A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IA1 with LVSI, IA2): study protocol of the LAUNCH 1 trial.

BACKGROUND: A retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial. METHODS: This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life. DISCUSSION: The results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04934982 , Registered on 22 June 2021).

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Splenic irradiation combined with tumor irradiation promotes T cell infiltration in the tumor microenvironment and helps in tumor control.

Locally applied radiation to the tumor is reported to stimulate systemic immune response. During radiotherapy to the abdominal cancer, spleen often receives certain dose, though as an important immune organ, little is known about the impact of splenic irradiation (SI) on systemic immune and local tumor control. Through a mice model, we found that the combination of SI with tumor irradiation (TI) helped in local control. The analysis of the tumor infiltrating leucocytes demonstrated that SI plus TI brought more T cell aggregation in the tumor microenvironment (TME), which helped in tumor control. Increased T cell infiltration may be partly due to higher expression of T cell chemokine in the TME and more expression of CXCR3 on the T cells in the spleen after SI. SI produced more IL-1ß in the spleen, IL-1ß stimulated the expression of CXCR3 on the T cells, and enhanced their migration ability. Taken together, radiation to the spleen combined with TI helped in local control through promoting T cell infiltration, and may be a considerable means to enhance the immunomodulatory of radiotherapy.

Prognostic value of lymph node ratio in survival of patients with locally advanced rectal cancer.

BACKGROUND: The lymph node ratio (LNR) has been shown to be an important prognostic factor in patients with gastric, breast, pancreatic and colorectal cancer. We investigated the prognostic impact of the LNR in addition to TNM classification in patients with locally advanced rectal cancer. METHODS: We retrospectively analyzed patients who underwent curative resection for locally advanced rectal cancer between July 2005 and December 2010. We determined the LNR cutoff value using a receiver operating characteristic curve. The Kaplan-Meier method was used to estimate survival curves, while Cox regression analyses were used to evaluate the relationship between LNR and survival. RESULTS: We included 180 patients aged 28-83 years with median follow-up of 41.8 months. The median number of lymph nodes examined and lymph nodes involved were 11.5 and 4, respectively, and the median LNR was 0.366. An LNR of 0.19 (19%) was the cutoff point to separate patients with regard to median overall survival. Median overall survival was 64.2 months for patients with an LNR of 0, 59.1 for an LNR of 0.19 or less and 37.6 for an LNR greater than 0.19 (p = 0.004). The median disease-free survival was 32.9 months for patients with an LNR of 0, 30.4 for an LNR of 0.19 or less and 17.8 for an LNR greater than 0.19 (p = 0.002). CONCLUSION: Our results suggest that LNR should be considered an additional prognostic factor in patients with locally advanced rectal cancer.

CONTEXTE: Il a été démontré que le ratio de ganglions lymphatiques positifs est un important facteur pronostique chez les patients atteints de cancer de l'estomac, de cancer du sein, de cancer du pancréas et de cancer colorectal. Nous avons étudié l'incidence pronostique de l'utilisation de ce ratio en plus de la classification TNM chez les patients présentant un cancer du rectum localement avancé. MÉTHODES: Nous avons analysé rétrospectivement des patients ayant subi une résection curative visant à traiter un cancer du rectum localement avancé entre juillet 2005 et décembre 2010. Nous avons déterminé la valeur seuil du ratio de ganglions lymphatiques positifs à l'aide d'une courbe caractéristique de la performance. La méthode de Kaplan-Meyer a été utilisée pour estimer les courbes de survie, tandis que le modèle de régression des hasards proportionnels de Cox a servi à évaluer la corrélation entre le ratio à l'étude et la survie. RÉSULTATS: Notre étude a porté sur 180 patients de 28 à 83 ans dont la durée médiane du suivi était de 41,8 mois. Les nombres médians de ganglions lymphatiques examinés et de ganglions lymphatiques positifs étaient de 11,5 et 4, respectivement, et le ratio médian de ganglions lymphatiques positifs était de 0,366. Nous avons utilisé une valeur seuil de 0,19 (19 %) pour séparer les patients en ce qui a trait à la survie globale médiane. Cette mesure était de 64,2 mois pour les patients présentant un ratio de 0, de 59,1 mois pour ceux présentant un ratio de 0,19 ou moins, et de 37,6 mois pour ceux dont le ratio était supérieur à 0,19 (p = 0,004). La survie sans récidive médiane était de 32,9 mois pour les patients présentant un ratio de 0, de 30,4 mois pour ceux présentant un ratio de 0,19 ou moins, et de 17,8 mois pour ceux dont le ratio était supérieur à 0,19 (p = 0,002). CONCLUSION: Nos résultats indiquent que le ratio de ganglions lymphatiques positifs devrait être envisagé comme facteur pronostique supplémentaire pour les patients atteints d'un cancer du rectum localement avancé.

Chinese national clinical practice guideline on diagnosis and treatment of biliary tract cancers.

BACKGROUND: Biliary tract carcinoma (BTC) is relatively rare and comprises a spectrum of invasive tumors arising from the biliary tree. The prognosis is extremely poor. The incidence of BTC is relatively high in Asian countries, and a high number of cases are diagnosed annually in China owing to the large population. Therefore, it is necessary to clarify the epidemiology and high-risk factors for BTC in China. The signs associated with BTC are complex, often require collaborative treatment from surgeons, endoscopists, oncologists, and radiation therapists. Thus, it is necessary to develop a comprehensive Chinese guideline for BTC. METHODS: This clinical practice guideline (CPG) was developed following the process recommended by the World Health Organization. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of evidence and make recommendations. The full CPG report was reviewed by external guideline methodologists and clinicians with no direct involvement in the development of this CPG. Two guideline reporting checklists have been adhered to: Appraisal of Guidelines for Research and Evaluation (AGREE) and Reporting Items for practice Guidelines in Healthcare (RIGHT). RESULTS: The guideline development group, which comprised 85 multidisciplinary clinical experts across China. After a controversies conference, 17 clinical questions concerning the prevention, diagnosis, and treatment of BTC were proposed. Additionally, detailed descriptions of the surgical principles, perioperative management, chemotherapy, immunotherapy, targeted therapy, radiotherapy, and endoscopic management were proposed. CONCLUSIONS: The guideline development group created a comprehensive Chinese guideline for the diagnosis and treatment of BTC, covering various aspects of epidemiology, diagnosis, and treatment. The 17 clinical questions have important reference value for the management of BTC.

Genomic Profiling and Immune Phenotyping of Neuroendocrine Bladder Cancer.

PURPOSE: Neuroendocrine bladder cancer (NEBC) poses a formidable clinical challenge and attracts keen interests to explore immunotherapy as a viable treatment option. However, a comprehensive immunogenomic landscape has yet to be thoroughly investigated. EXPERIMENTAL DESIGN: Leveraging a long-term cohort of natural NEBC cases, we employed a multimodal approach integrating genomic (n = 19), transcriptomic (n = 3), single-cell RNA sequencing (n = 1), and IHC analyses (n = 34) to meticulously characterize the immunogenicity and immunotypes of primary NEBC tumors. Information on clinical, pathologic, medical imaging, and treatment aspects was retrospectively retrieved and analyzed. RESULTS: Our study unveiled that despite a considerable mutational burden, NEBC was typically immunologically inactive, as manifested by the "immune-excluded" or "immune-desert" microenvironment. Interestingly, a subset of mixed NEBC with concurrent urothelial bladder cancer histology displayed an "immune-infiltrated" phenotype with prognostic relevance. When compared with urothelial bladder cancer, NEBC lesions were distinguished by a denser cellular composition and augmented peritumoral extracellular matrix, which might collectively impede lymphatic infiltration. As a result, single-agent immune checkpoint inhibitors demonstrated limited efficacy against NEBC, whereas pharmacologic immunostimulation with combination chemotherapy conferred a more favorable response. CONCLUSIONS: These new insights derived from genomic profiling and immune phenotyping pave the way for rational immunotherapeutic interventions in patients with NEBC, with the potential to ultimately reduce mortality from this otherwise fatal disease.

Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer.

BACKGROUND: Programmed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) combined with the PD-1 inhibitor toripalimab in patients with resectable ESCC. METHODS: From July 2020 to July 2022, 21 patients with histopathologically confirmed thoracic ESCC and clinical staged as cT1-4aN1-2M0/cT3-4aN0M0 were enrolled. Eligible patients received radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week) with concurrent chemotherapy of paclitaxel/cisplatin (paclitaxel 45 mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 and two cycles of toripalimab 240 mg every 3 weeks after nCRT for neoadjuvant therapy before surgery, four cycles of toripalimab 240 mg every 3 weeks for adjuvant therapy after surgery. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints were safety and survival outcomes. RESULTS: A total of 21 patients were included, of whom 20 patients underwent surgery, 1 patient refused surgery and another patient was confirmed adenocarcinoma after surgery. The MPR and pathological complete response (pCR) rates were 78.9% (15/19) and 47.4% (9/19) for surgery ESCC patients. 21 patients (100.0%) had any-grade treatment-related adverse events, with the most common being lymphopenia (100.0%), leukopenia (85.7%), neutropenia (52.4%). 14 patients (66.7%) had adverse events of grade 3 with the most common being lymphopenia (66.7%). The maximum standardized uptake value and total lesion glycolysis of positron emission tomography/CT after neoadjuvant therapy well predicted the pathological response. The peripheral CD4+%, CD3+HLA-DR+/CD3+%, CD8+HLA-DR+/CD8+%, and IL-6 were significant differences between pCR and non-pCR groups at different times during neoadjuvant therapy. Three patients had tumor relapse and patients with MPR have longer disease-free survival than non-MPR patients. CONCLUSIONS: nCRT combined with perioperative toripalimab is effective and safe for locally advanced resectable ESCC. Long-term survival outcomes remain to be determined. TRIAL REGISTRATION NUMBER: NCT04437212.

Single-Nucleus Transcriptome Profiling of Locally Advanced Cervical Squamous Cell Cancer Identifies Neural-Like Progenitor Program Associated with the Efficacy of Radiotherapy.

Radiotherapy is the first-line treatment for locally advanced cervical squamous cell cancer (CSCC). However, ≈50% of patients fail to respond to therapy and, in some cases, tumors progress after radical radiotherapy. Here, single-nucleus RNA-seq is performed to construct high-resolution molecular landscapes of various cell types in CSCC before and during radiotherapy, to better understand radiotherapy related molecular responses within tumor microenvironment. The results show that expression levels of a neural-like progenitor (NRP) program in tumor cells are significantly higher after radiotherapy and these are enriched in the tumors of nonresponding patients. The enrichment of the NRP program in malignant cells from the tumors of nonresponders in an independent cohort analyzed by bulk RNA-seq is validated. In addition, an analysis of The Cancer Genome Atlas dataset shows that NRP expression is associated with poor prognosis in CSCC patients. In vitro experiments on the CSCC cell line demonstrate that downregulation of neuregulin 1 (NRG1), a key gene from NRP program, is associated with decreased cell growth and increased sensitivity to radiation. Immunohistochemistry staining in cohort 3 validated key genes, NRG1 and immediate early response 3 from immunomodulatory program, as radiosensitivity regulators. The findings reveal that the expression of NRP in CSCC can be used to predict the efficacy of radiotherapy.

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IB3 and IIA2): study protocol of the LAUNCH 3 trial.

BACKGROUND: Cervical cancer is and will remain to be an important health problem in China, especially with an increasing proportion of younger patients who has more specific needs. In China, surgery to remove tumor burden followed by postoperative treatment with radiotherapy and chemotherapy based on clinicopathologic factors may be the best choice for stages IB3 and IIA2 patients. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology. The current trial is designed to evaluate whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB3 and IIA2) patient survival under stringent operation standards and consistent surgical oncologic principles. This paper reports the rationale, design, and implementation of the trial. METHODS/DESIGN: This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 1104 patients with stage IB3 and IIA2 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary end point will be 5-year overall survival, and secondary endpoints include 5-year progression-free survival, recurrence, and quality of life measurements. DISCUSSION: The study results will provide more convincing evidence-based information for stages IB3 and IIA2 cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04939831 , retrospectively registered on 25 June 2021.

Economic evaluation of radiotherapy for early breast cancer after breast-conserving surgery in a health resource-limited setting.

The primary objective was to assess the cost-effectiveness, from the Chinese societal perspective, of additional radiotherapy for women with early breast cancer after breast-conserving surgery (BCS). The Markov model was constructed to simulate women's transitions across various health states based on the clinical course of breast cancer (no recurrence, local or distant recurrence, and death) and treatment strategy (radiotherapy vs. no-radiotherapy). The clinical and utility data were estimated from published studies. Costs were estimated from the perspective of Chinese society. Quality-adjusted life-years (QALYs) and incremental cost-effective ratios (ICERs) were determined. Probabilistic and one-way sensitivity analyses were performed. The addition of radiotherapy following BCS was associated with improved overall survival (22.20 vs. 19.51 years) and QALYs (13.25 vs. 11.75) and reduced lifetime costs ($24,518.9 vs. $25,147.0). The ICER of radiotherapy vs. no-radiotherapy was -$420.56/QALY gained. Sensitivity, subgroup and scenario analyses indicated that these results were robust against plausible assumptions and variations. In health resource-limited settings, the addition of radiotherapy is a very cost-effective strategy in comparison to no-radiotherapy in women with early breast cancer.

Radiographic characteristics of bone metastases from hepatocellular carcinoma.

AIM OF THE STUDY: Different carcinomas have different characteristics, which may play a crucial role in diagnosis and treatment. Our study was aimed at understanding the development pattern of bone metastasis from hepatocellular carcinoma, based on its imaging characteristics, so as to provide a more targeted treatment. MATERIAL AND METHODS: Forty two patients (123 lesions) with hepatocellular carcinoma hospitalized from June 2006 to June 2011 underwent radiotherapy for bone metastasis in our department. Clinical and imaging data were analyzed retrospectively (based on CT imaging, also with reference to MRI, ECT, or PET-CT, etc.). RESULTS: One hundred of 123 lesions were vertebral metastases; 23 were non-vertebral. The major form of bone destruction was osteolytic change. Metastasis in the vertebral body was found in 87.8%, and lesions were well distributed in various sections. Vertebral appendix metastasis accounted for 52%, where lesions could be independent of vertebral body metastasis. Formation of a soft tissue mass in bone metastasis was found in 68.6% of all patients. The center of the mass from a vertebral body metastasis was mostly located at the site of the lesion; masses from the vertebral appendix and the pelvis, on the other hand, often presented as a "peripheral mass". Masses were not formed in lesions with pure osteoblastic changes. CONCLUSIONS: The most common radiographic feature is an osteolytic lesion, either replaced by soft tissue mass, or invaded by soft tissue mass from the vicinity, which often cause compression syndrome. Vertebral appendix metastasis can exist independently from vertebral body metastasis, which should be paid more attention to avoid missed diagnosis.

Hypoxia-Regulated lncRNA USP2-AS1 Drives Head and Neck Squamous Cell Carcinoma Progression.

The role of hypoxia-regulated long non-coding RNA (lncRNA) in the development of head and neck squamous cell carcinoma (HNSCC) remains to be elucidated. In the current study, we initially screened hypoxia-regulated lncRNA in HNSCC cells by RNA-seq, before focusing on the rarely annotated lncRNA USP2 antisense RNA 1 (USP2-AS1). We determined that USP2-AS1 is a direct target of HIF1α and is remarkably elevated in HNSCC compared with matched normal tissues. Patients with a higher level of USP2-AS1 suffered a poor prognosis. Next, loss- and gain-of-function assays revealed that USP2-AS1 promoted cell proliferation and invasion in vitro and in vivo. Mechanically, RNA pulldown and LC-MS/MS demonstrated that the E3 ligase DDB1- and CUL4-associated factor 13 (DCAF13) is one of the binding partners to USP2-AS1 in HNSCC cells. In addition, we assumed that USP2-AS1 regulates the activity of DCAF13 by targeting its substrate ATR. Moreover, the knockdown of DCAF13 restored the elevated cell proliferation and growth levels achieved by USP2-AS1 overexpression. Altogether, we found that lncRNA USP2-AS1 functions as a HIF1α-regulated oncogenic lncRNA and promotes HNSCC cell proliferation and growth by interacting and modulating the activity of DCAF13.

Identification of Cytosolic DNA Sensor cGAS-STING as Immune-Related Risk Factor in Renal Carcinoma following Pan-Cancer Analysis.

Background: The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays critical functions in innate immune responses via the production of the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which stimulates the adaptor stimulator of interferon genes (STING). However, the clinical relevance and prognostic value of the cGAS-STING pathway in human cancers remains largely unexplored. Methods: A gene signature related to the cGAS-STING score was identified. The pan-cancer landscape of cGAS-STING expression was calculated using the RNAseq data acquired from the TCGA cohort. Tumor-infiltrating immune cells (TIICs) were determined by the ssGSEA method. Kaplan-Meier curves, Cox regression analyses, and the area under the curve (AUC) were employed to decipher the predictive value of cGAS-STING risk score and TIICs across several human cancers. Results: Most tumor tissues displayed a higher cGAS-STING score compared with their corresponding nontumor tissues, except for prostate adenocarcinoma (PRAD) and uterine corpus endometrial carcinoma (UCEC). Higher cGAS-STING score was closely associated with poor clinical outcome of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP), whereas the cGAS-STING score predicted a better prognosis in pheochromocytoma and paraganglioma (PCPG). Enrichment analysis showed that cGAS-STING was profoundly implicated in diverse immune-related pathways in KIRC, KIRP, and PCPG. Significant positive correlations were noticed between cGAS-STING score and TIICs, including activated CD8+ T cells, activated CD4+ T cells, monocytes, and mast cells. Finally, the cGAS-STING score was revealed to be an independent prognostic factor for KIRC patients and possessed a strong predictive power for the prognostic evaluation of KIRC and KIRP patients. Conclusions: We constructed a cGAS-STING gene signature to predict survival and tumor immunity across human cancers, which can serve as a novel prognostic indicator and therapeutic target, especially in KIRC and KIRP.

Identifying key mutations of radioresponsive genes in esophageal squamous cell carcinoma.

Background: Radiotherapy plays an important effect on the standard therapy of esophageal squamous cell carcinoma (ESCC). However, the efficacy of the therapy is limited and a few patients do not achieve satisfactory treatment results due to the existence of radiation resistance. Therefore, it is necessary to identify the potential predictive biomarkers and treatment targets for ESCC. Methods: We performed the whole-exome sequencing to determine the germline and somatic mutations in ESCC. Functional enrichment and pathway-based protein-protein interaction analyses were used to ascertain potential regulatory networks. Cell survival and cell death after treatment with radiotherapy were determined by CCK-8 and LDH release assays in ESCC cells. The correlations of NOTCH1 and tumor immune infiltration were also analyzed in ESCC. Results: Our results showed that 344 somatic and 65 germline differentially mutated genes were detected to be radiosensitivity-related loci. The tumor mutational burdens (TMB) or microsatellite instability (MSI) were not significantly correlated with the response to radiotherapy in ESCC patients. Pathway-based protein-protein interaction analyses implied several hub genes with most nodes (such as PIK3CA, NOTCH1, STAT3 and KDR). The in vitro studies showed that the knockdown of NOTCH1 inhibited cell survival and rendered more cell death after the treatment with radiotherapy in ESCC cells, while NOTCH1 overexpression had the opposite effects. Moreover, NOTCH1, frequently up-regulated in ESCC, was negatively correlated with activated B cell and immature dendritic cell in ESCC. High expression of NOTCH1 was accompanied with the low levels of some immunotherapy-related cells, including CD8(+) T cells and NK cells. Conclusions: These results indicate the differences of the germline mutations and somatic mutations between the radiosensitive and radioresistence groups in ESCC and imply that NOTCH1 plays important roles in regulating the radiosensitivity of ESCC. The findings might provide the biomarkers and potential treatment targets for improving the sensitivity to radiotherapy in ESCC.

Genetic variant of ADH1C for predicting survival in esophageal squamous cell cancer patients who underwent postoperative radiotherapy.

Background: Single nucleotide polymorphisms (SNPs) of essential enzymes for alcohol metabolism ADH1B, ADH1C, and ALDH2 are commonly regarded as genetic biomarkers for esophageal squamous cell carcinoma (ESCC) susceptibility. However, there have not been any reports on relations between SNPs of these genes and the prognosis of postoperative radiotherapy in ESCC. The current study aimed to understand the associations between gene variants of alcohol metabolism and adjuvant radiotherapy's prognosis in ESCC. Methods: This study retrospectively analyzed 110 ESCC patients from our institution who received adjuvant radiotherapy after surgery. The SNPs of ADH1B rs1229984, ADH1C rs1789924, and ALDH2 rs671 were detected by Sanger sequencing using formalin-fixed paraffin-embedded tumor samples. A nomogram was drawn based on prognostic factors associated with overall survival (OS). Results: ADH1C rs1789924 (C>T) was associated with poor DFS and OS in ESCC patients undergoing adjuvant radiotherapy. Multivariate analysis showed that ADH1C rs1789924 (C>T) was one of the independent prognosis factors of DFS and OS. However, the genotypes of ADH1B SNP rs1229984 and ALDH2 rs671 were not associated with differences in the PFS and OS of these patients. Compared with the AJCC staging system, the nomogram containing the ADH1C genotype can more effectively and accurately predict the survival time of ESCC after surgery and adjuvant radiotherapy. Conclusion: ADH1C rs1789924 might be a prognostic genetic biomarker for ESCC patients undergoing surgery and postoperative radiotherapy.

The predictive value of peripheral blood cells and lymphocyte subsets in oesophageal squamous cell cancer patients with neoadjuvant chemoradiotherapy.

Purpose: Neoadjuvant chemoradiotherapy (nCRT) is a standard treatment option for patients with stage III oesophageal cancer. Approximately 30% of oesophageal cancer patients will have a pathological complete response (pCR) after nCRT. However, available clinical methods cannot accurately predict pCR for patients. We aimed to find more indicators that could be used to predict the pathological response to nCRT. Method: A total of 84 patients with stage III oesophageal squamous cell cancer were enrolled in this study. Ten patients failed to have surgery as a result of progressive disease (PD). Among the patients who underwent surgery, 32 patients had a pathologic complete response (pCR), whereas 42 patients showed no or partial response (npCR) after nCRT. Routine blood test results and lymphocyte subset assessments before and after nCRT were retrospectively analysed. Univariate and multivariate analyses were used to identify independent predictors of the clinical curative effect of nCRT. Eventually, nomograms were established for predicting the PD and pCR rates. Results: The numbers of lymphocytes, B lymphocytes, T lymphocytes, Th lymphocytes, Ts lymphocytes, and NK cells and the percentages of B lymphocytes and NK cells were decreased significantly after nCRT (P < 0.0001), whereas the percentages of T lymphocytes and Ts lymphocytes increased (P < 0.0001). Univariate analysis showed that age, the length of the lesion, the level of haemoglobin before nCRT, and the amount of change in haemoglobin were related to PD, and the percentage of NK cells after nCRT was related to pCR. Multivariate logistic analysis demonstrated that the length of the lesion, the neutrophil-to-lymphocyte ratio (NLR) before nCRT, and the amount of change in haemoglobin were independent predictors of PD, whereas the percentage of NK cells after nCRT was an independent predictor of pCR. Conclusion: Lymphocyte subsets changed dramatically during nCRT, and these changes together with baseline and posttreatment lymphocyte subsets have predictive value in determining the response to nCRT for oesophageal cancer.

A multicenter non-inferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stages IB1, IB2, and IIA1): study protocol of the LAUNCH 2 trial.

BACKGROUND: A retrospective study and a randomized controlled trial published in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early-stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology; therefore, this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB1, IB2, and IIA1) patient survival under stringent operation standards and consistent surgical oncologic principles. METHODS/DESIGN: This is an investigator-initiated, Prospective, Randomized, Open, Blinded End-point (PROBE)-controlled non-inferiority trial. A total of 780 patients with stage IB1, IB2, and IIA1 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary endpoint will be 5-year progression-free survival, and secondary endpoints include 5-year overall survival, recurrence, and quality of life measurements. DISCUSSION: The debate on laparoscopic versus abdominal RH is still ongoing, and high-quality evidences are needed to guide clinical practice. The study results will provide more convincing evidence-based information for early-stage cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. TRIAL REGISTRATION: ClinicalTrials.gov NCT04929769 . Registered on 18 June 2021.

Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of pancreatic cancer.

Pancreatic cancer is one of the leading causes of cancer-related mortality in both developed and developing countries. The incidence of pancreatic cancer in China accounts for about a quater of the global incidence, and the epidemiological characteristics and therapeutic strategies differ due to social, economic, cultural, environmental, and public health factors. Non-domestic guidelines do not reflect the clinicopathologic characteristics and treatment patterns of Chinese patients. Thus, in 2018, the Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts from all sub-specialties within the field of pancreatic oncology to compile the Chinese guidelines for the diagnosis and treatment of pancreatic cancer. The guidelines were made based on both the Western and Eastern clinical evidence and updated every one or two years. The experts made consensus judgments and classified evidence-based recommendations into various grades according to the regional differences, the accessibility of diagnostic and treatment resources, and health economic indexes in China. Here we present the latest version of the guidelines, which covers the diagnosis, treatment, and follow-up of pancreatic cancer. The guidelines might standardize the diagnosis and treatment of pancreatic cancer in China and will encourage oncologists to design and conduct more clinical trials about pancreatic cancer.

The Heterogeneity of Neutrophil Recruitment in the Tumor Microenvironment and the Formation of Premetastatic Niches.

The recruitment of neutrophil to the primary cancer has been shown to be steered by neoplastic cells or tumor-educated mesenchymal stromal cells and has a prometastatic effect. However, the neutrophil chemotaxis and their interaction with tumor cells in the distal metastasized tissues remain elusive. In this review, we discussed emerging research on the interaction between neutrophil recruitment and tumor metastasis, which is essential for studying tumor cell invasion and related immunotherapy.

TMEM100 negatively regulated by microRNA­106b facilitates cellular apoptosis by suppressing survivin expression in NSCLC.

Non­small cell lung cancer (NSCLC) is a common malignant tumour. Nevertheless, the 5­year survival rate of NSCLC patients remains poor. Thus, identifying critical factors involved in regulating the progression of NSCLC is important for providing potential treatment targets. In the present study, it was observed that transmembrane protein 100 (TMEM100) was significantly downregulated in NSCLC tissues compared with paired peritumoral tissues. Decreased TMEM100 expression was associated with poor clinical outcomes in NSCLC patients. Moreover, TMEM100 overexpression inhibited colony formation and facilitated apoptosis by suppressing survivin expression in NSCLC cells, whereas TMEM100 knockdown had the opposite effect. In addition, microRNA (miR)­106b, a miR with controversial roles in different human cancers, was upregulated in NSCLC and directly downregulated TMEM100 expression. The roles of miR­106b in cell survival were mitigated by the restoration of TMEM100. The aforementioned results indicated that TMEM100 induced cell apoptosis and inhibited cell survival by serving as a tumour suppressor and that miR­106b­mitigatedTMEM100 expression defined a potentially oncogenic pathway in NSCLC.