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Simple Summary: Radiochemotherapy (RCT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) causes side effects in healthy tissue such as the sternocleidomastoid muscle (SCM). These side effects depend on the interval between completion of RCT and restaging CT. For salvage surgery, the optimal time window for surgery is clinically postulated at between 6 and 12 weeks after completion of RCT. Thus, no extensive tissue fibrosis is to be expected. This interval is based on clinical studies exploring surgical complications. Studies directly exploring radiation-induced changes of the SCM in HNSCC patients are sparse. This study applied radiomics to quantify radiation-induced changes in the SCM and paravertebral musculature (PVM). In 98 locally advanced HNSCC patients, three radiomic key features (volume, mean positivity of pixels, uniformity) were analyzed in CT scans before and in the mean 8 weeks after treatment. No significant changes in radiomic key features were observed after adjustment for changes in body mass index (BMI). These data support the clinically postulated time window for salvage surgery of 6 to 12 weeks. Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) frequently require primary radiochemotherapy (RCT). Despite intensity modulation, the desired radiation-induced effects observed in HNSCC may also be observed as side effects in healthy tissue, e.g., the sternocleidomastoid muscle (SCM). These side effects (e.g., tissue fibrosis) depend on the interval between the completion of RCT and restaging CT. For salvage surgery, the optimal time window for surgery is currently clinically postulated at between 6 and 12 weeks after completion of RCT. Thus, no extensive tissue fibrosis is to be expected. This interval is based on clinical studies exploring surgical complications. Studies directly exploring radiation-induced changes of the SCM in HNSCC patients are sparse. The present study quantified tissue alterations in the SCM and paravertebral musculature (PVM) after RCT, applying radiomics to determine the optimal time window for salvage surgery. Three radiomic key parameters, (1) volume, (2) mean positivity of pixels (MPP), and (3) uniformity, were extracted with mint LesionTM in the staging CTs and restaging CTs of 98 HNSCC patients. Of these, 25 were female, the mean age was 62 (±9.6) years, and 80.9% were UICC Stage IV. The mean restaging interval was 55 (±28; range 29–229) days. Only the mean volume significantly decreased after RCT, from 9.0 to 8.4 and 96.5 to 91.9 mL for the SCM and PVM, respectively (both p = 0.007, both Cohen's d = 0.28). In addition, the mean body mass index (BMI) decreased from 23.9 (±4.2) to 21.0 (±3.6) kg/m² (p < 0.001; Cohen's d = 0.9). The mean BMI decreased significantly and was correlated with the volume decrease for the SCM (r = 0.27; p = 0.007) and PVM (r = 0.41; p < 0.001). If t-test p-values were adjusted for the BMI decrease, no significant change in volumes for the SCM and PVM was observed (both p > 0.05). The present data support the clinically postulated optimal interval for salvage surgery of 6 to 12 weeks. [ABSTRACT FROM AUTHOR]

Globally, over the next few decades, more than 2.5 billion people will suffer from hearing impairment, including profound hearing loss, and millions could potentially benefit from a cochlea implant. To date, several studies have focused on tissue trauma caused by cochlea implantation. The direct immune reaction in the inner ear after an implantation has not been well studied. Recently, therapeutic hypothermia has been found to positively influence the inflammatory reaction caused by electrode insertion trauma. The present study aimed to evaluate the hypothermic effect on the structure, numbers, function and reactivity of macrophages and microglial cells. Therefore, the distribution and activated forms of macrophages in the cochlea were evaluated in an electrode insertion trauma cochlea culture model in normothermic and mild hypothermic conditions. In 10-day-old mouse cochleae, artificial electrode insertion trauma was inflicted, and then they were cultured for 24 h at 37 °C and 32 °C. The influence of mild hypothermia on macrophages was evaluated using immunostaining of cryosections using antibodies against IBA1, F4/80, CD45 and CD163. A clear influence of mild hypothermia on the distribution of activated and non-activated forms of macrophages and monocytes in the inner ear was observed. Furthermore, these cells were located in the mesenchymal tissue in and around the cochlea, and the activated forms were found in and around the spiral ganglion tissue at 37 °C. Our findings suggest that mild hypothermic treatment has a beneficial effect on immune system activation after electrode insertion trauma. [ABSTRACT FROM AUTHOR]

Introduction: Local therapeutic hypothermia (32°C) has been linked experimentally to an otoprotective effect in the electrode insertion trauma. The pathomechanism of the electrode insertion trauma is connected to the activation of apoptosis and necrosis pathways, pro-inflammatory and fibrotic mechanisms. In a whole organ cochlea culture setting the effect of therapeutic hypothermia in an electrode insertion trauma model is evaluated. Material and Methods: The cochleae of C57Bl6/J mice (Charles River®, Freiburg, Germany) are cultured for 24 hours at 37°C and 32°C after inserting a fishing line through the round window simulating an insertion trauma. The resulting effect was evaluated for the apoptotic reaction - B-cell-Lymphoma-2-Associated-X-Protein (BAX), B-Cell-Lymphoma-2-Protein (BCL2) and Cleaved-Caspase-3 (CC3) -, the inflammatory response - Tumor-Necrosis-Factor-Alpha (TNFα), Interleukin-1-Beta (IL-1Imm) and Cyclooxygenase-2 (COX2) - and proliferation process - Transforming-Growth-Factor-Beta-1 (TGFβ1) - using immunohistochemistry and real-time PCR technique. A minimum of 12 cochlea per experiment were used. Results: A pro-apoptotic situation was observed in the normothermic group (BAX, CC3 > Bcl2) whereas an anti-apoptotic constellation was found at 32°C culture conditions (BAX, CC3 < Bcl2). Furthermore the effect of the IT knowing to effect the pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression has been reproduced. This reaction was reversed with the application of therapeutic hypothermia resulting in significant lower pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression. TGFβ1 was increased by hypothermia. Discussion: Concluding a protective effect of hypothermia on the experimental electrode insertion trauma can be described by an anti-apoptotic and antiinflammatory reaction. [ABSTRACT FROM AUTHOR]

Simple Summary: Locally-advanced head and neck squamous cell carcinoma (HNSCC) is mainly defined by the presence of pathologic cervical lymph nodes (LNs). Radiologic criteria to classify LNs as pathologic or non-pathologic are shape-based. However, significantly more quantitative information is contained within images. This information could be exploited to classify LNs in patients with locally-advanced HNSCC by means of artificial intelligence (AI). The present work systematically reviews original articles that specifically explore the role of AI to classify LNs in locally-advanced HNSCC. Between 2001 and 2022, 13 retrospective studies were identified. AI's mean diagnostic accuracy for LN-classification was 86% (range: 43–99%). Consequently, all of the identified studies concluded AI to be a potentially promising diagnostic support tool for LN-classification in HNSCC. However, adequately powered, prospective, randomized control trials are urgently required to further assess AI's role in LN-classification in locally-advanced HNSCC. Locally-advanced head and neck squamous cell carcinoma (HNSCC) is mainly defined by the presence of pathologic cervical lymph nodes (LNs) with or without extracapsular spread (ECS). Current radiologic criteria to classify LNs as non-pathologic, pathologic, or pathologic with ECS are primarily shape-based. However, significantly more quantitative information is contained within imaging modalities. This quantitative information could be exploited for classification of LNs in patients with locally-advanced HNSCC by means of artificial intelligence (AI). Currently, various reviews exploring the role of AI in HNSCC are available. However, reviews specifically addressing the current role of AI to classify LN in HNSCC-patients are sparse. The present work systematically reviews original articles that specifically explore the role of AI to classify LNs in locally-advanced HNSCC applying Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and the Study Quality Assessment Tool of National Institute of Health (NIH). Between 2001 and 2022, out of 69 studies a total of 13 retrospective, mainly monocentric, studies were identified. The majority of the studies included patients with oropharyngeal and oral cavity (9 and 7 of 13 studies, respectively) HNSCC. Histopathologic findings were defined as reference in 9 of 13 studies. Machine learning was applied in 13 studies, 9 of them applying deep learning. The mean number of included patients was 75 (SD ± 72; range 10–258) and of LNs was 340 (SD ± 268; range 21–791). The mean diagnostic accuracy for the training sets was 86% (SD ± 14%; range: 43–99%) and for testing sets 86% (SD ± 5%; range 76–92%). Consequently, all of the identified studies concluded AI to be a potentially promising diagnostic support tool for LN-classification in HNSCC. However, adequately powered, prospective, and randomized control trials are urgently required to further assess AI's role in LN-classification in locally-advanced HNSCC. [ABSTRACT FROM AUTHOR]

This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement. [ABSTRACT FROM AUTHOR]

Clinical lymph node staging in head and neck carcinoma (HNC) is fraught with uncertainties. Established clinical algorithms are available for the problem of occult cervical metastases. Much less is known about clinical lymph node overstaging. We identified HNC patients clinically classified as lymph node positive (cN+), in whom surgical neck dissection (ND) specimens were histopathologically negative (pN0) and in addition the subgroup, in whom an originally planned postoperative radiotherapy (PORT) was omitted. We compared these patients with surgically treated patients with clinically and histopathologically negative neck (cN0/pN0), who had received selective ND. Using a fuzzy matching algorithm, we identified patients with closely similar patient and disease characteristics, who had received primary definitive radiotherapy (RT) with or without systemic therapy (RT ± ST). Of the 980 patients with HNC, 292 received a ND as part of primary treatment. In 128/292 patients with cN0 neck, ND was elective, and in 164 patients with clinically positive neck (cN+), ND was therapeutic. In 43/164 cN+ patients, ND was histopathologically negative (cN+/pN−). In 24 of these, initially planned PORT was omitted. Overall, survival did not differ from the cN0/pN0 and primary RT ± ST control groups. However, more RT ± ST patients had functional problems with nutrition (p = 0.002). Based on these data, it can be estimated that lymph node overstaging is 26% (95% CI: 20% to 34%). In 15% (95% CI: 10% to 21%) of surgically treated cN+ HNC patients, treatment can be de-escalated without the affection of survival. [ABSTRACT FROM AUTHOR]

Background and Purpose: Diffusion‐weighted imaging(DWI) in MRI has been developed as an important tool for the detection of cholesteatoma. Various DWI sequences are available. This study aims to evaluate the importance of the observer's reliance level for the detection of cholesteatoma. Methods: Forty patients meeting the following criteria were included in the study: (1) chronic otitis media, (2) preoperative MRI including various DWI sequences, and (3) middle‐ear surgery. The MRI protocol contained the following sequences: (1) axial and (2) coronal echoplanar imaging (EPI) readout‐segmented (RESOLVE) DWI with Trace acquisition and (3) coronal non‐EPI half‐Fourier acquired single‐shot turbo spin‐echo (HASTE) DWI. Cholesteatoma diagnosis was based on standard diagnostic criteria for cholesteatoma with DWI. Additionally, the radiologists were asked to grade personal reliance on their diagnosis using a Likert‐type scale from 1 = very insecure to 5 = very secure. Results: Axial and coronal RESOLVE DWI showed a sensitivity of 77.3% and a specificity of 72.2%, respectively. The mean reliance was 3.9 for axial and 3.8 for coronal images. HASTE DWI had a sensitivity/specificity of 81.8%/66.7% with the highest reliance of all evaluated sequences (4.4). Cases with a reliance level of 5 showed a sensitivity/specificity of 100% in all sequences. A reliance level of 5 was given in the axial and coronal RESOLVE DWI in 32.5% of cases and in the HASTE DWI in 57.5%. Conclusion: The evaluated DWI sequences showed comparable results. The reliance level significantly improved the predictor of cholesteatoma disease with MRI techniques. [ABSTRACT FROM AUTHOR]

Abstract Background Experimental murine malaria has been shown to result in significant hearing impairment. Microscopic evaluation of the temporal bones of these animals has revealed regular morphology of the cochlea duct. Furthermore, the known vascular pathologic changes being associated with malaria could not be found. Immunohistochemistry for ICAM1 showed a strong marking in the stria vascularis, indicating a disturbance of the endocochlear potential. The aim of this study was to evaluate the role of apoptosis and the disturbance of the blood labyrinth barrier in the murine malaria associated hearing impairment. Methods The temporal bones of seven mice with cerebral malaria-four with hearing impairment, three without hearing impairment-were evaluated with immunohistochemistry for cleaved caspase 3 to detect apoptosis and connexin 26, a gap junction protein being a cornerstone in the endocochlear potassium recirculation. Furthermore five animals with cerebral malaria were treated with Evans blue prior to sacrification to detect disturbances of the blood labyrinth barrier. Results Cleaved caspase 3 could clearly be detected by immunohistochemistry in the fibrocytes of the spiral ligament, more intensively in animals with hearing impairment, less intensively in those without. Apoptosis signal was equally distributed in the spiral ligament as was the connexin 26 gap junction protein. The Evans blue testing revealed a strong signal in the malaria animals and no signal in the healthy control animals. Conclusion Malfunction of the fibrocytes type 1 in the spiral ligament and disruption of the blood labyrinth barrier, resulting in a breakdown of the endocochlear potential, are major causes for hearing impairment in murine cerebral malaria.

Abstract Background Plasmodium falciparum malaria has been suspected to cause hearing loss. Developmental, cognitive and language disorders have been observed in children, surviving cerebral malaria. This prospective study aims to evaluate whether malaria influences hearing in mice. Methods Twenty mice were included in a standardized murine cerebral malaria model. Auditory evoked brainstem responses were assessed before infection and at the peak of the illness. Results A significant hearing impairment could be demonstrated in mice with malaria, especially the cerebral form. The control group did not show any alterations. No therapy was used. Conclusion This suggests that malaria itself leads to a hearing impairment in mice.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity. [ABSTRACT FROM AUTHOR]

Introduction: Cochlea implants can cause severe trauma leading to intracochlear apoptosis, fibrosis, and eventually to loss of residual hearing. Mild hypothermia has been shown to reduce toxic or mechanical noxious effects, which can result in inflammation and subsequent hearing loss. This paper evaluates the usability of standard surgical otologic rinsing as cooling medium during cochlea implantation as a potential hearing preservation technique. Material and Methods: Three human temporal bones were prepared following standard mastoidectomy and posterior tympanotomy. Applying a retrocochlear approach leaving the mastoidectomy side intact, temperature probes were placed into the basal turn (n = 4), the middle turn (n = 2), the helicotrema, and the modiolus. Temperature probe positions were visualized by microcomputed tomography (μCT) imaging and manually segmented using Amira® 7.6. Through the posterior tympanotomy, the tympanic cavity was rinsed at 37°C in the control group, at room temperature (in the range between 22 and 24°C), and at iced water conditions. Temperature changes were measured in the preheated temporal bone. In each temperature model, rinsing was done for 20 min at the pre-specified temperatures measured in 0.5-s intervals. At least five repetitions were performed. Data were statistically analyzed using pairwise t -tests with Bonferroni correction. Results: Steady-state conditions achieved in all three different temperature ranges were compared in periods between 150 and 300 s. Temperature in the inner ear started dropping within the initial 150 s. Temperature probes placed at basal turn, the helicotrema, and middle turn detected statistically significant fall in temperature levels following body temperature rinses. Irrigation at iced conditions lead to the most significant temperature drops. The curves during all measurements remained stable with 37°C rinses. Conclusion: Therapeutic hypothermia is achieved with standard surgical irrigation fluid, and temperature gradients are seen along the cochlea. Rinsing of 120 s duration results in a therapeutic local hypothermia throughout the cochlea. This otoprotective procedure can be easily realized in clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: This study presents the data collected through a database on the type and incidence of cochlear implant device failures and major complications and quantifies the risk of failures across time based on the Association for the Advancement of Medical Instrumentation (AAMI) CI86:2017 standard. Methods: Information on reliability of MED-EL cochlear implants was collected from the MED-EL complaint database between 2003 and2013. Explants were categorized and device reliability was calculated according to the AAMI CI86:2017 standard principles. Results: Data were collected for 11662 devices (5462 children, 6200 adults). The mean duration of follow up was 46.16 months. The total failure rate for all devices and all subjects was 2.41%. Medical related explants (MRE) were significantly worse for children than for adults with the ceramic implants, C40+ (p = 0.008) and PULSAR (p = 0.020). Device failure explants (DFE) were significantly worse for children than for adults with all four devices in the study, the C40+ (p < 0.001), PULSAR (p < 0.001), SONATA (p < 0.001), and CONCERTO (p = 0.023). The mean annual failure rate for all subjects and devices was 0.63% (1.03% for children, 0.28% for adults). The mean annual failure rate was 0.90% for the C40+; 0.57% for the PULSAR; 0.46% for the SONATA; and 0.39% for the CONCERTO. Conclusions: Compared to adults, children had significantly worse MRE and DFE due to a higher risk of head trauma and more vulnerable skull anatomy. Further, the authors conclude that the AAMI standard will ensure a more comprehensive and transparent evaluation of cochlear implant reliability in the future. [ABSTRACT FROM AUTHOR]

Background/aims: Calcium-binding proteins in neurons buffer intracellular free Ca2+ ions, which interact with proteins controlling enzymatic and ion channel activity. The heterogeneous distribution of calretinin, calbindin, and parvalbumin influences calcium homeostasis, and calcium-related neuronal processes play an important role in neuronal aging and degeneration. This study evaluated age-related changes in calretinin, calbindin, and parvalbumin immune reactivity in spiral ganglion cells.Methods: A total of 16 C57BL/6J and 16 129/SvJ mice at different ages (2, 4, 7, and 12 months) were included in the study. Hearing thresholds were assessed using auditory brainstem response before inner ears were excised for further evaluation. Semiquantitative immunohistochemistry for the aforementioned calcium-binding proteins was performed at the cellular level.Results: The hearing thresholds of C57BL/6J and 129/SvJ mice increased significantly by 7 months of age. The average immune reactivity of calbin-din as well as the relative number of positive cells increased significantly with aging, but no significant alterations in calretinin or parvalbumin were observed.Conclusions: Upregulation of calbindin could serve as a protection to compensate for functional deficits that occur with aging. Expression of both calretinin and parvalbumin seem to be stabilizing factors in murine inner ears up to the age of 12 months in C57BL/6J and 129/SvJ mice. [ABSTRACT FROM AUTHOR]

Objective: To study the long-term evolution of speech and intelligence in a child with partial deafness and normal hearing in the low frequencies after sequentially receiving cochlear implants in both ears. Design: Retrospective chart review. Study sample: Male child aged 6 years was followed over a time period of four years. Results: The paediatric patient had normal hearing up to 1 kHz and profound hearing loss at all higher frequencies symmetrical in both ears. Deprivation of high-frequency sounds resulted in retarded development of speech, language and cognitive skills. The choice for rehabilitation was cochlear implantation with the aim of preserving a considerable amount of low-frequency hearing. With natural hearing at low frequencies and electrical stimulation at high frequencies, the child was able to compensate most of his developmental deficits. Moreover, spatial hearing was almost normal. Conclusions: Electro-natural stimulation without amplification of the low frequencies (electro-natural hearing) provides access to the whole audible frequency range for children, who suffer from partial deafness in the high frequencies and are normal hearing at low frequencies. Such provision allows for regular speech development and favours the development of spatial hearing. The case report also demonstrates a strong impact on intellectual performance. [ABSTRACT FROM AUTHOR]

Background: Severe malaria may influence inner ear function, although this possibility has not been examined prospectively. In a retrospective analysis, hearing impairment was found in 9 of 23 patients with cerebral malaria. An objective method to quickly evaluate the function of the inner ear are the otoacoustic emissions. Negative transient otoacoustic emissions are associated with a threshold shift of 20 dB and above. Methods: This prospective multicenter study analyses otoacoustic emissions in patients with severe malaria up to the age of 10 years. In three study sites (Ghana, Gabon, Kenya) 144 patients with severe malaria and 108 control children were included. All malaria patients were treated with parental artesunate. Results: In the control group, 92.6 % (n = 108, 95 % confidence interval 86.19-6.2 %) passed otoacoustic emission screening. In malaria patients, 58.5 % (n = 94, malaria vs controls < 0.001, 95 % confidence interval 48.4-67.9 %) p passed otoacoustic emission screening at the baseline measurement. The value increased to 65.2 % (n = 66, p < 0.001, 95 % confidence interval 53.1-75.5 %) at follow up 14-28 days after diagnosis of malaria. The study population was divided into severe non-cerebral malaria and severe malaria with neurological symptoms (cerebral malaria). Whereas otoacoustic emissions in severe malaria improved to a passing percentage of 72.9 % (n = 48, 95 % confidence interval 59-83.4 %) at follow-up, the patients with cerebral malaria showed a drop in the passing percentage to 33 % (n = 18) 3-7 days after diagnosis. This shows a significant impairment in the cerebral malaria group ( = 0.012 at days 3-7, 95 % confidence interval 16.3-56.3 %; = 0.031 at day 14-28, 95 % p p confidence interval 24.5-66.3 %). Conclusion: The presented data show that 40 % of children have involvement of the inner ear early in severe malaria. In children, audiological screening after severe malaria infection is not currently recommended, but is worth investigating in larger studies. [ABSTRACT FROM AUTHOR]

Background: Modification of allergens by glutaraldehyde in extracts used for immunotherapy reduces the risk for side effects, but therapeutic efficacy of such extracts requires further evaluation. The aim of this study was to evaluate the efficacy and safety of immunotherapy with PURETHAL Mites (PM), a single-strength glutaraldehyde-modified aluminum hydroxide-adsorbed extract of house-dust mites (HDM). Methods: In a multicenter, randomized, placebo-controlled double-blind setting, HDM-allergic subjects (n = 140) were treated with modified allergen extract or placebo over a 1-year period. The primary outcome parameter was a combined symptom and medication score (clinical index score [CIS]). Secondary efficacy parameters were the result of a titrated conjunctival provocation test (CPT), rhinitis/rhinoconjunctivitis quality of life (RQL) score, and serum concentrations of IgE and IgG against specific HDM allergens and a documentation of adverse events (AE). Results: We evaluated 140 patients (66 treatment and 74 placebo) for clinical efficacy. The allergoid treatment for 1 year resulted in significantly greater CIS improvement and higher RQL scores. The response threshold in the titrated CPT (p = 0.009) and the serum concentrations of IgG4 (p < 0.001) against Dermatophagoides pteronyssinus allergens after treatment were also significantly different between groups. In total, 88 patients (46 PM/42 placebo) out of a safety population of 145 reported 278 (158 PM/120 placebo) AE. Except for local reactions, no specific AE appeared to be associated with PURETHAL Mites (HAL-Allergy, Leiden, The Netherlands). Conclusion: The findings of this study indicate that allergen injection therapy with modified HDM extract is superior to placebo in allergic rhinitis therapy. The treatment was well tolerated and no serious drug-related AE were observed. [ABSTRACT FROM AUTHOR]