Low Clinical Value Research Articles

OphGLM: An ophthalmology large language-and-vision assistant

Vision computer-aided diagnostic methods have been used in early ophthalmic disease screening and diagnosis. However, the limited output formats of these methods lead to poor human–computer interaction and low clinical applicability value. Thus, ophthalmic visual question answering is worth studying. Unfortunately, no practical solutions exist before Large Language Models(LLMs). In this paper, we investigate the ophthalmic visual diagnostic interaction problem. We construct an ophthalmology large language-and-vision assistant, OphGLM, consisting of an image encoder, a text encoder, a fusion module, and an LLM module. We establish a new Chinese ophthalmic fine-tuning dataset, FundusTuning-CN, including the fundus instruction and conversation sets. Based on FundusTuning-CN, we establish a novel LLM-tuning strategy to introduce visual model understanding and ophthalmic knowledge into LLMs at a low cost and high efficiency. Leveraging the pre-training of the image encoder, OphGLM demonstrates strong visual understanding and surpasses open-source visual language models in common fundus disease classification tasks. The FundusTuning-CN enables OphGLM to surpass open-source medical LLMs in both ophthalmic knowledge and interactive capabilities. Our proposed OphGLM has the potential to revolutionize clinical applications in ophthalmology. The dataset, code, and models will be publicly available at https://github.com/ML-AILab/OphGLM.

Predictors of early-onset neonatal infections (review)

Predictors of early-onset neonatal infections (review)

Abstract 243: Organoid co-cultures with allogenic T cells to assess toxicity and efficacy of bispecific antibodies

Abstract Recent advances in cancer immunotherapy positively impacted the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies, druggable targets and biomarkers being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. For example, the emerging Bispecific T cell Engagers (BiTEs) designed to simultaneously target CD3 and tumor-specific antigens and promote T cell cytotoxicity have seen recent clinical success. While BiTEs have been approved for the treatment of hematologic malignancies, promising therapeutic developments for solid tumors face hurdles in translating preclinical findings into therapy since conventional two-dimensional cancer models fail to recapitulate the immune cell interactions in the tumor microenvironment and therefore hold low clinical predictive value. We developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures that maintain complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. Here, we show the development of a patient-relevant preclinical platform for immunotherapy development in which colorectal (CRC) and non-small cell lung cancer (NSCLC) organoids are co-cultured with allogenic or autologous T cells to evaluate the activity and assess the cytotoxic potential of a BiTEs. The expression of tumor-specific BiTE target antigens is determined in patient-derived organoids (PDOs) by flow cytometry. Following this assessment, T cell-induced organoid death is quantified and characterized in real-time by image-based analysis of fluorescent live/dead dyes. Additionally, we measure cytokine secretion as a read-out of T cell activation and function. In our co-cultures, T cell-induced PDO death was increased upon BiTEs treatment. Similarly, IFNγ secretion correlated with expression levels of the targeted tumor antigen. In addition, PDO apoptosis and IFNγ secretion increased in a dose-dependent fashion in the presence of the TA-targeting TCB. In summary, our organoids and T cell co-cultures offer a powerful platform for developing and validating immunotherapies such as T cell-bispecific antibodies and will significantly contribute to our understanding of the critical factors determining successful immunotherapies. Citation Format: Cesar Oyarce, Virginia Bruno, Lorenzo Spagnuolo, Claudia Beaurivage, Javier Frias Aldeguer, Farzin Pourfarzad, Robert G. Vries, Sylvia F. Boj. Organoid co-cultures with allogenic T cells to assess toxicity and efficacy of bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 243.

Abstract 4256: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development

Abstract Recent advances in cancer immunotherapy have had a positive impact on the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient-derived organoids are generated from normal and malignant tissues and stored as high-quality biobanks that yield highly reproducible results. HUB Organoids® recapitulate complex characteristics of the parental tissue, including molecular heterogeneity, as well as morphological and functional traits. Since cancer progression and response to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with paired tumor infiltrating lymphocytes (TIL) that are simultaneously expanded as a source of tumor reactive cells. Paired resources allow for the screening of immune-modulatory therapies under physiologic conditions, not depending on peptide-pulsing and alloreactivity. We quantify tumor organoid killing and TILs reactivity by combining imaging-based analysis of apoptotic cells with flow cytometry to measure cytokine release by cytotoxic TILs. Here, we show that our system is robust and reproducible with an establishment rate of 75%, allowing for expansion of TILs that preserve T cell receptor repertoires. First line expansion of both PDO and TIL components can be used to effectively build coculture models and probe the tumor and immune components, respectively. Our system offers a powerful tool for the development and validation of cancer immunotherapy and can help to stratify cancer patients for susceptibility to various types of immunotherapies. We certify that the research use of each of the HBS marked above was conducted according to the expectations of each institution. Citation Format: Claudia Beaurivage, BanuPriya Sridharan, Sumeyra Mucuk, Kimberly Nadwodny, Derek Poore, Anna Schepers, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4256.

Abstract 3611: A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors

Abstract Recent advances in cancer immunotherapy have positively impacted the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when embedded into the extracellular matrix. Patient-derived organoids are generated from healthy and malignant tissues, and they recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. Cell therapies have achieved positive results in treating haematological cancers. Recently, the unique tumour-targeting properties of γδ T cell receptors have been leveraged to develop safer and more effective strategies. HUB and Gadeta joined efforts to explore the therapeutic potential of GDT002 - i.e. αβ T cells engineered with a Gadeta proprietary new γδTCR - to target solid cancers. A preclinical basket trial was performed using patient-derived organoids from several tumour types (colorectal, breast, head and neck, ovarian cancers) cocultured with GDT002. The results showed broad reactivity of GDT002 against solid tumor PDOs. Interestingly, GDT002 was particularly efficient at killing ovarian cancer-derived PDOs, allowing Gadeta to move GDT002 to clinical trials for this indication confidently. This study reveals that our tumor organoid co-culture with engineered T cells platform holds significant value for the preclinical development of cellular therapies. Citation Format: Andrea Bisso, Rene Overmeer, Sjoerd Baardman, Chris Coomans, Cesar Oyarce, Sylvia F. Boj. A patient-derived organoid platform to assess the effectiveness of γδTCR cell therapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3611.

Abstract 2696: Tumor organoid and immune cells co-cultures to study myeloid cells-targeting immunotherapy

Abstract Cancer immunotherapy is one of the main pillars of oncology treatment due to the clinical success of approaches that enhance anti-tumoral T cell responses. Nonetheless, many patients do not benefit from these approaches, highlighting the need to develop novel immunomodulatory strategies. Exploiting the anti-tumor capacity of innate immune cells is a promising approach that can overcome specific limitations of T cell-targeting therapies and complement existing immunotherapies. Still, promising therapeutic developments face hurdles in translating preclinical findings into treatment since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures. Patient-specific organoids are generated from healthy and disease tissues and recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. To assess the efficacy of therapies that engage innate immune cells, we developed an assay in which organoids derived from colorectal (CRC) or breast cancer patients are co-cultured with PBMC-derived macrophages or monocytes to evaluate the cytotoxic potential of exogenously activated myeloid cells. We tested the ability of macrophages to phagocyte human CRC organoid cells in response to anti-CD47 antibody. The pro-phagocytic function of anti-CD47 was detected by several methods (i.e., flow cytometry, imaging), indicating the platform's suitability to evaluate ADCP-modulating compounds. Moreover, to assess whether our PBMC-organoids co-culture platform is suited to detect monocyte-mediated effects, Lipopolysaccharide (LPS) plus IFN-γ were used to activate monocytes in the co-culture assays. We observed an increase in cytokines secretion (i.e., CXCL10), immune cell activation and organoid killing, indicating that our assay allows the detection of monocyte activation through different types of readouts. In summary, our organoid-immune cell co-culture platform allows to study the response of tumor organoids to innate immune cells, holding significant value for the preclinical development of immunotherapies based on innate immune cells. Citation Format: Lorenzo Spagnuolo, Francisco Morales-Rodriguez, Alessandra Merenda, Cesar Oyarce, Farzin Pourfarzad, Robert G. Vries, Sylvia F. Boj. Tumor organoid and immune cells co-cultures to study myeloid cells-targeting immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2696.

Formal Radiologist Interpretations of Intraoperative Spine Radiographs Have Low Clinical Value.

Retrospective cohort. To evaluate the clinical relevance, usefulness, and financial implications of intraoperative radiograph interpretation by radiologists in spine surgery. Due to rising healthcare costs, spine surgery is under scrutiny to maximize value-based care. Formal radiographic analysis remains a potential source of unnecessary healthcare costs, especially for intra-operative radiographs. A retrospective cohort analysis was performed on all adult elective spine surgeries at a single institution between July 2020 and July 2021. Demographic and radiographic data was collected, including intraoperative localization and post-instrumentation radiographs. Financial data was obtained through the institution's price estimator. Radiographic characteristics included time from radiographic imaging to completion of radiologist interpretation report, completion of radiologist interpretation report prior to the conclusion of surgical procedure, clinical relevance, and clinical usefulness. Reports were considered clinically relevant if spinal level of the procedure was described and clinically useful if completed prior to conclusion of the procedure and deemed clinically relevant. 481 intraoperative localization and post-instrumentation radiographs from 360 patients revealed a median delay of 128 minutes between imaging and completion of interpretive report. Only 38.9% of reports were completed before conclusion of surgery. There were 79.4% deemed clinically relevant and only 33.5% were clinically useful. Localization reports were completed more frequently before conclusion of surgery (67.2% vs. 34.4%), but with lower clinical relevance (90.1% vs. 98.5%) and clinical usefulness (60.3% vs. 33.6%) than post-instrumentation reports. Each patient was charged $32-$34 for interpretation fee, cumulating a minimum total cost of $15,392. Formal radiographic interpretation of intraoperative spine radiographs was of low clinical utility for spine surgeons. Institutions should consider optimizing radiology workflows to improve timeliness and clinical relevance or evaluate the necessity of reflexive consultation to radiology for intraoperative imaging interpretation to ensure that value-based care is maximized during spine surgeries. 3.

Advancing acceptance: assessing acceptance of the ESR iGuide clinical decision support system for improved computed tomography test justification.

A clinical decision support system (CDSS), the European Society of Radiologists (ESR) iGuide, was developed to address gaps in the availability and use of effective imaging referral guidelines. This study aimed to assess the appropriateness of computed tomography (CT) exams with and without ESR iGuide use, as well as the usability and acceptance of the physician systems. A retrospective single-center study was conducted in which data from 278 consecutive CT tests referred by physicians were collected in the first phase (T1), and physicians used the ESR iGuide system for imaging referrals in the second phase (T2; n = 85). The appropriateness of imaging referrals in each phase was assessed by two experts, and physicians completed the System Usability Scale. The mean appropriateness level on a scale of 0-9 was 6.62 ± 2.69 at T1 and 7.88 ± 1.4 at T2. When using a binary variable (0-6 = non-appropriate; 7-9 = appropriate), 70.14% of cases were found appropriate at T1 and 96.47% at T2. Surgery physician specialty and post-intervention phase showed a higher likelihood of ordering an appropriate test (p = 0.0045 and p = 0.0003, respectively). However, the questionnaire results indicated low system trust and minimal clinical value, with all physicians indicating they would not recommend collegial use (100%). The study suggests that ESR iGuide can effectively guide the selection of appropriate imaging tests. However, physicians showed low system trust and use, indicating a need for further understanding of CDSS acceptance properties. Maximizing CDSS potential could result in crucial decision-support compliance and promotion of appropriate imaging.

Abstract 188: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, built on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with simultaneously expanded paired tumor infiltrating lymphocytes (TIL) as a source of tumor reactive cells. Our system allows robust expansion of TIL with preserved T-cell receptor repertoires and has an establishment rate of 75%. Paired resources allow for screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and allo-reactivity. For this purpose, we developed a organoid-TIL co-culture system which quantifies and characterizes tumor organoid apoptosis by combining image-based analysis with flow cytometry and cytokine release assays as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids. Our system offers a powerful tool for the development and validation of cancer immunotherapy and may help to stratify cancer patients for susceptibility of various types of immunotherapies. Citation Format: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 188.

Abstract 908: Tumour organoid-t cell co-culture assay to evaluate CAR t cell cytotoxicity

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, build on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumour microenvironment, we developed an assay in which various types of tumour organoids are co-cultured with T cells modified with chimeric antigen receptors (CAR T cells) to assess the cytotoxic potential. CAR-T cell therapy has been demonstrated to be efficacious against many hematological malignancies, however therapeutic application to treat solid cancers remains challenging. Our organoid-T cell co-culture assay offers a good platform to study the response of tumour organoids on the CAR T cells and will greatly contribute to our understanding of the critical factors that determine a successful CAR T cell therapy. In collaboration with GSK, HUB tested the cytotoxicity of GSK CAR T cells which target specific target antigen on human colorectal cancer (CRC) organoids. Six HUB CRC organoid models were selected based on differential expression levels of target antigen that was confirmed by FACS antibody staining. To evaluate GSK CAR T cell mediated organoid killing, caspase 3/7 expression was monitored at various timepoints and IFNγ secretion was measured by ELISA. For control, staurosporine and nonspecific-CAR T cells were included. Detected CRC-organoid killing demonstrated to be in line with antigen expression levels, indicating the specificity of the tested CAR T cells. Nevertheless, some CRC-organoid models demonstrated more resilient to CAR T cell mediated killing and further evaluation revealed upregulation of check point molecules such as PD-L1. This study reveals that tumour organoid-T cell co-culture assay hold value for preclinical development of CAR T-cell products and for evaluating tumour-evasion strategies. Moreover, this platform could potentially predict patient specific responses to CAR- T-cell therapy. Citation Format: Soura Mardpour, Mirella Georgouli, Ana Pereira Puri, Ravit Oren, Joshua Audu-Evans, Farzin Pourfarzad, Sara Brett, Pleun Hombrink, Sylvia F. Boj. Tumour organoid-t cell co-culture assay to evaluate CAR t cell cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 908.

Abstract 2924: Organoid co-cultures with autologous T cells to assess toxicity and efficacy of bispecific antibodies

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, build on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumour microenvironment, we developed an assay in which various types of tumour organoids are co-cultured with T cells modified with chimeric antigen receptors (CAR T cells) to assess the cytotoxic potential. CAR-T cell therapy has been demonstrated to be efficacious against many hematological malignancies, however therapeutic application to treat solid cancers remains challenging. Our organoid-T cell co-culture assay offers a good platform to study the response of tumour organoids on the CAR T cells and will greatly contribute to our understanding of the critical factors that determine a successful CAR T cell therapy. In collaboration with GSK, HUB tested the cytotoxicity of GSK CAR T cells which target specific target antigen on human colorectal cancer (CRC) organoids. Six HUB CRC organoid models were selected based on differential expression levels of target antigen that was confirmed by FACS antibody staining. To evaluate GSK CAR T cell mediated organoid killing, caspase 3/7 expression was monitored at various timepoints and IFNγ secretion was measured by ELISA. For control, staurosporine and nonspecific-CAR T cells were included. Detected CRC-organoid killing demonstrated to be in line with antigen expression levels, indicating the specificity of the tested CAR T cells. Nevertheless, some CRC-organoid models demonstrated more resilient to CAR T cell mediated killing and further evaluation revealed upregulation of check point molecules such as PD-L1. This study reveals that tumour organoid-T cell co-culture assay hold value for preclinical development of CAR T-cell products and for evaluating tumour-evasion strategies. Moreover, this platform could potentially predict patient specific responses to CAR- T-cell therapy. Citation Format: Lorenz Jahn, Maxime Kempers, Roel Verker, Wies van Dooremalen, Linda Steinacher, Pleun Hombrink, Farzin Pourfarzad, Robert G. Vries, Lauriane Cabon, Sylvia F. Boj. Organoid co-cultures with autologous T cells to assess toxicity and efficacy of bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2924.

Abnormal findings on abdominopelvic cross-sectional imaging in patients with microscopic colitis: a retrospective, multicenter study

Objectives Patients with microscopic colitis may have subtle macroscopic findings on colonoscopy such as erythema, edema, or altered vascular pattern; however, radiographic abnormalities on cross-sectional imaging have not been investigated. We aimed at identifying the abdominopelvic radiographic abnormalities in patients with microscopic colitis, as well as possible correlation with endoscopic findings and the need for extended duration of treatment. Materials and Methods This was a retrospective study of patients with biopsy-proven microscopic colitis at two tertiary centers between 1 January 2010 and 30 April 2020. Patients underwent computed tomography scan or magnetic resonance imaging within 30 days of a diagnostic flexible sigmoidoscopy or colonoscopy. Patients with colon ischemia and other causes of colitis were excluded. Radiographic abnormalities from imaging reports included bowel wall thickening, mucosal hyperenhancement and mesenteric fat stranding. Univariate and multivariable logistic regression models were used to identify predictors of radiographic abnormalities. Results 498 patients with microscopic colitis underwent abdominopelvic cross-sectional imaging within 30 days of flexible sigmoidoscopy/colonoscopy. Lymphocytic colitis was diagnosed in 54.6% of patients, and collagenous colitis in 45.4%. Endoscopic and radiographic abnormalities were identified in 16.1% and 12.4% of patients, respectively. Radiographic abnormalities were associated with the need for budesonide therapy (p = .029) and budesonide therapy long-term (p = .0028). Budesonide therapy long-term (p = .047) was associated with radiographic abnormalities in multivariate analysis. Conclusions Radiographic abnormalities may be present on abdominopelvic cross-sectional imaging in a minority of patients with biopsy-proven microscopic colitis, suggesting cross-sectional imaging has low clinical value in the evaluation and treatment of this disease.

Improved breast cancer histological grading using deep learning

The Nottingham histological grade (NHG) is a well-established prognostic factor for breast cancer that is broadly used in clinical decision making. However, ∼50% of patients are classified as grade 2, an intermediate risk group with low clinical value. To improve risk stratification of NHG 2 breast cancer patients, we developed and validated a novel histological grade model (DeepGrade) based on digital whole-slide histopathology images (WSIs) and deep learning. In this observational retrospective study, routine WSIs stained with haematoxylin and eosin from 1567 patients were utilised for model optimisation and validation. Model generalisability was further evaluated in an external test set with 1262 patients. NHG 2 cases were stratified into two groups, DG2-high and DG2-low, and the prognostic value was assessed. The main outcome was recurrence-free survival. DeepGrade provides independent prognostic information for stratification of NHG 2 cases in the internal test set, where DG2-high showed an increased risk for recurrence (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.24-6.97, P= 0.015) compared with the DG2-low group after adjusting for established risk factors (independent test data). DG2-low also shared phenotypic similarities with NHG 1, and DG2-high with NHG 3, suggesting that the model identifies morphological patterns in NHG 2 that are associated with more aggressive tumours. The prognostic value of DeepGrade was further assessed in the external test set, confirming an increased risk for recurrence in DG2-high (HR 1.91, 95% CI 1.11-3.29, P= 0.019). The proposed model-based stratification of patients with NHG 2 tumours is prognostic and adds clinically relevant information over routine histological grading. The methodology offers a cost-effective alternative to molecular profiling to extract information relevant for clinical decisions.

Alert-Based ICD Follow-Up: A Model of Digitally Driven Remote Patient Monitoring.

The goal of this study was to test whether continuous automatic remote patient monitoring (RPM) linked to centralized analytics reduces nonactionable in-person patient evaluation (IPE) but maintains detection of at-risk patients and provides actionable notifications. Conventional ambulatory care requires frequent IPEs. Many encounters are nonactionable, and additional unscheduled IPEs occur. Patients receiving implantable cardioverter-defibrillators for Class I/IIa indications were randomized (2:1) to RPM or conventional follow-up, and they were followed up for 15months. IPEs were conducted every 3months in the conventional care group but at 3 and 15months with RPM. Groups were compared for patient retention, nonactionable IPEs, and discovery of at-risk patients during 1 year of exclusive RPM. Frequency and value of RPM alerts were assessed. Patients enrolled (mean age 63.5 ± 12.8 years; male 71.9%; left ventricular ejection fraction 29.0 ± 10.7%; primary prevention 72.3%; n=1450) were similar between groups (977 RPM vs. 473 conventional care). Mean follow-up durations were 407 ± 103days for the RPM group versus 399 ± 111days for the conventional care group (p=0.165). Patient attrition to follow-up was 42% greater with conventional care (20.1% [87 of 431]) versus RPM (14.2% [129 of 908]; p=0.007). Nonactionable IPEs were reduced 81% by RPM (0.7 per patient year) compared with conventional care (3.6 per patient year; p<0.001) but event discoveries remained similar (2.9 per patient year). In RPM, alert rate was median 1 per patient (interquartile range: 0 to 3) with >50% actionability, indicating low volume but high clinical value. Unscheduled IPE was the basis for discovery of 100% of intercurrent problems in RPM and also 75% in conventional care, indicating limited value of appointment-based follow-up for problem discovery. The number of IPEs needed to discover an actionable event was 8.2 in Conventional, 4.9 in RPM, and 2.1 when alert driven (p<0.001). RPM transformed ambulatory care to IPE directed to those patients with clinically actionable events when required. Filtering patient information by digitally driven remote monitoring expends fewer clinic resources while providing a greater yield of actionable interventions. (Lumos-T Safely Reduces Routine Office Device Follow-up [TRUST]; NCT00336284).

Clinician-ordered peripheral blood smears have low reimbursement and variable clinical value: a three-institution study, with suggestions for operational efficiency

BackgroundPeripheral blood smears are performed to evaluate a variety of hematologic and non-hematologic disorders. At the authors’ institutions, clinician requests for pathologist-performed blood smear reviews have increased in recent years. Blood smears may contribute significantly to pathologists’ workloads, yet their clinical value is variable, and professional reimbursement rates are low. This study aimed to identify clinical scenarios in which smear review is likely to provide value beyond automated laboratory testing.MethodsBlood smear review practices at three institutions were examined, and the indications for and interpretations of clinician-initiated smears were reviewed to determine the percentage of smears with potential added clinical value. A smear review was classified as having added clinical value if the pathologist’s interpretation included a morphologic abnormality that had the potential to impact patient management, and that could not be diagnosed by automated complete blood count with white blood cell differential or automated iron studies alone.ResultsAmong 515 consecutive clinician-requested smears performed during the study timeframes, 23% yielded interpretations with potential added clinical value. When sorted by indication, 25, 19, and 13% of smear reviews requested for white blood cell abnormalities, red blood cell abnormalities, and platelet abnormalities, respectively, had findings with potential added clinical value. The proportion of smears with potential clinical value differed significantly across these three categories (p = 0.0375).ConclusionsSmear review ordering practices across three institutions resulted in a minority of smears with potential added clinical value. The likelihood of value varied according to the indication for which the smear was requested. Given this, efforts to improve the utilization and efficiency of smear review are worthwhile. Solutions are discussed, including engaging laboratory staff, educating clinicians, and modifying technology systems.

Septoplasty versus non-surgical management for nasal obstruction in adults with a deviated septum: economic evaluation alongside a randomized controlled trial

BackgroundFor years, the benefits of septoplasty have been questioned. Due to the scarce and inconclusive literature, several National Health Service (NHS) Clinical Commissioning Groups in England decided to add septal surgery to their list of restricted procedures with low clinical value. Recently, evidence was obtained that septoplasty is actually more effective than non-surgical management for nasal obstruction in adults with a deviated septum. However, the relation between costs and effects of septoplasty remains unknown.MethodsWe conducted an economic evaluation alongside an open, multicenter, pragmatic randomized controlled trial in two tertiary and 16 secondary referral hospitals in the Netherlands. Adults with nasal obstruction and a deviated septum were randomized to (1) septoplasty with or without concurrent turbinate surgery or (2) non-surgical management consisting of (a combination of) medical treatment and watchful waiting. Analyses were performed on an intention-to-treat basis. Single imputation nested in the bootstrap percentile method (using 5000 bootstrap replications) was performed to assess the effect of missing data. After 12 and 24 months, we assessed the incremental costs per quality-adjusted life year (QALY) gained from a healthcare and a societal perspective.ResultsA total of 203 adults were randomly assigned to septoplasty (N = 102) or non-surgical management (N = 101). After 12 months, the mean cost difference between septoplasty and non-surgical management using a healthcare or societal perspective was €1181 (95%CI €1038 to €1323) or €2192 per patient (95%CI €1714 to €2670), respectively. The mean QALY difference was 0.03 per patient (95%CI − 0.01 to 0.07). Incremental costs per QALY gained from a healthcare or societal perspective were €41,763 or €77,525, respectively. After 24 months, the mean cost difference between the two groups using a healthcare or societal perspective decreased to €936 (95%CI €719 to €1153) or €1671 per patient (95%CI €952 to €2390), respectively. The mean QALY difference increased to 0.05 per patient (95%CI − 0.03 to 0.14). Incremental costs per QALY gained from a healthcare or societal perspective became €17,374 or €31,024, respectively. Analyses of imputed data did not alter our findings.ConclusionsDepending on the selected perspective, cost-effectiveness threshold, and time horizon, septoplasty has the potential to be cost-effective. Despite considerable uncertainty, septoplasty seems to be cost-effective from a healthcare perspective, after 24 months against a threshold of €20,000 per QALY. From a societal perspective, septoplasty is not yet cost-effective after 24 months, but it comes closer to the cost-effectiveness threshold as time passes by.Trial registrationNederlands Trial Register, NTR3868 (https://www.trialregister.nl/trial/3698). Prospectively registered on February 21, 2013.

Variation in Proportion of Blood Cultures Obtained for Children With Skin and Soft Tissue Infections.

To identify variation in the proportion of blood cultures obtained for pediatric skin and soft tissue infections (SSTIs) among children's hospitals. We conducted a retrospective cohort study using the Pediatric Health Information System database, which we queried for emergency department (ED)-only and hospital encounters between 2012 and 2017 for children aged 2 months to 18 years with diagnosis codes for SSTI. The primary outcome was proportion of SSTI encounters during which blood cultures were obtained. Encounters with and without blood cultures were compared for length of stay, costs, and 30-day ED revisit and readmission rates, adjusted for patient factors and hospital clustering. We also identified encounters with bacteremia using billing codes for septicemia and bacteremia. We identified 239 954 ED-only and 49 291 hospital SSTI encounters among 38 hospitals. Median proportions of ED-only and hospital encounters with blood cultures were 3.2% (range: 1%- 11%) and 51.6% (range: 25%-81%), respectively. Adjusted ED-only encounters with versus without blood culture had higher costs ($1266 vs $460, P < .001), higher ED revisit rates (3.6% vs 2.9%, P < .001), and higher admission rates (2.0% vs 0.9%, P < .001). Hospital encounters with blood culture had longer length of stay (2.3 vs 2.0 days, P < .001), higher costs ($5254 vs $4425, P < .001), and higher readmission rates (0.8% vs 0.7%, P = .027). The overall proportion of encounters with bacteremia was 0.6% for ED-only encounters and 1.0% for hospital encounters. Despite multiple studies in which low clinical value was demonstrated and current Infectious Diseases Society of America guidelines arguing against the practice, blood cultures were obtained frequently for children hospitalized with SSTIs, with substantial variation across institutions. Few bacteremic encounters were identified.

Cost Analysis of Routine Examination of Pathology Specimens Following Ankle Arthroscopy.

Background:Routine submission of pathologic specimens for histologic analysis following orthopedic surgery is a common and often required practice in the United States. Prior orthopedic studies have determined that these histologic examinations are of limited cost effectiveness and low clinical value because rarely do the pathology findings alter patient management. The purpose of this study was to evaluate the cost effectiveness and clinical significance of routine histologic examination of tissue specimens removed during ankle arthroscopy.Methods:Between 2014 and 2018, 408 patients underwent ankle arthroscopy at a multi-center hospital system by 16 different orthopedic surgeons. The available pathology reports from these cases were retrospectively reviewed to determine if the routine histologic examination altered patient care. We compared the preoperative diagnosis to both the postoperative and histologic diagnoses. The total cost for these histologic examinations was estimated using 2017 Medicare physician fees released by the College of American Pathologists. Cost-effectiveness was estimated in 2017 US dollars by cost per discrepant and discordant diagnosis.Results:Of the 408 patients who underwent ankle arthroscopy, 361 pathology reports were available for review. The prevalence of concordant diagnosis was 98.9% (357/361); the prevalence of discrepant diagnoses was 1.0% (4/361). There were no cases identified with a discordant diagnosis. Total estimated cost for all pathology specimens was $46 381 in 2017 US dollars. Cost per discrepant diagnosis was $11 595.Conclusion:In our study, histologic examination of surgical specimens following ankle arthroscopy had no effect on patient management, yet it increased costs. Routine examination of these pathologic specimens had a low rate of discrepant and/or discordant diagnoses. Based on our results, routine pathologic examination of ankle arthroscopy tissue specimens should be sent solely at the discretion of the orthopedic surgeon as opposed to being a mandated policy.Level of Evidence:Level IV, case series.

Clinical Signs of Basilar Skull Fracture and Their Predictive Value in Diagnosis of This Injury.

Although clinical signs for the diagnosis of basilar skull fracture (BSF) are ambiguous, they are widely used to make decisions on initial interventions involving trauma patients. We aimed to assess the performance of early and late (within 48 hr posttrauma) signs for BSF diagnosis and to verify the correlation between the presence of these signs and head injury severity. We conducted a prospectively designed follow-up study at a referral hospital for trauma care in Sao Paulo, Brazil, and performed structured observations for 48 hr post-blunt head injury in patients aged 12 years or older. The following signs of BSF were considered: raccoon eyes, Battle's sign, otorrhea, and rhinorrhea. Among the 136 enrolled patients (85.3% male; mean age 40 ± 21.4 years), 28 patients (20.6%) had BSF. The clinical signs for the early or late detection of BSF had low accuracy (55.9% vs. 43.4%), specificity (52.8% vs. 30.5%), and positive predictive value (25.7% vs. 27.1%). However, the presence of these signs was correlated to head injury severity, indicated by the Glasgow Coma Scale (p = .041) and Maximum Abbreviated Injury Scale-Head region (p = .002). In view of the low accuracy of these signs, resulting low clinical value of their presence, and their high sensitivity in the late stage, the study results contraindicate the value of BSF signs for making decisions about using the nasal route for the introduction of catheters and tubes in initial trauma care.

Cost of treatments of 'low clinical value' rising despite prescriptions falling, researchers discover

Cost of treatments of 'low clinical value' rising despite prescriptions falling, researchers discover