Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence.

BACKGROUND: In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months. METHODS: A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans. RESULTS: PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive. CONCLUSIONS: HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

Progesterone receptors (PR)-B and -A regulate transcription by different mechanisms: AF-3 exerts regulatory control over coactivator binding to PR-B.

The two, nearly identical, isoforms of human progesterone receptors (PR), PR-B and -A, share activation functions (AF) 1 and 2, yet they possess markedly different transcriptional profiles, with PR-B being much stronger transactivators. Their differences map to a unique AF3 in the B-upstream segment (BUS), at the far N terminus of PR-B, which is missing in PR-A. Combined mutation of two LXXLL motifs plus tryptophan 140 in BUS, to yield PR-BdL140, completely destroys PR-B activity, because strong AF3 synergism with downstream AF1 and AF2 is eliminated. This synergism involves cooperative interactions among receptor multimers bound at tandem hormone response elements and is transferable to AFs of other nuclear receptors. Other PR-B functions-N-/C-terminal interactions, steroid receptor coactivator-1 coactivation, ligand-dependent down-regulation-also require an intact BUS. All three are autonomous in PR-A, and map to N-terminal regions common to both PR. This suggests that the N-terminal structure adopted by the two PR is different, and that for PR-B, this is controlled by BUS. Indeed, gene expression profiling of breast cancer cells stably expressing PR-B, PR-BdL140, or PR-A shows that mutation of AF3 destroys PR-B-dependent gene transcription without converting PR-B into PR-A. In sum, AF3 in BUS plays a critical modulatory role in PR-B, and in doing so, defines a mechanism for PR-B function that is fundamentally distinct from that of PR-A.

Progestins initiate a luminal to myoepithelial switch in estrogen-dependent human breast tumors without altering growth.

Although long-term clinical use of progestins is associated with an increased incidence of breast cancers, their role in established cancers is unclear. Estrogens are considered to be the main mitogens in the majority of breast cancers. Whether progesterone affects proliferation and/or differentiation is under debate. To assess the role of progesterone in established breast cancers, we used T47D human breast cancer cells that are estrogen receptor (ER) positive and either progesterone receptor (PR) negative or positive for PRA, PRB, or both. These cells were grown as strictly estrogen-dependent solid tumors in ovariectomized female nude mice. Progesterone or medroxyprogesterone acetate (MPA) alone did not support tumor growth, nor did progesterone or MPA given simultaneously with estrogen significantly alter estrogen-dependent tumor growth. However, treatment of mice bearing ER+PR+ but not ER+PR- tumors with either progesterone or MPA increased expression of the myoepithelial cytokeratins (CK) 5 and 6 in a subpopulation of tumor cells. These CK5+/CK6+ cells had decreased expression of luminal epithelial CK8, CK18, and CK19. We conclude that progestins exert differentiative effects on tumors characterized by transition of a cell subpopulation from luminal to myoepithelial. This may not be beneficial, however, because such a phenotype is associated with poor prognosis.

Surgical speech disorders.

Most speech disorders of childhood are treated with speech therapy. However, two conditions, ankyloglossia and velopharyngeal dysfunction, may be amenable to surgical intervention. It is important for surgeons to work with experienced speech language pathologists to diagnose the speech disorder. Children with articulation disorders related to ankyloglossia may benefit from frenuloplasty. Children with velopharyngeal dysfunction should have standardized clinical evaluation and instrumental asseessment of velopharyngeal function. Surgeons should develop a treatment protocol to optimize speech outcomes while minimizing morbidity.

A meta-analysis of voice outcome comparing calcium hydroxylapatite injection laryngoplasty to silicone thyroplasty.

OBJECTIVES: To compare the voice outcome of calcium hydroxylapatite (CaHA) injection laryngoplasty (IL) vs silicone medialization thyroplasty (MT) in the treatment of unilateral vocal fold paralysis (UVFP). DATA SOURCES: Systematic review of English literature from MEDLINE, Google Scholar, Web of Science, Scopus, and the Cochrane library from January 1, 1980, to December 31, 2010. REVIEW METHODS: Included studies reporting voice-related quality of life (Voice Handicap Inventory [VHI]) following IL with CaHA or MT with silicone. The primary outcome measure was the improvement in VHI. The secondary outcome was improvement in maximum phonatory time (MPT). RESULTS: Of the 742 abstracts screened for relevancy, 24 studies qualified for analysis. The mean (SD) VHI scores were 72.22 (11.06) before MT and 34.02 (6.48) after MT. The mean (SD) VHI scores were 68.36 (6.88) before IL and 32.24 (7.33) after IL. The paired difference mean of VHI improvement was 38.20 (95% confidence interval [CI], 17.05-59.32; P = .007) for MT and 36.11 (95% CI, 29.65-42.57; P = .001) for IL. The mean (SD) MPT scores were 7.40 (3.14) before IL and 13.00 (1.75) after IL. The mean (SD) MPT scores were 6.16 (1.90) before MT and 12.40 (2.72) after MT. The paired difference mean of MPT improvement was 6.23 (95% CI, 4.74-7.73; P < .001) for MT and 5.60 (95% CI, 2.95-8.25; P = .006) for IL. CONCLUSION: Injection laryngoplasty with CaHA and MT with silicone appear to achieve comparable voice improvement within 1 year, but a definitive conclusion is limited by a lack of standardized outcome measures.

Sleep medicine clinical and surgical training during otolaryngology residency: a national survey of otolaryngology residency programs.

OBJECTIVE: The authors sought to assess the otolaryngology residency training experiences in adult sleep medicine and sleep surgery in the United States. STUDY DESIGN: Internet survey. SETTING: US academic otolaryngology residency programs. SUBJECTS AND METHODS: This Internet survey was emailed to the program directors of 103 US Accreditation Council for Graduate Medical Education (ACGME)-approved otolaryngology residency programs in 2010. RESULTS: A total of 47 program directors responded, representing 46% of programs surveyed. In 59% of these programs, there was at least 1 faculty member with clinical practice dedicated to adult medicine. Most commonly, these clinicians spent less than 50% of their clinical time on adult sleep medicine. While most otolaryngology residents were reported being well trained in commonly performed procedures such as septoplasty and uvulopalatopharyngoplasty (UPPP), the training on hypopharyngeal or multilevel surgeries, such as partial glossectomy, tongue base resection, hyoid or tongue suspension, or geniotubercle advancement, was considered less frequent. The overall exposure to education regarding the interpretation of original data of laboratory-based sleep studies or portable home monitoring devices was infrequent. A significant portion of respondents indicated that they would like to expand their residents' exposure to adult sleep medicine and sleep surgery. CONCLUSION: This survey provides a starting point to further assess the rigor of sleep medicine/sleep surgery training in US residency programs. Continued assessment and strengthening of the current curriculum are crucial to keep residents up to date with this evolving field. This result calls attention to the importance of bolstering sleep medicine and surgery curriculum to meet the academic requirements of otolaryngology training.

Nicotine induces resistance to chemotherapy in nasal epithelial cancer.

BACKGROUND: Epidemiological and clinical data implicate that in patients with cancer, continued smoking causes progression of cancer growth and resistance to therapy. The carcinogens possess the ability to block apoptosis, an important mechanism in the development of tumors and resistance to chemotherapy. We previously showed that nicotine enhances growth and proliferation in lung cancer. However, the effects of nicotine, a tobacco carcinogen that inhibits apoptosis, have not been studied before in nasal epithelial carcinoma (NC). In this study, we sought to determine the effects of nicotine on chemotherapy-induced apoptosis in human NC. METHODS: Primary human NC cells were grown per protocol, treated with combination chemotherapy, and the apoptosis was assessed by TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling) and DNA fragmentation assays. The regulation of mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) signal transduction pathway was examined by real time quantitative polymerized chain reaction, and immunofluorescent staining assays. RESULTS: Combination chemotherapy with cisplatin (35 microM) plus etoposide (20 microM) caused a significant increase in NC apoptosis compared with single agent alone, and nicotine, in part, inhibited chemotherapy-induced apoptosis in NC. Furthermore, nicotine induced activation of AKT and MAPK pathways, while inhibition of MAPK using U0126 and AKT by phosphatidylinositol 3-kinase inhibitor, LY294002, in part, blocked the antiapoptotic effects of nicotine against cisplatin and etoposide-induced apoptosis in NC. CONCLUSION: Nicotine inhibits chemotherapy-induced apoptosis in NC via the AKT and MAPK-mediated signaling pathways. We speculate that nicotine may play a role in oncogenesis and resistance to cancer therapy in NC.

Progesterone receptors A and B differentially affect the growth of estrogen-dependent human breast tumor xenografts.

Sixty to seventy percent of all primary human breast cancers are estrogen-dependent and express both estrogen (ER) and progesterone receptors (PR). Whereas expression of the two naturally occurring PR isoforms, PR-A and PR-B, is close to equimolar in normal human tissues, the ratio of the two receptors varies extensively in tumors. This is important since the two PR are functionally distinct and have differential repressor effects on ER. The PR isoform content may, therefore, affect the outcome of endocrine therapies targeted at ER. Study of PR isoforms is difficult because the two receptors are co-expressed in cells under estradiol stimulation. We have engineered four sets of T47D human breast cancer cells that, independent of estrogen: (i) express only PR-A; (ii) express only PR-B; (iii) are PR-negative; or (iv) contain both PR isoforms. Each of these cell lines was grown into solid tumors in nude mice in a strictly 17beta-estradiol-dependent manner. Results show, first, that PR-A expressing cells grow into tumors that are approximately half the size of PR-B expressing tumors, and second, that the reduced growth of PR-A tumors occurs in the absence of PR ligand. Tamoxifen treatment preferentially inhibited the growth of PR-A tumors, whereas PR-B tumors were unaffected. Thus, PR are not just passive markers of functional ER; the prevalence of PR-A or PR-B may differentially influence tumor phenotype.