Walter C. Bell

Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-Blind, Placebo-Controlled Trial

Background Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). Methods A double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided. Results There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups. Conclusions Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

Cytogenetics and molecular biology of osteosarcoma

O steosarcoma is a relatively uncommon malignancy with about 1000 new cases diagnosed each year in the United States. It is, however, among the most common nonhematologic primary malignant tumors of bone in both children and adults (Bell and Siegal, 2002). The peak incidence of osteosarcoma occurs in the second decade with an additional smaller peak after age 50 (Dorfman and Czerniak, 1995). The tumors typically arise in the metaphyseal regions of long bones, with the distal femur, proximal tibia, and proximal humerus representing the three most common sites (Dahlin and Coventry, 1967; Marcove et al, 1970). Many types of osteosarcoma are currently recognized (Table 1), with classification primarily based on location of the lesion, associated bone (for example, the gnathic bones), or related disease entity. The conventional type, arising in the intramedullary cavity of the bone, represents approximately 75% of all osteosarcomas (Mertens et al, 1993). These tumors frequently penetrate and destroy the cortex of the bone and extend into the surrounding soft tissues. The typical gross appearance of these lesions is variable, with fragments of bone admixed with softer tissues that have a chondroid to fibrous consistency. Areas of necrosis are common, especially in specimens obtained after preoperative chemotherapy. The histologic appearance of conventional osteosarcoma allows this group to be further subdivided based on the primary differentiation of the mesenchymal component present. The most commonly recognized subtypes are osteoblastic, chondroblastic, and fibroblastic, with a number of less commonly observed patterns including epithelioid, giant-cell rich, small cell, and telangiectatic. The unifying histologic feature present in all types and subtypes of osteosarcoma is the presence of tumor osteoid produced by the neoplastic cells. The diagnosis of osteosarcoma requires a combination of clinical presentation, radiologic studies, and pathologic tissue evaluation. Although serum alkaline phosphatase may be elevated, laboratory studies are generally not helpful in establishing the diagnosis. The initial clinical symptom of these tumors is frequently pain in the affected area, which may also be associated with localized soft tissue swelling or limitation of motion in the adjacent joint (Dahlin and Coventry, 1967). Radiologic evaluation is vital in making the correct diagnosis. Typical findings include a lytic intramedullary lesion with scattered areas of new bone formation, often with destruction of the bony cortex and extension of mass into the surrounding soft tissue (Kumar et al, 1987; Lindbom et al, 1961). Reactive new bone formation may be seen under the periosteum forming a “Codman angle,” or “Codman’s triangle,” and invasion into adjacent soft tissues may produce a “sunburst” pattern of periosteal reaction (Ragsdale et al, 1981). Initial pathologic assessment is frequently performed on biopsy material in which typical histologic features together with the appropriate radiologic findings allow for the definitive diagnosis.

Race- and age-dependent alterations in global methylation of DNA in squamous cell carcinoma of the lung (United States)

Objective: The current study investigated the race- and age-dependent alterations in global DNA methylation on the development and progression of squamous cell carcinomas (SCCs) of the lung. Methods: Methylation status was evaluated in SCC and in the associated uninvolved bronchial mucosa (UBM) and epithelial hyperplasia (EH) of 53 Whites and 23 African Americans by using an antibody specific for 5-methylcytosine (5-mc). A low 5-mc score indicates global hypomethylation of DNA. Results: 5-mc scores of SCC were significantly lower compared to 5-mc scores of UBM and EH in Whites (p < 0.05). In African Americans, 5-mc scores of SCCs were not significantly different from 5-mc scores of UBM and EH, suggesting an involvement of methylation in the development of SCCs in Whites, but not in African Americans. 5-mc scores were lower in younger subjects compared to older subjects in Whites. Since cancers in younger subjects tend to be more aggressive than cancers in older subjects, these observations may suggest that hypomethylation may have contributed to aggressiveness cancers of younger Whites. Hypomethylation of SCCs in White men was associated with shorter survival from the disease. Conclusions: These preliminary results suggest that the methylation status of DNA may affect the development, aggressiveness, and prognosis of SCCs in Whites.

Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee.

Background The Organ Procurement Transplant Network Disease Transmission Advisory Committee (DTAC), a multidisciplinary committee, evaluates potential donor-derived transmission events (PDDTE), including infections and malignancies, to assess for donor transmitted events. Methods Reports of unexpected PDDTE to Organ Procurement Transplant Network in 2013 were fully reviewed by DTAC. A standardized algorithm was used to assess each PDDTE from a given donor and to classify each individual recipient from that donor. Results Of 443 total PDDTE submitted, 159 were triaged and not sent out to the full DTAC. Of 284 fully evaluated reports, 32 (11.3%) resulted in a proven/probable (P/P) transmission of infection, malignancy or other conditions to 42 recipients. Of 204 infection events, 24 were classified as P/P affecting 30 recipients, with four deaths. Bacteria were the most frequently reported type of infection, accounting for 99 reports but only 12 recipients from 11 donors experienced P/P transmission. There were 65 donors reported with potential malignancy events and 5 were classified as P/P transmissions with 8 affected recipients and 2 deaths. Additionally, there were 16 noninfection, nonmalignancy reports resulting in 3 P/P transmissions to 4 recipients and 1 death. Conclusions There was a 43% increase in the number of PDDTE reported and reviewed in 2013 over 2012. However, the percent with P/P transmission remains low, affecting recipients from 32 donors especially when compared with the more than 14,000 donors recovered annually in the United States. The continued use of the new standard algorithm and triaging process will enhance the reproducibility of DTAC assessments and allow more robust analysis of our aggregate DTAC experience.

Recurrent Retroperitoneal Sarcoma: Impact of Biology and Therapy on Outcomes

BACKGROUND Local recurrence remains the major cause of death in patients with retroperitoneal sarcoma (RPS). There is no consensus regarding management of patients with recurrent RPS. STUDY DESIGN We performed a retrospective review of patients with recurrent RPS managed at 2 tertiary care centers between 1983 and 2008. Presentation, treatments, and outcomes were analyzed. RESULTS Seventy-eight patients were identified and analyzed. Sixteen patients (22%) presented with concurrent metastatic disease; survival in this subset of patients was poor (median 12 months). Forty-eight patients underwent resection of the first local recurrence of RPS. Palliation of tumor-related symptoms was achieved in 79% with operation. Survival was significantly better in patients having complete (p = 0.001) and incomplete resection (p = 0.02) compared with patients having biopsy only. Among patients with first local recurrence, high grade tumor (p = 0.0001) and no resection (p = 0.007) were significantly associated with reduced survival. On multivariate analysis, radiation therapy, multifocality, histologic subtype, and time to local recurrence did not significantly correlate with survival. Second and third local recurrences occurred at shorter intervals compared with first local recurrence and were less likely to be completely resectable. Patients undergoing resection of second and third local recurrences had survival similar to that in patients undergoing resection of first local recurrence. CONCLUSIONS Tumor biology (high grade) is a significant prognostic factor for patients with recurrent RPS. Resection should be considered in patients with first and subsequent local recurrences (even if multifocal) of RPS because it is associated with improved survival. Operation should also be considered for palliation of symptoms in patients in whom resection is not possible.

Mammary analog secretory carcinoma, low-grade salivary duct carcinoma, and mimickers: a comparative study.

Mammary analog secretory carcinoma (MASC) is a recently recognized low-grade salivary carcinoma characterized by a specific ETV6 rearrangement. We describe 14 new MASCs and examine their immunophenotypic and genetic profiles in the context of look-alikes, namely, low-and high-grade salivary duct carcinoma and acinic cell carcinoma. ETV6 rearrangement, and robust expression of mammaglobin and S100, were demonstrated in 11/11, 14/14, and 12/14 MASCs, respectively. All low-grade salivary duct carcinomas coexpressed S100/mammaglobin (6/6); none harbored ETV6 rearrangements (0/5). Given that S100/mammaglobin coexpression and absence of zymogen granules are features of both MASC and low-grade salivary duct carcinoma, these two are best distinguished histologically. The former is predominantly an extraductal neoplasm with bubbly pink cytoplasm, whereas the latter is a distinct intraductal micropapillary and cribriform process. Querying ETV6 gene status may be necessary for difficult cases. No acinic cell carcinoma expressed mammaglobin (0/13) or harbored an ETV6 rearrangement (0/7); only 1/13 acinic cell carcinomas weakly expressed S100. DOG1 expression was limited or absent among all tumor types, except acinic cell carcinoma which expressed DOG1 diffusely in a canalicular pattern. Therefore, histology and immunohistochemistry (mammaglobin, S100, DOG1) suffices in distinguishing acinic cell carcinoma from both MASC and low-grade salivary duct carcinoma. HER2 (ERBB2) amplification was detected in only 1/10 acinic cell carcinomas, but none of the MASCs or low-grade salivary duct carcinomas tested. High-grade salivary duct carcinomas frequently expressed mammaglobin (11/18) and harbored HER2 amplifications (13/15); none harbored ETV6 rearrangements (0/12). High-grade salivary duct carcinomas can easily be distinguished from these other entities by histology and HER2 amplification.

Interaction of Nkx3.1 and p27kip1 in prostate tumor initiation

The homeodomain transcription factor Nkx3.1 and the cyclin-dependent kinase inhibitor p27kip1 have both been implicated in prostate tumor suppression. In addition, both of these molecules demonstrate haploinsufficiency for tumor suppression, in which loss of a single allele is sufficient to lead to the development of preneoplastic or neoplastic lesions. We have generated mice carrying compound mutant alleles of Nkx3.1 and p27 to explore the roles of these factors in prostate tumorigenesis. Our results indicate that Nkx3.1 and p27kip1 cooperate to suppress the proliferation of prostatic epithelial cells and the formation of preneoplastic lesions resembling prostatic intraepithelial neoplasia. Cooperativity was most evident with complete loss of at least one of the two genes because compound heterozygous mice exhibited a prostatic phenotype that was no more severe than that of single heterozygous mutants. Thus Nkx3.1 and p27kip1 regulate prostatic epithelial cell proliferation and tumor initiation by affecting both haploinsufficient and nonhaploinsufficient pathways.

Lower Risk of Cervical Intraepithelial Neoplasia in Women with High Plasma Folate and Sufficient Vitamin B12 in the Post-Folic Acid Fortification Era

The purpose of this study was to determine the influence of plasma folate and vitamin B12 concentrations on cervical cancer risk in the U.S. after the folic acid fortification era. The study included 376 premenopausal women of childbearing age who tested positive for infections with high-risk (HR) human papillomaviruses (HPVs) and were diagnosed with cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN 2+, cases) or ≤CIN 1 (noncases). CIN 2+ (yes/no) was the dependent variable in logistic regression models that specified plasma folate concentrations combined with plasma B12 concentrations as the independent predictors of primary interest, adjusting for age, race, education, smoking, parity, number of life-time male sexual partners, use of contraceptives, waist circumference, physical activity, healthy eating index, and circulating concentrations of vitamins A, C, tocopherol, and total carotene. Women with supraphysiologic concentrations of plasma folate (>19.8 ng/mL) who also had sufficient plasma vitamin B12 (≥200.6 pg/mL) had 70% lower odds of being diagnosed with CIN 2+ (P = 0.04) when compared with women with plasma folate of ≤19.8 ng/mL and plasma vitamin B12 of <200.6 pg/mL. Our results do not corroborate the concern that supraphysiologic plasma folate concentrations seen in the post-U.S. folic acid fortification era increase the risk of CIN in premenopausal women of childbearing age. In fact, higher folate is associated with significantly lower risk of CIN, especially when vitamin B12 is sufficient, demonstrating the importance of vitamin B12 in the high-folate environment created by the folic acid fortification program.

Organizational issues in providing high-quality human tissues and clinical information for the support of biomedical research.

Superior-quality human tissues are required to support many types of biomedical research. To be useful optimally in supporting research, not only must these tissues be accurately diagnosed, but also the specific aliquots of tissue supplied to investigators must be accurately described as part of the quality control analysis of the tissue. Tissues should be collected, processed, and stored uniformly. Some tissues are provided to investigators from tissue banks for which tissues have been collected and processed according to standard operating procedures (SOPs) of the tissue bank. Other tissues provided to support research are collected and processed according to SOPs modified to meet investigator needs and requirements, i.e., prospective collection/processing. These different models of tissue collection require different goals, designs, and SOPs. The objectives of tissue repositories also vary based on the types of tissues provided (e.g., fresh tissue aliquots, fixed paraffin-embedded tissue, paraffin tissue sections, etc.) and how the tissues are to be used in research. For example, the potential use of tissues affects the need for extensive annotation of the specimen including both clinical information (e.g., clinical outcomes) and demographics. Specifically, if the tissues are to be used for extraction of proteins or basic studies of disease processes, less clinical information, if any, may be needed than if the tissues are to be used for the correlation of an aspect of the disease process with clinical outcome or response to a specific therapy. In this review, we describe, based on our experience, the major issues that should be addressed in designing and establishing a tissue repository.

Sinonasal teratocarcinosarcoma: report of a case with review of literature and treatment outcome

Sinonasal teratocarcinosarcoma is a highly malignant, polymorphous neoplasm that combines features of carcinosarcoma and teratoma. We describe the clinicopathologic features and management of a well-documented example of this unique entity that involved a 41-year-old Hispanic man. The patient presented with a history of multiple episodes of epistaxis, nasal obstruction and frontal headaches. Computerized tomography scans and magnetic resonance imaging revealed a large mass filling the left nasal cavity and extending to the cribriform plate with involvement of the ethmoid sinuses, lamina papyracea, and orbit. The patient underwent a complex procedure for a T3N0 tumor. Histologic examination revealed a heterogeneous admixture of epithelial, mesenchymal, and neuroepithelial elements. The mesenchymal components consist of fibrous stroma and myxomatous areas, labeled with calponin and smooth muscle actin. The epithelial components vary from clear cells, nonkeratinizing epithelium to glandular pattern, and keratin containing cysts. Immature neuroepithelium and olfactory neuroblastomalike tissue are highlighted with neuroendocrine markers. Postoperatively, the patient had a rapid local recurrence of the tumor and underwent reexcision, and was treated with radiotherapy and chemotherapy. Twelve months after his primary resection, computerized tomography scans revealed an intrathoracic tumor with dominant mass in the left hilum and metastases to the mediastinum, left pleural space, and both lungs. The histologic nature of his chest mass remains undetermined. Among 54 cases of reported sinonasal teratocarcinosarcoma, 67% of patients with initial single surgical resection and 80% of patients primarily treated with radiotherapy had recurrence, or metastatsis, or unresponsiveness to treatment. The high rate of local recurrence and metastasis is indicative of its highly aggressive biologic behavior. Almost half of the patients died of tumor within 3 years of diagnosis, despite aggressive therapy. Seventy percent of the patients who survived more than 1 year had the initial therapeutic regiments of combined surgery and adjuvant therapies, suggesting that aggressive therapeutic approaches may improve the treatment outcome.