tbuckley/cabot-search huggingface dataset:
Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors.
Authors: Joanne Shaw, Brandon Ballard, Xiaohui Yi, Aditya Malankar, Matthew R. Collinson-Pautz, Carlos Roberto Becerra, Joseph Paul Woodard, Aaron E. Foster
Journal: Journal of Clinical Oncology (2020)

734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA + metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x10 6 /kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA + metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x10 6 /kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy &gt; 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA + metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.
Hepatic adverse events during treatment with immune checkpoint inhibitors (ICI) in cancer patients: A territory-wide patient cohort study.
Authors: Stephen Lam Chan, Terry Cheuk-Fung Yip, Vincent Wai-Sun Wong, Anthony W.H. Chan, Cathy Ka Kiu Tong, Yee Kit Tse, Becky Wing-Yan Yuen, Hester Wing-Sum Luk, Grace Chung-Yan Lui, Henry L.Y. Chan, Tony S. K. Mok, Grace Lai-Hung Wong
Journal: Journal of Clinical Oncology (2020)

508 Background: Hepatic adverse events (AEs) are commonly encountered during ICI treatment in cancer. We evaluated the incidence and impact of hepatic AEs in a territory-wide cohort of 1509 patients who received ICI for cancer treatment. Methods: This is a territory-wide retrospective observational cohort study in Hong Kong. We identified patients through the regional hospital database (CDARS), based on the drug record of ICIs from 1 Jan 2014 to 31 Oct 2018. Serial liver functions before, during and at 3-month after ICI, were retrieved. Hepatic AEs were graded according to CTCAE 4.0. Results: The mean age was 60 years and 65.4% were male with the commonest malignancies being lung cancer (37.0%), liver cancer (17.0%) and gastrointestinal (GI) cancer (8.4%). Grade 1-2 and grade 3-4 hepatic AE occurred 39.8% and 23.3% of patients, respectively, during or within 3 months after ICI. During ICI, 39.5% developed grade 1-2 and 13.0% had grade 3-4 hepatic AE. The most common manifestations of hepatic AE occurred as elevation of ALT/AST (grade 1-2: 38.7%; grade 3-4: 10.3%). The median time of duration from ICI 1 st dose to hepatic ≥ Grade 3 AE was 54 days (IQR: 22-124). Patients with liver cancer were more likely to develop hepatic AE (grade 1-2: 37.4%; grade 3-4: 55.5%). In all patients and cancer subgroup, patients with grade 3-4 hepatic AE had worse OS than grade 1-2 hepatic AE (Table). Conclusions: Hepatic AE occurs in more than half of the patients receiving ICI, with over 20% being grade 3-4 AE. Regardless of tumor types, development of hepatic AE during ICI is associated with poor prognosis. [Table: see text]
Genomic alterations in colitis-associated cancers in comparison to those found in sporadic colorectal cancer and present in precancerous dysplasia.
Authors: Walid Khaled Chatila, Henry S. Walch, Jamal Benhamida, Jaclyn Frances Hechtman, Francisco M. Barriga, Ritika Kundra, Dorina Ismalgeci, Vincent A. Miller, Karuna Ganesh, David Faleck, Nikolaus Schultz, Laura H. Tang, David Paul Kelsen, Rona Yaeger
Journal: Journal of Clinical Oncology (2020)

191 Background: Patients with inflammatory bowel disease (IBD) [Crohn’s disease (CD) and ulcerative colitis (UC)] are at increased risk for small bowel or colorectal cancers (Colitis Associated Cancers, CAC). Currently CAC is treated the same as sporadic colorectal cancer (CRC) with significantly shorter overall survival for advanced CAC compared to matched patients with CRC. In a pilot series, we found that tumors developing in IBD have distinct genomic alterations (GA) with potential implications for early detection and treatment. We now extend this analysis and characterize the relationship of GA in synchronous dysplasia and cancer. Methods: 104 CAC (54 UC-associated and 50 CD-associated) were sequenced with targeted-exome sequencing of &gt; 300 cancer-related genes. GA in CAC were compared to those reported for sporadic CRC. Whole exome sequencing was performed on paired mucosa, dysplasia and carcinoma samples obtained from 15 colectomy specimens; in these cases, expert pathology review confirmed normal appearing mucosa intervening between areas of dysplasia and CAC. Results: TP53 mutations (89%), MYC amplifications (24%), and cell cycle copy number alterations (20%) were significantly enriched in CAC compared to sporadic CRC, while APC alterations (21%) were significantly less common in CAC compared to sporadic CRC. Distinct GA in CAC consisted of IDH1 R132 mutations (7%) and FGFR pathway alterations (7%). While IDH1 R132 mutations and PI3K pathway alterations were more common in CD-associated CAC, MAPK ( BRAF/ MEK1) alterations were more common in UC-associated CAC. GA in CACs did not significantly vary by duration of preceding IBD. GA were often shared in dysplasia and carcinoma, despite normal-appearing intervening mucosa. GA involving TP53, APC, KRAS, and IDH1 mutations were identified in dysplasia and shared between CAC and dysplasia. Conclusions: CAC exhibit distinct GA compared to sporadic CRC with near universal TP53 mutation, increased copy number alterations involving transcription factors and cell cycle genes, and unique drivers. A field effect can be seen for GA between distant dysplasia and carcinoma, but many GA remain private to CAC.
Radiotherapy use in the treatment of gastrointestinal cancers in Medicare patients: An analysis of a CMS database.
Authors: Andre A. Konski, Laura Jean Havrilesky, Elizabeth Lin Jewell, Jason A. Efstathiou
Journal: Journal of Clinical Oncology (2020)

800 Background: CMS announced plans to pilot an alternative payment model (APM) utilizing a fixed payment per ICD-10 code for 17 malignancies. CMS released payment data used to calculate the base payments. The purpose of this study was to analyze radiotherapy use in patients with gastrointestinal malignancies to obtain baseline utilization and payment prior to the APM start. Methods: The CMS database, CY2015-2017, contained payment, anatomic site and limited patient data on 517,988 patients, 48,032 of which were identified as gastrointestinal (GI) cancers, (Anal (A) Colorectal (CR), Pancreatic (P), Upper GI (UGI), or Liver(L) cancers) all histologies included. Stata 15, College Station, Texas, was used to perform all statistical analysis. Payments were calculated using only CPT codes for radiotherapy and only include the first 90 days after a treatment planning charge was registered. Results: Anatomic site breakdown was 4940 A, 16,099 CR, 6,970 P, 14,750 UGI and 5,273 L cancers. Patient treatments by year were15,697 in 2015, 16,309 in 2016 and 16,026 in 2017. Use of proton therapy and IMRT increased from 2015-2017 (193 (1.2%) to 302 (1.9%) and 8,107(52%) to 8838 (55%), respectively) whereas use of conventional external beam decreased from 6544 (42%) in 2015 to 5377(34%) in 2017. Of interest, 10,336 (668 A, 3363 CR, 2847 L, 1083 P, and 2375 UGI) of the 48,032 patients receiving radiotherapy were coded as not receiving chemotherapy. Mean professional and technical payments were $28,380.97 (SD $6779.18) for proton beam therapy, $18,186.77 (SD $4534.3) for IMRT, $10,724.88 ($4797.19) for conventional external beam therapy, $13,967.66 (SD $5186.92) for stereotactic, and $19,707 (SD$7393.81) for brachytherapy. Results by anatomic site will be presented. Conclusions: This study provides a baseline for comparison for treatment technique and payment once the APM has been completed. These claims are limited by the lack of available information on specific age, stage or other co-morbidities. Use of proton beam therapy has increased in this population, but remains a small percentage of radiotherapy technique used. 25% of patients receiving radiotherapy were not coded as receiving chemotherapy.
Healthy lifestyle and life expectancy: fund prevention programmes to end the cycle of preventable morbidity
Authors: Gabriel L Van Duinen
Journal: BMJ (2020)

I thank Li and colleagues for their paper which adds to the significant body of evidence showing that adopting simple lifestyle modifications can improve life expectancy free of chronic disease.1

Health policy in Western countries does not give enough emphasis or funding to preventive care. In the UK, in the past five years, £900m (€1bn; $1.2bn) has been cut …
Stress erythropoiesis in hereditary spherocytosis
Authors: Anne Haughton, Steven Stylian, Barbara J. Bain
Journal: American Journal of Hematology (2020)

A 73-year-old male with history of hereditary spherocytosis presented for assessment and management of severe chronic pain in his right lower limb. Past medical history also included type 2 diabetes mellitus and cholecystectomy (for gallstones). Magnetic resonance imaging of the thoracolumbar spine and right hip was performed, which showed a right posterior disc protrusion at L4/5. The patient was also investigated for the presence of a possible malignancy. A bone scan did not show any evidence of a metastatic process. His blood count showed anemia with hemoglobin concentration 97 g/L, mean cell volume 100 fL, white cell count 10 × 109/L, platelet count 184 × 109/L, and reticulocyte count 203 × 109/L. His blood film showed spherocytes, minor polychromasia, and rare nucleated red blood cells. There were no dysplastic features. Bilirubin ranged from 33 to 78 μmol/L and lactate dehydrogenase from normal to 226 U/L. Eosin-5-maleimide (EMA) binding was reduced. Bone marrow examination was requested and performed to “exclude malignancy.” The bone marrow aspirate showed markedly increased cellularity for his age as a result of striking erythroid hyperplasia (80% of cells in the myelogram). There was significant dyserythropoiesis including numerous bi-, tri-, and multi-nucleated cells, erythroblasts with multilobated nuclei, and increased karryorhexis and formation of Howell-Jolly bodies (top and bottom left). Granulopoiesis and megakaryocytes were normal. Iron stores were moderately increased. Trephine biopsy sections confirmed the increase in cellularity with markedly increased erythroid elements and dyserythropoiesis (bottom right). There was no evidence of malignancy. Cytogenetic analysis showed a normal male karyotype. Striking dyserythropoiesis can be a feature of “stress erythropoiesis” in patients with hemolytic anemia. Similar observations to those reported here have been made in hereditary stomatocytosis,1 drug-induced hemolysis,2 sickle cell anemia,3 and in the presence of an unstable hemoglobin.4 Correct interpretation is important to avoid misdiagnosis as a myelodysplastic syndrome or as congenital dyserythropoetic anemia (including type II, in which EMA binding is reduced). Both hereditary spherocytosis and other congenital hemolytic anemias have been misdiagnosed as congenital dyserythropoietic anemia.5 Nothing to report.
Socioeconomic disparities and outcomes in midgut neuroendocrine tumors.
Authors: Nicholas Manguso, Jessica Crystal, Brian Cox, Shirley C Paski, Andrew Eugene Hendifar, Jun Gong, Alexandra Gangi
Journal: Journal of Clinical Oncology (2020)

613 Background: Demographic and socioeconomic disparities have been shown to effect cancer specific outcomes in numerous malignancies but the effect in midgut neuroendocrine tumors (mNETs) is unknown. We sought to investigate whether these factors are associated with survival in mNETs. Methods: The NCDB was queried to identify patients with mNETs between 2004 and 2015. Only patients treated at a single hospital with complete data were included. Overall Survival (OS) was compared based on demographic data, socioeconomic factors, insurance status and place of living. Results: A total of 14,083 patients were identified with a mean age of 72 years (range 18-90). The majority of patients were Caucasian (83.9%) and male (50.9%). Most patients had private insurance (50.5%) or medicare (41.3%). Patients typically lived in larger metropolitan areas (51.5%) and 60.7% lived in zip codes with median household incomes &gt; $48,000. Only 14.7% lived in zip codes where &gt; 20% did not graduate high school (no HSD). The majority were treated at community comprehensive cancer centers (43.8%) or academic/research centers (35.2%). Overall, 3358 (24.5%) presented with metastasis at diagnosis. The 5-year OS for the entire cohort was 78.5%. The 5-year survival was worse in patients with lower median income (73.8% [ &lt; $38,000] vs 81.5% [ &gt; $63,000],p &lt; 0.0001), lower education (74.9% [ &gt; 20% no HSD] vs 80.7% [ &lt; 7% no HSD], p &lt; 0.0001), those not living in proximity to a metro area (73.8% [not metro adjacent] vs 78.7% [metro/adjacent], p = 0.0004) and those treated at a community cancer center (73.6% [community] vs. 80.1% [academic], p &lt; 0.0001). Factors predictive of worse OS were lower income ( &lt; $38,000) (HR 1.16, 95% CI 1.04-1.28), lower education ( &gt; 20% no HSD) (HR 1.14, 95% CI 1.02-1.26), no insurance (HR 1.66, 95% CI 1.33-2.06) and not living in proximity to a metro area (HR 1.27, 95% CI 1.10-1.47). Conclusions: Socioeconomic factors shown to have worse OS in patients with mNETs were lower median income, lower education, treatment at a community cancer center and not living in proximity to a metro area. Patient demographic and socioeconomic factors play an important role in OS for patients with mNETs and access to care must be considered in this subpopulation of cancer patients.
Short term fixes have made parts of NHS financially unstable, auditors warn
Authors: Abi Rimmer
Journal: BMJ (2020)

NHS trusts are increasingly relying on short term measures, including one-off savings, to meet yearly financial targets, the National Audit Office (NAO) has warned.

In two reports published on 5 February, the public spending watchdog looked at the NHS’s financial and operational performance1 and how the NHS capital budget, which goes towards replacing and maintaining equipment and buildings, was being used.2

It found that the government had transferred £4.3bn (€5.1bn; $5.6bn) from capital to revenue budgets in the past five years, to cope with daily …
Histopathological subgrouping versus renal risk score for the prediction of end-stage renal disease in ANCA-associated vasculitis
Authors: Onay Gercik, Emre Bilgin, Dilek Solmaz, Fulya Cakalagaoglu, Arzu Saglam, Ozge Aybi, Riza Can Kardas, Zeki Soypacaci, Gokhan Kabadayi, Tolga Yildirim, Idil Kurut Aysin, Omer Karadag, Servet Akar
Journal: Annals of the Rheumatic Diseases (2020)

In patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and renal involvement, the development of end-stage renal disease (ESRD) remains an undesired issue. To date, reported predictors of renal outcome are mainly patients’ age, severe renal dysfunction and histopathological findings at presentation.1 2 Histopathological classification as defined by Berden et al was proposed to be helpful with the highest renal survival rates in the focal group and the poorest in the sclerotic group.3 4 Recently, Brix et al suggested the antineutrophil cytoplasmic antibody renal risk score (ARRS) to predict ESRD in patients with AAV.5 Unlike Berden's classification, ARRS combines histopathological findings (the percentage of normal glomeruli, tubular atrophy and interstitial fibrosis) with baseline glomerular filtration rate (GFR). Here, we aimed to assess the prognostic factors for renal survival and to evaluate the performances of Berden’s histopathological classification and ARRS for predicting ESRD.

We reviewed the medical records of all patients diagnosed …
Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination
Authors: Gerson Rothschild, Wanwei Zhang, Junghyun Lim, Pankaj Kumar Giri, Brice Laffleur, Yiyun Chen, Mingyan Fang, Yuling Chen, Lekha Nair, Zhi-Ping Liu, Haiteng Deng, Lennart Hammarström, Jiguang Wang, Uttiya Basu
Journal: Science Immunology (2020)

B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell-specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3' regulatory region (3'RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome-deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer's patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA ) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3'RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer's patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.
Trained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?
Authors: Siroon Bekkering, Christoph Saner, Niels P. Riksen, Mihai G. Netea, Matthew A. Sabin, Richard Saffery, Rinke Stienstra, David P. Burgner
Journal: Trends in Endocrinology and Metabolism (2020)
Propranolol: What is BLOCKing Its Clinical Investigation in Breast Cancer?
Authors: Anne H. Blaes, Evidio Domingo-Musibay, Kevin Kalinsky
Journal: Clinical Cancer Research (2020)

Presurgical propranolol modulates biomarkers associated with breast cancer progression. β-adrenergic signaling promotes invasion, epithelial-to-mesenchymal transition phenotype, and immune cell infiltration into the tumor microenvironment. Blockade of the β-adrenergic receptor signaling with propranolol, along with potential future combinatorial strategies, holds promise for reducing breast cancer progression and metastasis.See related article by Hiller et al., p. 1803.
Demoralization and depression in pancreatic cancer patients.
Authors: Jar-Yee Liu, Veronica Placencio-Hickok, Brian Anderson, Paul Eliezer Oberstein, Andrew L. Coveler, Crystal S. Denlinger, Jun Gong, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2020)

TPS778 Background: Demoralization is a maladaptive coping response to stressful situations characterized by thoughts of hopelessness, helplessness, and loss of meaning and purpose. Psychometrically, it is measured using the Demoralization-Scale II (DS-II), a validated questionnaire that yields a patient-reported quantification (scale 0-32) of demoralization. Previous studies involving patients with progressive disease have uncovered a strong positive correlation between demoralization and depression, respectively measured by the DS-II and Patient Health Questionnaire-9 (PHQ-9) surveys. Here, we aim to characterize demoralization and its relationship to depression in pancreatic cancer patients, a unique patient population in terms of its poor prognosis. We hypothesize that demoralization is highly prevalent in the pancreatic cancer patient population and strongly correlated with depression. Methods: Eligible patients with an active pancreatic cancer diagnosis, after consenting to an IRB approved protocol, will be administered the DS-II and PHQ-9 surveys to yield psychometric measurements for analysis. The primary objective of this project is to determine the association between demoralization (DS-II) and depression (PHQ-9) in pancreatic cancer patients. Secondary objectives include associations between demoralization and ethnicity, sexual orientation, suicidal ideation, education, cancer stage, and disease progression. Data will be analyzed via simple linear regression. An ANOVA will also be conducted using DS-II groups as the categorical variable and PHQ-9 scores as the continuous variable, and vice versa. This is a multi-institutional study to be conducted at Cedars-Sinai Medical Center, New York University, University of Washington, UC San Francisco, and Lewis Katz Schools of Medicine.