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Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC. Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma.

Objectives The optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Method We analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis. Results From November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3–68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4–7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8–16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively. Conclusions This retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study.

Abstract Context Recent studies suggest that the clinical characteristics and biological behavior of pituitary tumors (PITs) in patients with multiple endocrine neoplasia type 1 (MEN1) may not be as aggressive as previously reported. Increased imaging of the pituitary as recommended by screening guidelines identifies more tumors, potentially at an earlier stage. However, it is unknown if these tumors have different clinical characteristics in different MEN1 mutations. Objective To assess characteristics of patients with MEN1 with and without PITs, and compare among different MEN1 mutations. Methods Data of patients with MEN1 in a tertiary referral center from 2010 to 2023 were retrospectively analyzed. Results Forty-two patients with MEN1 were included. Twenty-four patients had PITs, 3 of which were invasive and managed with transsphenoidal surgery. One PIT enlarged during follow-up. Patients with PITs had a higher median age at MEN1 diagnosis than those without PITs. MEN1 mutations were identified in 57.1% of patients, including 5 novel mutations. In patients with PITs, those with MEN1 mutations (mutation+/PIT+ group) had more additional MEN1-associated tumors than those without (mutation−/PIT+ group). The mutation+/PIT+ group had a higher incidence of adrenal tumors and a lower median age at initial manifestation of MEN1 than the mutation−/PIT+ group. The most common neuroendocrine neoplasm was nonfunctional in the mutation+/PIT+ group and insulin-secreting in the mutation−/PIT+ group. Conclusion This is the first study comparing characteristics of patients with MEN1 with and without PITs harboring different mutations. Patients without MEN1 mutations tended to have less organ involvement and it might be reasonable for them to receive less intensive follow-up.

Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients’ responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches.

Background Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers. Methods A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively. Conclusion The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation. ClinicalTrials.gov Identifier NCT03162510 The results of this study revealed the maximal tolerated dose of oxaliplatin and preliminary efficacy of SOLAR in upper gastrointestinal cancers, which deserves further investigation.

Objectives: Mutation of the exon 3 of CTNNB1, the coding gene of β-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/β-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear. Methods: Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed. Results: A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features. Conclusion: In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC.

BackgroundBetel nuts in Taiwan might contribute to strong angiogenesis & invasion with resistance to traditional therapies. In our research, betel-nuts exposed HNSCC cell line, TW2.6, had high PDL1, defective p53 mutation, p16 loss, and BCL2 overexpression. PI3K/AKT/mTOR inhibitors, anti-angiogenesis therapies, CDK4/6 inhibitors, DDR interventions, and immunotherapy-containing regimens will be future backbones and reverse treatment refractoriness(AACR-AHNS2017). The genomic signature of TW2.6 has been figured out(AACR2020) mainly with PIK3CA H1047R mutation, high TMB(8.42 muts /Mb)/MSS, p53/MYC/HRAS/DDR2/ PDGFRbeta/ EPHB1/ATM mutations, FAT1 loss, amplification of VEGF-A/TERT/ FGF10/CCND3/SOX9/IL-7R/SDHA/RICTOR/FLCN, CDK12 loss of function, and deletions of STK11/ARID1B/MITF/TNFAIP3. CDK4/6 inhibitor was effective in HPV-negative and pRB-positive HNSCC and had strong immuno-modulation(suppress Treg, increase CTLs, enhance MHC I/II upregulation and antigen presentation). Palbociclib was effective on TW2.6 and could resensitize TW2.6 to docetaxel, afatinib, & radiation & enhance further response to BYL719& foretinib(VEGFR2/c-MET/Axl triple inhibitor). Western blotting showed (1) Slug, Snail, N-cadherin, Twist, Vimentin, Claudin-1, Axl, p-Akt and p70S6K decrease; (2) BMI-1, pRB, and PDL1 drop(ASCO218).MethodsSCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, and TW2.6 for (1)in vitro sensitivity to palbociclib, ribociclib, abemaciclib; (2)synergistic effects with other therapies by MTT assay, colony formation assay, and western blotting. NGS studies were used to study molecular biomarkers of CDK4/6 inhibitors efficacy.ResultsPalbociclib had greatest efficacy over SCC15(classical HPV-negative type with EGFR overexpression) followed by SCC25, SAS, TW2.6(HPV-negative EMT type), & CAL27; but little efficacy over KB. In HPV-positive cell lines, palbociclib had (1) promising response on SCC25(classical HPV+ type); (2) little response on FaDu(HPV+ mesenchymal type) & KB(basal type in TCGA). In other HNSCC cell lines with basal types, however, SAS & CAL27 responded well to palbocilclib. Palbociclib response seemed to correlate to CCND1 gain and CDKN2A deletion; but FaDu had not so good palbociclib response with these two changes and TW2.6 had good response even without these two. TW2.6 was most sensitive to palbociclib, moderately sensitive to ribociclib, and mildly sensitive to abemaciclib.ConclusionsTW2.6 is responsive to CDK4/6 inhibitor(palbociclib>ribociclib>abemaciclib). FAT1 loss, CCND1/3 overt amplification, PI3K/AKT/mTOR derangements, and FGFR amplification might confer CDK4/6 inhibitor resistance in our genomic study. Based on immuno-modulatory effects of CDK4/6 inhibitor, we have initiated a study using ribociclib with spartalizumab in R/M HNSCC(RISE-HN: NCT04213404). We might develop a ctDNA-driven(intact PTEN & FAT1, CDKN2A deletion, high CDK4/6 copy numbers, no CCND1/3 overt amplification or FGFR amplification or other PI3K/AKT/mTOR derangements) clinical trial with palbocilcib and avelumab in betel-nuts related R/M HNSCC in Taiwan. Abemaciclib may have better immune-modulation.

Drugs that target the EGFR have a major impact on the treatment of advanced non-small-cell lung cancer (NSCLC). EGFR mutations in NSCLC are associated with a dramatic and sustained response to EGFR tyrosine kinase inhibitors (TKIs). This review summarizes the results of randomized trials using EGFR TKIs or EGFR monoclonal antibodies with chemotherapy in the first-line setting, and discusses several unresolved issues regarding the use of the EGFR TKIs as the first-line therapy in advanced NSCLC.

Purpose To evaluate the preventive effects of topical skin disinfection with chlorhexidine on bloodstream infection (BSI) associated with totally implantable venous port (Port-A). Methods Two consecutive cohorts of solid cancer patients were prospectively followed for the occurrence of Port-A associated BSI (PABSI). The first cohort used povidone–iodine as topical skin disinfection and the second cohort used chlorhexidine. The primary endpoint was the time to first PABSI. Propensity score analysis was applied. The preventive effects of chlorhexidine were analyzed by Cox proportional hazards models. Results There were 396 patients (81,752 catheter-days) in the iodine cohort and 497 (99,977 catheter-days) in the chlorhexidine cohort. Gram-negative bacteria were the most common pathogens to cause first episode of PABSI (iodine cohort (I) vs chlorhexidine cohort (C) and 0.404 vs 0.450 per 1,000 catheter-day), followed by Gram-positive bacteria (I vs C and 0.269 vs 0.110 per 1,000 catheter-day), and fungi (I vs C and 0.098 vs 0.070 per 1,000 catheter-day). Three hundred forty-three patients were selected from each cohort by propensity score match analysis. Chlorhexidine use was associated with a significant improvement on time to first PABSI caused by Gram-positive bacteria (log-rank test, p  = 0.00175; HR = 0.35, 95 % CI, 0.14–0.85, p  = 0.02). No significant preventive effects of chlorhexidine on time to first PABSI caused by Gram-negative bacteria or fungi was found. Conclusions Chlorhexidine topical skin disinfection may prevent PABSI caused by Gram-positive bacteria in patients with solid cancers. The nonsignificant effect on preventing overall PABSI may be attributed to the high incidence of Gram-negative bacteria related PABSI.

Objectives: Mutation of the exon 3 of CTNNB1, the coding gene of β-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/β-catenin pathway, which is highly associated with the carcinogenesis of hepatocellular carcinoma (HCC). The prevalence and clinical significance of CTNNB1 mutations in advanced HCC remain unclear. Methods: Patients with advanced HCC and available pathologic tissues (either obtained when diagnosed at advanced or early stages) were enrolled in this study. Direct sequencing of exon 3 of CTNNB1 was performed to detect somatic mutations. The associations between CTNNB1 mutations and clinicopathologic features were analyzed. Results: A total of 115 patients were enrolled, among whom 78 (67.8%) had chronic hepatitis B virus infection. Twenty-one (18.3%) patients were found to have CTNNB1 mutations, all of which were missense mutations. The CTNNB1 mutation rates were similar among pathologic tissues obtained at advanced and early stages (17.5 and 20.0%, respectively). Patients aged over 60 years were more likely to have CTNNB1 mutations than patients younger than 60 years (32.6 vs. 8.7%, p = 0.001). The mutations were not associated with survival or other clinicopathologic features. Conclusion: In patients with advanced HCC, CTNNB1 mutations were not prognostically significant. No apparent increase of CTNNB1 mutations occurred during the progression of HCC. © 2014 S. Karger AG, Basel [PUBLICATION ABSTRACT]