A phase 1 study of biweekly nab-paclitaxel/oxaliplatin/S-1/LV for advanced upper gastrointestinal cancers: TCOG T1216 study.

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.

Traits of Patients With Pituitary Tumors in Multiple Endocrine Neoplasia Type 1 and Comparing Different Mutation Status.

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.

Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma.

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.

Short-course pembrolizumab and continuous afatinib therapy for recurrent or metastatic head and neck squamous cell carcinoma: a real-world data analysis.

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.

Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis.

PURPOSE: EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment. PATIENTS AND METHODS: The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx. RESULTS: From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy. CONCLUSIONS: Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.

Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma.

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy (n = 5) or in combination with chemotherapy or targeted therapy (n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110-674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0-2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6-10.8; P = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0-2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy (n = 142) or FOLFIRINOX regimen (n = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume.

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can reinvigorate T cells and activate the immune system to eliminate cancer cells. Head and neck squamous cell carcinoma (HNSCC) is a malignancy with a poor prognosis. The roles of ICIs for HNSCC treatments are emerging. METHOD: We reviewed the study results of Programmed-Death 1 (PD-1) and PD-ligand-1 (PD-L1) monoclonal antibodies for HNSCC. The ongoing trials of anti-PD-1 and anti-PD-L1 were also reviewed. RESULTS: Nivolumab showed a significant overall survival benefit in platinum-refractory HNSCC patients. For platinum-sensitive or first-line patients, pembrolizumab monotherapy (patients with PD-L1 Combined Positive Score ≥ 20) or pembrolizumab-platinum-fluorouracil improved overall survival vs the EXTREME (cetuximab-platinum-fluorouracil). Many HNSCC studies have combined anti-PD1/PD-L1 therapy with various anticancer agents or radiotherapy to improve treatment efficacy. CONCLUSION: ICIs demonstrate their efficacies for R/M HNSCC patients. The incorporation of ICIs showed a great impact on the treatment landscape of HNSCC.

A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing.

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma.

Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421-34. ©2017 AACR.

ß-catenin (CTNNB1) mutations are not associated with prognosis in advanced hepatocellular carcinoma.

OBJECTIVES: Mutation of the exon 3 of CTNNB1, the coding gene of ß-catenin, is a crucial molecular mechanism leading to aberrant activation of the Wnt/ß-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.

Chlorhexidine for the prevention of bloodstream infection associated with totally implantable venous ports in patients with solid cancers.

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.

EGFR inhibitors as the first-line systemic treatment for advanced non-small-cell lung cancer.

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.

Aggressive revascularization of acute internal carotid artery occlusion in patients with NIHSS>20 and poor collateral circulation: preliminary report.

BACKGROUND: Acute occlusion of internal carotid artery (ICA) is a clinical catastrophic entity with mortality as high as 50%. With innovative devices and technology, we want to clarify the benefit and risk of interventional treatment for those patients. METHODS AND RESULTS: From 2005 to 2009, 62 patients were enrolled and 7 patients were diagnosed as total ICA occlusion with severe neurological deficit and poor collateral circulation received endovascular interventions. Intra-arterial thrombolysis was performed in all the 7 patients. Besides, angioplasty was done in 2 patients, stenting in 3, and thrombosuction in 1. The average NIHSS was 23.3 (standard deviation=3.6) before revascularization, was 14.2(standard deviation=6.8) on day 7. Three patients had symptomatically hemorrhagic transformation and one developed severe brain edema after procedure. Decompressive craniotomy has been conducted in 3, who survived thereafter. One patient died for refusal of decompressive craniotomy. The 30-day modified Rankin scale was 1 in 1, 2 in 1, 3 in 1, and 4 in 3. All of our patients had distal residual lesions at anterior or middle cerebral artery area, and delayed recanalization was noted in 4. CONCLUSIONS: Endovascular therapy was promising as a hyperacute management for patients of ICA total occlusion leading to survival rate more than 80% and significant neurological recovery in 50% of our patients. Distal residual lesions were common in patients of total carotid occlusion after aggressive revascularization. Although the mechanism was not clear, delayed re-canalization was common in such patients.