tbuckley/cabot-search huggingface dataset:
Improved prognosis and evidence of enhanced immunogenicity in tumor and circulation of high-risk melanoma patients with unknown primary
Authors: Ahmad A Tarhini, Sandra J Lee, Aik-Choon Tan, Issam M El Naqa, F Stephen Hodi, Lisa H Butterfield, William A LaFramboise, Walter J Storkus, Arivarasan D Karunamurthy, Jose R Conejo-Garcia, Patrick Hwu, Howard Streicher, Vernon K Sondak, John M Kirkwood
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Melanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared with those with known primary melanoma enrolled in the E1609 adjuvant trial that tested ipilimumab at 3 and 10 mg/kg vs high-dose interferon-alfa (HDI). Patients and methods MUP status was defined as initial presentation with cutaneous, nodal or distant metastasis without a known primary. Relapse-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Gene expression profiling (GEP) was performed on the tumor biopsies of a subset of patients. Similarly, peripheral blood samples were tested for candidate soluble and cellular immune biomarkers. Results MUP cases represented 12.8% of the total population (N=1699) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, RFS (p=0.001) and overall survival (OS) (p=0.009) showed outcomes significantly better for patients with unknown primary. The primary tumor status remained prognostically significant after adjusting for treatment and stage in multivariate Cox proportional hazards models. Including only ipilimumab-treated patients, RFS (p=0.005) and OS (p=0.023) were significantly better in favor of those with unknown primary. Among patients with GEP data (n=718; 102 MUP, 616 known), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the MUP tumors compared with known primaries. Further investigation into infiltrating immune cell types estimated significant enrichment with CD8 +and CD4+T cells, B cells and NK cells as well as significantly higher major histocompatibility complex (MHC)-I and MHC-II scores in MUP compared with known primary. Among patients tested for circulating biomarkers (n=321; 66 unknown and 255 known), patients with MUP had significantly higher circulating levels of IL-2R (p=0.04). Conclusion Patients with MUP and high-risk melanoma had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of MUP as a distinct prognostic marker in patients with high-risk melanoma.
Author Correction: Mutations in PYCR1 cause cutis laxa with progeroid features
Authors: Bruno Reversade, Nathalie Escande-Beillard, Aikaterini Dimopoulou, Björn Fischer, Serene C. Chng, Yun Li, Mohammad Shboul, Puay-Yoke Tham, Hülya Kayserili, Lihadh Al-Gazali, Monzer Shahwan, Francesco Brancati, Hane Lee, Brian D. O’Connor, Mareen Schmidt-von Kegler, Barry Merriman, Stanley F. Nelson, Amira Masri, Fawaz Alkazaleh, Deanna Guerra, Paola Ferrari, Arti Nanda, Anna Rajab, David Markie, Mary Gray, John Nelson, Arthur Grix, Annemarie Sommer, Ravi Savarirayan, Andreas R. Janecke, Elisabeth Steichen, David Sillence, Ingrid Haußer, Birgit Budde, Gudrun Nürnberg, Peter Nürnberg, Petra Seemann, Désirée Kunkel, Giovanna Zambruno, Bruno Dallapiccola, Markus Schuelke, Stephen Robertson, Hanan Hamamy, Bernd Wollnik, Lionel Van Maldergem, Stefan Mundlos, Uwe Kornak
Journal: Nature Genetics (2022)
Managing neuropsychiatric symptoms in patients with dementia
Authors: Jennifer A Watt, Wade Thompson, Roger Marple, Deborah Brown, Barbara Liu
Journal: BMJ (2022)

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Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis
Authors: Verónica Prado, María Hernández-Tejero, Marcus M. Mücke, Francesc Marco, Wenyi Gu, Alex Amoros, David Toapanta, Enric Reverter, Carlos de la Peña-Ramirez, Laura Altenpeter, Octavi Bassegoda, Gabriel Mezzano, Fátima Aziz, Adria Juanola, Sergio Rodríguez-Tajes, Vanessa Chamorro, David López, Marta Reyes, Michael Hogardt, Volkhard A.J. Kempf, Philip G. Ferstl, Stefan Zeuzem, José Antonio Martínez, Jordi Vila, Vicente Arroyo, Jonel Trebicka, Javier Fernandez
Journal: Journal of Hepatology (2022)

It remains unclear whether rectal colonization with multidrug-resistant organisms (MDROs) is prevalent and predisposes to infections by the same pathogens in patients with cirrhosis.Two series of critically ill patients were evaluated. In the Barcelona cohort, 486 consecutive patients were prospectively evaluated, 129 with and 357 without cirrhosis (2015-2016). Rectal swabs were performed at admission and weekly thereafter (until intensive care unit [ICU] discharge) to detect MDRO colonization. Risk factors for colonization and infection by MDROs were evaluated. A retrospective cohort from Frankfurt (421 patients with cirrhosis; 2010-2018) was investigated to evaluate MDRO rectal colonization in another epidemiological scenario.In the Barcelona cohort, 159 patients were colonized by MDROs (32.7%), 102 (64.2%) at admission and 57 (35.8%) during follow-up. Patients with cirrhosis showed higher rates of rectal colonization at admission than those without cirrhosis (28.7% vs. 18.2%, p = 0.01) but similar colonization rates during ICU stay. Extended-spectrum beta-lactamase-Enterobacterales were the most frequent MDROs isolated in both groups. Colonization by MDROs independently increased the risk of infection by MDROs at admission and during follow-up. Risk of new infection by the colonizing strain was also significantly increased in patients with (hazard ratio [HR] 7.41) and without (HR 5.65) cirrhosis. Rectal colonization by MDROs was also highly prevalent in Frankfurt (n = 198; 47%; 131 at admission [66.2%] and 67 [33.8%] during follow-up), with vancomycin-resistant enterococci being the most frequent colonizing organism. Rectal colonization by MDROs was also associated with an increased risk of infection by MDROs in this cohort. Infections occurring in MDR carriers were mainly caused by the colonizing strain.Rectal colonization by MDROs is extremely frequent in critically ill patients with cirrhosis. Colonization increases the risk of infection by the colonizing resistant strain.Rectal colonization by multidrug-resistant organisms (MDROs) is a prevalent problem in patients with cirrhosis requiring critical care. The pattern of colonizing bacteria is heterogeneous with relevant differences between centers. Colonization by MDROs is associated with increased risk of infection by the colonizing bacteria in the short term. This finding suggests that colonization data could be used to guide empirical antibiotic therapy and de-escalation policies in patients with cirrhosis.
Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses
Authors: Claire F Friedman, Christine Spencer, Christopher R Cabanski, Katherine S Panageas, Daniel K Wells, Antoni Ribas, Hussein Tawbi, Katy Tsai, Michael Postow, Alexander Shoushtari, Paul Chapman, Joyson Karakunnel, Samantha Bucktrout, Pier Gherardini, Travis J Hollmann, Richard O Chen, Margaret Callahan, Theresa LaVallee, Ramy Ibrahim, Jedd Wolchok
Journal: Journal for ImmunoTherapy of Cancer (2022)

There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade. We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples. Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3-4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB. In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts. NCT02731729.
Expression of Concern: Clinical Characteristics and Outcomes of COVID-19–Infected Cancer Patients: A Systematic Review and Meta-Analysis
Authors: Hua Zhang, Han Han, Tianhui He, Kristen Labbe, Adrian Hernandez, Haiquan Chen, Vamsidhar Velcheti, Justin Stebbing, Kwok- Kin Wong
Journal: JNCI Journal of the National Cancer Institute (2021)
A 29‐gene signature associated with NOX2 discriminates acute myeloid leukemia prognosis and survival
Authors: Carla Ijurko, Nerea González‐García, Purificación Galindo‐Villardón, Ángel Hernández‐Hernández
Journal: American Journal of Hematology (2022)

The molecular complexity displayed in acute myeloid leukemia (AML) hinders patient stratification and treatment decisions. Previous studies support the utility of using specific gene panels for this purpose. Focusing on two salient features of AML, the production of reactive oxygen species (ROS) by NADPH oxidases (NOX) and metabolism, we aimed to identify a gene panel that could improve patient stratification. A pairwise comparison of AML versus healthy gene expression revealed the downregulation of four members of the NOX2 complex including CYBB (coding for NOX2) in AML patients. We analyzed the expression of 941 genes related to metabolism and found 28 genes with expression correlated to CYBB. This panel of 29 genes (29G) effectively divides AML samples according to their prognostic group. The robustness of 29G was confirmed by 6 AML cohort datasets with a total of 1821 patients (overall accuracies of 85%, 78%, 80%, 75%, 59% and 83%). An expression index (EI) was developed according to the expression of the selected discriminatory genes. Overall Survival (OS) was higher for low 29G expression index patients than for the high 29G expression index group, which was confirmed in three different datasets with a total of 1069 patients. Moreover, 29G can dissect intermediate-prognosis patients in four clusters with different OS, which could improve the current AML stratification scheme. In summary, we have found a gene signature (29G) that can be used for AML classification and for OS prediction. Our results confirm NOX and metabolism as suitable therapeutic targets in AML.
Microbiota of the prostate tumor environment investigated by whole-transcriptome profiling
Authors: Paul Vinu Salachan, Martin Rasmussen, Jacob Fredsøe, Benedicte Ulhøi, Michael Borre, Karina Dalsgaard Sørensen
Journal: Genome Medicine (2022)

Abstract Background With over 350,000 estimated deaths worldwide in 2018, prostate cancer (PCa) continues to be a major health concern and a significant cause of cancer-associated mortality among men. While cancer in general is considered a disease of the human genome, there is a growing body of evidence suggesting that changes to the healthy microbiota could play a vital role in cancer development, progression, and/or treatment outcome. Methods Using a metatranscriptomic approach, we annotated the microbial reads obtained from total RNA sequencing of 106 prostate tissue samples from 94 PCa patients (discovery cohort). We investigated microbial dysbiosis associated with PCa by systematically comparing the microbiomes between benign and malignant tissue samples, between less vs. more-aggressive PCa, and between patients who had biochemical recurrence as opposed to those who did not. We further performed differential gene expression and cell type enrichment analysis to explore the host transcriptomic and cellular responses to selected microbial genera. A public dataset (GSE115414) of total RNA sequencing reads from 24 prostate tissue samples (8 benign and 16 malignant) served as the validation cohort. Results We observed decreased species diversity and significant under-representation of Staphylococcus saprophyticus and Vibrio parahaemolyticus , as well as significant over-abundance of Shewanella in malignant as compared to benign prostate tissue samples in both the discovery ( p &lt; 0.01) and validation ( p &lt; 0.05) cohorts. In addition, we identified Microbacterium species ( p &lt; 0.01) to be significantly over-abundant in pathologically advanced T3 tumors compared to T2 in the discovery cohort. Malignant samples having high vs. low Shewanella counts were associated with downregulated Toll-like receptor signaling pathways and decreased enrichment of dendritic cells. Malignant samples having low vs. high V. parahaemolyticus counts were enriched for olfactory transduction and drug metabolism pathways. Finally, malignant samples were enriched for M1 and M2 macrophages as compared to benign tissue samples. Conclusions The results from this exploratory study support the existence of an important biological link between the prostate microbiota and PCa development/progression. Our results highlight Shewanella , V. parahaemolyticus , and Microbacterium sp. as interesting candidates for further investigation of their association with PCa.
TCT-712 “Cusp Overlap” View Facilitates Accurate Fluoro-Guided Implantation of Self-Expanding Valve in TAVR
Authors: Syed Zaid, Anoshia Raza, Iassen Michev, HASAN AHMAD, Ryan Kaple, Cenap Undemir, Angelica Poniros, Alexis Kearns, Joanne Bennett, Cheng Feng, Tanya Dutta, Amar Shah, Anthony Gilet, Martin Cohen, Steven Lansman, Gilbert Tang
Journal: Journal of the American College of Cardiology (2016)
Granulocyte microvesicles with a high plasmin generation capacity promote clot lysis and improve outcome in septic shock
Authors: Sylvie Cointe, Loris Vallier, Pierre Esnault, Mathilde Dacos, Amandine Bonifay, Nicolas Macagno, Karim Harti Souab, Corinne Chareyre, Coralie Judicone, Diane Frankel, Stéphane Robert, Sami Hraiech, Marie-Christine Alessi, Philippe Poncelet, Jacques Albanese, Françoise Dignat-George, Romaric Lacroix
Journal: Blood (2022)

Microvesicles (MVs) have previously been shown to exert profibrinolytic capacity, which is increased in patients with septic shock (SS) with a favorable outcome. We, therefore, hypothesized that the plasmin generation capacity (PGC) could confer to MVs a protective effect supported by their capacity to lyse a thrombus, and we investigated the mechanisms involved. Using an MV-PGC kinetic assay, ELISA, and flow cytometry, we found that granulocyte MVs (Gran-MVs) from SS patients display a heterogeneous PGC profile driven by the uPA (urokinase)/uPAR system. In vitro, these MVs lyse a thrombus according to their MV-PGC levels in a uPA/uPAR-dependent manner, as shown in a fluorescent clot lysis test and a lysis front retraction assay. Fibrinolytic activators conveyed by MVs contribute to approximately 30% of the plasma plasminogenolytic capacity of SS patients. In a murine model of SS, the injection of high PGC Gran-MVs significantly improved mouse survival and reduced the number of thrombi in vital organs. This was associated with a modification of the mouse coagulation and fibrinolysis properties toward a more fibrinolytic profile. Interestingly, mouse survival was not improved when soluble uPA was injected. Finally, using a multiplex array on plasma from SS patients, we found that neutrophil elastase correlates with the effect of high-PGC-capacity plasma and modulates the Gran-MV plasmin generation capacity by cleaving uPA-PAI-1 complexes. In conclusion, we show that the high PGC level displayed by Gran-MVs reduces thrombus formation and improves survival, conferring to Gran-MVs a protective role in a murine model of sepsis.
CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor
Authors: Serena Zilio, Silvio Bicciato, Donald Weed, Paolo Serafini
Journal: Journal for ImmunoTherapy of Cancer (2022)

Cancer-induced 'emergency' myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and in the tumor. Chemokine receptors (CCRs) and, in particular, CCR1, CCR2, CCR5, and CCR7 are emerging as key regulators of myeloid cell trafficking and function but their precise role has not been completely clarified yet because of the signal redundancy, integration, and promiscuity of chemokines and of the expression of these CCRs on other leukocyte subsets.We used the 4PD nanoparticle for the in vivo targeted silencing of CCR1, CCR2, CCR5, and/or CCR7 in the myeloid cells of tumor bearing mice to evaluate the effect of treatments on tumor growth, myeloid cell trafficking and polarization. We used flow and image cytometry and functional assays to monitor changes in the tumor microenvironment and depletion experiments and immune deficient mice to determine the role of Ly6G+cells during tumor progression. We further evaluated in vitro the impact of chemokine receptor inhibition and tumor derived factors on myeloid cell differentiation from mouse and human hematopoietic stem and precursors cells (HSPCs) using flow cytometry, transcriptome analysis, cytokines beads arrays, functional assays, and mice deficient for CCR1 or CCR5.4PD-mediated in vivo silencing of CCR1 and CCR5 on myeloid cells and myeloid precursors was necessary and sufficient to inhibit tumor progression. Functional studies indicated that this antitumor effect was not mediated by alteration of myeloid cell chemotaxes but rather by the repolarization of polymorphonuclear myeloid-derived suppressor cells (MDSCs) into tumoricidal neutrophils. Transcriptome functional and cytokine analysis indicated that tumor derived factors induced CCL3 and CCL4 in HSPCs that, through the autocrine engagement of CCR1 and CCR5, induced HSPCs differentiation in MDSCs. These finding were confirmed across mice with different genetic backgrounds and using HSPCs from umbilical cord blood and peripheral blood of patients with cancer.Our data support the notion that CCR1 and CCR5 and their ligands are a master immunological hub activated by several tumor derived factors. Activation of this pathway is necessary for the differentiation of MDSCs and protumoral macrophages.
Highlights of the NCCN Oncology Research Program
Authors: Amit Mahipal
Journal: Journal of the National Comprehensive Cancer Network (2021)

This is a single-arm, phase II trial to assess the efficacy of trifluridine/tipiracil in combination with irinotecan in advanced, refractory biliary tract cancers using a 2-stage design.In the first stage, 15 patients will be enrolled.If $2 patients are progression-free and alive at 16 weeks, an additional 10 patients will be enrolled.If #5 of 25 evaluable patients remain progression-free at 16 weeks, then the regimen will be considered ineffective.The total sample size of this study is 28 to account for 3 possible nonevaluable subjects.Patients will receive trifluridine/tipiracil at a dose of 25 mg/m 2 on days 1 through 5 and irinotecan, 180 mg/m 2 on day 1 of each 14-day cycle.Patients will receive treatment until disease progression or development of unacceptable toxicities.Patients will undergo restaging scans every 4 cycles, and will be monitored for adverse events from initiation of study drug administration to 28 days after the last dose.Blood samples will be collected for determination of cell-free DNA (cfDNA) and circulating tumor cells (CTCs) at baseline, after 4 cycles, and at disease progression.Tumor biopsy specimens will be collected before treatment initiation to develop patient-derived tumor organoid (PDO).
Table of Contents
Authors: S Derks, S Saw, D Tan, M Piccart, K Kalinsky, R Gray, W Barlow, C Poncet, F Cardoso, E Winer, J Sparano, N Reddy, V Subbiah, S Rao, M Guren, K Khan, G Brown, A Renehan, S Steigen, E Deutsch, E Martinelli, D Arnold, M Reck, D Carbone, M Garassino, F Barlesi, K Shitara, M Özgüro Glu, Y.-J Bang, M Bartolomeo, M Mandalà, M.-H Ryu, C Caglevic, H Chung, K Muro, E Van Cutsem, J Kobie, R Cristescu, D Aurora-Garg, J Lu, C.-S Shih, D Adelberg, Z Cao, C Fuchs, S Sugawara, J.-S Lee, J.-H Kang, H Kim, N Inui, T Hida, K Lee, T Yoshida, H Tanaka, C.-T Yang, M Nishio, Y Ohe, T Tamura, N Yamamoto, C.-J Yu, H Akamatsu, Y Namba, N Sumiyoshi
Journal: Annals of Oncology (2021)
Intrahepatic cholangiocarcinoma: Tumour heterogeneity and its clinical relevance
Authors: Mina Komuta
Journal: Clinical and Molecular Hepatology (2022)

Treatment of intrahepatic cholangiocarcinoma (iCCA) is currently at a significant turning point due to the identification of isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted with currently available therapies. Clinical trials of these targeted therapies have been promising, and the iCCA patients who may benefit from these targeted treatments can be identified by pathological examination prior to molecular investigations. This is because IDH mutations and FGFR fusions are mainly seen in the small duct type iCCA, a subtype of iCCA defined by the 5th World Health Organization classification, which can be recognized by the pathological diagnostic process. Therefore, pathology plays an important role in precision medicine for iCCA, not only in confirming the diagnosis, but also in identifying the iCCA patients who may benefit from targeted treatments. However, caution is advised with the pathological diagnosis, as iCCA shows tumour heterogeneity, making it difficult to distinguish small duct type iCCA from hepatocellular carcinoma (HCC), and combined HCC-CCA. This review focuses on the pathological/molecular features of both subtypes of iCCA (large and small duct types), as well as their diagnostic pitfalls, clinical relevance, and future perspectives.