tbuckley/cabot-search huggingface dataset:
Hospice length of service in patients with advanced gastrointestinal cancers treated at an NCI-designated cancer center.
Authors: Arjun Gupta, Ramy Sedhom, Emily Middleton, Rhonda Cooper, Louise Knight, Dan Laheru, Thomas J. Smith
Journal: Journal of Clinical Oncology (2020)

812 Background: Hospice Length of service (LOS) is a Quality Oncology Practice Initiative (QOPI) measure, and an established metric of end-of-life (EOL) care. Short hospice LOS is associated with lower-quality EOL care, poor symptom control, and patient and caregiver dissatisfaction. Oncologist- and/ or system-specific factors may contribute to shorter hospice LOS. Methods: We conducted a retrospective chart review of patients with advanced gastrointestinal (GI) cancers referred to hospice from a comprehensive cancer center in 2018, and compared data to 2015. We analyzed LOS under hospice care, looking specifically at median LOS and percent of short enrollments (%LOS ≤ 7 days), and examined the variation between individual oncologists within the GI oncology division. The coefficient of variation (Cv) represents degree of variability between oncologists, and was calculated based on median LOS for each oncologist. Mean and SD of oncologist LOS were calculated. Cv was defined as SD/mean; Cv &gt; 100% is typically considered a high variance distribution. Results: A total of 114 patients with advanced GI cancers were discharged to hospice in 2015, and 115 patients in 2018. The median age of patients was 66 years, 47% women, and 80% white. The number of GI oncologists were 9 in both years and median patients per oncologist were 12 in 2015, and 13 in 2018. The median hospice LOS was 16 days in 2015, which decreased to 9 days in 2018. The %LOS ≤ 7 days increased from 25% in 2015 to 47% in 2018. The Cv% was &lt; 100% in both 2015 (63%) and 2018 (44%). Conclusions: In this retrospective study of hospice LOS among patients with advanced GI cancer at a single cancer center, median hospice LOS declined, and %LOS ≤ 7 days increased from 2015 to 2018. We did not find significant variation in hospice referral patterns between oncologists within the GI oncology division. These data point to system level factors responsible for sub-optimal hospice LOS. We will present our data at division meetings, and use mixed-methods design for investigating and eventually addressing barriers to low hospice LOS.
Local Peroxynitrite Impairs Endothelial Transient Receptor Potential Vanilloid 4 Channels and Elevates Blood Pressure in Obesity
Authors: Matteo Ottolini, Kwangseok Hong, Eric L. Cope, Zdravka Daneva, Leon J. DeLalio, Jennifer D. Sokolowski, Corina Marziano, Nhiem Y. Nguyen, Joachim Altschmied, Judith Haendeler, Scott R. Johnstone, Mohammad Y. Kalani, Min S. Park, Rakesh P. Patel, Wolfgang Liedtke, Brant E. Isakson, Swapnil K. Sonkusare
Journal: Circulation (2020)

Background: Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The recognition that Ca 2+ signaling in endothelial cells promotes vasodilation has led to the hypothesis that endothelial Ca 2+ signaling is compromised during obesity, but the underlying abnormality is unknown. In this regard, transient receptor potential vanilloid 4 (TRPV4) ion channels are a major Ca 2+ influx pathway in endothelial cells, and regulatory protein AKAP150 (A-kinase anchoring protein 150) enhances the activity of TRPV4 channels. Methods: We used endothelium-specific knockout mice and high-fat diet–fed mice to assess the role of endothelial AKAP150-TRPV4 signaling in blood pressure regulation under normal and obese conditions. We further determined the role of peroxynitrite, an oxidant molecule generated from the reaction between nitric oxide and superoxide radicals, in impairing endothelial AKAP150-TRPV4 signaling in obesity and assessed the effectiveness of peroxynitrite inhibition in rescuing endothelial AKAP150-TRPV4 signaling in obesity. The clinical relevance of our findings was evaluated in arteries from nonobese and obese individuals. Results: We show that Ca 2+ influx through TRPV4 channels at myoendothelial projections to smooth muscle cells decreases resting blood pressure in nonobese mice, a response that is diminished in obese mice. Counterintuitively, release of the vasodilator molecule nitric oxide attenuated endothelial TRPV4 channel activity and vasodilation in obese animals. Increased activities of inducible nitric oxide synthase and NADPH oxidase 1 enzymes at myoendothelial projections in obese mice generated higher levels of nitric oxide and superoxide radicals, resulting in increased local peroxynitrite formation and subsequent oxidation of the regulatory protein AKAP150 at cysteine 36, to impair AKAP150-TRPV4 channel signaling at myoendothelial projections. Strategies that lowered peroxynitrite levels prevented cysteine 36 oxidation of AKAP150 and rescued endothelial AKAP150-TRPV4 signaling, vasodilation, and blood pressure in obesity. Peroxynitrite-dependent impairment of endothelial TRPV4 channel activity and vasodilation was also observed in the arteries from obese patients. Conclusions: These data suggest that a spatially restricted impairment of endothelial TRPV4 channels contributes to obesity-induced hypertension and imply that inhibiting peroxynitrite might represent a strategy for normalizing endothelial TRPV4 channel activity, vasodilation, and blood pressure in obesity.
A computed tomography-based nomogram for preoperative prediction of synchronous peritoneal carcinomatosis in colorectal cancer.
Authors: Zixu Yuan, Wuteng Cao, Hui Wang, Jian Cai, Lei Wu, Xiusen Qin
Journal: Journal of Clinical Oncology (2020)

14 Background: Peritoneal carcinomatosis (PC) of colorectal cancer remain poor and is considered to be the terminal stage. Early detection of PC can bring survival benefit for chances of complete cytoreductive surgery. In this study, we have developed and validated a CT-based nomogram for preoperative prediction of synchronous PC in CRC. Methods: The CT-based nomogram optimized for image classification of PC was developed and validated in a large cohort. The specific features of synchronous PC were extracted from preoperative CT arterial stage scans by radiologists. A CT-based model was constructed by Boruta algorithm and multivariate logistic regression in the training set and validated in the test set. A CT-based nomogram was then built to predict the risk value of PC. The performance and efficacy of this nomogram to discriminate PC were assessed. Results: A total of 170 eligible CRC patients with synchronous PC were randomly divided into a training set (n = 92) and a validation set (n = 78). After processing and partition, five items of PC-related features including tumor location, cT stage, distant metastasis, thickened greater omentum and pelvic nodules were enrolled into this CT-based model. In the training set, the ROC shows AUC of CT-based model was 0.929(95% CI: 0.764-0.946). The sensitivity was 73.2% and the specificity was 98.3%. The positive predictive value (PPV) was 82.26%, while the negative predictive value (NPV) was 100%. In the test set, AUC by the ROC was 0.855(95% CI: 0.764-0.946). The sensitivity of CT-based model was 72.7% and the specificity was 93.3%. The PPV was 82.35%, while the NPV was 88.89%. These results show high predicted accuracy of CT-based model in diagnosis of synchronous PC both in the training set and test set. A nomogram based on these five preoperative predictors of PC was created. This CT-based nomogram showed good diagnostic performance by calibration curve. The decision curves analysis revealed high benefit of this CT-based nomogram in clinical decision. Conclusions: The CT-based nomogram has shown great potential in the detection and diagnosis of synchronous peritoneal metastasis in colorectal cancer.
Systemic impact on tumor growth after combined immuno-thermal ablation in a murine model of colorectal cancer.
Authors: Ryan J. Slovak, Hong-Jai Park, William M. Kamp, Johannes M. Ludwig, Insoo Kang, Hyun S. Kim
Journal: Journal of Clinical Oncology (2020)

198 Background: Cryoablation exposes tumoral antigens capable of provoking an anti-cancer immune response. The addition of immunotherapy alongside cryoablation may synergistically promote a more robust systemic response. The purpose of this investigation was to study the growth of targeted and off-target tumors after combined cryoablation and dual immune checkpoint blockade (DICB). Methods: Sixty BALB/c mice were implanted with bilateral flank injections of 0.5 x 10 6 CT26.WT colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Tumor volume was measured every other day via caliper (LxW 2 ). Mice were randomly assigned to receive either sham injections (InVivoMAb IgG controls), dual anti-PD-1 and anti-CTLA-4 (DICB) (Clone J43 &amp; Clone 9D9; BioXcell, West Lebanon, NH, USA), or DICB plus either partial or full cryoablation of a single targeted tumor. Treatment day 0 began once tumors reached a volume of ~300mm 3 . Injections of antibodies were given on treatment day 0, 3, and 5. Cryoablation was performed on treatment day 2. Full ablation was achieved via two 3-minute cycles at 100% power and partial ablation was defined as a single 3 minute cycle at 70% power ablation (Visual-ICE System, Galil Medical, St. Paul MN). Animals were sacrificed at 7 and 14 days after treatment. Results: There was an average of 177.15% ± 75.22 (SD) increase in tumor volume among control animals and 14.47% ± 9.69 decrease in animals treated solely with DICB. Mice that received full ablation demonstrated an average 72.39% ± 29.21 decreased volume in the target tumors and 48.94% ± 25.97 decrease in the off-target tumors. Partially ablated mice averaged 81.21% ± 16.43 decreased volume in the target tumors and 35.87% ± 16.95 decreased volume in the off-target tumors. The mean change in volume of every group was significantly less than that of the control (p &lt; 0.05) and there was a significantly larger reduction in volume between both the full and the partial target tumors versus the DICB group (p &lt; 0.05). Conclusions: The addition of cryoablation to DICB resulted in a significant reduction in volume of the targeted tumors. Additionally, this combination led to larger volume reductions in off-target tumors as compared to immunotherapy alone.
Neoadjuvant therapy (NAT) and its role for pancreatic adenocarcinoma (PC) in the current era: Institutional experience.
Authors: Emily Walzer, Mengying Deng, Elizabeth A. Handorf, Aryeh Blumenreich, Lauren Pease, Marianna Dorta, Kristen Sorice, Shannon M. Lynch, Namrata Vijayvergia, Efrat Dotan
Journal: Journal of Clinical Oncology (2020)

672 Background: PC affects 57,000 people in the U.S. annually with poor long-term outcomes. NAT for localized disease has increasingly been used but lacks robust prospective data. We investigated the disease course and outcomes for patients (pts) undergoing NAT versus upfront surgery for PC at a high-volume academic center. Methods: Utilizing our IRB-approved retrospective database of metastatic PC pts (year 2000-2017), we identified pts who presented with localized disease and were considered for surgery and present the baseline tumor and treatment characteristics here. Fisher’s exact and Wilcoxon Rank-Sum tests were used for categorical data and Kaplan Meier (KM) curves for survival data when comparing those who had upfront surgery versus surgery following NAT. Results: 352 pts with localized disease at diagnosis were included in our analysis with median age of 65 y (range 38-89) and 45% females. NAT was used in 225 (64%) pts while 109 pts (31%) had upfront surgery and 18 pts (5%) received no treatment. Adjuvant therapy was given to 77% of pts after upfront surgery and 48% of pts after surgery following NAT. NAT regimen consisted of chemotherapy (CTx) and radiation for 48%, CTx alone for 8% and radiotherapy alone for 44% of pts. Of those receiving CTx, 24% received triple agent while 51% and 25% received dual and single agent therapy. Pt factors (age, CCI, gender, BMI, smoking status, race) did not differ between those receiving upfront surgery and surgery following NAT but upfront surgery was associated with a lower stage at diagnosis (p &lt; 0.0001). Surgical resection after NAT occurred in 79 pts (35%) with median overall survival of 26.3m vs 19.7m (p = 0.06) in those who had upfront surgery. Survival rates at year 1, 3, and 5 years were 94%, 34%, and 8% for those with NAT followed by surgery vs 76%, 17%, and 11% for those with upfront surgery (p = 0.06). Conclusions: Use of NAT is prevalent, yet only 35% of pts make it to surgical resection. Survival was improved for pts who underwent resection following NAT versus upfront, although the difference was not statistically significant. Additional research is warranted to define the optimal NAT approach for pts with borderline resectable PC.
チミジンホスホリラーゼ/血小板由来血管内皮細胞成長因子抑制薬の構造に基づく医薬品設計(SBDD)および抗癌剤に対する適用 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Tada Y, Yano S, Kazuno H, Satoh T, Fukushima K, Asao T
Journal: Clinical Cancer Research (1999)
Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency
Authors: Jonas Hultberg, Jan Ernerudh, Marie Larsson, Åsa Nilsdotter-Augustinsson, Sofia Nyström
Journal: Journal of Allergy and Clinical Immunology (2020)

BackgroundCommon variable immunodeficiency (CVID) is a disorder characterized by antibody deficiency. A significant fraction of the patients suffer from immune dysregulation, which leads to increased morbidity and mortality. The pathogenesis of this condition is poorly understood.ObjectiveOur aim was to find out whether the plasma protein signature in CVID is associated with clinical characteristics and lymphocyte aberrations.MethodsA highly sensitive proximity extension assay was used for targeted profiling of 145 plasma proteins in 29 patients with CVID. Phenotyping of peripheral lymphocytes was done by flow cytometry. The findings were correlated with the burden of immune dysregulation.ResultsUnsupervised clustering of plasma protein profiles identified 2 distinct groups of patients with CVID that differed significantly in terms of the degree of complications due to immune dysregulation and in terms of the frequency of activated B- and T-cell subpopulations. Pathway analysis identified IFN-γ and IL-1β as the top enriched upstream regulators associated with higher grade of immune dysregulation. In addition, CVID was found to be associated with increased plasma levels of the B-cell–attracting chemokine CXCL13.ConclusionClustering based on plasma protein profiles delineated a subgroup of patients with CVID with activated T cells and clinical complications due to immune dysregulation. Thus, data indicate that CVID-associated immune dysregulation is a TH1-mediated inflammatory process driven by the IFN-γ pathway.Graphical abstract
Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia
Authors: Myles Wolf, Janet Rubin, Maureen Achebe, Michael J. Econs, Munro Peacock, Erik A. Imel, Lars L. Thomsen, Thomas O. Carpenter, Thomas Weber, Vincent Brandenburg, Heinz Zoller
Journal: JAMA (2020)

Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia.To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose.Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B.Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7.The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35.In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117).In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference.ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.
A phase II trial of pembrolizumab in combination with cisplatin or carboplatin and etoposide in chemotherapy naive patients with metastatic or unresectable high-grade gastroenteropanncreatic or lung neuroendocrine carcinoma.
Authors: Robert A. Ramirez, Marc Ryan Matrana, Suma Satti, Ryan Patrick Griffin, Brianne A Voros, Yvette Bren-Mattison
Journal: Journal of Clinical Oncology (2020)

TPS635 Background: Combination chemotherapy (CTx) is the mainstay of treatment for patients with advanced high-grade gastroenteropancreatic neuroendocrine carcinoma (GEPNECs) and large cell neuroendocrine carcinomas (LCNECs) of the lung. Pembrolizumab (PEM) is a humanized antibody to the programmed cell death receptor (PD-1), which blocks the interaction with its cognate ligands, PD-L1 and PD-L2. PEM blocks the protective mechanism of cancer cells and allows the immune system to destroy them. Combination Ctx and immunotherapy has shown efficacy in other malignancies including small cell lung cancer. The purpose of this study is to test the efficacy, safety, and tolerability of combination CTx with PEM in patients with high-grade GEPNEC or LCNEC of the lung who are CTx naïve. Methods: This is an open label, phase II, single institution, multi-site trial using PEM in combination with either cisplatin or carboplatin and etoposide in patients with high grade GEPNECs or LCNEC of the lung who are CTx naïve. Patients with a histologic diagnosis of a GEPNECs with a Ki-67 of 55% or higher or a LCNEC of the lung will be eligible. Patients must be metastatic or unresectable; chemotherapy naïve; have at least one measurable lesion per RECIST 1.1, have an ECOG performance score of 0-1; and have a predicted life expectancy &gt; 3 months. Approximately 36 GEPNEC and 6 LCNEC of the lung patients will be enrolled. Patients will receive PEM 200mg IV in combination with cisplatin 80 mg/m2 or carboplatin AUC 6 on day 1 and etoposide 100mg/m2 on days 1-3 of a 21-day cycle. Tumor response will be assessed by CT scan every 6 weeks using RECIST 1.1. Those patients who have responsive or stable disease after 4-6 cycles of platinum-based CTx will move to maintenance PEM every 3 weeks for up to 2 years. The primary endpoint will be progression free survival. Results: This study is open to enrollment. Clinical trial information: NCT03901378.
Weight loss as an untapped early detection marker in pancreatic cancer.
Authors: Jonathan J. Hue, Sarah C. Markt, Ravi Kumar Kyasaram, John Shanahan, Goutham Rao, Jordan Michael Winter
Journal: Journal of Clinical Oncology (2020)

643 Background: Pancreatic cancer has the worst survival of common cancers and there are no reliable early detection tests. While prior reports link unintentional weight loss (&gt;5% decrease from baseline) to pancreatic cancer, there has never been a study documenting the frequency of this presenting sign using raw patient weight data. Methods: Patients at our institution with a pancreatic neoplasm (n=288) were queried using ICD-9 code 157.9 and ICD-10 code C25.9. Retrospective review identified 95 patients with pancreatic ductal adenocarcinoma and two or more prediagnosis weights (&gt;7 days apart). Date of diagnosis was defined by the date of positive biopsy or encounter with surgical or medical oncology. Standard statistical analysis was performed. Results: Among the 95 patients, there was a slight preponderance of female (65.3%) and Caucasian (54.7%) patients. The median age at diagnosis was 71 (range: 41-90) and the median BMI was 25.6 kg/m 2 (range: 15.4-49.5). 9.5% presented with clinical stage I disease, 27.3% with stage II, 9.5% with stage III, and 53.7% with stage IV. Within 1 year of diagnosis (range: 9-365 days), median weight loss was 7.1% of body weight (range: 0.2-34.5%). In this period, 71.6% of patients lost greater than 5% body weight and 32.6% lost over 10% (Table). In the 6 months before diagnosis (range: 9-180 days), median weight loss was 6.4% (range: 0.2-24.2%). A subgroup analysis of early (I, II) and late stage (III, IV) patients showed that those with late stage at presentation lost significantly more prediagnosis weight compared to the early stage patients (median 8.2% vs 5.6%, p=0.02) in a median of 175 days. Prior to diagnosis of late stage patients, 80.0% lost over 5% body weight and 38.3% lost over 10%. Conclusions: Diagnosis of pancreatic cancer is preceded by weight loss in the majority of cases, even at an early stage. Monitoring unintentional weight loss in otherwise asymptomatic patients may be an inexpensive and practical way to detect pancreatic cancer. [Table: see text]