tbuckley/cabot-search huggingface dataset:
Long-term outcomes and risk factors for early bacterial infection after pediatric liver transplantation: a prospective cohort study
Authors: Xicheng Sun, Xiaowei Sun, Tao Zhou, Peiying Li, Bingran Wang, Qi Pan, Aiwei Zhou, Yongbing Qian, Yongbo Liu, Yuan Liu, Qiang Xia
Journal: International Journal of Surgery (2024)

Background: Liver transplantation (LT) is the most efficient treatment for pediatric patients with end-stage liver diseases, while bacterial infection is the leading reason for post-transplant mortality. The present study is to explore the outcomes and risk factors of early bacterial infection (within 1 months) after pediatric LT. Methods: In this prospective cohort study, 1316 pediatric recipients [median (IQR) age: 9.1 (6.3–28.0) months; male: 48.0%; median (IQR) follow-up time: 40.6 (29.1–51.4) months] who received LT from September 2018 to April 2022 were included. Bacterial culture samples such as sputum, abdominal drainage, blood, and so on were collected when recipients were presented with infective symptoms. Kaplan–Meier analysis was applied to estimate the long-term survival rates and logistic regression was used to identify independent risk factors. To explore the role of pretransplant rectal swab culture (RSC) in reducing post-transplant bacterial infection rate, 188 infant LT recipients [median (IQR) age: 6.8 (5.5–8.1) months; male: 50.5%] from May 2022 to September 2023 were included. Log-binomial regression was used to measure the association of pretransplant RSC screening and post-transplant bacterial infection. The ‘Expectation Maximization’ algorithm was used to impute the missing data. Results: Bacterial infection was the primary cause for early (38.9%) and overall mortality (35.6%) after pediatric LT. Kaplan–Meier analysis revealed inferior 1-year and 5-year survival rates for recipients with post-transplant bacterial infection (92.6 vs. 97.1%, 91.8 vs. 96.4%, respectively; P &lt;0.001). Among all detected bacteria, Staphylococcus spp. (34.3%) and methicillin-resistant coagulase-negative Staphylococci (43.2%) were the dominant species and multidrug resistant organisms, respectively. Multivariable analysis revealed that infant recipients [adjusted odds ratio (aOR) 1.49; 95% CI: 1.01–2.20], male recipients (aOR, 1.43; 95% CI: 1.08–1.89), high graft-to-recipient weight ratio (aOR, 1.64; 95% CI: 1.17–2.30), positive post-transplant RSC (aOR, 1.45; 95% CI: 1.04–2.02) and nasopharyngeal swab culture (aOR 2.46; 95% CI: 1.72–3.52) were independent risk factors for early bacterial infection. Furthermore, RSC screening and antibiotic prophylaxis before transplantation could result in a relatively lower post-transplant infection rate, albeit without statistical significance (adjusted RR, 0.53; 95% CI: 0.25–1.16). Conclusion: In this cohort study, post-transplant bacterial infection resulted in an inferior long-term patient survival rate. The five identified independent risk factors for post-transplant bacterial infection could guide the prophylaxis strategy of post-transplant bacterial infection in the future. Additionally, pretransplant RSC might decrease post-transplant bacterial infection rate.
Prevention of sacituzumab govitecan (SG)-related neutropenia and diarrhea in patients (pts) with triple-negative or HR+/HER2- advanced breast cancer (ABC; PRIMED): A phase 2 trial.
Authors: José Manuel Pérez García, María Gión, Manuel Ruiz-Borrego, Isabel Blancas, Elena Lopez-Miranda, Salvador Blanch, Sabela Recalde, Lourdes Calvo, Xavier Gonzalez, Nerea Ancizar, Serafin Morales Murillo, Patricia Cortez, Javier Cardona, Eileen Shimizu, José Antonio Guerrero, Miguel Sampayo-Cordero, Alejandro Martinez-Bueno, Javier Cortes, Antonio Llombart-Cussac
Journal: Journal of Clinical Oncology (2024)

1101 Background: SG is a Trop-2 directed antibody-drug conjugate approved for pts with advanced, pretreated, triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer. The most common SG-related adverse events (AEs) are neutropenia and diarrhea which can lead to treatment modifications. Granulocyte colony-stimulating factor (G-CSF) and loperamide (L) are frequently used for managing these AEs. PRIMED is assessing if primary prophylaxis with G-CSF and L can improve the tolerability of SG. Methods: PRIMED (NCT05520723) is an open-label, single-arm, phase II trial. Pts had received between 1-2 previous chemotherapy regimens for ABC, including a taxane in any setting, unless contraindicated. HR+/HER2- pts had to be endocrine-resistant. Pts received SG (10 mg/kg IV, d 1 and 8, every 21 d) until disease progression (PD) or unacceptable toxicity. G-CSF (0.5 MU/kg/day SC, d 3, 4, 10, and 11) and L (2 mg orally, twice a day or 4 mg QD, d 2, 3, 4, 9, 10, and 11) were given during the first two cycles. The primary endpoints were incidence of ≥ grade (G) 3 neutropenia (H0: ≥40%; H1: ≤22%) or ≥ G 2 diarrhea (H0: ≥25%; H1: ≤10%) after two cycles. Results: A total of 50 pts were enrolled between February 2023 and September 2023 (TNBC, n = 32 [64%]). At data cut-off on October 18, 2023 (median follow-up, 4.3 months), 31 pts remained on treatment. The main reason for treatment discontinuation was PD, which was reported for 16 pts. After the first two cycles, incidence of any G neutropenia and diarrhea were 28% and 34%, respectively. Eight pts (16%) had ≥ G 3 neutropenia, meeting this primary endpoint (p=0.0002). Eight pts (16%) had ≥ G 2 diarrhea (4% G 3), showing numerical benefit of prophylactic L (p=0.084). No pts developed febrile neutropenia. The overall rate of AEs associated with dose reductions and treatment interruptions was 18% and 44%, respectively. No treatment discontinuations due to AEs were reported. Conclusions: Prophylactic administration of G-CSF and L resulted in a clinically relevant reduction of the incidence and severity of SG-related neutropenia and diarrhea and limited AE related dose reductions/interruptions and treatment discontinuations. Clinical trial information: NCT05520723 .
Immune checkpoint inhibitors (ICI): From cancer killers to electrolyte disruptors.
Authors: Parth J. Sampat, Devashish Desai, Myera Shahnawaz, Ghanshyam H. Ghelani, Mansi Kallem, Merima Ramovic-Zobic
Journal: Journal of Clinical Oncology (2024)

e24146 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Cancer patients, especially lung cancer (LCa), are at an increased risk of developing electrolyte imbalance due to several etiologies such as poor nutrition, paraneoplastic syndromes, etc. It is vital to address electrolyte disturbances with the use of ICIs. Objective: The study aims to understand the relationship between ICIs and electrolyte disturbance in LCa patients. Methods: TrinetX, a global federated research network, provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with LCa stages 2-4. The 2 groups were based on the presence or absence of IO (atezolizumab, durvalumab, pembrolizumab, nivolumab, ipilimumab). Further, propensity score matching (PSM) was carried out to match age, sex, race, chronic kidney disease, diarrhea. Compare outcome analytic function was utilized to map the co-relation with electrolyte imbalance. Results: 41,818 patients were identified, out of which 12.37% (n = 5172) patients received immunotherapy at some point in their cancer treatment. There was no statistical difference in age (65.9 ± 10.3 vs 65.9 ± 11.3, p = 0.8608) as well as gender in both groups. Caucasians (69% vs 66% for Causians (p &lt; 0.0001)) were the predominant race in both groups and were more likely to receive immunotherapy compared to African Americans (12% vs 14% in AA (p = 0.0004)). Diarrhea (30% vs 9%, p &lt; 0.0001) and Chronic kidney disease (CKD) (18% vs 8%, p &lt; 0.0001) were predominantly seen in IO group. Prior to matching, hypomagnesemia (HypoMg) (10.47% vs 5.85%, p &lt; 0.0001), hypocalcemia(HypoCa) (3.36% vs 2.03%, p &lt; 0.0001), hypokalemia (HypoK) (16.91% vs 11.02%, p &lt; 0.0001), hyperkalemia (HyperK) (7.69% vs 4.88%, p &lt; 0.0001), hyponatremia (HypoNa) (16.82% vs 10.66%, p &lt; 0.0001) and hypercalcemia (HyperCa) (5.26% vs 3.05%, p &lt; 0.0001) were seen higher in IO group while hypermagnesemia (HyperMg) (2.04% vs 2.62%, p = 0.0150) was more seen in the non IO group, with no significant difference in hypernatremia (HyperNa) (2.34% vs 1.95%, p = 0.0634). After PSM, HypoMg (10.48% vs 7.01%, p &lt; 0.0001), HypoK (16.92% vs 12.64%, p &lt; 0.0001), HyperK (7.69% vs 6.26%, p = 0.0060), HypoNa (16.80% vs 11.56%, p &lt; 0.0001) and HyperCa (5.26% vs 3.06%, p &lt; 0.0001) were seen more in IO group, while HyperMg (2.04% vs 2.67%, p = 0.0399) was higher in non IO and there was no significant difference for HypoCa (3.36% vs 2.77, p = 0.0829) and HyperNa (2.34% vs 1.89%, p = 0.1135). Conclusions: Our study demonstrated that there is correlation between ICI use and electrolyte imbalance. Providers should be vigilant about the potential electrolyte abnormalities when treating patients with ICI therapy.
Association between genetic susceptibility and mortality in triple-negative breast cancer.
Authors: Ogheneyoma Akpoviroro, Nathan Kyle Sauers, Queeneth Uwandu, Ifunanya Ekechukwu, Victoria Manyele, Myriam Castagne, Hema Malini Srinivasa, Namita Sharma
Journal: Journal of Clinical Oncology (2024)

e13130 Background: We sought to determine if positive germline genetic tests in patients with triple negative breast cancer (TNBC) was associated with mortality. Methods: Retrospective review. Inclusion criteria: female, 18-85, stage 1-3 TNBC, 2010-2015; 5-year follow-up period from date of cancer diagnosis, or follow-up until death if sooner. Results: Out of the total population of 219 patients, 37.9% (83/219) underwent genetic testing. All patients who underwent genetic testing were Caucasian; most were non-Hispanic (78/83, 94.0%). The average age of the population of patients who underwent genetic testing was 49.6; there were no differences in age between those with a positive genetic test (PT) versus(vs) a negative genetic test (NT) (p=0.963). The average ECOG score was 0.2 and this was similar between the PT and NT groups (p=0.725). The average tumor size was 25.3 and this was similar between PT and NT groups(p=0.992). Among those who underwent testing, a PT was observed in 22.9% (19/83) and a NT in 77.1% (64/83). Within the PT group, 15.8% (3/19) experienced recurrent disease, while 18.8% (12/64) in the NT group experienced recurrent disease (p=1.000).Within the PT group, 5.3% (1/19) were deceased compared with 28.1% (18/64) in the NT group (p=0.590). When recurrent versus nonrecurrent disease was compared regardless of genetic test results, 73.3% (11/15%) in the recurrence group were deceased, compared with 11.8% (8/68) in the non-recurrence group (p&lt;0.001). When the genetic test population was stratified by recurrence, there was no association between genetic test results and living status in recurrent disease (p=0.154), or non-recurrent disease (p=0.183). Conclusions: Most patients who underwent genetic testing were Caucasian, and the average age of the cohort was approximately 49 years. Otherwise, the demographic characteristics were comparable between patients with a positive genetic test and those with a negative genetic test. Positive genetic test results were not associated with recurrent TNBC, or tumor size. However, the presence of recurrence was associated with a higher incidence of mortality, irrespective of genetic test results. Our study shows that genetic susceptibility to breast cancer was not associated with greater mortality. More has to be done to determine if racial disparities occur in offering genetic testing to racial minorities who meet criteria.
A comprehensive analysis of portal vein thrombosis in malignancy.
Authors: Apurwa Prasad, Matthew Tyler Bartock, Mallika Gyawali, Anamol Acharya, Shweta Bhattarai, Priya Hotwani
Journal: Journal of Clinical Oncology (2024)

e24042 Background: Portal vein thrombosis (PVT) is a rare venous thromboembolism, is often linked to cirrhosis, infection, and malignancy. Advancements in imaging have noted an increasing incidence of PVT, particularly in solid cancers. Treating PVT with malignancy is challenging due to lack of data, poor recanalization, and substantial bleeding risk with anticoagulation. This study aims to enhance understanding of malignancy-related PVT, anticoagulation trends, and assess prognosis. Methods: We conducted a multicenter, observational retrospective analysis of patients diagnosed with PVT (ICD code 452,181) from 2013 to 2023. Inclusion criteria: age &gt; 18 and acute portal vein thrombosis. Exclusion criteria: presence of tumor thrombosis, and thrombus in other splanchnic vessels (e.g., mesenteric vein). Data entry was performed on a study-specific REDCap database. Patients with concomitant malignancy were identified and further assessed for cancer type, anticoagulation use, bleeding outcomes, and prognosis. Proportion analysis using Z test was done to compare outcomes between groups. Results: In our study of 583 patients, 236 (40.48%) had concurrent malignancy, predominantly male (144, 61.01%),and female (92, 38.98%) mean age 65. Common malignancies included HCC (28.38%), pancreatic (24.15%), colo-rectal (11.86%), cholangiocarcinoma (8.47%), myeloproliferative neoplasm, prostate, and gynecological cancers each (2.96%), and other cancers (18.22%). 41% had metastasis to liver. Cirrhosis was present in 40%, particularly in HCC patients (89%). Of the total,163 (69%) received anticoagulation; 26.38% showed improvement or re-canalization within a year. The primary anticoagulants were Direct Oral Anticoagulants (DOACs) (57%), with an increasing trend in the last 5 years (69.44%), followed by Low-Molecular-Weight Heparin (LMWH) (19%) and warfarin (14%). Most patients initiated on heparin infusion (9.81%) transitioned to hospice care. Bleeding events in patients receiving DOAC versus LMWH + Warfarin were 36.55% and 33.33%, respectively (p = 0.69). Patients without anticoagulation demonstrated a higher one-year mortality compared to those with anticoagulation (83.56% vs. 63.19%, p value &lt; 0.05). Overall,malignancy-associated PVT had a significantly higher case fatality rate than non-malignancy cases, regardless of anticoagulation (81.35% vs. 32.85%, p &lt; 0.05). Conclusions: There is a significant association between malignancy and PVT, particularly in HCC and pancreatic cancer. The increased mortality in malignancy-related PVT emphasizes the critical role of anticoagulation, which has demonstrated efficacy in improving outcomes, including one-year mortality. Although DOACs have seen increased use in the last 5 years, bleeding events have remained comparable. Further research is warranted to explore patient selection for optimal anticoagulation strategies.
Women’s insights on sexual health after breast cancer (WISH-BREAST).
Authors: Laila Agrawal, Eleonora Teplinsky, Yana Feygin, Theresa Kluthe, Corinne Menn
Journal: Journal of Clinical Oncology (2024)

12132 Background: Sexual health is a prevalent and distressing toxicity in women after cancer treatment. Sexual health needs and treatment require multidisciplinary management and despite the existence of guidelines on the management of sexual health, are often overlooked in the clinical setting. Methods: An anonymous online survey regarding sexual health for people with a current or prior breast cancer diagnosis was distributed through a social media platform (Instagram) and e-mail. Questions included demographics, breast cancer history and treatment, sexual health symptoms, and experience with medical care for sexual health symptoms. Results: Out of 1775 respondents, 1462 answered the question of whether or not sexual health changed after breast cancer diagnosis or treatment &amp; were included in this analysis. Mean age: 47.7 years. 87.3% of respondents identified as white and 1.6% as Black. Stage: 0 (8.5%), 1 (38.4%), 2 (34.2%), 3 (14.8%) &amp; 4 (2.9%). Estrogen receptor positive (81.5%), HER2 positive (27%), triple negative (12.9%). Breast cancer diagnosis or treatments caused a moderate to great deal of change to sexual health in 89.5% of respondents and a moderate to great deal of distress in 85%. The sexual health concerns are summarized in the table. 73% of participants did not receive information about sexual health from their healthcare team. Among participants who reported a change to sexual health, only 12% were satisfied with how their sexual health concerns were addressed. Treatment was not offered for sexual health concerns to 39% of respondents and 63% had not been referred to any specialists for sexual health concerns. 46% of participants had not been offered non-hormonal treatments for genitourinary concerns, 55% were told vaginal hormones were not an option, and 83% were not offered treatment for low libido despite lower sexual desire. 80% of respondents received information about sexual health from social media. Of those, 62% stated that their primary source of information on social media were health care professional accounts. Conclusions: In this online survey, sexual health concerns were highly prevalent and distressing after breast cancer diagnosis. There was a very low level of discussion with medical professionals and treatments were infrequently offered to patients, despite the existence of medical guidelines on sexual health care for women after cancer. Patients are turning to social media, &amp; specifically to medical professional accounts, for information. Future efforts to address sexual needs for breast cancer survivors and thrivers are warranted. [Table: see text]
Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis
Authors: Sven Wischnewski, Thomas Thäwel, Chiseko Ikenaga, Anna Kocharyan, Celia Lerma-Martin, Amel Zulji, Hans-Werner Rausch, David Brenner, Leonie Thomas, Michael Kutza, Brittney Wick, Tim Trobisch, Corinna Preusse, Maximilian Haeussler, Jan Leipe, Albert Ludolph, Angela Rosenbohm, Ahmet Hoke, Michael Platten, Jochen H. Weishaupt, Clemens J. Sommer, Werner Stenzel, Thomas E. Lloyd, Lucas Schirmer
Journal: Nature Aging (2024)

Abstract Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.
Complexin-1 enhances ultrasound neurotransmission in the mammalian auditory pathway
Authors: Meiling Liu, Changliang Wang, Lifang Huo, Jie Cao, Xiuguang Mao, Ziqing He, Chuanxia Hu, Haijian Sun, Wenjun Deng, Weiya He, Yifu Chen, Meifeng Gu, Jiayu Liao, Ning Guo, Xiangyang He, Qian Wu, Jiekai Chen, Libiao Zhang, Xiaoqun Wang, Congping Shang, Ji Dong
Journal: Nature Genetics (2024)
A high-density microfluidic bioreactor for the automated manufacturing of CAR T cells
Authors: Wei-Xiang Sin, N. Suhas Jagannathan, Denise Bei Lin Teo, Faris Kairi, Shin Yie Fong, Joel Heng Loong Tan, Dedy Sandikin, Ka-Wai Cheung, Yen Hoon Luah, Xiaolin Wu, Joshua Jebaraj Raymond, Francesca Lorraine Wei Inng Lim, Yie Hou Lee, Michaela Su-Fern Seng, Shui Yen Soh, Qingfeng Chen, Rajeev J. Ram, Lisa Tucker-Kellogg, Michael E. Birnbaum
Journal: Nature Biomedical Engineering (2024)
Diversifying the anthracycline class of anti-cancer drugs identifies aclarubicin for superior survival of acute myeloid leukemia patients
Authors: Xiaohang Qiao, Sabina Y. van der Zanden, Xiaoyang Li, Minkang Tan, Yunxiang Zhang, Ji-Ying Song, Merle A. van Gelder, Feija L. Hamoen, Lennert Janssen, Charlotte L. Zuur, Baoxu Pang, Olaf van Tellingen, Junmin Li, Jacques Neefjes
Journal: Molecular Cancer (2024)

Abstract The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.