Alternative therapies for chronic rhinosinusitis: A review.

The use of alternative medicine in chronic rhinosinus-itis (CRS) continues to increase in popularity, for the most part without meeting the burden of being based on sound clinical evidence. New and emerging treat-ments, both natural and developed, are numerous, and it remains a challenge for otolaryngologists as well as general practitioners to keep up to date with these therapies and their efficacy. In this systematic review, we discuss a number of alternative therapies for CRS, their proposed physiologic mechanisms, and evidence supporting their use. This analysis is based on our re-view of the English-language literature on alternative therapies for CRS (we did not include any therapies that are already recommended by accepted profession-al bodies). Data collection was performed using the PubMed database (not restricted to MEDLINE due to the nature of the subject matter), the Cochrane data-bases, and bibliography searches. We found that while many of the alternative therapies we reviewed might have a firm basis in science, they lack any clinical ev-idence to support their use specifically for CRS. Some emerging therapies, such as therapeutic ultrasonog-raphy and phonophoresis, show some promise, based on a growing body of positive evidence. In addition, the use of baby shampoo, thyme honey, and bromelain additives to saline lavage in CRS are all supported by clinical evidence, as is Sinupret, an oral preparation that contains echinacea. However, higher levels of ev-idence gleaned from large, well-designed, prospective, randomized, controlled trials are needed before any of these therapies can be recommended.

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated "risk of bias" tool to assess study quality. Four separate Phase I-II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5-34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I-III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.

Alternative therapies for chronic rhinosinusitis: A review.

The use of alternative medicine in chronic rhinosinusitis (CRS) continues to increase in popularity, for the most part without meeting the burden of being based on sound clinical evidence. New and emerging treatments, both natural and developed, are numerous, and it remains a challenge for otolaryngologists as well as general practitioners to keep up to date with these therapies and their efficacy. In this systematic review, we discuss a number of alternative therapies for CRS, their proposed physiologic mechanisms, and evidence supporting their use. This analysis is based on our review of the English-language literature on alternative therapies for CRS (we did not include any therapies that are already recommended by accepted professional bodies). Data collection was performed using the PubMed database (not restricted to MEDLINE due to the nature of the subject matter), the Cochrane databases, and bibliography searches. We found that while many of the alternative therapies we reviewed might have a firm basis in science, they lack any clinical evidence to support their use specifically for CRS. Some emerging therapies, such as therapeutic ultrasonography and phonophoresis, show some promise, based on a growing body of positive evidence. In addition, the use of baby shampoo, thyme honey, and bromelain additives to saline lavage in CRS are all supported by clinical evidence, as is Sinupret, an oral preparation that contains echinacea. However, higher levels of evidence gleaned from large, well-designed, prospective, randomized, controlled trials are needed before any of these therapies can be recommended.

Ectopic expression of protein kinase C-ß sensitizes head and neck squamous cell carcinoma to diterpene esters.

BACKGROUND: The objective of this study was to examine the effect of specific Protein kinase C (PKC) isoform re-expression in solid malignancies, particularly head and neck squamous cell carcinoma cell lines, and the impact this may have on treatment with known activators of PKC. MATERIALS AND METHODS: The constitutive expression of PKC isoforms were determined in six head and neck squamous cell carcinoma (SCC) cell lines. Cytotoxicity of the prototypic phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) and the novel diterpene ester PEP005 was established. Viral transduction to re-express PKCß isoforms in two of these cell lines was performed, and its effect on the sensitivity to the compounds was quantified. RESULTS: Tongue and hypopharyngeal SCC cell lines were resistant to both TPA and PEP005, with the concentration required to inhibit growth by 50% (IC50) being >1,000 ng/ml. CAL-27 (tongue SCC) and FaDu (hypopharyngeal SCC) cell lines re-expressing PKCßI and -ßII isoforms demonstrated IC50 of 1-5 ng/ml with TPA or PEP005. CONCLUSION: Re-expression of PKCß in head and neck SCC cell lines leads to cells one thousand-times more sensitive to the cytotoxic effects of phorbol or diterpene esters in culture. This highlights the importance of the isoform in tumor progression and presents the potential benefit of these compounds in malignancies expressing the protein, and in combination therapy.

Efficacy and safety of long-term antibiotics (macrolides) for the treatment of chronic rhinosinusitis.

Long-term treatment of airway inflammation/infection with macrolide antibiotics has now been in use for almost 30 years. Whereas the beneficial clinical effect in cystic fibrosis and COPD have been backed up by randomized controlled trials, the evidence from the upper airways is not as strong. We have identified 22 open studies in chronic rhinosinusitis, with and without polyps, but only 2 randomized controlled trials. Of the controlled trials, the one including CRS patients just without polyps, showed a significant effect in sino-nasal outcome test, saccharine transit time, nasal endoscopy, and IL-8 levels in lavage fluid after 12 weeks of roxithromycin, whereas, in the other RCT with a mixed study group of CRS patients with and without polyps, 12 weeks of azithromycin showed no effect compared to placebo. Concerns regarding the risk of macrolides to induce arrhythmia have been raised. Recent FDA guidelines changes has recommended caution in patients with risk factors such as long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia. Ototoxicity is another concern. Long-term macrolide antibiotics in the treatment of CRS patients is still a viable option in a select group of patients.

The effect of endoscopic sinus surgery on bacterial biofilms in chronic rhinosinusitis.

OBJECTIVE: To determine whether or not endoscopic sinus surgery (ESS) alters bacterial biofilms in patients with chronic rhinosinusitis (CRS) after three months of follow-up. STUDY DESIGN: Prospective study. SETTING: Department of Otorhinolaryngology-Head and Neck Surgery, University of Queensland. SUBJECTS AND METHODS: Participants with CRS from the Princess Alexandra Hospital Department of Otorhinolaryngology-Head and Neck Surgery and from Logan Hospital were enrolled in the study (2008-2009). The total number of patients was 28, and the age range was 18 to 65 years. All patients underwent pre- and post-ESS questionnaires, endoscopic scoring, and nasal swabs for bacterial culture. Crystal violet staining was used to assess biofilm formation on a 96-well culture plaque. RESULTS: ESS resulted in a statistically significant improvement in quality-of-life, subjective, and objective outcome measures after three months. A significant reduction was observed in biofilm density before and after ESS (2.63 versus 1.3, P = 0.043). No correlations between the reduction of bacterial biofilms with any of the subjective, objective, and quality-of-life outcomes were seen in our study. CONCLUSION: ESS was shown to be capable of reducing the prevalence of bacterial biofilms but did not eliminate them entirely. There was no correlation between altered biofilm formation and improved outcome measures in individual patients.

Anti-inflammatory effects of macrolides: applications in chronic rhinosinusitis.

The anti-inflammatory effects of macrolides are significant. The clinical impact on diffuse panbronchiolitis (DPB) has improved 10-year survival from 12% to more than 90% for these patients. The immunomodulatory activity of macrolides has been a source of mechanistic research as well as clinical research in non-DPB inflammatory airway disease. Suppression of neutrophilic inflammation of the airways has been demonstrated as the most robust immunomodulatory response from 14- and 15-membered ring macrolides. The inhibition of transcription factors, mainly nuclear factor-kB and activator protein 1, from alterations in intracellular cell signaling drives this mechanism. The suppression of interleukin-8 to a range of endogenous and exogenous challenges characterizes the alterations to cytokine production. The inflammatory mechanisms of chronic rhinosinusitis (CRS) have been a major non-DPB focus. Macrolides have been trialed in more than 14 prospective trials and are the focus of numerous research projects. Evidence for a strong clinical effect in CRS is mounting, but results may be tempered by researchers' inability to characterize the disease process. Eosinophilic dominated CRS is unlikely to respond, based on current research understanding and data from clinical trials. This article discusses the current concepts of macrolides and their application in the management of CRS.

Effects of long-term clarithromycin treatment on lavage-fluid markers of inflammation in chronic rhinosinusitis.

Macrolides can be clinically effective in chronic rhinosinusitis (CRS). However, little is known about how these drugs affect pathophysiological features of CRS in vivo. In the present study, patients with CRS were subjected to long-term treatment with clarithromycin. Nasal lavages with and without histamine (40 and 400 microg ml(-1)) were carried out prior to and late into the treatment period. Histamine was included as a tool to produce plasma exudation, a process known to move free cellular products from the mucosal tissue into the airway lumen thereby enriching nasal surface liquids with such products. Interleukin-8 (IL-8), myeloperoxidase (MPO), eosinophil cationic protein (ECP), alpha(2)-macroglobulin and fucose were monitored as indices of pro-inflammatory cytokine production, neutrophil and eosinophil granulocyte activities, plasma exudation and mucinous secretion, respectively. Clarithromycin reduced the lavage fluid levels of IL-8 at the low-dose histamine observation (P<0.001). There was a trend towards reduced MPO by the treatment, whereas ECP was significantly reduced at the low-dose histamine observation (P<0.05). alpha(2)-Macroglobulin was reduced by clarithromycin (saline lavages) (P = 0.05), whereas fucose was unaffected. The exudative responsiveness to high-dose histamine was significantly reduced by the treatment (P<0.05). Furthermore, significantly lower levels of fucose were observed at the low-dose histamine observation (P<0.01). We conclude that long-term clarithromycin treatment likely exerts an anti-inflammatory effect in CRS.

Macrolide therapy of chronic rhinosinusitis.

There is growing evidence that several antibiotics exert their beneficial effect not only by inhibiting or killing bacterial pathogens but also by down-regulating pro-inflammatory mechanisms. This review aims to give an overview of the immunomodulatory properties of macrolide antibiotics in chronic rhinosinusitis and to present a treatment algorithm for managing the difficult CRS patient with long-term, low-dose macrolide antibiotics. The most prominent effect of macrolides noted in vitro is the inhibition of pro-inflammatory cytokines such as interleukin-8. This effect is probably secondary to inhibition of the activation of transcription factor NF-kappaB. As a result an attenuation of neutrophilic inflammation takes place. Moreover, macrolides inhibit bacterial virulence and biofilm formation. In vivo, a reduction of pro-inflammatory cytokines is evident in nasal lavage as well as a reduction in nasal secretions. The clinical effect is shown in less facial pain, less headache, less post nasal drip, fewer exacerbations of sinusitis and improved quality of life. The treatment should be targeted towards the non-atopic patients with bilateral disease whereas in unilateral disease, surgery is the first option. Macrolide resistant bacterial strains have to be monitored, but to date they have not been of clinical importance.

Squamous cell carcinoma of the floor of the mouth: tumour thickness and the rate of cervical metastasis.

BACKGROUND: Increased thickness of oral cavity squamous cell carcinoma (SCC) has been shown to be associated with higher rates of cervical metastasis. Most of the previous studies have focused on SCC of the oral tongue. There are few studies that have examined solely carcinoma of the floor of the mouth and these studies differ in the thickness of tumour that is associated with significantly increased rates of cervical metastasis. METHODS: Patients with SCC of the floor of the mouth of all stages who were treated with excision and neck dissection were identified. Primary tumour thickness and other pathological features were determined in the pathological specimens and were correlated to the incidence of pathological cervical lymph node metastasis. Fisher's exact test and the unpaired t-test were used for statistical analysis. RESULTS: Fifty-three patients were studied (43 men and 10 women). The median age was 56.5 years (range 43-86 years). The median tumour thickness in patients with lymph node metastases (14.6 mm) differed significantly from those without metastases (8.6 mm) (P = 0.004). When T1 and T2 cases were looked at in isolation, the median tumour thickness of cases with lymph node metastases (11.1 mm) again was significantly greater than those without metastases (4.6 mm) (P = 0.04). Subgrouping tumours into those > or =7.5 mm or < 7.5 mm showed a significantly increased rate of lymph node metastasis (57% compared with 12%, P = 0.001). There was no statistically significant association between perineural invasion or tumour differentiation and the presence of lymph node metastases. CONCLUSION: Tumour thickness has been shown to be directly related to rates of cervical lymph node metastasis in floor of mouth SCC. The primary tumour thickness associated with significantly increased rates of metastasis is similar to that shown in previous studies examining SCC of the oral tongue.

A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis.

OBJECTIVES: The antiinflammatory effect of macrolide antibiotics has been well-established, as has their role in the treatment of certain disorders of chronic airway inflammation. Several studies have suggested that long-term, low-dose macrolides may be efficacious in the treatment of chronic rhinosinusitis; however, these studies have lacked a control group. To date, this effect has not been tested in a randomized, placebo-controlled study. METHOD: The authors conducted a double-blind, randomized, placebo-controlled clinical trial on 64 patients with chronic rhinosinusitis. Subjects received either 150 mg roxithromycin daily for 3 months or placebo. Outcome measures included the Sinonasal Outcome Test-20 (SNOT-20), measurements of peak nasal inspiratory flow, saccharine transit time, olfactory function, nasal endoscopic scoring, and nasal lavage assays for interleukin-8, fucose, and a2-macroglobulin. RESULTS: There were statistically significant improvements in SNOT-20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid (P<.05) in the macrolide group. A correlation was noted between improved outcome measures and low IgE levels. No significant improvements were noted for olfactory function, peak nasal inspiratory flow, or lavage levels for fucose and a2-macroglobulin. No improvement in any outcome was noted in the placebo-treated patients. CONCLUSION: These findings suggest that macrolides may have a beneficial role in the treatment of chronic rhinosinusitis, particularly in patients with low levels of IgE, and supports the in vitro evidence of their antiinflammatory activity. Additional studies are required to assess their place in clinical practice.

Anti-inflammatory effects of macrolide antibiotics in the treatment of chronic rhinosinusitis.

Apart from their obvious antibiotic effects, the macrolides have some potentially useful immunomodulatory properties. Which pathway dominates the clinical effect is debatable. Favoring the anti-inflammatory effects are the substantial in vitro data and serum concentrations well below minimal inhibitory concentrations for several pathogens. Furthermore, tissue reparative effects are seen in diffuse panbronchiolitis regardless of the presence of P. aeruginosa, a pathogen not sensitive to macrolide antibiotics. Clinical studies support the view that prolonged treatment is likely to be beneficial in most patients who have CRS. The evidence concerning CRS is still weak because placebo-controlled trials are missing. One should remember, however, the general lack of placebo-controlled trials even in the "more established" medical management of CRS. The concern for an increasing incidence of macrolide-resistant bacterial strains must be taken seriously. Therefore the authors advocate repeated nasal cultures during macrolide therapy. It is hoped that the future will bring larger, prospective, randomized, controlled trials that will investigate the efficacy and safety of macrolides in CRS.

Challenge-induced plasma exudation and mucinous secretion in human airways.

Secretion of mucins and exudation of plasma are distinct processes of importance to innate immunity and inflammatory disease. Yet, little is known about their relation in human airways. The objective of the present study was to use the human nasal airway to determine mucinous secretion and plasma exudation in response to common challenge agents and mediators. Ten healthy volunteers were subjected to nasal challenge-lavage procedures. Thus, the nasal mucosa was exposed to increasing doses of histamine (40 and 400 microg ml(-1)), methacholine (12.5 and 25 mg) and capsaicin (30 and 300 ng ml(-1)). Fucose was selected as a global marker of mucinous secretion and alpha(2)-macroglobulin as an index of exudation of bulk plasma. All challenge agents increased the mucosal output of fucose to about the same level (P<0.01-0.05). Once significant secretion had been induced the subsequently increased dose of the challenge agent, in the case of histamine and methacholine, failed to further increase the response. Only histamine increased the mucosal output of alpha(2)-macroglobulin (P<0.01). We conclude that prompt but potentially rapidly depleted mucinous secretion is common to different kinds of airway challenges, whereas inflammatory histamine-type mediators are required to produce plasma exudation. Along with the acknowledged secretion of mucins, a practically non-depletable, pluripotent mucosal output of plasma emerges as an important component of the innate immunity of human airways.

Effect of clarithromycin on nuclear factor-kappa B and transforming growth factor-beta in chronic rhinosinusitis.

OBJECTIVES: Long-term, low-dose macrolide therapy is effective in the treatment of chronic rhinosinusitis. It is believed that macrolide antibiotics produce this benefit through an anti-inflammatory effect. In this study, the effect of clarithromycin treatment on the expression of transforming growth factor (TGF)-beta and the key pro-inflammatory nuclear transcription factor, NF-kappa B, was examined in vitro and in vivo. STUDY DESIGN AND METHODS: In vitro: nasal mucosa was obtained from 10 patients with chronic sinusitis and was cultured for 24 hours in the presence of clarithromycin or control. Cellular expression of TGF-beta and NF-kappa B was determined by immunohistochemistry. In vivo: 10 patients with chronic rhinosinusitis were treated for 3 months with clarithromycin. Nasal mucosal biopsies were taken pre- and posttreatment. Cellular expression of TGF-beta and NF-kappa B was again determined by immunohistochemistry. RESULTS: Clarithromycin, when applied to nasal biopsies in vitro, reduced cellular expression of TGF-beta and NF-kappa B. Nasal biopsies taken before and after clarithromycin treatment showed no differences in cellular expression of NF-kappa B or TGF-beta. CONCLUSION: Clarithromycin can reduce cellular expression of TGF-beta and NF-kappa B when applied in vitro, but its action during clinical therapy is less clear. Clarithromycin is capable of inhibiting pro-inflammatory cytokines in vitro, and reductions of TGF-beta and NF-kappa B may represent additional mechanisms by which macrolides reduce inflammation in chronic airway disease. Discrepancies between the actions of clarithromycin on nasal biopsies in vitro and after clinical therapy warrant further investigation.

Chronic rhinosinusitis and eosinophils: do macrolides have an effect?

PURPOSE OF REVIEW: Long-term, low-dose macrolide therapy is effective in the treatment of chronic airway inflammation. It is believed that macrolide antibiotics produce this benefit through an antiinflammatory effect that is separate from their antibiotic effect. Eosinophils are key mediators in the inflammation seen in chronic rhinosinusitis. This review discusses the effect of macrolides on eosinophilic inflammation. RECENT FINDINGS: In vitro studies recently have suggested that macrolides increase eosinophil apoptosis and reduce production of eosinophil chemotactic cytokines and adhesion molecules. In vivo studies have shown a reduction in eosinophil count and activity in asthma and chronic rhinosinusitis. Clinical response to macrolide treatment is thought to be less likely in patients with atopy. SUMMARY: In contrast to the evidence supporting the effect of macrolides on neutrophilic inflammation, there are limited data to suggest an influence on eosinophilic inflammation. For this reason, patients with prominent eosinophilic inflammation may in the future be identified as being less likely to respond to treatment. Further in vitro and clinical studies are required to investigate this subject.

Massive splenomegaly is associated with significant morbidity after laparoscopic splenectomy.

OBJECTIVE: To evaluate the impact of spleen weight on operative and clinical outcome in a series of 108 consecutive laparoscopic splenectomies. BACKGROUND: Laparoscopic splenectomy as an alternative to open splenectomy for splenomegaly is regarded as controversial. METHODS: Patients underwent laparoscopic splenectomy for a range of hematological disorders between November 1992 and February 2000. Multiple linear and logistic regression analysis were used to assess the effect of massive splenomegaly (>1000 g) on perioperative mortality and morbidity, after adjusting for the joint effects of patient age, weight, pre- and postoperative full blood counts, operating time, estimated blood loss, conversion rate, reoperation rate, and duration of hospital stay. RESULTS: Massive splenomegaly was recorded in 27 of 108 (25%) cases. In this group, splenic weight ranged from 1000 to 4750 g (median, 2500 g). Patients with splenic weight >1000 g had a significantly longer median operating time (170 vs. 102 minutes, P < 0.01), conversion rate (5/27 vs. 4/81, P < 0.05), postoperative morbidity (15/27 vs. 4/81, P < 0.01), and median postoperative stay (5 vs. 3 days, P < 0.01). Multivariate analysis found splenic weight to be the most powerful predictor of morbidity (P < 0.01). Patients with splenomegaly (>1000 g) were 14 times likely to have post operative complications. One patient died 3 days after surgery, following a pulmonary embolus (spleen weight 500 g, mortality 1/108, 0.9%). CONCLUSIONS: Laparoscopic splenectomy is feasible in patients with giant spleens. However, it is associated with greater morbidity, and the advantages of minimal access surgery in this subgroup of patients are not so clear.

Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis.

OBJECTIVES: Long-term, low-dose macrolide therapy is effective in the treatment of chronic rhinosinusitis. The mechanism of its anti-inflammatory effect and how this differs from corticosteroids remains unclear. The effect of clarithromycin and prednisolone on interleukin-5, interleukin-8, and granulocyte-macrophage colony-stimulating factor production by cultured chronic sinusitis nasal mucosa was examined in the study. STUDY DESIGN AND METHODS: Nasal mucosa was obtained from 11 patients with chronic sinusitis. This tissue was cultured for 24 hours in the presence of clarithromycin or prednisolone at a variety of concentrations. Cytokine levels were determined by enzyme-linked immunoassay. RESULTS: Clarithromycin and prednisolone each produced significant reductions in interleukin-5, interleukin-8, and granulocyte-macrophage colony-stimulating factor production. There was no significant difference between the effects of clarithromycin and prednisolone. CONCLUSION: Macrolide antibiotics are capable of inhibiting pro-inflammatory cytokine production in vitro and are as potent as prednisolone. This mechanism is likely to be at least partly responsible for the clinical efficacy of macrolide antibiotics in chronic rhinosinusitis.