Systemic bevacizumab as adjuvant therapy for recurrent respiratory papillomatosis in children: A series of three pediatric cases and literature review.

Recurrent respiratory papillomatosis (RRP), a viral disease caused by human papillomavirus (HPV), is the most common benign neoplasm of the larynx among children and the second most frequent cause of infantile hoarseness. The course of the disease is variable; some patients experience spontaneous remission, while others may develop an aggressive respiratory compromise. Especially juvenile-onset RRP cases experience shorter intervals between surgical interventions and thus more surgeries overall, causing high rates of depression and voice-related quality of life. Various local adjuvant therapies have been studied with mixed efficacy and some early potential but have failed to show consistent effect across large cohorts of patients. Bevacizumab, a recombinant monoclonal antibody that inhibits VEGF, has shown efficacy in patients with rapid regrowth of papillomas with severe airway compromise, and/or distal multisite spread of disease. We present three juvenile-onset RRP cases successfully managed with systemically administered bevacizumab.

Benign Breast Papilloma without Atypia: Outcomes of Surgical Excision versus US-guided Directional Vacuum-assisted Removal or US Follow-up.

Background Recent studies suggest that US-guided directional vacuum-assisted removal (DVAR) is a satisfactory alternative to surgery for benign papilloma of the breast and recommend discretionary diagnostic US follow-up without intervention. Purpose To compare the outcomes of benign papilloma without atypia diagnosed with core needle biopsy (CNB) in patients who underwent US-guided DVAR, US follow-up without intervention, or surgery. Materials and Methods This retrospective review included consecutive patients with benign papilloma without atypia diagnosed with US-guided CNB between January 2005 and September 2015. Five hundred female patients who underwent surgical excision (n = 206), US-guided DVAR (n = 233), or more than 2 years of US follow-up without intervention (n = 61) were included. The clinical and radiologic findings and cancer upgrade rate were compared among the three groups. Propensity score matching was performed for comparison of the upgrade rate in the surgery and US-guided DVAR groups. Results The mean patient age (±standard deviation) was 46.4 years ± 9.6. The upgrade rate to malignancy was 1.8% (nine of 500 patients; 95% confidence interval [CI]: 0.9%, 3.4%) in the total study population, 1.9% (four of 206 patients; 95% CI: 0.8%, 4.9%) after surgery, 2.1% (five of 233 patients; 95% CI: 0.9%, 4.9%) after US-guided DVAR, and 0% (0 of 61 patients; 95% CI: 0.0%, 5.9%) after US follow-up without intervention (P = .80); after propensity-score matching, the upgrade rate was 1.9% in the surgery group (three of 151 patients; 95% CI: 0.6%, 5.6%) and 3.3% in the US-guided DVAR group (five of 151 patients; 95% CI: 1.4%, 7.5%; P = .48). The recurrence rate after US-guided DVAR was 3.6% (six of 166 patients) during 24-65 months of follow-up; all recurrences were confirmed as benign at subsequent surgery. Fifty-nine of the 61 lesions in the group with US follow-up without intervention (97%) remained stable in size with no growth during a mean follow-up of 43.3 months (range, 25-130 months). Conclusion Low rates of upgrade, recurrence, and growth after US-guided directional vacuum-assisted removal and US follow-up without intervention suggest that benign papilloma without atypia can be managed more conservatively rather than undergoing surgical excision. © RSNA, 2019 Online supplemental material is available for this article.

Plasma Bleomycin Concentrations during Electrochemotherapeutic Treatment of Fibropapillomas in Green Turtles Chelonia mydas.

Fibropapillomatosis of sea turtles is traditionally treated with surgical debulking techniques that are often associated with prolonged healing and tumor recurrence. Electrochemotherapy was recently described for green turtles Chelonia mydas and can be an alternative to surgery and even general anesthesia. The objectives of this study were to replicate an electrochemotherapy protocol from a previous report and add plasma bleomycin analysis to the treatment. After bleomycin injection into similarly sized tumors of two green turtles and immediate electroporation at two time points, plasma bleomycin reached detectable concentrations that were considerably lower than those found in human studies. At 3 months posttherapy, no healing complications or recurrences were encountered and only scar tissue remained. This study adds further support that electrochemotherapy with bleomycin has the potential to be used as an effective alternative treatment for this complex disease.

[Importance of Cryotherapy for Eyelid Papillomas]. / Kryotherapie in der Behandlung ausgedehnter Lidpapillome.

PURPOSE: Cryotherapy as a destructive procedure is an important alternative to the surgical excision of eyelid tumors. METHODS: We report our own experiences in the cryotherapy of large upper eyelid papillomas using spray- and contact-freezing. RESULTS/CONCLUSIONS: Cryotherapy gave excellent results in the treatment of unusually large papillomas. The preservation of collagen structures during cryotherapy provides a good aesthetic and functional outcome.

Multimodal treatment of a dog with disseminated cutaneous viral papillomatosis.

BACKGROUND: Canine papillomaviruses (CPVs) are associated with varied cutaneous manifestations. Spontaneous resolution typically occurs within one to 12 months. This case report describes multimodal treatment of a dog with severe disseminated papillomatosis. CLINICAL SUMMARY: An eight-month-old, female spayed, mixed breed dog was presented with a two month history of rapidly progressing papillomatosis and lack of response to oral azithromycin therapy. The dog was severely pruritic and malodorous; the weight and growth of lesions had progressed to affect the dog's gait and vision, and led to decreased quality of life. The dog was treated with substantial surgical debulking of lesions, followed by daily topical 5% imiquimod cream applied to nonexcisable lesions, and received five doses of an experimental recombinant CPV2 L1 vaccine every 14 days for 10 weeks. At the end of the 10 weeks, two lesions remained and were excised. No additional treatment was needed and 10 months post-treatment the dog was lesion free. CONCLUSION: New therapies need to be developed and assessed, in controlled treatment trials, to determine the efficacy of single modality therapeutic interventions for severe, persistent canine cutaneous papillomatosis.

Malignant Transformation of a Canine Papillomavirus Type 1-Induced Persistent Oral Papilloma in a 3-Year-Old Dog.

This case report describes a rare case of a persistent canine papillomavirus type 1 (CPV-1)-induced oral papilloma that underwent malignant transformation into an oral squamous cell carcinoma (OSCC) in a 3-year-old Labrador retriever cross. Initially, the patient had multiple and multifocal verrucous lesions populating the oral cavity exclusively. The papillomas persisted despite multiple surgical ablations, azithromycin, interferon α-2b, alternative medicines, and off-label drug use of an immunostimulant. After 1 year and 6 months, an aggressive lesion developed at the level of the left mandibular first molar (309) and progressed to a well-differentiated invasive OSCC. The presence of CPV-1 DNA in the OSCC, and the known oncogenic abilities of CPV-1, suggests that this virus might have played a significant role in the emergence of the OSCC that ultimately led to the patient's euthanasia due to poor quality of life. This is the first well-documented case where OSCC has developed from an oral papilloma caused by CPV-1 in which the presence of coinfection by another papillomavirus was excluded by multiple polymerase chain reaction tests using various primers.

[Papillomatosis of the larynx in children: the current state of the problem]. / Papillomatoz gortani u detei: sovremennoe sostoianie problemy.

There is the authors have considered variants of modern methods of medical and surgical treatment of laryngeal papillomatosis in children in the review, based on the etiology of the disease. The analysis of the effectiveness of new methods of combined treatment with the use of modern technologies, taking into account their advantages and disadvantages. The possible prospects for further study problems and develop new methods of adjuvant therapy.

[The combined endoscopic treatment of the patient presenting with a large orolaryngopharyngeal papilloma]. / Kombinirovannoe éndoskopicheskoe lechenie bol'nogo s bol'shoi papillomoi rotogortanoglotki.

The present article was designed to illustrate the potential for the combined treatment of a orolaryngopharyngeal papilloma under the conditions of an out-patient setting with the application of the minimally invasive endoscopic surgical intervention, the so-called photodynamic therapy (PDT). The authors describe the clinical case which demonstrate the possibilities for using photodynamic therapy as a component of the combined treatment of papilloma of the hypopharynx including its radical removal. The application of the PDT mdethod in the clinical case reported in the present article was aimed at preventing the recurrence of papillomatosis of the upper respiratory tract. The evaluation of the outcome of the treatment of the patient in the course of the follow-up period is expected to provide the data for the assessment of the clinical effectiveness of the adjuvant PDT technique.

[Minimally invasive Therapy of lacrimal Drainage System Stenosis]. / Minimalinvasive Therapie von Tränenwegstenosen.

Epiphora is one of the most common symptoms for clinical ophthalmological consultation. This symptom is mostly caused by stenosis of the lacrimal drainage system. Over a century, external dacryocystostomy according to Toti was the treatment of choice. Today, new very encouraging minimally invasive techniques for recanalisation of the lacrimal drainage system, such as microdrilldacryoplasty or laserdacryoplasty, as well as bypass-based techniques, such as transcanalicular laser-assisted dacryocystorhinostomy, become more important in the treatment of dacryostenosis.

The Use of Cryotherapy for Papilloma and Early Laryngeal Cancers: Long-term Results.

STUDY DESIGN: Retrospective chart review. OBJECTIVE: To determine the efficacy of adjuvant cryotherapy in the treatment of early glottic cancer and laryngeal papillomatosis. SUMMARY OF BACKGROUND DATA: The use of cryotherapy in conjunction with traditional modalities has recently been proposed to improve voice outcomes in patients with early laryngeal cancer as compared to pretreatment conditions. This study investigates its utility in improving oncological outcomes and decreasing recurrences of laryngeal papillomatosis. METHODS: Patients with either early glottic cancer or laryngeal papillomatosis that received cryotherapy as part of their surgical regimen were investigated. All patients were seen at a large tertiary care center within a 10-year window. Demographic data were collected and all postoperative notes were reviewed. Recurrences of the laryngeal cancer were noted, as was the duration of time between successive papillomatosis operations. RESULTS: The charts of 54 glottic cancer and 29 papillomatosis patients that received cryotherapy were reviewed. One patient from the papillomatosis cohort was excluded from statistical analysis due to lack of follow-up. Overall, 16 (30%) of the laryngeal cancer patient experienced a malignant recurrence. The overall 5-year survival of these patients was 98% and the 5-year disease-free survival was 74%. The use of adjuvant cryotherapy in the treatment of laryngeal papillomatosis extended the duration of time between surgeries by an average of 79 days (P=.23). CONCLUSION: The use of adjuvant cryotherapy in the treatment of early glottic cancer does not improve the rate of carcinoma recurrences. Additionally, cryotherapy does not result in a statistically significant increase in the duration of disease-free period for laryngeal papillomatosis patients, although the observed increase may be clinically important.

[Laryngeal Papillomatosis: A Statistical Analysis of 60 Cases].

Laryngeal papillomatosis is the most common benign neoplasm of the larynx. Juvenile onset laryngeal papillomatosis tends to recur. In patients with adult onset laryngeal papillomatosis, laryngeal cancer rarely develops. This paper reports a clinical analysis of 60 patients with laryngeal papillomatosis who were treated at our clinic between January 1971 and September 2009. We analyzed the sex ratio, age at the onset of papilloma, type of developing papilloma (single or multiple type), site of developing papilloma, recurrence rate, and therapeutic modalities. Furthermore, the clinical characteristics of the patients with malignant transformation were examined. The patients were classified according to their age at the onset of the papilloma and the type of developing papilloma. The patients were grouped into a juvenile-onset group and an adult-onset group according to their age at the onset of the papilloma. They were also classified into single-type or multiple-type according to whether the initial papilloma appeared singly or multiply. The male to female sex ratios were 1.2 in the juvenile-onset group and 5.1 in the adult-onset group. Among the patients who developed papilloma at an age of under 10 years old, most of the juvenile cases had experienced onset by 4 years of age. Furthermore, the frequency of multiple-type papilloma was significantly higher in the juvenile-onset group, compared with the adult-onset group. The vocal fold was the most frequent site of the papilloma. The recurrence rate in the juvenile-onset group was significantly higher than that of the adult-onset group. A stratified analysis according to the type of papilloma occurrence, however, showed no significant difference in recurrences between the juvenile-onset and adult-onset groups. A stratified analysis according to the age at the onset of papilloma showed that the recurrence rate of multiple-type papilloma was significantly higher than that of single-type papilloma in the adult-onset group. Among multiple therapeutic modalities, vaporization by carbon dioxide laser was the most frequently used. Adjuvant therapy was performed in 6 cases who suffered from multiple relapses. The injection of interferon was performed in 5 cases, and the local injection of cidofovir was performed in 1 case. Malignant transformation of the papilloma was confirmed in 3 cases. The periods between the onset of papilloma and the malignant transformation were 40 years, 14 years, and 3 years. The present study indicates that patients with laryngeal papilloma developing at multiple sites have a significantly higher rate of relapse, even in the adult-onset group. There was no tendency in the period observed between the onset of papilloma and malignant transformation. From the standpoint of recurrence and malignant transformation, patients with papillomatosis should be carefully followed up for a long period of time.

Coblation plus photodynamic therapy (PDT) for the treatment of juvenile onset laryngeal papillomatosis: case reports.

BACKGROUND: In treating juvenile-onset laryngeal papillomatosis, the most difficult aspect is preventing recurrence. After a single treatment, recurrence can begin after as soon as 20 days and the recurrent rate can be higher than 90%. The causes of recurrence include the presence of mucosal cells infected with papilloma virus, which are undetectable with the naked eyes, and surgery-induced infection. Photodynamic therapy (PDT) could effectively solve this problem. Virus-infected cells have a very high metabolic energy for capturing and internalizing the photosensitizer, which, after light stimulation, subsequently induces active oxygen species inside the nucleus, which kill infected cells. The second generation of photosensitizer agents (PA) are locally applied to avoid the intravenous systemic damage caused by first-generation PAs, and this method is widely used for the treatment of genital warts to very good effect. METHODS: We used the photodynamic method to treat laryngeal papillomatosis in children and obtained significant efficacy. We followed three juvenile subjects with recurrent laryngeal papillomatosis through a course of treatment (each course includes three PDT sessions), with a follow-up after 6 months. RESULTS: The characteristic procedures involve exposing the larynx with a laryngoscope and using low-temperature plasma technology to visualize the tumor resection, as the effects of plasma technology can reduce postoperative laryngeal edema and reduce intraoperative metastasis. PDT was performed during the first surgery, 20 days after and 30 days after surgery. At the 6-month follow-ups, there was no recurrence. CONCLUSION: This was the world's first successful reported case of the use of PDT treatment for juvenile laryngeal papillomatosis.

Electrochemotherapy for the treatment of fibropapillomas in Chelonia mydas.

Fibropapillomatosis continues to be an important cause of morbidity and mortality in sea turtles, particularly in Chelonia mydas. Turtles with this debilitating herpesvirus disease usually present with multiple, large, and ulcerated cutaneous masses that compromise both locomotion and feeding. There are very few available therapeutic strategies, with surgical excision being the most common. However, this surgical excision is associated with a high rate of local disease recurrence and secondary infections. Electrochemotherapy has been used for the treatment of epithelial neoplasm in several animal species. This technique is based on a combination of chemotherapy, usually with bleomycin or cisplatin, and electroporation. It consists of a series of short, high-voltage electric pulses that lead to increased membrane permeability and more efficient transport of antineoplastic drugs through the cellular membrane. Here, two C. mydas fibropapillomas were treated with a standard electrochemotherapy protocol using intralesional bleomycin sulfate injections followed by the application of electric pulses. Two sessions were performed, with a 33-day interval between sessions. Complete regression of lesions occurred without side effects or complications in each animal. There was no sign of local recurrence, even 1 yr after the end of treatment. Electrochemotherapy may be an effective therapeutic alternative for sea turtles with fibropapillomas.

Transitional cell tumours of the lacrimal drainage apparatus.

BACKGROUND: Tumours of the lacrimal drainage apparatus (LDA) are very rare, but can be life-threatening. Seventy percent of lacrimal sac tumours are of epithelial origin, and transitional cell tumours represent an interesting sub-group of these epithelial tumours. METHODS: A retrospective review of cases of LDA transitional cell tumours co-managed at the Royal National Throat Nose and Ear Hospital and Moorfields Eye Hospital, London. RESULTS: Twenty cases of transitional cell tumours of the LDA were identified, comprising 10 transitional cell papillomas (TCPs) and 10 transitional cell carcinomas (TCCs). All cases were resected through a modified lateral rhinotomy approach. Limited resection of orbital fat with preservation of orbital functions was required for 2 cases of TCC. Fractionated external beam radiotherapy was administered in 7 cases of TCC. The mean follow up was 80 months (range 11 months-16 years). Recurrences were detected in 4 cases, which were managed by further surgery. Two cases have been lost to follow-up, but the 18 other patients are currently alive and disease free. CONCLUSION: A favourable outcome can be achieved with transitional cell tumours of the LDA when an optimum management plan is followed.

Evolution and prognosis of bladder papillomatosis managed by endoscopic resection and endovesical BCG therapy : about 24 cases.

BACKGROUND: Bladder papillomatosis is a diffuse tumor proliferation even up almost all of the bladder mucosa. We analyzed prognosis of this rare entity after conservative treatment. METHODS: We retrospectively analyzed epidemiological, clinical, therapeutic and evolutive data in 24 patients with newly diagnosed bladder transitional cell carcinoma papillomatosis. All patients underwent a complete endoscopic transurethral resection (TUR) with curative intent. A second look was performed within 30 days. The intravesical therapy regimen consisted on weekly instillations for 6 weeks, and then monthly for 6 months. If the tumor recurred without muscle invasion, TUR was repeated with a second intravesical BCGtherapy regimen. Parameters investigated included age, gender, risk factors, cystoscopic findings (aspect, multiplicity and location of bladder lesion), tumor stage, tumor grade, recurrences and progression times from diagnosis to last follow up. RESULTS: The mean age of the patients at initial diagnosis was 64,9±6,1 years. They were males in 23 cases. Initial cancer staging was as follow: pTa (n=6) and pT1 (n=18). The recurring tumors were reported in 17 patients (70,8%). They were stage Ta in 5 patients and stage T1 in 12. The median interval of time between the initial TUR and the first recurrence was 10,3 months. Six patients remain tumor free. From the 17 recurrences, 6 patients developed progression with muscle invasion in 4 of them. Radical cystectomy with ileal conduit was performed in 3 patients and one patient died before radical treatment. Univariate analysis didn't reveal any prognostic factor: age (p=0,7), tumor location and aspect (p= 0,7 and p= 0,5 respectively), tumor stage (p=0,7) and grade (p=0,09). CONCLUSION: TCC bladder papillomatosis is a rare entity. TUR with intravesical BCG therapy may be indicated as a first option despite correct follow up. Radical cystectomy should be considered in cases of recurrent or non-resectable tumours.

The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic capable of enhancing HPV 6/11-specific T cell immunity. This first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates the overall safety and clinically meaningful benefit observed with PRGN-2012, with a 50% complete response rate in patients treated at the highest dose. Responders demonstrate greater expansion of peripheral HPV-specific T cells compared with nonresponders. Additional correlative studies identify an association between reduced baseline papilloma HPV gene expression, greater interferon responses and expression of CXCL9 and CXCL10, and greater papilloma T cell infiltration in responders. Conversely, nonresponders were characterized by greater HPV and CXCL8 gene expression, increased neutrophilic cell infiltration, and reduced T cell papilloma infiltration. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis.

Conjunctival papilloma treatment outcomes: a 12-year-retrospective study.

BACKGROUND: Conjunctival papilloma is often resistant to treatment. Various therapies have been reported with no gold standard. The purpose of this study was to compare treatment outcomes after various therapies. METHODS: A retrospective chart review of 30 conjunctival papilloma patients from 2009-2020. Data on demographics, tumour characteristics, primary treatment and outcomes were collected. The primary outcome was the frequency of complete tumour resolution and recurrence rate of each primary therapy. The secondary outcome was treatment related side effects. RESULTS: The mean age was 57.5 years (3-93 years) with male predominance (n = 22, 73.3%). Eleven eyes were treated with interferon α-2b (IFN), seven with 5-fluorouracil (5FU), and 10 with excision biopsy and cryotherapy (6 with adjuvant therapy with IFN). The frequency of tumour resolution was 36.4% (4/11), 28.5% (2/7), and 100% (10/10) in each group, respectively. The mean time to resolution was faster in the surgical group compared to the medical group (1 day vs 159 days, p < 0.001). There was higher tumour recurrence with 11% in the surgical vs 0% in the medical group at 6 months and at 12 months, 22% recurrence in the surgical and 0% in the medical group (p = 0.52). However, the differences were not statistically significant. CONCLUSION: Papilloma resolution is faster with surgical excision as compared to medical therapy. However, recurrences are more frequent after surgical versus medical treatment.