Thomas Sroka

The minimum element of a synthetic peptide required to block prostate tumor cell migration

Human prostate tumor cell invasion and metastasis is dependent in part on cell adhesion to extracellular matrix proteins and cell migration. We previously identified a synthetic D-amino acid tumor cell adhesion peptide called HYD1 (kikmviswkg) that supported adhesion of tumor cells derived from breast, prostate, ovary and pancreas tissue. Alanine substitution analysis and a peptide deletion strategy were used to determine the minimal element of HYD1 necessary for bioactivity in a prostate cancer cell line called PC3N. Bioactivity was measured by assays of cell adhesion, migration and ERK signaling. The most potent element of HYD1 necessary to support cell adhesion was kmvixw, the block to migration required xkmviswxx and activation of ERK signaling required ikmviswxx. The shortest sequence active in all three assays was iswkg. The HYD1 peptide contains overlapping elements required for adhesion, blocking migration and the activation of ERK signaling. These linear peptide sequences provide the starting point for development of novel compounds to target cancer cell adhesion and migration.

Impact of image-guided radiotherapy to reduce laryngeal edema following treatment for non-laryngeal and non-hypopharyngeal head and neck cancers

We would like to determine the effectiveness of image-guided radiotherapy (IGRT) to reduce laryngeal edema following treatment for head and neck cancer and to assess patient perception of voice and speech after treatment. We conducted a retrospective review of 44 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers. Endoscopic and/or mirror examinations of the larynx were performed following radiotherapy at each follow-up visit. Laryngeal edema was assessed based on the Radiation Therapy Oncology Group grading scale. Patients were also asked to rate about the voice and speech quality relative to their pre-radiotherapy status. The mean laryngeal dose was 16.3 Gy (range: 11.7-45.5 Gy). At a median follow-up of 14 months (range: 2-31 months), three patients (7%) developed laryngeal edema (one grade 1, two grade 2). The mean laryngeal dose was respectively 20.3 Gy in two patients and 20.7 Gy in the third patient developing laryngeal edema. Except for one patient who continued to smoke and drink after radiotherapy, no patient reported any significant change in voice and speech quality after treatment. IGRT results in low rates and low severity of laryngeal edema following treatment for non-laryngeal and non-hypopharyngeal head and neck cancers and may preserve voice quality.

The potential role of magnetic resonance spectroscopy in image-guided radiotherapy.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique to detect metabolites within the normal and tumoral tissues. The ability of MRS to diagnose areas of high metabolic activity linked to tumor cell proliferation is particularly useful for radiotherapy treatment planning because of better gross tumor volume (GTV) delineation. The GTV may be targeted with higher radiation dose, potentially improving local control without excessive irradiation to the normal adjacent tissues. Prostate cancer and glioblastoma multiforme (GBM) are two tumor models that are associated with a heterogeneous tumor distribution. Preliminary studies suggest that the integration of MRS into radiotherapy planning for these tumors is feasible and safe. Image-guided radiotherapy (IGRT) by virtue of daily tumor imaging and steep dose gradient may allow for tumor dose escalation with the simultaneous integrated boost technique (SIB) and potentially decrease the complications rates in patients with GBM and prostate cancers.

Potential Applications of Image-Guided Radiotherapy for Radiation Dose Escalation in Patients with Early Stage High-Risk Prostate Cancer

Patients with early stage high-risk prostate cancer (prostate specific antigen > 20, Gleason score > 7) are at high risk of recurrence following prostate cancer irradiation. Radiation dose escalation to the prostate may improve biochemical-free survival for these patients. However, high rectal and bladder dose with conventional three-dimensional conformal radiotherapy may lead to excessive gastrointestinal and genitourinary toxicity. Image-guided radiotherapy (IGRT), by virtue of combining the steep dose gradient of intensity-modulated radiotherapy and daily pretreatment imaging, may allow for radiation dose escalation and decreased treatment morbidity. Reduced treatment time is feasible with hypo-fractionated IGRT and it may improve patient quality of life.

Feasibility of Tomotherapy-Based Image-Guided Radiotherapy to Reduce Aspiration Risk in Patients with Non-Laryngeal and Non-Pharyngeal Head and Neck Cancer

Purpose The study aims to assess the feasibility of Tomotherapy-based image-guided radiotherapy (IGRT) to reduce the aspiration risk in patients with non-laryngeal and non-hypopharyngeal cancer. A retrospective review of 48 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers was conducted. All patients had a modified barium swallow (MBS) prior to treatment, which was repeated one month following radiotherapy. Mean middle and inferior pharyngeal dose was recorded and correlated with the MBS results to determine aspiration risk. Results Mean pharyngeal dose was 23.2 Gy for the whole group. Two patients (4.2%) developed trace aspiration following radiotherapy which resolved with swallowing therapy. At a median follow-up of 19 months (1–48 months), all patients were able to resume normal oral feeding without aspiration. Conclusion and Clinical Relevance IGRT may reduce the aspiration risk by decreasing the mean pharyngeal dose in the presence of large cervical lymph nodes. Further prospective studies with IGRT should be performed in patients with non-laryngeal and non-hypopharyngeal head and neck cancers to verify this hypothesis.

Effectiveness of radiotherapy for elderly patients with non‐melanoma skin cancer of the head

To assess the effectiveness of conventionally fractionated radiotherapy for local control and cosmesis in elderly patients (age 70 years or older) with non‐melanoma skin cancer of the head.

Feasibility of Tomotherapy-based image-guided radiotherapy for small cell lung cancer

Background: To assess the tolerance of patients with small cell lung cancer undergoing chemoradiation with tomotherapy-based image-guided radiotherapy (IGRT). Materials and Methods: A retrospective review of the toxicity profile for nine patients with small cell lung cancer of the limited stage who underwent chemoradiation delivered with helical tomotherapy (HT) has been conducted. Results: Acute grade 3–4 hematologic and esophagitis toxicities developed in two and three patients respectively. One patient developed a pulmonary embolism during radiotherapy. Seven patients had weight loss ranging from 0 to 30 pounds (median: 4 pounds). Three patients had treatment breaks ranging from 2 to 12 days. At a median follow-up of 11 months (range: 2–24 months), no patients developed any radiation related toxicities such as grade 3–4 pneumonitis or other long-term complications. The median survival was estimated to be 15 months. There were two local recurrences, three mediastinal recurrences, and six distant metastases. Conclusion: Grade 3–4 toxicities remained significant during chemoradiation when radiation was delivered with tomotherapy-based IGRT. However, the absence of grade 3–4 pneumonitis is promising and the use of HT needs to be investigated in future prospective studies.

Feasibility of tomotherapy to reduce cochlea radiation dose in patients with locally advanced nasopharyngeal cancer.

AIMS AND BACKGROUND To evaluate the effectiveness of tomotherapy-based image-guided radiotherapy (IGRT) on the radiation dose to the cochlea in patients with nasopharyngeal cancer. METHODS AND STUDY DESIGN A retrospective review of five patients undergoing concurrent chemoradiation with tomotherapy for locally advanced nasopharyngeal cancer was performed. RESULTS The mean dose to the right and left cochlea was 25 Gy and 35.3 Gy respectively, while the dose to the gross tumor ranged from 70 to 75 Gy. All patients had excellent clinical response to the treatment at a median follow-up of five months. CONCLUSIONS IGRT for head and neck cancer delivered by tomotherapy can significantly decrease the radiation dose to the cochlea without sacrificing target volume coverage.

Feasibility of tomotherapy for postoperative irradiation of lower extremity sarcomas.

Aims and Background To evaluate the effectiveness of helical tomotherapy-based image-guided radiotherapy (IGRT) following surgery for lower extremity sarcoma. Methods and Study Design A retrospective review of three patients undergoing postoperative irradiation with tomotherapy for lower extremity sarcoma was conducted. Planning target volume (PTV) coverage, acute side effects, long-term complications and functional results were assessed. Results Tomotherapy allows adequate coverage of the PTV without an excessive radiation dose to the normal adjacent structures. Radiotherapy side effects were acceptable with no treatment breaks. All patients were disease free with no complications and no impairment of their daily activity at the last follow-up. Conclusion IGRT delivered by tomotherapy may be ideally suited for sarcoma of the extremities because of its ability to achieve a high radiation dose along with excellent normal tissue sparing. Further prospective studies should be conducted to confirm this hypothesis.

Abstract 4345: Inadequate repair of ionizing radiation damage: A consequence of the invasive tumor phenotype

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL A major characteristic of the transition of prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer is the progressive loss of laminin 322 in the basal lamina and loss of A6B4 integrin, a laminin 322 adhesion receptor in the basal cells. Previous work from our group reported that the loss of interaction with laminin 322 decreased the ability of normal prostate cells to respond to DNA damage. The defect was manifested as an alteration of an ionizing radiation (IR) induced G2 progression block. In this study, the goal was to determine if an invasive phenotype of human tumor cells, expressing A6B1 integrin, a laminin 511 adhesion receptor, influenced a DNA damage response (DDR) to IR. DU145 tumor cells were grown on laminin 511 and DDR was determined under conditions of stimulated invasion via HGF. The DDR endpoint chosen was the production, resolution and persistence of nuclear H2AX phosphorylation foci as an indicator of damage, repair and inadequate repair, respectively. Similar to a recent report, we observed a fast and transient phosphorylation of H2AX in response to IR within the basal cells of the normal human prostate epithelium that was both dose and time dependent. Utilizing tissue culture conditions, we determined that under optimal growth conditions on laminin 511 there was a dose and time response of H2AX phosphorylation in response to IR treatment. Under conditions of HGF stimulation, the persistence of H2AX foci 24 hours after IR was two to four fold higher as compared to unstimulated cells. The amplified persistence of H2AX foci was observed at 1, 2, 4, 6 and 8 Gy at both 24 and 36 hours after IR treatment. Current studies are determining if the inadequate repair response to IR under conditions of stimulated invasion results in an increased tumor cell killing or an increased genomic instability of surviving tumor cells. (Supported in part by NIH Cancer Center Core Grant CA 23074 and DOD grant W81XWH-10-1-0496) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4345. doi:1538-7445.AM2012-4345