Epigenetic Reprogramming Potentiates ICAM1 Antibody Drug Conjugates in Preclinical Models of Melanoma.

Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1-DXd) is elucidated. DAC treatment significantly enhanced anti-tumor efficacy of I1-DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1-DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment.

Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis.

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m2, without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC.

Efficacy and safety of anlotinib combined with the STUPP regimen in patients with newly diagnosed glioblastoma: a multicenter, single-arm, phase II trial.

OBJECTIVE: Glioblastomas are highly vascularized malignant tumors. We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor, anlotinib, for a newly diagnosed glioblastoma. METHODS: This multicenter, single-arm trial (NCT04119674) enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020. Patients underwent treatment with the standard STUPP regimen [fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w × 6 w (total = 54-60 Gy)] or radiotherapy plus continuous daily temozolomide (TMZ) (75 mg/m2 of body surface area/d, 7 d/w from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant TMZ (150-200 mg/m2 × 5 d during each 28-d cycle) plus anlotinib (8 mg/d on d 1-14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy, 8 maximal cycles as adjuvant therapy, followed by maintenance at 8 mg/d. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). RESULTS: Thirty-three patients received the planned treatment. The median PFS was 10.9 months (95% CI, 9.9-18.7 months) and the 12-month PFS rate was 48.5%. The median OS was 17.4 months (95% CI, 14.5-21.1 months) and the 12-month OS rate was 81.8%. The most common AEs included hypertriglyceridemia [58% (n = 19)], hypoalbuminemia [46% (n = 15)], and hypercholesterolemia [46% (n = 15)] during concurrent chemoradiotherapy and leukopenia [73% (n = 24)], hypertriglyceridemia [67% (n = 22)], and neutropenia [52% (n = 17)] during adjuvant therapy. Five patients discontinued treatment due to AEs. HEG1 (HR, 5.6; 95% CI, 1.3-23.7; P = 0.021) and RP1L1 alterations (HR, 11.1; 95% CI, 2.2-57.2; P = 0.004) were associated with a significantly shorter PFS. CONCLUSIONS: Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity. HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors.

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice.

Ultrasound-Induced Tumor Perfusion Changes and Doxorubicin Delivery: A Study on Pulse Length and Pulse Repetition Frequency.

OBJECTIVES: To investigate the appropriate combination of pulse length (PL) and pulse repetition frequency (PRF) when performing ultrasound stimulated microbubble (USMB) to enhance doxorubicin (DOX) delivery to tumors. METHODS: A total of 48 tumor-bearing mice were divided into four groups, namely groups A-D. The mice in groups B-D were treated with chemotherapy and USMB treatment with different combinations of PL and PRF, and group A was control. Contrast-enhanced ultrasound imaging was conducted to analyze tumor blood perfusion. Fluorescence microscopy and high-performance liquid chromatography were used to qualitatively and quantitatively analyse DOX release. The structural changes of tumors were observed under light microscope and transmission electron microscope. Furthermore, another 24 tumor-bearing mice were treated with sonochemotherapy and some related inflammatory factors were measured to explore the underlying mechanism. RESULTS: With PL of three cycles and PRF of 2 kHz, the tumor perfusion area ratio increased by 26.67%, and the DOX concentration was 4.69 times higher than the control (P < .001). With PL of 34.5 cycles and PRF of 200 Hz, the tumor perfusion area ratio decreased by 12.7% and DOX did not exhibit increased extravasation compared with the control. Microvascular rupture and hemorrhage were observed after long PL and low PRF treatment. While vasodilation and higher levels of some vasodilator inflammatory factors were found after treatment with short PL and high PRF. CONCLUSIONS: USMB treatment using short PL and high PRF could enhance tumor blood perfusion and increase DOX delivery, whereas long PL and low PRF could not serve the same purpose.

Augmentation of tumour perfusion by ultrasound and microbubbles: A preclinical study.

BACKGROUND: Hypoperfusion and the resulting hypoxia in solid tumours are critical causes of treatment resistance. Ultrasound-stimulated microbubbles (USMB) enhance tumour perfusion in a mechanism named the "sononeoperfusion" effect, which may relieve tumour hypoperfusion and hypoxia. The aim of this study was to determine the optimal mechanical index (MI) and therapeutic ultrasound exposure time for the sononeoperfusion effect and preliminarily explore the mechanism of sononeoperfusion and its effect on tumours. METHODS: A total of 155 mice bearing MC38 tumours were included in this study. A modified diagnostic ultrasound and microbubbles (Zhifuxian) was used for USMB treatment. Tumour perfusion was evaluated by contrast-enhanced ultrasound (CEUS) and Hoechst 33342. The therapeutic pulse was operated with MIs of 0.1 to 0.5. The ultrasound exposure time was set from 150 s to 600 s. Endothelial nitric oxide synthase (eNOS) inhibition and NO, ATP, and phospho-eNOS (p-eNOS) detection were performed to explore the mechanisms of sononeoperfusion. Hypoxia-inducible factor-1α (HIF-1α) and tumour oxygen partial pressure (pO2) represent hypoxic tumour conditions. RESULTS: Tumour perfusion was increased after USMB treatment at MIs of 0.1-0.4 and ultrasound exposure times of 150 s to 600 s, with optimal augmentation achieved at an MI of 0.3 and ultrasound exposure time of 450 s. The mean fluorescence intensity of Hoechst 33342 after USMB treatment was stronger than that of the control group. Biochemical assays showed a significant increase in ATP, p-eNOS and NO after USMB treatment. PO2 in tumour tissue increased significantly after USMB treatment and was maintained for more than 20 min. CONCLUSIONS: The best sononeoperfusion effect was obtained with an MI of 0.3 and an ultrasound exposure time of 450 s. The effect is most likely related to NO and ATP increases. The sononeoperfusion effect might be a novel way to ameliorate tumour hypoperfusion and hypoxia.

PI3K/mTOR inhibitors promote G6PD autophagic degradation and exacerbate oxidative stress damage to radiosensitize small cell lung cancer.

Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.

Sononeoperfusion effect by ultrasound and microbubble promotes nitric oxide release to alleviate hypoxia in a mouse MC38 tumor model.

Tumor hypoperfusion not only impedes therapeutic drug delivery and accumulation, but also leads to a hypoxic and acidic tumor microenvironment, resulting in tumor proliferation, invasion, and therapeutic resistance. Sononeoperfusion effect refers to tumor perfusion enhancement using ultrasound and microbubbles. This study aimed to further investigate hypoxia alleviation by sononeoperfusion effect and explore the characteristics and mechanism of sononeoperfusion effect. To stimulate the sononeoperfusion effect, mice bearing MC38 colon cancers were included in this study and diagnostic ultrasound for therapy was set at a mechanical index (MI) of 0.1, 0.3, and 0.5, frequency of 3 MHz, pulse length of 5 cycles, and pulse repetition frequency of 2000 Hz. The results demonstrated that a single ultrasound and microbubble (USMB) treatment resulted in tumor perfusion enhancement at MI = 0.3, and nitric oxide (NO) concentration increased at MI = 0.3/0.5 (P < 0.05). However, there were no significant difference in the hypoxia-inducible factor-1α (HIF-1α) or D-lactate (D-LA) (P > 0.05) levels. Multiple sononeoperfusion effects were observed at MI = 0.3/0.5 (P < 0.05). For each treatment, USMB slightly but steadily improved the tumor tissue oxygen partial pressure (pO2) during and post treatment. It alleviated tumor hypoxia by decreasing HIF-1α, D-LA level and the hypoxic immunofluorescence intensity at MI = 0.3/0.5 (P < 0.05). The sononeoperfusion effect was not stimulated after eNOS inhibition. In conclusion, USMB with appropriate MI could lead to a sononeoperfusion effect via NO release, resulting in hypoxia amelioration. The tumors were not resistant to multiple sononeoperfusion effects. Repeated sononeoperfusion is a promising approach for relieving tumor hypoxia and resistance to therapy.

The Isolation, Genetic Analysis and Biofilm Characteristics of Listeria spp. from the Marine Environment in China.

Listeria monocytogenes is an important pathogen that can cause listeriosis. Despite the growing recognition of Listeria spp. as a foodborne and environmental pathogen, the understanding of its prevalence and characteristics of Listeria spp. in the marine environment remains unknown. In this study, we first investigated the genetic and phenotypic characteristics of Listeria species isolated in a coastal city in China. The findings revealed that the sequence type 87 (ST87) L. monocytogenes, a prevalent clinical and seafood strain in China, dominates in recreational beach sands and possesses a notable biofilm-forming capacity in seawater. The presence of ST87 L. monocytogenes in coastal environments indicates the potential health risks for both recreational activities and seafood consumption. Moreover, the ST121 isolates from sand had a versatile plasmid encoding multifunctional genes, including uvrX for UV resistance, gbuC for salt resistance, and npx for oxidative resistance and multiple transposases, which potentially aid in survival under natural environments. Black-headed gulls potentially facilitate the spread of L. monocytogenes, with similar ST35 strains found in gulls and beach sand. As a reservoir of microbes from marine environments and human/animal excrement, coastal sand would play an important role in the spread of L. monocytogenes and is an environmental risk for human listeriosis.

Exploration of the application of Grey-Markov models in the causality analysis of traffic accidents in roundabouts.

We propose a multivariate Grey-Markov model to quantify traffic accident risk from different causality factors in roundabouts that is uniquely suited for the scarce and stochastic traffic crash data from roundabouts. A data sample of traffic crashes occurring in roundabouts in the U.S. State of Michigan from 2016 to 2021 was collected to investigate the capabilities of this modeling methodology. The multivariate grey model (MGM(1,4)) was constructed using grey relational analysis to determine the best dimensions for model optimization. Then, the Markov chain is introduced to address the unfitness of stochastic, fluctuating data in the MGM(1,4) model. Finally, our proposed hybrid MGM(1,4)-Markov model is compared with other models and validated. This study highlights the superior predictive performance of our MGM(1,4)-Markov model in fore-casting roundabout traffic accidents under data-limited conditions, achieving a 3.02% accuracy rate, in contrast to the traditional GM(1,1) model at 8.30% and the MGM(1,4) model at 4.47%. Moreover, incorporating human, vehicle, and environmental risk factors into a multivariate crash system yields more accurate predictions than merely aggregating crash counts.

T1-2N1M0 nasopharyngeal carcinoma chemotherapy or not: A retrospective study.

BACKGROUND: Radiotherapy (RT) combined with chemotherapy is the standard treatment for T1-2N1M0 nasopharyngeal carcinoma (NPC) based on conventional radiotherapy. However, intensity-modulated radiotherapy (IMRT) has narrowed the treatment gap between RT and chemoradiotherapy. Thus, this retrospective study aimed to compare the efficacy of RT and chemoradiotherapy (RT-chemo) in treating T1-2N1M0 NPC in the IMRT era. MATERIALS AND METHODS: From January 2008 to December 2016, 343 consecutive patients with T1-2N1M0 NPC in two cancer centers were included. All patients received RT or RT-chemo, chemotherapy including induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT), CCRT, or CCRT + adjuvant chemotherapy (AC). The number of patients who received RT, CCRT, IC + CCRT, and CCRT + AC was 114, 101, 89, and 39. The survival rates were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariable analysis was performed to identify valuable prognostic factors. RESULTS: The median follow-up time for survivors was 93 (range: 55-144) months. The 5-year overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) for the RT-chemo and RT groups were 93.7%, 88.5%, 93.8%, 93.8% and 93.0%, 87.7%, 91.9%, 91.2%, respectively (P>0.05 for all outcomes). No significant survival differences were found between the two groups. The T1N1M0 or T2N1M0 subgroup analysis showed that treatment outcomes had no significant differences between the RT and RT-chemo groups. After adjusting for various factors, treatment mode was not identified as an independent prognostic factor for all survival rates. CONCLUSIONS: In this study, outcomes of T1-2N1M0 NPC patients treated by IMRT alone were comparable to chemoradiotherapy, supporting the omission or postponement of chemotherapy.

Radiotherapy opens the blood-brain barrier and synergizes with anlotinib in treating glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a poor prognosis and lacks effective treatment. Anlotinib is a multitargeted receptor tyrosine kinase inhibitor (TKI) that may have anti-tumor activity in the central nervous system (CNS). This study aimed to determine the therapeutic value of radiotherapy combined with anlotinib in GBM via preclinical research. METHODS: HPLC-MS/MS was used to assess the concentration of anlotinib in blood and brain samples. Cell proliferation assays, flow cytometry, and colony formation assays were performed in vitro. The potential value of anlotinib or in combination with radiotherapy for GBM treatment was estimated in vivo. Western blotting, immunohistochemistry, and immunofluorescent staining were performed to determine the underlying mechanism. RESULTS: Anlotinib effectively inactivated the JAK3/STAT3 pathway to inhibit growth and induce apoptosis in malignant glioma cells (MGCs) independent of MGMT expression. Meanwhile, anlotinib induces MGCs G2/M arrest and sensitizes MGCs to radiation. Radiation down-regulates claudin-5 and weakens the blood-brain barrier (BBB), which contributes to the increased distribution of anlotinib in the CNS by 1.0-2.9 times. Anlotinib restrains tumor growth (PCNA), inhibits tumor microvascular proliferation (CD31), and alleviated intratumor hypoxia (HIF 1α) in vivo. Anlotinib alone or in combination with radiation is effective and safe in vivo evaluation. CONCLUSIONS: We discovered that anlotinib, the original small molecule antiangiogenesis TKI, down-regulates JAK3/STAT3 axis with anti-cancer activity alone or in combination with radiation. Anlotinib combined with radiotherapy might be a promising treatment for newly diagnosed GBM in the clinic.

PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism: Potential targets to overcome radioresistance in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive tumor type for which limited therapeutic progress has been made. Platinum-based chemotherapy with or without thoracic radiotherapy remains the backbone of treatment, but most patients with SCLC acquire therapeutic resistance. Given the need for more effective therapies, better elucidation of the molecular pathogenesis of SCLC is imperative. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently activated in SCLC and strongly associated with resistance to ionizing radiation in many solid tumors. This pathway is an important regulator of cancer cell glucose metabolism, and its activation probably effects radioresistance by influencing bioenergetic processes in SCLC. Glucose metabolism has three main branches-aerobic glycolysis, oxidative phosphorylation, and the pentose phosphate pathway-involved in radioresistance. The interaction between the PI3K/AKT/mTOR pathway and glucose metabolism is largely mediated by hypoxia-inducible factor 1 (HIF-1) signaling. The PI3K/AKT/mTOR pathway also influences glucose metabolism through other mechanisms to participate in radioresistance, including inhibiting the ubiquitination of rate-limiting enzymes of the pentose phosphate pathway. This review summarizes our understanding of links among the PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism in SCLC radioresistance and highlights promising research directions to promote cancer cell death and improve the clinical outcome of patients with this devastating disease.

Explore the Usefulness of Concurrent Chemotherapy in Stage II Nasopharyngeal Carcinoma: A Retrospective Study.

Objective: This study aims to compare the treatment outcomes of concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in stage II nasopharyngeal carcinoma (NPC) patients. Methods: We retrospectively collected 601 stage II NPC patients treated in two hospitals between June 2003 to June 2016. All patients were divided into the CCRT group (n = 255) and the RT group (n = 346). Overall survival (OS), locoregional failure-free survival (LRFFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method. The log-rank test was used to compare the differences between the groups. The Cox-regression hazards model was performed to determine potential prognostic factors. Results: The median follow-up was 99 months. No significant difference was found in locoregional recurrence, distant metastasis, disease progression, and death between the two groups (all p > 0.05). In univariate analysis, the 5-years OS, PFS, LRFFS, and DMFS had no significant differences between the CCRT and RT groups (all p > 0.05). Two-dimensional radiotherapy (2DRT) sub-analysis showed that CCRT remarkably increased DMFS, PFS, and OS rates (all p < 0.05) but not LRFFS (p = 0.258) compared with RT alone. While intensity-modulated radiotherapy (IMRT) sub-analysis showed that the prognosis of the two groups had no significant differences (all p > 0.05). In multivariate analyses, age was significantly and inversely related to OS, PFS, LRFFS, and DMFS. IMRT was an independent favorable factor for improving LRFFS, PFS, and OS. Concurrent chemotherapy was an independent protective factor for DMFS. Conclusion: In the context of 2DRT, it is definite that concurrent chemotherapy provides survival benefits for patients with stage II NPC. While in the IMRT era, the impact of chemotherapy on survival in patients with stage II NPC is weakened. Prospective randomized controlled studies are required to confirm these results.

Explore the Value of Adding Induction Chemotherapy to Concurrent Chemoradiotherapy in T3-4N0M0 Nasopharyngeal Carcinoma Patients: A Retrospective Study.

PURPOSE: Patients with T3-4N0M0 nasopharyngeal carcinoma (NPC) are a unique subgroup of locoregional advanced NPC, which generally have a better prognosis than others and are often excluded in most randomized controlled clinical trials focusing on locoregional advanced NPC. The management of this population is still controversial. This study aims to evaluate the outcomes of T3-4N0M0 NPC patients treated with sequential induction chemotherapy and concurrent chemoradiotherapy (IC+CCRT) or chemoradiotherapy (CCRT) alone. PATIENTS AND METHODS: We included 362 patients diagnosed with T3-4N0M0 NPC from two hospitals between December 2005 and December 2014. All patients were received IC + CCRT (n=146) or CCRT (n=216). Locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were retrospectively estimated. RESULTS: The median follow-up was 95 (range: 11-168) months. Univariable analyses have shown that 5-year LRFFS, DFS and OS in the IC+CCRT group and the CCRT group were 87.4% vs 93.4% (P = 0.035), 80.4% vs 87.0% (P = 0.047) and 86.3% vs 93.0% (P = 0.040). Multivariate analyses demonstrated that only the T stage was the independent prognostic factor for LRFFS, DFS, and OS in the entire group analysis. Subgroup analysis revealed that patients with T3 tumors who received IC+CCRT had significantly lower LRFFS, DFS, and OS than those treated with CCRT. For T4 patients, the outcomes had no significant difference between the two groups. CONCLUSION: This retrospective study showed that T3N0M0 patients who received CCRT had better prognosis than those treated with IC+CCRT. In terms of T4N0M0 disease, treatment outcomes are similar in both treatment groups. However, these results require further confirmation of large sample size, prospectively, randomized controlled trials.

Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial.

IMPORTANCE: Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed. OBJECTIVE: To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021. INTERVENTIONS: Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone. MAIN OUTCOMES AND MEASURES: The primary end point was the 2-year overall survival rate using intention-to-treat analysis. RESULTS: Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02813967.

Predictive Model and Precaution for Oral Mucositis During Chemo-Radiotherapy in Nasopharyngeal Carcinoma Patients.

PURPOSE: To explore risk factors for severe acute oral mucositis of nasopharyngeal carcinoma (NPC) patients receiving chemo-radiotherapy, build predictive models and determine preventive measures. METHODS AND MATERIALS: Two hundred and seventy NPC patients receiving radical chemo-radiotherapy were included. Oral mucosa structure was contoured by oral cavity contour (OCC) and mucosa surface contour (MSC) methods. Oral mucositis during treatment was prospectively evaluated and divided into severe mucositis group (grade ≥ 3) and non-severe mucositis group (grade < 3) according to RTOG Acute Reaction Scoring System. Nineteen clinical features and nineteen dosimetric parameters were included in analysis, least absolute shrinkage and selection operator (LASSO) logistic regression model was used to construct a risk score (RS) system. RESULTS: Two predictive models were built based on the two delineation methods. MSC based model is more simplified one, it includes body mass index (BMI) classification before radiation, retropharyngeal lymph node (RLN) area irradiation status and MSC V55%, RS = -1.480 + (0.021 × BMI classification before RT) + (0.126 × RLN irradiation) + (0.052 × MSC V55%). The cut-off of MSC based RS is -1.011, with an area under curve (AUC) of 0.737 (95%CI: 0.672-0.801), a specificity of 0.595 and a sensitivity of 0.786. OCC based model involved more variables, RS= -4.805+ (0.152 × BMI classification before RT) + (0.080 × RT Technique) + (0.097 × Concurrent Nimotuzumab) + (0.163 × RLN irradiation) + (0.028 × OCC V15%) + (0.120 × OCC V60%). The cut-off of OCC based RS is -0.950, with an AUC of 0.767 (95%CI: 0.702-0.831), a specificity of 0.602 and a sensitivity of 0.819. Analysis in testing set shown higher AUC of MSC based model than that of OCC based model (AUC: 0.782 vs 0.553). Analysis in entire set shown AUC in these two method-based models were close (AUC: 0.744 vs 0.717). CONCLUSION: We constructed two risk score predictive models for severe oral mucositis based on clinical features and dosimetric parameters of nasopharyngeal carcinoma patients receiving chemo-radiotherapy. These models might help to discriminate high risk population in clinical practice that susceptible to severe oral mucositis and individualize treatment plan to prevent it.

The effectiveness of probiotics in prevention and treatment of cancer therapy-induced oral mucositis: A systematic review and meta-analysis.

Oral mucositis (OM) is a common and troublesome adverse side effect of many cancer therapy modalities (chemotherapy, radiotherapy, and chemo-radiotherapy), which can cause pain, ulceration, dysphagia, malnutrition, even treatment interruption. Probiotics may be effective in preventing and treating of cancer therapy-induced OM. We performed a systematic review and meta-analysis of the effectiveness of probiotics in prevention and treatment of cancer therapy-induced OM. Four databases and one trial registry were searched as of the 12th of May 2019 to identify all eligible randomized controlled trials (RCT). Five studies involving 435 patients were included in this study. Methodological quality and outcomes were evaluated in every study included. Pooled results showed a moderate heterogeneity (P = 0.15, I2 = 44%). The pooled RRs indicated that the use of probiotics decreased the risk of OM for grade ≥3 (RR = 0.66, 95%CI = 0.54-0.81, P < 0.0001) as well as all grades (RR = 0.83, 95% CI = 0.72-0.97, P = 0.02). There was no significant difference between probiotics and placebo for cancer therapy completion rate (RR = 1.14, 95%CI = 0.65-2.00, P = 0.64). The subgroup analysis indicated that the use of probiotics was not statistically significant for patients receiving chemo-radiotherapy (RR = 0.52, 95% CI = 0.26-1.04, P = 0.07). In conclusion, probiotics may reduce the incidence and mitigate the severity of cancer therapy-induced OM. Further trials with a randomized, double-blind and multicentric study design are needed to confirm this effect. The PROSPERO registration number of this systematic review and meta-analysis is CRD42019130414.

PK-tailored tertiary prophylaxis in patients with severe hemophilia A at Beijing Children's Hospital.

IMPORTANCE: Tertiary prophylaxis using a low-dose regimen is usually insufficient to prevent recurrent joint bleeding and deterioration in joint diseases in children with severe hemophilia A. Pharmacokinetic (PK) dosing is a useful approach to increase the precision and efficiency of prophylaxis. OBJECTIVE: To explore the efficacy of PK-tailored tertiary prophylaxis in children with severe hemophilia A. METHODS: We implemented a PK-tailored tertiary prophylaxis program for 15 boys with severe hemophilia A aged 5-16 years at Beijing Children's Hospital. Following PK testing and a 6-month evaluation period (phase I), 15 patients were divided in two groups according to individual PK data and actual bleeding: (1) a PK-tailored group [modified prophylaxis regimen according to PK data for the next 6 months (phase II); n = 8] and (2) a maintenance group (continued the original regimen for the next 6 months; n = 7). We compared the bleeding rate, infusion frequency, and factor VIII (FVIII) consumption between the two groups. RESULTS: In the PK-tailored group, the median annual joint bleeding rate was reduced from 7.8 in phase I to 1.4 in phase II, mean annual total factor consumption increased from 1619.0 IU/kg in phase I to 2401.9 IU/kg in phase II, and median infusion frequency for prophylaxis increased from 104 times/year in phase I to 156 times/year in phase II (P < 0.05). Although the FVIII consumption increased, it remained at approximately half of the standard method. INTERPRETATION: PK-tailored prophylaxis may represent a more efficient approach to individual prophylaxis in China, but further studies are required to verify this.