Kent Armeson

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

Using Endobronchial Ultrasound Features to Predict Lymph Node Metastasis in Patients With Lung Cancer

PURPOSES Reliable staging of the mediastinum determines TNM classification and directs therapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate predictors of mediastinal lymph node metastasis in patients undergoing endobronchial ultrasound (EBUS). METHODS Patients with known or suspected lung cancer undergoing EBUS for staging were included. Lymph node radiographic characteristics on chest CT/PET scan and ultrasound characteristics of size, shape, border, echogenicity, and number were correlated with rapid on-site evaluation (ROSE) and final pathology. Logistic regression (estimated with generalized estimating equations to account for correlation across nodes within patients) was used with cancer (vs normal pathology) as the outcome. ORs compare risks across groups, and testing was performed with two-sided α of 0.05. RESULTS Two hundred twenty-seven distinct lymph nodes (22.5% positive for malignancy) were evaluated in 100 patients. Lymph node size, by CT scan and EBUS measurements, and round and oval shape were predictive of mediastinal metastasis. Increasing size of lymph nodes on EBUS was associated with increasing malignancy risk (P = .0002). When adjusted for CT scan size, hypermetabolic lymph nodes on PET scan did not predict malignancy. Echogenicity and border contour on EBUS and site of biopsy were not significantly associated with cancer. In 94.8% of lymph nodes with a clear diagnosis, the ROSE of the first pass correlated with subsequent passes. CONCLUSIONS Lymph node size on CT scan and EBUS and round or oval shape by EBUS are predictors of malignancy, but no single characteristic can exclude a visualized lymph node from biopsy. Further, increasing the number of samples taken is unlikely to significantly improve sensitivity.

Acid ceramidase‐mediated production of sphingosine 1‐phosphate promotes prostate cancer invasion through upregulation of cathepsin B

Invasiveness is one of the key features of aggressive prostate cancer; however, our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype through downstream effectors that have not yet been well characterized. Here, we demonstrate that AC, through generation of sphingosine‐1‐phosphate (S1P), promotes Ets1 nuclear expression and binding to the promoter region of matrix‐degrading protease cathepsin B. Through confocal microscopy and flow cytometry, we found that AC overexpression promotes pericellular localization of cathepsin B and its translocation to the outer leaflet of the cell membrane. AC overexpressing cells have an increased abundance of cathepsin B‐enriched invasive structures and enhanced ability to invade through a collagen matrix, but not in the presence of an inhibitor of cathepsin B. In human prostate tissues, AC and cathepsin B overexpression were strongly associated and may relate to poor outcome. These results demonstrate a novel pathway by which AC, through S1P, promotes an invasive phenotype in prostate cancer by causing overexpression and secretion of cathepsin B through activation and nuclear expression of Ets1. As prostate cancer prognosis is dramatically worse when invasion has occurred, this study provides critical insight into the progression toward lethal prostate cancer.

Cetuximab Therapy for Head and Neck Squamous Cell Carcinoma A Systematic Review of the Data

Objective. To review the current state of the data on the use of cetuximab in head and neck squamous cell carcinoma (HNSCC). Data Sources. The National Center for Biotechnology Information’s PubMed and the Cochrane collection. Review Methods. Search terms included cetuximab and head and neck cancer. These results were reviewed, and a second search was performed using limits: meta-analysis, randomized controlled trial, and clinical trial. Results. The literature search yielded 412 articles. Fifteen were identified for analysis. For patients with recurrent/metastatic disease who received combination chemotherapy in phase I/II trials, the overall response (OR) was 18.7% (95% confidence interval [CI], 10.4%-27.0%). Phase III trial data for combination chemotherapy in recurrent/metastatic disease showed OR to be 17.0% (95% CI, 12.6%-21.4%) for platinum-based regimens and 34.2% (28.6%-39.7%) for platinum-based regimens with cetuximab. For this same group, the estimated aggregate hazard ratio comparing platinum-based therapy plus cetuximab to platinum therapy alone was 1.10 (95% CI, 0.78-1.54), indicating no significant improvement in overall survival in the aggregate analysis. Combination chemoradiation with cetuximab in both phase I/II trials and the single phase III trial shows enhanced responsiveness, but the data are difficult to interpret because it is not used with standard-of-care regimens for advanced-stage disease. Conclusion. Early evidence has shown cetuximab to be effective in the treatment of HNSCC, and it should be used to enhance, but not replace, current treatment paradigms until further phase III data are available.

Plasma Sphingolipids and Lung Cancer: A Population-Based, Nested Case–Control Study

Background: Sphingosine-1-phosphate (S1P) and ceramides are bioactive signaling sphingolipids that regulate pathways that are central to cancer pathogenesis. Methods: A nested case–control study was implemented to test whether prediagnostic circulating concentrations of S1P and ceramides were associated with future lung cancer risk. In the community-based CLUE II cohort study in Washington County, Maryland, the study consisted of 100 incident lung cancer cases, each matched to two cancer-free controls on age, sex, race, and cigarette smoking status. Plasma stored at −70°C at the beginning of follow-up in 1989 was assayed for sphingolipids using liquid chromatography/tandem mass spectrometry methodology (LC/MS-MS). Results: Compared with controls, geometric mean plasma concentrations of S1P and total ceramides were 2.9% (P = 0.10) and 5.1% (P = 0.02), respectively, greater in lung cancer cases. For S1P, the ORs and 95% confidence intervals (CI) for lung cancer risk were 2.7 (1.2–5.9), 2.7 (1.1–6.4), and 1.9 (0.8–4.5) for the second, third, and highest fourth, respectively, compared with the lowest fourth (overall P = 0.006). Compared with those with total ceramide concentrations in the lowest fourth, the ORs (and 95% CI) for lung cancer risk were 1.6 (0.7–3.3), 1.5 (0.7–3.4), and 2.1 (0.9–4.7) for the second, third, and highest fourth, respectively (Ptrend = 0.01). Conclusions: Higher concentrations of S1P and total ceramide in plasma were associated with increased future risk of lung cancer. Impact: These novel findings suggest that perturbation of sphingolipid metabolism and S1P generation may either contribute to the etiology of lung cancer or be a marker of latent lung cancer. Cancer Epidemiol Biomarkers Prev; 22(8); 1374–82. ©2013 AACR.

Cervical esophageal cancer: a population-based study.

The purpose of this study was to present our analysis of outcomes, prognostic factors, and treatment for cervical esophageal carcinoma using the Surveillance, Epidemiology, and End Results (SEER) database.

A Closer Look at Unmet Needs at the End of Primary Treatment for Breast Cancer: A Longitudinal Pilot Study

This study describes the nature of unmet needs (UN) as women with breast cancer transition from “patient” to “survivor.” Data are from a longitudinal study of 90 women with stage I–III breast cancer. Data were collected 2–3 weeks before, and 10 weeks after, completion of radiation. A modified Cancer Survivors’ Unmet Needs (CaSUN) instrument measured UN. Most participants reported ≥1 unmet need at baseline (80.00%) and follow-up (69.31%), with UN across physical, healthcare, information, psychosocial, and survivorship domains. Total number of UN declined over time, t(87) = 3.00, p < .01. UN likely to persist from baseline to follow-up involved cancer recurrence concerns, stress management, household responsibilities, and others not acknowledging/understanding cancer. Younger women (p = .01) and those with more severe (p < .01), life-interfering (p = .01) symptoms had greater burden of UN. This study highlights the dynamics of UN in the weeks before and after primary treatment. Future studies should identify long-term consequences of persistent UN.

The role of sentinel lymph node biopsy in select sarcoma patients: a meta-analysis.

BACKGROUND Sentinel lymph node (SLN) biopsy is a staging technique for occult lymph node disease. SLN biopsy has been applied to select patients with sarcoma, although the clinical utility remains uncertain. METHODS A PubMed/MEDLINE literature search was performed, and SLN biopsy outcomes were analyzed using a Bayesian meta-analytic approach to obtain point and interval estimates of rates of interest. RESULTS Sixteen studies involving SLN biopsy in patients with sarcoma were identified. Of 114 patients reported, 14 patients had positive SLNs (crude estimate, 12%; meta-analysis estimate, 17%). The meta-analysis false-negative rate was 29% (95% credible interval, 5%-59%). Recurrence and death rates in the SLN-positive group were higher than in the SLN-negative group. CONCLUSIONS This investigation highlights the current role of SLN biopsy in select patients with sarcoma for tumor staging. Questions regarding the high false-negative rate and management of micrometastatic lymphatic disease in patients with sarcoma still exist.

Role of Breast Ultrasound and Mammography in Evaluating Patients Presenting with Focal Breast Pain in the Absence of a Palpable Lump

To determine if ultrasound and/or mammography is helpful in detecting breast cancers in patients presenting with focal breast pain. Patients who presented between February 2008 and April 2011 with focal breast pain without a lump were included in the study. The mammographic and US findings were retrospectively reviewed. BIRADS 0, 4, and 5 were considered positive on mammogram while BIRADS 4 and 5 were considered positive on US. The efficacy of mammogram‐alone, ultrasound‐alone, and in combination to detect breast cancer was evaluated. The performance of mammography for detecting any mass lesions that were present on subsequent US was also evaluated. A total of 257 patients were evaluated with US and 206 (80.1%) of these also had mammograms prior to the US. Cancer incidence was 1.2% (n = 3). The sensitivity, specificity, PPV, and NPV of mammogram‐alone and US‐alone for detection of breast cancer in these patients were 100%, 87.6%, 10.7%, 100% and 100%, 92.5%, 13.6%, and 100%, respectively, while for combined mammogram and US was 100%, 83.7%, 8.3%, and 100%. The sensitivity, specificity, PPV, and NPV of mammogram for identifying an underlying suspicious mass lesion that was subsequently detected by US was 58%, 91%, 39%, and 95%. The NPV of a BIRADS 1 mammogram for any underlying mass lesion was 75%. Addition of an ultrasound to a mammogram did not detect additional cancers; likely due to low cancer incidence in these patients. However, US detected underlying mass lesions in 25% cases with a BIRADS 1 mammogram result.

Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction.

BackgroundTo define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement.Methods and MaterialsTwenty-three patients were identified who had undergone postmastectomy radiotherapy with tangent only fields. All patients had pre-radiation tissue expander placement and expansion. Thirteen patients had bilateral expander reconstruction. The level I/II axillary volumes were contoured using the RTOG contouring atlas. The patient-specific variables of expander volume, superior-to-inferior location of expander, distance between expanders, expander angle and axillary volume were analyzed to determine their relationship to the axillary volume and lung volume dose.ResultsThe mean coverage of the level I/II axillary volume by the 95% isodose line (VD95%) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung VD50% was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary VD95% in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung VD50% correlated with angle of the expander from midline (p = 0.05).ConclusionsIn patients undergoing PMRT with tissue expanders, incidental doses delivered by tangents to the axilla, as defined by the RTOG contouring atlas, do not provide adequate coverage. The posterior-superior region of level I and II is the region most commonly underdosed. Axillary volume coverage increased with increasing expander volumes in patients with bilateral reconstruction. Lung dose increased with increasing expander angle from midline. This information should be considered both when placing expanders and when designing PMRT tangent only treatment plans by contouring and targeting the axilla volume when axillary treatment is indicated.