The membrane hypothesis of aging proposes an association between reactive oxygen metabolites and aging processes. Reactive oxygen metabolites are a normal by-product of oxidative phosphorylation and are also formed under conditions of ischemia, hypoperfusion, and as a result of environmental contaminants. Among the many detrimental activities of reactive oxygen metabolites, also known as free oxygen radicals, is direct damage to mitochondrial DNA. Progressive accumulation of mitochondrial DNA damage renders cells unable to conduct oxidative phosphorylation reactions effectively, thereby leading to a bioenergetically deficient cell. Over time, mitochondrial DNA damage accumulates and leads to cellular dysfunction with subsequent organ failure, aging, and ultimately, death. This sequence forms the basis of the membrane hypothesis of aging.To determine if the membrane hypothesis of aging may be involved in the development of presbyacusis.Fischer rats from 4 age groups were tested for auditory sensitivity using the auditory brainstem response. Brain, stria vascularis, and auditory nerve tissues were harvested and mitochondrial DNA was amplified to identify the highly conserved cytochrome b and ND1-16S ribosomal RNA segment of the NADH genes, as well as a 4834-base pair (bp) deletion associated with aging.Fischer rats (n=28) from 4 age groups were used: young (2-4 months [n=9]), mid-young (9-11 months [n=5]), mid-old (18-20 months [n=5]), and old (30-34 months [n=9]).The results demonstrate a progressive reduction in auditory sensitivity with age. The mitochondrial DNA studies identify a significant increase in the presence of the 4834-bp deletion in the aged subjects compared with the young.These findings raise the possibility that the 4834-bp deletion may be associated with presbyacusis, as well as with aging.
OBJECTIVES Radiosurgery precisely delivers a single high dose or a few fractionated doses of radiation to a localized tumor via the stereotactic approach. Some head and neck sites are suitable for radiosurgery since there is minimal or no organ motion. The clinical studies were carried out to determine the accuracy of stereotactic radiosurgery and to demonstrate the effectiveness of radiosurgery in head and neck cancers. MATERIALS AND METHODS Thirteen patients were treated with either single‐dose or fractionated radio‐surgery to the tumor. All patients except one with cancer of the lip had received prior treatments including surgery, radiotherapy, and chemotherapy for the primary cancers. The dose ranged 12 to 18 Gy for single‐dose radiosurgery and 30 Gy in 5 or 6 fractions twice a week for fractionated radiosurgery. Tumor localization was achieved via the stereotactic approach. RESULTS Accuracy of radiosurgery was within 1.5 mm. Despite the recurrent disease from previous heavy treatments, 9 patients (70%) showed a significant response (complete or >50% tumor reduction) to radiosurgery, and 3 patients had stable disease. Complete tumor response was achieved in 6 patients. All patients had excellent pain relief with functional and cosmetic preservation. There was no acute and subacute radiation toxicity detected clinically during the minimal follow‐up of 6 months. CONCLUSION Image‐guided radiosurgery is effective in achieving the local tumor control and pain relief. Radiosurgery provided excellent functional and cosmetic preservation with minimal complication. The results indicate the potential of radiosurgery in the treatment of recurrent and selected primary head and neck cancers. (Otolaryngol Head Neck Surg 2004;130:690‐7.)
To characterize and compare quality of life (QOL) in patients with head and neck cancer shortly before initial treatment and 1 year later and to study the predictors of changes in QOL over 1 year.Prospective cohort study.Three otolaryngology clinics.Three hundred sixteen patients having newly diagnosed squamous cell head and neck cancer.Health-related QOL was assessed using the 36-item Short-Form Health Survey and a head and neck cancer-specific QOL scale.Over 1 year, QOL decreased for physical functioning measures and eating but improved for mental health QOL. Depression and smoking were major predictors of poor QOL at baseline. Major predictors of change in QOL from baseline to 1 year were treatment factors, especially feeding tube placement (9 scales), chemotherapy (3 scales), and radiation therapy (3 scales). Baseline smoking and depressive symptoms also remained significant predictors of several QOL scales at 1 year.Health-related physical QOL tended to decline over 1 year and mental health QOL improved. The major predictors of change in QOL were treatment factors, smoking, and depressive symptoms. Physicians should alert patients to the relative effects on QOL one may experience with different treatments.
Surgical excision of the primary tumor with safe margins remains the mainstay of treatment for oral cavity squamous cell carcinoma (OSCC). The standard of care for assessment of intraoperative margins is frozen section histopathology. Unfortunately the facility is not available at most centers in limited resource countries. Toluidine blue, a metachromatic dye, has been well described in clinical identification of malignant and premalignant lesion in the oral cavity. Considering this we decided to explore intraoperative use of toluidine blue staining, in comparison with frozen sections, for the assessment of tumor-free margins. After obtaining clearance from the in-house ethical review committee, a prospective study was conducted at Aga Khan University Hospital, Karachi, from August 15, 2009 to March 14, 2010. A sample of 56 consenting patients with biopsy-proven OSCC were included in the study, giving us 280 tumor margins. Margins were analyzed using toluidine blue staining and frozen section histopathology. A receiver operator curve (ROC) was then applied to compare assessment of margin status by toluidine blue and frozen section. Of the 280 examined margins 11 stained positive with toluidine blue, three were positive on frozen section biopsy, and three were positive on final histopathology. Toluidine blue staining had sensitivity and specificity of 100% and 97%, respectively. The diagnostic accuracy of toluidine blue was found to be 97.1% with a positive predictive value (PPV) of 27.2% and a negative predictive value (NPV) of 100%. Toluidine blue can be used as an effective screening modality for the assessment of intraoperative margins in resource limited environments and reducing the number of frozen section biopsies performed. Further by providing real-time clinical information within minutes it can reduce indirect costs such as operating room time. It may also be used as an ad hoc for frozen section biopsies where frozen section facilities are available.
Objectives To determine the accuracy of self‐reported comorbidities compared with medical record review and the clinical and sociodemographic characteristics associated with accuracy of self‐reported comorbidities. Study Design We conducted a prospective study of 458 newly diagnosed head and neck cancer patients using self‐administered questionnaire and medical chart review data. Overall and itemwise consistency between self‐report and chart review was evaluated. Social, clinical, and demographic characteristics of consistent versus inconsistent responders were analyzed. Results Seventy‐four percent of patients had at least one comorbidity. There was good overall consistency between self‐report and chart review (k = 0.50). Compared with consistent responders, inconsistent responders were found to be older ( P < 0.05), have lower sleep ( P < 0.05) and physical activity scores ( P < 0.05), be more depressed ( P < 0.05), and have more severe comorbidities ( P < 0.05). Conclusions and Significance Self‐report may be considered as an alternative to chart review for comorbidity assessment in head and neck cancer patients. Younger patients, those with good general health, fewer depressive symptoms, and mild comorbidities, are more likely to give responses consistent with chart review.
6039 Background: Studies have demonstrated better prognosis for patients (pts) with HPV-initiated OPC when compared to OPC caused by smoking. A small subset of pts however experience disease recurrence and have poor outcomes. We report our Cleveland Clinic experience with HPV-initiated OPC in an effort to identify determinants of a poor prognosis. Methods: We identified pts with stage III-IVb HPV-initiated OPC treated with definitive chemoradiotherapy between 2002 and 2012 from an IRB approved registry. HPV-initiated disease was determined by positivity for p16 by immunohistochemistry or HPV DNA by fluorescent in-situ hybridization. Radiation therapy was administered to a total dose of 70-74 Gy. Chemotherapy consisted of either cisplatin and 5-Fluorouracil, cisplatin or cetuximab. Kaplan-Meier estimates of disease-free survival (DFS) and overall survival (OS) were calculated. Univariate (UVA) and multivariate analyses (MVA) using Cox proportional hazards regression were performed to identify variables associated with inferior DFS and OS. Results: Of the 228 patients identified, 17% had T4 disease, 40% had N2c/3 disease, 51% had a smoking history (>10 pack years) while 31% were lifetime never smokers. Median follow up was 40 months. 3-year DFS and OS was 89% and 90% respectively. UVA revealed that DFS was inferior in pts with T4 (HR = 2.525; 95% CI = 1.089 to 5.848; P = 0.03) and N2c-N3 (HR = 2.364; 95% CI = 1.062 to 5.263; P = 0.04) disease. OS was also inferior in pts with T4 disease (HR = 2.123; 95% CI = 1.042 to 4.329; P = 0.04), and pts with a smoking history (HR = 2.475; 95% = CI 1.192 to 5.128; P = 0.02). On MVA, the most important predictors for an inferior DFS were smoking history, T4 and N2c-N3 disease. Patients with 2 or more of these risk factors had a significantly worse 3 –year DFS (77% vs. 94%; HR = 4.082; 95% CI = 1.828 - 9.091; P <0.001) and OS (83% vs. 93%, HR = 2.283; 95% CI = 1.193 - 4.367; P 0.01). Conclusions: Patients with HPV-initiated OPC and at least two high risk features, including T4, N2c/3, or >10 pack years of smoking, had significantly inferior DFS and OS. Such patients should not be considered for treatment de-intensification strategies.
Abstract The purpose of these experiments was to develop a method of isolation, amplification, and identification of cochlear mitochondrial DNA (mtDNA) from minute quantities of tissue. Additionally, studies were designed to detect mtDNA deletions (mtDNA del) from the cochlea that previously have been amplified from other organ systems and tissues. MtDNA del have been associated with many pathologies, including neurological disorders, sensorineural hearing loss, ischemia, cardiomyopathies, and aging. DNA was extracted from rat and human tissues, and polymerase chain reaction was used to amplify mtDNA sequences. A 360 base pair (bp) cytochrome‐ b gene product and the highly conserved ND1‐16S ribosomal ribonucleic acid regions found only in mtDNA were amplified from all tissues. Preliminary studies have identified a 4834 bp mtDNA del in aged rats and a corresponding 4977 bp mtDNA del in aged humans. Additionally, preliminary results in human archival temporal bone studies reveal the presence of the 4977‐bp mtDNA deletion in two out of three patients with presbycusis. The deletion was not evident in age‐matched control patients without a history of presbycusis. This technique of mtDNA identification makes it possible to investigate specific mtDNA defects from a single cochlea, promoting the study of hereditary hearing loss and presbycusis at a molecular biologic level.
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