tbuckley/cabot-search huggingface dataset:
Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma
Authors: Kevin T Lynch, Samuel J Young, Max O Meneveau, Nolan A Wages, Victor H Engelhard, Craig L Slingluff Jr, Ileana S Mauldin
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Tertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival. Methods Cutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID + ) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models. Results TLS were identified in 30 (47%) of 64 CMM (TLS + ) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS + lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21 + B-cells (HR 0.29, p=0.02) and shorter for those with low AID + fraction of B-cells (HR 2.74, p=0.03). Conclusions The presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.
HGG-13. BRAIN DISTRIBUTION AND CLEARANCE OF ALISERTIB IS LIMITED BY PGP AND BCRP EFFLUX PUMPS AND DEPENDENT UPON DELIVERY METHOD
Authors: Erica Power, Juhee Oh, Liang Zhang, William Elmquist, David Daniels
Journal: Neuro-Oncology (2021)

Abstract Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, uniformly fatal brain tumors that primarily occur in children. The blood-brain barrier (BBB), including drug efflux pumps, prevent numerous drugs from reaching CNS tumors at cytotoxic concentrations. Alisertib is an aurora kinase inhibitor that was previously identified in a drug screen as a compound of interest. However, its ability to penetrate the BBB is not well established. The goals of this study were two-fold: 1) determine the CNS distribution and clearance rates of alisertib following systemic delivery and if the BBB efflux pumps, Pgp and BCRP, alter distribution and clearance. 2) Compare alisertib distribution and clearance following convection-enhanced delivery to systemic results. WT and Pgp/BCRP knockout mice and Sprague-dawley rats underwent tail vein injection (mice and rats) or convection-enhanced delivery to the brainstem (rats only) of alisertib and sacrificed at 0, 2, 4, 8, 12, 16 and 24hours. The plasma and brain were collected and analyzed for alisertib concentration by HPLC-MS/MS. We found that in both mice and rats, alisertib concentration in the plasma and brain decreased biexponentially. Overall, Alisertib was found to be 3.14% brain penetrant. In Pgp/BCRP knockout mice, alisertib concentration in the plasma and brain decreased biexponentially, but was detected at higher concentration at all time points in the brain compared to WT mice. This resulted in a higher brain penetrance (17.26%). Differences based on anatomical brain region were significant in those rats which received convection-enhanced delivery. Alisertib was found in higher concentration in the pons and cerebellum compared to systemic delivery, but lower concentrations in the cortex and plasma. These results suggest that drug clearance may be a general mechanism limiting efficacy of drugs of interest and should be carefully considered during preclinical evaluation.
Pitfalls and opportunities in quantitative fluorescence-based nanomedicine studies – A commentary
Authors: Jens B. Simonsen, Emil B. Kromann
Journal: Journal of Controlled Release (2021)

Fluorescence-based techniques are prevalent in studies of nanomedicine-targeting to cells and tissues. However, fluorescence-based studies are rarely quantitative, thus prohibiting direct comparisons of nanomedicine-performance across studies. With this Commentary, we aim to provoke critical thinking about experimental design by treating some often-overlooked pitfalls in 'quantitative' fluorescence-based experimentation. Focusing on fluorescence-labeled nanoparticles, we cover mechanisms like solvent-interactions and fluorophore-dissociation, which disqualify the assumption that 'a higher fluorescence readout' translates directly to 'a better targeting efficacy'. With departure in recent literature, we propose guidelines for circumventing these pitfalls in studies of tissue-accumulation and cell-uptake, thus covering fluorescence-based techniques like bulk solution fluorescence measurements, fluorescence microscopy, flow cytometry, and infrared fluorescence imaging. With this, we hope to lay a foundation for more 'quantitative thinking' during experimental design, enabling (for example) the estimation and reporting of actual numbers of fluorescent nanoparticles accumulated in cells and organs.
External validation of a Dutch predictive nomogram for complete response to T-VEC in an independent American patient cohort.
Authors: Emma H.A. Stahlie, Michael Carr, Jonathan S. Zager, Alexander Christopher Jonathan Van Akkooi
Journal: Journal of Clinical Oncology (2021)

9563 Background: Talimogene Laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous, and nodal melanoma lesions in stage IIIB-IVM1a patients. Recently, Stahlie et al. published (Cancer Immunol Immunother '21) a model for predicting a complete response (CR) to T-VEC based on 3 easily accessible tumor characteristics identified using univariable and multivariable logistic regression analysis. The aim of this study was to externally validate this model in an independent, American patient cohort. Methods: A total of 76 patients with stage IIIB-IVM1a melanoma treated with T-VEC at Moffitt Cancer Center were included. A second nomogram was built incorporating the same predictive factors: tumor size (diameter of largest metastasis in mm), type of metastases (cutaneous, subcutaneous and nodal) and number of metastases (cut-off: &lt;20 and &gt;20). Predictive accuracy was assessed through calculation of overall performance, discriminative ability, and calibration. Outcomes and previously published outcomes were compared. Statistical analyses were done using R software. Results: Overall performance of the validation dataset nomogram was calculated with the Brier score and found to be 0.195, demonstrating good overall performance and similar to the original model Brier score of 0.182. Discriminative power, assessed by calculating the area under the receiver operating characteristic (ROC) curve was similar for both models, 0.767 and 0.755 for the NKI and Moffitt, respectively, resulting in a fair discriminative ability. The calibration curve showed mostly slight underestimation for predicated probabilities &gt;0.37 and slight overestimation &lt;0.37. Conclusions: An independent dataset externally validated a recently published predictive nomogram for CR to T-VEC in stage IIIB-IVM1a melanoma, with both models resulting in overall performances that were comparable and good. The second model reinforces the conclusion that for the best response to T-VEC, it should be used early on in the course of the disease, when the patient’s tumor burden is cutaneous with smaller diameter and fewer of metastases.[Table: see text]
Disparities in breast cancer by race and ethnicity.
Authors: Surbhi Warrior, Ruta D. Rao
Journal: Journal of Clinical Oncology (2021)

e18526 Background: Breast cancer is the most common female malignancy. While there have been significant advances in diagnosis and treatment of breast cancer, there are gaps in care leading to high mortality rates in low socio-economic populations and ethnic minorities. This inequality is attributed to poor access to care and later stages at diagnosis. Methods: All female breast cancer patients between 2000-2020 (N=8,444) were included. Statistical analysis was done with X 2 testing for categorical variables and T-tests for continuous variables. A univariate logistic regression was used to understand impact of each characteristic. Results: Black women were more likely to have poor prognostic factors for breast cancer compared to white women: distant metastatic disease at diagnosis (4.6% vs 3.2%, p=0.02), triple negative disease (25% vs 13.6%, p&lt;0.01), high oncotype dx score &gt;25 (37.2% vs 26.1%, p=0.04), recurrence (14.9% vs 12.1%, p=0.04), and mortality rate (24.2% vs 15.6%, p&lt;0.01). Despite these high-risk factors, white women were more likely to have a mastectomy than black women (43.8% vs 35.4%, p&lt;0.01), and the average age at diagnosis was higher in black women at 59.2±13.5 years compared to white women at 57.5±12.8 years (p&lt;0.01). The most prominent poor prognostic factor in black women was having triple negative breast cancer with OR 2.13 (95% CI 1.7- 2.6) compared to others in Table. Hispanic women were more likely to have higher stage at diagnosis (OR 1.21), lymph node involvement (OR 1.03), metastatic disease (OR 1.43), and tumor size &gt;1cm (OR 1.06) than nonHispanic women, but only lymph node involvement at diagnosis was statistically significant (29.1% vs 24.5%, p=0.02). Conclusions: There is a high prevalence of racial and ethnic disparities in women with breast cancer. Black women are more likely to have poor prognostic factors including metastatic disease at diagnosis and triple negative breast cancer, leading to higher recurrence and mortality rates. Hispanic women are also more likely to have poor prognostic factors, but this data was not statistically significant due to small sample size. Efforts to improve access to health care leading to earlier diagnosis may decrease the gap in mortality rate for minority women with predisposition to high-risk malignancies.[Table: see text]
EPEN-08. THE TREM1 POSITIVE HYPOXIC MYELOID SUBPOPULATION IN POSTERIOR FOSSA EPENDYMOMA
Authors: Nicholas Willard, Andrew Donson, Timothy Ritzmann, Richard Grundy, Andrew Jackson, Todd Hankinson, Andrea Griesinger, Nicholas Foreman
Journal: Neuro-Oncology (2021)

Abstract We have previously shown the importance of immune factors in posterior fossa ependymoma (PF EPN). Recently, we found eight transcriptionally unique subpopulations of myeloid cells infiltrating PF EPN with one population particularly enriched in PFA1 tumors. This subpopulation, denoted as hypoxia myeloid subpopulation, is defined by genes associated with angiogenesis, hypoxia response, wound healing, cell migration, neutrophil activation, and response to oxygen levels. TREM1 (Triggering receptor expressed on myeloid cells 1) was found to be expressed almost exclusively within this hypoxia myeloid subpopulation. TREM1 encodes for a receptor belonging to the immunoglobulin superfamily that is expressed on myeloid cells, and stimulates neutrophil and monocyte inflammatory responses. However, single-cell RNAseq give little data suggesting location of cells within the tumor microenvironment. We performed immunohistochemistry (IHC) on our bank of ~90 FFPE PFA EPN samples using TREM1 to characterize and identify the location of the hypoxia myeloid cells. The TREM1 positive cells have an ambiguous cytomorphology reminiscent of a monocyte with modest cytoplasm and a mono-lobated nucleus. IHC also showed that TREM1+ myeloid cells are largely localized to the interface of necrosis and viable tissue, most frequently in a perivascular and intravascular distribution. The latter finding suggests that the TREM1+ cells are derived from the bone marrow and that they may be associated with the mesenchymal tumor population (MEC), which we have previously described as being enriched in PFA1 tumors and localizing to perinecrotic zones. This is supported by parallel IHC analysis of subpopulation-specific markers in the same cohort of PFA EPN which showed the highest TREM1 correlation was with CAIX, a marker of MEC. In PFA matched primary/recurrent pairs, the proportion of TREM1+ cells were increased at recurrence in the majority of cases, suggesting an evolving interaction between this TREM1+ hypoxia myeloid subpopulation and neoplastic cells over the disease course.
Racial disparities in access to prostate cancer clinical trials: A county-level analysis.
Authors: Aasthaa Bansal, Wei-Jhih Wang, Caroline Savage Bennette, Scott David Ramsey
Journal: Journal of Clinical Oncology (2021)

6553 Background: African American men (AAs) have a higher burden of prostate cancer compared to other populations. We sought to determine if they experience disparities in access to prostate cancer clinical trials. Methods: We created a county-level database of all U.S. counties by linking together prostate cancer clinical trial data from the Aggregate Analysis of ClincalTrials.gov (AACT) database with county-level socioeconomic, demographic and healthcare facility data derived from several external data sources. Using this data linkage, we examined two specific potential access barriers. First, we investigated the relationship between %AAs in the county and access to NCI designated cancer facilities, adjusting for county population size and other characteristics. Then, among counties with cancer facilities, we investigated the relationship between the %AAs in the county and number of available prostate cancer treatment trials per capita per year. We used logistic and negative binomial regression models, respectively, to address these questions. Results: Between 2008 and 2015, 613 prostate cancer trial sites were found among 3,145 U.S. counties. Counties with higher %AAs were less likely to have cancer facilities (adjusted odds ratio = 0.85, 95% CI (0.78, 0.92)). Among counties with cancer facilities, those with higher %AAs had significantly fewer prostate cancer trials per capita per year (rate ratio per 10% increase in %AAs: 0.90, 95% CI (0.83,0.96)), after adjusting for county-level sociodemographic and healthcare system factors. Conclusions: Counties with higher proportions of AAs appear to be less likely to have access to NCI designated cancer facilities. Among counties with cancer facilities, those with higher proportions of AAs appear to have fewer available prostate cancer treatment trials per capita per year. Clinical trials in prostate cancer therapy should ensure adequate availability of enrollment sites in regions with high concentrations of AAs.
Evolution of airway inflammation in preschoolers with asthma-results of a two-year longitudinal study
Authors: P. Xepapadaki, P. Korovessi, Claus Bachert, S. Finotto, T. Jartti, J. Lakoumentas, M. L. Kowalski, A. Lewandowska-Polak, H. Lukkarinen, Nan Zhang, T. Zimmermann, N. G. Papadopoulos
Journal: Allergy (2020)

Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4-6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0-8.6; 6.0, CI: 2.8-12.0; 8.0, CI: 4.0-14.0; 8.5, CI: 4.4-14.5 ppb, respectively) increased with age (correlation p ≤ 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma.
Cancer therapy related dysphonia: Analysis of real-world FAERS data.
Authors: Shuai Wang, Anahat Kaur, Mariuxi Alexandra Viteri Malone, Tarek N. Elrafei, Lewis Steinberg, Abhishek Kumar
Journal: Journal of Clinical Oncology (2021)

e18794 Background: Dysphonia is a rare and under-reported adverse event. It is associated with the use of several cancer drugs. Dysphonia has been included as possible side effect on packet insert (PI) for some medications, like regorafenib, lenvatinib and axitinib. However, dysphonia has not been reported on multiple other drugs. We aimed to conduct a more comprehensive study to generate signal for dysphonia as adverse effect of drugs used for oncologic indications. Methods: The United States Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database, a pharmacovigilance database, was used to extract data. All reported cases of dysphonia in the database were filtered for an indication of cancer. Descriptive analysis was conducted using SPSS 26. Results: Total 41840 cases of dysphonia were extracted from FAERS database. Out of these, cancer as an indication for medication use was noted in 2996 cases. Dysphonia was reported as side effect of 30 medications. Some of the most common medications were regorafenib (n=463), cabozantinib (290), lenvatinib (178), axitinib (176) and palbociclib (126) as noted in Table. Dysphonia was not listed as adverse reaction on PI for cabozantinib, palbociclib, sorafenib and oxaliplatin. However, it has been reported for regorafenib, lenvatinib and axitinib. Median age at diagnosis was 66 years (interquartile range 59-73). Dysphonia was reported more commonly in males (51.5%) as compared to females (46.2%). Reactions were reported to the FDA more commonly by consumers (53.3% cases) as compared to healthcare professionals (44.5% cases). Conclusions: This study demonstrates signal of developing dysphonia in patients receiving certain cancer directed medications based on FAERS database. It is worth noting that some of the suspect medications identified in this study do not have dysphonia listed as known adverse effect on accompanying package insert. Further studies need to be conducted to confirm if causal relationship exists between use of these drugs and development of dysphonia. Detailed description of five drugs used for oncologic indications with highest reported cases of dysphonia as adverse effect.[Table: see text]
Abstract 14220: Neointimal Appearance of Late Clinical Event related Lesions after Bare-Metal Stent and Sirolimus-Eluting Stent Implantation Assessed by Optical Coherence Tomography
Authors: Yasushi Ino, Takashi Kubo, Hironori Kitabata, Yasutsugu Shiono, Kunihiro Shimamura, Makoto Orii, Takashi Tanimoto, Kohei Ishibashi, Tomoyuki Yamaguchi, Takashi Yamano, Shingo Oota, Hiroshi Aoki, Kumiko Hirata, Atsushi Tanaka, Toshio Imanishi, Takashi Akasaka
Journal: Circulation (2012)

Background: Late clinical event such as very late stent thrombosis (VLST) and late in-stent restenosis (ISR) after bare-metal stent (BMS) and drug-eluting stent (DES) is an important clinical issue...
<sup>177</sup>Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with somatostatin-expressing neuroendocrine tumors: A real-world retrospective review of efficacy and safety from an Australian tertiary cancer Center.
Authors: Mark Nalder, Rahul Ladwa, Anant Raina, Matthew E. Burge, Amanda Love, David A. Pattison, Stuart Ramsay, David Wyld
Journal: Journal of Clinical Oncology (2021)

e16198 Background: There is relatively limited data guiding optimal treatment algorithms for inoperable or metastatic neuroendocrine tumours (NETs). The randomised NETTER 1 study established PRRT as a standard of care in midgut NET. The aim of this study was to retrospectively review the efficacy and safety of patients treated with 177 Lu-DOTATATE at Royal Brisbane and Women’s Hospital. Methods: Consecutive patients with unresectable or metastatic NET who received their first 177 Lu-DOTATATE therapy between 2010 and 2017 were identified. Paragangliomas were excluded. Response rates, progression free survival (PFS) and overall survival (OS) were assessed via a combination of chart review, post-therapeutic 68 Ga DOTATATE PET/CT and multi-disciplinary meeting decisions. Gr3/4 haematological and renal safety data was analysed via chart review. Progression free survival (PFS) and overall survival (OS) were assessed via the Kaplan-Meier method. Results: 123 consecutive patients were included in the analysis (57% male, median age 61). Primary site: 41% gastroenteric, 34% pancreatic, 10% lung, 6% colon/rectum, 9% other. Grade 1 (42%), Grade 2 (31%) Grade 3 (6%), unknown (21%). 76% of patients had previously received somatostatin analogues. 80% received four cycles (with persistent myelosuppression the most common cause of ceasing therapy early). 20% of patients received concurrent chemotherapy (10% capecitabine, 10% capecitabine and temozolomide). For the entire cohort, median follow up was 51 months. Median PFS, 34.2 months (95% CI, 30.3 – 38.17) and median OS, 61 months (95% CI, 54.2– 67.8). There was no significant difference in PFS or OS between small bowel and pancreatic patients. Response rates to PRRT included complete response (n = 4, 3%), stable or responding disease (n = 96, 78%), progressive disease (n = 22, 18%), not assessable (1, 1%). Grade 3 or 4 thrombocytopenia, neutropenia or anaemia occurred in less than 1% of patients. Confirmed acute leukaemia occurred in three patients. One patient had grade 3 renal toxicity secondary to treatment. 26 patients received retreatment with 177 Lu-DOTATATE at progression with median time to re-treatment of 35 months. Conclusions: This single centre, retrospective audit confirms the efficacy of 177 Lu-DOTATATE in the treatment of unresectable and metastatic NETs. Treatment was associated with low rates of severe haematological or renal adverse events. Our results are comparable to similar published reviews.