Performance of a RAD51-based functional HRD test on paraffin-embedded breast cancer tissue.

PURPOSE: BRCA-deficient breast cancers (BC) are highly sensitive to platinum-based chemotherapy and PARP inhibitors due to their deficiency in the homologous recombination (HR) pathway. However, HR deficiency (HRD) extends beyond BRCA-associated BC, highlighting the need for a sensitive method to enrich for HRD tumors in an alternative way. A promising approach is the use of functional HRD tests which evaluate the HR capability of tumor cells by measuring RAD51 protein accumulation at DNA damage sites. This study aims to evaluate the performance of a functional RAD51-based HRD test for the identification of HRD BC. METHODS: The functional HR status of 63 diagnostic formalin-fixed paraffin-embedded (FFPE) BC samples was determined by applying the RAD51-FFPE test. Samples were screened for the presence of (epi)genetic defects in HR and matching tumor samples were analyzed with the RECAP test, which requires ex vivo irradiated fresh tumor tissue on the premise that the HRD status as determined by the RECAP test faithfully represented the functional HR status. RESULTS: The RAD51-FFPE test identified 23 (37%) of the tumors as HRD, including three tumors with pathogenic variants in BRCA1/2. The RAD51-FFPE test showed a sensitivity of 88% and a specificity of 76% in determining the HR-class as defined by the RECAP test. CONCLUSION: Given its high sensitivity and compatibility with FFPE samples, the RAD51-FFPE test holds great potential to enrich for HRD tumors, including those associated with BRCA-deficiency. This potential extends to situations where DNA-based testing may be challenging or not easily accessible in routine clinical practice. This is particularly important considering the potential implications for treatment decisions and patient stratification.

Systematic review and meta-analysis of the prognostic impact of lymph node micrometastasis and isolated tumour cells in patients with stage I-IIIA non-small cell lung cancer.

Lymph node micrometastases could be one of the reasons for the high recurrence rate after complete surgical resection in stage I-IIIA non-small cell lung cancer (NSCLC). The standard evaluation of a single haematoxylin and eosin (H&E) slide of a paraffin-embedded section of a lymph node is insufficient for the detection of micrometastases, and there is a need for additional histopathological evaluation. The association of lymph node micrometastases with survival remains as yet unresolved. The aim of this systematic review and meta-analysis is to investigate if lymph node micrometastases and isolated tumour cells in patients with stage I-IIIA NSCLC, detected with multiple sectioning and/or immunohistochemistry (IHC) and/or reverse transcriptase polymerase chain reaction (RT-PCR), are associated with overall survival (OS) and disease-free survival (DFS) after surgical resection. We performed a meta-analysis of time-to-event outcomes based on 15 articles using ancillary techniques to detect micrometastases. We extracted the OS and DFS every 3-6 months after surgery, for patients with and without occult lymph node micrometastasis, from the survival curves published in each article. These data were used to reconstruct OS and DFS for 'micrometastasis' and 'no micrometastasis' groups. Based on all included studies that used IHC, serial sectioning, or RT-PCR, we found a 5-year OS of 55% (micrometastasis) vs. 75% (no micrometastasis), and a 5-year DFS of 53% (micrometastasis) vs. 75% (no micrometastasis). Patients with stage I-IIIA NSCLC with lymph node micrometastases detected by ancillary histopathological and molecular techniques have a significantly poorer OS and DFS compared to patients without lymph node micrometastases.

Development and validation of a supervised deep learning algorithm for automated whole-slide programmed death-ligand 1 tumour proportion score assessment in non-small cell lung cancer.

AIMS: Immunohistochemical programmed death-ligand 1 (PD-L1) staining to predict responsiveness to immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) has several drawbacks: a robust gold standard is lacking, and there is substantial interobserver and intraobserver variance, with up to 20% discordance around cutoff points. The aim of this study was to develop a new deep learning-based PD-L1 tumour proportion score (TPS) algorithm, trained and validated on a routine diagnostic dataset of digitised PD-L1 (22C3, laboratory-developed test)-stained samples. METHODS AND RESULTS: We designed a fully supervised deep learning algorithm for whole-slide PD-L1 assessment, consisting of four sequential convolutional neural networks (CNNs), using aiforia create software. We included 199 whole slide images (WSIs) of 'routine diagnostic' histology samples from stage IV NSCLC patients, and trained the algorithm by using a training set of 60 representative cases. We validated the algorithm by comparing the algorithm TPS with the reference score in a held-out validation set. The algorithm had similar concordance with the reference score (79%) as the pathologists had with one another (75%). The intraclass coefficient was 0.96 and Cohen's κ coefficient was 0.69 for the algorithm. Around the 1% and 50% cutoff points, concordance was also similar between pathologists and the algorithm. CONCLUSIONS: We designed a new, deep learning-based PD-L1 TPS algorithm that is similarly able to assess PD-L1 expression in daily routine diagnostic cases as pathologists. Successful validation on routine diagnostic WSIs and detailed visual feedback show that this algorithm meets the requirements for functioning as a 'scoring assistant'.

Tumor-stroma ratio is associated with Miller-Payne score and pathological response to neoadjuvant chemotherapy in HER2-negative early breast cancer.

The tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2-negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin-stained sections of pre-treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller-Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi-square, Cochran-Armitage test for trend and regression analyses. A stroma-low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)-negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma-low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34-4.51, P = .004), which attenuated to 1.90 (95% CI 0.85-4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER-negativity (95% CI 1.19-29.48, P = .030) and 1.48 for ER-positivity (95% CI 0.73-3.01, P = .281). In conclusion, a low amount of stroma on pre-treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment.

Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial.

PURPOSE: In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial. METHODS: 131 patients with HER2-negative stage II/III breast cancer were recruited, of whom 129 were randomly assigned (1:1) to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and the day of neoadjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires EORTC-QLQ-C30 and EORTC-QLQ-BR23; the Brief Illness Perception Questionnaire (BIPQ) and the Distress Thermometer were used to assess these outcomes at baseline, halfway chemotherapy, before the last cycle of chemotherapy and 6 months after surgery. RESULTS: Overall QoL and distress scores declined during treatment in both arms and returned to baseline values 6 months after surgery. However, patients' perceptions differed slightly over time. In particular, patients receiving the FMD were less concerned and had better understanding of the possible adverse effects of their treatment in comparison with patients on a regular diet. Per-protocol analyses yielded better emotional, physical, role, cognitive and social functioning scores as well as lower fatigue, nausea and insomnia symptom scores for patients adherent to the FMD in comparison with non-adherent patients and patients on their regular diet. CONCLUSIONS: FMD as an adjunct to neoadjuvant chemotherapy appears to improve certain QoL and illness perception domains in patients with HER2-negative breast cancer. Trialregister ClinicalTrials.gov Identifier: NCT02126449.

The prognostic value of the tumor-stroma ratio is most discriminative in patients with grade III or triple-negative breast cancer.

The tumor-stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin-stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence-free survival (RFS; HR 1.35, 95% CI 1.10-1.66, p = 0.004). The interaction term was statistically significant for grade and triple-negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43-2.51, p < 0.001) and triple-negative tumors (HR 1.86, 95% CI 1.10-3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple-negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma-high tumor had a worse prognosis compared to patients with a stroma-low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple-negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.

Delivery of long-term-injectable agents for TB by lay carers: pragmatic randomised trial.

BACKGROUND: People with recurrent or drug-resistant TB require long courses of intramuscular injections. We evaluate a novel system in which patient-nominated lay carers were trained to deliver intramuscular injections to patients in their own homes. METHODS: A pragmatic, individually randomised non-inferiority trial was conducted at two hospitals in Malawi. Adults starting TB retreatment were recruited. Patients randomised to the intervention received home-based care from patient-nominated lay people trained to deliver intramuscular streptomycin. Patients receiving standard care were admitted to hospital for 2 months of streptomycin. The primary outcome was successful treatment (alive and on treatment) at the end of the intervention. RESULTS: Of 456 patients screened, 204 participants were randomised. The trial was terminated early due to futility. At the end of the intervention, 97/101 (96.0%) in the hospital arm were still alive and on treatment compared with 96/103 (93.2%) in the home-based arm (risk difference -0.03 (95% CI -0.09 to 0.03); p value 0.538). There were no differences in the proportion completing 8 months of anti-TB treatment; or the proportion experiencing 2-month sputum culture conversion. The mean cost of hospital-based management was US$1546.3 per person, compared to US$729.2 for home-based management. Home-based care reduced risk of catastrophic household costs by 84%. CONCLUSIONS: Although this trial failed to meet target recruitment, the available data demonstrate that training patient-nominated lay people has potential to provide a feasible solution to the operational challenges associated with delivering long-term-injectable drugs to people with recurrent or drug-resistant TB in resource-limited settings, and substantially reduce costs. Further data under operational conditions are required. TRIAL REGISTRATION NUMBER: ISRCTN05815615.

The intra-tumoural stroma in patients with breast cancer increases with age.

PURPOSE: The tumour microenvironment in older patients is subject to changes. The tumour-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoural stroma and to evaluate the prognostic value of the TSR in older patients with breast cancer (≥ 70 years). METHODS: Two retrospective cohorts, the FOCUS study (N = 619) and the Nottingham Breast Cancer series (N = 1793), were used for assessment of the TSR on haematoxylin and eosin stained tissue slides. RESULTS: The intra-tumoural stroma increases with age in the FOCUS study and the Nottingham Breast Cancer series (B 0.031, 95% CI 0.006-0.057, p = 0.016 and B 0.034, 95% CI 0.015-0.054, p < 0.001, respectively). Fifty-one per cent of the patients from the Nottingham Breast Cancer series < 40 years had a stroma-high tumour compared to 73% of the patients of ≥ 90 years from the FOCUS study. The TSR did not validate as an independent prognostic parameter in patients ≥ 70 years. CONCLUSIONS: The intra-tumoural stroma increases with age. This might be the result of an activated tumour microenvironment. The TSR did not validate as an independent prognostic parameter in patients ≥ 70 years in contrast to young women with breast cancer as published previously.

A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression.

Since the outbreak of the COVID-19 pandemic, much has been learned regarding its clinical course, prognostic inflammatory markers, disease complications, and mechanical ventilation strategy. Clinically, three stages have been identified based on viral infection, pulmonary involvement with inflammation, and fibrosis. Moreover, low and high elastance phenotypes can be distinguished in mechanically ventilated patients, based on lung mechanics, ventilation-to-perfusion ratio, and CT scans; these two phenotypes have presumed differences in their underlying pathophysiology. Although essential for therapeutic guidance, the pathophysiology of COVID-19 is poorly understood. Here, we systematically reviewed published case reports and case series in order to increase our understanding of COVID-19 pathophysiology by constructing a timeline and correlating histopathological findings with clinical stages of COVID-19. Using PRISMA-IPD guidelines, 42 articles reporting 198 individual cases were included in our analysis. In lung samples (n = 131 cases), we identified three main histological patterns: epithelial (n = 110, 85%), with reactive epithelial changes and DAD; vascular (n = 76, 59%) with microvascular damage, (micro)thrombi, and acute fibrinous and organizing pneumonia; and fibrotic (n = 28, 22%) with interstitial fibrosis. The epithelial and vascular patterns can present in all stages of symptomatic COVID-19, whereas the fibrotic pattern presents starting at ~3 weeks. Moreover, patients can present with more than one pattern, either simultaneously or consecutively. These findings are consistent with knowledge regarding clinical patterns of viral infection, development of hyperinflammation and hypercoagulability, and fibrosis. Close collaboration among medical staff is necessary in order to translate this knowledge and classification of pathophysiological mechanisms into clinical stages of disease in individual patients. Moreover, further research, including histopathological studies, is warranted in order to develop reliable, clinically relevant biomarkers by correlating these pathological findings with laboratory results and radiological findings, thus, increasing our understanding of COVID-19 and facilitating the move to precision medicine for treating patients.

Postoperative Upper Extremity Function in Implant and Autologous Breast Reconstruction.

BACKGROUND: After mastectomy and breast reconstruction, many patients experience upper extremity complications, such as pain, restriction in motion, and lymphedema. Despite an aesthetically satisfactory outcome, these occurrences can diminish a patient's postoperative quality of life. Several studies have investigated the causes and incidence of these complications. However, there is currently a paucity of data comparing postoperative upper extremity function according to reconstruction technique. METHODS: A review was performed of patients enrolled in a physical therapy (PT) program after mastectomy and immediate breast reconstruction. PT initial encounter evaluations were used to gather data on patients' postoperative upper extremity function. Hospital records were used to gather surgical and demographic data. For each patient, data were collected for each upper extremity that was ipsilateral to a reconstructed breast. Data were then compared between patients who underwent implant-based versus autologous deep inferior epigastric perforator flap reconstruction. RESULTS: A total of 72 patients were identified, including 39 autologous and 33 implant-based reconstruction cases. Proportions of patients who underwent sentinel lymph node biopsies and axillary lymph node dissections were similar between the two groups. The autologous-based reconstruction patients had significantly higher arm pain at rest (p = 0.004) and with activity (p = 0.031) compared with implant patients. Shoulder range of motion and manual muscle test results were similar between groups, with the exception of elbow flexion, which was weaker in implant patients (p = 0.030). Implant patients were also more likely to report "severe difficulty" or "inability" to perform activities of daily living (p = 0.022). Edema/swelling, axillary cording, and lymphedema girth measurements were similar between the two groups. CONCLUSION: Different techniques of breast reconstruction can result in different postoperative upper extremity complications. These data show specific areas where postoperative care and PT can be customized according to reconstruction type. Investigation is currently underway to determine the effect of PT on upper extremity function in these patients.

Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement.

OBJECTIVES: Neuropsychiatric (NP) involvement is a poorly understood manifestation of SLE. We studied post-mortem histopathology in relation to clinical NPSLE syndromes and complement deposition in brains of NPSLE and SLE patients and controls. Furthermore, we investigated the correlation between cerebral post-mortem histopathology and ex vivo 7 T MRI findings in SLE and NPSLE. METHODS: A nationwide search for autopsy material yielded brain tissue from 16 NPSLE and 18 SLE patients. Brains obtained from 24 patients who died of acute cardiac events served as controls. Apart from a histopathological evaluation, paraffin-embedded cortical tissue was stained for components of the classical, lectin and terminal complement pathways. RESULTS: Diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE than SLE patients and were absent in controls. Focal vasculopathy was found in both SLE patients and controls. Complement deposition was strongly associated with both SLE and NPSLE, but not with controls (P < 0.001). Microthrombi were found uniquely in NPSLE and were associated with C4d and C5b-9 deposits (P < 0.05). A 7 T MRI was unable to detect most small vessel injury that was visible histopathologically. CONCLUSION: Our study demonstrates that histopathological lesions in NPSLE represent a continuum, ranging from non-specific lesions such as focal vasculopathy, to more specific lesions including C4d- and C5b-9-associated microthrombi and diffuse vasculopathy related to clinical syndromes defining NPSLE. Complement deposition may be a key factor in the interaction between circulating autoantibodies and thromboischaemic lesions observed in NPSLE. Therefore, complement inhibition may have novel therapeutic potential in NPSLE.

Impact of shoulder internal rotation on normal sensory response during ulnar nerve-biased neurodynamic testing of asymptomatic individuals.

OBJECTIVE: To determine if substitution of shoulder internal rotation for external rotation during the upper limb neurodynamic test (ULNT3) evokes comparable ulnar nerve sensory responses in asymptomatic individuals. METHODS: Range of motion, quality, quantity, and distribution of sensory responses in 50 asymptomatic individuals during the traditional ULNT3 were compared to identical measures during an experimental maneuver using shoulder internal rotation. Quality and quantity of sensory responses were recorded using a 10-cm visual analog scale. RESULTS: Means of sensory responses for traditional and experimental maneuvers, respectively, were as follows: stretching, 3.84 ± 8.85 and 5.38 ± 2.85 cm; burning, 1.82 ± 2.82 and 2.50 ± 3.10 cm; tingling, 2.13 ± 3.12 and 2.18 ± 2.97 cm; and numbness, 1.04 ± 2.17 and 1.01 ± 2.03 cm. A moderate to strong correlation (ICC = 0.51-0.86) was shown to exist between maneuvers; this relationship was significant (p = .001). DISCUSSION: Results of this study provide evidence that there was no appreciable difference in sensory responses with regard to burning and tingling when substituting shoulder internal rotation for external rotation during the ULNT3. The results also suggest that there were only marginal differences in the sensory responses of stretching and numbness during the same substitution. CONCLUSION: Patients who have limited glenohumeral external rotation due to pain, instability, and/or articular limitation may benefit from this substitution when presenting with signs of ulnar nerve pathodynamics. Further research will be needed to validate this maneuver in a symptomatic population. LEVEL OF EVIDENCE: Level 2b.

Comparison Between Monochorionic and Dichorionic Placentas With Special Attention to Vascular Anastomoses and Placental Share.

Placental vascular anastomoses in twins lead to a shared circulation and may subsequently enable the development of severe complications such as twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). The presence of vascular anastomoses has frequently and systematically been studied in monochorionic (MC) placentas, but only rarely in dichorionic (DC) placentas. The aim of this study was to compare the prevalence of vascular anastomoses and evaluate the sharing discordance in MC and DC placentas. All consecutive placentas of MC and DC twins delivered at the Leiden University Medical Center (the Netherlands) and Medical University of Warsaw (Poland) from 2012 to 2015 were routinely injected with colored dye and included in the study. We excluded twin pregnancies treated with fetoscopic laser surgery. A total of 258 placentas were analyzed in this study, including 134 MC placentas and 124 DC placentas. Vascular anastomoses were present in 99% (133/134) of MC placentas and 0% of DC placentas (p < .01). Placental share discordance between MC twins was significantly larger compared to DC twins, 19.8 (interquartile range [IQR] 8.1-33.3) and 10.8 (IQR 6.2-19.0), respectively (p < .01). Vascular anastomoses associated complications occurred in 16% (22/134) MC twins. Our findings show that vascular anastomoses are almost ubiquitous in MC placentas, but non-existent in DC placentas. In addition, unequal placental sharing appears to be more common in MC than in DC placentas.

Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy.

Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can occur in a variety of clinical conditions. Promising results of recent trials with terminal complement-inhibiting drugs call for biomarkers identifying patients who might benefit from this treatment. The primary aim of this study was to determine the prevalence and localization of complement factor C4d in kidneys of patients with TMA. The secondary aims were to determine which complement pathways lead to C4d deposition and to determine whether complement activation results in deposition of the terminal complement complex. We examined 42 renal sections with histologically confirmed TMA obtained from a heterogeneous patient group. Deposits of C4d, mannose-binding lectin, C1q, IgM, and C5b-9 were scored in the glomeruli, peritubular capillaries, and arterioles. Notably, C4d deposits were present in 88.1% of TMA cases, and the various clinical conditions had distinct staining patterns within the various compartments of the renal vasculature. Classical pathway activation was observed in 90.5% of TMA cases. C5b-9 deposits were present in 78.6% of TMA cases and in 39.6% of controls (n=53), but the staining pattern differed between cases and controls. In conclusion, C4d is a common finding in TMA, regardless of the underlying clinical condition. Moreover, C5b-9 was present in >75% of the TMA samples, suggesting that terminal complement inhibitors may have a beneficial effect in these patients. C4d and C5b-9 should be investigated as possible diagnostic biomarkers in the clinical work-up of patients suspected of having complement-mediated TMA.

How Can eHealth Technology Address Challenges Related to Multimorbidity? Perspectives from Patients with Multiple Chronic Conditions.

BACKGROUND: Patient eHealth technology offers potential support for disease self-management, but the value of existing applications for patients with multiple chronic conditions (MCCs) is unclear. OBJECTIVES: To understand self-management and health care navigation challenges that patients face due to MCCs and to identify opportunities to support these patients through new and enhanced eHealth technology. DESIGN: After administering a screening survey, we conducted 10 focus groups of 3-8 patients grouped by age, sex, and common chronic conditions. Patients discussed challenges associated with having MCCs and their use of (and desires from) technology to support self-management. Three investigators used standard content analysis methods to code the focus group transcripts. Emergent themes were reviewed with all collaborators, and final themes and representative quotes were validated with a sample of participants. PARTICIPANTS: Fifty-three individuals with ≥3 chronic conditions and experience using technology for health-related purposes. KEY RESULTS: Focus group participants had an average of five chronic conditions. Participants reported using technology most frequently to search for health information (96%), communicate with health care providers (92%), track medical information (83%), track medications (77%), and support decision-making about treatment (55%). Three themes emerged to guide eHealth technology development: (1) Patients with MCCs manage a high volume of information, visits, and self-care tasks; (2) they need to coordinate, synthesize, and reconcile health information from multiple providers and about different conditions; (3) their unique position at the hub of multiple health issues requires self-advocacy and expertise. Focus groups identified desirable eHealth resources and tools that reflect these themes. CONCLUSIONS: Although patients with multiple health issues use eHealth technology to support self-care for specific conditions, they also desire tools that transcend disease boundaries. By addressing the holistic needs of patients with MCCs, eHealth technology can advance health care from a disease-centered to a patient-centered model.

Molecular analysis using SalvGlandDx improves risk of malignancy estimation and diagnosis of salivary gland cytopathology: An exploratory multicenter study.

BACKGROUND: Diagnosis of salivary gland neoplasms is challenging, especially on cytological specimens acquired by fine-needle aspiration. The recently implemented standardized Milan system for reporting salivary gland cytopathology provides an estimated risk of malignancy (ROM); yet, for two of the categories, the diagnosis of the lesion remains unclear. However, a precise diagnosis is desirable for optimal patient management, including planning of surgery and imaging procedures. METHODS: Cytological specimens (n = 106) were subjected to molecular analysis using the SalvGlandDx panel. The risk of malignancy was calculated for each detected alteration based on the diagnosis of the resection specimen. By taking into account the molecular alterations, their associated ROM, the clinical and cytological features, and the current literature, the Milan category was evaluated. RESULTS: Of n = 63 technically valid cases, 76% revealed a molecular alteration. A total of 94% of these molecularly altered cases could be assigned to a different Milan category when additionally taking molecular results into account. In only 2% of the salivary gland neoplasms of uncertain malignant potential, in which a molecular alteration was detected, the classification remained salivary gland neoplasms of uncertain malignant potential. CONCLUSION: Molecular analysis of cytological specimens provides a benefit in classifying salivary gland neoplasms on fine-needle aspiration. It can improve the ROM estimation and thus help to assign cases of formerly unknown malignant potential to clearly benign or malignant categories.

Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial.

BACKGROUND: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB. METHODS: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed. FINDINGS: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy. INTERPRETATION: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers.

Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause.

BACKGROUND: Different pathogenetic pathways have been proposed for neuropsychiatric (NP) manifestations in systemic lupus erythematosus (SLE). OBJECTIVE: To describe the patient characteristics of a large cohort of patients with SLE with NP manifestations (NPSLE) in a single centre and to review whether these and other data are compatible with immune-mediated mechanisms. METHODS: A total of 212 patients were identified from MRI scans of the brain ordered for suspected NPSLE. Data were collected from the medical records. NP syndromes were classified according to the American College of Rheumatology (ACR) nomenclature and case definitions. RESULTS: 155 patients fulfilled the criteria for SLE. In 102 patients NP manifestations were attributed to SLE itself (primary NPSLE) whereas, in the remaining patients, the NP symptoms were due to other causes. The median age at the time of SLE diagnosis in patients with primary NPSLE was 27.5 years and the median duration prior to NPSLE was 2.8 years. Forty patients (39%) had a NP manifestation in the first year of the disease. Cerebrovascular disease, cognitive dysfunction, seizures and headache were the most prevalent syndromes. In 47% of patients with primary NPSLE the MRI scan of the brain showed no abnormalities. CONCLUSIONS: Most NP manifestations in SLE occur early in the disease. This finding, as well as data from quantitative imaging studies and recent pathological studies, point to an immune-mediated pathogenesis.