Molecular characteristics of a pancreatic adenocarcinoma associated with Shwachman-Diamond syndrome.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is characterized by hypoplasia of the bone marrow and exocrine pancreas and a high risk of leukemia. It is unknown whether solid tumors are part of the disease phenotype. PROCEDURE: We performed copy number alterations using Affymetrix human SNP 6.0 array. Furthermore, we did direct sequencing of pancreatic cancer-related genes and immunohistochemical expression of selective proteins. RESULTS: Among 41 patients with SDS who enrolled on the registry, we identified one male patient with a solid tumor: moderately differentiated pancreatic ductal adenocarcinoma. The tumor harbored 41 copy number alterations (CNAs) and had no regions of loss of heterozygosity (LOH). None of these CNAs were exclusive to the tumor. One copy of the tumor suppressor genes CTNNA3 and LGALS9C was lost in both the peripheral blood and tumor. Direct sequencing of TP53, KRAS, and NRAS revealed no mutations. Immunohistochemical staining for cyclin D1, E-cadherin, p53 MLH1 and MSH2 and ß-catenin, was similar to that seen in non-hereditary pancreatic cancer. CONCLUSIONS: Our case raises the possibility that solid tumors are associated with SDS, thereby broadening the clinical phenotype of the disease. The relatively young age at cancer diagnosis and the specific involvement of the pancreas make the possibility of an association with SDS likely. Similar to leukemia in SDS, the pancreatic cancer developed in hypoplastic tissues. This observation and the relative genomic stability of the tumor strengthen the hypothesis of improved adaptation of malignant clones among a population of disadvantaged cells as a mechanism for tumor expansion in SDS.

A systematic review and meta-analysis of anti-pseudomonal penicillins and carbapenems in pediatric febrile neutropenia.

PURPOSE: Carbapenems represent a broad-spectrum alternative to anti-pseudomonal penicillin (APP) combination or single-agent therapy for the management of pediatric febrile neutropenia (FN). Our primary objective was to describe the risk of treatment failure in children treated with an APP or carbapenem as initial empiric treatment for FN. Our secondary objective was to compare outcomes of APP versus carbapenem therapy in this population. METHODS: An electronic search of Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials was performed. We limited studies to prospective pediatric trials of FN in which at least one treatment arm consisted of an APP (with or without an aminoglycoside) or a carbapenem. RESULTS: Of 7,281 articles reviewed, 27 studies comprising 30 treatment regimens were included for meta-analysis. Treatment failure, including antibiotic modification, occurred in 41% (95% confidence interval (CI) 32-50%), 34% (95% CI 27-41%), and 35% (95% CI 24-45%) of patients treated with APP-aminoglycoside, APP monotherapy, and carbapenem monotherapy regimens, respectively. There was no significant difference in treatment failure including antibiotic modification, infection-related mortality, or adverse events when comparing either APP regimen with carbapenem monotherapy. Although a limited number of studies were available, when stratified by FN risk group, no differences were seen in any outcome. CONCLUSIONS: Our meta-analysis suggests that APP-aminoglycoside, APP monotherapy, and carbapenem monotherapy are all efficacious therapeutic options for the empiric management of pediatric FN.

Psychometric properties of the Oral Mucositis Daily Questionnaire for child self-report and importance of mucositis in children treated with chemotherapy.

PURPOSE: The objectives of this study were to examine the psychometric properties of the self-report Oral Mucositis Daily Questionnaire (OMDQ) and to measure the importance of mucositis in children receiving intensive chemotherapy. METHODS: Children ≥ 12 years of age receiving intensive chemotherapy for leukemia/lymphoma or undergoing stem cell transplantation were asked to complete the OMDQ daily for 21 days after chemotherapy. Other measures of mucositis obtained concurrently with OMDQ included the World Health Organization (WHO) mucositis scale, the pain visual analog scale (VAS), and the Functional Assessment of Cancer Therapy Esophageal Cancer Sub-scale (FACT-ECS). The importance of mucositis was estimated using a VAS, time trade-off technique, and willingness to pay to avoid mucositis. RESULTS: Fifteen children participated. Test-retest reliability demonstrated at least moderate correlation for all questions within the OMDQ. Assessment of construct validity of the OMDQ revealed at least moderate correlation with WHO, VAS, and FACT-ECS for questions regarding pain, swallowing, drinking, and eating. Effect on sleeping and talking had lower correlations than that expected a priori. The diarrhea question of the OMDQ did not correlate with other measures of mucositis. Severe mucositis is important to children, while mild mucositis is less important to them. Children were willing to pay moderate amounts of money to prevent mucositis. CONCLUSIONS: The OMDQ exhibits test-retest reliability, and most questions show construct validity with the exceptions of the sleep, talking, and diarrhea questions. Therefore, the OMDQ should not be used unmodified as a self-report instrument in children with cancer. Severe mucositis is of importance to these children.

Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial.

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7-45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.

A Review of Management of Clostridium difficile Infection: Primary and Recurrence.

Clostridium difficile infection (CDI) is a potentially fatal illness, especially in the elderly and hospitalized individuals. The recurrence and rates of CDI are increasing. In addition, some cases of CDI are refractory to the currently available antibiotics. The search for improved modalities for the management of primary and recurrent CDI is underway. This review discusses the current antibiotics, fecal microbiota transplantation (FMT) and other options such as immunotherapy and administration of non-toxigenic Clostridium difficile (CD) for the management of both primary and recurrent CDI.

Evolution of clinical trial design in early drug development: systematic review of expansion cohort use in single-agent phase I cancer trials.

PURPOSE: To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. METHODS: We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. RESULTS: We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. CONCLUSION: The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.

A meta-analysis of antipseudomonal penicillins and cephalosporins in pediatric patients with fever and neutropenia.

BACKGROUND: Antipseudomonal penicillins (APP) and antipseudomonal cephalosporins (APC) play important roles in the management of pediatric patients with fever and neutropenia (FN). Our primary objective was to describe the risk of treatment failure in children treated with an APP or APC as initial empiric therapy for FN. Our secondary objectives were to compare APP with APC and third- with fourth-generation APC as initial empiric therapy in this population. METHODS: We performed electronic searches of Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials, limiting studies to prospective pediatric trials in FN in which at least 1 treatment arm consisted of an APP or APC antibiotic with or without an aminoglycoside. Data abstraction was conducted by 2 independent reviewers. RESULTS: From 7281 reviewed articles, 41 studies comprising 51 treatment regimens were included in the meta-analysis. Treatment failure, including antibiotic modification, occurred in 34% and 41% of patients treated with APP and APC monotherapy, respectively, and 41% and 33% of patients treated with APP- and APC-aminoglycoside combination therapy, respectively. There were no statistically significant differences in treatment failure including modification, mortality, or adverse events when comparing APP with APC monotherapy, APP with APC combination therapy, or third- with fourth-generation APC therapy. CONCLUSIONS: Our meta-analysis suggests that APP and APC monotherapy, as well as combination therapy with an aminoglycoside, are efficacious and safe therapeutic options for the empiric management of pediatric patients with FN. Specific antibiotic selection should be based on other important factors, such as cost, availability, and local epidemiologic and resistance patterns.

Fluoroquinolones in children with fever and neutropenia: a systematic review of prospective trials.

BACKGROUND: There has been reluctance to use fluoroquinolones in children because of arthropathy in animal models; experience in pediatric fever and neutropenia (FN) has been limited. Our primary objective was to describe the effectiveness and safety of fluoroquinolones as empiric therapy for children with FN. METHODS: We conducted electronic searches of Ovid Medline, EMBASE, the Cochrane Central Register of Controlled Trials, and limited studies to prospective pediatric trials in which any type of fluoroquinolone was administered as empiric therapy for FN. RESULTS: Of the 7281 reviewed articles, 10 were included in the meta-analysis that encompassed 740 episodes of FN. All studies consisted of low-risk FN episodes. The risk of treatment failure was 17% among those given ciprofloxacin monotherapy (n = 5 studies), 17% among those given nonciprofloxacin fluoroquinolone monotherapy (n = 2 studies), and 24% among those given fluoroquinolone combination therapy (n = 3 studies; P = 0.80). There were no cases of infectious deaths reported. Rates of sepsis and adverse events were very low. CONCLUSION: Experience with fluoroquinolones demonstrates excellent outcomes and short-term safety, although reported studies have been restricted to low-risk patients. Fluoroquinolones can be comfortably adopted for low-risk FN, although experience in high-risk FN is uncertain in pediatrics.