Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study

AbstractBackgroundMany patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes.Patients and MethodsIn the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated.ResultsThree months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs.ConclusionOverall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018

Clonal analysis of palmar fibromatosis: a study whether palmar fibromatosis is a real tumor

BACKGROUND: Palmar fibromatosis that arises in the palmar soft tissue is characterized by infiltrative growth with a tendency toward local recurrence but does not metastasize. This study investigated the clonality of this process in twelve female patients, each with a single lesion, by examining the pattern of X-chromosome inactivation. METHODS: Hematoxylin and eosin stained sections of formalin-fixed, paraffin-embedded tissues were microdissected by laser capture microdissection to obtain the proliferative spindle cells. Tumor cells were isolated from the sections of rectum adenocarcinoma, and used for positive control. The genomic DNAs was extracted with phenol-chloroform, digested with a methylation-sensitive restriction endonuclease HpaII, and amplified by polymerase chain reaction (PCR), using primers targeted to a highly polymorphic short tandem repeat (STR) of the human androgen receptor gene (HUMARA). RESULTS: Among the twelve samples, three samples failed amplification, one sample showed homozygosity which was not suitable for further analysis, eight samples were successfully amplified, and showed a random X chromosome inactivation pattern, suggesting polyclonality of these lesions. CONCLUSION: The current findings suggest that palmar fibromatosis is a reactive proliferation rather than a clonal neoplasm

Mechanisms of Intragastric pH Sensing

Luminal amino acids and lack of luminal acidity as a result of acid neutralization by intragastric foodstuffs are powerful signals for acid secretion. Although the hormonal and neural pathways underlying this regulatory mechanism are well understood, the nature of the gastric luminal pH sensor has been enigmatic. In clinical studies, high pH, tryptic peptides, and luminal divalent metals (Ca2+ and Mg2+) increase gastrin release and acid production. The calcium-sensing receptor (CaSR), first described in the parathyroid gland but expressed on gastric G cells, is a logical candidate for the gastric acid sensor. Because CaSR ligands include amino acids and divalent metals, and because extracellular pH affects ligand binding in the pH range of the gastric content, its pH, metal, and nutrient-sensing functions are consistent with physiologic observations. The CaSR is thus an attractive candidate for the gastric luminal sensor that is part of the neuroendocrine negative regulatory loop for acid secretion

Kinase inhibitors for the treatment of inflammatory and autoimmune disorders

Drugs targeting inhibition of kinases for the treatment of inflammation and autoimmune disorders have become a major focus in the pharmaceutical and biotech industry. Multiple kinases from different pathways have been the targets of interest in this endeavor. This review describes some of the recent developments in the search for inhibitors of IKK2, Syk, Lck, and JAK3 kinases. It is anticipated that some of these compounds or newer inhibitors of these kinases will be approved for the treatment of rheumatoid arthritis, psoriasis, organ transplantation, and other autoimmune diseases

Human Placental-Specific Epipolymorphism and its Association with Adverse Pregnancy Outcomes

Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic “on-or-off” pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%–25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia. A biological significance of these methylation allelic polymorphisms (MAPs) to human placental diversity is further implied by their placental specificity and absence in mouse. An extended study of blood suggests that MAPs may also be found in other tissues, implicating their utility for tissue-specific association with complex disorders. The identification of such “epipolymorphism” in other tissues and their use in association studies, should improve our understanding of interindividual phenotypic variability and complex disease susceptibility

Methylation at Global LINE-1 Repeats in Human Blood Are Affected by Gender but Not by Age or Natural Hormone Cycles

Previously, we reported on inter-individual and gender specific variations of LINE-1 methylation in healthy individuals. In this study, we investigated whether this variability could be influenced by age or sex hormones in humans. To this end, we studied LINE-1 methylation in vivo in blood-derived DNA from individuals aged 18 to 64 years and from young healthy females at various hormone levels during the menstrual cycle. Our results show that no significant association with age was observed. However, the previously reported increase of LINE-1 methylation in males was reconfirmed. In females, although no correlation between LINE-1 or Alu methylation and hormone levels was observed, a significant stable individual specific level of methylation was noted. In vitro results largely confirmed these findings, as neither estrogen nor dihydrotestosterone affected LINE-1 or Alu methylation in Hek293T, HUVEC, or MDA-kb2 cell lines. In contrast, a decrease in methylation was observed in estrogen-treated T47-Kbluc cell lines strongly expressing estrogen receptor. The very low expression of estrogen receptor in blood cells could explain the observed insensitivity of methylation at LINE-1 to natural hormonal variations in females. In conclusion, neither natural cycle of hormones nor age has a detectable effect on the LINE-1 methylation in peripheral blood cells, while gender remains an important factor

The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions

Listeria pathogenesis and molecular virulence determinants

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research