Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial.

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death.

Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies.

This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored.

Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies.

Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m/day (Days 1-14) or placebo plus capecitabine.

Pain questionnaire performance in advanced prostate cancer: comparative results from two international clinical trials.

Purpose: To compare pain assessment questionnaires commonly used in advanced prostate cancer trials and to determine the psychometric characteristics and longitudinal relationships by contrasting questionnaire data from two international phase 2 trials.

Methods: Scores from the Present Pain Intensity (PPI) question of the McGill Pain Questionnaire, the pain intensity scale of the Brief Pain Inventory (BPI), and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) were analyzed using Pearson correlation, intraclass correlation coefficient, and Cronbach's α, respectively. Concordance was evaluated with Cohen's kappa coefficient and McNemar test at baseline (n = 224) and two subsequent observations.

Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer.

Background: CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients.

Screening for iron overload: lessons from the hemochromatosis and iron overload screening (HEIRS) study.

Background: The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.

Methods: A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization.

Upper gastrointestinal bleeding from metastatic testicular cancer.

We report a 22-year-old man who presented with a 2-week history of intermittent melena and worsening scrotal and leg swelling. His medical history was significant for testicular cancer for which he had undergone orchiectomy, lymphadenectomy, and platinum-based chemotherapy. Esophagogastroduodenoscopy (EGD) performed revealed polypoid mass lesions in the second and third portions of the duodenum.

Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening.

Background: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.

Objective: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening.

Methods: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population.

How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known.

Biological variability of transferrin saturation and unsaturated iron-binding capacity.

Background: Transferrin saturation is widely considered the preferred screening test for hemochromatosis. Unsaturated iron-binding capacity has similar performance at lower cost. However, the within-person biological variability of both these tests may limit their ability at commonly used cut points to detect HFE C282Y homozygous patients.

HFE C282Y homozygotes aged 25-29 years at HEIRS Study initial screening.

We characterized HFE C282Y homozygotes aged 25-29 years in the HEmochromatosis and IRon Overload Screening (HEIRS) Study using health questionnaire responses, transferrin saturation (TfSat), serum ferritin (SF), and HFE genotyping. In eight homozygotes, we used denaturing high-performance liquid chromatography and sequencing to search for HFE2 (= HJV), TFR2, HAMP, SLC40A1 (= FPN1), and FTL mutations. Sixteen of 4,008 White or Hispanic participants aged 25-29 years had C282Y homozygosity (15 White, 1 Hispanic); 15 were previously undiagnosed.

Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS study initial screening.

There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25-29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL.

African Americans at risk for increased iron stores or liver disease.

Purpose: We sought to determine the prevalence of elevated measures of iron status in African Americans and whether the combination of serum ferritin concentration >200 microg/L for women or >300 microg/L for men and transferrin saturation in the highest quartile represents increased likelihood of mutation of HFE, self-reported iron overload or self-reported liver disease.

Subjects And Methods: A cross-sectional observational study of 27,224 African Americans > or =25 years of age recruited in a primary care setting was conducted as part of the multi-center, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study. Measurements included serum ferritin concentration, transferrin saturation, testing for HFE C282Y and H63D, and self-reported iron overload and liver disease.

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (> or =300 microg/L in men and >= or =200 microg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.

Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

Objective: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

Design: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group.

Mixture models of serum iron measures in population screening for hemochromatosis and iron overload.

Homozygosity for the C282Y mutation of the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. The authors describe and apply methodology developed for the analysis of phenotypic and genotypic data from 46,136 non-Hispanic Caucasians, a subset of the multi-ethnic cohort enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. For analysis of the distribution of transferrin saturation (TS), mixtures of normal distributions were considered and the expectation-maximization (EM) algorithm was applied for parameter estimation.

Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) study.

Objective: We evaluated the associations of self-reported diabetes with serum ferritin concentration, transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five field centers in the Hemochromatosis and Iron Overload Screening (HEIRS) study.

Research Design And Methods: Analyses were conducted on 97,470 participants. Participants who reported a previous diagnosis of diabetes and/or hemochromatosis or iron overload were compared with participants who did not report a previous diagnosis.

Case of chronic eosinophilic leukemia with deletion of chromosome 16 and hepatitis C.

Chronic eosinophilic leukemia is a rare entity, characterized by eosinophilia of >1.5 x 10(9)/L, persisting for >6 months after exclusion of other reactive and neoplastic causes of eosinophilia, and occurring in association with a clonal cytogenetic abnormality. Various chromosomal abnormalities have been associated with chronic eosinophilic leukemia.

Liver diseases in the hemochromatosis and iron overload screening study.

Background And Aims: The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 primary care participants for iron overload with serum transferrin saturation (TS), ferritin, and C282Y and H63D mutations of the HFE gene.

Methods: All C282Y homozygotes and participants with an increased TS (>45% women, >50% men) and serum ferritin level (> 200 microg/L women, >300 microg/L men) were recalled for a clinical history and physical examination, and blood tests including alanine transaminase (ALT) and aspartate transaminase levels. Hepatitis B surface antigen and anti-hepatitis C virus were measured if the ALT level was increased (>31 IU/L in women, >40 IU/L in men).

The association of serum ferritin and transferrin receptor concentrations with mortality in women with human immunodeficiency virus infection.

Background And Objectives: Whether degree of iron stores influences progression of human immunodeficiency virus (HIV) disease is controversial. We studied the relationship of indirect measures of iron stores with mortality in highly active antiretroviral therapy (HAART)-naive participants from the Women's Interagency HIV Study.

Design And Methods: One hundred and fifty-eight HIV-infected women who died before July 1996 were individually matched by CD4+ cell count (within +/- 50 cells/mL) and HIV RNA level (within +/- 0.

Low cobalamin levels in African Americans with and without sickle cell disease.

About 7% of the adult population has subclinical cobalamin (B12) deficiency. Subjects with sickle cell disease (SCD) may be at higher risk of cobalamin deficiency because of increased demand, inadequate supply, coexisting folate deficiency or malabsorption. We compared the clinical and laboratory characteristics of low serum cobalamin levels in patients with SCD with those patients without this hemoglobinopathy (non-SCD).

Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study.

We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Each underwent serum transferrin saturation (TfSat) and ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat more than 50% (men), more than 45% (women); and SF more than 300 ng/ml (men), more than 200 ng/ml (women).

Apoptosis induced by aspirin and 5-fluorouracil in human colonic adenocarcinoma cells.

Various biochemical, clinical and epidemiological studies have shown that aspirin (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) demonstrate antineoplastic properties, particularly in the gastrointestinal tract, inhibiting the proliferation of colorectal cancer cells. The mechanism of action may be prostaglandin mediated through inhibition of the COX enzymatic system. This includes two iso-enzymes, COX-I and COX-II, working in concert with the activation of apoptosis, activation of immune surveillance, inhibition of proliferation, and inhibition of carcinogen activation.

A phase II study of bortezomib in the treatment of metastatic malignant melanoma.

Background: Bortezomib is a proteasome inhibitor with manageable clinical toxicity and laboratory evidence of anti-melanoma activity. Therefore, it was considered for clinical testing in patients with metastatic melanoma.

Methods: Patients with metastatic melanoma and adequate hematologic, renal, and hepatic function were treated with bortezomib (a 1.

Evaluation of epothilone B analog in advanced soft tissue sarcoma: a phase II study of the phase II consortium.

Purpose: Epothilones are a new class of nontaxane tubulin polymerization agents that have activity in taxane-resistant tumors. Epothilone B (BMS-247550) is a semisynthetic analog of the natural product epothilone B. This study was performed to determine the activity of BMS-247550 in patients with soft tissue sarcomas (STSs) who had not received prior chemotherapy for metastatic disease.