A retrospective cohort of tumor-induced osteomalacia and case series of malignant disease.

OBJECTIVE: We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with tumor-induced osteomalacia (TIO), with a focus on patients with non-localizing and malignant TIO. METHODS: This is a retrospective cohort of TIO patients in an academic medical center, diagnosed between January 1998 to May 2023. We described their demographics, biochemistries, tumor features, localization, treatment and complications. RESULTS: Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. 20 (40%) had persistent disease due to wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus or baseline fibroblast growth factor-23 (FGF23) levels between localizing versus non-localizing groups, and malignant versus non-malignant groups. Lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. 60% of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R=0.566, p<0.001) but was not associated with malignancy risk (p=0.479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (p=0.025), and recurrence after initial cure (p=0.013) were factors significantly associated with malignancy. The non-localizing group had lower survival than localizing group (p=0.0097). CONCLUSIONS: TIO is a condition with significant morbidity. Very high FGF23 level and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in non-localizing TIO should be further explored.

Lack of observed interference by therapeutic monoclonal antibodies in select commonly utilized immunoassays.

BACKGROUND: Therapeutic monoclonal antibodies (tmabs) have been hypothesized to interfere with immunoassay measurements, although studies investigating this potential new class of interference are lacking. This study evaluated the effects of tmabs used in cancers ipilimumab (Bristol Myers Squibb), nivolumab (Bristol Myers Squibb), pembrolizumab (Merck) and autoimmune disorders adalimumab (AbbVie), infliximab (Janssen) and vedolizumab (Takeda) in common immunoassays used in the clinical laboratory. METHODS: Residual sera from 10 randomly chosen patients were split into two tubes and spiked with same volume (approximately 5 % final volume) of either saline (control) or 6 tmabs (final concentration of 100 µg/mL each). Concentrations from sixteen analytes in 19 different assays were assessed: TSH (Roche and Beckman), free thyroxine (Roche and Siemens), cortisol (Beckman), Cancer Antigens (CA): CA19-9 (Beckman), CA15-3 (Roche), CA125 (Roche), and CA27.29 (Siemens), carcinoembryonic antigen (Beckman), alpha-fetoprotein (Beckman), thyroglobulin (Beckman) and thyroglobulin antibodies (Beckman), thyroid peroxidase antibody (Beckman), beta-human chorionic gonadotropin (Roche and Beckman), total prostate-specific antigen (Roche), parathyroid hormone (Roche) and antinuclear antibodies IgG (Werfen). The tmab spiked residual sera were compared with matched saline spiked sera and percent error was assessed against allowable total error defined from biological variation or CLIA limits. RESULTS: None of the tested immunoassays were affected by the presence of the tmabs, in samples within or outside assay reference intervals. The median % error among all immunoassays ranged between -2.0% (for TSH) to 2.7% (for TPO Ab assay). CONCLUSION: These findings demonstrate no detectable tmab interference for the assessed immunoassays using spiked preparations of the tmabs in residual human sera. The findings are limited to the tmabs and immunoassays studied here.

Thyroglobulin and thyroglobulin antibody: an updated clinical and laboratory expert consensus.

OBJECTIVE: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. DESIGN: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. METHODS: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. RESULTS: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially anti-thyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. CONCLUSIONS: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance.

Genetic risk scores enhance the diagnostic value of plasma biomarkers of brain amyloidosis.

Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrolment and treatment monitoring in Alzheimer's disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer's disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analysing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, amyloid-ß42/40, glial fibrillary acidic protein or neurofilament light chain. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% versus 68%; P = 0.001). A machine learning approach incorporating plasma biomarkers, demographics and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set) and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity, which could non-invasively enhance the interpretation of blood-based AD biomarker profiles in the population.

Identification, Measurement, and Assessment of the Clinical Utility of Human Pancreatic Polypeptide by Liquid Chromatography-Tandem Mass Spectrometry.

Human pancreatic polypeptide (HPP) is a 36 amino acid peptide hormone that plays a role in the bidirectional communication between the digestive system and the brain. HPP measurements are used to assess vagal nerve function following sham feeding and to detect gastroenteropancreatic-neuroendocrine tumors. These tests have historically been conducted by radioimmunoassays, but liquid chromatography-tandem mass spectrometry (LC-MS/MS) has several advantages such as improved specificity and elimination of radioactive molecules. Here, we present our LC-MS/MS method. Initially, samples were immunopurified and subjected to LC-high resolution accurate mass tandem mass spectrometry (HRAM-MS/MS) to identify circulating forms of the peptide in human plasma. We identified 23 forms of HPP, including several glycosylated forms. The most abundant peptides then were used for targeted LC-MS/MS measurements. LC-MS/MS performance for precision, accuracy, linearity, recovery, limit of detection, and carryover met our acceptance criteria based on CLIA regulations. Additionally, we observed the expected physiological rise in HPP in response to sham feeding. Our results indicate that HPP measurement by LC-MS/MS produces clinically equivalent results to our established immunoassay when several peptides are monitored, making it a suitable replacement. The measurement of peptide fragments, including modified species, might have additional clinical value.

Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer's Disease and Vascular Pathology.

BACKGROUND: The National Institute on Aging-Alzheimer's Association Research Framework proposes defining Alzheimer's disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. OBJECTIVE: To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer's disease pathology measured by Aß42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). METHODS: Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aß42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). RESULTS: Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aß42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). CONCLUSION: The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders.

OBJECTIVE: Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions. METHODS: Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported. RESULTS: iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001). CONCLUSIONS: This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.

The effect of burosumab on intact and C-terminal FGF23 measurements.

OBJECTIVE: To investigate the effect of CRYSVITA® (burosumab-twza) on FGF23 measurements in an intact and a C-terminal immunoassay. METHODS: An intact serum FGF23 (MedFrontier) and a C-terminal plasma FGF23 assay (Immutopics) were used. Serum/plasma pools were spiked to span the burosumab therapeutic range (1.4-11.3 µg/ml) and FGF23 recovery was assessed. Patient serum and plasma samples obtained pre and post-burosumab treatment were evaluated on both assays and compared with corresponding phosphorus measurements RESULTS: Spiking burosumab (1.4-11.3 µg/ml) into sample pools resulted in a dose-dependent negative analytical interference on intact FGF23 measurements and no significant interference for C-terminal FGF23 measurements. However, more than a 500-fold median increase (post- vs. pre-burosumab administration) in in vivo FGF23 concentrations were observed by both assays. CONCLUSIONS: Therapeutic concentrations of burosumab result in a negative analytical interference of the intact, but not the C-terminal FGF23 immunoassay. Despite this in vitro analytical interference in the intact assay, relatively large elevations of both intact FGF23 and C-terminal FGF23 measurements were observed in vivo following burosumab administration. Following burosumab administration, FGF23 measurements must be interpreted within the clinical context of the patient and other relevant biomarker results. SUMMARY: This article describes a negative analytical interference by burosumab in an intact FGF23 immunoassay. The recovery of C-terminal FGF23 is not significantly affected by the presence of burosumab. In vivo, both assays demonstrate extreme FGF23 elevations in the presence of the drug. Furthermore, the measurement of FGF23 blocked by burosumab is not clinically useful regarding hypophosphataemia.

Thyroglobulin Assay Interferences: Clinical Usefulness of Mass-Spectrometry Methods.

Context: Thyroglobulin autoantibodies (TgAbs) affect thyroglobulin immunometric assays (TgIMAs), causing falsely low results. Conversely, heterophilic antibodies (HAs) may cause falsely elevated results. Thyroglobulin (Tg) measurements by mass spectrometry (MS) resist antibody interference. The most effective use of TgIMA/TgMS in the evaluation of Tg remains unclear. Objective: The objective of this work was to study the usefulness of TgMS vs TgIMA in the presence of Tg measurement interference by HA and TgAb. Methods: In 163 thyroid cancer patients, Tg was postoperatively measured by TgIMA and TgMS. When TgIMA was elevated and TgMS undetectable, HA was assessed by serial dilution and pretreatment with HA blocking reagent. TgIMA and TgMS were compared in TgAb-positive patients with well-characterized clinical status. Results: 6 out of 45 cases with TgIMA >1 ng/mL had undetectable TgMS. HA interference was confirmed by serial dilution and HA blocking reagent addition. In TgAb-positive cases, TgIMA and TgMS were highly correlated (R2 = 0.86). In patients with structural disease and TgAb, TgIMA and TgMS were detectable in 6/19 patients, and 9/19 cases, respectively. The TgMS concentration range in the 3 discrepant cases ranged from 0.5 to 2.0 ng/mL. Hence, the presence of TgAb was associated with inappropriately reduced Tg concentrations with both TgIMA and TgMS. Conclusion: HA cause falsely elevated TgIMA with undetectable TgMS with significant frequency. TgMS can be used to rule out HA interference. Albeit resistant to TgAb in vitro, TgMS detects little Tg in patients with TgAb and structural disease. Hence, TgAb may reduce Tg concentrations in vivo. The implication is that no assay design may be able to overcome this problem. TgMS may not detect structural disease in TgAb-positive patients.

Association of plasma biomarkers of amyloid and neurodegeneration with cerebrovascular disease and Alzheimer's disease.

The objective of this study was to determine the differential mapping of plasma biomarkers to postmortem neuropathology measures. We identified 64 participants in a population-based study with antemortem plasma markers (amyloid-ß [Aß] x-42, Aßx-40, neurofilament light [NfL], and total tau [T-tau]) who also had neuropathologic assessments of Alzheimer's and cerebrovascular pathology. We conducted weighted linear-regression models to evaluate relationships between plasma measures and neuropathology. Higher plasma NfL and Aß42/40 ratio were associated with cerebrovascular neuropathologic scales (p < 0.05) but not with Braak stage, neuritic plaque score, or Thal phase. Plasma Aß42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales. In participants predominantly with modest levels of Alzheimer's pathologic change, biomarkers of amyloid and neurodegeneration were associated with cerebrovascular neuropathology. NfL is a non-specific marker of brain injury, therefore its association with cerebrovascular neuropathology was expected. The association between elevated Aß42/40 and cerebrovascular disease pathology needs further investigation but could be due to the use of less specific amyloid-ß assays (x-40, x-42).

Alzheimer's disease cerebrospinal fluid biomarkers differentiate patients with Creutzfeldt-Jakob disease and autoimmune encephalitis.

BACKGROUND AND PURPOSE: Autoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt-Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE. METHODS: Patients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total-tau, phosphorylated181 tau and amyloid-ß42 levels were compared. RESULTS: Of 11 CJD cases, four were autopsy proven; the rest had positive real-time quaking-induced conversion testing. Disease-associated autoantibodies were detected in 8/15 cases of AE: leucine-rich glioma-inactivated 1 and neuronal intermediate filaments (two cases each), and N-methyl-d-aspartate receptor, contactin-associated protein-like 2, dipeptidyl-peptidase-like protein 6 and immunoglobulin-like cell adhesion molecule IgLON family member 5. Total-tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17-2.11, p < 0.05, c = 0.93). Total-tau was elevated in 91% of CJD cases (median > 1300, range 236->1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total-tau was elevated in 20% of AE cases (median 158, range 80->1300 pg/ml). CONCLUSION: Total-tau was greater in CJD than AE. Given that amyloid-ß42 and phosphorylated181 tau were comparable, the ratio differences were probably driven by elevated total-tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia.

Performance of plasma phosphorylated tau 181 and 217 in the community.

Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30-98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81-0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level.

Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds.

BACKGROUND: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. OBJECTIVE: To determine the association between plasma biomarkers (Aß40, Aß42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aß-PET imaging in patients with multiple CMBs. METHODS: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aß40, Aß42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aß-PET were evaluated using hurdle models and multivariable regression models. RESULTS: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aß42/Aß40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aß-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0). CONCLUSION: Lower plasma Aß42/Aß40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aß42/Aß40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Development of a PTHrP chemiluminescent immunoassay to assess humoral hypercalcemia of malignancy.

BACKGROUND: Parathyroid hormone related peptide (PTHrP) measurements are helpful in the evaluation and management of individuals suspected of humoral hypercalcemia of malignancy (HHM). AIM: To develop a chemiluminescent assay for PTHrP quantitation, establish reference intervals, and evaluate its clinical performance. METHOD: PTHrP 1-86 was measured using a polyclonal rabbit antibody (capture) and an acridinium ester labeled goat polyclonal antibody for chemiluminescent detection. RESULTS: Assay imprecision was < 9% (intra-assay) and < 15% (inter-assay). The analytical measuring range was 0.16-50.5 pmol/L. No significant cross-reactivity was observed for PTH (1-84), PTHrP (107-139), and PTHrP (1-36); whereas PTHrP (38-94) showed 8.3% cross-reactivity. Comparison with the pre-existing Mayo assay showed a positive bias: new assay = 2.24 (pre-existing assay)-0.30 and r2 = 0.96. The reference interval was ≤ 0.7 pmol/L, however, a cut-off of ≤ 4.2 pmol/L yielded increased specificity (98%). Comparison of patients with HHM versus those without HHM resulted in an area under the ROC curve of 0.99. A significant inverse relationship between eGFR and PTHrP was observed (r = 0.738). PTHrP concentrations in patients with Chronic Kidney Disease (CKD) were ≤ 4.2 pmol/L. CONCLUSION: This assay is specific for PTHrP 1-86. A clinical decision limit of 4.2 pmol/L was sensitive and specific for patients with HHM.

Performance characteristics of the BRAHMS KRYPTOR automated squamous cell carcinoma antigen assay.

BACKGROUND: Squamous cell carcinoma antigen (SCCA) is a glycoprotein biomarker for squamous cell carcinoma (SCC). SCCA elevations have also been noted in other conditions. The purpose of this study was to evaluate the analytical and clinical performance of an automated SCCA homogenous immunofluorescent assay (BRAHMS KRYPTOR). METHODS: Reference intervals were determined using 119 samples from healthy donors. To assess clinical performance, samples were collected from patients with cervical (n = 12), head and neck (n = 23), lung (n = 14), or cutaneous (n = 11) SCC in addition to hepatocellular carcinoma, psoriasis, or atopic dermatitis. RESULTS: Upper 95th percentile sex-specific reference intervals were 2.00 µg/L for males and 1.67 µg/L for females. Intra- and inter-assay CVs were less than 5%. Comparison of the BRAHMS KRYPTOR to an ELISA SCCA immunoassay exhibited a correlation coefficient of 0.8809. The mean sensitivity for all SCC positive patients was 23.3%. With the exception of psoriasis (58.6%) specificity exceeded 95% for the non-SCC populations. CONCLUSION: The BRAHMS KRYPTOR SCCA assay showed good analytical performance and acceptable overall clinical specificity. Consistent with previous studies, the sensitivity of SCCA for SCC was low. In the absence of other robust circulating markers, SCCA remains an imperfect yet useful tool in the evaluation of SCC.

Insulin-Like Growth Factor 1 in the Early Postoperative Assessment of Acromegaly.

OBJECTIVES: Assessment of surgical outcome in acromegaly is typically recommended at 3 to 6 months following surgery. The purpose of this study was to determine if insulin-like growth factor 1 (IGF-1) concentrations at 6 weeks were equally predictive of surgical outcomes compared with IGF-1 concentrations at 3 to 6 months postoperatively applying newer IGF-1 assays. METHODS: Retrospective review of patients with newly diagnosed acromegaly who had surgery between 2013 and 2020 and had postoperative IGF-1 measured by 6 weeks and 3 to 6 months. RESULTS: At 6 weeks, 20 (35%) of the total 57 had normal IGF-1 and became abnormal in 1 at 3 to 6 months, whereas 37 (65%) of 57 had abnormal IGF-1 concentrations at 6 weeks, which normalized in 1 patient by 3 to 6 months. In patients who changed clinical status, IGF-1 at 6 weeks was within ±0.1-fold of normal. Although a difference was seen between median IGF-1 concentrations (286 vs 267 ng/mL, P = .009) at 6 weeks and 3 to 6 months, the mean reduction was small (-19.9 ng/mL). CONCLUSIONS: Compared with 3 to 6 months, use of IGF-1 at 6 weeks was associated with a change in clinical status in 3.5% of patients. Therefore, in most patients, IGF-1 at 6 weeks can be used to assess clinical outcome via newer assays.

Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities.

INTRODUCTION: Blood-based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers. METHODS: Plasma markers (Aß42, Aß40, NfL, T-tau, Aß42/40 ratio) were measured on the Quanterix Simoa HD-1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years. All other data were collected during in-person MCSA visits or abstracted from the medical record. RESULTS: Among cognitively unimpaired (CU) participants, all plasma markers correlated with age. Linear regression models revealed multiple relationships. For example, higher Charlson Comorbidity Index and chronic kidney disease were associated with higher levels of all biomarkers. Some relationships differed between mild cognitive impairment and dementia participants. DISCUSSION: Multiple variables affect plasma biomarkers of amyloid pathology and neurodegeneration among CU in the general population. Incorporating this information is critical for accurate interpretation of the biomarker levels and for the development of reference ranges.

Blocking the Thyrotropin Receptor with K1-70 in a Patient with Follicular Thyroid Cancer, Graves' Disease, and Graves' Ophthalmopathy.

Background: We report the therapeutic use of K1-70™, a thyrotropin receptor (TSHR) antagonist monoclonal antibody, in a patient with follicular thyroid cancer (FTC), Graves' disease (GD), and Graves' ophthalmopathy (GO). Methods: A 51-year-old female patient, who smoked, presented in October 2014 with FTC complicated by GD, high levels of TSHR autoantibodies with high thyroid stimulating antibody (TSAb) activity, and severe GO. K1-70 was administered at 3 weekly intervals with the dose adjusted to block TSAb activity. Her cancer was managed with lenvatinib and radioiodine therapy. Results: Following initiation of K1-70 therapy, TSAb activity measured in serum decreased and GO (proptosis and inflammation) improved. On K1-70 monotherapy during the pause in lenvatinib, several metastatic lesions stabilized while others showed progression attenuation compared with that before lenvatinib therapy. Conclusions: These observations suggest that blocking TSHR stimulation with K1-70 can be an effective treatment for GO and may also benefit select patients with FTC and GD.

Evaluation of Phi Clinical Performance for the Detection of Prostate Cancer in Routine Clinical Practice.

Prostate Health Index (phi) and percent free PSA (%fPSA) are used in patients with a PSA concentration between 4-10 µg/L as an aid to distinguish prostate cancer (PCa) from benign conditions, and to assist in the decision of whether to proceed to biopsy. This study assesses the clinical performance and diagnostic accuracy of phi versus %fPSA in a cohort of Mayo Clinic's patients. Of 4065 phi orders received from May 2017-August 2018, concordance between phi and %fPSA results was evaluated on 2845 results with a total PSA within 4-10 µg/L. Retrospective chart review was performed on 201 Mayo Clinic patients, and %fPSA and phi results were compared with both the decision to biopsy and presence of PCa at biopsy. Receiver operating characteristic (ROC) curve analysis to evaluate the diagnostic accuracy of PSA, %fPSA and phi was performed. In this study 2.5% of the 2845 orders exhibited discordant PCa risk classifications between %fPSA and phi results. In the phi high risk category, 41.7% (versus 26.1% by %fPSA) of patients had biopsy and 100% (versus 66.6% by %fPSA) were positive for PCa. Phi exhibited the highest specificity and ROC area under the curve compared to %fPSA and PSA. phi was a better predictor than %fPSA for finding PCa at biopsy. These findings support continued utilization of phi in the evaluation of patients with a PSA in the 4-10 µg/L range.

Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)2D and normal FGF7 concentrations characterize patients with CKD.

BACKGROUND: Hyperphosphatemia confers adverse cardiovascular outcomes, and commonly occurs in late-stage CKD. Fibroblast growth factor 7 (FGF7) is a phosphaturic peptide which decreases renal phosphate transport in vitro and in vivo. Serum FGF7 concentrations are reduced in hyperphosphatemic patients with hypophosphatasia and are elevated in some hypophosphatemic patients with tumor-induced osteomalacia. No data, however, are available on whether circulating FGF7 concentrations increase to compensate for phosphate retention in CKD patients. METHODS: This was a cross-sectional study performed among 85 adult patients with varying estimated glomerular filtration rates (eGFR). We measured serum intact FGF7 (iFGF7) concentration using an iFGF7 immunoassay and determined its associated factors. Relationships between eGFR and mineral metabolism biomarkers [phosphate, iFGF7, iFGF23, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)2D)] were explored. RESULTS: For eGFRs of ≥ 60 (n = 31), 45-59 (n = 16), 30-44 (n = 11), 15-29 (n = 15), and < 15 mL/min/1.73 m2 (n = 12), median (IQ25-75) iFGF7 concentrations were 46.1 (39.2-56.9), 43.1 (39.0-51.5), 47.3 (38.3-66.5), 47.7 (37.7-55.8), and 49.6 (42.5-65.6) pg/mL, respectively (P = 0.62). Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25-25.51), respectively, while significant decreases in serum 1,25(OH)2D were observed at an eGFR of < 52 mL/min/1.73 m2 (95 % CI, 42.57-61.43). No significant correlation was found between serum iFGF7 and phosphate, iFGF23, PTH or 1,25(OH)2D. In multivariable analyses, body mass index (per 5 kg/m2 increase) was independently associated with the highest quartile of serum iFGF7 concentration (OR, 1.20; 95 % CI, 1.12-1.55). CONCLUSIONS: Compensatory decreases in circulating 1,25(OH)2D and increases in circulating iFGF23 and PTH, but not iFGF7, facilitate normalization of serum phosphate concentration in early stages of CKD. Whether other circulating phosphaturic peptides change in response to phosphate retention in CKD patients deserves further study.