Comparing Patient-Controlled Analgesia Versus Non-PCA Hydromorphone Titration for Severe Cancer Pain: A Randomized Phase III Trial.

BACKGROUND: Opioid titration is necessary to achieve rapid, safe pain relief. Medication can be administered via patient-controlled analgesia (PCA) or by a healthcare provider (non-PCA). We evaluated the efficacy of intravenous PCA versus non-PCA hydromorphone titration for severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]). PATIENTS AND METHODS: Patients with severe cancer pain were randomized 1:1 to PCA or non-PCA titration, stratified by opioid-tolerant or opioid-naïve status. The PCA pump was set to no continuous dose, with a hydromorphone bolus dose 10% to 20% of the total previous 24-hour equianalgesic (for opioid-tolerant patients) or 0.5 mg (for opioid-naïve patients). For the non-PCA group, the initial hydromorphone bolus dose was identical to that in the PCA group, with the subsequent dose increased by 50% to 100% (for NRS unchanged or increased) or repeated at the current dose (for NRS 4-6). Hydromorphone delivery was initiated every 15 minutes (for NRS ≥4) or as needed (for NRS ≤3). The primary endpoint was time to successful titration (TST; time from first hydromorphone dose to first occurrence of NRS ≤3 in 2 consecutive 15-minute intervals). RESULTS: Among 214 patients (PCA, n=106; non-PCA, n=108), median TSTs (95% CI) were 0.50 hours (0.25-0.50) and 0.79 hours (0.50-1.42) for the PCA and non-PCA groups, respectively (hazard ratio [HR], 1.64; 95% CI, 1.23-2.17; P=.001). TSTs in opioid-tolerant patients were 0.50 hours (0.25-0.75) and 1.00 hours (0.50-2.00) for the PCA and non-PCA groups, respectively (HR, 1.92; 95% CI, 1.32-2.78; P=.003); in opioid-naive patients, TST was not significantly different for the PCA versus non-PCA groups (HR, 1.35; 95% CI, 0.88-2.04; P=.162). Pain score (median NRS; interquartile range) over 24 hours was significantly lower in the PCA group (2.80; 2.15-3.22) than in the non-PCA group (3.00; 2.47-3.53; P=.020). PCA administration produces significantly higher patient satisfaction with pain control than non-PCA administration (P<.001). CONCLUSIONS: Intravenous hydromorphone titration for severe cancer pain was achieved more effectively with PCA than with non-PCA administration.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Comprehensive characterization of pyroptosis phenotypes with distinct tumor immune profiles in gastric cancer to aid immunotherapy.

OBJECTIVE: Pyroptosis is a form of programmed cell death that is essential for immunity. Herein, this study was conducted to uncover the implication of pyroptosis in immunomodulation and tumor microenvironment (TME) in gastric cancer. METHODS: Prognostic pyroptosis-related genes were extracted to identify different pyroptosis phenotypes and pyroptosis genomic phenotypes via unsupervised clustering analysis in the gastric cancer meta-cohort cohort (GSE15459, GSE62254, GSE84437, GSE26253 and TCGA-STAD). The activation of hallmark gene sets was quantified by GSVA and immune cell infiltration was estimated via ssGSEA and CIBERSORT. Through PCA algorithm, pyroptosis score was conducted. The predictors of immune response (TMB and IPS) and genetic mutations were evaluated. The efficacy of pyroptosis score in predicting immune response was verified in two anti-PD-1 therapy cohorts. RESULTS: Three different pyroptosis phenotypes with different prognosis, biological pathways and tumor immune microenvironment were established among 1275 gastric cancer patients, corresponding to three immune phenotypes: immune-inflamed, immune-desert, and immune-excluded. According to the pyroptosis score, patients were separated into high and low pyroptosis score groups. Low pyroptosis score indicated favorable survival outcomes, enhanced immune responses, and increased mutation frequency. Moreover, low pyroptosis score patients displayed more clinical benefits from anti-PD-1 and prolonged survival time. CONCLUSION: Our findings uncovered a nonnegligible role of pyroptosis in immunomodulation and TME multiformity and complicacy in gastric cancer. Quantifying the pyroptosis score in individual tumors may tailor more effective immunotherapeutic strategies.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

A Novel Exosome-Relevant Molecular Classification Uncovers Distinct Immune Escape Mechanisms and Genomic Alterations in Gastric Cancer.

Objective: Gastric cancer (GC) is a highly heterogeneous malignant carcinoma. This study aimed to conduct an exosome-based classification for assisting personalized therapy for GC. Methods: Based on the expression profiling of prognostic exosome-related genes, GC patients in The Cancer Genome Atlas (TCGA) cohort were classified using the unsupervised consensus clustering approach, and the reproducibility of this classification was confirmed in the GSE84437 cohort. An exosome-based gene signature was developed via Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Immunological features, responses to immune checkpoint inhibitors, and genetic alterations were evaluated via computational methods. Results: Two exosome-relevant phenotypes (A and B) were clustered, and this classification was independent of immune subtypes and TCGA subtypes. Exosome-relevant phenotype B had a poorer prognosis and an inflamed tumor microenvironment (TME) relative to phenotype A. Patients with phenotype B presented higher responses to the anti-CTLA4 inhibitor. Moreover, phenotype B occurred at a higher frequency of genetic mutation than phenotype A. The exosome-based gene signature (GPX3, RGS2, MATN3, SLC7A2, and SNCG) could independently and accurately predict GC prognosis, which was linked to stromal activation and immunosuppression. Conclusion: Our findings offer a conceptual frame to further comprehend the roles of exosomes in immune escape mechanisms and genomic alterations of GC. More work is required to evaluate the reference value of exosome-relevant phenotypes for designing immunotherapeutic regimens.

Development and Application of Patient-Derived Cancer Organoidsin Clinical Management of Gastrointestinal Cancer: A State-of-the-Art Review.

Human gastrointestinal cancer (e.g., gastric cancer and colorectal cancer) has been a leading cause of cancer-related deaths worldwide and has imposed a great threat to the public health. Although early-stage gastrointestinal cancer can be effectively treated by surgery, followed by postoperative chemotherapy, patients with advanced gastrointestinal cancer often exhibit poor prognosis and cancer relapse due to the absence of effective personalized treatment strategies. Patient-derived cancer organoid technology has been rapidly developed in recent years, and its emergence has opened up an unprecedented approach to model human cancers in vitro. Patient-derived cancer organoids involve the ex vivo culture of fragments of freshly resected human tumors that retain the histological features of original tumors. This review thoroughly discussed the evolutionary process of human gastrointestinal organoids cultured since 2009, and highlighted the potentials of patient-derived cancer organoids in clinical management of gastrointestinal cancer in terms of advances achieved in cancer modelling compared with conventional modelling methods, high-throughput drug screening, and development of personalized treatment selection. Additionally, the current limitations of patient-derived cancer organoids and the potential solutions to overcome these problems were summarized.

Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation.

The curative effect for patients with advanced gastric cancer is still unsatisfactory. Proton pump inhibitors could be a promising treatment strategy that could sensitize gastric cancer cells to antitumor drugs further; however, the underlying molecular mechanism remains to be further elucidated. In this research, it was found that omeprazole pretreatment could enhance the inhibitory effect of 5-Fu, DDP and TAX on gastric cancer cells. Interestingly, omeprazole pretreatment enhanced the total m6A level of cells due to the decreased FTO. TCGA analysis showed that FTO expression is up-regulated in GC tissues and is negatively correlated with disease-free survival of GC patients. It was also found that FTO inhibition induced by omeprazole enhanced the activation of mTORC1 signal pathway that inhibited the prosurvival autophagy so as to improve the antitumor efficiency of chemotherapeutic drugs on GC cells. Meanwhile, transcript level of DDIT3, which is an apoptosis-related tumor suppressor gene downstream of mTORC1, was regulated by omeprazole-induced FTO silence through an m6A-dependent mechanism. The present study, for the first time, found that m6A modification and its eraser FTO may play a role in the improvement of chemosensitivity mediated by proton pump inhibitor omeprazole.

TRAF6 Promoted Tumor Glycolysis in Non-Small-Cell Lung Cancer by Activating the Akt-HIFα Pathway.

TRAF6 has been reported to be associated with poor prognosis in non-small-cell lung cancer (NSCLC). However, its precise role in tumor development has not been elaborated. In the present study, the function and the mechanism by which TRAF6 contributes to development were intensively investigated. TRAF6 was found to be overexpressed in primary NSCLC tumor tissue and all tested cell lines. Knockdown of TRAF6 with shRNA substantially attenuated NSCLC cell proliferation and anchorage-independent growth. Moreover, tumor glycolysis, such as glucose consumption and lactate production, also significantly impaired. In TRAF6-deficient cells, hexokinase-2 expression was significantly reduced, which was caused by the decrease of HIF-1α transcriptional activity. Further investigations demonstrated that TRAF6 played an important role in the regulation of Akt activation, and exogenous overexpression of constitutively activated Akt substantially rescued glycolysis suppression in TRAF6 knockdown cells. The results of the xenograft model confirmed that downregulation of TRAF6 in NSCLC tumor cells dramatically restrained tumor growth in vivo. Taken together, our studies revealed the mechanism by which TRAF6 exerts its role in NSCLC development and suggested TRAF6 maybe was a promising candidate target for lung cancer prevention and therapy.

Proton pump inhibitor pantoprazole inhibits the proliferation, self­renewal and chemoresistance of gastric cancer stem cells via the EMT/ß­catenin pathways.

The cancer stem cell (CSC) model suggests that a small subset of cancer cells possess stem cell properties and plays a crucial role in tumor initiation, metastasis and resistance to anticancer therapy. Exploration of the specific therapies targeting at CSCs has been a crucial issue in antitumor research. Gastric cancer (GC) cells often exist in an ischemic microenvironment with acidic conditions in vivo, thus maintenance of cellular pH homeostasis is important for the survival and function of GC cells. Proton pump inhibitors (PPIs) may prevent intracellular proton extrusions which consequently reduce cancer cell survival under acidic conditions. The effects of PPIs on the suppression of the viability and invasiveness of GC cells have been reported, but the functional role of pantoprazole (PPZ) in GC cells remains unknown. In this study, we found that when cells were treated with PPZ, the 5­fluorouracil (5­FU) chemosensitivity was upregulated, meanwhile the sphere formation ability and the relative expression levels of stem cell markers CD44, CD24, ABCG2, EpCAM and Lgr5 were significantly decreased. It was hypothesized that PPZ inhibits the GC CSCs. Successively a sphere formation culture was performed to establish CSC models and the effect of PPZ on GC CSCs from SGC-7901 and HGC­27 cells was explored. The addition of PPZ reduced the relative expression of CSC markers and anti­drug markers accompanied by a decrease in proliferation, 5­FU chemoresistance and self­renewal capacity via epithelial­mesenchymal transition (EMT)/ß­catenin pathways. The study suggests that PPZ could be a promising novel specific therapeutic strategy for targeting GC CSCs.