Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

A phase I trial of autologous RAK cell immunotherapy in metastatic renal cell carcinoma.

BACKGROUND: Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge worldwide. Here, we introduced a phase I trial of autologous RAK cell therapy in patients with mRCC whose cancers progressed after prior systemic therapy. Although RAK cells have been used in clinic for many years, there has been no dose-escalation study to demonstrate its safety and efficacy. METHODS: We conducted a phase I trial with a 3 + 3 dose-escalation design to investigate the dose-related safety and efficacy of RAK cells in patients with mRCC whose cancers have failed to response to systemic therapy (ChiCTR1900021334). RESULTS: Autologous RAK cells, primarily composed of CD8+ T and NKT cells, were infused intravenously to patients at a dose of 5 × 109, 1 × 1010 or 1.5 × 1010 cells every 28 days per cycle. Our study demonstrated general safety of RAK cells in a total of 12 patients. Four patients (33.3%) showed tumor shrinkage, two of them achieved durable partial responses. Peripheral blood analysis showed a significant increase in absolute counts of CD3+ and CD8+ T cells after infusion, with a greater fold change observed in naive CD8+ T cells (CD8+CD45RA+). Higher peak values of IL-2 and IFN-γ were observed in responders after RAK infusion. CONCLUSION: This study suggests that autologous RAK cell immunotherapy is safe and has clinical activity in previously treated mRCC patients. The improvement in peripheral blood immune profiling after RAK cell infusion highlights its potential as a cancer treatment. Further investigation is necessary to understand its clinical utility.

Alteration of the gut microbiota changes during the one-year Antarctic deployment in a group of Chinese Han population.

BACKGROUND: It is common knowledge that people's intestinal microbiota is significantly influenced by the external environment. Although the Antarctic continent has been discovered for nearly 200 years, it is still unclear how this environment affects the human intestinal microbiota, especially that of the Chinese Han population. METHODS: Twelve explorers underwent a one-year Antarctic deployment from December 2017 to December 2018. The gut microbiota and clinical indexes at five time points, including two months (T1), five months (T2), eight months (T3), 11 months (T4) of residence in Antarctica and 7 months after returning to China (T5), were investigated. RESULTS: The intestinal microbiota of the participants was changed after one-year Antarctic deployment even after they left Antarctica. For the microbiota tested after returning to China (T5), the amount of Citrobacter, Akkermansia and conditional pathogens such as Escherichia-Shigella increased significantly (P < 0.05). The concentration of the major biochemical indicators in the serum exhibited an increasing trend before T3, and decreased significantly at T4. When tested again at T5, most of the serum concentrations increased, only 5-hydroxytryptamine was significantly decreased. Spearman correlation analysis showed the change in the relative abundance of Anaerotruncus was negatively associated with the changes in the concentration of total thyroxine, alanine transaminase, γ-glutamyl transpeptidase, serum cystatin C and apolipoprotein A1. The relative abundance change in Citrobacter was positively associated with the change in the concentration of uric acid. CONCLUSION: By objectively analyzing the influence of the Antarctic environment on the change of intestinal microbiota, we were able to provide theoretical support for subsequent Antarctic related research.

Phase Ib study of anlotinib combined with TQB2450 in pretreated advanced biliary tract cancer and biomarker analysis.

BACKGROUND AND AIMS: We evaluated the efficacy and safety of the antiangiogenic tyrosine kinase inhibitor anlotinib plus TQB2450, a programmed death-ligand 1 inhibitor in pretreated advanced biliary tract cancers (BTCs). APPROACH AND RESULTS: In this pooled analysis of two single-center, phase Ib clinical trials (TQB2450-Ib-05 and TQB2450-Ib-08 trials), 66 patients with advanced BTCs who had progressed or declined or were ineligible for first-line chemotherapy were included. With the treatment of anlotinib plus TQB2450, two patients achieved complete response, and 12 had a partial response assessed by Response Evaluation Criteria in Solid Tumors 1.1, yielding an objective response rate of 21.21%, a disease control rate (DCR) of 72.73%, and a clinical benefit rate (CBR) of 42.42%. With a median follow-up of 19.68 months, median progression-free survival (PFS) and overall survival (OS) were 6.24 (95% confidence interval [CI], 4.11-8.25) and 15.77 (95% CI, 10.74-19.71) months, respectively. Adverse events (AEs) were reported in 64 (96.97%) patients, and the most common grade 3 or worse treatment-related AEs included elevated levels of aspartate aminotransferase (7.58%), alanine aminotransferase (6.06%), and hypertension (6.06%). Patients with high tumor mutational burden (TMB; ≥5 mutations/Mbp) had a better CBR (70.8% vs. 22.2%), longer OS (14.32 vs. 9.64 months), and a trend toward longer PFS (7.03 vs. 4.06 months). Patients with kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations showed a lower CBR (12.5% vs. 58.8%) and shorter PFS (2.02 vs. 6.80 months) and OS (10.53 vs. 13.13 months). CONCLUSIONS: Anlotinib combined with TQB2450 showed promising efficacy and was well tolerated in advanced BTCs. KRAS mutation and high TMB might serve as predictors of treatment efficacy.

Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Reclassification of therapeutic response of unresectable hepatocellular carcinoma to anti-angiogenic therapy and immunotherapy using alpha RECIST.

OBJECTIVES: To assess the therapeutic response of HCC to antiangiogenic therapy plus immunotherapy by integrating RECIST 1.1 and alpha-fetoprotein (AFP) response at the 6th week to predict overall survival (OS). METHODS: This retrospective study included 150 and 214 patients with HCC who received combination therapy in training and validation cohorts. The medical images and AFP levels obtained at baseline and 6th week were collected. AFP response stratification: partial response (PR): AFP% ≥ 75% decline; stable disease (SD): AFP% < 75% decline and ≤ 10% elevation; progressive disease (PD): AFP% > 10% elevation. The alpha-RECIST was: PR: RECIST 1.1-PR or AFP-PR; PD: AFP-PD or RECIST 1.1-PD and does not satisfy AFP-PR; SD: neither PR nor PD. OS was compared using Kaplan-Meier curves. The predictive ability of various criteria was evaluated using the concordance index and time-dependent area under the receiver-operating characteristic curve. RESULTS: RECIST 1.1 achieved significant OS stratification (p = 0.020) for AFP < 20 ng/mL. For AFP ≥ 20 ng/mL, alpha-RECIST showed better performance than RECIST 1.1, mRECIST, and AFP response according to C-index (0.73 vs 0.66 vs 0.68 vs 0.69). The National Cancer Center (NCC) strategy utilized RECIST 1.1 for AFP < 20 ng/mL and alpha-RECIST for AFP ≥ 20 ng/mL and showed better performance than RECIST 1.1, mRECIST and AFP response according to C-index (0.73 vs 0.67 vs 0.69 vs 0.64). The performances of alpha-RECIST and NCC Strategy were confirmed in the validation cohort (C-index = 0.77 and 0.74). CONCLUSIONS: The alpha-RECIST and NCC Strategy achieved better survival stratification in patients with HCC under combination therapy in the AFP ≥ 20 ng/mL group and the whole cohort compared to the RECIST 1.1, mRECIST, and AFP response. CLINICAL TRANSLATIONAL RELEVANCE: The alpha-RECIST and National Cancer Center strategy are optimal methods for determining therapeutic response to a combination of anti-angiogenic therapy plus immunotherapy and facilitating accurate prognostic stratification for HCC in the AFP ≥ 20 ng/mL group and the whole cohort, which may help oncologists for early identification of responders and progression at 6 weeks and clinical decision-making. KEY POINTS: • RECIST 1.1 is indicated for patients with baseline alpha-fetoprotein (AFP) < 20 ng/mL. • For patients with baseline AFP ≥ 20 ng/mL, integrating RECIST 1.1 and AFP response (alpha-RECIST) may aid in the early identification of survival benefits and progression definition prior to the administration of additional efficacious drugs. • The National Cancer Center strategy is an optimal stratified strategy for determining therapeutic response to a combination of anti-angiogenic therapy and immunotherapy for HCC based on baseline AFP levels.

Perioperative chemotherapy with docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) for the treatment of locally advanced gastric or gastro-esophageal junction adenocarcinoma (MATCH): an open-label, randomized, phase 2 clinical trial.

BACKGROUND: It remains unclear whether addition of docetaxel to the combination of a platinum and fluoropyrimidine could provide more clinical benefits than doublet chemotherapies in the perioperative treatment for locally advanced gastric/gastro-esophageal junction (LAG/GEJ) cancer in Asia. In this randomized, phase 2 study, we assessed the efficacy and safety of perioperative docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) in LAG/GEJ adenocarcinoma patients. METHODS: Patients with cT3-4 Nany M0 G/GEJ adenocarcinoma were randomized (1:1) to receive 4 cycles of preoperative DOS or SOX followed by D2 gastrectomy and another 4 cycles of postoperative chemotherapy. The primary endpoint was major pathological response (MPR). RESULTS: From Aug, 2015 to Dec, 2019,154 patients were enrolled and 147 patients included in final analysis, with a median age of 60 (26-73) years. DOS resulted in significantly higher MPR (25.4 vs. 11.8%, P = 0.04). R0 resection rate, the 3-year PFS and 3-year OS rates were 78.9 vs. 61.8% (P = 0.02), 52.3 vs. 35% (HR 0.667, 95% CI: 0.432-1.029, Log rank P = 0.07) and 57.5 vs. 49.2% (HR 0.685, 95% CI: 0.429-1.095, Log rank P = 0.11) in the DOS and SOX groups, respectively. Patients who acquired MPR experienced significantly better survival. DOS had similar tolerance to SOX. CONCLUSIONS: Perioperative DOS improved MPR significantly and tended to produce longer PFS compared to SOX in LAG/GEJ cancer in Asia, and might be considered as a preferred option for perioperative chemotherapy and worth further investigation.

Is early bilateral compression ultrasonography and D-dimer monitoring appropriately for prophylaxis and diagnosis of deep venous thrombosis after cesarean section women: a single-center observation study of Chinese Han population.

BACKGROUND: Venous thromboembolism (VTE) is most prevalent among parturients following a cesarean section (CS). The objective of this study was to assess the practical utility of bilateral compression ultrasonography (CUS) of the lower limbs, coupled with D-dimer monitoring, in the early diagnosis of VTE within the Han Chinese population. METHODS: Our prospective observational study included 742 women who underwent CUS and D-dimer testing on the first day post-CS. Subsequently, telephone or outpatient follow-ups were conducted until 42 days postpartum. States of hypercoagulation and thrombosis, as indicated by CUS, were classified as CUS abnormal. A D-dimer level ≥ 3 mg/l was considered the D-dimer warning value. Early ambulation and mechanical prophylaxis were universally recommended for all parturients post-CS. A sequential diagnostic strategy, based on the 2015 RCOG VTE risk-assessment tool, was employed. Therapeutic doses of low-molecular-weight heparin (LMWH) were administered for the treatment of thromboembolic disease. Prophylactic doses of LMWH were given for VTE prophylaxis in parturients with hypercoagulative status accompanied by D-dimer levels ≥ 3 mg/l. All high-risk women (RCOG score ≥ 4 points) were additionally treated with preventive LMWH. Statistical analyses were conducted using the R statistical software, with a two-sided P value < 0.05 considered statistically significant. RESULTS: Fifteen cases of VTE and 727 instances without VTE were observed. The overall VTE rate post-CS was 2.02% (15/742), with 66.7% (10/15) being asymptomatic. Eleven patients received a VTE diagnosis on the first postpartum day. Among the 41 parturients exhibiting hypercoagulation ultrasound findings and D-dimer levels ≥ 3 mg/l, despite receiving pharmacological VTE prophylaxis with LMWH, 4.88% (2/41) in the high-risk group were eventually diagnosed with VTE. A total of 30.86% (229/742) exhibited normal ultrasound findings and D-dimer levels < 3 mg/l on the first day post-CS, with no VTE occurrences in the postpartum follow-up. According to RCOG's recommendation, 78.03% (579/742) of cesarean delivery women should receive prophylactic anticoagulation, while only 20.62% (153/742) met our criterion for prophylactic anticoagulation. CONCLUSION: The strategy of timely routine bilateral CUS and D-dimer monitoring is conducive to the early diagnosis and treatment of VTE, significantly reducing the use of LMWH in the Chinese Han population.

The GRAPHS-CRAFITY score: a novel efficacy predictive tool for unresectable hepatocellular carcinoma treated with immunotherapy.

OBJECTIVES: To investigate MR features associated with prognosis of unresectable HCC receiving immunotherapy and establish a MR feature-based scoring system to predict efficacy of immunotherapy. METHODS: This retrospective study included patients with unresectable HCC who received immunotherapy at 2 hospitals between August 2018 and February 2022. The last follow-up was October 2022. Clinical variables and MR features were assessed using univariate and multivariate Cox regression analyses. A new scoring system was constructed based on independent risk factors and the CRAFITY score consisting of AFP (≥ 100 ng/ml) and CRP (≥ 1 mg/dl). And the predictive performance of CRAFITY core and new score were compared by receiver-operating-characteristics curves (ROCs), area under ROCs (AUCs), and calibration curves. RESULTS: A total of 166 patients (55.6 ± 10.4 years) were included in training cohort and 77 patients (55.4 ± 10.7 years) were included in validation cohort. There were significant differences in BCLC stage, max size, macrovascular invasion, intratumoral artery, and enhancing capsule between the 2 groups. Based on independent risk factors (gross GRowtH type, intratumoral fAt, enhancing tumor caPsule, Sex and CRAFITY score), a novel efficacy predictive tool named the GRAPHS-CRAFITY score was developed to predict OS. The OS was significantly different among the 3 groups according to GRAPHS-CRAFITY score (p value < 0.001). The GRAPHS-CRAFITY score could predict tumor response and disease control (p value < 0.001, p value < 0.001). CONCLUSIONS: The GRAPHS-CRAFITY score is a reliable and easily applicable tool to predict the efficacy of unresectable HCC receiving immunotherapy.

Abnormal generation of IL-17A represses tumor infiltration of stem-like exhausted CD8+ T cells to demote the antitumor immunity.

BACKGROUND: Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1). METHODS: Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined. RESULTS: Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3-, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6-Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase. CONCLUSIONS: Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.

Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC.

BACKGROUND: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER: NCT04460066.

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

Biweekly oxaliplatin plus S1 for Chinese elderly patients with advanced gastric or gastroesophageal junction cancer as the first-line therapy: a single-arm, phase 2 study.

BACKGROUND: SOX (oxaliplatin and S1, every 3 weeks) is one of the most common first-line chemotherapy for advanced or metastatic G/GEJ (gastric or gastroesophageal junction) cancer in Asia, but it has noticeable hematological and neurological toxicity. In China, the majority of gastric cancer patients are middle-aged and elderly with poor tolerance to 3-weekly chemotherapy. Therefore, we aimed to assess efficacy and safety of biweekly SOX for Chinese advanced G/GEJ cancer patients aged ≥ 60 years as the first-line treatment in a single arm phase 2 study. METHODS: Oxaliplatin was administered intravenously on day 1 at 85 mg/m2. S-1 was given at 80, 100 or 120 mg/day, depending on the body surface area (< 1.25 m2, 1.25 to < 1.5 m2, or ≥ 1.5 m2), twice daily, on day 1-10, every 2 weeks. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. RESULTS: Between May 2016 and Sep 2018, 42 patients were enrolled. The median follow-up was 43.6 months. The ORR and DCR were 52.4% and 85.7%, respectively. The median PFS was 4.6 months (95%CI 2.486-6.714), and the median OS was 11.1 months (95%CI 8.001-14.199). The most common treatment-related adverse events (TRAEs) of any grade included thrombocytopenia (59.5%), neutropenia (57.1%), appetite loss (57.1%) and nausea (54.8%). Only two patients suffered from grade 3 TRAEs (4.8%), including neutropenia (1 patient, [2.4%]) and diarrhea (1 patient, [2.4%]). No ≥ grade 4 TRAEs occurred. CONCLUSIONS: Biweekly SOX seemed to have favorable tolerance without compromising the efficacy as the first-line therapy in Chinese elderly patients aged ≥ 60 years with advanced G/GEJ cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04694404 (5/1/2021). This study was approved by the Ethical Committee of National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, (17-048/1303).

Comparative evaluation of Sensititre YeastOne and VITEK 2 against the Clinical and Laboratory Standards Institute M27-E4 reference broth microdilution method for the antifungal susceptibility testing of Cryptococcus neoformans and Cryptococcus gattii.

The present study collected 280 isolates of Cryptococcus neoformans and 22 isolates of Cryptococcus gattii and evaluated the consistencies between Sensititre YeastOne (SYO), VITEK 2, and the reference broth microdilution (BMD) method for the antifungal susceptibility testing of fluconazole, voriconazole, and flucytosine. For amphotericin B, SYO was replaced with the BIO KONT amphotericin B microbroth dilution kit. The essential agreements (EAs) by SYO and VITEK 2 for C. neoformans var. grubii and C. neoformans var. neoformans were 98.15-99.63% and 88.89-100%, respectively, with fluconazole, voriconazole, and flucytosine. The EA for C. gattii VG â…  against fluconazole was 29.41% by VITEK 2, while the other EAs for C. gattii strains were 100% by SYO and VITEK 2. The categorical agreements (CAs) by SYO and VITEK 2 for C. neoformans and C. gattii were 94.12-100%, while VITEK 2 failed to distinguish 5/6 fluconazole-resistant non-wild-type C. neoformans var. grubii isolates; this finding confirmed the limitation of testing fluconazole against C. neoformans as documented in the manufacturer's package insert. The EAs for amphotericin B were 97.42-100% for C. neoformans and C. gattii, but the CAs were 17.65-60% by BIO KONT and VITEK 2. Thus, SYO can be used for susceptibility testing of C. neoformans and C. gattii against fluconazole, voriconazole, and flucytosine, and VITEK 2 can be used for susceptibility testing of C. neoformans against voriconazole and flucytosine. Further studies using amphotericin B-resistant isolates are required to assess the agreement between VITEK 2, BIO KONT, and BMD. LAY SUMMARY: Sensititre YeastOne showed a good agreement with the CLSI broth microdilution method for C. neoformans and C. gattii against voriconazole and flucytosine. The limitation regarding fluconazole testing against C. neoformans documented in VITEK 2 manufacturer's package insert was confirmed.

Novel cut-off values of time from diagnosis to systematic therapy predict the overall survival and the efficacy of targeted therapy in renal cell carcinoma: A long-term, follow-up, retrospective study.

OBJECTIVES: Metastatic renal cell carcinoma can occur synchronously or metachronously. We characterized the time from diagnosis to systematic therapy as a categorical variable to analyze its effect on the overall survival and first-line treatment efficacy of metastatic renal cell carcinoma patients. METHODS: We initially enrolled 949 consecutive metastatic renal cell carcinoma patients treated with targeted therapies retrospectively from December 2005 to December 2019. X-tile analysis was used to determine cut-off values of time from diagnosis to systematic therapy referring to overall survival. Patients were divided into different groups based on the time from diagnosis to systematic therapy and then analyzed for survival. RESULTS: Of 358 eligible patients with metastatic renal cell carcinoma, 125 (34.9%) had synchronous metastases followed by cytoreductive nephrectomy, and 233 (65.1%) had metachronous metastases. A total of 28 patients received complete metastasectomy. Three optimal cut-off values for the time from diagnosis to systematic therapy (months) - 1.1, 7.0 and 35.9 - were applied to divide the population into four groups: the synchro group (time from diagnosis to systematic therapy ≤1.0), early group (1.0 < time from diagnosis to systematic therapy ≤ 7.0), intermediate group (7.0 < time from diagnosis to systematic therapy < 36.0) and late group (time from diagnosis to systematic therapy ≥36.0). The targeted therapy-related overall survival (P < 0.001) and progression-free survival (P < 0.001) values were significantly different among the four groups. Patients with longer time from diagnosis to systematic therapy had better prognoses and promising efficacy of targeted therapy. With the prolongation of time from diagnosis to systematic therapy, complete metastasectomy was more likely to achieve and bring a better prognosis. CONCLUSIONS: The time from diagnosis to systematic therapy impacts the survival of metastatic renal cell carcinoma patients treated with targeted therapy. The cutoff points of 1, 7 and 36 months were statistically significant. The statistical boundaries might be valuable in future model establishment.

Chinese expert recommendations on management of hepatocellular carcinoma during COVID-19 pandemic: a nationwide multicenter survey.

BACKGROUND: This study aimed to investigate the work status of clinicians in China and their management strategy alteration for patients with hepatocellular carcinoma (HCC) during the COVID-19 pandemic. METHODS: A nationwide online questionnaire survey was conducted in 42 class-A tertiary hospitals across China. Experienced clinicians of HCC-related specialties responded with their work status and management suggestions for HCC patients during the pandemic. RESULTS: 716 doctors responded effectively with a response rate of 60.1%, and 664 were included in the final analysis. Overall, 51.4% (341/664) of clinicians reported more than a 60% reduction of the regular workload and surgeons declared the highest proportion of workload reduction. 92.5% (614/664) of the respondents have been using online medical consultation to substitute for the "face-to-face" visits. Adaptive adjustment for the treatment strategy for HCC was made, including the recommendations of noninvasive and minimally invasive treatments such as transcatheter arterial chemoembolization for early and intermediate stage. Targeted therapy has been the mainstay for advanced stage and also as a bridge therapy for resectable HCC. DISCUSSION: During the COVID-19 pandemic, online medical consultation is recommended to avoid social contact. Targeted therapy as a bridge therapy is recommended for resectable HCC considering the possibility of delayed surgery.

Tislelizumab in Asian patients with previously treated locally advanced or metastatic urothelial carcinoma.

Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This single-arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD-L1-positive urothelial carcinoma who progressed during/following platinum-containing therapy and had no prior PD-(L)1 inhibitor treatment. Patients were considered PD-L1 positive if ≥ 25% of tumor/immune cells expressed PD-L1 when using the VENTANA™ PD-L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow-up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy-evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression-free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment-related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3-4 treatment-related adverse events and occurred in ≥ 5% of patients. Three investigator-assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD-L1-positive urothelial carcinoma and had a manageable safety profile.

Efficacy and safety of oncolytic viruses in advanced or metastatic cancer: a network meta-analysis.

BACKGROUND: Oncolytic viruses (OVs) have shown prospects in advanced and metastatic cancer, and many clinical trials have been carried out. To compare OV therapies comprehensively and provide a categorized profile and ranking of efficacy and safety, a network meta-analysis was conducted. METHODS: A total of 5948 studies were screened and 13 randomized controlled trials with 1939 patients, of whom 1106 patients received OV therapies, comparing four OVs (NTX-010, pexastimogene devacirepvec (Pexa-Vec), talimogene laherparepvec (T-VEC), and pelareorep) were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: objective response rate (ORR) and grade ≥ 3 adverse events. RESULTS: Compared to systemic treatments alone, talimogene laherparepvec (T-VEC) (OR 7.00, 95% CI 1.90-26.00) and T-VEC plus systemic treatment (2.90, 0.80-11.00) showed better objective response rates (ORRs), whereas Pexa-Vec 1 * 109 pfu plus systemic treatment (0.91, 0.26-3.00) and pelareorep plus systemic treatment (1.10, 0.61-2.00) were found to be comparable. The grade ≥ 3 adverse event ranking of the treatments from worst to best was as follows: T-VEC (ranking probability 24%), Pexa-Vec 1 * 109 pfu plus systemic treatment (21%), Pexa-Vec 1 * 109 pfu (17%), T-VEC plus systemic treatment (13%), pelareorep plus systemic treatment (13%), systemic treatments (18%), Pexa-Vec 1 * 108 pfu (12%), and NTX-010 (20%). CONCLUSIONS: Compared with other oncolytic virus therapies for patients with advanced or metastatic cancer, T-VEC and T-VEC plus systemic treatment appear to provide the best ORR therapy in terms of monotherapy and combination respectively, but should be given with caution to grade ≥ 3 adverse events. Conversely, combining OVs with chemotherapy or target agents was demonstrated not to improve efficacy compared with chemotherapy or target agents alone. Combining OV therapies with immune-checkpoint inhibitors, instead of chemotherapy or target agents, tended to provide better ORRs without causing severe adverse events. This study will guide treatment choice and optimize future trial designs for investigations of advanced or metastatic cancer.

High PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor in urothelial carcinoma.

Aims: To explore the prognostic value of high PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (TIIC) in urothelial carcinoma (UC). Patients & methods: 162 UC specimens were evaluated for PD-L1 expression on TIIC and TC with the SP263 assay. High PD-L1 expression was defined as ≥25% staining. Results: High PD-L1 expression on TC in UC patients with stage T1-4 disease was associated with poor overall survival. However, high PD-L1 expression on TIIC in UC patients with stage T1-4 disease revealed favorable disease-free and overall survival; more significant differences were observed in patients with stages T2-4. Multivariate analysis revealed that high PD-L1 expression on TIIC was an independent prognostic predictor for better disease-free and overall survival. Conclusion: High PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in UC.

Lay abstract Bladder cancer is the tenth most common form of cancer worldwide, and urothelial carcinoma is the most common type of bladder cancer. PD-L1 is a protein that can be expressed on the surface of many tissue types, including tumor cells (TC) and tumor-infiltrating immune cells (TIIC). PD-L1 can help the tumor evade the body's natural immune defense system. The expression of PD-L1 not only related to the response of immunotherapy but is also associated with the prognosis in bladder cancer. However, the prognostic significance of PD-L1 expression on TC and TIIC remains controversial. This study drew a conclusion that high PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in urothelial carcinoma.