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.

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.

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.

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.

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.

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.

The Prognostic Value of Tumor Size, Volume and Tumor Volume Reduction Rate During Concurrent Chemoradiotherapy in Patients With Cervical Cancer.

Objective: This study aimed to investigate the relationship between prognostic and tumor parameters of cervical cancer patients, such as tumor size (TS), tumor volume (TV), and tumor volume reduction rate (TVRR) after external beam radiotherapy. Methods: A total of 217 patients with advanced cervical cancer, classified as Federation of Gynecology and Obstetrics (FIGO) IIa-IVa, were enrolled in the study. Pre- and mid-RT pelvic magnetic resonance imaging (MRI) were performed twice, during RT and just before brachytherapy. Results: The median follow-up time was 51 months (range, 7-111 months). The 5-year overall survival (OS), progression-free survival (PFS), and local failure-free survival (LFFS) rates were 81.3, 85.1, and 92.9%, respectively. Multivariate analysis revealed that tumor parameters including FIGO stage >II (Hazard Ratio, 2.377 and 95% confidence interval [CI], 1.091-5.182; P = 0.029), pre-RT TV >61.6 cm3 (HR, 0.417 and 95% CI, 0.188-0.926; P = 0.032), and mid-RT TV >11.38 cm3 (HR, 3.192 and 95% CI, 1.094-9.316; P = 0.034) were observably associated with OS. Univariate analysis showed that the tumor volume reduction rate (TVRR) was dramatically associated with overall survival (HR, 0.204 and 95% CI 0.033-1.282; P <0.001) and local failure-free survival (P = 0.050). Conclusions: In this retrospective study, TVRR and mid-radiotherapy tumor volume are independent and strong prognostic parameters for patients with local advanced cervical cancer receiving CCRT.

CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma.

BACKGROUND: Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it's role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. METHODS: In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. RESULTS: As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p < 0.05). Meanwhile, high CDC6 expression was associated with poor overall survival (OS) in glioma patients, especially in different clinical subgroups. Furthermore, a univariate Cox analysis showed that high CDC6 expression was correlated with poor OS in glioma patients. Functional enrichment analysis indicated that CDC6 was mainly involved in pathways related to DNA transcription and cytokine activity, and Gene Set Enrichment Analysis (GSEA) revealed that MAPK pathway, P53 pathway and NF-κB pathway in cancer were differentially enriched in glioma patients with high CDC6 expression. Single-sample gene set enrichment analysis (ssGSEA) showed CDC6 expression in glioma was positively correlated with Th2 cells, Macrophages and Eosinophils, and negative correlations with plasmacytoid dendritic cells, CD8 T cells and NK CD56bright cells, suggesting its role in regulating tumor immunity. Finally, CCK8 assay, flow cytometry and transwell assays showed that silencing CDC6 could significantly inhibit proliferation, migration, invasion, and promoted apoptosis of U87 cells and U251 cells (p < 0.05). CONCLUSION: In conclusion, high CDC6 expression may serve as a promising biomarker for prognosis and correlated with immune infiltrates, presenting to be a potential immune therapy target in glioma.

"Sandwich Therapy"-Immunotherapy Plus Concurrent Chemoradiotherapy for Advanced Esophagogastric Junction Carcinoma: Report of Two Cases and Literature Review.

Introduction: Esophagogastric junction (EGJ) carcinomas develop in the transition zone between the esophagus and stomach. The incidence of EGJ carcinoma has steadily increased over the past few decades. Most patients are first diagnosed at an advanced stage, which renders them ineligible for surgery. Current methods for the treatment of advanced EGJ carcinoma include surgery, chemotherapy, local palliative therapy, and supportive care; however, none of these treatment methods has provided satisfactory therapeutic effects when used alone. Case Report: We report two cases of patients with EGJ carcinoma who were sequentially treated with immunotherapy plus induction chemotherapy, followed by immunotherapy plus concurrent chemoradiotherapy and maintenance immunotherapy. Both patients achieved extended overall survival times with good quality of life with this new therapeutic approach. Conclusion: Immunotherapy plus chemoradiotherapy may therefore be a reasonable option for treatment of selected EGJ carcinoma patients. However, well-designed trials for the acquisition of additional evidence are required to validate the findings in this study.

Prognostic and incremental value of computed tomography-based radiomics from tumor and nodal regions in esophageal squamous cell carcinoma.

Objective: This study aimed to evaluate the prognostic value of preoperative radiomics and establish an integrated model for esophageal squamous cell cancer (ESCC). Methods: A total of 931 patients were retrospectively enrolled in this study (training cohort, n=624; validation cohort, n=307). Radiomics features were obtained by contrast-enhanced computed tomography (CT) before esophagectomy. A radiomics index was set based on features of tumor and reginal lymph nodes by using the least absolute shrinkage and selection operator (LASSO) Cox regression. Prognostic nomogram was built based on radiomics index and other independent risk factors. The prognostic value was assessed by using Harrell's concordance index, time-dependent receiver operating characteristics and Kaplan-Meier curves. Results: Twelve radiomic features from tumor and lymph node regions were identified to build a radiomics index, which was significantly associated with overall survival (OS) in both training cohort and validation cohort. The radiomics index was highly correlated with clinical tumor-node-metastasis (cTNM) and pathologic TNM (pTNM) stages, but it demonstrated a better prognostic value compared with cTNM stage and was almost comparable with pTNM stage. Multivariable Cox regression showed that the radiomics index was an independent prognostic factor. An integrated model was constructed based on gender, preoperative serum sodium concentration, pTNM and the radiomics index for clinical usefulness. The integrated model demonstrated discriminatory ability better compared with the traditional clinical-pathologic model and pTNM alone, indicating incremental value for prognosis. Conclusions: CT-based radiomics for primary tumor and reginal lymph nodes was sufficient in predicting OS for patients with ESCC. The integrated model demonstrated incremental value for prognosis and was robust for clinical applications.

Deep learning based time-to-event analysis with PET, CT and joint PET/CT for head and neck cancer prognosis.

OBJECTIVES: Recent studies have shown that deep learning based on pre-treatment positron emission tomography (PET) or computed tomography (CT) is promising for distant metastasis (DM) and overall survival (OS) prognosis in head and neck cancer (HNC). However, lesion segmentation is typically required, resulting in a predictive power susceptible to variations in primary and lymph node gross tumor volume (GTV) segmentation. This study aimed at achieving prognosis without GTV segmentation, and extending single modality prognosis to joint PET/CT to allow investigating the predictive performance of combined- compared to single-modality inputs. METHODS: We employed a 3D-Resnet combined with a time-to-event outcome model to incorporate censoring information. We focused on the prognosis of DM and OS for HNC patients. For each clinical endpoint, five models with PET and/or CT images as input were compared: PET-GTV, PET-only, CT-GTV, CT-only, and PET/CT-GTV models, where -GTV indicates that the corresponding images were masked using the GTV contour. Publicly available delineated CT and PET scans from 4 different Canadian hospitals (293) and the MAASTRO clinic (74) were used for training by 3-fold cross-validation (CV). For independent testing, we used 110 patients from a collaborating institution. The predictive performance was evaluated via Harrell's Concordance Index (HCI) and Kaplan-Meier curves. RESULTS: In a 5-year time-to-event analysis, all models could produce CV HCIs with median values around 0.8 for DM and 0.7 for OS. The best performance was obtained with the PET-only model, achieving a median testing HCI of 0.82 for DM and 0.69 for OS. Compared with the PET/CT-GTV model, the PET-only still had advantages of up to 0.07 in terms of testing HCI. The Kaplan-Meier curves and corresponding log-rank test results also demonstrated significant stratification capability of our models for the testing cohort. CONCLUSION: Deep learning-based DM and OS time-to-event models showed predictive capability and could provide indications for personalized RT. The best predictive performance achieved by the PET-only model suggested GTV segmentation might be less relevant for PET-based prognosis.