Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice.

Cigarette smoking (CS) is a leading cause of death worldwide. The aryl hydrocarbon receptor (AHR) is partially responsible for tobacco-induced carcinogenesis although the underlying mechanisms involving early effector genes have yet to be determined. Here, we report that adrenomedullin (ADM) significantly contributes to the carcinogenicity of tobacco-activated AHR. CS and AHR activating ligands induced ADM in vitro and in vivo but not in AHR-deficient fibroblasts and mice. Ectopic transfection of AHR rescued ADM expression in AHR(-/-) fibroblasts whereas AHR blockage with siRNA in wild type cells significantly decreased ADM expression. AHR regulates ADM expression through two intronic xenobiotic response elements located close to the start codon in the ADM gene. Using tissue microarrays we showed that ADM and AHR were coupregulated in lung tumor biopsies from smoker patients. Microarray meta-analysis of 304 independent microarray experiments showed that ADM is elevated in smokers and smokers with cancer. In addition, ADM coassociated with a subset of AHR responsive genes and efficiently differentiated patients with lung cancer from nonsmokers. In a novel preclinical model of CS-induced tumor progression, host exposure to CS extracts significantly elevated tumor ADM although systemic treatment with the ADM antagonist NSC16311 efficiently blocked tobacco-induced tumor growth. In conclusion, ADM significantly contributes the carcinogenic effect of AHR and tobacco combustion products. We suggest that therapeutics targeting the AHR/ADM axis may be of clinical relevance in the treatment of tobacco-induced pulmonary malignancies.

Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells.

Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.

Liver directed therapy for renal cell carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) to the liver portrays a poor prognosis and liver directed therapy remains controversial. We aimed to determine potential selection criteria for patients who might benefit from this strategy. MATERIALS AND METHODS: We evaluated 247 consecutive patients with RCC metastatic to the liver from a prospectively maintained database. RESULTS: Eighteen patients received liver directed therapy (18/247, 7%). Ten patients underwent liver resection (10/247, 4%) and eight patients underwent radiofrequency ablation (RFA, 8/247, 3%). All were rendered free of disease in the liver. Five had synchronous liver disease and underwent synchronous resections with their primary. Mortality was 0%. Fourteen had single (surgery 7, RFA 7) and four (surgery 3, RFA 1) had multiple liver lesions, respectively. Median size of lesions was 5cm (0.5 - 10cm) and 2.5cm (1 - 6cm) in the surgery and RFA groups, respectively. Median DFI was 10 months, and no difference was observed in those with a longer vs. shorter than median DFI (p = 0.95); liver specific progression free survival for the surgery and RFA groups were 4 and 6 months, respectively (p= 0.93). 1, 3 and 5-year actuarial survivals for the whole group were 89%, 40%, 27%. Median survival for the surgery group was 24 (3 to 254+) months, and for the RFA group 15.6 (7-56+) months (p = 0.56). Metachronous liver disease was associated with prolonged survival (p = 0.02). CONCLUSIONS: Liver directed therapy for RCC is safe. For highly selected patients with metachronous liver RCC metastases, liver directed therapy should be considered in a multidisciplinary manner.

Operative management for recurrent and metastatic adrenocortical carcinoma.

OBJECTIVE: A review of all resections for recurrent or metastatic ACC was performed to identify patients who might benefit from a surgical approach, and to identify factors that might aid in prognosis among patients with metastatic disease. SUMMARY BACKGROUND DATA: Adrenocortical carcinoma (ACC) is a rare tumor, with frequent recurrences and metastases even after complete resection. Chemotherapy has limited efficacy, and surgical resection of metastatic ACC remains controversial. METHODS: A retrospective review was performed of all patients who underwent surgical intervention for metastatic ACC in a single tertiary center from 1977 to 2009. All available clinicopathologic data were analyzed to determine potential factors associated with response to treatment and survival. RESULTS: Fifty-seven patients underwent 116 procedures for recurrent or metastatic disease. Twenty-three resections were for liver metastases, 48 for pulmonary metastases, 22 for abdominal disease including local recurrences, and 13 were for metastases at other sites. Median and 5-year survivals from time of first metastasectomy were 2.5 years, and 41%, respectively. The median survival of patients with DFI <12 months was 1.7 years, compared to 6.6 years for patients with DFI >12 months (P = 0.015). Median survival for right versus left-sided primaries was 1.9 years versus 3.8 years (P = 0.03). Liver metastases were more common with right-sided primaries (67% vs. 41%, P = 0.05). Chemotherapy had no impact on survival. CONCLUSIONS: Resection of recurrent or metastatic ACC is safe, and may result in prolongation of survival in selected patients with DFI greater than 1 year.

Do breast columnar cell lesions with atypia need to be excised?

Columnar cell lesion with atypia (CCLA) is a newly recognized pathologic entity seen in breast specimens. The breast cancer risk associated with this finding is unclear, although CCLA had been found adjacent to both in situ and invasive carcinomas, but the incidence is unknown. Breast specimens from patients with a columnar cell lesion were reviewed by a pathologist for atypia. Twenty-one specimens with CCLA were identified [core biopsy (8), excisional biopsy (11), and simple mastectomy (2)]. Six of eight specimens with CCLA on core had adjacent abnormal pathology: infiltrating ductal carcinoma (IDC)/lobular carcinoma in situ (LCIS) (1), ductal carcinoma in situ (DCIS)/LCIS (1), DCIS (1), LCIS (1), and papillomatosis (2). Five of 11 specimens with CCLA on excisional biopsy had adjacent abnormal pathology: IDC (3), DCIS/LCIS (1), and atypical ductal hyperplasia/papilloma (1). Two of two simple mastectomy specimens had CCLA associated with IDC (1) and DCIS (1). Overall, abnormal pathology was found adjacent to CCLA in 62 per cent of specimens (13/21). Breast pathologic specimens containing a columnar cell lesion should be carefully examined for atypia. Surgical excision is warranted for CCLA found on core biopsy. The future risk of breast cancer based on the finding of CCLA alone requires further investigation.

Cutaneous effects of cryogen spray cooling on in vivo human skin.

BACKGROUND: Despite widespread clinical use of cryogen spray cooling (CSC) in conjunction with laser dermatologic surgery, in vivo cutaneous effects have not been systematically evaluated. OBJECTIVE: The authors characterize the in vivo cutaneous effects for Fitzpatrick skin types I through VI after CSC exposures of varying spurt durations and spurt delivery patterns (single vs. multiple spurts). MATERIALS AND METHODS: Twenty-seven normal human subjects were exposed to single cryogen spurts from 10 to 80 milliseconds, and multiple spurt patterns consisting of two 20-millisecond spurts, four 10-millisecond spurts, and eight 5-millisecond spurts. Subjects were evaluated by clinical observation and photography at 1 hour, 1 day, and 1, 4, 8, and 12 weeks after CSC exposure. RESULTS: Acute erythema and urticaria (1-24 hours) were noted in 14 of 27 and 3 of 27 subjects, respectively. Transient hyperpigmentation occurred in 4 of 27 subjects (skin types III-VI) but resolved spontaneously without medical intervention in all subjects by 8 weeks. No permanent skin changes were noted in any subjects. Skin reactions were more common with longer single-spurt durations (50 milliseconds or greater) and multiple spurt patterns. CONCLUSION: Acute erythema, urticaria, and, less commonly, transient hyperpigmentation were observed after CSC exposure. Permanent skin injury was not observed and is unlikely.