Ketogenic Diet with Concurrent Chemoradiation in Head and Neck Squamous Cell Carcinoma: Preclinical and Phase 1 Trial Results.

Ketogenic diets (KD) are high in fat and low in carbohydrates, forcing cells to utilize mitochondrial fatty acid oxidation for energy production. Since cancer cells demonstrate increased mitochondrial oxidative stress relative to normal cells, we hypothesized that a KD may selectively enhance metabolic oxidative stress in head and neck cancer cells, sensitizing them to radiation and platinum-based chemotherapy without causing increased toxicity in surrounding normal tissues. This hypothesis was tested in preclinical murine xenografts and in a phase 1 clinical trial (NCT01975766). In this study, mice bearing human head and neck cancer xenografts (FaDu) were fed either standard mouse chow or KetoCal® KD (90% fat, 8% carbohydrate, 2% protein) and exposed to ionizing radiation. Tumors were harvested from mice to test for glutathione, a biomarker of oxidative stress. In parallel, patients with locally advanced head and neck cancer were enrolled in a phase 1 clinical trial where they consumed KD and received radiation with concurrent platinum-based chemotherapy. Subjects consumed KetoCal KD via percutaneous endoscopic gastrostomy (PEG) tube and were also allowed to orally consume water, sugar-free drinks, and foods approved by a dietitian. Oxidative stress markers including protein carbonyls and total glutathione were assessed in patient blood samples both pre-KD and while consuming the KD. Mice bearing FaDu xenografts that received radiation and KD demonstrated a slight improvement in tumor growth rate and survival compared to mice that received radiation alone; however a variation in responses was seen dependent on the fatty acid composition of the diet. In the phase 1 clinical trial, a total of twelve patients were enrolled in the study. Four patients completed five weeks of the KD as per protocol (with variance in compliance). Eight patients did not tolerate the diet with concurrent radiation and platinum-chemotherapy (5 were patient decision and 3 were removed from study due to toxicity). The median number of days consuming a KD in patients who did not complete the study was 5.5 (range: 2-8 days). Reasons for discontinuation included "stress of diet compliance" (1 patient), grade 2 nausea (3 patients), and grade 3 fatigue (1 patient). Three patients were removed from the trial due to dose-limiting toxicities including: grade 4 hyperuricemia (2 patients) and grade 3 acute pancreatitis (1 patient). Median weight loss was 2.95% for the KD-tolerant group and 7.92% for patients who did not tolerate the diet. In conclusion, the ketogenic diet shows promise as a treatment combined with radiation in preclinical mouse head and neck cancer xenografts. A phase 1 clinical trial evaluating the safety and tolerability of KD demonstrated difficulty with diet compliance when combined with standard-of-care radiation therapy and cisplatin chemotherapy.

Altered expression of alpha-methylacyl-coenzyme A racemase in prostatic adenocarcinoma following hormone therapy.

alpha-Methylacyl-coenzyme A racemase (AMACR) is a sensitive and specific tissue marker for the diagnosis of prostatic carcinoma. However, limited data are available on AMACR expression in residual prostatic carcinoma following hormone therapy. We analyzed 64 residual or recurrent prostatic adenocarcinomas following hormonal therapy for the expression of AMACR using a monoclonal antibody (P504S) to AMACR. In 20 localized cases, AMACR staining was absent in 11 (55%), 1+ in 6 (30%), and 2+ or 3+ in 3 (15%). However, in 15 metastatic cases, AMACR was absent in 1 (7%), 1+ in 3 (20%), and 2+ or 3+ in 11 (73%). None of the 29 postradiotherapy cases showed complete absence of AMACR staining: 2 (7%) were 1+, and 27 (93%) were 2+ or 3+. AMACR expression was reduced significantly in the majority of posthormonal residual carcinomas, whereas in postradiotherapy and in hormone-refractory metastatic prostatic adenocarcinoma, AMACR expression was retained. Therefore, the diagnosis of residual prostatic carcinoma after hormonal therapy using AMACR immunostaining must be interpreted with caution. Furthermore, AMACR might have a role in the recurrence of prostatic adenocarcinoma after medical therapy.

Detection of alpha-methylacyl-coenzyme A racemase in postradiation prostatic adenocarcinoma.

OBJECTIVES: To assess the utility of alpha-methylacyl-coenzyme A racemase (AMACR), also known as P504S, immunohistochemistry in the detection of postradiation prostatic adenocarcinoma in surgical specimens. Pathologic diagnosis of postradiation prostate cancer is difficult because of the radiation-induced cytologic changes in benign and malignant epithelial cells. AMACR/P504S is a recently identified molecular marker for prostatic adenocarcinoma. It has been demonstrated that AMACR is overexpressed in the vast majority of prostatic adenocarcinoma cases by cDNA microarray, RNA analysis, Western blotting, and immunohistochemistry. METHODS: A total of 80 prostate glands, including 40 irradiated prostate specimens (28 with adenocarcinoma and 12 benign prostates) and 40 nonirradiated prostate specimens (20 with adenocarcinoma and 20 benign prostates), were examined. The specimens were obtained after salvage radical prostatectomy (n = 25), transurethral resection (n = 4), or needle biopsy (n = 11). All samples were immunohistochemically analyzed for AMACR. RESULTS: All 48 carcinoma cases (28 of 28 irradiated and 20 of 20 nonirradiated specimens) showed strongly positive AMACR/P504S immunostaining. AMACR immunostaining was negative for all irradiated (n = 12) and nonirradiated (n = 20) benign prostates, as well as the irradiated benign glands adjacent to carcinoma. 34betaE12 confirmed the presence of basal cells in all benign prostates (32 of 32) and the absence of basal cells in carcinoma (0 of 48). CONCLUSIONS: Our results demonstrate that AMACR is a highly specific and sensitive indicator of postradiation prostate cancer. AMACR immunostaining facilitates the challenging differentiation between prostatic adenocarcinoma and radiation-induced atypia in benign prostatic epithelium and may be of exceptional value in limited needle biopsies.