Regulation of Mitochondrial Quality Control of Intestinal Stem Cells in Homeostasis and Diseases.

Significance: Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases. Recent Advances: In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological conditions and protects against intestinal injury remains to be comprehensively reviewed. Critical Issues: In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy, and proteostasis impact ISC proliferation, differentiation, and regeneration, respectively. Future Directions: We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases.

Spatially fractionated radiotherapy (Lattice SFRT) in the palliative treatment of locally advanced bulky unresectable head and neck cancer.

Objectives: Locally advanced bulky unresectable head neck cancer causes significant tumor mass effects, leading to severe symptoms. This study aims to report the safety and outcomes in patients undergoing Lattice spatially fractionated radiotherapy (Lattice SFRT) for locally advanced bulky unresectable head and neck cancer. Methods: Patients with bulky head and neck cancer received Lattice SFRT between June 2022 and June 2023. Lattice SFRT was administered in 2-3 fractions of 12 Gy (Gy) using 6-megavolt (MV) photon beams through a multileaf collimator (MLC) based on VMAT technology. The primary endpoints were symptomatic and tumor response rates. Secondary endpoints were overall survival, local control, and acute and late toxicity rates. Results: 19 consecutive patients meeting the study criteria were identified, predominantly with squamous cell carcinoma histology. The median patient age was 62 years (range 39-79 years), and the median tumor volume was 208 cc (cc) (range 48-701 cc). All patients completed radiotherapy. Among all investigated patients, 16 of 19 (84.2 %) patients achieved an objective response, including 10 individuals achieved a partial response (PR), with 3 of them exhibiting regression exceeding 75 %. 17 patients showed symptom improvement to varying degrees. Acute toxicity of Radiation Therapy Oncology Group (RTOG) grade 1 or higher occurred in 5 patients, while no grade 3 adverse events was observed. Conclusions: Lattice SFRT proves to be a viable treatment option for the palliative management of bulky head and neck cancer. In the palliative setting, Lattice SFRT offers timely symptom relief, enhancing patient quality of life. Treatment toxicity remains within an acceptable range. Continued optimization of Lattice SFRT delivery and patient selection can benefit from further data on the feasibility and efficacy of this radiation modality.

Dose tracking assessment for magnetic resonance guided adaptive radiotherapy of rectal cancers.

BACKGROUND: Magnetic resonance-guided adaptive radiotherapy (MRgART) at MR-Linac allows for plan optimisation on the MR-based synthetic CT (sCT) images, adjusting the target and organs at risk according to the patient's daily anatomy. Conversely, conventional linac image-guided radiotherapy (IGRT) involves rigid realignment of regions of interest to the daily anatomy, followed by the delivery of the reference computed tomography (CT) plan. This study aims to evaluate the effectiveness of MRgART versus IGRT for rectal cancer patients undergoing short-course radiotherapy, while also assessing the dose accumulation process to support the findings and determine its usefulness in enhancing treatment accuracy. METHODS: Nineteen rectal cancer patients treated with a 1.5 Tesla MR-Linac with a prescription dose of 25 Gy (5 Gy x 5) and undergoing daily adapted radiotherapy by plan optimization based on online MR-based sCT images, were included in this retrospective study. For each adapted plan ([Formula: see text]), a second plan ([Formula: see text]) was generated by recalculating the reference CT plan on the daily MR-based sCT images after rigid registration with the reference CT images to simulate the IGRT workflow. Dosimetry of [Formula: see text] and[Formula: see text]was compared for each fraction. Cumulative doses on the first and last fractions were evaluated for both workflows. The dosimetry per single fraction and the cumulative doses were compared using dose-volume histogram parameters. RESULTS: Ninety-five fractions delivered with MRgART were compared to corresponding simulated IGRT fractions. All MRgART fractions fulfilled the target clinical requirements. IGRT treatments did not meet the expected target coverage for 63 out of 94 fractions (67.0%), with 13 fractions showing a V95 median point percentage decrease of 2.78% (range, 1.65-4.16%), and 55 fractions exceeding the V107% threshold with a median value of 15.4 cc (range, 6.0-43.8 cc). For the bladder, the median [Formula: see text] values were 18.18 Gy for the adaptive fractions and 19.60 Gy for the IGRT fractions. Similarly the median [Formula: see text] values for the small bowel were 23.40 Gy and 25.69 Gy, respectively. No statistically significant differences were observed in the doses accumulated on the first or last fraction for the adaptive workflow, with results consistent with the single adaptive fractions. In contrast, accumulated doses in the IGRT workflow showed significant variations mitigating the high dose constraint, nevertheless, more than half of the patients still did not meet clinical requirements. CONCLUSIONS: MRgART for short-course rectal cancer treatments ensures that the dose delivered matches each fraction of the planned dose and the results are confirmed by the dose accumulation process, which therefore seems redundant. In contrast, IGRT may lead to target dose discrepancies and non-compliance with organs at risk constraints and dose accumulation can still highlight notable dosimetric differences.

Toripalimab plus chemotherapy and radiotherapy for treatment-naive advanced esophageal squamous cell carcinoma: a single-arm phase 2 trial.

This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.

Epidermal growth factor receptor­targeted antibody nimotuzumab combined with chemoradiotherapy improves survival in patients with locally advanced head and neck squamous cell carcinoma: a propensity score matching real-world study.

Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have poor survival outcomes. The real-world efficacy of nimotuzumab plus intensity modulated radiotherapy (IMRT)-based chemoradiotherapy in patients with LA-HNSCC remains unclear. A total of 25,442 HNSCC patients were screened, and 612 patients were matched by propensity score matching (PSM) (1:1). PSM was utilized to balance known confounding factors. Patients who completed at least five doses of nimotuzumab were identified as study group. The primary end point was 3-year overall survival (OS) rate. Log-rank test examined the difference between two survival curves and Cloglog transformation test was performed to compare survival at a fixed time point. The median follow-up time was 54.2 (95% confidence interval [CI]: 52.7-55.9) months. The study group was associated with improved OS (hazard ratio [HR] = 0.75, 95% CI: 0.57-0.99, p = 0.038) and progression-free survival (PFS) (HR = 0.74, 95% CI: 0.58-0.96, p = 0.021). Subgroup analysis revealed that aged 50-60 year, IV, N2, radiotherapy dose ≥ 60 Gy, without previous surgery, and neoadjuvant therapy have a trend of survival benefit with nimotuzumab. Nimotuzumab showed favorable safety, only 0.2% had nimotuzumab-related severe adverse events. Our study indicated the nimotuzumab plus chemoradiotherapy provides survival benefits and safety for LA-HNSCC patients in an IMRT era.

Synthesis and preclinical evaluation of 11C-labeled 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine radioligands for RIPK1 positron emission tomography imaging.

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic strategy for various neurodegenerative disorders. The development of a positron emission tomography (PET) probe for brain RIPK1 imaging could offer a valuable tool to assess therapeutic effectiveness and uncover the neuropathology associated with RIPK1. In this study, we present the development and characterization of two new PET radioligands, [11C]PB218 and [11C]PB220, which have the potential to facilitate brain RIPK1 imaging. [11C]PB218 and [11C]PB220 were successfully synthesized with a high radiochemical yield (34 % - 42 %) and molar activity (293 - 314 GBq/µmol). PET imaging characterization of two radioligands was conducted in rodents, demonstrating that both newly developed tracers have good brain penetration (maximum SUV = 0.9 - 1.0) and appropriate brain clearance kinetic profiles. Notably, [11C]PB218 has a more favorable binding specificity than [11C]PB220. A PET/MR study of [11C]PB218 in a non-human primate exhibited good brain penetration, desirable kinetic properties, and a safe profile, thus supporting the translational applicability of our new probe. These investigations enable further translational exploration of [11C]PB218 for drug discovery and PET probe development targeting RIPK1.

Elucidating Hedgehog pathway's role in HNSCC progression: insights from a 6-gene signature.

With the emergence of targeted inhibition strategies for Hedgehog signaling in cancer, multiple Hedgehog signaling pathway-related biomarkers have become the focus of research. SsGSEA algorithm was employed to analyze the Hedgehog pathway scores of samples in TCGA-HNSC dataset and divide them into two groups. Weighted co-expression network analysis was performed to identify modules strongly associated with the Hedgehog pathway. Differentially up-regulated genes in tumor samples in comparison to the normal ones were screened by Limma, in which genes belonging to modules strongly related to Hedgehog pathway were further filtered by LASSO reduction and multivariate Cox regression analysis to develop a model. ESTIMATE and CIBERSORT were served to characterize the tumor microenvironment (TME). TIDE assessed immunotherapy response. Hedgehog pathway activity was significantly higher in head and neck squamous cell carcinoma (HNSCC) tissues than in normal tissues and was correlated with HNSCC survival, glycan, cofactors and vitamins, drug metabolism, and matrix scores. Six genes (SLC2A3, EFNB2, OAF, COX4I2, MT2A and TXNRD1) were captured to form a Hedgehog associated 6-gene signature, and the resulting risk score was an independent indicator of HNSCC prognosis. It was significantly positively correlated with stromal score, metabolism, angiogenesis and inflammatory response. Patients in low-risk group with a low TIDE score had higher immunotherapy sensitivity relative to those in high-risk group. This study revealed novel findings of the Hedgehog pathway in HNSCC progression and opened up a Hedgehog pathology-related signature to help identify risk factors contributing to HNSCC progression and help predict immunotherapy outcomes.

The roles of tissue resident macrophages in health and cancer.

As integral components of the immune microenvironment, tissue resident macrophages (TRMs) represent a self-renewing and long-lived cell population that plays crucial roles in maintaining homeostasis, promoting tissue remodeling after damage, defending against inflammation and even orchestrating cancer progression. However, the exact functions and roles of TRMs in cancer are not yet well understood. TRMs exhibit either pro-tumorigenic or anti-tumorigenic effects by engaging in phagocytosis and secreting diverse cytokines, chemokines, and growth factors to modulate the adaptive immune system. The life-span, turnover kinetics and monocyte replenishment of TRMs vary among different organs, adding to the complexity and controversial findings in TRMs studies. Considering the complexity of tissue associated macrophage origin, macrophages targeting strategy of each ontogeny should be carefully evaluated. Consequently, acquiring a comprehensive understanding of TRMs' origin, function, homeostasis, characteristics, and their roles in cancer for each specific organ holds significant research value. In this review, we aim to provide an outline of homeostasis and characteristics of resident macrophages in the lung, liver, brain, skin and intestinal, as well as their roles in modulating primary and metastatic cancer, which may inform and serve the future design of targeted therapies.

A prospective, single-arm trial of PD-1 inhibitors plus chemoradiotherapy for solitary metachronous metastasis nasopharyngeal carcinoma.

PURPOSE: Initial treatment for Recurrent/Metastatic Nasopharyngeal Carcinoma (R/M NPC) often involves Gemcitabine plus cisplatin with or without PD-1 inhibitors. However, PD-1 inhibitors' effectiveness varies, prompting for better treatments. This study explores effect and safety of combining PD-1 inhibitors with chemoradiotherapy for oligometastatic NPC patients. METHODS: Oligometastatic NPC patients underwent radical treatment with PD-1 inhibitors and chemotherapy, followed by concurrent PD-1 inhibitors and chemoradiotherapy, and then maintenance PD-1 inhibitors. Objective response rate (ORR) and disease control rate (DCR) were calculated by irRECIST-1.1, and CTCAE-4.0 was used to evaluate the toxicity. RESULTS: The study enrolled 47 patients with a median age of 46. The median follow-up lasted 16.5 months, with metastatic lesions receiving a median radiation dose of 45 Gy. The median courses of PD-1 inhibitors and chemotherapy were 9.5 and 5 respectively. The metastasis sites included lung (40.8 %), liver (21.1 %), mediastinal lymph node (7.9 %), abdominal lymph nodes (3.9 %), bone (21.1 %), adrenal gland (3.9 %), and brain (1.3 %). ORR and DCR were 85.1 % and 100 % at 3 months after radiotherapy. The median survival was not reached yet, and 1 and 2-year OS rates were 93.1 % and 78.4 %. The median PFS was 18 months, with 1 and 2-year PFS rates of 70.2 % and 47.7 % respectively. PD-L1 expression showed a positive correlation for PFS. Twenty-five patients experienced grade 3 or 4 adverse events (AE) that were possibly related to chemotherapy. No grade 5 AE was observed. CONCLUSIONS: The synergy of concurrent PD-1 inhibitors and chemoradiotherapy shows promising efficacy and an acceptable toxicity for oligometastasis NPC patients.

Implanted, Wireless, Self-Powered Photodynamic Therapeutic Tablet Synergizes with Ferroptosis Inducer for Effective Cancer Treatment.

The effective and targeted treatment of resistant cancer cells presents a significant challenge. Targeting cell ferroptosis has shown remarkable efficacy against apoptosis-resistant tumors due to their elevated iron metabolism and oxidative stress levels. However, various obstacles have limited its effectiveness. To overcome these challenges and enhance ferroptosis in cancer cells, we have developed a self-powered photodynamic therapeutic tablet that integrates a ferroptosis inducer (FIN), imidazole ketone erastin (IKE). FINs augment the sensitivity of photodynamic therapy (PDT) by increasing oxidative stress and lipid peroxidation. Furthermore, they utilize the Fenton reaction to supplement oxygen, generating a greater amount of reactive oxygen species (ROS) during PDT. Additionally, PDT facilitates the release of iron ions from the labile iron pool (LIP), accelerating lipid peroxidation and inducing ferroptosis. In vitro and in vivo experiments have demonstrated a more than 85% tumor inhibition rate. This synergistic treatment approach not only addresses the limitations of inadequate penetration and tumor hypoxia associated with PDT but also reduces the required medication dosage. Its high efficiency and specificity towards targeted cells minimize adverse effects, presenting a novel approach to combat clinical resistance in cancer treatment.

Stereotactic ablative radiotherapy and FAPα-based cancer vaccine suppresses metastatic tumor growth in 4T1 mouse breast cancer.

BACKGROUND AND PURPOSE: This study tested the hypothesis that a novel combination of stereotactic ablation radiotherapy (SABR) and a cancer vaccine against fibroblast activation protein-alpha (FAPα) can suppress established tumor growth and impede potential metastasis. METHODS: The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were randomly assigned to five treatment groups: (1) untreated control, (2) FAPα-based cancer vaccine, (3) SABR, (4) SABR + pCDH (lentiviral control vector), (5) SABR + FAPα-based cancer vaccine (SABR/FAPα-Vax). FAPα-based cancer vaccine were administered subcutaneously every week for a total of three treatments. SABR was delivered to the primary tumor by 3 × 8 Gy after the first vaccination. RESULTS: Consistent with the poorly immunogenic nature of 4T1, tumor-bearing mice receiving FAPα-based cancer vaccine or SABR monotherapy showed a modest reduction in tumor volume and increased animal lifespan. In contrast, SABR/FAPα-Vax was well-tolerated, significantly reduced tumor burden, and increased survival compared to monotherapy. The increased survival correlated with inhibition of extracellular matrix (ECM) production, tumor vascularization and lymphangiogenesis. SABR/FAPα-Vax also resulted in an abscopal effect capable of eliminating lung metastases. SABR/FAPα-Vax recruited and activated CD8 + T cells to attack tumor cells and FAPα + stromal cells, and initiated suppressor cell reprogramming, including facilitating macrophage polarization toward an anti-tumor (M1) state, as well as depleting myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). CONCLUSION: These findings provide a novel therapeutic combination of radiation and FAPα-based cancer vaccine with promising results against poorly immunogenic metastatic cancer. This study may pave the way to overcome the therapeutic resistance caused by FAPα + CAFs.

Establishment of nucleic acid sensing pathways-based model in predicting response to immunotherapy and targeted drug in hepatitis virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) accounts for 80% of liver cancers, while 70%-80% of HCC developed from chronic liver disease with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as the major etiology. Immunotherapy is assuming a role as a pillar of HCC treatment, but the remarkable immune-mediated responses are restricted in a minority of patients. Nucleic acid sensing (NAS) pathways are the central pathway of the innate immune system and antiviral immune response to viral infection, but their role in hepatitis virus-related HCC remains undetermined. In our study, we performed a comprehensive bioinformatics analysis based on transcriptomic data of hepatitis virus related-HCC tissues collected from multiple public data sets. Two subgroups were validated based on NAS-related genes in virus-related HCC patients, which were defined as NAS-activated subgroups and NAS-suppressed subgroups based on the expression of NAS-related genes. On this basis, a NAS-related risk score (NASRS) predictive model was established for risk stratification and prognosis prediction in the hepatitis virus-related HCC (TCGA-LIHC and ICGC cohorts). The predictive values of the NASRS in prognosis and immunotherapy were also verified in multiple data sets. A nomogram was also established to facilitate the clinical use of NASRS and demonstrate its effectiveness through different approaches. Additionally, six potential drugs binding to the core target of the NAS signature were predicted via molecular docking strategy. We subsequently evaluated the cytotoxic capabilities of potential drug in vitro and in vivo. Based on these results, we conclude that the NASRS model could serve as a power prognostic biomarker and predict responses to immunotherapy, which is meaningful in clinical decision-making of hepatitis virus-related HCC patients.

A novel nucleic acid sensing-related genes signature for predicting immunotherapy efficacy and prognosis of lung adenocarcinoma.

BACKGROUND: As a novel pillar for lung adenocarcinoma (LUAD) treatment, immunotherapy has limited efficiency in LUAD patients. The nucleic acid sensing (NAS) pathways are critical in the anti-tumor immune response, but their role in LUAD remains controversial. OBJECTIVE: The study aims to develop a classification system to identify immune subtypes of LUAD based on nucleic acid sensing-related genes so that it can help screen patients who may respond to immunotherapy. METHODS: We performed a comprehensive bioinformatics analysis of the NAS molecule expression profiles across multiple public datasets. Using qRT-PCR to verify the NAS genes in multiple lung cancer cell lines. Molecular docking was performed to screen drug candidates. RESULTS: The NAS-activated subgroup and NAS-suppressed subgroup were validated based on the different patterns of gene expression and pathways enrichment. The NAS-activated subgroup displayed a stronger immune infiltration and better prognosis of patients. Moreover, we constructed a seven nucleic acid sensing-related risk score (NASRS) model for the convenience of clinical application. The predictive values of NASRS in prognosis and immunotherapy were subsequently fully validated in the lung adenocarcinoma dataset and the uroepithelial carcinoma dataset. Additionally, five potential drugs binding to the core target of the NAS signature were predicted through molecular docking. CONCLUSION: We found a significant correlation between nucleic acid sensing function and the immune treatment efficiency in LUAD. The NASRS can be used as a robust biomarker for the predicting of prognosis and immunotherapy efficiency and may help in clinical decisions for LUAD patients.

Initial analysis of the synergy of programmed cell death-1 (PD-1) inhibitor and concurrent chemoradiotherapy treatment for recurrent/metastatic head and neck squamous cell carcinoma patients.

BACKGROUND: Programmed cell death-1 (PD-1) inhibitor was proven to be useful for the recurrent/metastatic head and neck squamous carcinoma (R/M HNSCC) patients. Though both PD-1 inhibitor alone and combination with chemotherapy showed some benefit for PFS and OS, the survival outcome was still not satisfactory. Some studies showed the possible benefit for PD-1 inhibitors combination with radiation for head and neck squamous carcinoma, however there was few studies concerned about synergy of concurrent PD-1 inhibitor combination with chemoradiotherapy for R/M HNSCC. So, we aimed to explore the potential effect and toxicity of the concurrent PD-1 inhibitor and chemoradiotherapy for R/M HNSCC. METHODS: We consecutively enrolled the R/M HNSCC patients treated with concurrent PD-1 inhibitor and chemoradiotherapy from August 2018 to April 2022 in Sichuan Cancer hospital. All the patients received the combination of PD-1 inhibitor and chemotherapy, and followed with synergy of concurrent PD-1 inhibitor and chemoradiotherapy, then maintenance PD-1 inhibitor. ORR and DCR was calculated by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST-1.1), and Common terminology criteria for adverse events (CTCAE-4.0) was used to evaluate the toxicity.The Kaplan-Meier method was used to analyze OS and PFS. RESULTS: 40 R/M HNSCC patients were enrolled in our stuty. The median follow up time was 14 months. 22 patients had recurrent disease only, 16 patients had metastatic disease only, and 2 patients had both recurrence and metastasis disease. For the recurrent lesions, 23 patients received a median radiation dose of 64 Gy (range 50-70 Gy). 18 patients received a median dose of 45 Gy (range 30-66 Gy) for metastatic lesions. The median courses of PD-1 inhibitors and chemotherapy were 8 and 5 respectively. After the treatment, the ORR and DCR were 70.0% and 100%. The median OS was 19 months (range 6.3-31.7 months), with 1 and 2-years OS rates of 72.8% and 33.3%. The median PFS was 9 months (range 3.1-14.9 months), with 6 and 12 months PFS rates of 75.5% and 41.4% respectively. The PFS had no statistical significance in PD-L1 negative and positive group (7 vs 12 months, p = 0.059). The most common grade 3 or 4 adverse events(AE) were leucopenia (25.0%), neutropenia (17.5%), anemia (10.0%), thrombocytopenia (5.0%), hyponatremia (2.5%), and pneumonia(2.5%). No grade 5 AE was observed. CONCLUSIONS: The synergy of concurrent PD-1 inhibitor treatment with chemoradiotherapy shows promise as a treatment strategy and an acceptable toxicity for the R/M HNSCC patients.

Recurrent/metastatic head and neck squamous carcinoma (R/M HNSCC) patients face limited treatment choices and poor prognosis. As a new treatment method, immune checkpoint inhibitor plays an important role for the R/M HNSCC patients recently. However, there were still some controversies for the combination of chemoradiotherapy and immunotherapy, such as timing, radiation dose, fractionation, and et al. In our study, the synergy of concurrent chemoradiotherapy with PD-1 inhibitor showed a promising results for the R/M HNSCC patients, with improved objective response rate (ORR) (70.0%, 95% CI 55.8% to 84.2%) and disease control rate (DCR) (100%, 95% CI 100% to 100%). The median progression-free survival (PFS) and overall survival (OS) were prolonged to 9 months (range 3.1­14.9 months) and 19 months (range 6.3­31.7 months) respectively. The toxicity was tolerable during the treatment, the total incidence rate of grade 3 or 4 adverse events were 65%, similar with other study.

Anlotinib as Monotherapy or Combination Therapy for Recurrent High-Grade Glioma: A Retrospective Study.

Background: Anlotinib is a multi-target anti-angiogenic agent. The retrospective study was conducted to evaluate the safety and effectiveness of anlotinib as monotherapy or combination therapy for the treatment of recurrent high-grade gliomas. Methods: In this retrospective study, patients with recurrent high-grade glioma (according to the 2021 World Health Organization classification as levels III-IV) at Sichuan Cancer Hospital from June 2019 to June 2022 were included. The patients were divided into an anlotinib-monotherapy group and an anlotinib-combination group, and received oral anlotinib 8 to 12 mg once a day, with 2 weeks on/1 week off. The primary endpoint was progression-free survival (PFS). The Secondary endpoints included overall survival (OS), 6-month PFS rate, objective response rate (ORR), and disease control rate (DCR). Also, adverse events were evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE version 5.0). Results: A total of 29 patients (including 20 glioblastomas, 1 diffuse midline glioma, 5 anaplastic astrocytoma, and 3 anaplastic oligodendroglioma) were included in this study. Of these, 34.48% of the patients were treated with anlotinib alone and 65.52% with anlotinib combination therapy. The median follow-up time was 11.6 months (95% confidence interval [CI]: 9.4-15.7). The median PFS was 9.4 months (95% CI: 6.5-12.3), and the 6-month PFS rate was 62.1%. The median OS was 12.7 months (95% CI: 9.7-15.7), and the 12-month OS rate was 48.3%. Evaluation of treatment response was performed according to RANO (response assessment in neuro-oncology, RANO) criteria, including 21 partial response, 6 stable disease, and 2 PFS events. The ORR and DCR were 72.4%, and 93.1%, respectively. Grade III AEs occurred in 2 patients, and the others were less than grade III. The most common AE was thrombocytopenia, with an incidence rate of 31.0%. All AEs were alleviated and controlled by symptomatic treatment. No treatment-related deaths occurred. Conclusion: Anlotinib had a low incidence of AEs and good safety in the treatment of recurrent high-grade glioma. Moreover, it showed good short-term effectiveness and significantly prolonged the PFS of patients, which may become a promising therapeutic option for recurrent high-grade glioma and lay a foundation for further clinical studies.

Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma.

Neoadjuvant chemoimmunotherapy (NACI) has shown promise in the treatment of resectable esophageal squamous cell carcinoma (ESCC). The microbiomes of patients can impact therapy response, and previous studies have demonstrated that intestinal microbiota influences cancer immunotherapy by activating gut immunity. Here, we investigated the effects of intratumoral microbiota on the response of patients with ESCC to NACI. Intratumoral microbiota signatures of ß-diversity were disparate and predicted the treatment efficiency of NACI. The enrichment of Streptococcus positively correlated with GrzB+ and CD8+ T-cell infiltration in tumor tissues. The abundance of Streptococcus could predict prolonged disease-free survival in ESCC. Single-cell RNA sequencing demonstrated that responders displayed a higher proportion of CD8+ effector memory T cells but a lower proportion of CD4+ regulatory T cells. Mice that underwent fecal microbial transplantation or intestinal colonization with Streptococcus from responders showed enrichment of Streptococcus in tumor tissues, elevated tumor-infiltrating CD8+ T cells, and a favorable response to anti-PD-1 treatment. Collectively, this study suggests that intratumoral Streptococcus signatures could predict NACI response and sheds light on the potential clinical utility of intratumoral microbiota for cancer immunotherapy. SIGNIFICANCE: Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.

Automatic tumor segmentation and metachronous single-organ metastasis prediction of nasopharyngeal carcinoma patients based on multi-sequence magnetic resonance imaging.

Background: Distant metastases is the main failure mode of nasopharyngeal carcinoma. However, early prediction of distant metastases in NPC is extremely challenging. Deep learning has made great progress in recent years. Relying on the rich data features of radiomics and the advantages of deep learning in image representation and intelligent learning, this study intends to explore and construct the metachronous single-organ metastases (MSOM) based on multimodal magnetic resonance imaging. Patients and methods: The magnetic resonance imaging data of 186 patients with nasopharyngeal carcinoma before treatment were collected, and the gross tumor volume (GTV) and metastatic lymph nodes (GTVln) prior to treatment were defined on T1WI, T2WI, and CE-T1WI. After image normalization, the deep learning platform Python (version 3.9.12) was used in Ubuntu 20.04.1 LTS to construct automatic tumor detection and the MSOM prediction model. Results: There were 85 of 186 patients who had MSOM (including 32 liver metastases, 25 lung metastases, and 28 bone metastases). The median time to MSOM was 13 months after treatment (7-36 months). The patients were randomly assigned to the training set (N = 140) and validation set (N = 46). By comparison, we found that the overall performance of the automatic tumor detection model based on CE-T1WI was the best (6). The performance of automatic detection for primary tumor (GTV) and lymph node gross tumor volume (GTVln) based on the CE-T1WI model was better than that of models based on T1WI and T2WI (AP@0.5 is 59.6 and 55.6). The prediction model based on CE-T1WI for MSOM prediction achieved the best overall performance, and it obtained the largest AUC value (AUC = 0.733) in the validation set. The precision, recall, precision, and AUC of the prediction model based on CE-T1WI are 0.727, 0.533, 0.730, and 0.733 (95% CI 0.557-0.909), respectively. When clinical data were added to the deep learning prediction model, a better performance of the model could be obtained; the AUC of the integrated model based on T2WI, T1WI, and CE-T1WI were 0.719, 0.738, and 0.775, respectively. By comparing the 3-year survival of high-risk and low-risk patients based on the fusion model, we found that the 3-year DMFS of low and high MSOM risk patients were 95% and 11.4%, respectively (p < 0.001). Conclusion: The intelligent prediction model based on magnetic resonance imaging alone or combined with clinical data achieves excellent performance in automatic tumor detection and MSOM prediction for NPC patients and is worthy of clinical application.

Efficacy and safety of PLDR-IMRT for the re-irradiation of recurrent NPC: A prospective, single-arm, multicenter trial.

Salvage treatment of locoregionally recurrent nasopharyngeal carcinoma (NPC) requires weighing the benefits of re-irradiation against increased risks of toxicity. Here, we evaluated the outcomes of patients treated with intensity-modulated-based pulsed low-dose-rate radiotherapy (PLDR-IMRT) to enhance the curative effect of salvage treatment and reduce RT-related SAEs. A prospective clinical trial was conducted from March 2018 to March 2020 at multiple institutions. NPC patients who experienced relapse after radical therapy were re-irradiated with a median dose of 60 Gy (50.4-70 Gy)/30 f (28-35 f) using PLDR-IMRT. Thirty-six NPC patients who underwent PLDR-IMRT for locoregional recurrence were identified. With a median follow-up of 26.2 months, the objective response rate (ORR) of the entire cohort was 91.6%. The estimated mPFS duration was 28 months (95% CI: 24.9-31.1), and the estimated mLRFS duration was 30.4 months (95% CI: 25.2-35.5). The overall survival (OS) rate for all patients was 80.6%, the progression-free survival (PFS) rate was 75% and the cancer-specific survival (CSS) rate was 88.9% at 1 year. The LRFS and DMFS rates were 88.9% and 91.7%, respectively, at 1 year. A combination of systematic therapies could provide survival benefits to patients who experience NPC relapse (p < 0.05), and a Karnofsky performance status (KPS) score of ≥90 was a favorable factor for local control (p < 0.05). The incidence of acute SAEs (grade 3+) from PLDR was 22.2%, and the incidence of chronic SAEs was 19.4% among all patients. PLDR-IMRT combined with systematic therapy can effectively treat patients with locoregionally recurrent nasopharyngeal carcinoma and causes fewer adverse events than the rates expected with IMRT.

Outcome of primary intraosseous carcinoma: Case review of a single institution.

OBJECTIVE: The purpose of this study was to investigate the prognostic factors and treatment of primary intraosseous carcinoma (PIOC). METHODS: Patients diagnosed with POIC and received treatment in Sichuan Cancer Hospital from 2000 to 2019 were followed up and retrospectively reviewed. RESULTS: A total of 28 patients were included in the study, with a mean age of 60 years (60 ± 10.11). The 2-year and 5-year overall survival (OS) were 60.7% and 38.5%, respectively. In the univariate analysis, surgery combined with adjuvant therapy improved the OS compared with surgery or radiotherapy alone (p = 0.035), and patients who received postoperative adjuvant radiotherapy had a higher OS than those who received radical radiotherapy (p = 0.01). In addition, patients with well-differentiated tumors have increased progression-free survival (p = 0.01). Multivariate analyses showed that radiotherapy was an independent indicator for OS (p = 0.007). CONCLUSIONS: Surgery combined with adjuvant therapy is the superior treatment strategy for PIOC at present. This study is the first to confirm the positive role of radiotherapy in treating PIOC with data to back it up.

Clinical outcomes of conventional HDR intracavitary brachytherapy combined with complementary applicator-guided intensity modulated radiotherapy boost in patients with bulky cervical tumour.

OBJECTIVE: To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). DESIGN: A retrospective cohort study. SETTING: Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre, China. POPULATION: Large high-risk clinical target volume (HR-CTV) volume (>40 ml) at the time of brachytherapy cervical cancer patients were recruited. METHODS: This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemoradiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) was adminstered with cisplatin chemotherapy treatment before IC/IMRT. The IMRT plan was optimised using the ICBT plan base dose plan by an inverse dose optimisation tool which allows the use of DVH constraints on the total dose of ICBT. A seven-field gantry angle IMRT plan was devised to avoid hotspots when optimising the boost plan. The prescription dose for HR-CTV and IR-CTV were 6 and 5 Gy per fraction for five fractions, respectively. RESULTS: Mean HR-CTV was 65.8 ± 23.6 ml at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7 ± 3.6 Gy and 78.1 ± 2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8 ± 3.8, 64.6 ± 4.9, 63.9 ± 5.3 and 56.7 ± 8.7 Gy, respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence-free survival rate, metastasis recurrence-free survival rate, disease-free survival rate and cancer-special survival rate were 87.6, 82.4, 70.9 and 76.3%, respectively. The grade 1 + 2 gastrointestinal and urinary late toxicities were 15.8 and 21.1%, and grade 3 late toxicities were 3.9 and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. CONCLUSIONS: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved excellent local control and overall survival with low toxicity for bulky residual cervical tumour.