tbuckley/cabot-search huggingface dataset:
Considerations for conducting and interpreting long-term follow-up of intervention studies: avoiding spoiled milk
Authors: Iain Stewart, Chloe I Bloom
Journal: Thorax (2021)

Multiple early life exposures have been shown to influence the development of allergic disease in infancy and childhood. The timing of exposure to food allergens has been of particular interest. Two landmark trials, Learning Early About Peanut and the Enquiring About Tolerance studies, found early introduction of peanuts reduced peanut allergy in children,1 2 a fundamental difference from previously accepted beliefs. The impact from cow’s milk is less clear, with the most recent trial suggesting avoidance of early cow’s milk supplementation decreased the risk of childhood asthma,3 while others have found an increased risk or no effect on childhood allergy.4 5 In the current issue of Thorax , Hand and colleagues have further added to the ongoing cow’s milk debate by studying the effect of early avoidance on adult allergy.6 

Investigating if early life exposures influence adult disease requires extended follow-up of participants. Trials are usually designed to investigate immediate or short-term outcomes, but it is possible to proficiently plan and execute long-term follow-up of an intervention during infancy, such as in the Promotion of Breastfeeding Intervention Trial trial, where participants were followed up until adolescence.7 However, due to the nature of extended longitudinal follow-up, such trials are prone to considerable limitations that must be carefully considered in the design, analysis and interpretation.

In the current study, Hand et …
PRIME-HCC: Phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.
Authors: David James Pinato, Alessio Cortellini, Madhava Pai, Duncan Spalding, Thomas Talbot, Robert D. Goldin, Aneta Gupta, Tom Cole, Caroline Ward, Vincent S. Yip, Tony Singh Dhillon, Sarah Slater, Mikael Sodergren, Paul Tait, Nagy A. Habib, Robert Thomas, Rohini Sharma
Journal: Journal of Clinical Oncology (2021)

e16131 Background: There are no approved peri-operative anti‐cancer therapies for patients with hepatocellular cancer (HCC) who are candidates for liver resection (LR). Combination immunotherapy induces radiologically measurable responses in &gt; 25% of patients with HCC, providing a rationale for neoadjuvant use in surgical candidates. Methods: PRIME‐HCC is a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab (3 mg/kg, day 1 and day 22) plus ipilimumab (1mg/kg, day 1 only) combination prior to LR in early-stage HCC. The primary objective of the study is to determine the treatment-related adverse events (trAE) and delays to surgery. Efficacy endpoints include overall response rates (ORR) by RECIST v1.1 and pathologic responses on resection specimens. Results: At the data censoring time of Jan 29 th 2021, 7 patients were enrolled, all were of Child-Pugh class A, with cirrhosis (n = 6, 85.7%) secondary to viral etiology (n = 4, 57.2%). Male/female ratio was 6/1 and median age was 66 (range: 57-70). The median diameter of the dominant liver lesion was 3.3 cm (inter quartile range, IQR 1.2, range 1.1-4.1 cm) and the median number of nodules was 2 (IQR 0.5; range 1-3). Study part I (n = 6) was completed with no surgical delays. TrAEs of all grade were observed in 6/7 safety-evaluable patients (85%). TrAEs of grade &gt;2 occurred in 3 patients (42%) and included grade 3 transaminitis (n = 1), grade 2 thyroid toxicity (n = 1), grade 2 infusion reaction (n = 1) and fatigue (n = 1). One patient was diagnosed with cholangiocarcinoma after dosing and was removed from efficacy analyses. ORR according to RECIST v1.1 criteria in efficacy-evaluable patients (n = 5) was 20%, including 1 partial response and 4 disease stabilisations. Pathological responses were observed in 3 out of 5 pathologically evaluable patients (60%). Conclusions: Neoadjuvant immunotherapy with nivolumab plus ipilimumab is tolerable, does not compromise management of patients on a radical pathway of care and is characterised by anti-tumour efficacy in early-stage HCC. Clinical trial information: NCT03682276.
Is the Strongest Level of Medical Evidence Always Required for Guidelines Recommendations?
Authors: Matteo Ravaioli, Fabio Piscaglia, Umberto Cillo, Giovanni Brandi, Maurizio Sessa, Giuliana Germinario, Rita Golfieri, Alberta Cappelli, Maria C. Morelli, Antonio Siniscalchi, Antonietta D’Errico, Matteo Cescon, Primiano Iannone, Franco Trevisani
Journal: Liver Cancer (2021)
Investigating intra-tumor microbes, blood microbes, and CEA for development of non-invasive biomarkers in colorectal cancer.
Authors: Pannaga G. Malalur, Xiaokui Mo, Rebecca Hoyd, John L. Hays, David Paul Carbone, Daniel Spakowicz
Journal: Journal of Clinical Oncology (2021)

3551 Background: The development of non-invasive biomarkers has the potential to revolutionize clinical care for colorectal cancer (CRC) patients. The presence of bacteria in CRC tumor biopsies has been shown to contribute to CRC development. In a previous study, our group showed some intra-tumor microbes in CRC tumor biopsies correlated with overall survival in CRC patients. However, the correlations between microbes in tumor vs blood, and between non-invasive serum marker carcinoembryonic antigen (CEA) and microbes are unknown. We hypothesize that tumor microbes will also be found in blood, and that CEA will correlate with certain microbes. Methods: We obtained RNA-seq data from CRC tumor biopsies from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. RNA-seq from CRC tumor biopsies as well as peripheral blood at the Cancer Genome Atlas (TCGA) consortium were processed by the same method. Results: The analyzed ORIEN cohort included 93 CRC patients with an age range from 30-83 years, 60.2% male, 87.1% adenocarcinoma, and 47.3% with metastatic CRC. The TGCA cohort included 495 CRC patients with an age range from 31-90 years, 53.3% male, 85.1% adenocarcinoma, and 15.5% with metastatic CRC. Over fifteen exogenous phyla (including bacteria, viruses, fungi) were observed in both ORIEN and TCGA cohorts. Several of the samples were dominated by viral sequences while others by bacteria, suggesting considerable tumor microbiome heterogeneity. Evaluation of the fraction of microbes in tumor and blood showed that nearly all the microbes found in blood (97.6%) were also observable in tumor in the TCGA cohort. Microbial abundances of various taxa, including Fusobacterium, significantly correlated between blood and tumor. Several bacteria including members of the genera Bacillus and Staphylococcus were positively associated with tumor stage (metastatic vs non-metastatic), but microbial relative abundances were not correlated with the location of tumor in colon (right, left, transverse colon). Certain microbial species from the ORIEN cohort were found to positively correlate with CEA, (including from the genera Fusobacterium, Lactobacillus, Pseudomonas, Vibrio, Clostridium) and these associations remained when adjusted for alcohol and smoking by multivariate analysis. Conclusions: Nearly all the microbes found in blood were found in tumor and abundances of various taxa were significantly correlated, suggesting that blood-based cancer microbiome analysis has great potential. Serum CEA has a low diagnostic ability when used alone, but combining this with blood microbiome could improve diagnostic/prognostic utility as a non-invasive biomarker.
Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis
Authors: John Mascarenhas, Rami S. Komrokji, Francesca Palandri, Bruno Martino, Dietger Niederwieser, Andreas Reiter, Bart L. Scott, Maria R. Baer, Ronald Hoffman, Olatoyosi Odenike, Alessandro M. Vannucchi, Jacqueline Bussolari, Eugene Zhu, Esther Rose, Laurie Sherman, Souria Dougherty, Libo Sun, Fei Huang, Ying Wan, Faye M. Feller, Aleksandra Rizo, Jean-Jacques Kiladjian
Journal: Journal of Clinical Oncology (2021)

PURPOSE Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086 ). PATIENTS AND METHODS Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety. RESULTS Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias. CONCLUSION In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.
Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease
Authors: Lukas M. Braun, Robert Zeiser
Journal: HemaSphere (2021)

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versus-host disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and low-dose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.
High Expression of the DNMT3A Embedded Pri- Mir -1301 Associates with Improved Outcome in Patients with Acute Myeloid Leukemia
Authors: Janine Häntschel, Madlen Jentzsch, Juliane Grimm, Marius Bill, Stefanie Beinicke, Laura K. Schmalbrock, Lynn Bonifacio, Luba Schuhmann, Julia Schulz, Karoline Goldmann, Michael Cross, Georg-Nikolaus Franke, Vladan Vucinic, Wolfram Pönisch, Gerhard Behre, Dietger Niederwieser, Sebastian Schwind
Journal: Blood (2017)
Fifteen-year follow-up of relapsed indolent non-Hodgkin lymphoma patients vaccinated with tumor-loaded dendritic cells
Authors: Giovanni Fucà, Margherita Ambrosini, Luca Agnelli, Silvia Brich, Francesco Sgambelluri, Roberta Mortarini, Serenella M Pupa, Michele Magni, Liliana Devizzi, Paola Matteucci, Antonello Cabras, Roberta Zappasodi, Francesca De Santis, Andrea Anichini, Filippo De Braud, Alessandro M Gianni, Massimo Di Nicola
Journal: Journal for ImmunoTherapy of Cancer (2021)

We previously published the results of a pilot study showing that vaccination with tumor-loaded dendritic cells (DCs) induced both T and B cell response and produced clinical benefit in the absence of toxicity in patients with relapsed, indolent non-Hodgkin lymphoma (iNHL). The purpose of the present short report is to provide a 15-year follow-up of our study and to expand the biomarker analysis previously performed. The long-term follow-up highlighted the absence of particular or delayed toxicity and the benefit of active immunization with DCs loaded with autologous, heat-shocked and UV-C treated tumor cells in relapsed iNHL (5-year and 10-year progression-free survival (PFS) rates: 55.6% and 33.3%, respectively; 10-year overall survival (OS) rate: 83.3%). Female patients experienced a better PFS (p=0.016) and a trend towards a better OS (p=0.185) compared with male patients. Of note, we observed a non-negligible fraction of patients (22%) who experienced a long-lasting complete response. In a targeted gene expression profiling of pre-treatment tumor biopsies in 11 patients with available formalin-fixed, paraffin-embedded tissue, we observed that KIT , ATG12 , TNFRSF10C , PBK , ITGA2 , GATA3 , CLU , NCAM1 , SYT17 and LTK were differentially expressed in patients with responder versus non-responder tumors. The characterization of peripheral monocytic cells in a subgroup of 14 patients with available baseline blood samples showed a higher frequency of the subset of CD14 ++ CD16 + cells (intermediate monocytes) in patients with responding tumors. Since in patients with relapsed iNHL the available therapeutic options are often incapable of inducing a long-lasting complete remission and can be sometimes characterized by intolerable toxicity, we think that the encouraging results of our long-term follow-up analysis represent a stimulus to further investigate the role of active vaccination in this specific setting and in earlier lines of therapy and to explore novel combinatorial strategies encompassing other innovative immunotherapy agents, such as immune-checkpoint inhibitors.
India grapples with second wave of COVID-19
Authors: Udani Samarasekera
Journal: The Lancet Microbe (2021)

India's devastating second wave of COVID-19 has overwhelmed its health system and the country. In several cities and states, oxygen supplies have been critical, hospitals have turned patients away, and crematoriums have run out of space. As of May 18, India had reported more than 26·4 million confirmed cases and over 274 000 deaths from COVID-19.
Evaluation of age, gender, prenatal characteristics, and treatment results of 380 babies with infantile hemangioma.
Authors: Eda Suzen Orhan, Emel Cabi Unal, Nurdan Tacyildiz, Handan Dincaslan
Journal: Journal of Clinical Oncology (2021)

e22018 Background: Infantile hemangiomas' incidence is 5% &amp; are locally proliferated vascular structures. Methods: Fourhundred cases were analyzed,380 are presented. Results: Majority pts dx between 0-3 mos(88.8%), females (64.5 %), 26.6% had preterm birth,21.8% lbw 2500g. Maternal characteristics 17.1% were &gt; age35, 8.5% multipar, 61.5% multiple gestation. Placental anomaly in 5.5%, preeclampsia in 10.3%, gestational diabetes in 7%, intervention in pregnancy 4.9%, smoking 7.6%, hyperemesis 29.9%. Treatment modality was topical timolol drops in 41.9%, oral propranolol solution in 37.6%, wait&amp;see group 13.5%,surgical excision in 5.6%. Conclusions: Hemangioma, a multifactorial disease, lbw is an important risk factor.Oral propranolol solution for the babies &lt;1yr of age avoided the use of intralesional steroids. It is essential to treat the babies especially who have the risk of developing amblyopia or other functional/cosmetic sequelae.
Differential responses to taxanes and PARP inhibitors (PARPi) in <i>ATM-</i> versus <i>BRCA2-</i>mutated metastatic castrate-resistant prostate cancer (mCRPC) patients (pts).
Authors: Christopher T Su, Emily Nizialek, Jacob E Berchuck, Panagiotis J. Vlachostergios, Ryan Ashkar, Alexandra Sokolova, Pedro C. Barata, Rahul Raj Aggarwal, Heather McClure, Nellie Nafissi, Alan Haruo Bryce, A. Oliver Sartor, Heather H. Cheng, Nabil Adra, Cora N. Sternberg, Mary-Ellen Taplin, Marcin Cieslik, Emmanuel S. Antonarakis, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2021)

5040 Background: PARPi have shown promise in mCRPC pts with mutations in DNA repair, but ATM- and BRCA2-altered pts may respond differently to PARPi. We hypothesized that differences may also exist for taxane therapy, aiding in treatment sequencing decisions. Methods: mCRPC pts (N = 137) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were identified from 8 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed for time-to-treatment-discontinuation (TTD), as well as overall survival (OS), from time of first taxane or PARPi therapy. Cox hazard ratio (HR) regression analyses were performed, adjusting for Gleason sum (≤7 vs. 8-10). For OS, receipt of subsequent therapies following first taxane or PARPi was also included as a covariate. Results: 50 ATM- and 87 BRCA2-mutated pts were identified. 40/50 (80%) of ATM-mutated pts received taxane only or taxane prior to PARPi, while 10/50 (20%) received PARPi only or PARPi prior to taxane. ATM-mutated pts showed a trend towards longer TTD when taxane was given first vs PARPi given first (P = 0.08, adjusted HR for taxane treatment 0.50 [95% CI: 0.24–1.08]). Considering all pts who received taxane first, ATM-mutated pts had longer TTD than BRCA2-mutated pts who received taxane first ( P= 0.04, adjusted HR for ATM 0.61 [CI: 0.37–0.99]). Among ATM-mutated pts, OS was longer in those receiving taxane first ( P= 0.06, adjusted HR for taxane treatment 0.33 [CI: 0.10–1.05]). Among BRCA2-mutated pts, 43/87 (49%) received taxane first and 44/87 (51%) received PARPi first. BRCA2-mutated pts had longer TTD when PARPi was given first vs taxane given first ( P&lt; 0.0001, adjusted HR for PARPi treatment 0.32 [CI: 0.19–0.56]). Considering all pts who received PARPi first, BRCA2-mutated pts also had longer TTD than ATM-mutated pts who received PARPi first ( P= 0.0031, adjusted HR for BRCA2 0.29 [CI: 0.12–0.66]). There was no significant OS difference in BRCA2-mutated pts regarding which treatment was given first ( P= 0.63, adjusted HR for PARPi treatment 1.18 [CI: 0.59–2.35]). Conclusions: Our data in ATM- and BRCA2-mutated mCRPC pts suggests a trend towards improved clinical outcomes when taxanes are used prior to PARPi in ATM-mutated pts, while the reverse sequence appears to be better for BRCA2-mutated pts.[Table: see text]
Letter to the Editor: Entecavir Treatment Restores the Anti‐HBV Immune response?
Authors: Boris J.B. Beudeker, Harry L.A. Janssen, Andre Boonstra
Journal: Hepatology (2021)

TO THE EDITOR: With great interest, we read the manuscript by De Pasquale et al.(1) They convincingly showed that dendritic cells (DCs), generated in vitro from monocytes of patients with HBV, have a detrimental effect on the function of natural killer (NK) cells, leading to the insufficient anti-HBV response observed in patients with chronic HBV. However, many years ago, we conducted a similar study.(2) In our study, we did not use monocyte-derived DCs, but only ex vivo isolated blood dendritic cell antigen 1–positive (BDCA1+) DCs, and examined the DC–NK interaction in a larger and prospectively designed cohort study of 39 patients with HBV and 16 healthy controls. Given the complexity of these type of studies, we were pleased to learn that the study by De Pasquale et al. supported our earlier findings. In one challenging experiment of our earlier study, we co-cultured pretreatment NK cells with BDCA1+ DCs isolated from the same patient before and during 6 months of entecavir treatment. We observed that antiviral therapy enhanced the production of multiple DC-derived cytokines (including IL-12p70), and consequently improved the anti-HBV-associated DC–NK cell function. Our ex vivo experiments clearly show, as in the current study by De Paquale et al., that altered DC function in patients with chronic HBV leads to impairment of NK cell activity, which can be reversed by antiviral treatment. We were intrigued to read that a soluble factor in the serum of patients with chronic HBV impaired co-cultured DC function, something not observed when using sera from entecavir-treated patients. De Pasquale et al. suggested a role for IL-10; however, many cytokines are known to respond to entecavir treatment. For instance, during entecavir treatment, plasma levels of immune-suppressive TGF-β1 and pro-inflammatory IL-17 and IL-23 gradually decrease, while IL-4-stimulating and DC-stimulating interferon-γ increase.(3) We conclude that the soluble serum factor that modulates the DC–NK cross talk leading to impaired NK cell activity is not just IL-10, but rather a complex serum cytokine milieu, deserving of better characterization.