SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. ...Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (
< 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.
Given the need to improve the sensitivity of non-invasive methods to detect colorectal neoplasia, particularly adenomas, we compared a fecal test using a monoclonal antibody (Mab) raised against ...constituents of colonic adenomas designated Adnab-9 (Adenoma Antibody 9), recognizing an N-linked 87 kDa glycoprotein, to gFOBT, which is shown to reduce CRC mortality. p87 immunohistochemistry testing is significantly more sensitive (OR 3.64CI 2.37-5.58) than gFOBT (guaiac-based fecal occult blood test) for adenomas (<3 in number), advanced adenomas (OR 4.21CI 2.47-7.15), or a combination of the two (OR 3.35CI 2.47-4.53). p87 immunohistochemistry shows regional Paneth cell (PC) expression mainly in the right-sided colon and is significantly reduced in the ceca of African Americans (
< 0.0001). In a subset of patients, we obtained other body fluids such as urine, colonic effluent, and saliva. Urine tests (organ-specific neoantigen) showed a significant difference for advanced adenomas (
< 0.047). We conclude that fecal p87 testing is more sensitive than gFOBT and Adnab-9 and could be used to better direct the colonoscopy screening effort.
Colorectal cancer (CRC) outcomes in terms of incidence and mortality are significantly worse in African Americans than other Americans. While differences in primary preventions for neoplasia (diet, ...obesity remediation, aspirin prophylaxis) are being elucidated, genetic mutations affecting premalignant lesions and immune response mechanisms may possibly also explain the increased incidence and mortality, particularly from right-sided disease. Objective: Our team therefore examined colonic segments seeking to test the hypothesis that the immune response and somatic genetic profiles of the colonic anatomic segments may vary and thus account for variations in neoplasia risk among the various colonic segments revealing an antigenic relationship with precancerous lesions. The p87 antigenic field effect is recognized via Adnab-9 antibody immunohistochemistry to be significantly less in the right colon in African Americans, particularly in the cecum. Method: Since small high-grade dysplastic adenomas (SHiGDA) likely missed by CRC screening may progress to cancer, we used Ion Torrent™ sequencing of DNA extracted from four normal colonic segments (two left-sided and two right) of patients with SHiGDAs. We also contrasted unique mutational fields in one patient with a large HiGDA (APC with unique mutations) and one patient who prospectively developed a SHiGDA (JAK3). Result: The SHiGDA (small high-grade dysplastic polyp) patient was p87 negative for any extracted stool, saliva, or colonic effluent via ELISA (enzyme linked immunoadsorbant assay). Furthermore, mean values of expression in segments from the right colon were reduced with respect to the means obtained from the left segments in 233 patients evaluated for a p87 field effect. This has recently been shown to be the case in a large cohort of AA and Caucasian 2294 patients, possibly explaining the right-sided CRC disparity in African Americans and the subsequent increase in mortality. This field effect disparity is also true for two cancers contracted by the SHiGDa patient (lung and prostate). Conclusion: Thus, this pilot study suggests that the reduction in p87 in the right colon is possibly correlated with JAK3 mutations. If confirmed, JAK3 mutations, known to be associated with immune aberrations, may provide a mechanistic explanation for the lack of a p87 (protein 87 kilodaltons) field in some patients with HGD polyps who might benefit from possible intervention such as more intensive screening. Limited microbiome studies were also performed on two patients with familial cancer syndromes and these compared favorably with controls available from the literature.
Patients with
mutant lung cancer have no approved targeted therapies after disease progression on first-line osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase ...inhibitor (TKI). Preclinical studies suggest that tumors with both
-sensitizing alteration and acquired second-site EGFR resistance alterations after treatment with osimertinib retain sensitivity to second-generation EGFR TKIs. We hypothesized that dacomitinib, a pan-human epidermal growth factor receptor TKI, may be effective in this setting.
In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate.
We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired
resistance mutations (two C797S and one G724S) met the response criteria. The patient with EGFR G719A has an ongoing response at 17 months, which exceeds prior time on osimertinib (11 months).
In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit.
Abstract
Current screening for lung cancer (LC) reduces mortality but tests are not ideal. Low-dose CT scans are expensive, incur radiation exposure, and high false positive rates. Although sputum ...cytology is unhelpful, saliva biomarker testing is promising but no prospective data are available.
Methods: In conducting a study using stool markers in a high risk colorectal neoplasia population we prospectively collected saliva and stool samples. Subsequently, 11 with available saliva; 8 with stool specimens but without significant personal or family history of GI neoplasia or symptoms, had contracted LC. We used 3 monoclonal antibodies to test reactivity in saliva (Adnab-9, BAC 18.1, COX-2). These are biomarkers of innate immune system, cell-mediated immunity, and inflammation, respectively. We used ELISA with either alkaline phosphatase (ALP) or immunoperoxidase (IMP) substrate and contrasted reactivity in LC patients and asymptomatic controls with no advanced polyps, and chemiluminescent dot blots with manual or Bel-blotter 96-well replicating tool.
Results: Saliva IMP testing was positive in 73% of 11 LC patients and 50% of 8 controls contrasted with ALP ELISA for stool Adnab-9 in 75% of 8 LC patients and 32% in 34 controls (OR 6.27:CI1.09-36.25;p<0.05).Specificity was 68%. Sensitivity for Adnab-9 for IMP manual and bel-blotting was 73 and 9% respectively; specificities were 37 and 64% respectively. BAC 18.1 sensitivities were 73 and 55% respectively; specificities 13 and 29%. COX-2 sensitivity for bel-blotting only was 27% and specificity was 71%. Inherent salivary peroxidase activity (OD<0.1/1μg protein) was negative in all 7 LC versus 9 of 23 (39%) of non-LC patients (p=0.07). The peroxidase absorbance meansSD were significantly different (0.0770.014 versus (0.1160.056;p<0.007). Equivalent inherent alkaline phosphatase of saliva samples was negative in both groups and means were not significantly different. The approximate time from saliva collection to diagnosis of LC was 3.76 years and 3.89 for stool.
Conclusions: Adnab-9 sensitivity was moderate but promising due to the ability to make an early preclinical diagnosis. While this was only significantly different from controls in stool ALP ELISA, inherent IMP activity could be blocked to improve specificity. Significantly suppressed inherent peroxidase activity in LC saliva may explain the insensitivity of the Bac18.1 and Cox2 inflammatory biomarkers. The Bel-blotter volume capacity is 4-10μl/blot and may explain the lower sensitivity using this tool. A battery of tests, including Adnab-9 in an ALP ELISA format may allow for early disease intervention.
Citation Format: Yosef Y. Tobi, Fadi Antaki, MaryAnn Rambus, Martin Tobi. Prospective lung cancer diagnostic screening using whole, unstimulated saliva versus stool abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 727. doi:10.1158/1538-7445.AM2017-727
Abstract
Lung cancer is the biggest cancer killer Worldwide with a limited prognosis despite personalized treatment regimens. Low-dose CT scanning as a means to early diagnosis has been disappointing ...due to the high false positive rate. Other non-invasive means of testing need to be developed that offer both timely diagnosis and predict prognosis. Methods: In the course of stool testing in a large scale testing of patients at increased risk of CRC we were able to ascertain 55 patients documented to have prospectively been diagnosed with lung cancer. Stool and colonic effluents were tested for anti-adenoma antibody (Adnab-9) reactivity by ELISA and Western blot. Survival data were obtained where available. Results: Of 55 cancers 40% were squamous (SSC), 23.7 were adenocarcinoma, 14.6 small, 12.7 large cell and 9% were designated NSCLC. 49.1% of the lung cancer patients had adnab-9 testing. Overall 53.6% (14 of 26) had positive testing compared to 2 of 11 controls (18.2%) which bordered on significance (OR5(CI1-29)). Cancers with higher lethality were more likely to test positive (67% for both small and large cell lung cancers, 50% SCC and adenocarcinoma, 33% NSCLC). In the larger groups overall survival was worse in those testing positive (474 versus 844 days in SCC and 54 versus 749 days in adenocarcinoma patients). Most importantly the time from a positive test to the clinical diagnosis ranged from 2.72 years for small cell, 3.13 for adenocarcinoma, 5.07 for NSCLC, 6.07 for SSC, and 6.24 for large cell cancer). In excluded cases where lung cancer was believed to be metastatic 75% of cancers were positive. Conclusions: At a projected real world sensitivity of 0.53 and specificity of 0.82 and the ability to predate diagnosis by up to 4.7 years overall, this test could help direct lung cancer screening. In addition, the Adnab-9 testing selectively detects worse tumor types (67%) and those with worse prognosis amongst the more common, favorable phenotypes thus making early diagnosis possible in those patients who stand to benefit most from this strategy. Metastatic lung cancer also detected by the test should be identified by the follow-up imaging studies and therefore would not be considered to be a major pitfall.
Citation Format: Martin Tobi, Yosef Y. Tobi, Fadi Antaki, MaryAnn Rambus, Michael Lawson. Preliminary data of a stool test for lung cancer from a prospective study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4519.
The basic concept of this book is that in spite of the borrowed Arabic poetical values, medieval Hebrew poetry stubbornly distanced itself from Arabic poetry. The conclusive result of an in-depth ...comparative examination is that Hebrew poetry combined selective Arabic poetical values with ethical Jewish values to create a distinctive poetical school.
