Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study.

BACKGROUND: The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. METHODS: EQA sample results provided by 6 EQA providers (INSTAND [Germany], Korean Association of External Quality Assessment Service [KEQAS, South Korea], National Center for Clinical Laboratories [NCCL, China], United Kingdom National External Quality Assessment Service [UK NEQAS, United Kingdom], Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek [SKML, the Netherlands], and the Royal College of Pathologists of Australasia Quality Assurance Programs [RCPAQAP, Australia]) between 2020 and 2021 were used. The consensus means, calculated from the measurement procedures present in all EQA programs (Abbott Alinity, Beckman Coulter DxI, Roche Cobas, and Siemens Atellica), was used as reference values. Per measurement procedure, the relative difference between consensus mean for each EQA sample and the mean of all patient-pool-based EQA samples were calculated and compared to minimum, desirable, and optimal allowable bias criteria based on biological variation. RESULTS: Between 19040 (CA15-3) and 25398 (PSA) individual results and 56 (PSA) to 76 (AFP) unique EQA samples were included in the final analysis. The mean differences with the consensus mean of patient-pool-based EQA samples for all measurement procedures were within the optimum bias criterion for AFP, the desirable bias for PSA, and the minimum bias criterion for CEA. However, CEA results <8 µg/L exceeded the minimum bias criterion. For CA125, CA15-3, and CA19-9, the harmonization status was outside the minimum bias criterion, with systematic differences identified. CONCLUSIONS: This study provides relevant information about the current harmonization status of 6 tumor markers. A pilot harmonization investigation for CEA, CA125, CA15-3, and CA19-9 would be desirable.

Quantitative assessment of circulating tumor cells in cerebrospinal fluid as a clinical tool to predict survival in leptomeningeal metastases.

PURPOSE: Circulating tumor cells in cerebrospinal fluid are a quantitative diagnostic tool for leptomeningeal metastases from solid tumors, but their prognostic significance is unclear. Our objective was to evaluate CSF-CTC quantification in predicting outcomes in LM. METHODS: This is a single institution retrospective study of patients with solid tumors who underwent CSF-CTC quantification using the CellSearch® platform between 04/2016 and 06/2019. Information on neuroaxis imaging, CSF results, and survival was collected. LM was diagnosed by MRI and/or CSF cytology. Survival analyses were performed using multivariable Cox proportional hazards modeling, and CSF-CTC splits associated with survival were identified through recursive partitioning analysis. RESULTS: Out of 290 patients with CNS metastases, we identified a cohort of 101 patients with newly diagnosed LM. In this group, CSF-CTC count (median 200 CTCs/3 ml) predicted survival continuously (HR = 1.005, 95% CI: 1.002-1.009, p = 0.0027), and the risk of mortality doubled (HR = 2.84, 95% CI: 1.45-5.56, p = 0.0023) at the optimal cutoff of ≥ 61 CSF-CTCs/3 ml. Neuroimaging findings of LM (assessed by 3 independent neuroradiologists) were associated with a higher CSF-CTC count (median CSF-CTCs range 1.5-4 for patients without radiographic LM vs 200 for patients with radiographic LM, p < 0.001), but did not predict survival. CONCLUSION: Our data shows that CSF-CTCs quantification predicts survival in newly diagnosed LM, and outperforms neuroimaging. CSF-CTC analysis can be used as a prognostic tool in patients with LM and provides quantitative assessment of disease burden in the CNS compartment.

Lower Rate of Seropositivity to Measles Among Young Healthcare Personnel in New York City.

We examined the prevalence of measles antibody among 12 349 newly hired HCP between 2009 and 2019. Younger HCP were significantly more likely to have no immunity. Compared with a 92.2% seropositive rate among 1057 persons hired at age >50 years, only 84.4% of approximately 10 000 HCP aged <40 years had protective antibody.

Myocarditis Surveillance in Patients with Advanced Melanoma on Combination Immune Checkpoint Inhibitor Therapy: The Memorial Sloan Kettering Cancer Center Experience.

This letter to the editor describes myocarditis screening among patients undergoing combination immune checkpoint inhibitor therapy, in light of the consensus document from the Checkpoint Inhibitor Safety Working Group.

Limited role of Chromogranin A as clinical biomarker for pancreatic neuroendocrine tumors.

BACKGROUND: Serum Chromogranin A (CgA) is widely used as a biomarker for pancreatic neuroendocrine tumors (PanNETs). The aim of this study was to investigate the value of CgA as a diagnostic and prognostic marker for well-differentiated PanNETs. METHODS: Patients with well-differentiated PanNET and a baseline CgA measurement, between 2011 and 2016 were reviewed. The diagnostic value was determined by comparing CgA values from patients with PanNETs to those with other pancreatic neoplasms and healthy controls. The Kaplan-Meier method was used to investigate the CgA prognostic significance. RESULTS: Ninety-nine patients met inclusion criteria. As a diagnostic marker, CgA had a sensitivity of 66%, specificity of 95%, and overall accuracy of 71%. The use of PPIs was associated with a higher CgA level (p = 0.015). When excluding patients on PPIs, CgA accuracy in distinguishing PanNETs from other pancreatic neoplasms was 66%, the sensitivity and specificity were 60% and 75% respectively. Elevated CgA (p = 0.004), Ki67% (p < 0.001), tumor grade (p < 0.001) and stage of disease (p = 0.036) were associated with disease-specific survival. CONCLUSION: CgA has a limited role as a diagnostic biomarker for well-differentiated PanNETs. An elevated CgA level may have prognostic value but its role should be further investigated with respect to other known pathological factors.

Evaluation and Management of Testosterone Deficiency: AUA Guideline.

PURPOSE: There has been a marked increase in testosterone prescriptions in the past decade resulting in a growing need to give practicing clinicians proper guidance on the evaluation and management of the testosterone deficient patient. MATERIALS AND METHODS: A systematic review utilized research from the Mayo Clinic Evidence Based Practice Center and additional supplementation by the authors. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/). RESULTS: This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with testosterone deficiency and the safe and effective management of men on testosterone therapy. Additional statements were developed to guide the clinician on the appropriate care of patients who are at risk for or have cardiovascular disease or prostate cancer as well as patients who are interested in preserving fertility. CONCLUSIONS: The care of testosterone deficient patients should focus on accurate assessment of total testosterone levels, symptoms, and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated. Future longitudinal observational studies and clinical trials of significant duration in this space will improve diagnostic techniques and treatment of men with testosterone deficiency as well as provide more data on the adverse events that may be associated with testosterone therapy.

Fecal calprotectin concentrations in cancer patients with Clostridium difficile infection.

Fecal calprotectin (fCPT) has been used as a surrogate marker for assessment of intestinal inflammation. We explore the utility of fCPT values as a diagnostic aid in cancer patients with suspected Clostridium difficile infection (CDI). A total of 232 stool specimens submitted for GeneXpert C. difficile PCR testing were included in the study. All specimens were tested for fCPT and toxin/GDH antigens. Clinical severity of CDI cases was determined by the IDSA/SHEA criteria. Significant differences of median fCPT values between CDI (n = 117, Median 183.6 µg/g) and non-CDI (n = 115, 145.6 µg/g, p = 0.006) patients were seen. In CDI patents, significantly lower fCPT values were found in patients with mild to moderate (n = 95, 182.1 µg/g) than those with severe and severe to complicated (n = 22, 218.5 µg/g, p = 0.014) scores, and among those that were toxin positive (n = 24, 200.2 µg/g) vs. toxin negative (n = 86, 182.8 µg/g, p = 0.044). Despite this overall trend, wide variations in fCPT values were found in all categories examined. A logistic regression analysis revealed that the fCPT values correlated independently with the severity of clinical manifestations (OR = 2.021, 95%CI = 1.132-3.608); however, it did not correlate with other clinical outcomes. Our study findings show that high fecal calprotectin levels correlate with toxin-positive and clinically severe CDI; however, wide variations in individual measurements preclude establishment of reliable cut-offs for routine diagnostic use in cancer patients.

Exercise and QUality diet After Leukemia (EQUAL): A randomized weight loss trial among adult survivors of childhood leukemia in the Childhood Cancer Survivor Study.

BACKGROUND: Obesity is prevalent in childhood cancer survivors and interacts with cancer treatments to potentiate risk for cardiovascular (CV) death. We tested a remote weight-loss intervention that was effective among adults with CV risk factors in a cohort of adult survivors of childhood acute lymphoblastic leukemia (ALL) with overweight/obesity. METHODS: In this phase 3 efficacy trial, survivors of ALL enrolled in the Childhood Cancer Survivor Study with body mass index (BMI)≥25 kg/m2 were randomized to a remotely-delivered weight-loss intervention versus self-directed weight loss, stratified by history of cranial radiotherapy (CRT). The primary endpoint was the difference in weight loss at 24-months in an intent-to-treat analysis. Analyses were performed using linear mixed effects models. RESULTS: Among 358 survivors (59% female, median attained age: 37 years, IQR: 33-43), baseline mean (SD) weight was 98.6 kg (24.0) for the intervention group (n=181) and 94.9 kg (20.3) for controls (n=177). Adherence to the intervention was poor; 15% of individuals in the intervention completed 24/30 planned coaching calls. Weight at 24-months was available for 274 (77%) participants. After controlling for CRT, sex, race/ethnicity, and age, the mean (SE) change in weight from baseline to 24-months was -0.4 kg (0.8) for intervention and 0.2 kg (0.6) for control participants (p=0.59). CONCLUSIONS: A remote weight-loss intervention that was successful among adults with CV conditions did not result in significant weight loss among adult survivors of childhood ALL. IMPACT: Future interventions in this population must be tailored to the unique needs of survivors to encourage engagement and adherence.

Uterine washings as a novel method for early detection of ovarian cancer: Trials and tribulations.

Given the tubal origin of high-grade serous ovarian cancer (HGSC), we sought to investigate intrauterine lavage (IUL) as a novel method of biomarker detection. IUL and serum samples were collected from patients with HGSC or benign pathology. Although CA-125 and HE4 concentrations were significantly higher in IUL samples compared to serum, they were similar between IUL samples from patients with HGSC vs benign conditions. In contrast, CA-125 and HE4 serum concentrations differed between HGSC and benign pathology (P =.002 for both). IUL and tumor samples from patients with HGSC were subjected to targeted panel sequencing and droplet digital PCR (ddPCR). Tumor mutations were found in 75 % of matched IUL samples. Serum CA-125 and HE4 biomarker levels allowed for better differentiation of HGSC and benign pathology compared to IUL samples. We believe using IUL for early detection of HGSC requires optimization, and current strategies should focus on prevention until early detection strategies improve.

Extracellular Vesicular Analysis of Glypican 1 mRNA and Protein for Pancreatic Cancer Diagnosis and Prognosis.

Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late-stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes-rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles-rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early-stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late-stage PDAC patients undergoing chemotherapy, lower GPC1 tMV-mProtein and Exo-mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.

Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies.

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING signaling in mice inhibits DNA damage-induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

Detection of ovarian cancer via the spectral fingerprinting of quantum-defect-modified carbon nanotubes in serum by machine learning.

Serum biomarkers are often insufficiently sensitive or specific to facilitate cancer screening or diagnostic testing. In ovarian cancer, the few established serum biomarkers are highly specific, yet insufficiently sensitive to detect early-stage disease and to impact the mortality rates of patients with this cancer. Here we show that a 'disease fingerprint' acquired via machine learning from the spectra of near-infrared fluorescence emissions of an array of carbon nanotubes functionalized with quantum defects detects high-grade serous ovarian carcinoma in serum samples from symptomatic individuals with 87% sensitivity at 98% specificity (compared with 84% sensitivity at 98% specificity for the current best clinical screening test, which uses measurements of cancer antigen 125 and transvaginal ultrasonography). We used 269 serum samples to train and validate several machine-learning classifiers for the discrimination of patients with ovarian cancer from those with other diseases and from healthy individuals. The predictive values of the best classifier could not be attained via known protein biomarkers, suggesting that the array of nanotube sensors responds to unidentified serum biomarkers.

Hematopoietic Cell Transplantation is Feasible in Patients with Prior COVID-19 Infection.

There are limited data on outcomes of patients with prior Coronavirus disease 2019 (COVID-19) who proceeded to autologous or allogeneic hematopoietic cell transplantation (HCT). Whether these patients are more susceptible to poor outcomes and recurrence of COVID-19 is unknown. We report a retrospective analysis of outcomes of 15 consecutive patients with hematologic malignancies who experienced COVID-19 and subsequently underwent autologous (n = 8) or allogeneic (n = 7) HCT between June 17, 2020, and February 17, 2021. The cohort included patients with asymptomatic past infections or symptomatic COVID-19 disease. Data were obtained from chart review. Descriptive statistics were used to summarize patient characteristics. Among eight patients who underwent autologous HCT, four had a diagnosis of multiple myeloma and four had a diagnosis of non-Hodgkin's lymphoma. Four of these eight patients did not test positive for anti-SARS-CoV-2 IgG antibody at any point during the course of treatment. The other four patients had detectable anti-SARS-CoV-2 IgG antibodies before undergoing autologous HCT, but only two of these patients remained anti-SARS-CoV-2 IgG antibody-positive at their last follow-up. One patient died from progression of disease. Seven patients with prior COVID-19 underwent allogeneic HCT for acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), chronic myelogenous leukemia in lymphoid blast crisis (n = 1), myelodysplastic syndrome (n = 1), or myelofibrosis (n = 1). Three of the seven patients tested positive for anti-SARS-CoV-2 IgG antibodies following the initial COVID-19 diagnosis; however, only one of these patients retained anti-SARS-CoV-2 IgG antibody following allogeneic HCT. One patient died of infection (fungal and Pneumocystis jirovecii pneumonia) occurring in the context of ongoing treatment for graft-versus-host disease. None of the 15 patients had recurrent COVID-19 infection. Based on our experience, autologous and allogeneic HCT can be safely performed in selected patients with previous COVID-19 infection.

Predictors of Humoral Response to SARS-CoV-2 Vaccination after Hematopoietic Cell Transplantation and CAR T-cell Therapy.

Cellular therapies including allogeneic hematopoietic cell transplant (allo-HCT) and autologous hematopoietic cell transplant (auto-HCT) and chimeric antigen receptor (CAR) T-cell therapy render patients severely immunocompromised for extended periods after therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti-SARS-CoV-2 spike IgG Ab (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n = 149; auto-HCT, n = 61; CAR T-cell therapy, n = 7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity compared with 100% for both in 54 concurrent healthy controls. Time from cellular therapy to vaccination and immune recovery post-cellular therapy were associated with response. Vaccination against COVID-19 is an important component of post-cellular therapy care, and predictors of quantitative and qualitative response are critical in informing clinical decisions about optimal timing of vaccines and the requirement for booster doses. Significance: Identifying predictors of response to vaccination against SARS-CoV-2 in patients following cellular therapy is critical to managing this highly vulnerable patient population. To date, this is the most comprehensive study evaluating quantitative and qualitative responses to vaccination, providing parameters most predictive of response and potentially informing booster vaccination strategies.See related article by Chung et al., p. 568. This article is highlighted in the In This Issue feature, p. 549.

Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti-SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20-directed therapies, and anti-CD38/B-cell maturation antigen-directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not. Significance: Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577. This article is highlighted in the In This Issue feature, p. 549.

The New York State SARS-CoV-2 Testing Consortium: Regional Communication in Response to the COVID-19 Pandemic.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2, created an unprecedented need for comprehensive laboratory testing of populations, in order to meet the needs of medical practice and to guide the management and functioning of our society. With the greater New York metropolitan area as an epicenter of this pandemic beginning in March 2020, a consortium of laboratory leaders from the assembled New York academic medical institutions was formed to help identify and solve the challenges of deploying testing. This report brings forward the experience of this consortium, based on the real-world challenges which we encountered in testing patients and in supporting the recovery effort to reestablish the health care workplace. In coordination with the Greater New York Hospital Association and with the public health laboratory of New York State, this consortium communicated with state leadership to help inform public decision-making addressing the crisis. Through the length of the pandemic, the consortium has been a critical mechanism for sharing experience and best practices in dealing with issues including the following: instrument platforms, sample sources, test performance, pre- and post-analytical issues, supply chain, institutional testing capacity, pooled testing, biospecimen science, and research. The consortium also has been a mechanism for staying abreast of state and municipal policies and initiatives, and their impact on institutional and laboratory operations. The experience of this consortium may be of value to current and future laboratory professionals and policy-makers alike, in dealing with major events that impact regional laboratory services.