process. Meanwhile, combination of therapies has been shown to be effective, and novel approaches are to be developed as adjuvant to RT and ICIs therapy.

The oxidation of (-)-epigallocatechin-3-gallate inhibits T-cell acute lymphoblastic leukemia cell line HPB-ALL via the regulation of Notch1 expression.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and commonly associated with activating mutations in the Notch1 pathway. (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant and active catechin and has been shown to regulate Notch signaling. Taking into account the highly oxidizable and unstable of EGCG, we proposed that EGCG oxides may have greater potential to regulate Notch signaling than EGCG. In this study, we isolated and identified EGCG oxides (compound 2-4), using a chemical oxidation strategy, and evaluated for cytotoxicity against T-cell acute lymphoblastic leukemia cell line (HPB-ALL) by using the MTS assay. We found compound 3 significantly induced cell proliferation inhibition (38.3858 ± 1.67106 µM), cell apoptosis and cell cycle arrest in a dose-dependent manner. Remarkably, compound 3 inhibited expression of Notch1 compared with EGCG in HPB-ALL cells. Meanwhile, we found that compound 3 significantly inhibited c-Myc and Hes1, which are downstream target genes of Notch1. The findings demonstrate for the first time that an oxidation product of EGCG (compound 3) inhibits T-cell acute lymphoblastic leukemia cell line (HPB-ALL) and is a promising agent for cancer therapy deserving further research.