Examining the Factors That Affect the Diagnosis of Patients with Positive Fecal Occult Blood Test Results.

Due to the threat of colorectal cancer (CRC) to health, Taiwan included the fecal occult blood test (FOBT) under preventive health services in 2010. We examined the factors that affect the diagnosis of people with positive FOBT results. Data were retrospectively collected from the CRC screening database. In the model predicting factors that affect the diagnosis of 89,046 people with positive FOBT results, the risks of disease in the CRC group were lower in medical institutions that conducted follow-up examinations in regions such as Northern Taiwan compared to that in Eastern Taiwan (p = 0.013); they were lower in the age group of 50 to 65 years than those in the age group of 71 to 75 years (p < 0.001, p = 0.016), and lower in the outpatient medical units that conducted follow-up examinations than those in the inpatient medical units by 0.565 times (p < 0.001, 95% CI: 0.493−0.647). Factors affecting the diagnosis of patients with positive FOBT results were gender, the region of the medical institution, medical unit for follow-up examinations, age, screening site, family history, type of follow-up examinations, and follow-up time. Therefore, the identification of characteristics of patients with positive FOBT results and the promotion of follow-up examination are important prevention strategies for CRC.

Factors affecting the follow-up time after a positive result in the fecal occult blood test.

In 2010, Taiwan included the fecal occult blood test (FOBT) under preventive health insurance services. For patients whose test positive, receiving follow-ups is paramount. This study investigated factors affecting the follow-up time of these patients. This retrospective study used data from the colorectal cancer screening archives. The study period was from 2010 to 2013, and the subjects were 50-75-year-old persons who tested positive for FOBT. The t test, one-way ANOVA, and multiple regression were performed to address the differences in the mean tracking period between variables such as the population's demographic characteristics. The mean follow-up time for the 98,482 participants whose screening results were positive exhibited significant differences (p < 0.001) according to medical unit region and classification, age, screening location, family history, examination method, and diagnosis. The model predicting the mean follow-up time predicted a period of 10.079 days longer for those whose hospital was on an offshore island than that of those whose hospital was in the eastern regions. The follow-up time was 1.257 days shorter for people who were inpatients than those who were outpatients and was 8.902 days longer for people who underwent double contrast barium enema plus flexible sigmoidoscopy than those who underwent other examination methods. Patients with a family history of colorectal cancer and those whose examination results indicated cancer had a follow-up time of 2.562 and 2.476 days shorter than those who did not know their family history and those with other results, respectively. Factors affecting the follow-up time of people whose FOBT results were positive consisted of the location and classification of the follow-up institution, age, screening location, family history, examination method, and diagnosis. This provides valuable references for improving the cancer screening program.

Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma.

Radiotherapy can facilitate the immune recognition of immunologically "cold" tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically "cold" tumors throughout the body responsive to ICIs and immunologically "hot". Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent.

The Toll-like receptor 8 (TLR8) agonist VTX-2337 (motolimod) is an anti-cancer immunotherapeutic agent that is believed to augment natural killer (NK) and dendritic cell (DC) activity. The goal of this work is to examine the role of TLR8 expression/activity in head and neck squamous cell carcinoma (HNSCC) to facilitate the prediction of responders to VTX-2337-based therapy. The prognostic role of TLR8 expression in HNSCC patients was assessed by TCGA and tissue microarray analyses. The anti-tumor effect of VTX-2337 was determined in SCCVII/C3H, mEERL/C57Bl/6 and TUBO-human EGFR/BALB/c syngeneic mouse models. The effect of combined VTX-2337 and cetuximab treatment on tumor growth, survival and immune cell recruitment was assessed. TLR8 expression was associated with CD8+ T cell infiltration and favorable survival outcomes. VTX-2337 delayed tumor growth in all 3 syngeneic mouse models and significantly increased the survival of cetuximab-treated mice. The anti-tumor effects of VTX-2337+ cetuximab were accompanied by increased splenic lymphoid DCs and IFNγ+ CD4+ and tumor-specific CD8+ T cells. Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression.

In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy.

BACKGROUND: CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model. METHODS: Immune cell activation in response to CMP-001±anti-Qß was performed using co-cultures of peripheral blood mononuclear cells and HPV+/HPV- HNSCC cells and then analyzed by flow cytometry. In situ vaccination with CMP-001 alone and in combination with anti-PD-1 was investigated in C57BL/6 mice-bearing mEERL HNSCC tumors and analyzed for anti-Qß development, antitumor response, survival and immune cell recruitment. The role of antitumor immune response due to CMP-001+anti-PD-1 treatment was investigated by the depletion of natural killer (NK), CD4+ T, and CD8+ T cells. RESULTS: Results showed that the activity of CMP-001 on immune cell (pDCs, monocytes, CD4+/CD8+ T cells and NK cells) activation depends on the presence of anti-Qß. A 2-week 'priming' period after subcutaneous administration of CMP-001 was required for robust anti-Qß development in mice. In situ vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. In situ vaccination of CMP-001 in combination with anti-PD-1 therapy induced durable tumor regression at injected and distant tumors and significantly prolonged mouse survival compared with anti-PD-1 therapy alone. The antitumor effect of CMP-001+anti-PD-1 was accompanied by increased interferon gamma (IFNγ)+ CD4+/CD8+ T cells compared with control-treated mice. The therapeutic and abscopal effect of CMP-001+ anti-PD-1 therapy was completely abrogated by CD8+ T cell depletion. CONCLUSIONS: These results demonstrate that in situ vaccination with CMP-001 can induce both local and abscopal antitumor immune responses. Additionally, the antitumor efficacy of CMP-001 combined with α-PD-1 therapy warrants further study as a novel immunotherapeutic strategy for the treatment of HNSCC.

A preliminary analysis of interleukin-1 ligands as potential predictive biomarkers of response to cetuximab.

BACKGROUND: The epidermal growth factor receptor (EGFR) monoclonal IgG1 antibody cetuximab is approved for first-line treatment of recurrent and metastatic (R/M) HNSCC as a part of the standard of care EXTREME regimen (platinum/5-fluorouracil/cetuximab). This regimen has relatively high response and disease control rates but is generally not curative and many patients will experience recurrent disease and/or metastasis. Therefore, there is a great need to identify predictive biomarkers for recurrence and disease progression in cetuximab-treated HNSCC patients to facilitate patient management and allow for treatment modification. The goal of this work is to assess the potential of activating interleukin-1 (IL-1) ligands (IL-1 alpha [IL-1α], IL-1 beta [IL-1ß]) as predictive biomarkers of survival outcomes in HNSCC patients treated with cetuximab-based chemotherapy. METHODS: Baseline gene, serum and tumor expression of interleukin-1 (IL-1) ligands were analyzed from The Cancer Genome Atlas (TCGA) database or clinical trials of cetuximab-based therapies and interrogated for associations with clinical outcome data. RESULTS: High tumor gene expression of IL-1ß was associated with a more favorable overall survival in cetuximab-treated HNSCC patients but not in non-cetuximab-treated patients. In HNSCC patients treated with cetuximab-based chemotherapy, higher gene and circulating levels of IL-1α and IL-1ß were correlated with a more favorable progression free survival compared to patients with low or undetectable levels of IL-1 ligands. CONCLUSIONS: These findings suggest that IL-1 ligands may function as predictive biomarkers for tumor response to cetuximab-based chemotherapy in HNSCC patients and warrants further investigation and validation in larger clinical studies.

Proper management of lead-contaminated agricultural lands against the exceedance of lead in agricultural produce: Derivation of local soil criteria.

The Measures for Management of Soil Environment in Agricultural Land (Trial, Nov. 01, 2017, China) recently came into effect and highlighted the proper management of contaminated croplands to lower risks of exceedances of contaminants, especially toxic trace metals in agricultural produce. We aimed to develop local soil criteria for lead (Pb) in Hezhang county of southwestern China by the inverse use of reliable models linking Pb contamination levels between soils and vegetables. Dilute nitric acid (0.43 M) extraction, a new ISO standard (ISO-17586:2016) for extracting the geochemically reactive Pb fraction (PbNA), and calcium chloride (0.01 M) extraction (ISO-14255: 1998) for estimating the plant-available Pb (PbCC) were performed in fifty historically polluted and newly Pb-spiked soils with differing soil types, properties (pH 4.1-8.0), and total soil Pb levels (PbT, 20-6153 mg kg-1). Greenhouse experiments for Brassica pekinensis L., and in-situ soil porewater measurement for Pb were conducted to investigate the mechanism of Pb uptake, and to establish reliable Pb soil-plant relationships. The results indicated that about 83% of the variation for Pb concentrations in vegetable (PbCL, 0.009-1.06 mg kg-1) was contributable to free Pb2+ activity in soil porewater, which was mainly influenced by pH and dissolved organic matter. PbCL was satisfactorily predicted using PbNA and key soil properties (adj. R2 0.852). Soil Pb criteria for PbT and PbNA are then derived based on food standard. The full implementation of criteria derived for PbNA (i.e., 27-127 mg kg-1, soil pH 5.5-8.0) can avoid the exceedance of Pb in 95% of cabbage samples in this study, 95% of cabbage cultivars by model extrapolation, and one widely cultivated root vegetable, radish, in the study region. We provide a successful case study that has effectively tackled the challenge for the complexity of the soil management in contaminated croplands.

Derivation of reliable empirical models describing lead transfer from metal-polluted soils to radish (Raphanus sativa L.): Determining factors and soil criteria.

Reliable models describing Pb transfer from soils to food crops are useful in the improvement of soil protection guidelines. This study provides mechanistic insights from in-situ soil solution measurement on the Pb uptake in the root tissues (RF) of radish, grown in 25 representative Pb-contaminated agricultural soils. Lead speciation and regression analysis indicate that >88.6% of the variation in RF Pb is attributable to free Pb2+ activity (aPb2+) in the soil solution, which is predominantly controlled by pH and DOC. Higher DOC would increase the total dissolved Pb (CSol-Pb) in the soil solution but reduce the bioavailability of Pb to radish. CSol-Pb performs poorly in predicting RF Pb unless pH and DOC are included. However, 0.01M CaCl2 extractable Pb (CCC-Pb) alone can satisfactorily predict RF Pb, attributable to the fact that CCC-Pb is consistent with aPb2+. CCC-Pb can be predicted using CSol-Pb and pH. Total soil Pb (CT-Pb), or 0.43M HNO3 extractable Pb (CNA-Pb) has a strong, non-linear correlation with CSol-Pb or CCC-Pb and it is therefore not surprising that CT-Pb or CNA-Pb, together with pH and CEC, can also satisfactorily predict RF Pb. Derived models are effective in identification of soils where RF Pb exceeds the food quality standard (FQS). Soil Pb criteria based on CT-Pb, CNA-Pb and CCC-Pb are derived by inverse use of empirical models. The derived Pb criterion (target value) based on CCC-Pb is 0.02mgkg-1 and the stricter criterion (safe value) is 0.01mgkg-1, which allows a 5% probability for RF Pb to exceed FQS. Safe values based on CT-Pb and CNA-Pb ranged from 26 to 1036mgkg-1 and 9 to 745mgkg-1, respectively.

Debromination of polybrominated diphenyl ethers by attapulgite-supported Fe/Ni bimetallic nanoparticles: Influencing factors, kinetics and mechanism.

To enhance the removal efficiency of 2,2',4,4'-tetrabromodiphenylether (BDE47) in aqueous solutions, novel attapulgite-supported Fe/Ni bimetallic nanoparticles (A-Fe/Ni), which were characterized by a core-shell nanoparticle structure and with an average diameter of 20-40 nm, were synthesized for use in BDE47 degradation. The presence of attapulgite in bimetallic systems could reduce Fe/Ni nanoparticle aggregation and enhance their reactivity. BDE47 was degraded with a significant improvement in removal efficiency of at least 96% by A-Fe/Ni that played a reductive role in the reaction. The degradation kinetics of BDE47 by A-Fe/Ni complied with pseudo-first-order characteristics. To better understand the removal mechanism, detailed analyses were performed for several influential parameters. The improved dosage of A-Fe/Ni was found to be beneficial, and higher values of initial concentration, pH, and methanol/water ratio hindered the degradation rate, which, for example, decreased significantly in mixtures with a methanol proportion higher than 50%. The identification of BDE47 degradation products revealed a stepwise debromination from n-bromo-DE to (n-1)-bromo-DE as a possible pathway, wherein the para-Br was more easily eliminated than ortho-Br. Our findings provide insight into the removal mechanism and evidence for polybrominated diphenyl ether debromination by clay-Fe/Ni bimetallic nanoparticles.