Haeseong Park

Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children.

CONTEXT. Hydroxyurea is the only approved medication for the treatment of sickle cell disease in adults; there are no approved drugs for children. OBJECTIVE. Our goal was to synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea in children with sickle cell disease. METHODS. Medline, Embase, TOXLine, and the Cumulative Index to Nursing and Allied Health Literature through June 2007 were used as data sources. We selected randomized trials, observational studies, and case reports (English language only) that evaluated the efficacy and toxicity of hydroxyurea in children with sickle cell disease. Two reviewers abstracted data sequentially on study design, patient characteristics, and outcomes and assessed study quality independently. RESULTS. We included 26 articles describing 1 randomized, controlled trial, 22 observational studies (11 with overlapping participants), and 3 case reports. Almost all study participants had sickle cell anemia. Fetal hemoglobin levels increased from 5%–10% to 15%–20% on hydroxyurea. Hemoglobin concentration increased modestly (∼1 g/L) but significantly across studies. The rate of hospitalization decreased in the single randomized, controlled trial and 5 observational studies by 56% to 87%, whereas the frequency of pain crisis decreased in 3 of 4 pediatric studies. New and recurrent neurologic events were decreased in 3 observational studies of hydroxyurea compared with historical controls. Common adverse events were reversible mild-to-moderate neutropenia, mild thrombocytopenia, severe anemia, rash or nail changes (10%), and headache (5%). Severe adverse events were rare and not clearly attributable to hydroxyurea. CONCLUSIONS. Hydroxyurea reduces hospitalization and increases total and fetal hemoglobin levels in children with severe sickle cell anemia. There was inadequate evidence to assess the efficacy of hydroxyurea in other groups. The small number of children in long-term studies limits conclusions about late toxicities.

Acute Changes in N-Terminal Pro-B-Type Natriuretic Peptide During Hospitalization and Risk of Readmission and Mortality in Patients With Heart Failure

The level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of adverse events in patients with heart failure. We examined the relation between acute changes in NT-proBNP during a single hospitalization and subsequent mortality and readmission. The data from a cohort of 241 consecutive patients aged ≥ 25 years who had been admitted to an urban tertiary care hospital with a primary diagnosis of heart failure were analyzed. Creatinine and NT-proBNP were measured at admission and at discharge of the first admission. The patient demographics, co-morbidities, and length of stay were collected. The patients were prospectively grouped into 2 categories according to the acute changes in NT-proBNP: a decrease of ≥ 50% or <50% from admission to discharge. The primary composite outcome was readmission or death within 1 year of the first hospital admission. The unadjusted hazard ratio of readmission/death was 1.40 (95% confidence interval 0.97 to 2.01; p = 0.07) for those with a < 50% decrease in NT-proBNP compared to their counterparts with a ≥ 50% decrease. After adjustment for age, gender, race, and admission creatinine and NT-proBNP, the risk of readmission/death was 57% greater for those with a < 50% decrease (hazard ratio 1.57, 95% confidence interval 1.08 to 2.28; p = 0.02). An adjustment for co-morbidity, length of stay, and left ventricular ejection fraction did not significantly change this relation. Reductions in NT-proBNP of < 50% during an acute hospitalization for heart failure might be associated with an increased hazard of readmission/death, independent of age, gender, race, creatinine, admission NT-proBNP, co-morbidities, left ventricular ejection fraction, and length of stay. In conclusion, patients with a < 50% reduction in NT-proBNP might benefit from more intensive medical treatment, monitoring, and follow-up.

Usefulness of Cystatin C and Prognosis Following Admission for Acute Heart Failure

Cystatin C is a novel marker of renal function that has been found to predict adverse cardiovascular outcomes in ambulatory patients. The aim of this study was to investigate whether this biomarker predicts the length of hospitalization and adverse outcomes in patients hospitalized for heart failure. Two hundred forty consecutive patients aged > or =25 admitted to Johns Hopkins Hospital with exacerbations of heart failure were prospectively enrolled. Cystatin C levels were measured on admission. Patients were followed for 1 year. The primary outcome measure was the length of hospitalization. Secondary outcomes included all-cause mortality and readmission for heart failure. Cystatin C showed no significant association with the length of hospitalization. Patients in the highest quartile (quartile 4) of cystatin C level were at increased risk for death (hazard ratio 2.07 for quartile 4 vs quartiles 1 to 3, p = 0.01) and death or rehospitalization (hazard ratio 1.61 for quartile 4 vs quartiles 1 to 3, p = 0.01). The association between cystatin C and the combined end point of death or rehospitalization during 1-year follow-up remained significant after adjusting for age, race, gender, co-morbidities, and creatinine. Cystatin C was more predictive of these end points than creatinine, and the combination of cystatin C and creatinine was more predictive than either variable alone. In conclusion, cystatin C may be useful in addition to creatinine for predicting outcomes after admission for acute heart failure exacerbations.

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL+ leukemia cells

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

North Central Cancer Treatment Group N10C2 (Alliance): a double-blind placebo-controlled study of magnesium supplements to reduce menopausal hot flashes.

ObjectiveHot flashes are a common symptom in breast cancer survivors that can negatively impact quality of life. Preliminary data suggested that magnesium might be used as an effective low-cost treatment of hot flashes with minimal adverse effects. MethodsA four-arm, double-blind, placebo-controlled, randomized trial was conducted. Postmenopausal women with a history of breast cancer and bothersome hot flashes were randomized into treatment groups of magnesium oxide 800 or 1,200 mg daily or corresponding placebo groups at a 2:2:(1:1) ratio. Hot flash frequency and hot flash score (number × mean severity) were measured using a validated hot flash diary. A 1-week baseline period preceded initiation of study medication. The primary endpoint was intrapatient difference in mean hot flash score between baseline and treatment periods, comparing each magnesium group with the combined placebo groups using a gatekeeping procedure. Results were analyzed using repeated-measures and growth curve models on weekly hot flash scores based on a modified intent-to-treat principle. ResultsTwo hundred eighty-nine women enrolled between December 2011 and March 2013. Study groups were well balanced for baseline characteristics. Mean hot flash scores, mean hot flash frequencies, and associated changes during the treatment period were similar for each group. An increased incidence of diarrhea and a corresponding lower incidence of constipation were reported in magnesium arms compared with placebo. No statistically significant difference in other toxicities or quality-of-life measures was observed. ConclusionsThe results of this trial do not support the use of magnesium oxide for hot flashes.

Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy

Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (−78%) and perivascular epithelioid tumor (−54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma.

Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer

Background Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma. Methods A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles. Results The trial was discontinued prior to reaching the planned accrual due to an FDA hold on pacritinib and a lack of treatment benefit. Eleven patients were enrolled and seven were evaluated for response. Median baseline C-reactive protein level was 12.1 (2.1-147) mg/L. One patient had stable disease at eight weeks by RECIST criteria and six progressed. There were no grade 4 or 5 adverse events while patients were on study. The grade 2 and lower AE events experienced were consistent with prior pacritinib trials. Conclusions In seven evaluable patients there were no objective responses. The trial was discontinued prior to completing planned accrual based on a low likelihood that the progression free survival goal of 4 months would be met.

Progress in PD-1–based Immunotherapy: New Mechanistic Insight May Provide Expanded Hope for Application to Colon and Gastrointestinal Cancers

Marcia Cruz-Correa, Section Editor David Schwartz, Section Editor 65 66 STAFF OF CONTRIBUTORS 67 68 69 70 71 72 73 74 75 Joseph Anderson, White River Junction, VT Johanna L. Chan, Houston, TX Matthew A. Ciorba, St. Louis, MO Massimo Colombo, Milan, Italy Gregory A. Cote, Charleston, SC Evan S. Dellon, Chapel Hill, NC Alex Ford, Leeds, United Kingdom Lauren B. Gerson, San Francisco, CA David S. Goldberg, Philadelphia, PA Samir Gupta, San Diego, CA

Comprehensive Genomic Profiling of Hodgkin Lymphoma Reveals Recurrently Mutated Genes and Increased Mutation Burden

A better understanding of the underlying disease biology that leads to improvement in treatment outcomes is needed. Investigation of the genomic landscape of Hodgkin lymphoma has been difficult because of the low tumor content in these inflammatory cell‐ and stroma‐rich tissue samples. A comprehensive genomic profiling with targeted next‐generation sequencing panel was performed to test for genomic aberrations in archival tumor samples from patients with Hodgkin lymphoma to identify potentially actionable molecular targets.

Abstract CT405: A phase 1 study of neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel, followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in locally advanced pancreatic cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: A third of pancreatic tumors initially deemed borderline or unresectable at diagnosis are ultimately able to undergo resection after neoadjuvant therapy. Survival rates improve significantly when curative resection with negative margins is achieved. Gemcitabine-based chemoradiation following combination chemotherapy is a common neoadjuvant regimen. Combination of gemcitabine and nab-paclitaxel is shown to be beneficial in metastatic disease, and is undergoing evaluation for use in neoadjuvant setting. Sorafenib is shown to reduce activation of c-kit, ERK, and VEGFR2 while gemcitabine inhibits Akt phosphorylation, leading to the synergistic inhibition of cell proliferation and the induction of apoptosis. Vorinostat has also been shown to sensitize pancreatic cancer cell lines to gemcitabine by enhancing the pro-apoptotic actions of gemcitabine, as evidenced by increased levels of the cleaved form of PARP and caspase 3 activities. Sorafenib and vorinostat kill carcinoma cells synergistically by activating CD95. Vorinostat appears to enhance tyrosine-phosphorylation of CD95 in a Src-dependent fashion, which also increases PDGFRβ inhibition by sorafenib. The combination also potently radiosensitizes pancreatic cancer cells in vivo by inducing cytosolic calcium, increasing reactive oxygen species and promoting CD95 activation. Full-dose radiation therapy with both agents has not been investigated in the clinical setting to date, and this represents a novel treatment modality appropriate for phase 1 study in a disease with limited treatment options. Methods: This is a phase 1 study using a traditional 3+3 dose-escalation design for the treatment combination dose escalation to determine appropriate phase 2 doses of sorafenib, vorinostat, and gemcitabine with radiation. Patients are treated with two cycles of combination chemotherapy with gemcitabine and nab-paclitaxel initially, followed by chemoradiation with the investigational agents with 50.4Gy of radiation. Patients will have locally advanced, non-metastatic pancreatic cancer with borderline resectable, unresectable, or node-positive disease, with ECOG performance status of 0 or 1, and preserved hepatic and endocrine pancreatic function with adequate bone marrow reserve by laboratory values. Patients who had prior radiation therapy, known intolerance to the agents, or other significant comorbidities such as poor cardiac function and prolonged QT interval are excluded. In correlative portion of the study, peripheral blood will be analyzed for circulating tumor cells, CD95 surface density and the degree of HDAC inhibition. Pretreatment biopsies obtained for diagnosis will be evaluated for CD95 expression, stromal density along with MCL1, SPARC, and PDGFR expression in tumor and desmoplastic stroma. Citation Format: Haeseong Park, Andrew Poklepovic. A phase 1 study of neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel, followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in locally advanced pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT405. doi:10.1158/1538-7445.AM2014-CT405