tbuckley/cabot-search huggingface dataset:
TMO-Net: an explainable pretrained multi-omics model for multi-task learning in oncology
Authors: Feng-ao Wang, Zhenfeng Zhuang, Feng Gao, Ruikun He, Shaoting Zhang, Liansheng Wang, Junwei Liu, Yixue Li
Journal: Genome biology (2024)

Abstract Cancer is a complex disease composing systemic alterations in multiple scales. In this study, we develop the Tumor Multi-Omics pre-trained Network (TMO-Net) that integrates multi-omics pan-cancer datasets for model pre-training, facilitating cross-omics interactions and enabling joint representation learning and incomplete omics inference. This model enhances multi-omics sample representation and empowers various downstream oncology tasks with incomplete multi-omics datasets. By employing interpretable learning, we characterize the contributions of distinct omics features to clinical outcomes. The TMO-Net model serves as a versatile framework for cross-modal multi-omics learning in oncology, paving the way for tumor omics-specific foundation models.
Trastuzumab deruxtecan in patients with breast cancer with brain metastases: The DE-REAL study.
Authors: Andrea Botticelli, Alessandra Fabi, Alessandro Rossi, Roberta Caputo, Simona Pisegna, Francesco Pantano, Giuliana D'Auria, Luisa Carbognin, Palma Fedele, Agnese Fabbri, Claudio Vernieri, Michela Palleschi, Gianluigi Ferretti, Ida Paris, Elena Di Monte, Francesco Pavese, Ornella Garrone, Diana Giannarelli, Michelino De Laurentiis, Giovanni Scambia
Journal: Journal of Clinical Oncology (2024)

1032 Background: Almost 30-50% of patients with human epidermal growth factor (HER2)-positive breast cancer (BC) will develop brain metastases (BMs) in their treatment journey. Despite impressive results achieved for extracranial disease, the central nervous system (CNS) compartment remains highly challenging, and local approaches must now be associated with a prompt and adequate systemic intervention. Trastuzumab deruxtecan (T-Dxd) obtained impressive results both in heavily pretreated patients previously received TDM-1 and in the comparative DESTINY BREAST03 phase III trial. However, patients with active CNS involvement were traditionally excluded from clinical trials and BM-related outcomes are not often included among study endpoints. Moreover, a real-world evidence focused on intracranial activity for patients with BMs treated with T-Dxd is still lacking. In an effort to add further information on the clinical activity and safety of T-Dxd in both naïve and previously treated patients with BMs, we performed a sub-analysis of an Italian large retrospective database, the DE-REAL study. Methods: We reviewed a database of 143 patients with HER2-positive BC from 11 Italian Oncological Units, and obtained a total of 39 patients with CNS involvement treated in various lines setting with T-Dxd between April 2021 and October 2022. Results: Overall intracranial response rate (icRR) was 59% (43.5-74.4), with an imPFS of 14.1 months (9.3-18.9). Intracranial disease control rate (icDCR) was 94.9% (87.9-100.0), duration of response (icDoR) was 11.9 months (10.1-13.7), and clinical benefit rate (icCBr) at 6 and 12 months were 69.2% and 59%, respectively. IntracranialOS was not reached, with an overall rate of 76.6% of patients alive at 12 months. When comparing intracranial responders (CR/PR/SD) to non-responders (PD), median PFS was 15.5 months (13.7-17.3) vs 7.9 months (6.4-9.5), p&lt;0.001. Toxicities were in line with what previously reported in larger registered clinical trials. Conclusions: Our real-world analysis indicated a clinically meaningful intracranial activity of T-Dxd in patients with HER2-positive BC and BMs, and supports its use for both patients with treated/stable and untreated/active lesions.
The infected blood scandal: lessons for clinical research
Authors: Emma Cave, Bobbie Farsides
Journal: BMJ (2024)

The six-year Infected Blood Inquiry investigated the causes and impacts of NHS treatment with infected blood products in the 1970s and 80s. 1 Thousands of adults and children were infected with HIV and Hepatitis C. The impacts of the biggest treatment disaster in the NHS are wide-ranging.Here we focus on research.
Multiple alternative splicing of HER2 transcripts and exon skipping with potential consequences on function and antibody-based therapy.
Authors: Maher Albitar, Hong Zhang, Ahmad Charifa, Andrew Ip, Sally Agersborg, Arash Mohtashamian, Deena Mary Atieh Graham, Donna M. McNamara, Stanley E. Waintraub, Martin Gutierrez, Andrew L Pecora, Andre Goy
Journal: Journal of Clinical Oncology (2024)

1033 Background: Multiple studies have demonstrated that ERBB2 (HER2) exon 16 skipping is associated with resistance to antibody-based therapy. However, ERBB2 gene contains 30 exons with potential for alternative splicing involving all exons. With the increasing utilization of antibody-drug conjugates (ADC) in treating patients, it is important to evaluate the various ERBB2 isoforms that are expressed in various tumors. Toward this goal we evaluated the various splicing forms and exons skipping in domains II and III that are involved in dimerization and binding to pertuzumab, and in domain IV, which is a juxtamembrane domain and involved in trastuzumab binding. Methods: RNA was extracted from 3170 FFPE tissue from various types of tumors including breast, ovary, endometrium, lung, colon, stomach, esophagus, and others. RNA was sequenced using a hybrid capture-targeted panel. Data analysis is focused on ERBB2 gene. Results: Of the 3170 tested solid tumor samples, 824 (26%) showed high expression meeting the criteria for gene amplification and “low-HER2”. Of these cases, 199 (24%) samples showed exon skipping in domains II and III ranging from exons 6 to 14. Skipping in domain IV was detected in 236 cases (29%) involving exons from 13 to 29. However, 107 samples of the 824 (13%) showed skipping of exons in both domains II/III and domain IV. The most common exon skipping were in exons 6 to 7 and in exon 16. Most of the cases with exon 16 skipping (1.5% of total) also showed skipping in exons 6 and 7. Conclusions: Alternative splicing and exon skipping in HER2 transcripts is common and involves critical functional domains of the protein. The percentage of skipped transcripts is low. However, since these isoforms have deficiency in critical domains for membrane anchoring and for dimerization, the biological effects might be more significant than that expected from percentage of abnormal protein. Further studies are needed to correlate exon skipping with efficacy and outcome of antibody-based therapy. [Table: see text]
Challenges to the optimisation of cystic fibrosis exacerbation treatment outcomes
Authors: Christopher H. Goss, Donald R. VanDevanter
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Evidence continues to build regarding management of pulmonary exacerbation in cystic fibrosis. This editorial comments on the work by Waters and colleagues, noting evidence continues to build regarding the lack of efficacy of steroids in exacerbation.</b>https://bit.ly/4arA9ID
Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement
Authors: Zhoujie Ding, Maree Hagan, Feng Yan, Nick W.Y. Schroer, Jack Polmear, Kim L. Good-Jacobson, Alexandra R. Dvorscek, Catherine Pitt, Kristy O’Donnell, Stephen L. Nutt, Dimitra Zotos, Craig McKenzie, Danika L. Hill, Marcus J. Robinson, Isaak Quast, Frank Koentgen, David M. Tarlinton
Journal: The Journal of Experimental Medicine (2024)

The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen–receptor gene rearrangements occurred. We identified that Ki67 was required for normal global chromatin accessibility involving regulatory regions of genes critical for checkpoint stages in B cell lymphopoiesis. In line with this, mRNA expression of Rag1 was diminished and gene rearrangement was less efficient in the absence of Ki67. Transgenes encoding productively rearranged immunoglobulin heavy and light chains complemented Ki67 deficiency, completely rescuing early B cell development. Collectively, these results identify a unique contribution from Ki67 to somatic antigen–receptor gene rearrangement during lymphopoiesis.
<i>Primum non nocere, secundum cavere, tertium sanare</i>: lessons on the management of pulmonary hypertension associated with COPD
Authors: Gabor Kovacs, Marc Humbert
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The results of the PERFECT trial do not support the use of inhaled treprostinil in patients with pulmonary hypertension associated with COPD. Further data from well-designed prospective RCTs are needed on the efficacy and safety of PH drugs in PH-COPD.</b>https://bit.ly/3WpP56z
Myosteatosis on computed tomography as a predictor of therapeutic response to CDK4/6 inhibitors plus aromatase inhibitors in patients with advanced breast cancer.
Authors: Min Hwan Kim, Hyunwook Kim, Seungjin Baek, Sookyeong Han, Gun Min Kim, Joohyuk Sohn, Yumie Rhee, Namki Hong
Journal: Journal of Clinical Oncology (2024)

1030 Background: Recent evidence indicates that a dysregulated host metabolism influences treatment outcomes in patients with breast cancer. We investigated the association of computed tomography (CT)-derived body composition indices as imaging biomarkers of host metabolic status with therapeutic responses in patients with hormone receptor-positive, HER2-negative advanced breast cancer (ABC) on endocrine plus CDK4/6 inhibitor (CDK4/6i) treatment. Methods: The study involved a prospective cohort of patients with ABC at the Yonsei Cancer Center who received CDK4/6i and aromatase inhibitors as first-line therapy. Body composition parameters were estimated from the pretreatment non-enhanced CT images of the third lumbar spine. Myosteatosis was defined as skeletal muscle radiodensity (SMD) of low tertile (≤28.7 Hounsfield Units). The primary outcome was progression-free survival (PFS). Results: Among the 247 participants (mean age, 54.8 years; body mass index [BMI], 23.7 kg/m 2 ), 45.7% had events during a median follow-up of 36.4 months. Low SMD was an independent predictor of worse PFS after adjusting for age and visceral metastases (adjusted hazard ratio [HR]=1.20 per standard deviation decrement, p=0.041), whereas BMI, muscle area, and fat area did not. Participants with myosteatosis had a higher risk of progression than those without (PFS, 27.2 vs. 51.1 months; p=0.009; adjusted HR 1.84, p=0.003). Strong associations between myosteatosis and poor PFS were observed in groups with pre-menopause status (HR, 3.04 vs. 1.19 in post-menopause; p for interaction &lt;0.05) and without visceral metastases (HR, 2.95 vs. 1.19 in with visceral metastases; p for interaction &lt;0.05). Conclusions: CT-derived myosteatosis predicts poor treatment outcomes in patients with ABC undergoing first-line treatment with aromatase inhibitors and CDK4/6i.
Mind the gap: challenges to overcome in airway clearance
Authors: Meghan Marmor, Pamela J. McShane
Journal: European Respiratory Journal (2024)

Chronic cough and sputum production, the characteristic clinical features of bronchiectasis [1], significantly diminish quality of life. For many bronchiectasis patients, constant coughing results in physical exhaustion, depression and social isolation [2]. There is a large gap between the recommendation and implementation of airway clearance techniques in bronchiectasis <https://bit.ly/4b0rrl5>
OPTIMAL: Titration of anti-IL5 biologics in severe asthma - An open label randomised controlled trial
Authors: Marianne Baastrup Soendergaard, Anne-Sofie Bjerrum, Linda Makowska Rasmussen, Sofie Lock-Johansson, Ole Hilberg, Susanne Hansen, Anna von Bulow, Celeste Porsbjerg
Journal: European Respiratory Journal (2024)

Background Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic. Methods In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible. Results Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout. Conclusion This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future.
Poor cardiac output reserve in pulmonary arterial hypertension is associated with right ventricular stiffness and impaired interventricular dependence
Authors: Ilton M. Cubero Salazar, Andrew C. Lancaster, Vivek P. Jani, Margaret J. Montovano, Matthew Kauffman, Alexandra Weller, Bharath Ambale-Venkatesh, Stefan L. Zimmerman, Catherine E. Simpson, Todd M. Kolb, Rachel L. Damico, Stephen C. Mathai, Monica Mukherjee, Ryan J. Tedford, Paul M. Hassoun, Steven Hsu
Journal: European Respiratory Journal (2024)

Background Pulmonary arterial hypertension (PAH) is characterised by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure–volume ( P – V ) loop analysis to characterise the impact of RV diastology on poor flow augmentation during exercise in PAH. Methods RV P – V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index (CI) during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance ( E ed )) and ventricular interdependence (left ventricular transmural pressure (LVTMP)) were compared at matched exercise stages. Results Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49 mL·m −2 ; p=0.0001), with higher associated exercise afterload (effective arterial elastance ( E a ) 1.76 versus 0.90 mmHg·mL −1 ; p&lt;0.0001), RV stiffness ( E ed 0.68 versus 0.26 mmHg·mL −1 ; p=0.003) and right-sided pressures (right atrial pressure 14 versus 8 mmHg; p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP −4.6 versus 3.2 mmHg; p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV–PA coupling. Conclusions Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiological PAH differences unapparent at rest.
Revolutionising obstructive sleep apnoea therapy: polysomnography unveils hidden clues to help provide precision care
Authors: Clemens Heiser, Najib T. Ayas
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Personalised treatment for OSA is within reach. After identifying individual collapse sites, therapies can be tailored, improving effectiveness and quality of life for patients. Precision medicine offers hope for a brighter future in OSA management.</b>https://bit.ly/4bKumz1
Ferroptosis: principles and significance in health and disease
Authors: Fangquan Chen, Rui Kang, Daolin Tang, Jiao Liu
Journal: Journal of Hematology & Oncology (2024)

Abstract Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia–reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease.
[<sup>68</sup>Ga]Ga-ABY-025 PET in HER2-positive breast cancer: Benefits and pitfalls in staging of axillary disease.
Authors: Ali Alhuseinalkhudhur, Henrik Lindman, Per Liss, Fredrik Y. Frejd, Joachim Feldwisch, Nikolai C. Brun, Mark Lubberink, Irina Velikyan, Jens Sörensen
Journal: Journal of Clinical Oncology (2024)

1035 Background: [ 68 Ga]Ga-ABY-025 PET showed promising results in quantifying human epidermal growth factor receptor Type 2 (HER2) expression in breast cancer patients [1]. In this study we extend the findings from [ 68 Ga]Ga-ABY-025 PET with data from both treatment-naïve patients and previously treated patients with recurrences, mimicking the clinical situation other sites might encounter when HER2-targeting imaging is made more widely available. The focus of this additional data analysis is on staging, potential pitfalls and changes in uptake patterns associated with previous treatments. Methods: [ 68 Ga]Ga-ABY-025 PET and [ 18 F]-FDG PET images from 50 women with biopsy confirmed HER2 positive breast cancer were examined. Each patient underwent both scans within 1 week. A follow-up [ 18 F]-FDG PET was performed after 2 courses of HER2-targeted treatment to assess metabolic response. Results: Twelve out of 50 patients showed heterogeneous [ 68 Ga]Ga-ABY-025 uptake. Three out of these 12 patients presented with a wider local spread that was only detectable using [ 68 Ga]Ga-ABY-025 PET as distinct uptake in lymph nodes of 2-5 mm size. Based on the additional information from [ 68 Ga]Ga-ABY-025 PET, restaging was evaluated in two of the three cases, both of which had lobular carcinoma, and resulted in modifications in treatment plans. Two patients who received COVID-19 vaccine closely before undergoing PET scans showed high uptake on [ 18 F]-FDG PET in lymph nodes ipsilateral to the vaccine injection site, but not on [ 68 Ga]Ga-ABY-025 PET. Additionally, the physiological [ 68 Ga]Ga-ABY-025 uptake in thyroid gland and axillary sweat glands was inversely correlated with the number of previous treatments and was significantly more pronounced in treatment-naïve patients. Conclusions: [ 68 Ga]Ga-ABY-025 PET provided additional information that, in conjunction with [ 18 F]-FDG PET findings, might help in accurate staging, particularly in cases with very small lymph node metastases. It also helped reduce false positive results as [ 68 Ga]Ga-ABY-025 uptake was so far not seen in any benign inflammatory lesions. Physiological uptake can be seen in thyroid and apocrine glandular tissues but gradually disappear with subsequent HER2-targeted therapies. 1,Alhuseinalkhudhur, A. et al. J Nucl Med, 2023 64(9): p. 1364-1370. Clinical trial information: NCT03655353 .
A woman with dry cough and breathlessness
Authors: Henry Tyzack-Clark, Barry Jackson
Journal: BMJ (2024)

A woman in her 40s presented with a 10 day history of breathlessness, fever, a non-productive cough, and myalgia. She had asthma and used a salbutamol inhaler as needed. On assessment, her pulse was 110 beats/min, oxygen saturation 85% on air, respiratory rate 25 breaths/min, and blood pressure 108/76 mm Hg. Widespread crepitations were present on auscultation, but a systemic examination was otherwise unremarkable. Chest x ray identified hilar lymphadenopathy, and her D-dimer level was elevated. Based on suspicion of infection and possible pulmonary embolism, a computed tomography pulmonary angiogram was performed. This showed centrilobular ground glass nodules and focal consolidation with bilateral hilar and mediastinal lymphadenopathy. Pulmonary embolism was excluded. Table 1 displays laboratory test results. These indicated that the patient had acute anaemia and prompted a request for a blood film (fig 1) and a direct agglutination test. View this table: Table 1 Laboratory test results Fig 1 Blood film
Lymphoma With a Skin Rash
Authors: Abhinav Singhal, Aparna Sharma, Kalpa Jyoti Das
Journal: JAMA Oncology (2024)

A 62-year-old female had a generalized vesiculobullous rash on her face for 4 months. It started over the lips and gradually progressed to involve the oral mucosa and skin of the whole body. What is your diagnosis?
Immunotherapy For US Patients With Metastatic Cancer at the End of Life
Authors: Hirotaka Higashi, Akihiko Shimomura, Chikako Shimizu
Journal: JAMA Oncology (2024)

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Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial
Authors: Roger Li, Paras H. Shah, Tyler F. Stewart, Jong Kil Nam, Trinity J. Bivalacqua, Donald L. Lamm, Edward M. Uchio, Daniel M. Geynisman, Joseph M. Jacob, Joshua J. Meeks, Rian Dickstein, Shane M. Pearce, Seok Ho Kang, Seung Il Jung, Ashish M. Kamat, James M. Burke, Kirk A. Keegan, Gary D. Steinberg
Journal: Nature Medicine (2024)