NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes.

Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti-tumor and anti-virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in-solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live-cell-based single-molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force-strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force-induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force-dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force-induced ligand conformational changes.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

A case of dMMR/MSI-H/TMB-H colon cancer with brain metastasis treated with PD-1 monoclonal antibody. / PD-1单抗治疗一例dMMR/MSI-H/TMB-Håž‹ç»“è‚ ç™Œä¼´é¢ å† è½¬ç§»ç˜¤æ‚£è€ ä¸´åºŠå®Œå ¨ç¼“è§£.

A 70-year-old man had radical surgery for colon cancer one year before the symptoms of memory loss and decreasing cognitive function. Subsequent magnetic resonance imaging revealed a brain mass, which was surgically resected and confirmed to be metastatic intestinal adenocarcinoma. Immunohistochemistry of the primary tumor and brain metastasis showed mismatch repair deficiency. The patient received adjuvant chemotherapy after surgery. However, the brain metastasis relapsed one month after the last chemotherapy. Genetic testing on the resected colon tumor samples confirmed microsatellite instability-high with a high tumor mutation burden by 77.7 muts/Mb. The patient was subsequently treated with programmed death-1 (PD-1) monoclonal antibody pembrolizumab (keytruda). The brain metastatic lesions were completely shrunk, and a complete clinical response was achieved.

China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: A multicenter, noninterventional, controlled study.

Formal multidisciplinary team (MDT) discussions in clinical practice require time and space but have unclear survival benefits for advanced gastrointestinal cancer patients. Our study aimed to investigate the long-term survival of patients with advanced gastrointestinal cancer after MDT decision. From June 2017 to June 2019, continuous MDT discussions on advanced gastrointestinal cancer were conducted in 13 medical centers in China. MDT decisions and actual treatment received by patients were prospectively recorded. The primary endpoint was the difference in overall survival (OS) between patients in the MDT decision implementation and nonimplementation groups. The secondary endpoints included the implementation rate of MDT decisions and subgroup survival analysis. A total of 461 MDT decisions of 455 patients were included in our study. The implementation rate of MDT decisions was 85.7%. Previous treatment had an impact on MDT decision-making. The OS was 24.0 months and 17.0 months in the implementation and nonimplementation groups, respectively. The implementation of MDT decisions significantly reduced the risk of death in multivariate analyses (hazard ratio = 0.518; 95% confidence interval: 0.304-0.884, P = .016). Subgroup analysis showed a significant difference in survival of patients with colorectal cancer, but not in survival of patients with gastric cancer. The rate of secondary MDT discussion was only 5.6% among patients who the MDT decisions were discontinued due to changes in their condition. MDT discussion can prolong the OS of patients with advanced gastrointestinal cancer, especially those with colorectal cancer. Timely scheduling of the subsequent MDT discussion is necessary when the disease condition changes.

Dual targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: A phase 2 trial.

This trial was initiated to evaluate the efficacy and safety of pyrotinib in combination with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent/metastatic colorectal cancer (CRC). In this single-arm, open-label, multicenter, phase 2 trial patients with HER2-positive recurrent/metastatic CRC were enrolled and received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was the objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), duration of response, and safety were assessed as secondary endpoints. From December 2019 to October 2021, a total of 20 patients were enrolled and 18 of them were evaluable for response. All patients were B-rapidly accelerated fibrosarcoma (BRAF) wild type. Four patients achieved partial response, with an ORR of 22.2% (4/18, 95% confidence interval [CI] 6.4-47.6) and DCR of 61.1% (11/18, 95% CI 35.8-82.7), while the ORR and DCR were 33.3% (4/12, 95% CI 13.8-60.9) and 83.3% (10/12, 95% CI 51.6-97.9), respectively, in RAS wild-type patients. At the time of cut-off day, median follow-up was 10.7 months (range 3.8-13.8). The median PFS was 3.4 months (95% CI 1.8-4.3) in the overall population and 4.3 months (95% CI 3.2-8.5) in the RAS wild-type group. The most common adverse event of grade ≥3 was diarrhea (13/20, 65.0%). Pyrotinib combined with trastuzumab showed promising antitumor activity and a manageable safety profile in patients with RAS/BRAF wild-type HER2-positive advanced CRC.

TOD-CUP: a gene expression rank-based majority vote algorithm for tissue origin diagnosis of cancers of unknown primary.

Gene expression profiling holds great potential as a new approach to histological diagnosis and precision medicine of cancers of unknown primary (CUP). Batch effects and different data types greatly decrease the predictive performance of biomarker-based algorithms, and few methods have been widely applied to identify tissue origin of CUP up to now. To address this problem and assist in more precise diagnosis, we have developed a gene expression rank-based majority vote algorithm for tissue origin diagnosis of CUP (TOD-CUP) of most common cancer types. Based on massive tissue-specific RNA-seq data sets (10 553) found in The Cancer Genome Atlas (TCGA), 538 feature genes (biomarkers) were selected based on their gene expression ranks and used to predict tissue types. The top scoring pairs (TSPs) classifier of the tumor type was optimized by the TCGA training samples. To test the prediction accuracy of our TOD-CUP algorithm, we analyzed (1) two microarray data sets (1029 Agilent and 2277 Affymetrix/Illumina chips) and found 91% and 94% prediction accuracy, respectively, (2) RNA-seq data from five cancer types derived from 141 public metastatic cancer tumor samples and achieved 94% accuracy and (3) a total of 25 clinical cancer samples (including 14 metastatic cancer samples) were able to classify 24/25 samples correctly (96.0% accuracy). Taken together, the TOD-CUP algorithm provides a powerful and robust means to accurately identify the tissue origin of 24 cancer types across different data platforms. To make the TOD-CUP algorithm easily accessible for clinical application, we established a Web-based server for tumor tissue origin diagnosis (http://ibi. zju.edu.cn/todcup/).

Construction of TME and Identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma.

Liver cancer accounts for 6% of all malignancies causing death worldwide, and hepatocellular carcinoma (HCC) is the most common histological type. HCC is a heterogeneous cancer, but how the tumour microenvironment (TME) of HCC contributes to the progression of HCC remains unclear. In this study, we investigated the immune microenvironment by multiomics analysis. The tumour immune infiltration characteristics of HCC were determined at the genomic, epigenetic, bulk transcriptome and single-cell levels by data from The Cancer Genome Atlas portal and the Gene Expression Omnibus (GEO). An epigenetic immune-related scoring system (EIRS) was developed to stratify patients with poor prognosis. SPP1, one gene in the EIRS system, was identified as an immune-related predictor of poor survival in HCC patients. Through receptor-ligand pair analysis in single-cell RNA-seq, SPP1 was indicated to mediate the crosstalk between HCC cells and macrophages via SPP1-CD44 and SPP1-PTGER4 association. In vitro experiments further validate SPP1 can trigger the polarization of macrophages to M2-phenotype tumour-associated macrophages (TAMs).

GdClean: removal of Gadolinium contamination in mass cytometry data.

MOTIVATION: Mass cytometry (Cytometry by Time-Of-Flight, CyTOF) is a single-cell technology that is able to quantify multiplex biomarker expressions and is commonly used in basic life science and translational research. However, the widely used Gadolinium (Gd)-based contrast agents (GBCAs) in magnetic resonance imaging (MRI) scanning in clinical practice can lead to signal contamination on the Gd channels in the CyTOF analysis. This Gd contamination greatly affects the characterization of the real signal from Gd-isotope-conjugated antibodies, severely impairing the CyTOF data quality and ruining downstream single-cell data interpretation. RESULTS: We first in-depth characterized the signals of Gd isotopes from a control sample that was not stained with Gd-labeled antibodies but was contaminated by Gd isotopes from GBCAs, and revealed the collinear intensity relationship across Gd contamination signals. We also found that the intensity ratios of detected Gd contamination signals to the reference Gd signal were highly correlated with the natural abundance ratios of corresponding Gd isotopes. We then developed a computational method named by GdClean to remove the Gd contamination signal at the single-cell level in the CyTOF data. We further demonstrated that the GdClean effectively cleaned up the Gd contamination signal while preserving the real Gd-labeled antibodies signal in Gd channels. All of these shed lights on the promising applications of the GdClean method in preprocessing CyTOF datasets for revealing the true single-cell information. AVAILABILITY AND IMPLEMENTATION: The R package GdClean is available on GitHub at https://github.com/JunweiLiu0208/GdClean. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Advances in CAR-T cell therapy for malignant solid tumors.

T cells modified by chimeric antigen receptor (CAR) have the advantage of major histocompatibility complex-independent recognition of tumor-associated antigens, so can achieve efficient response to tumor targets. Chimeric antigen receptor (CAR) T cell therapy has shown a good therapeutic effect in hematological malignancies; however, its efficacy is generally not satisfactory for solid tumors. The reasons include the lack of tumor specific antigen target on solid tumors, the uncertainty of homing ability of engineered T cells and the inhibitory immune microenvironment of tumors. In clinical trials, the targets of CAR-T cell therapy for solid tumors are mainly disialoganglioside (GD2), claudin-18 isoform 2 (CLDN18.2), mesenchymal, B7 homolog 3 (B7H3), glypican (GPC) 3 and epidermal growth factor receptor variant Ш (EGFRvШ)Ⅲ. Combination of CAR-T cells with oncolytic viruses, tyrosine kinase inhibitors, and programmed death ligand-1 monoclonal antibodies may increase its efficacy. The CAR-T cell therapy for solid tumors can be optimized through gene editing to enhance the activity of CAR-T cells, adding corresponding regulatory components to make the activation of CAR-T cells safer and more controllable, and enhancing the persistence of CAR-T cells. In this article, we review the latest advances of CAR-T cell therapy in solid tumors to provide new insights for clinical application.

Emerging treatment evolutions and integrated molecular characteristics of biliary tract cancers.

Biliary tract cancers (BTCs) consist of a group of highly heterogeneous malignancies that are characterized by genomic differences among tumors from different anatomic sites. The current treatment for BTC includes surgery, chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected. Chemotherapy has been considered the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next-generation sequencing, has opened the door for the identification of drug targets and candidate molecules. A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review.

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer.

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events-caused by irinotecan-and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.

Depiction of the genomic and genetic landscape identifies CCL5 as a protective factor in colorectal neuroendocrine carcinoma.

BACKGROUND: Colorectal neuroendocrine carcinomas (CRNECs) are highly aggressive tumours with poor prognosis and low incidence. To date, the genomic landscape and molecular pathway alterations have not been elucidated. METHODS: Tissue sections and clinical information of CRNEC (n = 35) and CR neuroendocrine tumours (CRNETs) (n = 25) were collected as an in-house cohort (2010-2020). Comprehensive genomic and expression panels (AmoyDx® Master Panel) were applied to identify the genomic and genetic alterations of CRNEC. Through the depiction of the genomic landscape and transcriptome profile, we compared the difference between CRNEC and CRNET. Reverse transcription-polymerase chain reaction and immunofluorescence staining were performed to confirm the genetic alterations. RESULTS: High tumour mutation load was observed in CRNEC compared with CRNET. CRNECs showed a "cold" immune landscape and increased endothelial cell activity compared with NETs. Importantly, PAX5 was aberrantly expressed in CRNEC and predicted a poor prognosis of CRNECs. CCL5, a factor that is considered an immunosuppressive factor in several tumour types, was strongly expressed in CRNEC patients with long-term survival and correlated with high CD8+ T cell infiltration. CONCLUSION: Through the depiction of the genomic landscape and transcriptome profile, we demonstrated alterations in molecular pathways and potential targets for immunotherapy in CRNEC.

Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels tumour heterogeneity plus M2-like tumour-associated macrophage infiltration and aggressiveness in TNBC.

Triple-negative breast cancer (TNBC) is characterized by a more aggressive clinical course with extensive inter- and intra-tumour heterogeneity. Combination of single-cell and bulk tissue transcriptome profiling allows the characterization of tumour heterogeneity and identifies the association of the immune landscape with clinical outcomes. We identified inter- and intra-tumour heterogeneity at a single-cell resolution. Tumour cells shared a high correlation amongst stemness, angiogenesis, and EMT in TNBC. A subset of cells with concurrent high EMT, stemness and angiogenesis was identified at the single-cell level. Amongst tumour-infiltrating immune cells, M2-like tumour-associated macrophages (TAMs) made up the majority of macrophages and displayed immunosuppressive characteristics. CIBERSORT was applied to estimate the abundance of M2-like TAM in bulk tissue transcriptome file from The Cancer Genome Atlas (TCGA). M2-like TAMs were associated with unfavourable prognosis in TNBC patients. A TAM-related gene signature serves as a promising marker for predicting prognosis and response to immunotherapy. Two commonly used machine learning methods, random forest and SVM, were applied to find the genes that were mostly associated with M2-like TAM densities in the gene signature. A neural network-based deep learning framework based on the TAM-related gene signature exhibits high accuracy in predicting the immunotherapy response.

Ultra-stable Biomembrane Force Probe for Accurately Determining Slow Dissociation Kinetics of PD-1 Blockade Antibodies on Single Living Cells.

Immune checkpoint blockade with monoclonal antibodies (mAbs) that target programmed cell death protein-1 (PD-1) has remarkably revolutionized cancer therapy. Their binding kinetics measured by surface plasmon resonance does not always correlate well with their immunotherapeutic efficacies, mainly due to the lack of two-dimensional cell plasma membrane and the capability of force sensing and manipulation. In this regard, based on a more suitable and ultra-sensitive biomechanical nanotool, biomembrane force probe (BFP), we developed a Double-edge Smart Feedback control system as an ultra-stable platform to characterize ultra-long bond lifetimes of receptor-ligand binding on living cells. We further benchmarked the dissociation kinetics for three clinically approved PD-1 blockade mAbs (Nivolumab, Pembrolizumab, and Camrelizumab), intriguingly correlating well with the objective response rates in the hepatocellular carcinoma second-line treatment. This ultra-stable BFP potentially provides a compelling kinetic platform to direct the screening, optimization, and clinical selection of therapeutic antibodies in the future.

Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial.

BACKGROUND: Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma. METHODS: This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed. FINDINGS: Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure). INTERPRETATION: Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients. FUNDING: Jiangsu Hengrui Medicine.

Dynamic alterations of genome and transcriptome in KRAS G13D mutant CRC PDX model treated with cetuximab.

BACKGROUND: KRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment. However, studies indicate that not all KRAS mutations are associated with equivalent treatment outcomes. KRAS G13D mutations were observed to account for approximately 16% of all KRAS mutations in advanced colorectal cancer patients, and whether these patients can benefit from cetuximab has not been determined. METHODS: An established KRAS G13D mutant colorectal cancer (CRC) patient-derived xenograft (PDX) model was treated with cetuximab. After repeated use of cetuximab, treatment-resistant PDX models were established. Tissue samples were collected before and during treatment, and multiomics data were subsequently sequenced and processed, including whole-exome, mRNA and miRNA data, to explore potential dynamic changes. RESULTS: Cetuximab treatment initially slowed tumor growth, but resistance developed not long after treatment. WES (whole-exome sequencing) and RNA sequencing found that 145 genes had low P values (< 0.01) when analyzed between the locus genotype and its related gene expression level. Among these genes, SWAP70 was believed to be a probable cause of acquired resistance. JAK2, PRKAA1, FGFR2 and RALBP1, as well as 10 filtered immune-related genes, also exhibited dynamic changes during the treatment. CONCLUSIONS: Cetuximab may be effective in KRAS G13D mutation patients. Dynamic changes in transcription, as determined by WES and RNA sequencing, occurred after repeated drug exposure, and these changes were believed to be the most likely cause of drug resistance.

Disease characteristics and treatment patterns of Chinese patients with metastatic colorectal cancer: a retrospective study using medical records from China.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer in China but few large-scale studies were conducted to understand CRC patients. The current study is aimed to gain a real-world perspectives of CRC patients in China. METHODS: Using electronic medical records of sampled patients between 2011 and 2016 from 12 hospitals in China, a retrospective cohort study was conducted to describe demographics and disease prognosis of CRC patients, and examine treatment sequences among metastatic CRC (mCRC) patients. Descriptive, comparative and survival analyses were conducted. RESULTS: Among mCRC patients (3878/8136, 48%), the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most widely-used first-line treatment (42%). Fluorouracil, leucovorin, irinotecan (FOLFIRI) and other irinotecan-based regimens dominated the second-line (40%). There was no a dominated regimen for the third-line. The proportion of patients receiving chemotherapy with targeted biologics increased from less than 20% for the first- and second- lines to 34% for the third-line (p < 0.001). The most common sequence from first- to second-line was from FOLFOX and other oxaliplatin-based regimens to FOLFIRI and other irinotecan-based regimens (286/1200, 24%). CONCLUSIONS: Our findings reflected a lack of consensus on the choice of third-line therapy and limited available options in China. It is evident o continue promoting early CRC diagnosis and to increase the accessibility of treatment options for mCRC patients. As the only nationwide large-scale study among CRC and mCRC patients before more biologics became available in China, our results can also be used as the baseline to assess treatment pattern changes before and after more third-line treatment were approved and covered into the National Health Insurance Plan in China between 2017 and 2018.

Nutrition and metabolism status alteration in advanced hepatocellular carcinoma patients treated with anti-PD-1 immunotherapy.

PURPOSE: The aim of this study was to evaluate the nutrition and metabolism status alteration during immunotherapy in advanced hepatocellular carcinoma (HCC) patients. METHODS: Patients with advanced HCC who participated in the clinical trials of single-agent anti-PD-1 immunotherapy or sorafenib were retrospectively included. We analyzed self-comparison of the nutritional and metabolic indices of patients in the anti-PD-1 and sorafenib treatment group. We conducted mutual-comparison of the mentioned indices between the disease progression group and disease control group among anti-PD-1 treatment patients. We further analyzed those indices with statistical differences by partial correlation and survival analysis. RESULTS: Both self-comparison before and after treatment in the anti-PD-1 group and mutual-comparison of disease progression and the control group showed significant differences in multiple indices, but we did not observe significant differences in the sorafenib group. Strikingly, albumin (ALB)/prognostic nutritional index (PNI, calculated by serum albumin and lymphocyte count) decreased distinctly in the immunotherapy disease progression group patients. However, changes in ALB/PNI were not significant in disease progression patients from the sorafenib group or in the disease control patients with immunotherapy. Partial correlation analysis suggested that ALB and PNI were positively correlated with the efficacy of immunotherapy. Furthermore, survival analysis showed that the median progression-free survival and median overall survival of patients in the ALB/PNI decreased group were significantly shorter than those of patients from the ALB/PNI increased group. CONCLUSION: Anti-PD-1 immunotherapy might alter the nutritional and metabolic status in advanced HCC patients. We also should pay attention to the nutritional and metabolic status of patients when drug resistance is detected.