tbuckley/cabot-search huggingface dataset:
The clinical significance of telomerase reverse transcriptase (<i>TERT</i>) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (<i>MGMT</i>) promoter methylation status in newly diagnosed and recurrent <i>IDH</i>-wildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study.
Authors: Giuseppe Lombardi, Silvia Giunco, Francesco Cavallin, Chiara Angelini, Mario Caccese, Giulia Cerretti, Pasquale De Bonis, Anita De Rossi, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2021)

2053 Background: the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large mono-institutional study to better investigate their impact and their interaction on clinical outcomes Methods: TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio Results: characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0-1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07-0.40). No gene interaction was significant. Conclusions: for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status.
Bacteroides-dominant gut microbiome of late infancy is associated with enhanced neurodevelopment
Authors: Sukhpreet K. Tamana, Hein M. Tun, Theodore Konya, Radha S. Chari, Catherine J. Field, David S. Guttman, Allan B. Becker, Theo J. Moraes, Stuart E. Turvey, Padmaja Subbarao, Malcolm R. Sears, Jacqueline Pei, James A. Scott, Piush J. Mandhane, Anita L. Kozyrskyj
Journal: Gut Microbes (2021)

Dysbiosis of gut microbiota has been retrospectively linked to autism spectrum disorders but the temporal association between gut microbiota and early neurodevelopment in healthy infants is largely unknown. We undertook this study to determine associations between gut microbiota at two critical periods during infancy and neurodevelopment in a general population birth cohort.Here, we analyzed data from 405 infants (199 females) from the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study. Neurodevelopmental outcomes were objectively assessed using the Bayley Scale of Infant Development (BSID-III) at 1 and 2 years of age. Microbiota profiling with 16S rRNA gene sequencing was conducted on fecal samples obtained at a mean age of 4 and 12 months.Using clustering methods, we identified three groups of infants based on relative abundance of gut microbiota at 12 months: Proteobacteria-dominant cluster (22.4% higher abundance at 12 months), Firmicutes-dominant cluster (46.0% higher abundance at 12 months) and Bacteroidetes-dominant cluster (31.6% higher abundance at 12 months). Relative to the Proteobacteria-dominant cluster, the Bacteroidetes-dominant cluster was associated with higher scores for cognitive (4.8 points; FDRp = .02), language (4.2 points; FDRp≤0.001), and motor (3.1 points; FDRp = .03) development at age 2 in models adjusted for covariates. When stratified by sex, only male infants with a Bacteroidetes-dominant microbiota had more favorable cognitive (5.9 points, FDRp = .06) and language (7.9 points; FDRp≤0.001) development. Genus Bacteroides abundance in gut microbiota was positively correlated with cognitive and language scores at age 2. Fully adjusted linear mixed model analysis revealed a positive association between Bacteroidetes-dominant cluster and change in cognitive and language performance from 1 to 2 years, predominantly among males. No associations were evident between 4-month microbiota clusters and BSID-II scores. Noteworthy is that enhanced sphingolipid synthesis and metabolism, and antagonism or competition between Bacteroides and Streptococcus were characteristic of a Bacteroidetes-dominant gut microbiota.This study found strong evidence of positive associations between Bacteroidetes gut microbiota in late infancy and subsequent neurodevelopment, most prominently among males but not females.
Association of tumor infiltrating lymphocytes with pathological response after neoadjuvant therapy in breast cancer: A retrospective study.
Authors: Punita Grover, Kim Phan, Tara Magge, Andrew Chou, Rand Naffouje, Roman Jandarov, Lisa Grate, Benjamin H Hinrichs, Mahmoud Charif
Journal: Journal of Clinical Oncology (2021)

e12621 Background: Tumor infiltrating lymphocytes (TILs) are thought to represent favorable host anti-tumor immunity and play an important role in mediating response to chemotherapy in breast cancer. TILs are heterogenous across breast cancer subtypes and are increasingly being studied as prognostic and predictive biomarkers. We undertook a retrospective study to establish the relationship between pre-treatment density of TILs and subsequent quality of response to neoadjuvant chemotherapy in patients with early-stage breast cancer. Methods: We retrospectively identified women with breast cancer who had received neoadjuvant therapy (NAT) at the University of Cincinnati from 2012-2018. Clinical and pathological variables were extracted from medical records. Pre-treatment core biopsies were assessed for intra-tumoral TILs through independent pathology review and were graded as mild (grade 1), moderate (grade 2) or severe (grade 3). Post-treatment resection samples were assessed for pathological complete response (pathCR). Univariate analysis was done to determine the association between TILs and pathCR. Results: We identified 148 patients with breast cancer who received NAT, median age 53 years (25-90), 77 were Caucasian. 32 patients had stage I disease at diagnosis, 87 stage II and 29 stage III. Most patients had tumor grade 2 (n=50) or 3 (n=91). 50 patients were HER2+, 65 ER/PR+ HER2- (HR+) and 33 had triple negative breast cancer (TNBC). 69 patients received anthracycline based NAT, 29 non-anthracycline based NAT and all HER2+ patients received anti-HER2 therapy. 72 patients had TILs grade 1, 54 grade 2 and 22 had grade 3. 50 patients achieved pathCR. On univariate analysis grade 2 and 3 TILs were associated with higher likelihood of pathCR compared to grade 1 (42.1% vs 25%, OR 2.18, [1.08 – 4.4], p = 0.029). There was no difference in pathCR between grade 2 and grade 3 TILs (40.7% vs 45.5%, OR 1.21 [0.45-3.29], p=0.12). Tumor grade 3 was associated with higher pathCR than grade 1 or 2 (41.8 vs 21.1%, OR 2.69 [1.26-5.75], p=0.01). Amongst breast cancer subtypes, pathCR was lower in HR+(13.8%) compared to TNBC (45.5%) or HER2+ (52%) with OR 0.15 (0.06-0.36), p&lt;0.01. Age, race, stage and type of chemotherapy were not associated with pathCR. On multivariate analysis, none of the variables retained significance. Conclusions: Our analysis shows that increased TILs density (grade 2 or 3) and higher tumor grade are associated with pathCR whereas HR+ breast cancer have a lower rate of pathCR after NAT. Immune characterization of TILs might be helpful in further refining the prognostic impact of TILs.[Table: see text]
A PGE2-MEF2A axis enables context-dependent control of inflammatory gene expression
Authors: Francesco Cilenti, Giulia Barbiera, Nicoletta Caronni, Dario Iodice, Elisa Montaldo, Simona Barresi, Eleonora Lusito, Vincenzo Cuzzola, Francesco Maria Vittoria, Luca Mezzanzanica, Paolo Miotto, Pietro Di Lucia, Dejan Lazarevic, Daniela Maria Cirillo, Matteo Iannacone, Marco Genua, Renato Ostuni
Journal: Immunity (2021)

Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E2 (PGE2) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE2. The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE2 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE2 interfered with LPS-mediated activation of ERK5, a known transcriptional partner of MEF2. This study highlights principles of plasticity and adaptation in cells exposed to a complex environment and uncovers a transcriptional circuit for IFN I induction with relevance for infectious diseases or cancer.
Improving the inclusion rate in clinical trials of bladder cancer despite COVID-19 pandemic by using ASCO quality training program.
Authors: Natalia Vidal, Juan Gomez, Isabel Galante, Jose Luis Senovilla, Jose-Luis Gonzalez-Larriba, Carmen Toledano, Irene de la Parra, Tamara Jerez, Lorena Fernandez-Montarroso, Enrique Redondo, Jesús Moreno, Pedro Perez, Javier Puente
Journal: Journal of Clinical Oncology (2021)

e18674 Background: In 2019, we used the American Society of Clinical Oncology (ASCO) Quality Training Program (QTP) as an instrument to improve the inclusion rate in clinical trials (CTs) for bladder cancer patients from 24% in 2018 to 43,75% in 2019. CTs play an important role in developing new treatments, expanding or refining treatments that are already available, and/or identifying behavioral changes that can prolong or improve the lives of subjects. Therefore, we believe it is important for patients and for society to maintain the inclusion rate in clinical trials despite COVID-19 pandemic. Methods: We collected the number of bladder cancer patients evaluated for the first time in the Oncology department, the number of patients who were offered a clinical trial, the screen failures and the number of patients enrolled in CTs. Results: In 2019, we were able to increase the enrollment rate in CTs for bladder cancer patients to from 24% to 43,75% thanks to the ASCO-QTP. With this program we created a list of measures and identified the ones that would have a greater impact. The one that seems to have had the highest impact is the diffusion of CTs in the Investigation Unit and the Genitourinary (GU) board. In 2020, thanks to this measure and despite the COVID-19 pandemic, we were able to maintain a 40,81% enrollment rate. When analyzing the patients evaluated for the first time in the Oncology department, 48 in 2019 and 49 in 2020, there were some interesting differences. In 2020, 42,86% had stage IV disease with respect to 39,6% in 2019, and only 22,44% had non-muscle invasive disease (NMIBC) versus 33,33% in 2019. However, thanks to the diffusion of CTs in the Investigation Unit and in the GU-board, which translates in an early derivation of patients to Medical Oncology and an increase in the number of available CTs, we were able to offer a CT to 73,5% of patients in 2020 against 60,4% in 2019. Although there was an increase of screen failures in 2020 (32,65% vs. 16,66%), 50% of them were due to the absence of a biomarker in a biomarker driven CT, with respect to 25% in 2019. Conclusions: Using ASCO-QTP as an instrument, we identified the importance of the diffusion of CTs and the close collaboration between departments. Maintaining these measures, we were able to uphold the inclusion rate in CTs for bladder cancer patients in 40,81% despite the later diagnosis of patients due to COVID-19 pandemic.
The impact of clinical decision making in a molecular tumor board at a tertiary care center.
Authors: Meena Sadaps, Kathryn Demski, Ying Ni, Vicky Konig, Brandie Leach, Emily Mazzei, Pauline Funchain
Journal: Journal of Clinical Oncology (2021)

3128 Background: Multidisciplinary molecular tumor boards were first established with the onset of precision oncology (PO), as many clinicians were unfamiliar with the interpretation and incorporation of the information into clinical practice. PO has since rapidly evolved and integrated itself into standard of care practices for most cancer patients, yet molecular tumor boards have not grown accordingly and in fact some have been discontinued. There remains a paucity of data in regards to the value and impact of molecular tumor board discussions themselves. We previously reported on our longitudinal experiences in PO ( Sadaps et al, 2018), focusing on the therapeutic impact of matched therapy. Here, we report on the utility of our molecular tumor board in clinical decision making. Methods: We conducted a retrospective review of patients seen at Cleveland Clinic with a solid tumor malignancy who had large panel, next-generation-sequencing (NGS) performed via any commercial platform from November 2019-January 2021. Cases were filtered through a local therapeutic algorithm and then reviewed individually. Initial review was performed by a core genomics committee comprised of 2 oncologists and 2 genetic counselors. Interesting and/or complex cases were flagged for discussion at our bimonthly molecular tumor board, which is regularly attended by medical oncologists, pathologists, genetic counselors, bioinformaticians, and patient care coordinators. Data analyzed included categorization of treatment recommendations and the percentage of cases for which initial recommendations were changed based on tumor board discussion. Results: Of 782 total cases, 575 (73.5%) had a clinically relevant genomics tumor board (GTB) recommendation as compared to 51.7% from our previously reported study. 16.7% of patients had on label recommendation(s) and 86.4% had off label/ clinical trial recommendation(s). 179 (22.9%) patients were recommended for genetic counseling (GC). During our bimonthly GTB, we discussed 173 (22.1%) of these cases. Of the discussed cases, the most common tumor types were hepatobiliary (18.5%), lower gastrointestinal (17.3%), and breast (16.2%). Topics of discussion at GTB included such things as pathologic/histologic/molecular testing, prioritization of available trials, appropriateness of an off label therapy, and need for a genetics consult. Discussion at GTB resulted in a change in treatment recommendation in 63 (36.4%) cases. Conclusions: Discussions from multidisciplinary molecular tumor board impacted treatment decisions for our patients. Referral to GC was also common and should be considered an integral part of somatic sequencing review. Molecular tumor boards remain a crucial platform for treatment guidance and clinical management, especially given the increase in “actionability” over the years due to newly discovered targets and targeted therapies in this rapidly evolving field.
Isolation of clade 2.3.4.4b A(H5N8), a highly pathogenic avian influenza virus, from a worker during an outbreak on a poultry farm, Russia, December 2020
Authors: Olga G Pyankova, Ivan M Susloparov, Anastasia A Moiseeva, Natalia P Kolosova, Galina S Onkhonova, Aleksey V Danilenko, Elena V Vakalova, Gennady L Shendo, Natalia N Nekeshina, Lyudmila N Noskova, Julia V Demina, Natalia V Frolova, Elena V Gavrilova, Rinat A Maksyutov, Aleksandr B Ryzhikov
Journal: Eurosurveillance (2021)

This study presents the isolation of influenza A(H5N8) virus clade 2.3.4.4b from a poultry worker during an outbreak of highly pathogenic avian influenza A(H5N8) among chickens at a poultry farm in Astrakhan, Russia in December 2020. Nasopharyngeal swabs collected from seven poultry workers were positive for influenza A(H5N8), as confirmed by RT-PCR and sequencing. The influenza A(H5N8) virus was isolated from one of the human specimens and characterised. Sporadic human influenza A(H5)2.3.4.4. infections represent a possible concern for public health.
MAPKAP1 (Sin1), a Key Component of the MTORC2 Complex, Confers Resistance to Sorafenib and Correlates with Adverse Clinical Outcomes in Acute Myeloid Leukemia
Authors: Joseph David Khoury, Ioanna Xagoraris, Nikolaos Tsesmetzis, Ida Hed Hed Myrberg, Thale Kristin Olsen, Siok Bian Ng, Wee-Joo Chng, Benedict Yan, Chin Hin Ng, Michael Andreeff, L. Jeffrey Medeiros, Hagop M. Kantarjian, Herold Nikolas, Dan Grander, George Rassidakis
Journal: Blood (2017)
Brigatinib (BRG) in ALK+ crizotinib (CRZ)-refractory non-small cell lung cancer (NSCLC): Final results of the phase 1/2 and phase 2 (ALTA) trials.
Authors: Scott N. Gettinger, Rudolf M. Huber, Dong-Wan Kim, Lyudmila Bazhenova, Karin Holmskov Hansen, Marcello Tiseo, Corey J. Langer, Luis G. Paz-Ares, Howard West, Karen L. Reckamp, Glen J. Weiss, Egbert F. Smit, Maximilian Hochmair, Sang-We Kim, Myung-Ju Ahn, Edward S. Kim, Harry J.M. Groen, Joanna Pye, Florin Vranceanu, D. Ross Camidge
Journal: Journal of Clinical Oncology (2021)

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]
Does multiplicity of synchronous multiple lung primaries (SMLPs) affect prognosis.
Authors: RuoBing Xue, Satish Maharaj, Rohit Kumar, Goetz H. Kloecker
Journal: Journal of Clinical Oncology (2021)

e20530 Background: SMLPs are detected more commonly due to advancements in screening technology. Their workup and classification; however, are still lacking a clear standard. T stage of the largest lesion has been used as the major prognostic marker. This; however, does not take the number of SMLPs and their genomic drivers into consideration. This study aims to identify and review common risk factors associated with SMLPs and determine whether the number of primaries influence the prognosis. Methods: A systematic review of the literature published between 2000 and 2021 was conducted through PubMed and Medline by using the combination of keywords, including: “synchronous multiple primary lung cancer”, “simultaneous multifocal lung cancer”, “synchronous solitary lung metastasis”, “risk factor” and “prognosis”. A total of fifty studies were identified, among them only sixteen retrospective research articles and two review articles were relevant to the study at hand. Results: Sixteen retrospective studies including a total of 1685 eligible patients were reviewed. Thirteen of these studies reported the main histology type to be adenocarcinoma with a ratio ranging from 35% to 96.8%. Eight studies have reported the numbers of synchronous primary lung cancers, including one study found 11 SMLPs. Among these, one study by van Rens found number of SMLPs impact prognosis adversely compared to a single lung cancer. However, three other studies demonstrated multiple SMPLs do not adversely affect survival (Finley et al, 2010; Kocaturk et al, 2011; Li et al, 2020). Four of the sixteen studies analysed the effect of multiple lobes involvement and distance between tumors, with varying conclusions; two studies reported no difference in prognosis while one study revealed worse survival with multiple lobe involvement and one study found favorable outcome. Most studies confirm the usual prognostic factors for SMLPs, including: gender, smoking, type of surgery, comorbidities and adjuvant therapy. The median 5 year OS reported for SMLPs is 66%, with a wide range from 19% to 95.8%.The 3 year OS is 75% in most studies. Conclusions: The data on how the number of SMLPs affects the prognosis is uncertain. The current recommendation to base the decision for adjuvant therapy on the highest T stage is not supported by prospective evidence or consistent among published case series. Considering the recent approval of targeted therapies in early stage lung cancers, a better prognostic scoring system for SMLPs is required.
NK Cell Diversity Influences Outcomes after Cord Blood Transplantation
Authors: Li Li, Muharrem Muftuoglu, Han Chen, Duncan Mak, Jared K Burks, Rohtesh S. Mehta, Yuanxin Xi, Jiangxing Lv, Bingqian Hu, Juan Jimenez, Mecit Kaplan, Hila Shaim, Nobuhiko Imahashi, Pinaki P Banerjee, Lucila Nassif Kerbauy, Mayela Carolina Mendt, Francesca Lorraine Wei Inng Lim, May Daher, April Depombo, Rafet Basar, Michael Andreeff, Jing Wang, David Costa Marin, Richard E. Champlin, Elizabeth J Shpall, Katy Rezvani
Journal: Blood (2017)