Liposome-encapsulated curcumin suppresses growth of head and neck squamous cell carcinoma in vitro and in xenografts through the inhibition of nuclear factor kappaB by an AKT-independent pathway.

PURPOSE: The purpose of this study was to determine whether a liposomal formulation of curcumin would suppress the growth of head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and UM-SCC1 in vitro and in vivo. EXPERIMENTAL DESIGN: HNSCC cell lines were treated with liposomal curcumin at different doses and assayed for in vitro growth suppression using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A reporter gene assay was done on cell lines to study the effect of liposomal curcumin on nuclear factor kappaB (NFkappaB) activation. Western blot analysis was done to determine the effect of curcumin on the expression of NFkappaB, phospho-IkappaBalpha, phospho-AKT (pAKT), phospho-S6 kinase, cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S. Xenograft mouse tumors were grown and treated with intravenous liposomal curcumin. After 5 weeks, tumors were harvested and weighed. Immunohistochemistry and Western blot analyses were used to study the effect of liposomal curcumin on the expression of NFkappaB and pAKT. RESULTS: The addition of liposomal curcumin resulted in a dose-dependent growth suppression of both cell lines. Liposomal curcumin treatment suppressed the activation of NFkappaB without affecting the expression of pAKT or its downstream target phospho-S6 kinase. Expression of cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S were reduced, indicating the effect of curcumin on the NFkappaB pathway. Nude mice xenograft tumors were suppressed after 3.5 weeks of treatment with i.v. liposomal curcumin, and there was no demonstrable toxicity of liposomal curcumin upon autopsy. Immunohistochemistry and Western blot analysis on xenograft tumors showed the inhibition of NFkappaB without affecting the expression of pAKT. CONCLUSIONS: Liposomal curcumin suppresses HNSCC growth in vitro and in vivo. The results suggest that liposomal curcumin is a viable nontoxic therapeutic agent for HNSCC that may work via an AKT-independent pathway.

Healthcare costs of acute and chronic tonsillar conditions in the pediatric population in the United States.

OBJECTIVE: To determine the prevalence and healthcare costs associated with the diagnosis and treatment of acute and chronic tonsillar conditions (ACT) in children. DESIGN: Cross-sectional analysis of the 2006, 2008, and 2010 Medical Expenditure Panel Surveys. METHODS: Pediatric patients (age < 18 years) were examined from the above mentioned database. From the linked medical conditions file, cases with a diagnosis of ACT were extracted. Ambulatory visit rates, prescription refills, and ambulatory healthcare costs were then compared between children with and without a diagnosis of ACT and acute versus chronic tonsillitis, with multivariate adjustment for age, sex, ethnicity, region, insurance coverage and comorbid conditions (e.g., asthma and otitis media). RESULTS: A total of 74.3 million children (mean age 8.55 years, 51% male) were sampled (raw N = 28,873). Of these, 804,229 children (1.1 ± 0.1%) were diagnosed with ACT annually (mean age 7.24 years, 49.1% male); 64.6 ± 2.0% had acute tonsillitis diagnoses and 35.4 ± 2.0% suffered from chronic tonsillitis. Children with ACT incurred an additional 2.3 office visits and 2.1 prescription fills (both p < 0.001) annually compared with those without ACT, adjusting for demographic variables and medical comorbidities, but did not have an increase in emergency department visits (p = 0.123). Children with acute tonsillar diagnoses carried total healthcare expenditures of $1303 ± 390 annually versus $2401 ± 618 for those with chronic tonsillitis (p = 0.193). ACT was associated with an incremental increase in total healthcare expense of $1685 per child, annually (p < 0.001). CONCLUSION: The diagnosis of ACT confers a significant incremental healthcare utilization and healthcare cost burden on children, parents and the healthcare system. With its prevalence in the United States, pediatric tonsillitis accounts for approximately $1.355 billion in incremental healthcare expense and is a significant healthcare utilization concern. LEVEL OF EVIDENCE: 2C.

Liposome encapsulated curcumin-difluorinated (CDF) inhibits the growth of cisplatin resistant head and neck cancer stem cells.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with 600,000 new cases every year worldwide. Although chemotherapeutics exist, five-year survival is only 50%. New strategies to overcome drug resistance are required to improve HNSCC treatment. Curcumin-difluorinated (CDF), a synthetic analog of curcumin, was packaged in liposomes and used to evaluate growth inhibition of cisplatin resistant HNSCC cell lines CCL-23R and UM-SCC-1R generated from the parental cell lines CCL-23 and UM-SCC-1 respectively. Growth inhibition in vitro and expression levels of the CD44 (cancer stem cell marker), cytokines, and growth factors were investigated after liposomal CDF treatment. The in vivo growth inhibitory effect of liposomal CDF was evaluated in the nude mice xenograft tumor model of UM-SCC-1R and the inhibition of CD44 was measured. Treatment of the resistant cell lines in vitro with liposomal CDF resulted in a statistically significant growth inhibition (p < 0.05). The nude mice xenograft study showed a statistically significant tumor growth inhibition of UM-SCC-1R cells and a reduction in the expression of CD44 (p < 0.05), indicating an inhibitory effect of liposomal CDF on CSCs. Our results demonstrate that delivery of CDF through liposomes may be an effective method for the treatment of cisplatin resistant HNSCC.

Coblation total tonsillectomy and adenoidectomy versus coblation partial intracapsular tonsillectomy and adenoidectomy in children.

OBJECTIVES/HYPOTHESIS: To evaluate the postoperative course of children who underwent coblation T&A versus those who underwent coblation partial intracapsular tonsillectomy and adenoidectomy (PITA). STUDY DESIGN: Retrospective cohort study. METHODS: Records of children undergoing consecutive tonsillectomies from July 2009 to October 2012 were analyzed. All surgeries used a coblation device. Outcomes including intraoperative and postoperative bleeding, pain, and return to preoperative diet were analyzed comparing the coblation T&A and coblation PITA patients. RESULTS: Of 415 patients evaluated, 258 (62.2%) underwent coblation T&A and 157 (37.8%) underwent coblation PITA. Seventeen (4.1%) patients experienced postoperative hemorrhage, 15 (88.2%) of whom underwent T&A and two (11.8%) of whom underwent PITA (P = 0.024). Multivariate analysis demonstrated that coblation T&A was a significant contributor to postoperative hemorrhage, with an odds ratio of 4.8 (95% confidence interval [CI]: 1.08-21.21) compared to coblation PITA. Patients who underwent T&A resumed normal diets significantly later (8 days, SD 4.6) than those who underwent PITA (5.4 days, standard deviation [SD]: 3.4) (P = 0.022). In terms of pain severity, more T&A patients reported "severe" pain and more PITA patients reported "moderate" pain (P = 0.047). More T&A patients experienced a "post-op dip," defined as increased pain during postoperative days 5-9, than did PITA patients (P < 0.001). CONCLUSIONS: Coblation PITA is a safe procedure that has a lower incidence of intraoperative and postoperative bleeding in children compared to coblation T&A. Patients may have less pain and return to preoperative diets sooner than those undergoing coblation T&A.

Comparison of dental health of patients with head and neck cancer receiving IMRT vs conventional radiation.

OBJECTIVE: To analyze the dental health of patients with head and neck cancer who received comprehensive dental care after intensity-modulated radiation therapy (IMRT) compared with radiation therapy (RT). STUDY DESIGN: Historical cohort study. SETTING: Veteran Affairs (VA) hospital. SUBJECTS AND METHODS: In total, 158 patients at a single VA hospital who were treated with RT or IMRT between 2003 and 2011 were identified. A complete dental evaluation was performed prior to radiation treatment, including periodontal probing, tooth profile, cavity check, and mobility. The dental treatment plan was formulated to eliminate current and potential dental disease. The rates of dental extractions, infections, caries, mucositis, xerostomia, and osteoradionecrosis (ORN) were analyzed, and a comparison was made between patients treated with IMRT and those treated with RT. RESULTS: Of the 158 patients, 99 were treated with RT and 59 were treated with IMRT. Compared with those treated with IMRT, significantly more patients treated with RT exhibited xerostomia (46.5% vs 16.9%; P < .001; odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.52), mucositis (46.5% vs 16.9%; P < .001; OR, 0.24; 95% CI, 0.11-0.52), and ORN (10.1% vs 0%; P = .014; OR, 0.07; 95% CI, 0.00-1.21). However, significantly more patients treated with IMRT were edentulous by the conclusion of radiation treatment (32.2% vs 11.1%; P = .002; OR, 3.8; 95% CI, 1.65-8.73). CONCLUSION: Patients who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT and more so with a complete dental evaluation prior to treatment.

Uncommon presentation of a benign nasopharyngeal mass in an adolescent: comprehensive review of pediatric nasopharyngeal masses.

Nasopharyngeal masses in the pediatric population are quite rare, and the majority of these are benign. In adolescent boys, there should be a high index of suspicion for juvenile nasopharyngeal angiofibromas. When malignant, the most common lesions encountered are rhabdomyosarcomas, carcinomas, and lymphomas. We report a single case from a tertiary care institution of an adolescent male with an unusual presentation of a benign nasopharyngeal mass and provide a comprehensive review of pediatric nasopharyngeal masses. Whenever possible, radiographic imaging should be obtained, in addition to biopsy, to assist in the diagnosis of pediatric nasopharyngeal masses.

Swallow preservation exercises during chemoradiation therapy maintains swallow function.

OBJECTIVE: To evaluate a swallow preservation protocol (SPP) in which patients received swallow therapy before, during, and after radiation treatment and its efficacy in maintaining swallowing function in head and neck cancer patients. DESIGN: Case series with chart review. SETTING: Tertiary care academic medical center. SUBJECTS AND METHODS: Eighty-five patients who received radiation (RT) or chemoradiation (CRT) participated in the SPP from 2007 to 2012. Subjects were divided into 2 groups: compliant and noncompliant with SPP. At each SPP visit, the diet of each patient was recorded as regular (chewable), puree, liquid, or gastrostomy tube (G-tube) dependent, along with their compliance with the swallow exercises. Patients were stratified by age, gender, tumor stage, type of treatment, radiation dose, diet change, dysguesia, odynophagia, pain, and stenosis. Statistical analysis was performed comparing the 2 compliance groups in regards to swallowing-related outcomes at 1 month after completion of therapy. RESULTS: Fifty-seven patients were compliant and 28 were noncompliant with SPP during treatment. The compliant group had a higher percentage of patients tolerating a regular diet (54.4% vs 21.4%, P = .008), a lower G-tube dependence (22.8% vs 53.6%, P = .008), and a higher rate of maintaining or improving their diet (54.4% vs 25.0%, P = .025) compared to noncompliant patients. CONCLUSION: A swallow preservation protocol appears to help maintain or improve swallow function in head and neck cancer patients undergoing RT or CRT. Patients who are able to comply with swallow exercises are less likely to worsen their diet, receive a G-tube, or develop stenosis.

Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKß protein of the NFκB pathway.

Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations of cisplatin showed a significant suppressive effect compared with treatment with either agent alone. Reduced expression of cyclin D1, IκBα, phospho-IκBα, and IKKß occurred in cisplatin- and curcumin-treated cell lines. Confocal microscopy showed expression of IKKß in the nucleus of the cell lines. Chromatin immunoprecipitation assay on DNA isolated from IKKß immunoprecipitated samples showed PCR amplification of interleukin-8 promoter sequences, a binding site of NFκB, indicating an interaction between IKKß and NFκB. Curcumin inhibited IKKß in the cytoplasm and nucleus, leading to reduced NFκB activity, with no effect on phospho-AKT. In vivo studies showed significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. The suppressive effect of curcumin was mediated through inhibition of cytoplasmic and nuclear IKKß, resulting in inhibition of NFκB activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of subtherapeutic doses of cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects of cisplatin.

Recovery of vocal fold paralysis after cardiovascular surgery.

OBJECTIVES/HYPOTHESIS: To review the incidence and time course of recovery of vocal fold paralysis (VFP) in adult patients after cardiovascular surgery. STUDY DESIGN: Retrospective cohort study of adults after cardiovascular surgery at a tertiary care academic medical center. METHODS: Patients with VFP after cardiovascular surgery were identified from a database of hospitalized patients undergoing voice and swallow evaluation. VFP was confirmed using transnasal fiberoptic laryngoscopy within 1 week of surgery. Follow-up laryngoscopy was performed in those with VFP in the outpatient clinic. Those with persistent paralysis were followed and the time course of recovery was noted. RESULTS: Eighty-six adult postoperative cardiovascular surgery patients (ages 34 to 83 years, mean 68) were identified from the inpatient voice and swallowing evaluation database. There were 20 patients (23%) with unilateral VFP. Thirteen patients followed-up for outpatient laryngoscopy. Ten of the thirteen patients (77%) ultimately had complete resolution of VFP. Three patients had persistent paralysis at a mean follow-up of 18 months. There was no obvious correlation between type of cardiovascular surgery and VFP. Signs of recovery were generally evident prior to 6 months and no recovery was seen beyond 12 months. CONCLUSIONS: Most patients with VFP after cardiovascular surgery recover fully. In accordance with previous laryngeal electromyography findings, neuropraxia during cardiovascular surgery will usually recover within 6 months.

Effectiveness of femoral nerve blockade for pain control after total knee arthroplasty.

Control of postoperative pain is a major concern for patients undergoing total knee arthroplasty (TKA). The purpose of this study was to investigate pain control and opioid use, as well as length of stay, ambulation time, antiemetic use, and degree of mobilization for patients undergoing total knee arthroplasty, comparing those receiving femoral nerve block (FNB) to those receiving no femoral nerve block. Using retrospective patient record data, 133 subjects from an acute care community hospital in western Canada were split into three groups: no FNB (control group, n = 49), single-shot FNB (n = 33), and continuous FNB (n = 51). There was a statistically significant improvement in pain control on day of surgery for the FNB group compared with the no-FNB group, and reduction in opioid usage on days 0, 1, and 2 in the continuous FNB group compared with the no-FNB and single-shot group. Also noted was a statistically significant reduction in antiemetic use in the FNB compared with the no-FNB group on the day after surgery. This study is in accordance with earlier studies that support continuous FNB as an effective method for achieving postoperative pain control and reducing opioid use for patients undergoing TKA.