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Artificial Intelligence (AI) can support diagnostic workflows in oncology by aiding diagnosis and providing biomarkers directly from routine pathology slides. However, AI applications are vulnerable to adversarial attacks. Hence, it is essential to quantify and mitigate this risk before widespread clinical use. Here, we show that convolutional neural networks (CNNs) are highly susceptible to white- and black-box adversarial attacks in clinically relevant weakly-supervised classification tasks. Adversarially robust training and dual batch normalization (DBN) are possible mitigation strategies but require precise knowledge of the type of attack used in the inference. We demonstrate that vision transformers (ViTs) perform equally well compared to CNNs at baseline, but are orders of magnitude more robust to white- and black-box attacks. At a mechanistic level, we show that this is associated with a more robust latent representation of clinically relevant categories in ViTs compared to CNNs. Our results are in line with previous theoretical studies and provide empirical evidence that ViTs are robust learners in computational pathology. This implies that large-scale rollout of AI models in computational pathology should rely on ViTs rather than CNN-based classifiers to provide inherent protection against perturbation of the input data, especially adversarial attacks. Artificial Intelligence can support diagnostic workflows in oncology, but they are vulnerable to adversarial attacks. Here, the authors show that convolutional neural networks are highly susceptible to white- and black-box adversarial attacks in clinically relevant classification tasks.

Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1–4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6–26·3) with CF and 26·1 months (22·5–29·7) with ECX (hazard ratio 0·90 (95% CI 0·77–1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Interest in HER2-low breast cancer has grown in recent years due to advancements in novel anti-HER2 antibody-drug conjugates. This study examined the impact of HER2-low expression on survival outcomes in triple-negative breast cancer (TNBC) of high-grade special histological type (ST) and no special type (NST) and investigated the prognostic significance of TNBC subtype (high-grade ST vs. NST) within HER2 0 and HER2-low expression subgroups. Clinicopathological and survival data of 504 patients with stage I-III TNBC, with or without neoadjuvant chemotherapy (NAC), were analyzed, including 400 patients with TNBC NST and 104 patients with high-grade TNBC ST. HER2-low status was not identified as an independent prognostic factor for survival in the overall cohort, nor within the high-grade TNBC ST and TNBC NST subgroups. Among patients who did not receive NAC, TNBC subtype (high-grade ST vs. NST) was independently associated with DDFS and DFS in the HER2 0 subgroup, but not in the HER2-low subgroup. Patients with HER2 0 high-grade TNBC ST exhibited significantly worse OS ( p = 0.008), DDFS ( p < 0.001), and DFS ( p < 0.001) compared to those with HER2 0 TNBC NST. Among patients with either HER2 0 or HER2-low tumors treated with NAC, no significant survival difference was observed between high-grade TNBC ST and TNBC NST. These findings suggest that the prognostic impact of TNBC subtype (high-grade ST vs. NST) on survival outcomes may be modulated by HER2 status in a subset of TNBC patients.

Interest in HER2-low breast cancer has grown in recent years due to advancements in novel anti-HER2 antibody-drug conjugates. This study examined the impact of HER2-low expression on survival outcomes in triple-negative breast cancer (TNBC) of high-grade special histological type (ST) and no special type (NST) and investigated the prognostic significance of TNBC subtype (high-grade ST vs. NST) within HER2 0 and HER2-low expression subgroups. Clinicopathological and survival data of 504 patients with stage I-III TNBC, with or without neoadjuvant chemotherapy (NAC), were analyzed, including 400 patients with TNBC NST and 104 patients with high-grade TNBC ST. HER2-low status was not identified as an independent prognostic factor for survival in the overall cohort, nor within the high-grade TNBC ST and TNBC NST subgroups. Among patients who did not receive NAC, TNBC subtype (high-grade ST vs. NST) was independently associated with DDFS and DFS in the HER2 0 subgroup, but not in the HER2-low subgroup. Patients with HER2 0 high-grade TNBC ST exhibited significantly worse OS (p = 0.008), DDFS (p < 0.001), and DFS (p < 0.001) compared to those with HER2 0 TNBC NST. Among patients with either HER2 0 or HER2-low tumors treated with NAC, no significant survival difference was observed between high-grade TNBC ST and TNBC NST. These findings suggest that the prognostic impact of TNBC subtype (high-grade ST vs. NST) on survival outcomes may be modulated by HER2 status in a subset of TNBC patients.

We evaluated the utility of transmission electron microscopy (TEM) in transbronchial lung cryobiopsy (TBLC) samples from 16 consecutive patients undergoing routine evaluation of fibrotic interstitial lung disease (ILD). Next to routine pathology examination, 1 to 2 TBLC samples were prepared for TEM analysis and evaluated using a Zeiss LEO EM 910. Subpleural cryobiopsies and unfrozen excision biopsies from fresh lobectomy tissue of non-ILD lung cancer patients served as controls. TEM provided high-quality images with only minor cryoartifacts as compared to controls. Furthermore, in several ILD patients we found marked microvascular endothelial abnormalities like luminal pseudopodia-like protrusions and inner surface defects. These were extensively present in four (25%), moderately present in seven (43.8%), and largely absent in five (31.3%) patients. A higher degree of TEM endothelial abnormalities was associated with younger age, non-specific interstitial pneumonia pattern, higher broncho-alveolar lavage lymphocyte count, positive autoantibodies, and lower spirometry, diffusion capacity and oxygenation biomarkers. We conclude that TEM evaluation of TBLC samples from ILD patients is feasible, while the observed microvascular alterations warrant further evaluation.

Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. DD patients often have skin involvement characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. The aim of this study was to characterize the cutaneous immune infiltrate in DD skin lesions in detail and to identify new therapeutic targets. Using gene and protein expression profiling assays including scRNA sequencing, we demonstrate enhanced expression of Th17-related genes and cytokines and increased numbers of Th17 cells in six DD patients. We provide evidence that targeting the IL-17/IL-23 axis in a case series of three DD patients with monoclonal antibodies is efficacious with significant clinical improvement. As DD is a chronic, relapsing disease, our findings might pave the way toward additional options for the long-term management of skin inflammation in patients with DD. The use of IL-17/IL-23 blocking therapy for rare inflammatory skin diseases needs proof of principle data for larger clinical trials. Here the authors show that patients with Darier disease have enhanced Th17 cells and, using IL-17/IL-23 blockers, they show that the immune gene signatures are altered in localised skin biopsies.

Autonomic and vascular failures are common phenotypes of sepsis, typically characterized by tachycardia despite corrected hypotension/hypovolemia, vasopressor resistance, increased arterial stiffness and decreased peripheral vascular resistance. In a 5-day swine experiment of polymicrobial sepsis we aimed at characterizing arterial properties and autonomic mechanisms responsible for cardiovascular homeostasis regulation, with the final goal to verify whether the resuscitation therapy in agreement with standard guidelines was successful in restoring a physiological condition of hemodynamic profile, cardiovascular interactions and autonomic control. Twenty pigs were randomized to polymicrobial sepsis and protocol-based resuscitation or to prolonged mechanical ventilation and sedation without sepsis. The animals were studied at baseline, after sepsis development, and every 24 h during the 3-days resuscitation period. Beat-to-beat carotid blood pressure (BP), carotid blood flow, and central venous pressure were continuously recorded. The two-element Windkessel model was adopted to study carotid arterial compliance, systemic vascular resistance and characteristic time constant τ. Effective arterial elastance was calculated as a simple estimate of total arterial load. Cardiac baroreflex sensitivity (BRS) and low frequency (LF) spectral power of diastolic BP were computed to assess autonomic activity. Sepsis induced significant vascular and autonomic alterations, manifested as increased arterial stiffness, decreased vascular resistance and τ constant, reduced BRS and LF power, higher arterial afterload and elevated heart rate in septic pigs compared to sham animals. This compromised condition was persistent until the end of the experiment, despite achievement of recommended resuscitation goals by administered vasopressors and fluids. Vascular and autonomic alterations persist 3 days after goal-directed resuscitation in a clinically relevant sepsis model. We hypothesize that the addition of these variables to standard clinical markers may better profile patients’ response to treatment and this could drive a more tailored therapy which could have a potential impact on long-term outcomes.

Breast lymphomas, though rare, present a unique spectrum of clinical and pathological characteristics. This multicenter retrospective study evaluates 92 cases from four international institutions over a ten-year period to provide a comprehensive analysis of primary breast lymphomas (PBLs), secondary breast lymphomas (SBLs), and related subtypes, including breast implant-associated lymphomas (BIA-ALCL) and intra-mammary lymph node lymphomas. Primary breast lymphomas accounted for 46.7% of cases, with a predominance of diffuse large B-cell lymphoma (DLBCL). Secondary breast involvement, observed in 43.5% of cases, displayed a more diverse histological distribution, with follicular lymphoma being the most common subtype. Breast implant-associated lymphomas (BIA-ALCL) constituted 6.5% of cases, exclusively involving anaplastic large cell T-cell lymphoma, ALK-negative. The study highlights significant differences in patient demographics, clinical presentation, and survival outcomes. PBLs primarily affected older patients (mean age: 68.4 years) and were associated with longer lymphoma-specific survival compared to SBLs (76.12 vs. 59.45 months; p  = 0.001). Notably, survival differences were evident within histological subtypes, emphasizing the impact of disease origin on prognosis. BIA-ALCL cases were distinct in clinical features and histology, with a younger mean age (47.5 years) and frequent association with unilateral effusion. This analysis underscores the necessity for precise diagnostic and therapeutic strategies tailored to the unique biology of breast lymphomas. Future research should aim to elucidate molecular mechanisms and optimize management protocols to improve patient outcomes.

Background Computational pathology uses deep learning (DL) to extract biomarkers from routine pathology slides. Large multicentric datasets improve performance, but such datasets are scarce for gastric cancer. This limitation could be overcome by Swarm Learning (SL). Methods Here, we report the results of a multicentric retrospective study of SL for prediction of molecular biomarkers in gastric cancer. We collected tissue samples with known microsatellite instability (MSI) and Epstein–Barr Virus (EBV) status from four patient cohorts from Switzerland, Germany, the UK and the USA, storing each dataset on a physically separate computer. Results On an external validation cohort, the SL-based classifier reached an area under the receiver operating curve (AUROC) of 0.8092 (± 0.0132) for MSI prediction and 0.8372 (± 0.0179) for EBV prediction. The centralized model, which was trained on all datasets on a single computer, reached a similar performance. Conclusions Our findings demonstrate the feasibility of SL-based molecular biomarkers in gastric cancer. In the future, SL could be used for collaborative training and, thus, improve the performance of these biomarkers. This may ultimately result in clinical-grade performance and generalizability.

Background Nonoperative management of uncomplicated appendicitis is currently being promoted as treatment option, albeit 0.7–2.5% of appendectomies performed due to suspected acute appendicitis show histologically malignant findings. The purpose of this study was to investigate the incidence of neoplasm and malignancy of the appendix in patients presenting with suspected acute appendicitis in real world setting. Methods This is a retrospective single-centre investigation of 457 patients undergoing appendectomy between the years 2017–2020. The patients’ demographics, symptoms and diagnosis, intraoperative findings, and histopathological results were analysed. Results In 3.7% ( n  = 17) histological analysis revealed neoplasms or malignancies. Median age was 48 years (20–90 years), without sex predominance. Leukocytes (11.3 ± 3.7 G/l) and C-reactive protein (54.2 ± 69.0 mg/l) were elevated. Histological analysis revealed low-grade mucinous appendiceal neoplasia ( n  = 3), sessile serrated adenoma of the appendix ( n  = 3), neuroendocrine tumours ( n  = 7), appendiceal adenocarcinoma of intestinal type ( n  = 3), and goblet cell carcinoma ( n  = 1). Additional treatment varied between no treatment or follow-up due to early tumour stage ( n  = 4), follow-up care ( n  = 3), additional surgical treatment ( n  = 8), or best supportive care ( n  = 2). Conclusions Preoperative diagnosis of appendiceal tumours is difficult. Nonoperative management of patients with acute, uncomplicated appendicitis potentially prevents the correct diagnosis of malignant appendiceal pathologies. Therefore, close follow-up or surgical removal of the appendix is mandatory.