tbuckley/cabot-search huggingface dataset:
Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma
Authors: Joseph J Sacco, Richard D Carvajal, Marcus O Butler, Alexander N Shoushtari, Jessica C Hassel, Alexandra Ikeguchi, Leonel Hernandez-Aya, Paul Nathan, Omid Hamid, Josep M Piulats, Matthew Rioth, Douglas B Johnson, Jason J Luke, Enrique Espinosa, Serge Leyvraz, Laura Collins, Chris Holland, Takami Sato
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM. Patients and methods Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed. Results 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing. Conclusions This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.
Book Review: Cosmetic procedures in skin of color
Authors: Dirk M. Elston
Journal: Journal of the American Academy of Dermatology (2024)

Cosmetic Procedures in Skin of Color is a well-organized and illustrated text that fills a critical need in our specialty. Tables, key points, and clinical pearls make this a quick and informative read that should be on every dermatologist's shelf. Don't leave it on the shelf—read it in its entirety and keep it handy as a reference and for teaching. The text is concise and covers all aspects of cosmetic procedures in diverse populations. Dr Alexis and his team of contributors deserve accolades for a job well done. They have produced a text which will endure and will improve outcomes for our patients. None disclosed.
Blinatumomab as postremission therapy replaces consolidation and substantial parts of maintenance chemotherapy and results in stable MRD negativity in children with newly diagnosed B-lineage ALL
Authors: Ekaterina Mikhailova, Alexander Popov, Julia Roumiantseva, Oleg Budanov, Svetlana Lagoyko, Liudmila Zharikova, Natalia Miakova, Dmitry Litvinov, Lili Khachatryan, Alexey Pshonkin, Natalia Ponomareva, Elmira Boichenko, Svetlana Varfolomeeva, Julia Dinikina, Galina Novichkova, Guenter Henze, Alexander Karachunskiy
Journal: Journal for ImmunoTherapy of Cancer (2024)

The bispecific T cell-binding antibody blinatumomab (CD19/CD3) is widely and successfully used for the treatment of children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here, we report the efficacy of a single course of blinatumomab instead of consolidation chemotherapy to eliminate minimal residual disease (MRD) and maintain stable MRD-negativity in children with primary BCP-ALL. Between February 2020 and November 2022, 177 children with non-high-risk BCP-ALL were enrolled in the ALL-MB 2019 pilot study ( NCT04723342 ). Patients received the usual risk-adapted induction therapy according to the ALL-MB 2015 protocol. Those who achieved a complete remission at the end of induction (EOI) received treatment with blinatumomab immediately after induction at a dose of 5 μg/m 2 /day for 7 days and 21 days at a dose of 15 μg/m 2 /day, followed by 12 months of maintenance therapy. MRD was measured using multicolor flow cytometry (MFC) at the EOI, then immediately after blinatumomab treatment, and then four times during maintenance therapy at 3-month intervals. All 177 patients successfully completed induction therapy and achieved a complete hematological remission. In 174 of these, MFC-MRD was measured at the EOI. 143 patients (82.2%) were MFC-MRD negative and the remaining 31 patients had varying degrees of MFC-MRD positivity. MFC-MRD was assessed in all 176 patients who completed the blinatumomab course. With one exception, all patients achieved MFC-MRD negativity after blinatumomab, regardless of the MFC-MRD score at EOI. One adolescent girl with high MFC-MRD positivity at EOI remained MFC-MRD positive. Of 175 patients who had completed 6 months of maintenance therapy, MFC-MRD data were available for 156 children. Of these, 155 (99.4%) were MFC-MRD negative. Only one boy with t(12;21) (p13;q22)/ ETV6::RUNX1 became MFC-MRD positive again. The remaining 174 children had completed the entire therapy. MFC-MRD was examined in 154 of them, and 153 were MFC-MRD negative. A girl with hypodiploid BCP-ALL showed a reappearance of MFC-MRD with subsequent relapse. In summary, a single 28-day course of blinatumomab immediately after induction, followed by 12 months of maintenance therapy, is highly effective in achieving MRD-negativity in children with newly diagnosed non-high risk BCP-ALL and maintaining MRD-negative remission at least during the treatment period.
Characterizations of multi-kingdom gut microbiota in immune checkpoint inhibitor-treated hepatocellular carcinoma
Authors: Chengpei Zhu, Chenchen Zhang, Shanshan Wang, Ziyu Xun, Dongya Zhang, Zhou Lan, Longhao Zhang, Jiashuo Chao, Yajun Liang, Zilun Pu, Cong Ning, Xinting Sang, Xiaobo Yang, Hanping Wang, Xianzhi Jiang, Haitao Zhao
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The association between gut bacteria and the response to immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) has been studied; however, multi-kingdom gut microbiome alterations and interactions in ICI-treated HCC cohorts are not fully understood. Methods From November 2018 to April 2022, patients receiving ICI treatment for advanced HCC were prospectively enrolled. Herein, we investigated the multi-kingdom microbiota characterization of the gut microbiome, mycobiome, and metabolome using metagenomic, ITS2, and metabolomic data sets of 80 patients with ICI-treated HCC. Results Our findings demonstrated that bacteria and metabolites differed significantly between the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups, whereas the differences were smaller for fungi. The overall diversity of bacteria and fungi before treatment was higher in the DCB group than in the NDB group, and the difference in diversity began to change with the use of immunotherapy after 6–8 weeks. We also explored the alterations of gut microbes in the DCB and NDB groups, established 18 bacterial species models as predictive biomarkers for predicting whether immunotherapy is of sustained benefit (area under the curve=75.63%), and screened two species of bacteria ( Actinomyces_sp_ICM47 , and Senegalimassilia_anaerobia ) and one metabolite (galanthaminone) as prognostic biomarkers for predicting survival in patients with HCC treated with ICI. Conclusions In this study, the status and characterization of the multi-kingdom microbiota, including gut bacteria, fungi, and their metabolites, were described by multiomics sequencing for the first time in patients with HCC treated with ICI. Our findings demonstrate the potential of bacterial taxa as predictive biomarkers of ICI clinical efficacy, and bacteria and their metabolites as prognostic biomarkers.
Authors' Reply: Utility of Urinary CD4+ T-Cell Count in Detecting ANCA-Associated Vasculitis Renal Relapse
Authors: Luka Prskalo, Adrian Schreiber, Philipp Enghard
Journal: Journal of the American Society of Nephrology (2024)

We thank Brousse et al. for their comments1 on our article "Urinary CD4+ T Cells Predict Renal Relapse in ANCA-Associated Vasculitis."2 In retrospect, we agree that instead of choosing the wording "outperforming," it would have been wise to use a more neutral terminology, such as stating that urinary T cells yield numerically higher area under the curve values. In principle, the only statistically robust finding of our study is that urinary T cells can predict future kidney flares in ANCA-associated vasculitis. This was the predefined primary end point of our study, which we therefore were able to report with statistic precision. All other analyses are secondary end points, and it can be debated how helpful P values, multiple testing, and conventional significance thresholds are for interpreting these findings. DeLong test for comparison of urinary T cells with routine clinical biomarkers yielded P values of 0.026 for hematuria, 0.062 for creatinine, 0.076 for albuminuria, 0.072 for cANCA levels, and 0.003 for pANCA levels, which should be interpreted in context with the known limited ability of these single markers (when used in isolation) for flare prediction. More importantly, we completely agree with the second aspect that Broussee and colleagues1 raise in their comment: the aim should not be to establish one single biomarker "to rule them all" but instead aim for a meaningful combination of biomarkers for optimal prediction. Therefore, we agree that the category "outperformance of other biomarkers" may be misleading. Instead, as suggested, various biomarkers could be combined in a model. However, we believe that such a model should be derived from a larger dataset than our study. We envision that in the future, ANCA-associated vasculitis disease activity and risk of relapse will be determined by a combination of biomarkers that reflect different elements of the pathogenesis of ANCA-associated vasculitis: serologic activity (i.e., ANCA levels, complement products), damage (i.e., proteinuria, hematuria, creatinine), and active intrarenal inflammation (i.e., urinary T cells, urinary sCD163). These elements could be combined in a model as a score, or as reflection of individual aspects of pathology, which could mandate different treatments. Either way, we agree that a combination of biomarkers may pave the way to modern, personalized treatment of ANCA-associated vasculitis.
Measuring the impact of maternal critical care admission on short- and longer-term maternal and birth outcomes
Authors: John A. Masterson, Imad Adamestam, Monika Beatty, James P. Boardman, Louis Chislett, Pamela Johnston, Judith Joss, Heather Lawrence, Kerry Litchfield, Nicholas Plummer, Stella Rhode, Timothy Walsh, Arlene Wise, Rachael Wood, Christopher J. Weir, Nazir I. Lone
Journal: Intensive Care Medicine (2024)

Factors increasing the risk of maternal critical illness are rising in prevalence in maternity populations. Studies of general critical care populations highlight that severe illness is associated with longer-term physical and psychological morbidity. We aimed to compare short- and longer-term outcomes between women who required critical care admission during pregnancy/puerperium and those who did not. This is a cohort study including all women delivering in Scottish hospitals between 01/01/2005 and 31/12/2018, using national healthcare databases. The primary exposure was intensive care unit (ICU) admission, while secondary exposures included high dependency unit admission. Outcomes included hospital readmission (1-year post-hospital discharge, 1-year mortality, psychiatric hospital admission, stillbirth, and neonatal critical care admission). Multivariable Cox and logistic regression were used to report hazard ratios (HR) and odds ratios (OR) of association between ICU admission and outcomes. Of 762,918 deliveries, 1449 (0.18%) women were admitted to ICU, most commonly due to post-partum hemorrhage (225, 15.5%) followed by eclampsia/pre-eclampsia (133, 9.2%). Over-half (53.8%) required mechanical ventilation. One-year hospital readmission was more frequent in women admitted to ICU compared with non-ICU populations [24.5% (n = 299) vs 8.9% (n = 68,029)]. This association persisted after confounder adjustment (HR 1.93, 95% confidence interval [CI] 1.33, 2.81, p < 0.001). Furthermore, maternal ICU admission was associated with increased 1-year mortality (HR 40.06, 95% CI 24.04, 66.76, p < 0.001), stillbirth (OR 12.31, 95% CI 7.95,19.08, p < 0.001) and neonatal critical care admission (OR 6.99, 95% CI 5.64,8.67, p < 0.001) after confounder adjustment. Critical care admission increases the risk of adverse short-term and long-term maternal, pregnancy and neonatal outcomes. Optimizing long-term post-partum care may benefit maternal critical illness survivors.
Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis
Authors: Jiajun Yu, Bo Long, Ziyong Li, Xiaolong Tian, Dairong Li, Jianling Long, Yujue Wang, Yue Chen, Fang Zhang, Haixia Liu, Cheng Qian, Juanjuan Shan
Journal: Cardiovascular Research (2024)

Abstract Aims The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carries the risk of immune-related adverse events. ICI-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICI-associated myocarditis. Methods and results Using the peripheral blood of patients with ICI therapy and of ICI-treated mice with transplanted tumours, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICI therapy showed an increase in NK cells and myeloid cells in the peripheral blood, while T cells significantly decreased. Among T cells, there was an imbalance of CD4/CD8 ratio in the peripheral blood of myocarditis patients, with a significant decrease in central memory CD4+ T (CD4+ TCM) cells. RNA sequencing revealed that CD4+ TCM cells in myocarditis patients were immunosuppressive cell subsets, which highly express the immunosuppressive factor IL-4I1. To elucidate the potential mechanism of the decrease in CD4+ TCM cells, protein array was performed and revealed that several inflammatory factors gradually increased with the severity of myocarditis in the myocarditis group, such as IL-1B/CXCL13/CXCL9, while the myocardial protective factor IL-15 decreased. Correlation analysis indicated a positive correlation between IL-15 and CD4+ TCM cells, with high expression of IL-15 receptor IL15RA. Furthermore, in vivo studies using an anti-PDL1 antibody in a mouse tumour model indicated a reduction in CD4+ TCM cells and an increase in effector memory-expressing CD45RA CD8+ T (TEMRA) cells, alongside evidence of cardiac fibrosis. Conversely, combining anti-PDL1 antibody treatment with IL-15 led to a resurgence of CD4+ TCM cells, a reduction in CD8+ TEMRA cells, and a mitigated risk of cardiac fibrosis. Conclusion Our data highlight CD4+ TCM cells’ crucial role in cardiac protection during ICI therapy. IL-15, IL-4I1, and CD4+ TCM cells can serve as therapeutic targets to reduce ICI-associated myocarditis in cancer patients.
Atrial septal defect closure in children at young age is beneficial for left ventricular function
Authors: Pia Sjöberg, Henning Clausen, Håkan Arheden, Petru Liuba, Erik Hedström
Journal:  (2024)

Atrial septal defects (ASDs) lead to volume-loaded right ventricles (RVs). ASD closure does not always alleviate symptoms or improve exercise capacity, which is possibly explained by impaired left ventricular (LV) haemodynamics. This study evaluated the effect of ASD closure in children using non-invasive LV pressure-volume (PV) loops derived from cardiac magnetic resonance (CMR) imaging and brachial blood pressure, compared with controls.
phyloBARCODER: A web tool for phylogenetic classification of eukaryote metabarcodes using custom reference databases
Authors: Jun Inoue, Chuya Shinzato, Junya Hirai, Sachihiko Itoh, Yuki Minegishi, Shin-ichi Ito, Susumu Hyodo
Journal: Molecular Biology and Evolution (2024)

Abstract We developed phyloBARCODER (https://github.com/jun-inoue/phyloBARCODER), a new web tool that can identify short DNA sequences to the species level using metabarcoding. phyloBARCODER estimates phylogenetic trees based on the uploaded anonymous DNA sequences and reference sequences from databases. Without such phylogenetic contexts, alternative, similarity-based methods independently identify species names and anonymous sequences of the same group by pairwise comparisons between queries and database sequences, with the caveat that they must match exactly or very closely. By putting metabarcoding sequences into a phylogenetic context, phyloBARCODER accurately identifies (i) species or classification of query sequences and (ii) anonymous sequences associated with the same species or even with populations of query sequences, with clear and accurate explanations. Version 1 of phyloBARCODER stores a database comprising all eukaryotic mitochondrial gene sequences. Moreover, by uploading their own databases, phyloBARCODER users can conduct species identification specialized for sequences obtained from a local geographic region or those of nonmitochondrial genes, e.g. ITS or rbcL.
Daily oral administration of probiotics engineered to constantly secrete short-chain fatty acids effectively prevents myocardial injury from subsequent ischemic heart disease
Authors: Quynh Hoa Pham, Thi Van Anh Bui, Woo-Sup Sim, King Hoo Lim, Carmen Oi Kwan Law, Wanyu Tan, Ri Youn Kim, Kwan Ting Chow, Hun-Jun Park, Kiwon Ban, Terrence Chi Kong Lau
Journal: Cardiovascular Research (2024)

Given the extremely limited regeneration potential of the heart, one of the most effective strategies to reduce the prevalence and mortality of coronary artery disease is prevention. Short-chain fatty acids (SCFAs), which are by-products of beneficial probiotics, have been reported to possess cardioprotective effects. Despite their beneficial roles, delivering SCFAs and maintaining their effective concentration in plasma present major challenges. Therefore, in the present study, we aimed to devise a strategy to prevent coronary heart disease effectively by using engineered probiotics to continuously release SCFAs in vivo.
Ipilimumab and nivolumab plus UV1, an anticancer vaccination against telomerase, in advanced melanoma.
Authors: Paul Lorigan, Theresa Medina, Marta Nyakas, Annemie Rutten, Lynn G. Feun, Charles Lance Cowey, Miranda Payne, Israr Hussain, Timothy Kuzel, Steven O'Day, Amna Sheri, Philip Adam Friedlander, Satish Kumar, Jens Bjorheim, Oliver Edgar Bechter
Journal: Journal of Clinical Oncology (2024)

LBA9519 Background: The combination of ipilimumab (IPI) and nivolumab (NIVO) remains a standard of care for patients with advanced melanoma, especially those with poor prognostic factors, albeit with a significant risk of toxicity. Therapeutic cancer vaccines are ideally positioned to improve outcomes without significantly increasing toxicity. UV1 is a therapeutic cancer vaccine generating T-cell responses against the universal cancer antigen telomerase. In a Phase I trial in melanoma (N = 30), UV1 plus pembrolizumab demonstrated a tolerable safety profile, a complete response rate of 33%, median PFS of 18.9 months, and 2-year OS rate of 73.3%. Recently, results from a randomized Phase II trial indicated a longer overall survival and a higher response rate for previously treated patients with advanced mesothelioma receiving UV1 in combination with IPI-NIVO (1). Methods: In this Phase II, open-label, multicenter study, we randomly assigned treatment-naïve patients with unresectable or metastatic melanoma (stage IIIb-IIId or IV) to IPI 3mg/kg + NIVO 1mg/kg for 4 cycles, followed by NIVO 480 mg as maintenance, with or without 8 intradermal injections of 300 µg UV1 (+GM-CSF). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety. Results: A total of 156 patients underwent randomization; 78 patients were assigned to the IPI-NIVO-UV1 arm and 78 patients to the IPI-NIVO arm. The median age was 60, 48% had M1C or D disease, 38% had LDH &gt;upper limit of normal, and 42% had a positive BRAF mutation status. With a minimum follow-up of 18 months, the 12-month PFS rate was 57% in both arms (HR 0.95, 95% CI 0.59-1.55, p value 0.845). The ORR was similar with IPI-NIVO-UV1 compared to IPI-NIVO, at 60% vs 59%, respectively (Odds ratio 1.12, 95% CI 0.58-2.16, p value 0.867). The 12-month OS rate was 87% and 88%, respectively (HR 1.15, 95% CI 0.60-2.20, p value 0.674). The occurrence of grade &gt;3 adverse events was similar in both treatment arms. Conclusion: UV1 did not improve on outcomes of IPI-NIVO, in terms of PFS. Longer follow-up is required for the accurate assessment of OS. No significant toxicity increases were observed with the addition of UV1. Data from a biomarker driven cohort are awaited. 1. Helland et al, Eur J Cancer 2024. Clinical trial information: NCT04382664 .