CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment.</p

OrgaSegment: deep-learning based organoid segmentation to quantify CFTR dependent fluid secretion

Epithelial ion and fluid transport studies in patient-derived organoids (PDOs) are increasingly being used for preclinical studies, drug development and precision medicine applications. Epithelial fluid transport properties in PDOs can be measured through visual changes in organoid (lumen) size. Such organoid phenotypes have been highly instrumental for the studying of diseases, including cystic fibrosis (CF), which is characterized by genetic mutations of the CF transmembrane conductance regulator (CFTR) ion channel. Here we present OrgaSegment, a MASK-RCNN based deep-learning segmentation model allowing for the segmentation of individual intestinal PDO structures from bright-field images. OrgaSegment recognizes spherical structures in addition to the oddly-shaped organoids that are a hallmark of CF organoids and can be used in organoid swelling assays, including the new drug-induced swelling assay that we show here. OrgaSegment enabled easy quantification of organoid swelling and could discriminate between organoids with different CFTR mutations, as well as measure responses to CFTR modulating drugs. The easy-to-apply label-free segmentation tool can help to study CFTR-based fluid secretion and possibly other epithelial ion transport mechanisms in organoids

Ninety-day complication rate based on 532 Latarjet procedures in Dutch hospitals with different operation volumes

Background: In this study, we aimed to provide insight into the 90-day complication rates following the Latarjet procedure. Data from 2015 were collected from multiple hospitals in the Netherlands, with different volumes of Latarjet procedures. Our second aim was to examine which patient and surgical factors were associated with complications.Methods: We conducted a retrospective chart review of 13 hospitals between 2015 and 2022. Data regarding complications within 90 days of Latarjet procedures were extracted. The effect of sex, age, body mass index (BMI), smoking, previous shoulder operations, fixation material, hospital volume, screw size, and operation time on the complication rate was assessed by multivariable logistic regression analysis.Results: Of the 532 included patients, 58 (10.9%) had complications. The most common complications were material failure (n = 19, 3.6%) and nerve injury (n = 13, 2.4%). The risk of complications was lower for male patients than for female patients (odds ratio, 0.40; 95% confidence interval, 0.21-0.77; P = .006). Age, BMI, smoking, previous shoulder operations, type of fixation material, hospital volume, screw size, and operation time were not associated with complications.Conclusion: The 90-day complication rate after the Latarjet procedure was 10.9% and was higher in female patients than in male patients. Age, BMI, smoking, previous shoulder operations, type of fixation material, hospital volume, screw size, and operation time did not affect complication rates. We advise setting up a national registry to prevent under-reporting of complications.</p

CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes.

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator ( CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment

Successful conservative management of symptomatic bilateral dorsal patellar defects presenting with cartilage involvement and bone marrow edema : MRI findings

The dorsal patellar defect is a relatively rare entity that involves the superolateral quadrant of the patella. It is usually considered to represent a delayed ossification process, although its exact origin remains unclear. Because of its usually innocuous nature and clinical course, invasive interventions are generally deemed unnecessary, although curretage has been successfully performed on symptomatic cases. This case report presents a rather unusual case of symptomatic bilateral dorsal patellar defects with cartilage involvement and widespread surrounding bone marrow edema as demonstrated by magnetic resonance imaging (MRI). Both cartilage involvement and bone marrow edema should be considered part of the spectrum of associated MRI findings that can be encountered in this entity. Furthermore, the presented case shows that symptomatic dorsal patellar defects can be treated conservatively with success and that (decrease of) pain symptoms are likely related to (decrease of) bone marrow edema

The conceptually equivalent Dutch version of the Western Ontario Rotator Cuff Index (WORC)(c)

BACKGROUND: The WORC is a quality of life questionnaire designed for patients with disorders of the rotator cuff, originally developed in English. The purpose of this study was to cross-culturally adapt the WORC for use in the Dutch population and to evaluate reliability, agreement and floor and ceiling effects of this Dutch version in a population of patients with rotator cuff disease. METHODS: Reliability was tested by measuring the Cronbach’s alpha for internal consistency and intraclass correlation coefficients (ICC) for test-retest reliability. Agreement was measured using the Standard Error of Measurement (SEM(agreement)); and the smallest detectable change (SDC) was calculated based on the SEM. Pearson Correlations Coefficients were used to comparing the WORC with the RAND-36, the Constant Score and 11-point shoulder hindrance scale. RESULTS: Fifty-seven patients entered into this study of whom 50 were available for test-retest validation. The internal consistency of the Dutch WORC tested by Cronbach’s alpha was 0.95 for the total questionnaire. The ICC for the WORC is 0.91 with a 95% confidence interval of 0.85-0.95. Standard Error of Measurement was 6.0 points with a Smallest Detectable Change of 16.7 points on a 0-100 scale. Pearson Correlations Coefficients showed a significant positive correlation between the Dutch WORC and Constant Score (r = 0.60) and a strong reversed correlation with the shoulder hindrance scale (r = -0.75). CONCLUSION: The Dutch WORC seems to be a reliable health-related quality of life questionnaire for patients with rotator cuff disorders. TRIAL REGISTRATION: NCT01532492

OrgaSegment: deep-learning based organoid segmentation to quantify CFTR dependent fluid secretion

Abstract Epithelial ion and fluid transport studies in patient-derived organoids (PDOs) are increasingly being used for preclinical studies, drug development and precision medicine applications. Epithelial fluid transport properties in PDOs can be measured through visual changes in organoid (lumen) size. Such organoid phenotypes have been highly instrumental for the studying of diseases, including cystic fibrosis (CF), which is characterized by genetic mutations of the CF transmembrane conductance regulator (CFTR) ion channel. Here we present OrgaSegment, a MASK-RCNN based deep-learning segmentation model allowing for the segmentation of individual intestinal PDO structures from bright-field images. OrgaSegment recognizes spherical structures in addition to the oddly-shaped organoids that are a hallmark of CF organoids and can be used in organoid swelling assays, including the new drug-induced swelling assay that we show here. OrgaSegment enabled easy quantification of organoid swelling and could discriminate between organoids with different CFTR mutations, as well as measure responses to CFTR modulating drugs. The easy-to-apply label-free segmentation tool can help to study CFTR-based fluid secretion and possibly other epithelial ion transport mechanisms in organoids

Prognostic and predictive performance of R-ISS with SKY92 in older patients with multiple myeloma: The HOVON-87/NMSG-18 trial

The standard prognostic marker for multiple myeloma (MM) patients is the revised International Staging System (R-ISS). However, there is room for improvement in guiding treatment. This applies particularly to older patients, in whom the benefit/risk ratio is reduced because of comorbidities and subsequent side effects. We hypothesized that adding gene-expression data to R-ISS would generate a stronger marker. This was tested by combining R-ISS with the SKY92 classifier (SKY-RISS). The HOVON-87/NMSG-18 trial (EudraCT: 2007-004007-34) compared melphalan-prednisone-thalidomide followed by thalidomide maintenance (MPT-T) with melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R). From this trial, 168 patients with available R-ISS status and gene-expression profiles were analyzed. R-ISS stages I, II, and III were assigned to 8%, 75%, and 7% of patients, respectively (3-year overall survival [OS] rates: 80%, 65%, 33%, P 5 8 3 1023). Using the SKY92 classifier, 13% of patients were high risk (HR) (3-year OS rates: standard risk [SR], 70%; HR, 28%; P,.001). Combining SKY92 with R-ISS resulted in 3 risk groups: SKY-RISS I (SKY-SR 1 R-ISS-I; 15%), SKY-RISS III (SKY-HR 1 R-ISS-II/III; 11%), and SKY-RISS II (all other patients; 74%). The 3-year OS rates for SKY-RISS I, II, and III are 88%, 66%, and 26%, respectively (P 5 6 3 1027). The SKY-RISS model was validated in older patients from the CoMMpass dataset. Moreover, SKY-RISS demonstrated predictive potential: HR patients appeared to benefit from MPR-R over MPT-T (median OS, 55 and 14 months, respectively). Combined, SKY92 and R-ISS classify patients more accurately. Additionally, benefit was observed for MPR-R over MPT-T in SKY92-RISS HR patients only