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Summary The computational aspects of the problem in this paper involve, firstly, selective mapping of methylated DNA clones according to methylation level and, secondly, extracting motif information from all the mapped elements in the absence of prior probability distribution. Our novel implementation of algorithms to map and maximize expectation in this setting has generated data that appear to be distinct for each lymphoma subtype examined. A “clone” represents a polymerase chain reaction (PCR) product (on average ~500 bp) which belongs to a microarray of 8544 such sequences preserving CpG-rich islands (CGIs) [ 1 ]. Accumulating evidence indicates that cancers including lymphomas demonstrate hypermethylation of CGIs “silencing” an increasing number of tumor suppressor (TS) genes which can lead to tumorigenesis. Availability Algorithms are available on request from the authors Contact papageorgioc@health.missouri.edu Supplementary Information available on page 453.

The aim of this phase 2 study was to evaluate the safety and efficacy of ixabepilone plus cetuximab in patients with advanced pancreatic cancer.Eligible patients had advanced pancreatic adenocarcinoma that was metastatic or not amenable to resection, a Karnofsky performance status ≥70%, and no prior therapy for advanced disease. Patients received ixabepilone 32 mg/m(2) (3-hour IV infusion) every 3 weeks and cetuximab 250 mg/m(2) (1-hour IV infusion) weekly. The primary efficacy end point was the 6-month survival rate. Secondary end points included tumor response rate, overall survival, progression-free survival, and tolerability.A total of 54 patients were enrolled on this study. The 6-month survival rate was 57% (31/54: 95% CI: 43-71%) with a median overall survival of 7.6 months (95% CI: 5.5-12.2 months). Patients who developed acneiform rash (n = 36) had a median survival of 8.8 months, compared with 2.6 months for those without rash (n = 18). Of 31 patients with measurable disease (defined as response-evaluable), 4 had confirmed partial responses and an additional 24 had stable disease. The combination was generally well-tolerated with the most common grade 3/4 hematological toxicities being leucopenia (39%) and neutropenia (33%). The most common grade 3/4 nonhematologic toxicity was fatigue (17%).The combination of ixabepilone and cetuximab was active and had acceptable toxicity. The efficacy results are similar to single-agent ixabepilone and gemcitabine-based combination therapies in patients with advanced pancreatic cancer. Exploratory analyses suggest a trend toward improved survival for patients who experienced rash.

Background and Objective: Circulating tumor cells have been shown to correlate positively with metastatic disease state in patients with advanced cancer. We have demonstrated the ability to detect melanoma cells in a flow system by generating and detecting photoacoustic waves inmelanomacells.Thismethodissimilartoflowcytometry, although using photoacoustics rather than fluorescence. Previously, we used piezoelectric films as our acoustic sensors. However, such films have indicated false-positive signals due to unwanted direct interactions between photons from the high laser fluence in the flow system and the film itself. We have adapted an optical detection scheme that obviates the need for piezoelectric films. Study Design/Materials and Methods: Our photoacoustic system comprised a tunable laser system with an output of 410‐710nm with a pulse duration of 5nanoseconds. The light was delivered by optical fiber to a glass microcuvette that contained saline buffer suspensions of melanoma and white blood cells. We used a continuous HeNe laser to provide a probe beam that reflected off of a glass and water interface in close proximity to the microcuvette. The beam was detected by a high-speed photodiode. When a photoacoustic wave was generated in the microcuvette, the wave propagated and changed the reflectance of the beam due to index of refraction change in the water. This perturbation was used to detect the presence of melanoma cells. Results: We determined a detection threshold of about one individual melanoma cell with no pyroelectric noise indicated in the signals. Conclusions: The optical reflectance method provides sensitivity to detect small numbers of melanoma cells without created false-positive signals from pyroelectric interference, showing promise as a means to perform tests for circulating melanoma cells in blood samples. Lasers Surg. Med. 42:274‐281, 2010. ! 2010 Wiley-Liss, Inc.

Melanoma is the deadliest form of skin cancer and has the fastest growth rate of all cancer types. Proper staging of melanoma is required for clinical management. One method of staging melanoma is performed by taking a sentinel node biopsy, in which the first node in the lymphatic drainage path of the primary lesion is removed and tested for the presence of melanoma cells. Current standard of care typically involves taking fewer than ten histologic sections of the node out of the hundreds of possible sections available in the tissue. We have developed a photoacoustic method that probes the entire intact node. We acquired a lymph node from a healthy canine subject. We cultured a malignant human melanoma cell line HS 936. Approximately 1×106 cells were separated and injected into the lymph node. We also had a healthy lymph node in which no melanoma cells were implanted. We used a tunable laser system set at 532 nm to irradiate the lymph nodes. Three piezoelectric acoustic detectors were positioned near the lymph node to detect photoacoustic pulses generated within the lymph nodes. We also acquired lymph nodes from pigs and repeated the experiments with increased amplification and improved sensors. We detected photoacoustic responses from a lymph node with as few as 500 melanoma cells injected into the tissue, while normal lymph nodes showed no response. Photoacoustic generation can be used to detect melanoma micrometastasis in sentinel lymph nodes. This detection can be used to guide further histologic study of the node, increasing the accuracy of the sentinel lymph node biopsy.

Clinical and experimental work supports the view that the epidermal growth factor receptor (EGFR) is a relevant target for cancer therapy. Expression of EGFR is exaggerated in pancreatic adenocarcinoma and activation of EGFR appears to have an important role in the growth and differentiation of this and other types of cancers. EGFR-targeted therapeutic approaches have shown clinical activity in advanced human cancers for which chemotherapy over the last 30 years has sustained a mere palliative role at best. Therefore, the need remains for novel anti-cancer therapies that effectively and specifically target epithelial tumor cells while minimizing the toxic side-effects commonly associated with cytotoxic conventional therapies. Agents capable of inhibiting EGFR activity with resultant inhibition of cell proliferation and angiogenesis have significant potential as chemotherapeutic agents for the treatment of pancreatic adenocarcinomas as well as multiple other malignancies.

The tumor suppressor protein p53 is a transcription factor that is frequently mutated in human cancers. In response to DNA damage, unmutated or wild-type (wt) p53 protein is stabilized and activated by post-transcriptional modifications that enable it to induce either apoptosis or cell cycle arrest. Using a yeast p53-dissociator assay, we identified MAGED2 as a potential negative regulator of wt p53 activity. Subsequently, using co-immunoprecipitation and reporter gene assays in human cultured cells that are often adopted for functional analysis of p53 we demonstrated that MAGED2 interacted physically with p53 and modified its activity. Finally, we were able to illustrate expression of both p53 and MAGED2 within the same subcellular compartment, i.e. either nucleus or cytoplasm, in 2,682 human cancer tissue specimens using a common cancer tissue microarray and antibodies against MAGED2 and p53. The present results implicate MAGED2, a novel protein, as a p53-dissociator.

The high level of interpatient variation in response to chemotherapy and the lack of objective tools to select chemotherapy regimens for a given tumor type have created a clinical problem. A possible solution may be pharmacogenetics: the study of inherited DNA polymorphisms that influence drug disposition and effects in order to individualize drug treatment. Because unpredictable efficacy and high levels of systemic toxicity are common in cancer chemotherapy, pharmacogenetics is particularly appealing to oncologists. Polymorphisms in drug metabolism, drug transport, drug target, and DNA repair genes have been implicated interpatient variability in response to many chemotherapy agents. This review will discuss recent clinically relevant examples of cancer pharmacogenetics and how genetic differences are helping to shape the future of individualized cancer chemotherapy.

Although an increased risk of hematologic malignancies in children with Neurofibromatosis-1 (NF-1) is well established, whether adults with NF-1 have an increased risk of such malignancies is unclear. We currently describe two adult patients with NF-1 who rapidly developed secondary myelodysplastic syndromes with abnormalities of chromosome 7 following chemotherapy for AML. We propose that adults with NF-1 also have abnormalities of hematologic progenitor cells.