ABSTRACT We report one patient with cardiofaciocutaneous (CFC) syndrome. He presented with clinical findings characteristic of this condition such as: cutaneous abnormalities, including ichthyosis, widespread keratosis pilaris, a peculiar craniofacial appearance with sparse, curly hair and low‐set posteriorly rotated ears; congenital heart defects; and mild mental and motor retardation. We submit a comprehensive review of previously published articles regarding the dermatological findings in CFC syndrome (recently shown to be a variant of Noonan syndrome) emphasizing diagnostic criteria and its differentiation from the Costello syndrome.
Abstract Background. Small-cell lung cancer (SCLC) accounts for ∼15% of all lung cancers, and is the most aggressive form of lung cancer. Drug resistance to chemotherapeutics is particularly crippling in SCLC as there are limited treatment options. We previously examined gene expression in platinum-resistant SCLC cell lines, and reported aberrant expression of a subset of hedgehog pathway related genes, among which Gli1 was particularly significant. Gli1 is a known transcription factor that is involved with regulation of a number of key genes in cell fate determination and proliferation. In recent years, its role in oncogenesis and cancer progression has been studied. Herein, we test the hypothesis that increased Gli1 expression contributes to cisplatin and etoposide resistance in SCLC. Methods. Two SCLC cell lines, H69 and H526, were transduced with a Gli1 over-expressing (o/e) vector (Kasper et al, 2007) to create two lines expressing the gene: H69-Gli1 and H526-Gli1. Gli1 expression was verified by qRT-PCR. Cellular proliferation was measured over 96 hours. To study the drug dose response, Gli1 o/e and parental lines were treated with single-agent or combination dosing of cisplatin and etoposide (standard first-line SCLC therapy), and cell viability was assessed after 72 hours. Relative Gli1 expression was compared with cisplatin response in four additional SCLC cell lines (H146, H187, H345, H1688). To further understand aberrant cellular signaling in Gli1 o/e cells, gene expression analysis was performed on H69-Gli1 and H69 parental cells (2 replicates) using Agilent 44K expression arrays. Data was normalized and analyzed using Genespring software. Changes greater than 2 fold were considered significant. Results. Compared to parental cells, Gli1 expression was 11 fold and 149 fold higher in H69-Gli1 and H526-Gli1, respectively. Proliferation assays showed no significant differences in parental vs. Gli1 o/e cells. Drug dose response experiments showed at least a 1.5 fold shift in cisplatin resistance in H69-Gli1 compared to H69. The same trend was also observed in combination dosing of cisplatin and etoposide. H526-Gli1 showed no significant change in cisplatin resistance compared to H526. In the four additional SCLC lines a positive trend was observed where increased Gli1 expression correlated with increased cisplatin resistance. Gene expression analysis showed that there are over 1200 genes significantly differentially-expressed in H69-Gli1 cells as compared to parental cells. Conclusions. Gli1 over-expression leads to increased platinum resistance in SCLC cells. We are currently in the process of performing pathway analysis on the gene expression data to study the pathways affected by Gli1 over-expression in H69 cells, leading to increased platinum resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1729. doi:10.1158/1538-7445.AM2011-1729
Tumor responses in advanced basal cell carcinoma (BCC) have been observed in clinical trials with vismodegib, a SMO antagonist. The result of SMO antagonism is inhibition Hedgehog Signaling Pathway (HHSP) downstream target genes. HHSP inhibition has been shown to affect stem cells responsible for blood, mammary, and neural development. We report on our experience of treating two patients with advanced BCC participating. These two patients have had no new BCCs develop for at least 2.25 years. Both patients have been receiving ongoing daily treatment with vismodegib for greater than 2.75 years without experiencing any significant side effects. After prolonged continuous daily dosing with a SMO antagonist, we have not observed a significant alteration in hematologic parameters or physical abnormalities of the pectoral regions of two patients with advanced BCC.
Authorship in biomedical publications is critical for establishing accountability and contribution toward clinical and scientific research. We examined the frequency of discordance in authorship between presentations of clinical trial data at annual meetings of the American Society of Clinical Oncology and the subsequent peer-reviewed publications. We found that more than 70% of subsequent publications had additional authors not originally present on the abstract despite there being no changes in trial accrual or trial design. This pervasive discordance in authorship demonstrates a lack of uniformity and accountability in authorship reporting standards.
2516 Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.
3547 Background: IPI-504 is a water-soluble heat shock protein 90 (Hsp90) inhibitor. IPI-504 causes the degradation of a variety of mutated or amplified oncoproteins, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The combination of IPI-504 and docetaxel demonstrates additive efficacy in murine xenograft models. This Phase 1b trial was undertaken to identify the maximum tolerated dose (MTD) of IPI-504 in combination with docetaxel. Methods: Eligible patients (pts) had advanced solid tumors that were either refractory to available therapies or for which docetaxel alone was an appropriate therapy. Intravenous (IV) 75 mg/m 2 docetaxel was given once every three weeks (q 3- weekly). IPI-504 was administered IV q 3-weekly, with 3 pts per cohort and inter-cohort dose escalation. All pts were evaluated for safety, pharmacokinetics (PK), and tumor response. Results: 16 pts have been enrolled at 3 dose levels of IPI-504 (7 at 300 mg/m 2 , 6 at 450 mg/m 2 , and 3 at 550 mg/m 2 ). 6 pts had non-small cell lung cancer (NSCLC). Median age was 59 yrs (range 33–77). Median number of cycles received was 3 (1–11), with 5 pts currently on study. There have been 4 dose-limiting toxicities (DLTs): 1 at 300 mg/m 2 (Grade 3 febrile neutropenia); 1 at 450 mg/m 2 (Grade 3 fatigue); and 2 at 550 mg/m 2 (Grade 1 asymptomatic sinus bradycardia requiring hospitalization for observation, and Grade 3 elevated AST with Grade 3 acute respiratory distress syndrome). All DLTs resolved on trial. No PK interactions between docetaxel and IPI-504 have been observed. The regimen of IPI-504 450 mg/m 2 with docetaxel 75 mg/m 2 has been identified as the recommended phase 2 dose on a q 3-weekly schedule. Conclusions: In this Phase 1b trial, the MTD of IPI-504 plus docetaxel q 3-weekly was identified. Toxicities were reversible and similar to those seen with docetaxel or IPI-504 alone in this patient population. Given the activity of single-agent IPI-504 against NSCLC and the standard use of docetaxel in that disease, an expanded evaluation of this regimen in pts with previously treated NSCLC is on-going. The combination of IPI-504 and docetaxel on a weekly schedule is also being explored. [Table: see text]
At the age of 83, a woman presented with an extremely rare cancer, basal cell adenocarcinoma (BCAC) of the supraglottic larynx. Pathology revealed a stage IVA tumor, pathological stage T4N0M0. She was treated with surgery and did not receive any adjuvant chemotherapy or radiation therapy. At the age of 93, during a routine examination, the patient was found to have palpable adenopathy and underwent a fine needle aspiration in June 2010. Pathology revealed similar histologic characteristics of her 2001 BCAC diagnosis, and further IHC stains revealed positive estrogen receptor staining.
