External Validation of Association of Baseline Circulating Tumor Cell Counts with Survival Outcomes in Men with Metastatic Castration-Sensitive Prostate Cancer.

Approximately 20% of men with metastatic castration-sensitive prostate cancer (mCSPC) progress within 1 year of treatment, and biomarkers to identify them up front are lacking. In a randomized phase III trial in men with mCSPC (SWOG S1216), higher baseline circulating tumor cells (CTCs) were prognostic of inferior outcomes. We aimed to validate these findings and interrogate corresponding tumor genomic profiles.

Genomic landscape of advanced prostate cancer patients with versus mutations as detected by comprehensive genomic profiling of cell-free DNA.

-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to -mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of versus co-segregating genes.

SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis-Targeted Therapy in De Novo Metastatic Castration-Sensitive Prostate Cancer.

Purpose: Intensification of androgen deprivation therapy (ADT) with either docetaxel or androgen receptor axis-targeted therapies (ARAT) are the current standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC). However, biomarkers guiding treatment selection are lacking. We hypothesized that ADT intensification with ARAT, but not with docetaxel, would be associated with improved outcomes in patients with de novo (dn)-mCSPC harboring SPOP mutations.

Survival of Patients with Metastatic Prostate Cancer After Disease Progression on an Androgen Receptor Axis-Targeted Therapy Given in the Metastatic Castration-Sensitive Versus Metastatic Castration-Resistant Prostate Cancer Setting.

Androgen receptor axis-targeted therapies (ARATs; androgen receptor or androgen synthesis inhibitors) have been approved for the treatment of patients with metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) on the basis of improved overall survival (OS) in randomized clinical trials. However, it is not clear whether the OS for patients after progression on first-line ARAT differs if the first ARAT was administered in the mCSPC versus mCRPC setting and what its estimates are. We assessed the OS after disease progression on ARAT given as first-line therapy in mCSPC versus mCRPC.

Identification of Somatic Gene Signatures in Circulating Cell-Free DNA Associated with Disease Progression in Metastatic Prostate Cancer by a Novel Machine Learning Platform.

Purpose: Progression from metastatic castration-sensitive prostate cancer (mCSPC) to a castration-resistant (mCRPC) state heralds the lethal phenotype of prostate cancer. Identifying genomic alterations associated with mCRPC may help find new targets for drug development. In the majority of patients, obtaining a tumor biopsy is challenging because of the predominance of bone-only metastasis.

Quest for Ideal Composite Biomarkers for Response to Immunotherapies.

In the CheckMate 275 study, composite biomarkers appear to better predict response to immunotherapy over individual ones. Nevertheless, the path forward needs consensus guidelines for biomarker interpretation. Thereafter, prospective validation with real-time, serial biospecimen collection along with the development of composite biomarker models leads to the goal of personalized therapy.

Comprehensive Analysis of AR Alterations in Circulating Tumor DNA from Patients with Advanced Prostate Cancer.

Background: Somatic alterations in circulating tumor DNA (ctDNA) may be associated with treatment response or prognosis in prostate cancer (PCa). The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in ctDNA from patients with PCa and to further understand the somatic genetic heterogeneity of advanced prostate cancer.

Patients And Methods: This study included a heterogeneous group of 892 patients with advanced PCa (predominantly castrate-resistant prostate cancer) with AR alterations detected in ctDNA that underwent next-generation sequencing of 54 to 73 genes via Guardant360 testing (Guardant Health, Inc.

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.

Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.

Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients.

Germline Variant in and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC).

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that genotype could predict response to abiraterone acetate for men with advanced prostate cancer.

Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer.

Background: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC).

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA.

Background: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies.

Siblings with severe pyruvate kinase deficiency and a complex genotype.

Siblings presented as neonates with severe jaundice and transfusion-dependent hemolytic anemia. Next-generation sequencing revealed both to have three heterozygous mutations in the gene encoding erythrocyte pyruvate kinase (PKLR), plus a heterozygous splice mutation in the beta-spectrin gene (SPTB). In addition, both have a different 5th mutation in a gene encoding other erythrocyte membrane proteins.

Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias.

Hereditary haemolytic anaemias are genetically and phenotypically heterogeneous disorders characterized by increased red cell destruction, with consequences ranging from innocuous to severe life-threatening anaemia. Diagnostic laboratories endeavour to assist clinicians reach the exact patient diagnosis by using tests principally based on morphological and biochemical techniques. However, these routine studies may be inconclusive, particularly in newborn infants and when transfusions have recently been administered.

Increased frequency of co-existing JAK2 exon-12 or MPL exon-10 mutations in patients with low JAK2(V617F) allelic burden.

The frequency of co-existing JAK2(V617F)/MPL and JAK2(V617F)/JAK2 exon-12 mutations has not been previously investigated in MPNs. Poor survival was reported in primary myelofibrosis with low JAK2(V617F) allelic burden. However, mutational status of JAK2 exon-12 or MPL were not reported in these patients.

Improved harmonization of eosin-5-maleimide binding test across different instruments and age groups.

Background: The eosin-5'maleimide (EMA) binding test has been studied extensively for the detection of hereditary spherocytosis (HS). Its performance characteristics have been compared to NaCl-based or glycerol lysis-based red cell osmotic fragility tests and cryohemolysis. HS samples are also better identified when both mean channel fluorescence (MCF) of EMA relative to controls and the coefficient of variation (CV) are analyzed.

Novel α-spectrin mutation in trans with α-spectrin causing severe neonatal jaundice from hereditary spherocytosis.

We evaluated a neonate with severe jaundice but a negative family history. Spherocytes were present and suspected hereditary spherocytosis was confirmed by osmotic fragility and eosin-5-maleimide erythrocyte staining. We found he was a compound heterozygote for two pathogenic mutations in the gene encoding α-spectrin: a previously reported α(LEPRA) inherited from his asymptomatic mother, and a novel α-spectrin mutation in intron 45 +1 disrupting the consensus splice site, from his asymptomatic father.

A previously unknown mutation in the pyruvate kinase gene (PKLR) identified from a neonate with severe jaundice.

We report a neonate with early and severe hemolytic jaundice and low erythrocyte pyruvate kinase enzymatic activity (<2 U/g hemoglobin, reference interval 9-22). We found her asymptomatic mother to be heterozygous for a novel PKLR mutation (c.1573delT) with an erythrocyte PK activity of 6.

Deparaffinization with mineral oil: a simple procedure for extraction of high-quality DNA from archival formalin-fixed paraffin-embedded samples.

Extracting DNA from formalin-fixed paraffin-embedded (FFPE) archival samples remains difficult. Successful polymerase chain reactions (PCR) with DNA extracted from FFPE samples is still very low. We extracted DNA from 12 recent and old archival FFPE bone marrow trephine biopsies by use of a simple protocol on the basis of deparaffinization with molecular biology-grade mineral oil followed by DNA extraction with the Qiagen FFPE kit.

Variations in both α-spectrin (SPTA1) and β-spectrin ( SPTB ) in a neonate with prolonged jaundice in a family where nine individuals had hereditary elliptocytosis.

We cared for a neonate who had problematic hyperbilirubinemia born into a family where nine first-degree relatives had hereditary elliptocytosis (HE). As neonates, the nine relatives did not have any significant jaundice or anemia that was recognizable. Blood films on the proband suggested a diagnosis of pyropoikilocytosis.

Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects.

Hereditary pyropoikilocytosis is a severe hemolytic anemia caused by spectrin deficiency and defective spectrin dimer self-association, typically found in African populations. We describe two Utah families of northern European ancestry including 2 propositi with atypical non-microcytic hereditary pyropoikilocytosis, 7 hereditary elliptocytosis members and one asymptomatic carrier. The underlying molecular defect is a novel mutation in the alpha(α) spectrin gene, SPTA(R34P) that impairs spectrin tetramer formation.

Identification of one or two α-globin gene deletions by isoelectric focusing electrophoresis.

Objectives: To investigate the utility of isoelectric focusing electrophoresis (IEF) for identifying patients with α-thalassemia, which results from the deletion of 1 or more of the α-globin genes.

Methods: Samples were selected based on their hemoglobin H (HbH) concentration observed using IEF. The samples were analyzed for the most common α-globin gene deletions using molecular analysis.

Acute kernicterus in a neonate with O/B blood group incompatibility and a mutation in SLC4A1.

We cared for a term female newborn, who at 108 hours of age, with a total serum bilirubin of 15.4 mg/dL, was discharged from the hospital on home phototherapy. At a return appointment 44 hours later, her total serum bilirubin was 41.

Glycoinositolphospholipids from Trypanosomatids subvert nitric oxide production in Rhodnius prolixus salivary glands.

Background: Rhodnius prolixus is a blood-sucking bug vector of Trypanosoma cruzi and T. rangeli. T.