tbuckley/cabot-search huggingface dataset:
Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans
Authors: Kevin O’Gallagher, Francesca Puledda, Owen O’Daly, Matthew Ryan, Luke Dancy, Philip J Chowienczyk, Fernando Zelaya, Peter J Goadsby, Ajay M Shah
Journal: Cardiovascular Research (2021)

Abstract Aims Neuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity. Methods and results We investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n = 19). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an ∼4% decrease in resting global CBF [−2.3 (−0.3, −4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T = 7.0; x = 36; y = −32; z = −12; P &amp;lt; 0.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T = 5.02; x = −14; y = −56; z = 74; P = 0.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7 mmHg (+1.8, +15.6), mean (95% CI), P = 0.009]. Conclusions These data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease.
Advanced breast cancer at presentation (ABC-p) in octogenarian women (OW): Specific elderly-devoted risk tests(SEDRT) (CARG+CRASH) as new tools to prevent serious/irreversible adverse reactions (AR) in frail patients.
Authors: Ignazio Ugo Carreca, Viviana Bazan, Antonio Galvano, Anna Paola Carreca, Stefania Cusenza, Antonio Russo
Journal: Journal of Clinical Oncology (2021)

e12510 Background: Due to current lengthening of average lifespan and progressive increase of malignant tumors in mankind, more new strategies must be constantly sought especially for thirdage neoplasms. Nevertheless because severe toxicity developed in the majority of frail patients, administration of therapy may cause high risk of life-threatening AIM: We have considered in this paper ABC in frail patients like OW. Purpose of the study is preliminary detection of the overall toxicity (OTox) through the possible use of specifics tests adopted specially in frail patients such as OW, to ensure greater control in drugs administration with good effectiveness. AIM: We have considered in this paper ABC in frail patients like OW. Methods: Sixty-two patients with advanced breast cancer at presentation ABC-p were enrolled between January 2018 and December 2019. Eligibility criteria: • women aging eighty or older; • acquired written consensus; • confirmed diagnosis of ABC; • one or two measurable lesions (bone or visceral or both); • no brain secondarisms; • Charlson’s Comorbidity Scale 1-3 score points; CGA Evaluation permissive for treatment. CARG-TS (Cancer and Aging Research Group-Test Score) and CRASH-TS (Chemotherapy Risk Assessment Scale for High-Age Patients Test S) are rated for predictive assessment of the risk of severe chemotox in all patients. Further Evaluations tools: Clinical Benefit according to ESMO CB scale v2a; Tox Profile CTCAE v3.0 Criteria; QoL by EORTC QLQ-C20 Results: CARG-TS predicts severe OTox; CRASH-TS predicts hematologic non-hematologic toxicity. Using a combination of CGA-ES+CARG-TS+CRASH-TS, we were able to divide patients into three categories: • LR -Low risk (score0-5); • MR-Medium risk (score 5-10); • HR High risk (score over 10). On this basis HR people was directed to receive endocrine therapy (if ER+PGR+) or RT alone. The MR group experienced a reduced schedule of eribulin (0.90mg/sqm d1,d28 until P-progression or INT-intolerable toxicity). Finally LR group received a schedule with eribulin alone(E 0.96-1.1 mg/sqm IV on d1, d21 dosage depending on creatinine clearance value according to the Kintzel-Dorr’s method and until P or INT-toxicity). Conclusions: With contemporary use of CGA-ES, CARG-TS, CRASH-TS we obtained two diagrams: the first “predicted risk” ; the second “observed risk” for each patient. The first curve was almost perfectly in line (p&lt;0.001) with that of the “observed risk”. This allowed to have extremely personalized treatments, negligible OTox, and very good values for both CB and QoL.
HGG-05. NEURONAL ACTIVITY PROMOTES PEDIATRIC HIGH-GRADE GLIOMA GROWTH THROUGH A NLGN3-CSPG4 SIGNALING AXIS
Authors: Shawn Gillespie, Yoon Kim, Anna Geraghty, Pamelyn Woo, Michelle Monje
Journal: Neuro-Oncology (2021)

Abstract High-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), are a lethal group of cancers whose progression is strongly regulated by neuronal activity {Venkatesh 2015}{Venkatesh 2017}{Venkatesh 2019}. One way in which glioma cells sense neuronal activity is via interaction with the ectodomain of post-synaptic adhesion protein neuroligin-3 (NLGN3), which is cleaved and released into the tumor microenvironment (TME) by the sheddase ADAM10. This interaction drives glioma growth, but the relevant binding partner of shed NLGN3 (sNLGN3) on glioma cells is currently unknown. Here, we report that sNLGN3 binds to chondroitin sulfate proteoglycan 4 (CSPG4), in turn inducing regulated intramembrane proteolysis (RIP) of CSPG4, and initiating a signaling cascade within DIPG cells to promote tumor growth. CSPG4 RIP involves activity-regulated ectodomain shedding by ADAM10 and subsequent gamma secretase-mediated release of the intracellular domain in healthy oligodendroglial precursor cells (OPCs), putative cells of origin for several forms of high-grade glioma {Sakry 2014}{Nayak 2018}. Incubation of high-grade glioma cells or healthy OPCs with recombinant NLGN3 is sufficient to augment ADAM10-mediated ectodomain release of CSPG4 and subsequent gamma secretase-mediated cleavage of the CSPG4 intracellular domain (ICD). Pre-treatment of glioma cells or OPCs with an ADAM10 inhibitor entirely blocks NLGN3-induced CSPG4 shedding. Acute depletion of CSPG4 via CRISPR gene editing renders glioma cells insensitive to the growth-promoting effects of NLGN3 application in vitro. We are now performing experiments to better discern how the CSPG4 ICD regulates signaling consequences downstream of sNLGN3 binding. In addition, we are using surface plasmon resonance to investigate whether the shed ectodomains of NLGN3 and CSPG4 remain in complex or only transiently interact. Altogether, our data form a critical missing link in understanding how glioma cells sense, translate and respond to neuronal activity in the TME and identify a new therapeutic target to disrupt neuron-glioma interactions.
Clinicopathologic characteristics of distinct molecular subtypes of endometrial carcinoma in Chinese population.
Authors: Qing Zhang, Xinyue Ma, Wenyu Cao, Huan Wu, Xiaomeng Dong, Chenggong Sun, Kun Song, Beihua Kong
Journal: Journal of Clinical Oncology (2021)

e17568 Background: Stratifying endometrial carcinoma (EC) based on molecular profiling is of importance. While, spectrum of molecular subtypes of EC in Chinese population needs to be elucidated. Conventional approaches involve methodologies including Sanger sequencing as well as immunohistochemistry which is highly dependent on experience of pathologists. This study is of first time to display clinical and pathological characters of molecular subtypes of EC which were defined by a simplified NGS panel in Chinese population. Methods: Paraffin-embedded tissues of 135 consented EC patients were retrospectively collected from Qilu Hospital, Shandong Province, China. Genomic DNA was extracted and subjected to a simplified panel covering POLE, TP53 as well as 55 MSI loci for massive parallel sequencing. Mutations annotated as Tier I, II were applied for subtyping. MSI was defined as instability in 22 or more microsatellite loci. Subtypes were stratified as POLE, MSI, TP53-wt or TP53-mut group. Correlations of clinicopathological characters as well as prognosis were further conducted. Results: Histology of collected samples were mostly Endometrioid EC (EEC, 93.33%). Most of samples were at stage I (80%). The fractions of POLE (n=10), MSI (n=29), TP53-wt (n=84) and TP53-mut (n=12) group were 7.41%, 21.48%, 62.22%, and 8.89%, respectively. POLE group was associated with earlier stage (Stage I, 90%), EEC (80%) and less lympho-vascular space invasion (LVSI) (10%). TP53-mutant subtype was correlated to later stage (Stage II-IV, 41.67%), higher grade (G2+G3, 83.33%), serous histology (25%) and higher rate of LVSI (25%). The median follow-up was 74 (1.5-122) months. The 8-year overall (OS) and disease-specific survival (DSS) rate were 100% in POLE group, while only 58.3% and 75% in TP53 mutant cases (P&lt;0.001 for OS, P=0.01 for DSS). Conclusions: Molecular subtypes of EC significantly correlated with clinicopathologic characters, especially with patients’ prognosis. This simplified NGS-panel could accurately delineate different EC subgroups.[Table: see text]
Effect of influenza vaccination on immune-related adverse events in patients receiving single-agent immune checkpoint inhibitors for the treatment of cancer.
Authors: Naga Malleswari Vutukuri, Calette Corcoran, Jill Comeau, Elizabeth Stephenson, Kavitha Beedupalli, Runhua Shi
Journal: Journal of Clinical Oncology (2021)

e18763 Background: Recent single-center, retrospective reviews have evaluated the effect of influenza vaccinations on the incidence and severity of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICI). Methods and outcomes in these studies vary. The most common medication investigated was ipilimumab, an Anti-CTLA-4 monoclonal antibody. There is limited data evaluating the incidence of irAEs in those receiving the specific ICIs, program death-1 (PD-1) and program death ligand-1 (PD-L1) inhibitors. Methods: A retrospective chart review was conducted including patients 18 to 89 years old who received single-agent pembrolizumab, nivolumab, atezolizumab, or durvalumab at an academic medical center from August 2015 to August 2019. The primary objective was to evaluate the incidence of irAEs in those who received an influenza vaccine compared to those who did not. Electronic health records, and the Louisiana Immunization Network for Kids (LINKS), which now collects adult information, were utilized for data collection. Chi-square tests were used to evaluate all endpoints. Results: Of the 217 charts screened, 133 were included in this study Fifty-three patients were included in the influenza vaccination group and 80 patients in the group that did not receive influenza vaccinations. The median age in those who received an influenza vaccine and in those who did not were 61 years and 62 years, respectively. The most common cancer diagnoses were lung cancer and melanoma. Ninety-one percent of patients in the vaccination group versus 81% in the group who did not receive an influenza vaccine received either nivolumab or pembrolizumab (PD-1 inhibitors). There was no statistical difference in irAEs in those who received an influenza vaccine versus those who did not (30% versus 45%, p = 0.15). The only significant secondary outcome found was the rate of irAEs in patients receiving a PD-1 inhibitor versus a PD-L1 inhibitor regardless of vaccination (42.2% versus 11.1%, p = 0.03). The majority of irAEs were grade 1 or 2. Conclusions: Based on this study, receiving an influenza vaccine does not have an influence on the risk of irAEs in those receiving ICI, specifically PD-1 and PD-L1 inhibitors. These outcomes may have been affected by adherence issues with yearly influenza vaccinations, inaccurate vaccine records, and receiving vaccines out of state. The statistically significant secondary outcome may have been affected by the disproportionate number of patients who were receiving a PD-1 inhibitor in this study. Larger population studies are needed to validate these findings and identify both the risk and benefit of patients receiving their yearly influenza vaccine while receiving ICI.
Monitoring C-reactive protein facilitates early discontinuation of immune oncology without compromising outcomes in stage IV non-small cell lung cancer.
Authors: Tyler Fugere, Ples Spradley, Ahmad Mazen Safar
Journal: Journal of Clinical Oncology (2021)

e21107 Background: C-Reactive Protein (CRP) is a non-specific inflammatory marker and reflects tissue destruction seen in metastatic cancer (ca). We have observed a tight correlation with CRP trends mirroring ca activity, hence it may prove to be a valuable marker to monitor response to Immuno-Oncology (IO) in non-small cell lung cancer (NSCLC) patients (pts). Once CRP levels stabilized, IO discontinuation was offered, and consenting pts were closely observed. This strategy resulted in shortened IO duration and impressive treatment-free progression-free survival (tf-PFS). We sought to examine the validity of this strategy using the rate of return to any form of ca therapy within 6 months after stopping IO. Methods: We analyzed all pts of a single provider since 2016 with stage IV NSCLC who had CRP checked while on IO, totaling 23 pts. We excluded pts who stopped IO for reasons besides stable CRP values (5 progressed on IO, 3 died while on IO, 1 had side effects, 1 stopped for a clinical trial, 1 opted to complete 2 years of IO, and 2 are still on IO). Of the remaining 10 patient cohort, all pts were males treated at the VA with ages between 56-75 years at diagnosis. 50% of the cohort had adenocarcinoma and 50% had squamous cell carcinoma. Results: Using the CRP trend to shorten the duration of IO resulted in durable drug-free holidays with none of the cohort returning to any form of ca therapy within 6 months and comparable rates of overall survival (OS) despite shorter IO duration. In KEYNOTE-042, the median OS for pts on the pembrolizumab arm was 16.7 months in the overall population and 20 months in the TPS ≥50% subgroup. Pts were treated for up to 35 months. In our cohort, median OS was 38 months, with all pts currently still alive, and median number of doses of IO was 9 cycles, or approximately 7 months. Our pts had ongoing progression free survival (PFS) after stopping treatment, which we report as tf-PFS. The median tf-PFS of our cohort was 23.5 months. Conclusions: In pts with stage IV NSCLC treated with IO, CRP appears promising as a marker to tailor IO therapy addressing tumor and clinical heterogeneity. Responding pts with stable CRP levels can be safely taken off IO. CRP should be monitored with stable values indicating continued PFS. tf-PFS rather than PFS may serve as a surrogate for cure and carries significant impact for pts financially, socially, and psychologically. [Table: see text]
Total triage is the future for general practice
Authors: Vasumathy Sivarajasingam
Journal: BMJ (2021)

Before the pandemic, general practitioners struggled with “patient access” and managing workload. Since remote consultations (video, email, telephone) have been introduced, we can prioritise and manage our workload efficiently, with added flexibility and improved staff morale, without compromising the care and support of our patients.

Rather than increasing face-to-face appointments, as the NHS has suggested,1 our focus should …
Assessing the risk of severe post-treatment (tx) cancer-related fatigue (CRF) among breast cancer survivors (BCS) in the CANcer TOxicity (CANTO) cohort.
Authors: Antonio Di Meglio, Julie Havas, Elise Martin, Barbara Pistilli, Gwenn Menvielle, Agnes Dumas, Cecile Charles, Sibille Everhard, Anne-Laure Martin, Charles Coutant, Carole Tarpin, Laurence Vanlemmens, Christelle Levy, Olivier Rigal, Suzette Delaloge, Patricia A. Ganz, Ann H. Partridge, Fabrice Andre, Stefan Michiels, Ines Maria Vaz Duarte Luis
Journal: Journal of Clinical Oncology (2021)

12022 Background: CRF is among the most common and troublesome symptoms experienced by BCS. While preventing severe post-tx CRF is a major survivorship need, limited tools exist to predict this risk. We aimed to describe the long-term prevalence rates and to identify BCS that are more likely to develop severe CRF. Methods: CANTO is a multicenter, prospective clinical study of stage I-III BCS (NCT01993498). Longitudinal data were collected at diagnosis (dx), 0.5 (T1), 1 (T2) and 3 (T3) years post-tx. The primary outcome of interest was severe post-tx global CRF (score ≥ 40/100, EORTC QLQ-C30). Secondary outcomes were physical, emotional and cognitive dimensions of CRF (QLQ-FA12). Multivariable logistic regression models retained associations with severe CRF by bootstrapped Augmented Backwards Elimination, validated using 10-fold internal cross-validation and overoptimism-corrected AUC. Results: Among 6619 BCS, mean age at dx was 56.5 years (SD 11.5), mean BMI was 25.9 Kg/m 2 (SD 5.4), 53.3% and 80.8% received chemotherapy (CT) and hormonotherapy (HT), respectively. Prevalence rates of severe global CRF were 25.0% (dx), 35.6% (T1), 34.0% (T2) and 31.6% (T3). Severe post-tx global CRF was consistently associated with higher BMI, worse insomnia and pain, and severe pre-tx CRF. Receipt of CT increased odds of severe CRF at T1, whereas associations of HT with CRF emerged at T2 and T3 (Table). The estimated risk of severe CRF at T3 was 14% for a BCS with BMI 23.0 Kg/m 2 and no concomitant symptoms at dx, whereas it was 82% for a BCS with BMI 32.0 Kg/m 2 , severe insomnia, pain and pre-tx CRF, receiving HT. Anxiety and depression at dx were consistently retained in models of severe post-tx emotional and cognitive CRF (all p &lt;.05). Conclusions: Over 1/3 BCS endured persistent, severe global CRF, particularly those that were medically more fragile and reported heavier pre-tx symptom burden. A transient impact of CT on CRF was evident on the short aftermath of tx, whereas exposure to HT seemed to affect CRF on the longer run. Consistent factors flag BCS whose risk of severe CRF is high and who should be upfront targeted and aggressively helped. Dimension-specific risk factors can guide prevention of distinct CRF symptoms. Clinical trial information: NCT01993498. [Table: see text]
Estimates of stage-specific preclinical sojourn time across 21 cancer types.
Authors: Michael S. Broder, Sikander Ailawadhi, Himisha Beltran, L. Johnetta Blakely, George Thomas Budd, Laurie Carr, Michael Cecchini, Patrick Wayne Cobb, Sarah N. Gibbs, Anuraag Kansal, Ashley Kim, Bradley J. Monk, Lee S. Schwartzberg, Deborah J.L. Wong, Irina Yermilov
Journal: Journal of Clinical Oncology (2021)

e18584 Background: Cancer progression rates following diagnosis are readily measured. However, the progression rate of cancer during the preclinical sojourn time is generally unobserved. Understanding the duration of preclinical stages (“dwell time”) would allow clinicians to better identify appropriate screening intervals for cancer. We therefore elicited estimates of progression rate during the preclinical sojourn time for a wide variety of malignancies from a panel of clinical experts. Methods: We used a validated consensus methodology (RAND/UCLA modified Delphi panel method) to elicit per-stage dwell time estimates for 20 solid cancers and lymphoma from experts. Eleven experienced oncologists (general and subspecialists) from community and academic centers reviewed literature on the natural history of disease and estimated in number of years (&lt;1 to 9+ years) how long it would take each cancer to progress from the beginning of clinically detectable Stage I/II/III to the beginning of the next stage in untreated adults. Cancer histological subtypes were grouped and experts were asked to provide an overall rating. Ratings were completed before and after a discussion of areas of disagreement. Results: Expert estimates and range of dwell time for 21 cancer types are provided in Table. Prostate and thyroid cancer were estimated to be the slowest growing, taking approximately 7 and 5 years respectively to progress through Stage I (range 4-8), 5 years to progress through Stage II (range 3-7), and 3 and 4 (range 2-5) years respectively to progress through Stage III. Esophageal, lung, liver/intrahepatic bile-duct, gallbladder, and pancreatic cancers were estimated to progress quickly through all three stages (1-2 years per stage). Conclusions: These findings summarize practicing oncologists’ estimates of dwell time in preclinical disease. Experts agreed on dwell times although ranges were large and differences in cancer subtypes were not captured. Generally, estimates trend with published data on survival with treatment: cancers with higher survival (e.g., prostate, thyroid) were estimated to grow slower, while cancers with lower survival (e.g., pancreatic, liver/intrahepatic bile-duct, gallbladder) were estimated to grow faster. These estimates could be useful when determining screening intervals for these or any subset of these cancers. [Table: see text]