Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.
CRP is named such for its ability to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae. This polypeptide acute phase reactant is a sensitive systemic marker of inflammation, malignancy and tissue damage. ABX Diagnostics developed a hematology analyzer (Micros CRP), which rapidly measures 16 routine hematological parameters plus whole blood CRP. The CRP value, determined by specific antigen-antibody induced optical turbidity, is available within 5 minutes with sensitivity to 0.10 mg/dl. Normal whole blood values range between 0.0 to 0.2 mg/dl. We evaluated the added clinical benefit of immediate CRP determinations in an outpatient cancer clinic in 155 patients undergoing observation and aggressive chemotherapy. Blood was obtained from all patients each visit and routine CBC, Platelet count and CRP were recorded, immediately provided to the physician in the presence of the patient and automatically stored in a database (HemaLink). Correlations were made between changes of CRP, WBC, AGC, and clinical condition. Routine measurement of CRP and its immediate availability for clinical interpretation was found to add a valuable new diagnostic dynamic for cancer patient care. Elevated CRP and its relative change were found to be a leading indicator of serious and frequently subclinical infection and were the earliest clues when compared to WBC or AGC. Relative changes of CRP were found to be indicative of clinical course. Diagnostic value of the WBC in cancer patients was lost in those undergoing myelosuppressive therapy and in those receiving leukocyte colony stimulating factors. The immediate availability of CRP allowed for preemptive diagnostics and therapy. Real-time knowledge of CRP either changed or significantly influenced therapy in 38% of patients. Study supported in part by ThinkTwice Technologies.
We measured serum folic acid, total serum vitamin B12, B12 complexed to transcobalamin as holotranscobalamin (HTCII), total homocysteine (tHcy), serum creatinine and estimated creatinine clearance (eCrCl) in 37 cancer patients presenting with newly diagnosed solid tumors. Serum HTCII was measured by the glass adsorption technique developed in this laboratory (Vu, T et al. Am J. Hem 42: 202–211 1993). Pearson’s r values were calculated for tHcy as a function of serum folate, total B12, HTCII, or eCrCl. R values reflect the degree of linear relationship between two variables. We found that 15 of 37 (40.5%) newly diagnosed and untreated cancer patients had serum homocysteine levels above 12 μM/L. The mean tHCY = 11.43 μM/L, median = 10.7 μM/L, range = 2.5 to 22.4 μM/L. One of the 36 (2.8%) patients for whom folate data was available had folate deficiency (folate = 4.2 ng/mL; pancreatic cancer). Mean folate = 19.35 ng/mL, median = 20.0 ng/mL, range = 4.2–40.2 ng/mL. Serum folate was only weakly inversely related to tHcy (r = −0.29551). Serum eCrCl was strongly inversely related to tHcy (r = −0.57927, p < 0.0002). Twenty-seven of 37 patients (73%) had a low creatinine clearance (<74 ml/min). The mean eCrCl = 63.3 mL/min, median = 62 mL/min, range = 24–131 ml/min. Serum HTCII and total B12 levels were moderately inversely related to tHcy (r = −0.3718 for HTCII, r = −0.33085 for total B12). Fourteen of 28 (50.0%) cancer patients had cobalamin insufficiency as their HTCII (the metabolically active form of B12) was measured at levels of <70 pg/mL. Only 1 of 37 patients (2.7%) in a group that included the HTCII deficient patients was deficient in total B12 at the <200 pg/ml level. Seven of 37 (18.9%) patients in this group were deficient in total B12 at the <300 pg/mL level. Four of the 14 HTCII deficient patients (28.6%) were diagnosed as B12 deficient at the <300 pg/mL level, while no patients were B12 deficient at the <200 pg/ml level. The routine measurement of total B12 levels (deficiency <300 pg/mL) identified less than one third of patients with HTCII deficiency. HTCII deficiency is frequent and not measurable by total B12, the most widely used test. Total homocysteine is frequently elevated in cancer patients and may cause thrombophilia and osteoporosis. Total homocysteine in cancer patients is more a function of renal failure (as indicated by low eCrCl) than of folate or B12 deficiency. It appears that serum folate deficiency in the new millenium (post January 1998 when the FDA required all enriched grain products to contain 140 mcg of folic acid per 100 grams) is uncommon even in cancer patients with their increased demand for folate. The effects of vitamin B12 supplements on chemotherapy toxicity and treatment outcome for newly diagnosed cancer patients about to undergo therapy should be studied. B12 prophylaxis for cancer prevention warrants study as well since breast cancer incidence may be 2.5–4 fold higher for B12 deficient patients (Wu, K. et al. Cancer Epidemiol. 1999. 8:209–17). Supported in part by a grant from ThinkTwice Technologies. This work is dedicated to the memory of Dr. Victor Herbert whose teachings continue to inspire our research efforts.
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