Revealing RB1 loss in an emerging entity: report of two cases of PRRX1-rearranged mesenchymal tumours.

AIMS: PRRX1-rearranged mesenchymal tumours are a recently identified and rare subgroup of soft tissue neoplasms with distinct morphological features and genetic alterations. This study aims to further investigate the immunohistochemical profile and underlying genetic alterations in these tumours in order to get more insight on their underlying biology and the unique profile of these tumours. METHODS: Two new molecular confirmed cases of PRRX1-rearranged mesenchymal tumours were thoroughly studied with immunohistochemical stainings (RB1, CD34, ALK and pan-TRK), fluorescence in situ hybridisation (FISH) RB1/13q12 and RNA-based next-generation sequencing. RESULTS: Both cases exhibited typical morphological and molecular features, confirming the diagnosis of PRRX1-rearranged mesenchymal tumours. Immunohistochemistry revealed RB1 loss in both cases, which was subsequently confirmed through FISH analysis. Additionally, one case showed focal positivity for CD34, ALK and pan-TRK on immunohistochemistry. CONCLUSIONS: We identified loss of RB1 in two cases of PRRX1-rearranged mesenchymal tumours. This could suggest a potential association with RB1-deficient soft tissue tumours, although further research is necessary. Furthermore, the finding of focal positivity for CD34, ALK and pan-TRK on immunohistochemistry enriches the immunohistochemical profile of these tumours.

Immediate effects of straw phonation in air or water on the laryngeal function and configuration of female speech-language pathology students visualised with strobovideolaryngoscopy: A randomised controlled trial.

BACKGROUND: A promising way to obtain vocal economy and efficiency is by semi-occluding the vocal tract while phonating. Current knowledge about the immediate effects of semi-occluded vocal tract (SOVT) phonation on the laryngeal function and configuration is based mainly on computer modelling or excised larynges studies. In in vivo SOVT studies, electroglottography (EGG) has been the most commonly used laryngeal outcome, showing contradictory results between studies. Therefore, exploring these aspects by direct visualisation of the human larynx during SOVT phonation using strobovideolaryngoscopy (SVL) is needed. AIMS: The aim of this study was to investigate and compare the immediate effects of straw phonation (SP) in air, SP in 2 cm water, and SP in 5 cm water (with stirring straws), on the laryngeal function and configuration of a homogeneous group of vocally healthy female speech-language pathology students, visualised with flexible SVL. METHODS & PROCEDURE: A randomised controlled trial was used. Fifty-two female speech-language pathology students (mean age: 18.7 years, SD: 0.6) were assigned randomly to one of three experimental groups or a control group: (1) SP in air, (2) SP in 2 cm water, (3) SP in 5 cm water or (4) [u] phonation with similar soft onset and slightly pursed lips as in SP but without a straw (control group). The participants underwent flexible SVL during habitual [u] phonation, followed by the specific SOVT exercise of their group assignment. All video samples were evaluated randomly and blindly by two experienced investigators using the Voice-Vibratory Assessment with Laryngeal Imaging (VALI) rating form, first independently and then by consensus. OUTCOME & RESULTS: Compared to habitual phonation, the vibrational amplitude decreased during SP in 5 cm water and SP in 2 cm water, being more prominent in the first, more flow-resistant exercise. The mucosal wave also decreased during SP in 5 cm water. The anteroposterior (AP) supraglottic compression similarly increased during SP in air, SP in 2 cm water, and SP in 5 cm water. Further, a rise in mediolateral (ML) compression and a decrease in phase symmetry and regularity were found during SP in 2 cm water. A similar decrease in regularity was observed during SP in 5 cm water. CONCLUSIONS & IMPLICATIONS: Both SP in air and SP in water cause positive immediate laryngeal effects for voice training opportunities. More AP supraglottic activity found during each SP exercise might indicate epilarynx narrowing, an economic phenomenon associated with SOVT. Immersing the straw in water additionally diminished the vibrational amplitude, lowering vocal fold impact stress and risk for phonotrauma during the exercise. The decreased regularity of the vibrational cycles during SP in water might be due to the varying back pressure created by the water bubbling. The impact of SP in water on ML supraglottic compression needs further investigation. WHAT THIS PAPER ADDS: What is already known on the subject A promising way to obtain vocal economy and efficiency is by semi-occluding the vocal tract while phonating. Current knowledge about the immediate effects of semi-occluded vocal tract (SOVT) phonation on the laryngeal function and configuration is based mainly on computer modelling or excised larynges studies. In in vivo SOVT studies, electroglottography (EGG) has been the most commonly used laryngeal outcome, showing contradictory results between studies. Therefore, exploring these aspects by direct visualisation of the human larynx during SOVT phonation using strobovideolaryngoscopy (SVL) is needed. What this paper adds to existing knowledge Group results of the current study generally support earlier computer modelling and in vivo studies, strengthening the current SOVT knowledge. Both SP in air and SP in water cause positive immediate laryngeal effects for voice training opportunities. More anteroposterior (AP) supraglottic activity found during each SP exercise might indicate epilarynx narrowing, an economic phenomenon associated with SOVT. Immersing the straw in water additionally diminished the vibrational amplitude, lowering vocal fold impact stress and risk for phonotrauma during the exercise. The decreased regularity of the vibrational cycles during SP in water might be due to the varying back pressure created by the water bubbling. The impact of SP in water on ML supraglottic compression needs further investigation. What are the potential or actual clinical implications of this work? Current results support that both SP in air and SP in water can be useful exercises in voice training. SP in water has shown the additional gain of lowering the vibrational amplitude during the exercise, hence supporting its appropriateness for vocal warm-ups by minimising vocal fold impact stress and the risk of phonotrauma. In the future, large-scale randomised controlled trials in other subgroups of voice users, including dysphonic patients, are needed to support evidence-based practice. SVL can facilitate the search for individualised training and therapy approaches.

Ultrasound-guided core needle biopsy and incisional biopsy of the parotid gland are comparable in diagnosis of primary Sjögren's syndrome.

OBJECTIVES: Salivary gland lymphocytic infiltrates are a hallmark of primary SS (pSS), but traditional biopsy techniques hold several disadvantages. Ultrasound-guided core needle (US-guided CN) parotid gland biopsy is minimally invasive and reliable for diagnosis of lymphoma in pSS. This proof-of-concept study aimed to explore this technique in the diagnostic work-up of pSS and is the first to address its value in a consecutive cohort independently of the presence of salivary gland swelling. METHODS: Combined incisional and US-guided CN parotid biopsy was performed in 20 patients with suspected or confirmed pSS from the Belgian Sjögren's Syndrome Transition Trial (BeSSTT). Surface area and presence of a focus score (FS) of at least one, germinal centres and lymphoepithelial lesions were recorded. RESULTS: Salivary gland tissue was interpretable in 19 patients. Fourteen patients had ≥4 mm2 salivary gland tissue by both techniques, in four US-guided CN biopsies salivary gland tissue was <4 mm2. Paired biopsies ≥4 mm2 displayed a concordance of 90% for FS ≥ 1. Presence of lymphoepithelial lesions and germinal centres showed absolute concordance. Of four US-guided CN biopsies <4 mm2, three interpretable incisional biopsies were available, 2/3 with perfect concordance. When including biopsies of <4 mm2 salivary gland tissue, presence of FS ≥ 1 or germinal centres gave a sensitivity of 70% in incisional and of 69% in US-guided CN biopsy. CONCLUSIONS: US-guided CN biopsy of the parotid gland is at least equivalent to incisional biopsy of the parotid gland in the diagnostic work-up of pSS.

The value of separate detection of anti-Ro52, anti-Ro60 and anti-SSB/La reactivities in relation to diagnosis and phenotypes in primary Sjögren's syndrome.

OBJECTIVES: Autoantibody detection is an essential step in pSS diagnosis. However, the value of separate anti-Ro52, anti-Ro60 and anti-SSB/La detection in pSS diagnosis and phenotyping has not been extensively studied. This study aimed to explore disease characteristics of anti-SSA/Ro positive, suspected and definite pSS patients, in relation to serological profiles based on anti-Ro52, anti-Ro60 and anti-SSB/La reactivity. METHODS: Of 187 anti-SSA/Ro positive patients included in the Belgian Sjögren's Syndrome Transition Trial (BeSSTT), 155 were considered definite pSS patients, due to fulfilment of the 2016 ACR-EULAR classification criteria, and 32 suspected, due to reactivity against SSA/Ro without presence of other criteria. None of the patients met any of the ACR-EULAR exclusion criteria for pSS. Patients were grouped based on the presence of anti-Ro52, anti-Ro60 and anti-SSB/La antibodies. RESULTS: Mono-reactivity against Ro60 or Ro52, double reactivity against Ro52/Ro60 and triple reactivity against Ro52/Ro60 and SSB was detected in respectively 30, 23, 70 and 60 patients. Mono-anti-Ro60 positive patients showed the least pSS features. Mono-anti-Ro52 positive patients reported a significantly higher dryness burden (p=0.016) and tended toward more salivary gland ultrasound (SGUS) abnormalities (p=0.054) than mono-anti-Ro60 positives. Double positive patients showed similar characteristics as mono-anti-Ro52 positive patients, whereas triple positive patients showed lowest unstimulated salivary flow rates (p=0.002) and Schirmer tests (p=0.002), highest ocular staining scores (p<0.001), most positive labial salivary gland biopsies (p=0.039), most laboratory abnormalities compatible with B-cell hyperactivity and highest SGUS scores (p<0.001) compared to other patient groups. CONCLUSIONS: These data indicate that separate detection of anti-Ro52, anti-Ro60 and anti-SSB/La reactivity is not only relevant towards pSS diagnosis, but markedly aids in patient stratification and evaluation of disease burden. Our results suggest a stepwise model in which mono-reactivity against Ro60 displayed the least objective and subjective glandular pSS features, whereas glandular abnormalities and signs of B-cell hyperactivity were most present in patients showing triple reactivity against Ro60, Ro52 and SSB/La.

Discriminative power of salivary gland ultrasound in relation to symptom-based endotypes in suspected and definite primary Sjögren's Syndrome.

OBJECTIVES: Salivary gland ultrasound (SGUS) is emerging as essential tool in primary Sjögren's Syndrome (pSS), but its link to symptom-based endotypes is unknown. Therefore, we explored SGUS outcomes in relation to endotypes in patients with definite and suspected pSS. METHODS: Definite pSS patients (n = 171) fulfilling the 2016 ACR/EULAR classification criteria, and suspected pSS patients (n = 119), positive for at least one criterion, were included in the Belgian Sjögren's Syndrome Transition Trial (BeSSTT). Stratification into endotypes according to the Newcastle Sjögren's Stratification Tool resulted in low symptom burden (LSB), pain dominant with fatigue (PDF), dryness dominant with fatigue (DDF) and high symptom burden (HSB). SGUS was assessed with Hocevar score (0-48). The dataset was randomly divided into a discovery (n = 203) and replication (n = 87) cohort. RESULTS: SGUS had strong discriminative power for pSS classification (AUC=0.74), especially in DDF (AUC=0.89). In definite pSS, Hocevar scores in DDF were high compared to other endotypes (38 (20-44) versus 18 (9-33); p < 0.001). Patients with highest SGUS-scores showed more sicca and laboratory abnormalities. Moreover, a subset of young, anti-SSA/Ro positive patients not fulfilling classification criteria showed clear SGUS abnormalities. Replication showed similar results. CONCLUSIONS: SGUS-scores were significantly higher in definite pSS with DDF endotype, providing the first evidence of imaging abnormalities in salivary glands matching distinct biological profiles ascribed to pSS endotypes. Additionally, a subset of patients with potential early disease was detected based on presence of anti-SSA antibodies and high SGUS-scores. These results underscore the role of SGUS as powerful tool both in pSS classification and stratification.

The impact of cleft lip and/or palate on parental quality of life: A pilot study.

BACKGROUND: Cleft lip and/or palate (CL/CP/CLP) is one of the most common congenital anomalies. Children may suffer from a variety of health problems including difficulties with feeding and speech, middle ear problems, hearing loss and associated psychosocial concerns. The extent of impact of this disorder on the parents, however, has not yet been thoroughly evaluated. This pilot study was performed to evaluate the impact of having a child with CL/CP/CLP on the parents' quality of life (QoL) and family functioning and to compare between cleft subgroups. METHODS: Forty-five parents with children aged 6 months to 6 years with CL/CP/CLP, followed by the multidisciplinary orofacial cleft team of Ghent University Hospital, completed following standardized questionnaires: Impact on Family Scale (IOFS), Family Impact Scale (FIS) and Care-Related Quality of Life Instrument (CarerQoL). Subgroups were compared with diverse unpaired statistical tests. RESULTS: Younger children (6m-2y) with CL/CP/CLP entail more impact on parental QoL compared to children aged 2-4y old (p=0.04, ε²=0.15/p=0.02, ε²=0.17/p=0.02, ε²=0.17). Families from children with a syndromic cleft also encounter more impact (p=0.04, r=0.32 /p=0.01, r=0.37 /p=0.008, r=0.40/p=0.003, r=0.45). Prenatal orofacial cleft diagnosis is associated with a higher reporting of family conflicts (p=0.04, r=0.32). In case of non-syndromic clefts, families having children with CLP report more family conflicts compared to CL or CP (p=0.02, ε²=0.46). Parental education and number of children within the household showed no significant impact on parental QoL. CONCLUSION: This cross-sectional study confirms that having a child with CL/CP/CLP impacts the parental QoL. This study was performed as a pilot-study for larger multicentre studies, future development of effective screening tools and identification of subgroups at risk. Long-term multidisciplinary follow-up should involve family-centred support.

Ear- and hearing-related impact on quality of life in children with cleft palate: Development and pretest of a health-related quality of life (HRQOL) instrument.

OBJECTIVES: To investigate to what extent middle ear problems and associated hearing loss affect quality of life (QoL) of children born with a cleft palate. METHODS: Fifty-five children aged between 6 and 18 years, born with non-syndromic cleft palate ±â€¯cleft lip (CP/L) were included. A new health-related quality of life (HRQOL) questionnaire was generated with consideration of the following domains of QoL: communication, hearing loss, physical symptoms, limitation of activities and socio-emotional impact. RESULTS: Major psychosocial problems were not reported in the majority of children as a result of their ear and hearing problems. However, according to their parents, 2 out of 3 children, had difficulty speaking clearly and understandably. These communication problems led to behavioural problems and social isolation in 1 out of 5 children. Scholastic achievement was negatively influenced by two factors: hearing loss and sleep disturbance due to ear problems. CONCLUSIONS: To our knowledge this is the first study to quantitatively measure the ear- and hearing-related impact on QoL in children born with CP/L. Large-scale, multicentre studies are needed to further research and expand on the findings of this pilot study.

The diagnostic value of SE MRI and DWI of the spine in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma.

OBJECTIVES: To evaluate DWI of the bone marrow in the differentiation of monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma (SMM) and multiple myeloma (MM). METHODS: The retrospective study includes 64 patients with MGUS, 27 with SMM, 64 with new MM and 12 controls. Signal intensity (SI) of spinal SE-MRI and DWI (b0-1000) as well as apparent diffusion coefficients (ADC) were measured in the T10 and L3. Qualitative assessment of b-images was performed by one experienced radiologist. RESULTS: ADC600 and ADC1000 are the best ADC values in differentiating patient groups (p < 0.030). SIT2, SIb1000 and ADC1000 are higher and SIT1 lower in L3 compared to T10 (p < 0.050). All quantitative parameters of L3 can differentiate significantly between MGUS and MM (p < 0.050) and between patients with percentage plasma cells (PC%) between 0-10 % compared to >50 % (p = 0.001). Only SIT2 for L3 can differentiate MGUS from SMM (p = 0.044) and PC%0-10 from PC%10-25 (p = 0.033). Qualitative interpretation of b1000 images allows differentiating MM patients from those with MGUS or SMM (p < 0.001). CONCLUSIONS: Spinal SE-MRI can differentiate among MGUS, SMM, MM and control subjects. DWI based on the SI on b1000 images and ADC values is increased in MM compared to MGUS and SMM. Qualitative assessment of b-images can differentiate MM from MGUS or SMM. KEY POINTS: • ADC values are higher in patients with MM compared to MGUS • DWI parameters change late in disease evolution • DWI is sensitive but not specific in diagnosing patients with MM • Qualitative DWI assessment is good in detecting myeloma patients.