Application study of infrared free-electron lasers towards the development of amyloidosis therapy.

Amyloidosis is known to be caused by the deposition of amyloid fibrils into various biological tissues; effective treatments for the disease are little established today. An infrared free-electron laser (IR-FEL) is an accelerator-based picosecond-pulse laser having tunable infrared wavelengths. In the current study, the irradiation effect of an IR-FEL was tested on an 11-residue peptide (NFLNCYVSGFH) fibril from ß2-microglobulin (ß2M) with the aim of applying IR-FELs to amyloidosis therapy. Infrared microspectroscopy (IRM) and scanning electron microscopy showed that a fibril of ß2M peptide was clearly dissociated by IR-FEL at 6.1 µm (amide I) accompanied by a decrease of the ß-sheet and an increase of the α-helix. No dissociative process was recognized at 6.5 µm (amide II) as well as at 5.0 µm (non-specific wavelength). Equilibrium molecular dynamics simulations indicated that the α-helix can exist stably and the probability of forming interchain hydrogen bonds associated with the internal asparagine residue (N4) is notably reduced compared with other amino acids after the ß-sheet is dissociated by amide I specific irradiation. This result implies that N4 plays a key role for recombination of hydrogen bonds in the dissociation of the ß2M fibril. In addition, the ß-sheet was disrupted at temperatures higher than 340 K while the α-helix did not appear even though the fibril was heated up to 363 K as revealed by IRM. The current study gives solid evidence for the laser-mediated conversion from ß-sheet to α-helix in amyloid fibrils at the molecular level.

Treatment of Localized Amyloid Light Chain Amyloidosis With External Beam Radiation Therapy.

PURPOSE: Localized amyloidosis is a condition characterized by deposits of fibrillary proteins confined to a single organ. The most common subtype is amyloid light chain amyloidosis, which is caused by secretion of amyloidogenic light chain by a monoclonal population of plasma cells. We present a review and discussion of the literature in the context of a case presentation of localized amyloid light chain amyloidosis of the nasopharynx treated with radiation alone. METHODS AND MATERIALS: We reviewed literature relevant to this topic from 1970 to the present. Relevant studies, reports, and articles were summarized in table form. RESULTS: Surgical resection has historically been the primary therapeutic modality for these patients, with radiation being reserved for recurrent lesions or for those unfit for surgery. Although the data are limited to small retrospective series, radiation has been shown to provide good control with mild toxicity that is as good as or better than surgery. Doses range from 20 to 45 Gy, conventionally fractionated. There is no known risk of progression to systemic disease without local therapy. CONCLUSIONS: We recommend local therapy for symptomatic patients after systemic disease has been excluded. We generally recommend radiation in the setting of recurrent lesions, unacceptable toxicity with surgery, poor surgical candidates, and as the initial modality in select patients (elderly individuals with bothersome but nonobstructive lesions).

Orbital amyloidosis and radiotherapy: A case report and review of literature.

An 80 year-old woman was referred for a one-eyed palpebral edema. She had ptosis and oblique diplopia resistant to corticotherapy. An orbit magnetic resonance imaging showed a mass infiltrating the optic nerve, with an enhancement of the whole orbital musculature. Biopsies of the lacrimal gland were positive for immunoglobulin light chain amyloidosis. Debulking surgery is the main treatment modality for symptomatic patients with localized orbital amyloidosis. Diffuse orbital involvement may make excision difficult. We managed to treat her through radiation therapy to allow a surgical procedure, delivering 20Gy in 10 fractions. The main aim of radiation therapy was to eradicate the B cells that produced the amyloid light chain deposition. After radiation therapy, the orbital inflammatory caused by the lymphoid infiltration diminished and corticotherapy could be stopped. The surgery could be performed with excellent clinical results. At 2-year follow-up, neither tumor regrowth nor late complications were detected.

Low-Dose Radiation Therapy Reduces Amyloid Load in Young 3xTg-AD Mice.

BACKGROUND: Low-dose radiation therapy (LD-RT) has been shown to decrease amyloidosis or inflammation in systemic diseases and has recently been proposed as possible treatment of Alzheimer's disease (AD). A positive effect of LD-RT on tauopathy, the other marker of AD, has also been suggested. These effects have been shown in preclinical studies, but their mechanisms are still not well understood. OBJECTIVE: This study aimed to evaluate if anti-amyloid and anti-inflammatory effects of LD-RT can be observed at an early stage of the disease. Its impact on tauopathy and behavioral alterations was also investigated. METHODS: The whole brain of 12-month-old 3xTg-AD mice was irradiated with 10 Gy in 5 daily fractions of 2 Gy. Mice underwent behavioral tests before and 8 weeks post treatment. Amyloid load, tauopathy, and neuroinflammation were measured using histology and/or ELISA. RESULTS: Compared with wild-type animals, 3xTg-AD mice showed a moderate amyloid and tau pathology restricted to the hippocampus, a glial reactivity restricted to the proximity of amyloid plaques. LD-RT significantly reduced Aß42 aggregated forms (-71%) in the hippocampus and tended to reduce other forms in the hippocampus and frontal cortex but did not affect tauopathy or cognitive performance. A trend for neuroinflammation markers reduction was also observed. CONCLUSION: When applied at an early stage, LD-RT reduced amyloid load and possibly neuroinflammation markers, with no impact on tauopathy. The long-term persistence of these beneficial effects of LD-RT should be evaluated in future studies.

Gut flora-targeted photobiomodulation therapy improves senile dementia in an Aß-induced Alzheimer's disease animal model.

BACKGROUND: Emerging evidence suggests that the gut microbiota plays an important role in the pathological progression of Alzheimer's disease (AD). Photobiomodulation (PBM) therapy is believed to have a positive regulatory effect on the imbalance of certain body functions, including inflammation, immunity, wound healing, nerve repair, and pain. Previous studies have found that the intestinal flora of patients with AD is in an unbalanced state. Therefore, we have proposed the use of gut flora-targeted PBM (gf-targeted PBM) as a method to improve AD in an Aß-induced AD mouse model. METHODS: PBM was performed on the abdomen of the mice at the wavelengths of 630 nm, 730 nm, and 850 nm at 100 J/cm2 for 8 weeks. Morris water maze test, immunofluorescence and proteomic of hippocampus, and intestinal flora detection of fecal were used to evaluate the treatment effects of gf-targeted PBM on AD rats. RESULTS: PBM at all three wavelengths (especially 630 nm and 730 nm) significantly improved learning retention as measured by the Morris water maze. In addition, we found reduced amyloidosis and tau phosphorylation in the hippocampus by immunofluorescence in AD mice. By using a quantitative proteomic analysis of the hippocampus, we found that gf-targeted PBM significantly altered the expression levels of 509 proteins (the same differentially expressed proteins in all three wavelengths of PBM), which involved the pathways of hormone synthesis, phagocytosis, and metabolism. The 16 s rRNA gene sequencing of fecal contents showed that PBM significantly altered the diversity and abundance of intestinal flora. Specifically, PBM treatment reversed the typical increase of Helicobacter and uncultured Bacteroidales and the decrease of Rikenella seen in AD mice. CONCLUSIONS: Our data indicate that gf-targeted PBM regulates the diversity of intestinal flora, which may improve damage caused by AD. Gf-targeted PBM has the potential to be a noninvasive microflora regulation method for AD patients.

Comparing the efficacy of pulsed dye laser, Q-Switched Nd-YAG, CO2, and combined CO2 and Q-Switched Nd-YAG lasers for the treatment of cutaneous macular amyloidosis.

BACKGROUND: No topical and systemic treatment is proven to be effective on Cutaneous Macular Amyloidosis (CMA). The physical removal of the deposited protein by lasers may be a better choice. OBJECTIVE: To compare the efficacy of different lasers including Pulsed dye laser (PDL), 1064 mode of Q-Switched Nd-YAG, CO2, and combined CO2 and Q-Switched Nd:YAG lasers for the treatment of CMA. PATIENTS AND METHOD: 17 adult female patients with clinical CMA and histopathological confirmation were included in this study. Four close 1 by 1 cm2 areas were treated simultaneously with PDL, Q-Switched Nd-YAG, CO2 and combined CO2 and Nd-YAG Lasers. The energy used for 585 nm PDL were 9 J/cm2 with the spot size of 5 mm. The energy used for 1064 nm mode of Nd-YAG laser was 5 Joules/cm2, with the spot size of 4 mm, and the frequency of 10 hertz. The energies used for CO2 laser were 4 and 3.5 Micro Joules for the first and second Passes. RESULTS: No desirable result obtained after PDL therapy. The Q-Switched Nd-YAG was effective in only 3 patients. All areas treated with CO2 laser were cleared. CONCLUSION: The CO2 laser is seems to be the most effective laser treatment of CMA.

Long-term Follow-up After Radiation Therapy for Laryngeal Amyloidosis.

OBJECTIVES: Laryngeal amyloidosis (LA) is a rare disease characterized by extracellular protein deposition within the larynx. Treatment is difficult due to the frequently submucosal and multifocal nature of disease. The mainstay of treatment is surgical resection; however, recurrence rates are high. Recently, use of radiotherapy (RT), either alone or postoperatively, for LA has been adapted from the management of extramedullary plasmacytoma and has been shown to provide local disease control. Here, we describe the experience with adjuvant RT for LA at our center. STUDY DESIGN: Retrospective case series. METHODS: Retrospective study of patients with amyloidosis of the larynx, with or without other disease sites, seen at a tertiary academic center between 2011 and 2019. Outcomes included disease characteristics, recurrence rates, treatment modalities, and pre- and posttreatment voice handicap index (VHI)-10. RESULTS: Ten patients met eligibility criteria. Mean follow-up time for all patients was 62.0 ± 41.0 months; mean follow-up time after last treatment was 51 ± 55 months. All but one patient underwent surgical resection of disease. Seven patients underwent subsequent RT. Of these seven, six underwent RT at our institution; five received a dose of 45 Gray (Gy); and one received a dose of 20 Gy. All seven completed RT without toxicity-related interruption. Patients undergoing RT underwent 2.1 ± 1.3 surgical procedures prior to RT; no patients required surgery after RT. Mean pretreatment VHI-10 was 22.9 ± 8.1; mean posttreatment VHI-10 was 12.9 ± 13.3. CONCLUSION: RT after surgery for LA can provide good local control without unacceptable toxicity and may decrease the need for further surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1810-1815, 2021.

Solitary extramedullary plasmacytoma of the larynx: a rare cause of dysphonia.

Solitary extramedullary plasmacytoma (SEP) of the larynx is a rare haematological malignancy and an infrequent cause of persisting dysphonia. We present the case of a 54-year-old woman with a long-standing history of dysphonia. While clinical examination showed a rather inconspicuous prominent right vestibular fold, an MRI revealed a laryngeal mass with erosion of the thyroid cartilage. A biopsy taken during rigid endoscopy demonstrated plasma cell infiltration with light chain restriction amidst amyloid deposits. After exclusion of systemic involvement, the diagnosis of an SEP of the larynx with secondary amyloidosis was made. The patient received primary radiation therapy. Another biopsy taken 3 months after the end of therapy did not show any signs of ongoing neoplastic plasma cell disease. The patient was therefore considered to be in remission. She is currently receiving regular follow-up and has not shown signs of persistent or progressive disease for the past 18 months.

External beam radiation for localized periocular amyloidosis: a case series.

Purpose: To evaluate the effectiveness of low dose external beam radiation therapy to halt progression of localized periocular light chain (AL) amyloidosis, a clonal plasma cell disorder. Methods: This is a retrospective review of patients referred to a tertiary care center for external beam radiation treatment of biopsy proven localized periocular light chain amyloidosis. The primary outcome measure was clinical disease stability at one year following radiation therapy as evidenced by slit lamp exam and external photography. Pre and post radiation MRI imaging of the affected area were also used as a means to monitor disease progression. Results: Four symptomatic patients with localized periocular AL amyloidosis received external beam radiation therapy ranging from 20-30 Gy fractioned over 10-20 fractions. Three of the four patients had prior surgical debulking with or without ptosis repair. Amyloid deposition did not progress in any patient at one year. Further follow-up of two patients revealed amyloid progression at two years post radiation. Conclusions: External beam radiation therapy for localized periocular AL amyloidosis demonstrated efficacy at halting disease progression at one year; however, the long-term efficacy is unknown. Monitoring of periocular amyloid is best achieved with slit lamp exam and external photography as opposed to MRI.

Endobronchial brachytherapy-A novel approach for the management of airway amyloidosis.

PURPOSE: Airway amyloidosis is an uncommon condition and may have variable clinical course. There is no proven systemic therapy, and the management mainly relies on local invasive treatments. Several reports have found external beam radiotherapy to produce durable responses. The optimal dose and fractionation has not been determined. Endobronchial brachytherapy (EBB) has never been reported to affect this disease. METHODS: The study includes a retrospective chart review of all patients with airway amyloidosis treated with EBB at the Davidoff Cancer Center. Data include symptoms, radiotherapy method and dose, treatment outcomes, and toxicities. RESULTS: Three patients were included. Patients were either symptomatic with extensive airway involvement or have undergone multiple local procedures with rapid recurrence of the amyloid deposits. Two patients had upper and 1 patient had lower airway involvement. Two were treated with external beam radiotherapy and EBB and 1 was treated with EBB only. All patients achieved rapid improvement of symptoms with visible improvement in followup bronchoscopies. EBB doses ranged from 7.5 to 10 Gy. Of the seven lesions treated with EBB, only one lesion recurred 6 months from treatment. No major toxicities were reported. CONCLUSIONS: EBB is effective and safe for the management of airway amyloidosis and can offer long-term control. This is the first report of EBB for this indication. EBB should be further explored as means of minimizing the irradiated lung volume.

Intensity-modulated radiotherapy for localized nasopharyngeal amyloidosis : Case report and literature review.

BACKGROUND: Primary localized amyloidosis is characterized by the deposition of amyloid proteins restricted to one organ, without systemic involvement. Primary nasopharyngeal amyloidosis is an exceedingly rare condition, for which the standard treatment remains unknown. Because of its challenging anatomical position, surgery alone hardly results in complete resection of the localized amyloidosis. Therefore, an interdisciplinary planning board to design optimal treatment is of particular importance. PATIENT AND METHODS: A 39-year-old man presented with a several-week history of nasal obstruction and epistaxis. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed the presence of a retro-odontoid nonenhancing soft tissue mass. RESULTS: The endoscopic biopsy demonstrated that the mass was amyloid in nature. An extensive systemic workup revealed an absence of inflammatory process, systemic amyloidosis, or plasma cell dyscrasia. The patient was treated with a combination of surgery and radiotherapy, showing no evidence of recurrence or progression at his 1­year follow-up. CONCLUSION: Primary solitary amyloidosis is a rare form of amyloidosis. To the best of our knowledge, this is the first report of a nasopharyngeal amyloidosis case treated with excision and radiation leading to complete remission. Because of the difficulty for surgeons to achieve radical resection with such lesions, radiotherapy proved to be an excellent adjuvant treatment in this case.

The Efficacy of Q-Switched ND:YAG 1064 nm Laser in Recalcitrant Macular Amyloidosis: A Case Report.

Macular amyloidosis typically presents as small, dusky-brown or greyish pigmented macules, the result of altered keratin deposition. Treatment of these hyperpigmented regions with topical and systemic therapies remains challenging, however Q-Switched neodymi- um-doped yttrium aluminum garnet (ND:YAG) laser has proven to be an effective treatment modality to reduce hyperpigmentation. In this case report we investigated the ef cacy of Q-Switched Nd:YAG laser treatment on a 34-year old woman with recalcitrant macular amyloidosis who failed to respond to over-the-counter bleaching creams. The patient was treated with 7 treatment sessions of Q- Switched Nd:YAG laser at one month intervals. According to our photographic analysis and patient self-assessment, the patient ap- peared to improve with each treatment session. Post-recurrence of the lesion after reaction to Triluma ( uocoinolone actetonide 0.01%, hydroquinone 4%, tretinoin 0.05%), the patient has been continuing to respond well to a second round of treatment with Q-switched Nd:YAG laser at 1064 nm. J Drugs Dermatol. 2016;15(11):1456-1458..

How to deal with laryngeal amyloidosis? Experience based on 16 cases.

INTRODUCTION: Amyloidosis is characterized by the deposition of amorphous fibrillar protein (amyloid) in the intercellular or intracellular space. Localized amyloidosis is rare in the head and neck area. In Polish literature of the last decade it has been the subject of case studies. AIM: The goal of the study was to carry out a retrospective analysis of patients treated for amyloidosis in the Department of Otolaryngology and Head and Neck Surgery of the Poznan University of Medical Sciences in the period from 2000 to 2009. Based on the collected clinical material, the authors made an attempt to determine the most frequent anatomical location of amyloid deposits and the most frequently affected organs, the type and duration of symptoms, the therapeutic approach, further diagnostic measures taken and the final outcome of the treatment. The next goal was to assess the number of microlaryngoscopies performed in patients with amyloidosis affecting the larynx as compared to the overall number of such procedures. MATERIAL: The detailed analysis included 16 patients with laryngeal amyloidosis. RESULTS: Amyloidosis of the larynx was found in only 0.52% of patients undergoing microlaryngoscopies in the period from 2000 to 2009. In the vast majority of patients (11 of 16), there was no suspicion of amyloidosis in the initial diagnosis. Only the histopathological assessment definitely confirmed the nature of pathological changes in the larynx. Glottis was the most common location of amyloid deposits in the study group. In all cases, additional studies and long-term monitoring of the postoperative course excluded generalized amyloidosis. CONCLUSIONS: Laryngeal amyloidosis is very rare, however it should be considered in the differential diagnosis in patients with laryngeal dysfunction. Surgery remains the treatment of choice in most patients, although the attempts of radiotherapy are undertaken. Preserving the normal function of the organ remains the priority.

Complete resolution of laryngeal amyloidosis with radiation treatment.

BACKGROUND: Localized amyloidosis of the larynx is a rare entity of unclear etiology. Surgical debulking is the primary treatment modality but often is not curative. METHODS AND RESULTS: A 41-year-old woman presenting with increasing hoarseness, dysphagia, dyspnea, and weight loss was found to have a submucosal mass in the left false vocal fold. Biopsy of the specimen revealed amyloid. After negative work-up for systemic disease, the patient underwent surgical debulking. Specimens revealed a population of clonal plasma cells demonstrating lambda restriction. The patient was treated with adjuvant external beam radiation to a dose of 45 Gy. At 11 months, the patient's voice, breathing, and swallowing have all improved substantially. CONCLUSIONS: Recent pathologic studies suggest that localized amyloidosis of the larynx is caused by a localized, nonmalignant plasma cell disorder. Because full resection is difficult, we recommend a combination of surgery and radiation therapy to cure this disease.