Scott V. Smith

Telephone support to improve antiretroviral medication adherence: a multisite, randomized controlled trial.

Objective:To determine whether proactive telephone support improves adherence to antiretroviral therapy (ART) and clinical outcomes when compared to standard care. Methods:A multisite, randomized controlled trial (RCT) was conducted with 109 ART-naive subjects coenrolled in AIDS Clinical Trials Group (ACTG) 384. Subjects received standard clinic-based patient education (SC) or SC plus structured proactive telephone calls. The customized calls were conducted from a central site over 16 weeks by trained registered nurses. Outcome measures (collected over 64 weeks) included an ACTG adherence questionnaire and 384 study endpoints. Results:For the primary endpoint, self-reported adherence, a significantly better overall treatment effect was observed in the telephone group (P = 0.023). In a post hoc analysis, composite adherence scores, taken as the first 2 factor scores from a principal components analysis, also found significant intervention benefit (P = 0.023 and 0.019 respectively). For the 384 primary study endpoint, time to regimen failure, the Kaplan-Meier survival curve for the telephone group remained above the SC group at weeks 20 to 64; a Cox proportional hazard model that controlled for baseline RNA stratification, CD4, gender, age, race/ethnicity, and randomized ART treatment arm suggested the telephone group tended to have a lower risk for failure (hazard ratio = 0.68; 95% confidence interval: 0.38 to 1.23). Conclusions:Findings indicate that customized, proactive telephone calls have good potential to improve long-term adherence behavior and clinical outcomes.

Follicular Lymphoma With a Burkitt Translocation—Predictor of an Aggressive Clinical Course: A Case Report and Review of the Literature

Follicular lymphoma is an indolent lymphoma characterized by the (14;18) translocation, which leads to aberrant expression of Bcl-2. Translocations involving 8q24 are most commonly associated with Burkitt lymphoma and result in c-Myc overexpression. We report a case of follicular lymphoma of predominant small cleaved-cell type (grade 1) associated with both a t(14;18)(q32;q21) and a t(8;22)(q24;q11). The 8q24 translocation predicted an aggressive clinical course, as the lymphoma transformed into acute lymphoblastic leukemia within a year of initial diagnosis. Routine cytogenetic analysis is recommended at initial diagnosis of follicular lymphoma to better identify abnormalities that may predict prognosis and influence therapy.

PTEN deficiency mediates a reciprocal response to IGFI and mTOR inhibition.

Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies. Implications: PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials. Mol Cancer Res; 12(11); 1610–20. ©2014 AACR.

The Autopsy in Pediatrics and Pediatric Oncology: A Single-Institution Experience

Autopsy rates and clinicopathologic correlations for pediatric autopsies and the subgroup of pediatric oncology autopsies in a large teaching hospital were studied to evaluate the utility of autopsy in these populations. Autopsy records of the University of North Carolina hospitals from 1982 to 2001 were reviewed for all patients less than 18 years of age. Autopsies performed during 1982 to 1991 (decade 1) were compared to those from 1992 to 2001 (decade 2) with respect to absolute numbers of autopsy and rates of unexpected postmortem diagnoses. Postmortem diagnostic discrepancies were subclassified into major and minor categories. The mean number of autopsies per year for decade 1 was 110 ± 24.5, compared with 77.5 ± 40.9 for decade 2 (P < 0.001), a change largely due to a decline in fetal/perinatal (patients < 7 days of age) autopsies. Of 533 pediatric autopsies, 43 were in patients with a primary diagnosis of a neoplasia. At least one antemortem misdiagnosis and/or clinically occult process was identified in 20.5% of all pediatric autopsy cases, and in 25.6% of pediatric oncology cases. These rates did not change significantly over time. In 10 of 43 pediatric oncology cases (23.3%), autopsies provided diagnostic information that was previously unknown to the clinicians. Three of these patients died shortly after presentation. Although autopsy rates for fetal/perinatal cases have declined, those for nonperinatal and pediatric oncology patients remain stable. Autopsy continues to provide diagnostic information that is unknown during the antemortem period, and remains a valuable tool for pediatricians and pediatric oncologists.

Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m2 intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75–100 mcg/ml. Tem was started at an initial dose of 60 mg/m2/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m2/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug–drug interactions will be important in future multiagent trials including Tem.

Characterization of a new hereditary thrombopathy in a closed colony of Wistar rats

A new hereditary thrombopathy has been identified in a closed colony of Wistar rats. A simple and reproducible cuticle bleeding time test was developed as a rapid screening procedure for the bleeding diathesis. Affected animals exhibit markedly prolonged bleeding times and complete absence of platelet aggregation either with adenosine diphosphate (ADP) or with thrombin. Inheritance data suggest an autosomal dominant inheritance pattern with variable penetrance. Coagulation tests, platelet counts, plasma von Willebrand factor (vWF) activity, and clot retraction are within normal limits in thrombopathic animals. GPIb-dependent botrocetin-induced platelet agglutination was present in washed thrombopathic rat platelets. No discernible abnormality of intraplatelet organelles or granules was seen by transmission electron microscopy of thrombopathic platelets. A qualitative morphologic assessment of intraplatelet fibrinogen in thrombopathic rat platelets showed no discernible difference as compared with control rat platelets. Thrombopathic rat platelets exhibit decreased glycoprotein IIb/IIIa (GPIIb/IIIa) antigen by flow cytometric analysis and markedly decreased iodine 125-labeled fibrinogen binding to platelet GPIIb/IIIa after ADP activation. This rat colony demonstrates a unique thrombopathy, distinct from previously described animal thrombopathies, with some characteristics of variant Glanzmanns thrombasthenia. This animal model may provide further insight into the regulatory mechanisms and pathophysiology of platelet GPIIb/IIIa.

The Hypermetabolic Giant: 18F-FDG avid Giant Cell Tumor identified on PET-CT

An 87 year-old white female presented with a two-year history of intermittent discomfort in her left foot. PET-CT identified intense18F-fluorodeoxyglucose (FDG) uptake corresponding to the lesion. Histology of a fine needle aspiration and open biopsy were consistent with a benign giant cell tumor (GCT) of the bone. GCT of bone is an uncommon primary tumor typically presenting as a benign solitary lesion that arises in the end of the long bones. While GCT can occur throughout the axial and appendicular skeleton, it is exceedingly uncommon in the bone of the foot. While 18F-FDG has been established in detecting several malignant bone tumors, benign disease processes may also be identified. The degree of 18F-FDG activity in a benign GCT may be of an intensity that can be mistakenly interpreted as a malignant lesion. Therefore, GCT of the bone can be included in the differential diagnosis of an intensely 18F-FDG-avid neoplasm located within the tarsal bones.

Sclerosing mesenteritis successfully treated with a TNF antagonist.

A 29-year-old female presented with intermittent nausea, vomiting, fevers, abdominal pain and fatigue. CT scans of the abdomen revealed inflammatory changes within the mesentery and small bowel. Histopathology of the mesentery and omentum showed chronic inflammation and fibrosis, supporting a diagnosis of sclerosing mesenteritis. Over the past 2 years, the patient suffered debilitating paroxysmal abdominal pain despite treatment with prednisone, azathioprine, sulfasalazine and narcotics. Additionally, she developed sacroiliitis diagnosed clinically and on radiographs. Intravenous infliximab (5 mg/kg intravenous) was initiated and continued every 6 weeks for 3 years. The patient has since had a dramatic improvement in her back and abdominal symptoms and has tapered off of prednisone, azathioprine and narcotics. Erythrocyte sedimentation rate, anaemia, leukocytosis and radiographic findings improved after initiation with infliximab. In conclusion, the authors report successfully treating sclerosing mesenteritis with sacroiliitis by the addition of infliximab. This may implicate a role for tumour necrosis factor α in disease pathogenesis.

Thymic carcinoma in a child with HIV infection

HIV infection predisposes to cancer during childhood. In addition to the AIDS‐defining non‐Hodgkin lymphoma (NHL) and Kaposi sarcoma, a range of other lymphoid malignancies and solid tumors have been described. We report the first case of an HIV‐positive child with thymic carcinoma in the setting of regressing thymic cysts. The tumor expressed CKIT but failed to respond to imatinab mesylate after a transient response to multiagent chemotherapy. This case extends the spectrum of pediatric malignancy in the setting of HIV and suggests that patients with presumed benign thymic cysts require ongoing surveillance. Pediatr Blood Cancer 2007;49:1004–1007.

Inconsistency in classifying vascular anomalies: What's in a name?

Vascular anomalies are a heterogeneous group of disorders seen in children and adults. A standard nomenclature for classification has been offered by the International Society for the Study of Vascular Anomalies. Its application is important for communication among the multiple specialties involved in the care of patients and for planning treatment, as well as for research and billing. We hypothesized that terminology still is not uniformly applied, and that this could have an impact on treatment.