tbuckley/cabot-search huggingface dataset:
Association of pancreatic cancer stem cells with tumor stroma type.
Authors: Ibrahim Halil Sahin, Gokce Askan, Joanne F Chou, Marinela Capanu, Kenneth H. Yu, Olca Basturk, Christine A Iacobuzio-Donahue, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2019)

e15771 Background: Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease with distinct stroma features. Cancer stem cells (CSC) in PDA may express CD44 (C) +/- Epithelial Specific Antigen (E). We investigated the relationship of CSC markers with tumor stroma and clinical outcomes in PDA patients (pts) who had surgical resection. Methods: Pts who underwent PDA resection with IRB #00-032/#06-107 consent between 01/2012-06/2014 at Memorial Sloan Kettering were identified. C and E immunohistochemical (IHC) expression scored as follow: 0, none; 1, 1%–10%; 2, 11%–50%; 3, 51%–80%; 4, 81%–100%. Staining intensity was scored as 0, none; 1, weak; 2, moderate; 3, strong. The total scores (0-12) were averaged and was considered positive when average score &gt; median. Stroma was classified as loose, moderate and dense based on fibroblast content using H&amp;E stain. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier and compared by log-rank test; association between CSC markers and stroma type was assessed by Fisher`s exact test. Results: N = 93 PDA pts identified. PDA with C(+) E(-) had significantly higher loose stroma and PDA with C(-) E(+) and C(-) E(-) had more moderate and dense stroma (p = 0.0033). The number of PDA pts with dense, moderate, and loose stroma was: 11, 31, and 51 respectively. No local recurrence in pts with dense stroma observed and 8/11 had either lung or liver recurrence. Six of 31pts with loose stroma had a local recurrence and 13/31 pts had either liver or lung recurrence. No statistically significant difference in OS and RFS were observed among subgroups (P = 0.089). Median time from relapse to death was: 2, 11.5, 10,5 and months 7 in C+/E-, C-/E+, C+/E+, and C-/E- groups respectively. Conclusions: PDA CSCs appears to have an association with PDA stroma type. We also observed different recurrence patterns among stroma subgroups. Respecting small sample size, these data indicate CSCs may have an important role in stroma differentiation in PDA. CSC markers do not predict OS and RFS, however, resected PDA with C(+) E(-) may have more aggressive behavior following recurrence. [Table: see text]
Human acute leukemia engraftment, microenvironment, kinetic and spreading in three NOD/SCID-related strains
Authors: Alice Agliano, Ines Martin-Padura, Paola Marighetti, Patrizia Mancuso, Cristina Rabascio, Leonard Shultz, Francesco Bertolini
Journal: Cancer Research (2007)

3050  Different strains of immunodeficient mice have been studied in the past to generate models of human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). These models have been used to investigate AML and ALL stem cells, biology, and drug sensitivity. We investigated the engraftment behavior of three AML cell lines (HL-60, KG-1 and NB-4), two ALL cell lines (MOLT-16 and 697) and AML primary cells from three AML patients in three different strains of NOD/LtSz-Prkdcscid (NOD/SCID, NS)-related immunodeficient mice. NS, NS/β2 null (NSB) and NOD/SCID/IL-2rγ null (NSG) mice were injected ip with 10x106 AML or ALL cells. Mice were observed daily and sacrificed when leukemia-related symptoms were evident. Leukemia-related symptoms were observed in 62, 73 and 79% of NS, NSB and NSG mice, respectively (n=58, p
The role of different TGFβ signatures in predicting outcome in high grade serous ovarian carcinoma.
Authors: Haider Mahdi, Peter Graham Rose, Fadi W Abdul-Karim, Bradley J. Monk, Ying Ni
Journal: Journal of Clinical Oncology (2019)

e14262 Background: Ovarian cancer (OV) is the most lethal gynecologic cancer in the US. Despite initial responsiveness to chemotherapy, &gt; 50% experience recurrence. Recurrent disease is characterized by low response to chemotherapy and poor prognosis, especially platinum-resistant disease. Thus, there is an urgent need to identify new targeted therapy to improve the outcome of this aggressive cancer. The Transforming Growth Factor (TGFβ) family controls different cellular responses in development and cell homeostasis. Disruption of TGFβ signaling has been implicated in many cancers, including OV, but with paradox effects. It is unclear if TGFβ family genes can serve as a predictive marker and be selected for future therapy target in OV. Methods: We used quantified RNAseq data from 374 OV samples in The Cancer Genomic Atlas (TCGA) to extract 4 different sets of TGFβ pathway genes including: 3-gene ( TGFB1, TGFB2, TGFB3), 6-gene ( TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3), 43-genes from cBioPortal, or 173-genes from Calon et al, 2012 to predict colorectal cancer relapse. Expression counts for these genes were normalized and log transformed to generate a TGFβ score based on the quartiles of the average. Samples were categorized in to low (lowest quartile), medium (middle 2 quartiles), and high (highest quartile) expression groups. Overall (OS) and progression-free (PFS) survivals were compared among groups using Kaplan-Meier method. Results: Interestingly, the minimum TGFβ 6-gene set can predict high grade serous ovarian cancer patient survival among all 4 gene panels using TCGA data, with average age of 60 years (range: 38 –81). Majority of the patients were stage IIIIV. OV patients with highest quartile, TGFβ signature expression have in general less somatic mutations and copy number alterations (average mutation count = 41, average CNA fraction = 0.5) compared to lowest quartile TGFβ expression group (average mutation count = 52, average CNA fraction = 0.6). Patients with TGFB 6-gene expression scored high showed worse OS (36.2 months vs 63.5 months, log-rank p = 0.001) and worse PFS (18.6 months vs 31.4 months, log-rank p = 0.09). Details of outcome by each specified gene signature will be outlined later. Conclusions: Our analysis suggested that the narrowed 6-gene TGFβ family expression profile could potential serve as a prognosis biomarker for OV. With proper validation and mechanistic investigation, existing TGFβ inhibitors may hold promise for targeted or combination therapies for OV. Targeting both TGFβ and PD1 might be of therapeutic value.
Use of prophylactic percutaneous endoscopic gastrostomy (pPEG) tube in head and neck cancer (HNC) patients and correlation of weight loss with treatment interruptions.
Authors: Deepali Pandey, Lisa Gibbs, Kamal Kant Sahu, Ahmad Daniyal Siddiqui
Journal: Journal of Clinical Oncology (2019)

e17509 Background: HNC patients are at risk for weight loss which can cause treatment interruptions, and poorer outcomes. There is no consensus on optimal timing of PEG tube placement in HNC patients undergoing concurrent ChemoTherapy (CT) and RadioTherapy (RT). The aim of this study is to determine if pPEG tube would decrease weight loss (WL) in HNC patients. We also analyzed correlation between WL and CT interruptions (CTI), RT interruptions (RTI), and intravenous fluid requirements (IVFr). Methods: This is a prospective study. A total of 16 HNC patients undergoing concurrent CT, RT were included. Before treatment initiation, a PEG tube placement was recommended as a mode of nutrition. 13 patients chose to get pPEG tube and 3 refused. We collected data on weight at 0 and 2 months, CTI, RTI, and IVFr. CTI included missed as well as reduced chemotherapy doses. RTI included missed radiations. Statistical tests used - t-test, Levene’s test for equality of variances and point biserial correlation. Results: Median age - 63 years; Gender: 14 Male/2 Female; Tumor location - Oral cavity - 31.3%; Oropharynx - 43.7%; Larynx - 25%; Nasopharynx and Hypopharynx- 0%. Stages were - II (6.2%), III (37.5%) and IV (56.3%). 2 patients were non-smoker and 4 were Human Papilloma Virus positive. Mean WL(lb) in pPEG (n = 11) vs non-PEG (n = 3) group was 10.3 vs 20.3 (p = 0.045, one-tailed t-test). Average percentage of WL: PEG vs non-PEG - 5.8 vs 8.2; RTI vs not - 8.9 vs 5.3; CTI vs not - 6.9 vs 5.8; IVFr vs not - 6.8 vs 4.5 ( &gt; 7.5% WL over 3 months is significant (ADA/ASPEN)). CTI, RTI and IVFr were positively correlated to WL (correlation coefficient: 0.16; 0.32; 0.17 respectively). CTI and RTI in pPEG group were 23.1% and 38.5% respectively. CTI and RTI in non-PEG group were 33.3% and 66.7% respectively. 2 patients in pPEG group had average weight gain of 2.75 lb. Only 3 patients had PEG tube related complications - infections and clogging. Conclusions: pPEG tube decreases weight loss in locally advanced HNC patients. Patients with higher weight loss had more chemoradiation interruptions and IVFr. HNC patients undergoing concurrent CT, RT should be encouraged to maintain weight and get a PEG tube.
Human papillomavirus, radiation dose and survival of patients with anal cancer.
Authors: Rafi Kabarriti, Patrik Brodin, Nitin Ohri, Rahul Narang, Renee Huang, Jennifer W. Chuy, Lakshmi Rajdev, Shalom Kalnicki, Chandan Guha, Madhur Garg
Journal: Journal of Clinical Oncology (2019)

e15071 Background: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS. Methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 – 2015. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates. Results: We identified 5,927 patients with tumor HPV status for this analysis, 3,523 (59.4%) had HPV positive disease and 2,404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR=0.81 (95%CI: 0.68-0.96), p=0.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR=1.11 (95%CI:0.86-1.43), p=0.43). In the unmatched cohort, there was an increase in 3-year OS for patients with HPV positive tumors or early stage disease up to 45-49.9 Gy (p&lt;0.001), whereas for patients with HPV negative and locally advanced disease there was an increase in survival from 46% at 30-44.9 Gy, to 64% at 45-49.9 Gy (p=0.093) and further to 71% at 50-54.9 Gy (p=0.005). Conclusions: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 50-55 Gy was associated with better OS, mainly for locally advanced disease in HPV negative patients. Multivariable Cox proportional hazards regression for OS. [Table: see text]
Evaluation of readmission rates for gastrointestinal bleeds in high risk oncologic patients.
Authors: Laila Babar, Veli Bakalov, Dulabh K. Monga, Zena Chahine, Obaid Ashraf
Journal: Journal of Clinical Oncology (2019)

e23031 Background: Gastrointestinal bleeding (GIB) results in high rates of hospital admissions, readmissions, significant morbidity and high healthcare cost. To lower readmission rates, Medicare mandates public reporting, however it does not differentiate between patient populations. GIB is a complex disease with treatment selection and patient outcome changing with different patient populations. We must identify vulnerable groups and high risk characteristics. Malignancy is a hypercoaguable disease and when combined with atrial fibrillation or history of clots, it can increase stroke and pulmonary embolism risk. These patients require anticoagulation putting them at a higher risk of bleeding. In our study, we identified cancer patients with atrial fibrillation and evaluated reasons for differences in readmission rates for GIB. Methods: We queried our EMR for a list of patients from April 2016-April 2018. Inclusion criteria was admission for GIB, a history of cancer, atrial fibrillation, DVT or PE. Patients were divided into groups with and without readmission for GIB, and differences in characteristics were analyzed. Odds ratios(OR) with p-value 0.05 and confidence interval (CI) 95% were calculated. Results: Of 111 patients, 57 met our inclusion criteria, 32 male and 25 female with average age 78.8 years. 18 patients required readmission, 12 for GIB. 32% of our population was readmitted within 30 days of discharge, 21% was readmitted for a GIB. BMI &gt; 30(OR:0.28; CI 0.15-0.54; p = 0.0002), ICU admission during hospitalization(OR:0.083; CI 0.019-037; p = 0.0011), and lower GI tract as site of bleeding (OR:0.54; CI 0.30-0.98; p = 0.04) were associated with a lower incidence of readmission for GIB. Administration of blood transfusion (OR:2.80; CI 1.58-4.99; p = 0.0004)and discharge disposition to skilled facility(OR:1.93; CI 1.04-3.57; p = 0.036) was associated with a higher incidence of readmission. There was no difference with type of anticoagulation. Conclusions: The readmission rates for GIB in our population (32%) was higher than the national average (12%). Cancer patients requiring anticoagulation have a drastically different hospital course and outcomes than healthy patients and should have different quality metrics and treatment algorithms. This will also make Medicare penalties more accurate.
Somatic mutations in non-small cell lung cancer and their correlation with overall survival, tumor mutation burden, and programmed-death cell ligand-1 (PD-L1) status.
Authors: Jennifer Dotson, Muhammad Jamil
Journal: Journal of Clinical Oncology (2019)

e14752 Background: In recent years, treatments for non-small cell lung cancer (NSCLC) have expanded to include targeted therapies and immune checkpoint inhibitors in addition to traditional treatments. These newer modalities of treatment require testing with next-generation sequencing (NGS) testing, which offers testing for hundreds of somatic mutations, both with known and unknown significance. Tumor mutation burden (TMB), which is the number of mutations per coding sequence, is also reported on NGS. Patients with targetable mutations or a high TMB have been found to have improved survival and higher responses to immunotherapy, respectively. We wanted to investigate whether the total number of mutations (both with known and unknown significance) had any association with PD-L1 status, TMB and overall survival. Methods: This was a single institution, retrospective study of 51 patients with stage I-IV NSCLC. Results: In our study, we found that there was a significant correlation between the number of mutations and TMB in all patients with NSCLC (p = 0.001), including adenocarcinoma (p = 0.005). We found that the number of known mutations, mutations of unknown significance and total overall mutations did not have a significant correlation with survival (p = 0.708, p = 0.808, and p = 0.639, respectively) or PD-L1 status (p = 0.214). In a subset analysis of patients with metastatic NSCLC, there was also no correlation between the total number of mutations and overall survival (p = 0.821). Conclusions: In our study, we determined that there was a positive correlation between TMB and higher number of mutations, though the number of mutations did not correlate with PD-L1 status or overall survival. As TMB is associated with higher immunogenic responses, this data may have future therapeutic implications. Additional investigation of the most frequent mutations is ongoing.
Clinical analysis of cancer associated venous thromboembolism in hospitalized patients with malignant solid tumors in real-world practices.
Authors: Da Jiang, Xue Zhang, Haiying Yang, Jing Zuo, Hui Jin, Ying Li, Fang Huang
Journal: Journal of Clinical Oncology (2019)

e14686 Background: According to previous reports, 1% to 30% patients with malignant tumors developed venous thromboembolism (VTE) and an increased risk of VTE in hospitalized patients. However, real-world clinical analysis of VTE in Chinese hospitalized patients with malignant solid tumors is scarce. Methods: We utilized the collaborative Linkdoc database to retrospectively analyze hospitalized cancer patients in Department of Medical Oncology of the Fourth Hospital of Hebei Medical University from May 2014 to November 2018. Patients who were pathologically confirmed malignant solid tumor, ≥ 18 years of age, ECOG PS 0-4, median overall survival ≥ 1 months, and absence of serious diseases of vital organs such as heart, liver, kidney and blood system or the above chronic diseases in inactive period were included in this study. Results: A total of 3831 patients were enrolled, of whom 180 (4.70%) patients had VTE. The highest incidence of VTE in solid tumors was gynecological cancer (61/1288, 11.90%), followed by gastric cancer (42/701, 5.71%), other cancers (11/206, 5.33%), lung cancer (61/1288, 4.74%), colorectal cancer (18/399, 4.51%), breast cancer (34/903, 3.77%), and esophageal cancer (6/250, 2.40%). Of the enrolled patients, 21.11% (809/3831) underwent relevant imaging examinations to screen for VTE as required by the guidelines of cancer associated VTE. Based on the imaging examinations, the anticoagulant rates of patients with or without VTE were 100% (61/61) and 34.09% (255/748), respectively. Notably, only one patient received the anticoagulant therapy (both anticoagulant dose and time) in lines with the guidelines. Conclusions: This single-center real-world study showed the overall rates of VTE in hospitalized cancer patients was similar with the data previously reported. Referring to the guidelines of cancer associated VTE, the proportion of Chinese cancer patients receiving normative imaging examinations and anticoagulant therapy is seriously low currently, which should be paid more attention to in clinical practices by Chinese medical workers.
Discovery of a novel Toll-like Receptor 7 agonist for systemic immunotherapy of cancer.
Authors: James Richard Appleman, Stephen Evan Webber
Journal: Journal of Clinical Oncology (2019)

e14246 Background: While ICPIs (immune checkpoint inhibitors) have fundamentally changed the practice of cancer therapy for tumors arising from many different tissues, ways to increase both response rate and durability are critically needed. On theoretical grounds, combining stimulators of innate immunity with activators of adaptive immunity should lead to better outcomes. We have therefore created a series of novel Toll-like receptor 7 (TLR7) agonists that are intended to be combined with activators of adaptive immunity for the treatment of cancer. We have previously reported a series of unusual properties that must be met for successful drug candidates targeting TLR7 intended for chronic and systemic administration for the treatment of cancer. Methods: Key assays in our testing cascade include: cellular reporter assays and hPBMC assays to evaluate selectivity and potency; characterization in cynomolgus monkeys: appropriate PK with active TLR7 agonist, efficient oral delivery into systemic circulation with prodrugs of the TLR7 agonist, and targeted pharmacodynamic response at relevant oral dose (gating for candidate selection); antitumor activity alone and in combination with other immunotherapeutics in syngeneic rodent tumor models. Results: Appropriate potency at and specificity for TLR7 was achieved early in this discovery program. Furthermore, the PK profile after IV administration met our previously defined criteria. However, oral absorption of candidate prodrugs of two lead molecules was limited. In one class of prodrugs this was due to insufficient lipophilicity; in another class this was a consequence of MDR1 activity. Next-generation candidates have been synthesized; these candidates are expected to have substantially better oral delivery in vivo based upon results in predictive in vitro models. Testing in advanced animal models is in progress. Conclusions: From our original starting point - a relatively weak TLR7 agonist with no oral bioavailability - we have invented a novel series of molecules that are designed to be dosed QOD continuously over a 24-month period to appropriately engage innate immunity at a level that is well-tolerated by the patient while increasing treatment response rate and durability.
Treatment patterns, survival rate, and Parts A and B costs by line of therapy for FDA-approved/NCCN Category 1 treatments for patients with metastatic pancreatic cancer.
Authors: L. Daniel Muldoon, Jared Hirsch, Gabriela Dieguez, Paul Cockrum
Journal: Journal of Clinical Oncology (2019)

e18357 Background: There is currently limited real-world evidence regarding metastatic pancreatic cancer (m-PANC) FDA-approved/NCCN Category 1 treatment patterns, resource utilization, and survival rate. We analyzed these outcomes in the Medicare fee-for-service (FFS) population by chemotherapy regimen and line of therapy (LOT). Methods: We identified patients with m-PANC using ICD-9/10 diagnosis codes in the 2013-2017 Medicare 100% Limited Data Set claims, which include all Medicare paid FFS claims, except professional services, for 45 million Medicare FFS beneficiaries. We studied mean costs and survival rate by regimen and LOT. Patients in our study had two or more claims with a pancreatic cancer (PANC) diagnosis more than 30 days apart and one or more claims with a secondary malignancy (metastasis) diagnosis on or after the first PANC diagnosis date. We defined index date as the earliest metastasis diagnosis date. We excluded patients with pre-index non-PANC malignancies and those without six months pre-index and three months (or until death, if earlier) post-index Medicare FFS enrollment. LOTs were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. Results: Gemcitabine monotherapy, gemcitabine/nab-paclitaxel, and FOLFIRINOX were most commonly used as first line (1L) therapy (91%, 80%, and 80%, respectively). Mean total Parts A and B (excluding professional) cost for 1L gemcitabine monotherapy was lower than gemcitabine/nab-paclitaxel or FOLFIRINOX ($14,601, $32,447, and $33,628, respectively), but FOLFIRINOX had a higher 90-day survival rate (86%) than gemcitabine-based regimens (76-79%). Liposomal irinotecan was most commonly used in second and third lines (2L, 3L) (54% and 28%, respectively); 97% of these patients previously received gemcitabine, consistent with approved labeling. Despite disease progression, 2L and 3L liposomal irinotecan had similar costs ($36,350 and $35,010, respectively) to 1L gemcitabine/nab-paclitaxel and FOLFIRINOX. As expected, 2L and 3L liposomal irinotecan 90-day survival rates were lower (68% and 73%, respectively). Conclusions: Mean total Parts A and B (excluding professional) costs for common 1L-3L regimens varied from less than $15,000 to greater than $30,000. 90-day survival rates for common regimens varied between 1L (86%) to 3L (68%).