[Advances in the use of bevacizumab for the treatment of respiratory papilloma].

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

Systemic bevacizumab for recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a benign tumor of the respiratory tract associated with human papillomavirus 6 and 11. Patients undergo multiple surgical debridements for management of growing papilloma. Adjuvant treatment options for RRP in children are often ineffective and do not decrease the need for repeated surgical debridement. We report on three patients with severe disease refractory to surgery who were treated with 10 mg/kg systemic bevacizumab every 4 weeks. All patients had improvement in voice and reduced need for surgical debridement. Interval between bevacizumab doses was gradually increased to every 8-12 weeks. Adverse events included mild proteinuria and self-resolving epistaxis.

Clinical application of photodynamic therapy for malignant airway tumors in China.

With the development of interventional pulmonology, photodynamic therapy (PDT) is gradually being used in the treatment of respiratory malignant tumors because of its low level of trauma, high specificity, and compatibility with traditional or common therapies. However, at present, the data of clinical evidence-based medicine for PDT applied in central airway tumors is very limited, and derives mainly from case reports or series of case studies which lack consensus on clinical diagnosis and treatment. In order to further disseminate China's experience, the Tumor Photodynamic Therapy Committee of China Anti-Cancer Association and the World Endoscopy Association-Respiratory Endoscopy Association invited experts from relevant fields to form an expert committee. After several rounds of discussion and revision by this committee, and following a vote, the consensus was formulated for reference by physicians in respiratory, oncology and other related disciplines to refer to the practice of tumor photodynamic therapy.

Outcomes of bevacizumab and cidofovir treatment in HPV-associated recurrent respiratory papillomatosis - review of the literature.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is caused by human papilloma virus types 6 and 11 and occurs in both children and adults. It is characterized by the proliferation of benign squamous papillomas within the aerodigestive tract. The problem with recurrent respiratory papillomatosis treatment is the high recurrence of papilloma growth after surgical removal. METHOD: A literature review was carried out through surveys based on electronic data in public domains: MedLine (USA National Library of Medicine), PubMed and SciELO, using the keywords recurrent respiratory papillomatosis, adjuvant treatment, cidofovir, and bevacizumab. All types of papers written in English were included (cross-sectional, prospective and retrospective clinical trials, review papers, and case reports). RESULTS: In the recent literature, several types of treatment such as surgery with mechanical debulking or laser and adjuvant therapies are mentioned. Intralesional bevacizumab and cidofovir treatment may increase the interval between surgical procedures and decrease the number of procedures per year. CONCLUSIONS: There is still an ongoing discussion within the European Laryngological Society regarding the balance between effectiveness and side effects of RRP adjuvant treatment, but recent results show promising long-term effects. Bevacizumab and cidofovir in aggressive RRP give hope for improved treatment outcomes.

Adjuvant antiviral therapy for recurrent respiratory papillomatosis.

BACKGROUND: This is an update of a Cochrane Review originally published in Issue 4, 2005 of The Cochrane Library and previously updated in 2010.Recurrent respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the upper airway. It can affect both adults and children causing airway obstruction and voice change. Treatment usually involves repeated surgical debulking of the papillomata. Several agents have been proposed as adjuvants to surgical debulking, including antivirals, administered systemically or injected into the lesions. OBJECTIVES: To assess the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children and adults. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 24 February 2012. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: We identified 143 references from the searches. Forty-three were appropriate for retrieval and assessed for eligibility by the authors. One randomised controlled trial met the inclusion criteria, involving 19 participants. We contacted the authors to obtain additional data to facilitate the review. MAIN RESULTS: The included study was a single-institution, randomised, double-blind, placebo-controlled trial of intralesional cidofovir administered at the time of surgical debulking. Adults (n = 15) and children (n = 4) were included. We judged the study to have a reasonably low risk of bias. After a 12-month trial period, no difference was found between the cidofovir and placebo groups. Both groups showed a significant reduction in disease extent (as assessed at the time of surgery using the Derkay Scoring System), but no significant change in health-related quality of life. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the efficacy of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children or adults. The included randomised controlled trial showed no advantage of intralesional cidofovir over placebo at 12 months. The study was limited by a small sample size and a change in the cidofovir concentration midway through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. An adequately powered randomised controlled trial of intra-lesional cidofovir, consistently using higher concentrations of cidofovir in comparison with injected placebo, would be required to determine effectiveness convincingly. Future studies must include health-related quality of life and symptom-based outcome measures.

Propranolol is an effective treatment for airway haemangiomas: a critical analysis and meta-analysis of published interventional studies.

Haemangiomas represent the most common benign tumours in infancy, affecting 1-2% of newborns. The present meta-analysis aimed to critically review the current evidence on the efficacy of propranolol in the management of airway haemangiomas, and explore potential adverse events and treatment failures. A literature review was performed in Medline and other available database sources, along with critical analysis of pooled data. Seventeen studies were included in the analysis. No study represented Level I evidence. The total number of treated patients was 61; 14 patients received propranolol as single-treatment. The comparative effectiveness of propranolol vs. systemic steroids was documented in 35 children, and showed superior outcome in the vast majority (94%, p < 0.001). The mean obstruction before propranolol administration was 72%, and after intervention was 20% (p < 0.001). The mean referral-age for children with airway haemangiomas was 2.4 months, the mean starting-age of propranolol treatment was 5.1 months and the mean follow-up period was 8.4 months. Four children failed to respond (6.5%), and in seven the haemangioma relapsed after discontinuation of treatment (11.5%). The results of the present study suggest that propranolol can be recommended for the treatment of airway haemangiomas, as it was found to be effective and outperformed the previously-considered gold standard treatment methods, with fewer side-effects. Immediate treatment with propranolol should be initiated once a diagnosis of symptomatic airway haemangioma is confirmed, and cardiovascular assessment has been performed. Children should remain on propranolol until the haemangioma enters the phase of involution. Active parental monitoring is essential to ensure treatment safety.

Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways.

BACKGROUND: Non-sinonasal neuroendocrine carcinomas (NSNECs) of the head and neck are considered an unfrequent clinico-pathological entity. Combined modality treatment represents an established therapeutic option for undifferentiated forms where distant metastasis is a common pattern of failure. METHODS: We report on a case of NSNEC treated with sequential chemo-radiation consisting of 6 cycles of cisplatin and etoposide followed by loco-regional radiation to the head and neck and simultaneous prophylactic cranial irradiation to prevent from intracranial spread, delivered with helical tomotherapy with the 'hippocampal avoidance' technique in order to reduce neuro-cognitive late effects. RESULTS: One year after the end of the whole combined modality approach, the patient achieved complete remission, with no treatment-related sub-acute and late effects. CONCLUSIONS: The present report highlights the importance of multidisciplinary management for NSNECs of the head and neck, as the possibility to achieve substantial cure rates with mild side effects with modern radiotherapy techniques.

Difficult central venous access removal: case reports of the use of endovascular snare shearing of endothelialized tetherings.

Although a fibrin sheath occurs in most long-standing central venous catheters, they do not typically interfere with complete removal of the catheter. We present 2 cases of long-standing catheters that could not be removed with simple surgical techniques because of endotheliazation via fibrous attachments to the venous wall. Both catheters were successfully removed using a modified snare technique through the right femoral vein.

Malignant respiratory-digestive fistulas.

PURPOSE OF REVIEW: Malignant tracheoesophageal or bronchoesophageal or, less commonly, esophageal-lung parenchyma fistulas are late developments of advanced cancer of the esophagus, lung or mediastinum. Patients present mainly with intractable cough and repeated respiratory infections. Rapid deterioration and death results if this condition is left untreated. RECENT FINDINGS: The use of the antiangiogenesis drug bevacizumab along with radiation therapy have been linked to the development of malignant tracheoesophageal fistula/malignant bronchoesophageal fistula in patients treated for both small-cell and nonsmall-cell lung carcinoma. Three case series have been published during 2009 presenting characteristics, treatment options and associated complications. The best palliation for this malignant condition is achieved with endoscopic placement of esophageal, respiratory or parallel stenting (esophagus and airway). Dual stenting appears to work better than single prosthesis both for palliation and safety. There were also some reports of unusual complications related to prosthesis placement as treatment of this condition. Particular attention has to be paid to tracheal compression/erosion secondary to esophageal stents. SUMMARY: Respiratory-digestive fistulas are devastating complications of advanced cancer. Research has brought new understanding relevant to clinical practice.

[The schedule of intralesional papillomatosis treatment with cidofovir]. / Schemat postepowania i wstepne wyniki leczenia brodawczakow krtani dotkankowym preparatem cidofovir.

INTRODUCTION: Recurrent respiratory papillomatosis (RRP) is a rare disease in children and adults. It is characterized by proliferation of benign squamous cell papillomas within the respiratory-digestive tract, predominantly the larynx. Standard treatment consists of surgical excision of papillomata to maintain airway patency and voice quality. For last several years cidofovir is the most contemporary adjuvant anti-viral treatment for recurrent respiratory papillomatosis and its topical use is widely described. MATERIAL AND METHODS: Intralesional cidofovir therapy was given to 20 patients treated for laryngeal papillomas in the Department of Otolaryngology in Poznan between I-XII.2009. The character of the lesion differed: from one anatomical site and moderate growth to four or five localizations with heavy extension. The number of cidofovir injections per patient varied from one to six times and the volume of solution ranges from 1-12 ml. The cidofovir injections were combined with laser or mechanical excision of the lesions. In disperse papillomata the injections administered in particular anatomical sites in 4-6 weeks period. In massive lesions injections were repeated in the same anatomical site. RESULTS: Complete remission was observed in 3 out of 20 patients. 12 patients show remission in a place of cidofovir injection. In 4 patients during the 4 week observation new foci of papillomatosis occurred. In two patients hepatic toxic side effect were observed. CONCLUSIONS: Intralesional cidofovir injection has been shown to be an effective an safe therapy for laryngeal papilloma and should be considered in those patients who experienced disease relapse.

Molecular networks in respiratory epithelium carcinomas.

Current anti-cancer research is focused on cell surface receptors targeting, mainly epidermal growth factor receptor and vascular endothelial growth factor receptor, against which a few targeted agents are now available in clinical practice. Recent improvements of our understanding on the intracellular networks that participate in respiratory epithelium carcinogenesis have further elucidated the role of a variety of molecules that represent attractive targets for novel therapeutic strategies. The aim of this review is to explore the potential therapeutic opportunities of the manipulation of these pathways.

Degrees of dysplasia and the use of cidofovir in patients with recurrent respiratory papillomatosis.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a benign disease characterized by recurrent lesions in the airway. The prevalence and degree of dysplasia that is present in the natural course of RRP is not well established. Adjuvant therapies, such as cidofovir, have been tried with the goal of decreasing the interval between repeat surgical treatments, the mainstay of therapy. Although, the off-label use of cidofovir to treat RRP has been common, there have been concerns regarding carcinogenic transformation following the use of cidofovir. This study aims to explore the association between increasing degree of papilloma dysplasia and the use of cidofovir in the context of the natural progression of dysplasia in RRP. STUDY DESIGN: Retrospective case series. METHODS: Demographic data and surgical history were obtained through chart reviews for this retrospective case series of 13 patients with RRP who had histopathologic biopsies done before and after exposure to cidofovir. Pathologic data collected over 10 years from serial excisions at the University of Iowa Hospitals were reviewed by a single pathologist, and the highest degree of dysplasia was noted per excision time. RESULTS: Of the 176 specimens collected in these 13 patients with serial papilloma biopsies, 5.7% had no dysplasia, 57.4% had mild dysplasia (grade 1), 28.4% had moderate dysplasia (grade 2), and 8.5% had severe dysplasia (grade 3). A comparison of each patient's multiple biopsies across time suggested that the dysplastic grade was worse in two patients, better in four patients, and virtually unchanged in seven patients. There was no clear-cut pattern between the use of cidofovir and the degree of dysplasia over time. CONCLUSIONS: These results strongly suggest that intralesional cidofovir therapy does not correlate with worsening dysplastic progression. Dysplasia is relatively common in the setting of RRP; however, the prognostic significance of this finding is unknown. Additional research is needed to delineate the natural progression of dysplasia and its clinical significance in RRP, as well as the efficacy of cidofovir.

Adjuvant antiviral therapy for recurrent respiratory papillomatosis.

BACKGROUND: This is an update of a Cochrane Review originally published in Issue 4, 2005 of The Cochrane Library.Recurrent respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the upper airway. It can affect both adults and children causing airway obstruction and voice change. Treatment usually involves repeated surgical debulking of the papillomata. Several agents have been proposed as adjuvants to surgical debulking, including antivirals, administered systemically or injected into the lesions. OBJECTIVES: To assess the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children and adults. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; mRCT and additional sources for published and unpublished trials. The date of the most recent search was 30 September 2009. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: We identified 143 references from the searches. Forty-three were appropriate for retrieval and assessed for eligibility by the authors. One randomised controlled trial met the inclusion criteria, involving 19 participants. We contacted the authors to obtain additional data to facilitate the review. MAIN RESULTS: The included study was a single-institution, randomised, double-blind, placebo-controlled trial of intralesional cidofovir administered at the time of surgical debulking. Adults (n = 15) and children (n = 4) were included. After a 12-month trial period, no difference was found between the cidofovir and placebo groups. Both groups showed a significant reduction in disease extent (as assessed at the time of surgery using the Derkay Scoring System), but no significant change in health-related quality of life. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the efficacy of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children or adults. The included randomised controlled trial showed no advantage of intralesional cidofovir over placebo at 12 months. The study was limited by a small sample size and a change in the cidofovir concentration midway through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. An adequately powered randomised controlled trial of intra-lesional cidofovir, consistently using higher concentrations of cidofovir in comparison with injected placebo, would be required to determine effectiveness convincingly. Future studies must include health-related quality of life and symptom-based outcome measures.

Potential risk factors associated with the use of cidofovir to treat benign human papillomavirus-related disease.

BACKGROUND: Cidofovir is currently being used off-licence to treat different viral infections, such as benign low-risk human papillomavirus (HPV)-related recurrent respiratory papillomatosis (RRP). There are concerns over the safety of this practice as rat studies demonstrated a high malignant transformation rate. As yet, there are no clinical reports of cidofovir-induced malignant changes in humans. METHODS: Telomerase immortalised human keratinocytes (hTert) stably expressing E6 proteins from either low-risk HPV6b or high-risk HPV16 and vector control cells were treated with either low-dose (5 microg/ml) or higher dose (30 microg/ml) cidofovir for 2 days and the effects evaluated by clonogenic survival assays. Based on these results, gene expression microarray analysis was performed on cidofovir-treated low-risk E6 and vector cells before, during and after drug treatment, and the results verified by real-time PCR. RESULTS: Both low-risk and high-risk E6-expressing cells show significantly improved long-term survival compared with vector control cells when exposed to 5 microg/ml cidofovir for 2 days, (hTert T6E6 P=0.0007, hTert T16E6 P=0.00023 and hTert vector control P=0.62). Microarray and real-time PCR analyses of low-dose cidofovir-treated low-risk E6-expressing cells revealed changes in gene expression that are known to be associated with malignant progression, which were not observed in drug-treated vector control cells. CONCLUSIONS: This is the first report that cidofovir can both increase cell survival and induce alterations in gene expression that are known to be associated with malignant transformation in cells transduced only with the E6 gene from low-risk HPV. It is our belief that these data provide cause for concern over the off-license use of this drug to treat RRP.

Cidofovir efficacy in recurrent respiratory papillomatosis: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: We performed a prospective, double-blind, placebo-controlled, longitudinal adjuvant therapy trial to determine the efficacy of cidofovir in the treatment of severe recurrent respiratory papillomatosis (RRP). Although results of case series suggest that cidofovir may decrease the frequency and rapidity of papilloma regrowth, no blinded placebo-controlled studies have demonstrated efficacy. METHODS: Adults and children (n = 19) with aggressive RRP received either active drug (cidofovir) or placebo. When surgical intervention was needed, drug or placebo was injected into affected areas after surgical removal of disease. The following measures were made at baseline and at 2-month intervals for the course of 12 months: Derkay papilloma severity grading scale, Voice Handicap Index, Health-Related Quality of Life, and total number of procedures performed over 12 months. RESULTS: At 2- and 12-month follow-ups, there was a significant (p < .05) improvement in the Derkay Severity Score within the cidofovir and placebo groups, but no difference between groups, and no difference between groups in the number of procedures performed. Significant improvement was found in Voice Handicap Index scores in the cidofovir group at the 12-month follow-up. No differences were seen in Health-Related Quality of Life. CONCLUSIONS: A randomized, blinded, placebo-controlled trial is necessary in the study of RRP, because the natural history of the disease can include remissions and reactivations. We found a significant improvement in the Derkay Severity Score 12 months after the baseline assessment in patients treated with cidofovir. This effect, however, was also seen in the placebo group. Accordingly, we were unable to provide proof of efficacy of cidofovir in the treatment of RRP.

Cidofovir modulated gene expression in recurrent respiratory papillomatosis.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is a benign aerodigestive tract neoplasm. Cidofovir, an antiviral drug, has demonstrated efficacy in slowing and/or reducing RRP recurrence. This investigation examined the differential gene expression of RPP before and after cidofovir use in vivo. METHODS: Papillomas were harvested from two patients pre- and post-cidofovir treatment. RNA was extracted from the tissues and separate Serial Analysis of Gene Expression (SAGE) libraries created. Overall gene expression as well as relative gene expression in the four libraries was compared. RESULTS: Over 19,000 tags were found in each of the libraries, with over 6000 unique transcripts identified in the pre-treatment and over 6000 identified in the post-cidofovir libraries of both patient 1 and 2. Following cidofovir treatment, the greatest up-regulation was in gene families associated with cell proliferation, metabolism, transport and response to biotic stimuli. Post-treatment up-regulation was seen in numerous specific genes, such as Interferon Regulatory Factor 7 (P=0.000014), which has been associated with virus-host interactions, passive viral induction of host immune response, and response to DNA damage stimulus. Down-regulation was demonstrated in gene families associated with transcription, regulation of nucleic acid metabolism, and signal transduction. DISCUSSION: Creation of RRP SAGE libraries demonstrates a broad list of genes expressed in RRP, as well as significant differences in gene expression after exposure to cidofovir, potentially allowing for a more thorough understanding of important genetic pathways in RRP treatment. In addition, over 1400 unique transcripts were identified, which will facilitate new gene discovery in RRP research.

Scientific and clinical aspects of the use of cidofovir in recurrent respiratory papillomatosis.

OBJECTIVE: Cidofovir is the most contemporary adjuvant treatment for recurrent respiratory papillomatosis (RRP) and its use is increasing. Cidofovir is potentially harmful. Otolaryngologists should understand the science of cidofovir and review the current published data on the effects of this therapy. METHOD: Pubmed was searched using the terms cidofovir and papillomatosis. Comparisons were made between published articles. RESULTS: Thirteen articles were identified between 1998 and 2006, representing the treatment of 142 patients. Cidofovir did result in a significant improvement of papillomatous lesions in the majority (60%) of patients despite the use of different regimes of cidofovir administration. There was no unifying protocol in use. A partial response was demonstrated in 29% of patients. 7.5% had no response however, an additional 3.5% patients were lost to follow-up. No malignant change was reported. CONCLUSION: Cidofovir does appear to be effective in improving the outcome of patients with RRP. There are no reports of malignant transformation despite concerns raised by toxicology studies.

Cidofovir: to use or not to use?

PURPOSE OF REVIEW: Cidofovir is an antiviral agent that has been used increasingly in the last decade as an adjuvant therapy for recurrent respiratory papillomatosis. It has been used in patients with moderate to severe recurrent respiratory papillomatosis requiring frequent surgical intervention or if there is evidence of distal spread. Intralesional administration after surgical debulking delivers the medication directly to the site of disease and is thought to have fewer systemic side effects than intravenous infusion. This review examines recent publications for evidence of safety and efficacy. RECENT FINDINGS: Despite its growing popularity, the potential risks related to cidofovir use in recurrent respiratory papillomatosis have not been well documented. It is known to be nephrotoxic when administered intravenously and there remains concern that cidofovir has carcinogenic potential based on animal studies (mammary adenocarcinoma in rats). A review of the literature reveals no randomized controlled trials, one case-control study, multiple case series and case reports only. Study populations are small, however complete response rates have consistently been reported in approximately 60%. SUMMARY: Based on current opinion and research, it is likely that intralesional cidofovir will continue to have a role in the management of moderate to severe recurrent respiratory papillomatosis. Further studies are required to assess long-term outcomes.