ABSTRACT
BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.
Subject(s)
Algorithms , Alzheimer Disease , Amyloid beta-Peptides , Biomarkers , Brain , Mass Spectrometry , Peptide Fragments , Positron-Emission Tomography , tau Proteins , Humans , Amyloid beta-Peptides/blood , Female , Male , tau Proteins/blood , Alzheimer Disease/blood , Alzheimer Disease/diagnosis , Alzheimer Disease/diagnostic imaging , Aged , Peptide Fragments/blood , Brain/diagnostic imaging , Brain/metabolism , Biomarkers/blood , Middle Aged , Aged, 80 and over , ROC CurveABSTRACT
OBJECTIVES: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are well-established in research settings, but their use in routine clinical practice remains a largely unexploited potential. Here, we examined the relationship between CSF biomarkers, measured by a fully automated immunoassay platform, and brain ß-amyloid (Aß) deposition status confirmed by amyloid positron emission tomography (PET). METHODS: One hundred ninety-nine CSF samples from clinically diagnosed AD patients enrolled in a clinical study and who underwent amyloid PET were used for the measurement of CSF biomarkers Aß 1-40 (Aß40), Aß 1-42 (Aß42), total tau (t-Tau), and phosphorylated tau-181 (p-Tau181) using the LUMIPULSE system. These biomarkers and their combinations were compared to amyloid PET classification (negative or positive) using visual read assessments. Several combinations were also analyzed with a multivariable logistic regression model. RESULTS: Aß42, t-Tau, and p-Tau181, and the ratios of Aß42 with other biomarkers had a good diagnostic agreement with amyloid PET imaging. The multivariable logistic regression analysis showed that amyloid PET status was associated with Aß40 and Aß42, but other factors, such as MMSE, sex, t-Tau, and p-Tau181, did not significantly add information to the model. CONCLUSIONS: CSF biomarkers measured with the LUMIPULSE system showed good agreement with amyloid PET imaging. The ratio of Aß42 with the other analyzed biomarkers showed a higher correlation with amyloid PET than Aß42 alone, suggesting that the combinations of biomarkers could be useful in the diagnostic assessment in clinical research and potentially in routine clinical practice.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/cerebrospinal fluid , Amyloid/metabolism , Biomarkers/cerebrospinal fluid , Positron-Emission Tomography , Brain/metabolismABSTRACT
BACKGROUND: Clinicians, researchers, and patients alike would greatly benefit from more accessible and inexpensive biomarkers for neural ß-amyloid (Aß). We aimed to assess the performance of fully automated plasma Aß immunoassays, which correlate significantly with immunoprecipitation mass spectrometry assays, in predicting brain Aß status as determined by visual read assessment of amyloid positron emission tomography (PET). METHODS: The plasma Aß42/Aß40 ratio was measured using a fully automated immunoassay platform (HISCL series) in two clinical studies (discovery and validation studies). The discovery and validation sample sets were retrospectively and randomly selected from participants with early Alzheimer's disease (AD) identified during screening for the elenbecestat Phase 3 program. RESULTS: We included 197 participants in the discovery study (mean [SD] age 71.1 [8.5] years; 112 females) and 200 in the validation study (age 70.8 [7.9] years; 99 females). The plasma Aß42/Aß40 ratio predicted amyloid PET visual read status with areas under the receiver operating characteristic curves of 0.941 (95% confidence interval [CI] 0.910-0.973) and 0.868 (95% CI 0.816-0.920) in the discovery and validation studies, respectively. In the discovery study, a cutoff value of 0.102 was determined based on maximizing the Youden Index, and the sensitivity and specificity were calculated to be 96.0% (95% CI 90.1-98.9%) and 83.5% (95% CI 74.6-90.3%), respectively. Using the same cutoff value, the sensitivity and specificity in the validation study were calculated to be 88.0% (95% CI 80.0-93.6%) and 72.0% (95% CI 62.1-80.5%), respectively. CONCLUSIONS: The plasma Aß42/Aß40 ratio measured using the HISCL series achieved high accuracy in predicting amyloid PET status. Since our blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it may contribute to the diagnosis of AD in routine clinical practice.
Subject(s)
Alzheimer Disease , Amyloidosis , Aged , Alzheimer Disease/diagnostic imaging , Amyloid , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Female , Humans , Immunoassay , Peptide Fragments/cerebrospinal fluid , Positron-Emission Tomography , Retrospective StudiesABSTRACT
Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-ß (Aß) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aß42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aß42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aß42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aß42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.
Subject(s)
Alzheimer Disease , Amyloidosis , Cognitive Dysfunction , Aged , Alzheimer Disease/diagnostic imaging , Amyloid , Amyloid beta-Peptides/analysis , Apolipoproteins E/genetics , Cognitive Dysfunction/diagnostic imaging , Cohort Studies , Cross-Sectional Studies , Female , Humans , Male , Peptide Fragments , Plaque, Amyloid/diagnostic imaging , Positron-Emission Tomography , Probability , Prospective StudiesABSTRACT
Stimulator of interferon genes (STING) is an innate immune receptor activated by natural or synthetic agonists to elicit antitumoral immune response via type I IFNs and other inflammatory cytokines. Bacillus Calmette-Guerin (BCG) is the standard of care as intravesical therapy for patients with high-risk non-muscle invasive bladder cancer (NMIBC). There are limited options available for patients with NMIBC who developed BCG unresponsiveness. In this study, we characterized in vitro and in vivo antitumor effects of E7766, a macrocyle-bridged STING agonist, via intravesical instillation in two syngeneic orthotopic murine NMIBC tumor models resistant to therapeutic doses of BCG and anti-PD-1 agents. E7766 bound to recombinant STING protein with a Kd value of 40 nmol/L and induced IFNß expression in primary human peripheral blood mononuclear cells harboring any of seven major STING genotypes with EC50 values of 0.15 to 0.79 µmol/L. Intravesical E7766 was efficacious in both NMIBC models with induction of effective immunologic memory in the treated animals. Pharmacologic activation of the STING pathway in the bladder resulted in IFN pathway activation, infiltration of T cells and natural killer (NK) cells, dendritic cell activation, and antigen presentation in bladder epithelium, leading to the antitumor activity and immunity. In addition, measurements of the pharmacodynamic markers, Ifnß1 and CXCL10, in bladder, urine, and plasma, and of STING pathway intactness in cancer cells, supported this mode of action. Taken together, our studies reveal an antitumor immune effect of pharmacologic activation of the STING pathway in bladder epithelium and thus provide a rationale for subsequent clinical studies in patients with NMIBC.
Subject(s)
Phosphatidylinositol 3-Kinases , Urinary Bladder Neoplasms , Animals , BCG Vaccine/pharmacology , Cell Line, Tumor , Cell Proliferation , Humans , Leukocytes, Mononuclear/metabolism , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Urinary Bladder/metabolism , Urinary Bladder/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: This phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma. METHODS: Part A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only). RESULTS: MTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw). CONCLUSIONS: An intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy.
Subject(s)
Lactones/administration & dosage , Lactones/pharmacokinetics , Melanoma/drug therapy , Melanoma/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Lactones/adverse effects , Male , Maximum Tolerated Dose , Middle AgedABSTRACT
OBJECTIVES: Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions-enzyme inhibition or induction-and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. METHODS: A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the perampanel dose. Pharmacokinetic parameters of perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of perampanel in the presence or absence of concomitant ketoconazole. RESULTS: Single oral doses of 1mg perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum perampanel plasma concentration (Cmax) and time to Cmax showed no apparent differences when perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in perampanel AUC (P<0.001). This increase, although statistically significant, was a<2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. CONCLUSIONS: Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as perampanel that have a long t1/2. Although a negligible effect on perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and perampanel (<3 times the t1/2 of perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.
Subject(s)
Anticonvulsants/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Enzyme Inhibitors/pharmacology , Pyridones/pharmacokinetics , Adult , Analysis of Variance , Anticonvulsants/blood , Area Under Curve , Computer Simulation , Cross-Over Studies , Drug Interactions , Healthy Volunteers , Humans , Ketoconazole/pharmacology , Male , Models, Chemical , Nitriles , Pyridones/blood , Therapeutic Equivalency , Time Factors , Young AdultABSTRACT
OBJECTIVE: This study assessed the impact of varying lenvatinib crystalline forms in 10-mg lenvatinib capsules on drug bioavailability in healthy volunteers. MATERIALS: Lenvatinib 10-mg capsules (low C and high C forms). METHODS: This randomized, three-period- crossover study compared the pharmacokinetics and safety of two crystalline forms of capsules (low C-form, <4% crystalline; high C-form, 38% crystalline) to a standard (ref Cform, 15% crystalline). RESULTS: 59 subjects were evaluable for pharmacokinetics. Test/reference ratios of the geometric least squares means (LSM) and 90% confidence intervals (CI) for AUC0-t (t up to 120 hours), AUC0-∞, and Cmax for low C-form vs. ref C-form were 101 (94.8, 107), 101 (95.3, 107), and 98.7 (88.6, 110), respectively; and for high C-form vs. ref C-form were 96.0 (92.1, 100), 96.5 (92.5, 101), and 90.6 (83.5, 98.4), respectively. The incidence of treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE) were comparable between all formulations (TEAE range 20-24%; TRAE range 15-19%). One serious TRAE (spontaneous abortion) occurred in the low C-form group. CONCLUSIONS: For both comparisons, the 90% CIs of the test/reference ratios were within the regulatory acceptance range (80-125%), suggesting that both test formulations (low Cform and high C-form) were bioequivalent to the reference formulation for Cmax, AUC0-t, and AUC0-∞.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/pharmacokinetics , Adolescent , Adult , Cross-Over Studies , Female , Healthy Volunteers , Humans , Male , Middle Aged , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Therapeutic Equivalency , Young AdultABSTRACT
Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 µCi) dose of (14)C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Neoplasms/metabolism , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/pharmacokinetics , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carbon Radioisotopes/blood , Carbon Radioisotopes/pharmacokinetics , Carbon Radioisotopes/urine , Feces/chemistry , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Phenylurea Compounds/adverse effects , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Quinolines/adverse effects , Quinolines/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: To identify clinical and biometric features associated with overall survival of patients with advanced refractory non-small-cell lung cancer (NSCLC) treated with gefitinib. EXPERIMENTAL DESIGN: One hundred and nine diagnostic NSCLC samples were analysed for EGFR mutation status, EGFR immunohistochemistry, histologic morphometry and quantitative immunofluorescence of 15 markers. Support vector regression modelling using the concordance index was employed to predict overall survival. RESULTS: Tumours from 4 of 87 patients (5%) contained EGFR tyrosine kinase domain mutations. A multivariate model identified ECOG performance status, and tumour morphometry, along with cyclin D1, caspase-3 activated, and phosphorylated KDR to be associated with overall survival, concordance index of 0.74 (hazard ratio (HR) 5.26, p-value 0.0002). CONCLUSIONS: System-based models can be used to identify a set of baseline features that are associated with reduced overall survival in patients with NSCLC treated with gefitinib. This is a preliminary study, and further analyses are required to validate the model in a randomised, controlled treatment setting.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Quinazolines/therapeutic use , Aged , Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Caspase 3/analysis , Cyclin D1/analysis , ErbB Receptors/analysis , ErbB Receptors/genetics , Female , Gefitinib , Humans , Immunohistochemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Male , Middle Aged , Mutation , Prognosis , Proportional Hazards Models , Survival RateABSTRACT
BACKGROUND: Models are available to accurately predict biochemical disease recurrence (BCR) after radical prostatectomy (RP). Because not all patients experiencing BCR will progress to metastatic disease, it is appealing to determine postoperatively which patients are likely to manifest systemic disease. METHODS: The study cohort consisted of 881 patients undergoing RP between 1985 and 2003. Clinical failure (CF) was defined as metastases, a rising prostate-specific antigen (PSA) in a castrate state, or death from prostate cancer. The cohort was randomized into training and validation sets. The accuracy of 4 models to predict clinical outcome within 5 years of RP were compared: 'postoperative BCR nomogram' and 'Cox regression CF model' based on standard clinical and pathologic parameters, and 2 CF 'systems pathology' models that integrate clinical and pathologic parameters with quantitative histomorphometric and immunofluorescent biomarker features ('systems pathology Models 1 and 2'). RESULTS: When applied to the validation set, the concordance index for the postoperative BCR nomogram was 0.85, for the Cox regression CF model 0.84, for systems pathology Model 1 0.81, and for systems pathology Model 2 0.85. CONCLUSIONS: Models predicting either BCR or CF after RP exhibit similarly high levels of accuracy because standard clinical and pathologic variables appear to be the primary determinants of both outcomes. It is possible that introducing current or novel biomarkers found to be uniquely associated with disease progression may further enhance the accuracy of the systems pathology-based platform.
Subject(s)
Prostatectomy , Prostatic Neoplasms/surgery , Systems Theory , Treatment Failure , Aged , Humans , Male , Middle Aged , Neoplasm Metastasis , Predictive Value of Tests , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/mortality , Sensitivity and Specificity , Validation Studies as TopicABSTRACT
We present a study of image features for cancer diagnosis and Gleason grading of the histological images of prostate. In diagnosis, the tissue image is classified into the tumor and nontumor classes. In Gleason grading, which characterizes tumor aggressiveness, the image is classified as containing a low- or high-grade tumor. The image sets used in this paper consisted of 367 and 268 color images for the diagnosis and Gleason grading problems, respectively, and were captured from representative areas of hematoxylin and eosin-stained tissue retrieved from tissue microarray cores or whole sections. The primary contribution of this paper is to aggregate color, texture, and morphometric cues at the global and histological object levels for classification. Features representing different visual cues were combined in a supervised learning framework. We compared the performance of Gaussian, k-nearest neighbor, and support vector machine classifiers together with the sequential forward feature selection algorithm. On diagnosis, using a five-fold cross-validation estimate, an accuracy of 96.7% was obtained. On Gleason grading, the achieved accuracy of classification into low- and high-grade classes was 81.0%.
Subject(s)
Algorithms , Artificial Intelligence , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Pattern Recognition, Automated/methods , Prostatic Neoplasms/classification , Prostatic Neoplasms/pathology , Color , Colorimetry/methods , Humans , Male , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
We hypothesized that amplification or overexpression of HER-2 (c-erbB-2), the Ki-67 antigen (Mib1), cyclin D-1 (CD1), interleukin-6 (IL-6), or the transforming growth factor beta II receptor, (TGFbetaRII), would predict relapse in women with early stage, estrogen (ER) and/or progesterone receptor (PR) positive breast cancer treated with tamoxifen. Conditional logistic regression models and a new novel analytic method - support vector machines (SVM) were used to assess the effect of multiple variables on treatment outcome. All patients had stage I-IIIa breast cancer (AJCC version 5). We paired 63 patients who were disease-free on or after tamoxifen with 63 patients who had relapsed (total 126); both disease-free and relapsed patients were matched by duration of tamoxifen therapy and time to recurrence. These 126 patients also served as the training set for SVM analysis and 18 other patients used as a validation set for SVM. In a multivariate analysis, larger tumor size, increasing extent of lymph node involvement, and poorer tumor grade were significant predictors of relapse. When HER-2 or CD1 were added to the model both were borderline significant predictors of relapse. The SVM model, after including all of the clinical and marker variables in the 126 patients as a training set, correctly predicted relapse in 78% of the 18 patient validation samples. In this trial, HER-2 and CD1 proved of borderline significance as predictive factors for recurrence on tamoxifen. An SVM model that included all clinical and biologic variables correctly predicted relapse in >75% of patients.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Neoplasm Recurrence, Local , Receptors, Steroid/metabolism , Tamoxifen/therapeutic use , Breast Neoplasms/pathology , Cyclin D1/metabolism , Female , Humans , Interleukin-6/metabolism , Middle Aged , Models, Biological , Multivariate Analysis , Neoplasm Staging , Predictive Value of Tests , Protein Serine-Threonine Kinases , Receptor, ErbB-2/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Receptors, Transforming Growth Factor beta/metabolismABSTRACT
We have developed an integrated, multidisciplinary methodology, termed systems pathology, to generate highly accurate predictive tools for complex diseases, using prostate cancer for the prototype. To predict the recurrence of prostate cancer following radical prostatectomy, defined by rising serum prostate-specific antigen (PSA), we used machine learning to develop a model based on clinicopathologic variables, histologic tumor characteristics, and cell type-specific quantification of biomarkers. The initial study was based on a cohort of 323 patients and identified that high levels of the androgen receptor, as detected by immunohistochemistry, were associated with a reduced time to PSA recurrence. The model predicted recurrence with high accuracy, as indicated by a concordance index in the validation set of 0.82, sensitivity of 96%, and specificity of 72%. We extended this approach, employing quantitative multiplex immunofluorescence, on an expanded cohort of 682 patients. The model again predicted PSA recurrence with high accuracy, concordance index being 0.77, sensitivity of 77% and specificity of 72%. The androgen receptor was selected, along with 5 clinicopathologic features (seminal vesicle invasion, biopsy Gleason score, extracapsular extension, preoperative PSA, and dominant prostatectomy Gleason grade) as well as 2 histologic features (texture of epithelial nuclei and cytoplasm in tumor only regions). This robust platform has broad applications in patient diagnosis, treatment management, and prognostication.
Subject(s)
Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/pathology , Pathology/methods , Prostatic Neoplasms/pathology , Systems Biology/methods , Cell Nucleus/metabolism , Disease-Free Survival , Humans , Male , Models, Biological , Neoplasm Recurrence, Local/metabolism , Prostate-Specific Antigen/blood , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Sensitivity and Specificity , Survival Rate , Tissue Array AnalysisABSTRACT
PURPOSE: Standard imaging studies are limited as outcome measures for patients with metastatic prostate cancer. We tested the hypothesis that serial fluorodeoxyglucose positron emission tomography (FDG-PET) scans can serve as an outcome measure for patients with castrate metastatic prostate cancer treated with antimicrotubule chemotherapy. EXPERIMENTAL DESIGN: FDG-PET scans were done at baseline, 4, and 12 weeks of treatment. The average maximum standardized uptake value (SUVmaxavg) was measured in up to five lesions and was tested as the quantitative outcome measure. Prostate-specific antigen (PSA) at 4 weeks and PSA, bone scan, and soft tissue imaging at 12 weeks were considered standard outcome measures. The change in SUVmaxavg that distinguished clinically assessed progression from nonprogression was sought. RESULTS: Twenty-two PET scans were reviewed and compared with PSA at 4 weeks; 18 PETs were compared at 12 weeks with standard outcome measures. Applying the PSA Working Group Consensus Criteria guideline that a 25% PSA increase constitutes progression to the SUVmaxavg, PET correctly identified the clinical status of 20 of 22 patients (91%) at 4 weeks and 17 of 18 patients at 12 weeks (94%). The accuracy of PET could be further optimized if a >33% increase in PSA and SUVmaxavg were used to define progression. CONCLUSION: FDG-PET is promising as an outcome measure in prostate cancer. As a single modality, it can show treatment effects that are usually described by a combination of PSA, bone scintigraphy, and soft tissue imaging. Preliminarily, a >33% increase in SUVmaxavg or the appearance of a new lesion optimally dichotomizes patients as progressors or nonprogressors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fluorodeoxyglucose F18 , Positron-Emission Tomography/methods , Prostatic Neoplasms/diagnostic imaging , Disease Progression , Humans , Male , Microtubules/drug effects , Neoplasm Metastasis , Orchiectomy , Prostate-Specific Antigen/blood , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/drug therapy , Sensitivity and Specificity , Treatment OutcomeABSTRACT
PURPOSE: The purpose of this retrospective study was to compare the functional outcomes of patients who had mandibular resection and reconstruction with and without prosthetic intervention, and to identify predictive factors that may have an impact on functional outcomes. MATERIALS AND METHODS: Two hundred twenty head and neck cancer patients who had undergone mandibular resection and reconstruction with at least 6 months of postoperative convalescence formed the basis of this retrospective review. Patients who did not receive prosthetic intervention formed group I (n = 142); those who received prosthetic intervention formed group II (n = 78). Functional outcomes were measured using four individual assessments (nutritional status, swallowing, masticatory performance, and speech) and one that combined the information from these assessments, the global measure of functional outcome (GMFO). Statistical analyses were used to compare the baseline characteristics and functional outcome between groups I and II and to analyze independent predictors for GMFO. RESULTS: Of the 220 patients reviewed, 78 (35%) had prosthetic intervention; group II patients had better individual functional outcome measures and GMFO. Use of a prosthesis remained associated with GMFO after controlling for other significant predictors; other independent predictors were xerostomia, number of remaining mandibular teeth, number of tooth-to-tooth contacts, type of reconstruction, flap interference, and tongue defect. Patients who had fewer mandibular teeth and received a smaller prosthesis had better overall outcome than patients who received a larger prosthesis. CONCLUSION: Patients who had prosthetic intervention after mandibular reconstruction had significantly better functional outcomes than patients who did not receive prosthetic intervention, even after adjusting for confounding variables.
Subject(s)
Dental Prosthesis, Implant-Supported , Denture, Complete, Lower , Mandible/surgery , Mandibular Neoplasms/rehabilitation , Oral Surgical Procedures , Adult , Aged , Aged, 80 and over , Analysis of Variance , Carcinoma, Squamous Cell/rehabilitation , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Plastic Surgery Procedures , Recovery of Function , Retrospective Studies , Surgical Flaps/blood supply , Tongue Neoplasms/rehabilitationABSTRACT
The differential overexpression of self-antigens on tumor cells is a prime feature of malignant transformation. Thomsen-Friedenreich (TF), a core disaccharide of O-glycosylated complex glycoproteins, is one of many "self" antigens expressed on malignantly transformed cells that has served as a target for immune recognition and attack. Previously, we conducted clinical trials with a series of synthetic glycolipid, peptide and carbohydrate antigens conjugated to the immunological carrier keyhole limpet hemocyanin (KLH) mixed with the immunological saponin adjuvant, QS21. These trials resulted in the generation of high-titer IgM and IgG antibody responses specific for the individual antigens, and, in several cases, the capacity of those antibodies to mediate complement lysis. Four groups of five patients who had evidence of a biochemical relapse defined as rising prostate-specific antigens (PSAs) following primary therapy for prostate cancer with either prostatectomy or radiation were treated with escalating doses of 1, 3, 10 and 30 microg of synthetic TF in a clustered formation (c) which was conjugated to KLH and given with 100 microg of QS21. Patients received a total of five subcutaneous vaccines over 6 months and were monitored expectantly with scans every 3-4 months. Serum samples were obtained at weeks 1, 2, 3, 7, 9, 13, 19, 26, 50 and every 3 months. Antibody titers were monitored by ELISA and antibody binding to the cell surface of prostate cell lines was performed by flow cytometry. Complement-dependent cytotoxicity was performed on selected patients. Twenty evaluable patients were accrued to the study, of whom only one did not receive all six vaccinations. All patients developed maximum IgM and IgG antibody titers by week 9. The median IgM antibody titer by week 7 was 1/1,280 at 10 microg, 1/320 at 30 microg, 1/1,280 at 3 microg and 1/1,280 at 1 microg dose groups. The IgM titers from all groups remained greater than 1/320 by week 32 and beyond through week 50. We report here the results of a dose-escalating trial of a TF(c)-KLH conjugate vaccine in patients in the clinical state of a rising PSA in the absence of radiographic disease. For the first time, a synthetically made TF trimer or cluster (c) was made with three TF disaccharides attached to three sequential threonines on a peptide backbone. TF(c) doses of 1, 3, 10 and 30 microg were conjugated to KLH and administered with QS21. All doses induced high-titer IgM and IgG antibodies against TF. Unlike our findings in previous dose-escalating phase I trials, there did not appear to be increased antibody production with increasing doses of vaccine; higher titers of IgM and IgG antibodies developed at the lowest dose level (1 microg). An anti-tumor effect in the form of a change in post-treatment versus pretreatment logPSA slopes was also observed. The results justify the inclusion of TF(c) at a dose of 1 microg as a relevant antigenic target in a multivalent phase II vaccine trial in patients in the high-risk minimal disease state.
Subject(s)
Antigens, Neoplasm/immunology , Antigens, Tumor-Associated, Carbohydrate/immunology , Cancer Vaccines/therapeutic use , Hemocyanins/immunology , Prostatic Neoplasms/therapy , Saponins/immunology , Vaccines, Conjugate/therapeutic use , Adjuvants, Immunologic , Aged , Cancer Vaccines/immunology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/prevention & control , Neoplasm Recurrence, Local/therapy , Prostate-Specific Antigen/blood , Prostatic Neoplasms/immunology , Vaccination , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunologyABSTRACT
BACKGROUND: Restoration of speech after surgical resection for oropharyngeal cancer traditionally includes maxillofacial prosthetic intervention. Relatively few publications with objective speech outcomes exist. The purpose of this study was to evaluate speech outcome relative to the size of the surgical defect, the type of speech prosthesis, and the height and position of the speech bulb in relation to the posterior pharyngeal wall in the nasopharynx. METHODS: Fifty-five patients treated at the Memorial Sloan-Kettering Cancer Center Dental Service who underwent ablative cancer therapy were evaluated. All patients were 4 months or longer after surgery and were using a speech aid or obturator prosthesis at the time of the study. Speech samples for percent intelligibility and perceptual evaluation were collected and analyzed, in addition to aeromechanical measurements of palatopharyngeal function. Lateral cephalograms were taken while wearing the prosthesis using a radiopaque marker placed on the posterior aspect of the prosthesis for evaluating the height and position of the prosthesis obturator-speech bulb component. RESULTS: After adjustment for the differences between listeners, findings revealed that as the percentage of resection of palate or tongue increased, the intelligibility of speech decreased. Aeromechanical assessment of speech was the only outcome measure sensitive to the type of speech prosthesis. The position of the speech bulb component, as well as the angle measured, was correlated with the percent intelligibility. The amount of the prosthesis physically contacting the posterior pharyngeal wall was not significantly associated with any of the functional outcome measures. CONCLUSIONS: Speech aid and obturator prostheses contribute to a higher percentage of intelligible speech. A difference in intelligibility exists in relationship to the position of the prosthesis and the anterior tubercle of the atlas vertebrae (C1), both statistically and clinically. The position for optimal speech could not be specifically located mathematically (ie, 3 mm or 3 degrees inferior to the anterior tubercle of the atlas vertebrae) from the analysis. Subjective ratings of the efficacy of the obturator-speech bulbs by the clinicians did not correspond to the percent intelligibility. A strong statistical and clinical correlation exists supporting the efficacy of speech bulb-obturator intervention after velopharyngeal insufficiency for improved intelligibility of both words and sentences.
Subject(s)
Head and Neck Neoplasms/surgery , Maxillofacial Prosthesis , Palatal Obturators , Velopharyngeal Insufficiency/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Cephalometry , Female , Humans , Male , Middle Aged , Velopharyngeal Insufficiency/etiologyABSTRACT
BACKGROUND: The PML gene is fused to the RARalpha gene in the vast majority of acute promyelocytic leukemias (APL) and has been implicated in the control of key tumor-suppressive pathways. However, its role in the pathogenesis of human cancers other than APL is still unclear. We therefore assessed the status and expression of the PML gene in solid tumors of multiple histologic origins. METHODS: We created tumor tissue microarrays (TTMs) with samples from patients with colon adenocarcinoma (n = 109), lung carcinoma (n = 19), prostate adenocarcinoma (n = 36), breast carcinoma (n = 38), central nervous system (CNS) tumors (n = 51), germ cell tumors (n = 60), thyroid carcinoma (n = 32), adrenal cortical carcinoma (n = 12), and non-Hodgkin's lymphoma (n = 251) and from normal tissue corresponding to each histotype and analyzed PML protein and mRNA expression by immunohistochemistry and in situ hybridization, respectively. Tumor cell lines (n = 64) of various histologic origins were analyzed for PML protein and mRNA expression by immunofluorescence and northern blotting, respectively. DNA from microdissected tumor samples and cell lines was analyzed for PML mutations and loss of heterozygosity (LOH). For some tumor types, the association between PML expression and tumor stage and grade was analyzed. Statistical tests were two-sided. RESULTS: All normal tissues expressed PML protein. PML protein expression was reduced or abolished in prostate adenocarcinomas (63% [95% confidence interval [CI] = 48% to 78%] and 28% [95% CI = 13% to 43%], respectively), colon adenocarcinomas (31% [95% CI = 22% to 40%] and 17% [95% CI = 10% to 24%]), breast carcinomas (21% [95% CI = 8% to 34%] and 31% [95% CI = 16% to 46%]), lung carcinomas (36% [95% CI = 15% to 57%] and 21% [95% = 3% to 39%]), lymphomas (14% [95% CI = 10% to 18%] and 69% [95% CI = 63% to 75%]), CNS tumors (24% [95% CI = 13% to 35%] and 49% [95% CI = 36% to 62%]), and germ cell tumors (36% [95% CI = 24% to 48%] and 48% [95% CI = 36% to 60%]) but not in thyroid or adrenal carcinomas. Loss of PML protein expression was associated with tumor progression in prostate cancer (the progression from prostatic intraepithelial neoplasia to invasive carcinoma was associated with complete PML loss; P<.001), breast cancer (complete PML loss was associated with lymph node metastasis; P =.01), and CNS tumors (complete PML loss was associated with high-grade tumors; P =.003). PML mRNA was expressed in all tumor and cell line samples. The PML gene was rarely mutated and was not subject to LOH. CONCLUSIONS: PML protein expression is frequently lost in human cancers of various histologic origins, and its loss associates with tumor grade and progression in some tumor histotypes.