Radiation-induced lymphopenia (RIL) has been demonstrated in types of solid tumors. This study aimed to assess the association between dosimetric and clinical variables and RIL in patients with brain metastases after brain radiotherapy (RT). The craniofacial bones of 140 patients were retrospectively delineated, and absolute lymphocyte counts (ALC) were collected both prior to RT (pre-RT) and 1 month after completing RT (post-RT). Linear regression analyses were conducted to identify associations between dosimetric variables of the craniofacial bones (V5-V40), mean dose, clinical parameters, and post-RT ALC. Logistic regression analysis was used to evaluate independent predictors of RIL (ALC < 1000 cells/µL). The relationships between dosimetric and clinical variables and overall survival (OS) were analyzed using a Cox regression model. After completing RT, ALC decreased in both the whole brain RT (WBRT) and focal RT subgroups (p < 0.05). Linear regression analysis suggested that pre-RT ALC, gross tumor volume (GTV), and the V5 of the craniofacial bones were independent risk factors for the decrease in post-RT ALC. Logistic regression analysis demonstrated that lower pre-RT ALC (OR: 31.969, 95

Alterations in 3D chromatin conformation may disrupt the interplay between promoters and distal enhancers. How gene regulatory circuits are reshaped during ionizing radiation-induced tumorigenesis remains unclear, and little is known about the mediators that drive these processes. To decipher the chromatin alterations in radiation-induced lung cancer, we performed ATAC-seq, RNA-seq and Hi-C analyses of human bronchial epithelial cells and corresponding radiation-induced malignantly transformed cell lines. We found that this malignant transformation is accompanied by chromatin switching from the inactive B compartment to the active A compartment, an increased number of TADs and gained ATAC-seq peaks that mediate new distal chromatin contacts. We identified tumour protein 63 (TP63) as a mediator of new chromatin-accessible sites that anchor tumour-specific chromatin contacts in radiation-induced tumour cells. A TP63-mediated accessible chromatin site anchors a tumour-specific TAD boundary and multiple tumour-specific chromatin loops, which might underlie MYC oncogene activation during malignant transformation.

IBI351 (also known as fulzerasib or GFH925), an irreversible covalent inhibitor of KRASG12C, has demonstrated promising anti-tumour activity in patients with solid tumours. In this study, data were pooled from the phase I part of two clinical studies (NCT05005234 and NCT05497336), aiming to evaluate the efficacy and safety of IBI351 monotherapy in KRASG12C inhibitor-naïve Chinese patients with KRASG12C-mutated metastatic colorectal cancer (CRC). The objective response rate (ORR) was the primary endpoint. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). As of December 13, 2023, 56 patients treated with IBI351 monotherapy were included. The median duration of treatment was 7.7 months (range: 0.3–16.7). The confirmed ORR was 44.6% (95% CI: 31.3–58.5), with a DCR of 87.5% (95% CI: 75.9–94.8). With a median follow-up of 13.8 months, the median PFS was 8.1 months (95% CI: 5.5–13.8). The median OS was 17.0 months (95% CI: 12.6–not reached). Treatment-related adverse events (TRAEs) occurred in 53 patients (94.6%), with grade 3 TRAEs in 14 patients (25.0%). No grade 4 or 5 TRAEs were observed. The most common grade 3 TRAEs were anaemia (n = 4, 7.1%) and gamma-glutamyltransferase increased (n = 3, 5.4%). TRAEs led to dose interruption in 12 patients (21.4%) and dose reduction in six patients (10.7%). No TRAEs resulted in treatment discontinuation. IBI351 demonstrated encouraging clinical efficacy and a manageable safety profile in KRASG12C inhibitor-naïve Chinese patients with KRASG12C-mutated metastatic CRC.

INTRODUCTION:KRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. METHODS:Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. RESULTS:As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). CONCLUSIONS:IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

BACKGROUND:IBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation. METHODS:In phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated. RESULTS:As of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months. CONCLUSIONS:IBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation.

Background As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs. Methods Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for cellular PK in co-culture models. Results CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP. Conclusion The simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

BackgroundImmune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been widely used in treating different malignancies. Several studies have reported that the gut microbiota modulates the response and adverse events (AEs) to ICIs in melanoma, non–small cell lung cancer (NSCLC), renal cell cancer and hepatocellular carcinoma, but data on other cancer types and ICI combination therapy are limited.MethodsStool samples were collected from patients with cancer who received anti–PD-1 and chemotherapy combination treatment and were analyzed by fecal metagenomic sequencing. The microbiota diversity and composition were compared between the responder (R) and non-responder (NR) groups and the AE vs. the non-AE (NAE) groups. In addition, associated functional genes and metabolic pathways were identified.ResultsAt baseline, the microbiota diversity of the groups was similar, but the genera Parabacteroides, Clostridia bacterium UC5.1_2F7, and Bifidobacterium dentium were enriched in the R group, whereas Bacteroides dorei and 11 species of Nocardia were enriched in the NR group. At 6 weeks, the beta diversity was significantly different between the R and NR groups. Further analysis found that 35 genera, such as Alipes, Parabacteroides, Phascolarctobacterium, Collinsella, Ruminiclostridium, Porphyromonas, and Butyricimonas and several genera of the Fibrobacteraceae family, were frequently distributed in the R group, whereas 17 genera, including Enterococcus, Lachnoclostridium, Hungatella, and Bilophila and several genera of the Pseudonocardiaceae and Beijerinckiaceae families, were more abundant in the NR group. A total of 66 and 52 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs (KOs) were significantly enriched in the R and NR groups, respectively. In addition, pathway analysis revealed functional differences in the gut microbacteria in the R group, including the enrichment of anabolic pathways and DNA damage repair (DDR) pathways. Dynamic comparisons of the bacterial composition at baseline, 6 weeks, and 12 weeks showed that the abundance of Weissella significantly increased in the R group at 6 weeks and the abundance of Fusobacterium and Anaerotruncus significantly increased in the NR group at 12 weeks. Linear discriminant analysis effect size analysis indicated that bacteria of Bacteroidetes, especially Bacteroides, were enriched in the NAE group, whereas flora of Firmcutes, such as Faecalibacterium prausnitzii, Bacteroides fragilis, and Ruminococcus lactaris, were enriched in the AE group.ConclusionBeta diversity and differences in the gut microbiota modulated AEs and the response to anti–PD-1 blockade combined with chemotherapy, by regulating related anabolic and DDR pathways. Dynamic changes in the intestinal microbiome may predict the efficacy of PD-1 inhibitor–based therapy.

AbstractChemotherapy in combination with immune checkpoint inhibitor (ICI) or bevacizumab has demonstrated a superior effect for non‐squamous non‐small cell lung cancer (NS‐NSCLC). There are still few randomized controlled trials (RCTs) investigating the differences between ICI plus chemotherapy (ICI‐chemotherapy) and bevacizumab plus chemotherapy (Bev‐chemotherapy) in first‐line treatment of NS‐NSCLC. We identified RCTs in databases and conference abstracts presented at international conferences by Sep 1, 2021. Bayesian network meta‐analysis was performed using randomized effect consistency model to estimate hazard ratio (HR) and odds ratio (OR). The outcomes included overall survival (OS), progression‐free survival (PFS), overall response rate (ORR), and grade ≥ 3 treatment‐related adverse events (TRAEs). Fifteen RCTs (17 articles) of 6561 advanced NS‐NSCLC patients receiving ICI‐chemotherapy, Bev‐chemotherapy, or chemotherapy at first‐line were eligible for analysis. NMA results showed that first‐line ICI‐chemotherapy prolonged OS (HR 0.79, 0.66–0.94) in patients with advanced NS‐NSCLC compared with Bev‐chemotherapy, while no differences were in PFS, ORR, and grade ≥ 3 TRAEs (p > 0.05). Ranking plots suggested that ICI‐chemotherapy had the most probability to offer the best OS (probability 0.993), PFS (probability 0.658), and ORR (probability 0.565), and Bev‐chemotherapy had the most risks of grade ≥ 3 TRAEs (probability 0.833). Therefore, our findings showed that first‐line ICI‐chemotherapy was associated with better OS than Bev‐chemotherapy in patients with advanced NS‐NSCLC, and more clinical trials are warranted to confirm these results.

Background: Advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS) are likely to receive programmed cell death 1 (PD-1) inhibitors, despite limited evidence. The aim of the present study was to report the clinical outcomes and potential prognostic biomarkers in advanced NSCLC patients with poor PS receiving PD-1 inhibitors. Methods: We conducted a retrospective study enrolling 101 advanced NSCLC patients from our hospital. Data of patients with poor PS 2-4 receiving PD-1 inhibitors were retrieved from medical records. Patients were stratified based on dichotomized baseline neutrophil-to-lymphocyte ratio (NLR), change in NLR (Delta NLR; 6 weeks post-treatment NLR minus baseline NLR), and their combination. The receiver-operating characteristic curve was used to assess the best cutoff for NLR. Multivariate Cox analysis was used to evaluate the prognostic value of NLR and Delta NLR for patients' survival. Results: The optimal cutoff for NLR was 4.5. The median follow-up was 25.7 months, baseline NLR >= 4.5, and Delta NLR >= 0, which were independently and significantly associated with shorter overall survival (both P=0.002) and progression-free survival (P=0.004 for NLR and P<0.001 for Delta NLR). Furthermore, simultaneous elevation of the 2 factors was associated with worsened prognosis; patients with both NLR >= 4.5 and Delta NLR >= 0 had significantly increased risk of death [hazards ratio (HR): 10.79, 95% confidence interval (CI): 4.30-27.10] and disease progression (HR: 10.49, 95% CI: 4.39-25.09), compared with both low NLR and Delta NLR patients. Patients with either NLR >= 4.5 or Delta NLR >= 0 showed an intermediate risk for death (HR: 3.12, 95% CI: 1.35-7.21) and progression (HR: 3.45, 95% CI: 1.62-7.36). Conclusions: High baseline NLR and increased post-treatment NLR might aid in the stratification of high progression and death risk groups in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.

Aims Combination of anti-angiogenesis therapy and immunotherapy has showed synergistic effects in non-small cell lung cancer (NSCLC). The aim of this retrospective study was to investigate the efficacy and safety of anlotinib with and without immunotherapy in NSCLC. Methods Pathologically confirmed NSCLC patients (stage IIIB-IV) receiving anlotinib between November 2018 and February 2020 were enrolled for retrospective analysis. The outcomes and safety of overall patients were evaluated, and the efficacies of anlotinib plus immunotherapy and anlotinib alone was compared. The primary endpoint was progression-free survival (PFS). Results A total of 80 patients (median age: 62 years, range: 29-86 years) were included. Overall median PFS was 4.3 months (95% confidence interval (CI): 2.7-5.9 months). In univariate analysis, patients without EGFR mutation, previous EGFR target therapy, and brain metastasis had significantly longer PFS. Cox regression analysis showed that only brain metastasis was an independent predictor of PFS. The median PFS of patients receiving anlotinib plus immunotherapy was slightly longer than that of patients receiving anlotinib alone (4.2 vs 3.1 months); however, the difference was not statistically significant. A tendency of longer median PFS was observed in patients with adenocarcinoma, EGFR wild type, stage IV, no liver metastasis, former smoker, ≥2 previous treatment lines, no previous VEGF or EGFR target therapies in anlotinib plus immunotherapy group. Treatments with anlotinib alone or anlotinib plus immunotherapy were well tolerable. The most common adverse events were fatigue, decreased hemoglobin count, hypertension, hand-foot syndrome, oral mucositis and hoarseness. Conclusion Anlotinib is well tolerable and effective in advanced NSCLC patients. Brain metastasis is an independent predictor of PFS in NSCLC patients receiving anlotinib. Future prospective studies with larger sample size and extended follow-up are needed to confirm the clinical benefit in NSCLC patients treated with anlotinib combined with immunotherapy.

Background Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens. Methods Published articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata. Results A total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09–24.03), a median TTR of 2.05 months (m) (95%CI: 1.85–2.26), and a median DOR of 10.65 m (95%CI: 7.78–13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02–57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47–21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56–22.94]), while I+C (8.09 m [95%CI: 6.86–9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60–17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations. Conclusions PD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.

BACKGROUND:Immune checkpoint inhibitors (ICIs) represent a great breakthrough in the treatment of advanced non-small cell lung cancer (aNSCLC). However, whether immunotherapy beyond progression (IBP) is effective for aNSCLC has yet to be established. Therefore, a retrospective clinical study was conducted to investigate the efficacy of IBP in patients with aNSCLC under real-world conditions.METHODS:A total of 125 Chinese patients with aNSCLC who experienced progressive disease (PD) after receiving monotherapy or combination therapy (combined with chemotherapy or/and antiangiogenic therapy) with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors between January 2015 and March 2019 were enrolled. Patients who were treated with ICIs for more than 6 weeks after PD were defined as IBP (n=39), while those who received ICI treatment for less than 6 weeks or discontinued it due to PD were defined as non-IBP (n=86). Patient clinical characteristics were evaluated. An optimization-based method was applied to balance the clinical baseline characteristics between the two groups.RESULTS:In total population, the IBP group had longer overall survival (median OS, 26.6 vs. 9.5 months; HR, 0.40; 95% CI: 0.23-0.69; P<0.001) and progression-free survival (median PFS, 8.9 vs. 4.1 months; HR, 0.41; 95% CI: 0.26-0.65; P<0.001), compared with the non-IBP group. Despite no significant difference in objective response rate (ORR, 15.4% vs. 11.6%, P=0.560), disease control rate (DCR) was significantly higher in the IBP group (89.7% vs. 61.6%, P<0.001). After balancing baseline covariates, the IBP group also had longer OS (median: 26.6 vs. 10.7 months; HR, 0.40; 95% CI: 0.19-0.84; P=0.015) and PFS (median: 9.7 vs. 4.3 months; HR, 0.28; 95% CI: 0.15-0.51; P<0.001), with a benefit in either of patients previously treated with ICI monotherapy or in combination therapy and with non-response to the previously ICI.CONCLUSIONS:IBP is associated with longer OS and PFS in patients with aNSCLC. Our findings may suggest new therapeutic options for patients with aNSCLC who experienced disease progression after initial immunotherapy.

Anti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK . By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment.

Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited. Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events. PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.

BACKGROUND:Lung immune prognostic index (LIPI) refers to a biomarker combining derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH). Its prognostic effect on advanced small cell lung cancer (SCLC) patients receiving programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors plus chemotherapy as first-line treatment remains unclear. Our research investigated the relationship between pretreatment LIPI and the prognosis of patients receiving first-line PD-1/PD-L1 inhibitors plus chemotherapy.METHODS:Advanced SCLC patients receiving PD-1/PD-L1 inhibitors plus chemotherapy as first-line treatment from Jan 2015 to Oct 2020 were included. Based on the values of dNLR and LDH, the study population was divided into two groups: LIPI good and LIPI intermediate/poor. The Kaplan-Meier method was used to compute the median survival time and the log-rank test was used to compare the two groups. Univariate and multivariate analyses were used to examine the correlation between the pretreatment LIPI and clinical outcomes.RESULTS:One hundred patients were included in this study, of which, 64% were LIPI good (dNLR < 4.0 and LDH < 283 U/L), 11% were LIPI poor (dNLR ≥ 4.0 and LDH ≥ 283 U/L), and the remaining 25% were LIPI intermediate. The LIPI good group had better progression-free survival (PFS) (median: 8.4 vs 4.7 months, p = 0.02) and overall survival (OS) (median: 23.8 vs 13.3 months, p = 0.0006) than the LIPI intermediate/poor group. Multivariate analysis showed that pretreatment LIPI intermediate/poor was an independent risk factor for OS (HR: 2.34; 95%CI, 1.13, 4.86; p = 0.02). Subgroup analysis showed that pretreatment LIPI good was associated with better PFS and OS in males, extensive disease (ED), PD-1 inhibitor treatment, smokers, and liver metastasis (p < 0.05).CONCLUSIONS:Pretreatment LIPI could serve as a prognostic biomarker for advanced SCLC patients receiving first-line PD-1/PD-L1 inhibitors plus chemotherapy.

背景 免疫检查点抑制剂在尿路上皮癌(urothelial carcinoma,UC)的治疗中显示出较好疗效,但PD-1单抗联合化疗作为晚期UC患者一线治疗方案的疗效鲜有研究.目的 比较晚期尿路上皮癌患者一线应用PD-1单抗联合化疗与单纯化疗的疗效及安全性.方法 收集解放军总医院第一医学中心肿瘤内科2017年3月-2020年4月一线治疗的局部进展期或转移性UC患者.51例接受吉西他滨或紫杉醇(白蛋白结合型)联合铂类化疗的患者为化疗组,30例接受PD-1单抗联合化疗的患者为免疫联合化疗组.结果 两组基线资料差异无统计学意义(P>0.05).免疫联合化疗组的中位无进展生存期为15.8个月(95％CI:8.135～23.598),较化疗组的7.17个月(95％CI:5.94～8.40)显著延长(P=0.020).免疫联合化疗组与化疗组的客观缓解率分别为46.7％和49.0％(P=0.999),疾病控制率分别为90.0％和80.4％(P=0.353),不良反应发生率分别为83.3％和84.3％(P=0.908),Ⅲ～Ⅳ级不良反应发生率分别为33.3％和35.3％(P=0.858),差异均无统计学意义.结论 在晚期尿路上皮癌患者的一线治疗中,PD-1单抗联合化疗较单纯化疗有更好的疗效,两组不良反应相当.

Based on the ESTIMATE algorithm, we acquired the immune/stromal scores of cervical squamous cell carcinoma (CSCC) patients collected from The Cancer Genome Atlas (TCGA) dataset. Subsequently, we analyzed the DEGs between high- and low immune score groups using R package edgeR and performed K-M analysis to illustrate the relationship between differentially expressed genes (DEGs) and the overall survival to select survival-related DEGs. Then the LASSO regression model was constructed with the package “glmnet” in R to evaluate the riskscore of each patient. Finally, we developed a nomogram composing riskscore and clinicopathological characteristics to predict the overall survival (OS) of CSCC patients. The R software v3.6.1 was used for statistical analyses. All statistical tests were two-tailed.

Abstract Background Breast cancer (BC) represents a most common cancer among women worldwide. The outcomes of this disease remain dismal due to frequent recurrence and metastasis. Inositol‐1,4,5‐trisphosphate‐3‐kinase‐A (ITPKA) plays an important role in regulating calcium signaling and actin dynamics. The dysregulation of ITPKA has been observed in several human cancers. The present study aimed to assess ITPKA expression and its prognostic value in BC. Methods ITPKA expression was examined via quantitative real‐time polymerase chain reaction (qRT‐PCR) and immunohistochemistry (IHC) methods. In addition, Kaplan–Meier survival analysis and Cox regression analysis were performed to evaluate prognostic value of ITPKA in BC. Results Upregulated ITPKA expression was found in BC samples, according to both qRT‐PCR and IHC analyses (all p < .05). ITPKA expression was positively correlated with lymph node metastasis (p = .021) and TNM stage (p = .009). Moreover, BC patients with high expression of ITPKA had poor overall survival compared with those with low expression (log‐rank p < .05). Cox analysis verified that ITPKA expression was an independent prognostic factor for BC patients (HR = 4.239, 95%CI = 2.221–8.093 and p = .000). Conclusion BC cases show increased expression of ITPKA. ITPKA may act as an independent prognostic biomarker in BC.

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.