tbuckley/cabot-search huggingface dataset:
Clinical implication of monitoring PD-L1+ circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC) receiving immunotherapy.
Authors: Andrew Daniel Hoffmann, Andrew A. Davis, Wade Thomas Iams, Michael S Oh, Robert William Lentz, Young Kwang Chae, Huiping Liu
Journal: Journal of Clinical Oncology (2019)

e14044 Background: CTCs not only constitute a cellular component of liquid biopsy for dynamic, longitudinal information of malignancies, but also pose a continuous threat to seed new metastasis. Detection of these cells can help identify patients with residual disease and poor prognosis. However, it is unknown if heterogeneous CTCs can be profiled to monitor cancer stemness and immunotherapy response for patients. Limited clinical data exist for monitoring CTCs for markers of cancer stem cells, such as CD44 or CD166, and immunotherapy therapeutic targets including PD-L1. We hypothesized that dynamic monitoring of CTC positivity for these markers would correlate with responses to immune checkpoint inhibitor treatment for patients with NSCLC. Methods: As part of a prospective analysis of peripheral blood cells, 30 patients with NSCLC undergoing immunotherapy (pembrolizumab or atezolizumab) or combination therapy with chemotherapy had blood samples collected at 3-4 week intervals for up to 24 weeks. Peripheral blood mononuclear cells were isolated and analyzed for CD45, to identify non-leukocyte putative CTCs, CD166 and CD44, to identify cancer stem cell markers among potential CTCs, and PD-L1. Patients were evaluated for response based on RECIST criteria. Statistical analysis was performed using one-way ANOVA on samples from each time point. Results: A decrease in PD-L1+ CD45- cells (CTCs) at the second interval was most strongly associated with initial response. In contrast, increasing number of PD-L1+ CD45- cells were found among patients with progressive disease as compared to those with stable disease or a partial response (p = 0.01). (1) CD45- cells, (2) CD44+; CD45- cells and (3) CD166+; CD45- cells demonstrated no significant association with clinical outcomes. Baseline PD-L1 level on CTCs did not correlate with the PD-L1 level on tissue. Conclusions: We report the feasibility and potential clinical significance of monitoring surface markers on CTCs in the blood before and after initiation of immunotherapy. Our findings that PD-L1+ CTCs increased among non-responders to immunotherapy warrant further validation. Testing is ongoing to evaluate how these changes predict long-term outcome to treatment for patients.
Detection of the burnout syndrome, empathy, and psychosocial profile of the health team of the oncology service, UANL University Center Against Cancer (CUCC).
Authors: Adelina Alcorta-Garza
Journal: Journal of Clinical Oncology (2019)

e18274 Background: The Burnout Syndrome, a set of somatic and behavioral signs given by the physical and mental exhaustion that arises from the workings of a person. In particular, health personnel in the oncology area have been exposed to this syndrome. Occupational exhaustion can affect the quality of life of individuals, in a way that also affects their performance at work. Also the staff burnout damages the attention given to the patient, so that the latter can also perceive it. Therefore, it is a priority in our center to determine the frequency and severity of exhaustion among the staff of the Oncology Service and its association with the quality of self-reported empathy towards patients. Methods: It is an observational, cross-sectional and correlation study. With the informed consent of the subjects, questionnaires were applied to assess the subjet´s psychosocial profile, the presence or absence of work exhaustion (Maslach), and empathy. A database was collected with the results obtained from validated questionnaires. The instruments were applied to 1060 staff members working in the Oncology Service of the CUCC, including physicians, students, nurses and administrative health personnel. Results: Among the sample, 413 (38.96%) Burnout cases were found. The age range was from 18 to 61 years. The most prevalent subscale was personal fulfillment with 247 cases, followed by depersonalization with 199 cases, and finally, emotional fatigue with 94 cases. When analyzing the Burnout cases according to their severity, 313 (29.52%) presented a subscale, 73 (6.88%) presented two and 27 (2.54%) presented three (% based on the total of n). The most affected age group was between 20 and 51 years old and, in general, had a higher level of Burnout than women (56.65 vs 43.35%). Regarding the type of personnel, the students showed a higher prevalence (402/1001, 40.15%) than the workers (11/59, 18.64%). As a group, there is a greater loss of empathy in association with burnout. For men and students, the severity and presentation of exhaustion are greater than for workers and non-workers. Conclusions: Among the other variables, the most correlated with the Burnout syndrome were empathy, the general health questionnaire and family malfunction. among others. We suggest starting a special program to help vulnerable staff for their own quality of life and a better service for patients.
Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.
Authors: Michael B. Atkins, John M. Kirkwood, Jedd D. Wolchok, Margaret K. Callahan, Harriet M. Kluger, Michael A. Postow, Neil Howard Segal, Alexander M. Lesokhin, Agnes Balogh, Sandra Re, Mario Sznol
Journal: Journal of Clinical Oncology (2019)

9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.
Phase Ib study of pembrolizumab and trebananib (angiopoietin-2 inhibitor [Ang-2]): Preliminary analysis of the colorectal cancer (CRC) cohort.
Authors: Osama E. Rahma, James M. Cleary, Benjamin L. Schlechter, Kimmie Ng, Jessica Eno, Amanda Stroiney, Anita Giobbie-Hurder, David F. McDermott, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2019)

e14160 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling and in hypoxic microenvironments. Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing monocyte activation. Our group demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival (OS) in patients treated with PD-1 blockade. Methods: We initiated a phase 1b trial to evaluate the safety, efficacy, and immunological effect of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody, in solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the preliminary data in the fully enrolled CRC expansion cohort. Results: The study enrolled a total of 18 microsatellite stable (MSS) heavily pretreated CRC patients. There were no DLTs and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib (3 in dose escalation, 12 in dose expansion) plus pembrolizumab. Nine patients (60%) were female and the median age was 51 years (43-63). The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria (each reported in 40% of the patients). One grade 3 transaminitis and one grade 4 pneumonitis related to pembrolizumab were reported. As of the date of data retrieval, 11 patients were off treatment and four were continuing with a median follow-up of 6.1 months. The response rate was 7% (1 partial response for 14 months) and the disease control rate was 33% (4 stable disease with CEA trending down). Median time to progression and OS were 2.8 (90% CI: 1.5 to 4.9 months) and 11.4 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in heavily pretreated MSS CRC. Paired biopsies and blood were collected for planned correlative immune analyses which will be presented at the meeting. Clinical trial information: NCT03239145.
Impact of race/ethnicity in the clinical presentation and outcomes of patients with multiple myeloma in an underserved urban population.
Authors: Christian Torres, Xavier Alberto Andrade Gonzalez, Vatsala Katiyar, Juan Del Cid, Andres Mendez Hernandez, Ezequiel Munoz, Luis David Sumoza
Journal: Journal of Clinical Oncology (2019)

6570 Background: Patients with multiple myeloma (MM) who are part of racial/ethnic minority groups have been typically underrepresented in large descriptive and randomized-controlled studies. Despite the identification of biological and genetic risk factors, the impact of race/ethnicity in the outcomes of patients with MM remains largely unknown. We aimed to describe the racial/ethnic differences in clinical presentation and outcomes of patients with MM in an ethnically-diverse underserved urban population. Methods: We conducted a single-center retrospective study of patients with MM from Jan 1 st 2008 – Dec 31 st 2016 using ICD coding from our tumor registry. We abstracted demographic, clinical and treatment variables. We used Chi-square to compare categorical variables and Kaplan-Meier method for survival analysis. Statistical analysis was performed using IBM SPSS version 25. Results: We identified 73 patients with MM with a median follow up time of 42 months (Range 1 to 81 months). Patients had a median age of 59 years (Interquartile Range [IQR] =17) and were predominantly male (54.8%). The most frequent racial/ethnic group was African American (AA) (59%) followed by Hispanic (27%) and Caucasian (8%). When compared to other ethnicities, patients who were AA had higher ISS-3 scores (41% vs 23% p=0.101) worse cytogenetic risk (65% vs 30% p=0.009) and worse response after induction (Complete response [CR] 47% vs 77% p=0.047). They were also more likely to have medical insurance coverage than other ethnicities (67% vs 27% p=0.003) but had similar access to autologous bone marrow transplant (23% vs 23% p= 0.99). Overall, AA patients had worse overall survival (OS) compared to all other ethnic groups (mean OS: 58.3 months vs 79 months p=0.014). Conclusions: AA patients with MM had more aggressive disease and worse OS compared to other ethnicities which may suggest an underlying genetic predisposition towards high-risk genetic features. Improvement of access to autologous bone marrow transplantation may improve survival in high-risk racial/ethnic groups.
KX-ORAX-001: An open label, randomized, multicenter, phase III registrational study to determine the safety, tolerability, and tumor response of oraxol (HM30181A + oral paclitaxel) and its comparability to IV paclitaxel in patients with metastatic breast cancer (MBC).
Authors: Gerardo Antonio Umanzor Funez, Rosa Haydee Vassallo, Marco Antonio Chivalan Castro, Suyapa A. Bejarano, Julio Roberto Ramirez Velasquez, Ruben Kowalyszyn, Luis Enrique Fein, David Cutler, John Goldfinch, Taryn Moore, Douglas Kramer, Rudolf Kwan, Francisco Barrios
Journal: Journal of Clinical Oncology (2019)

TPS1116 Background: Paclitaxel is used in multiple cancer types including the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Due to poor oral absorption, paclitaxel is administered IV and is associated with extra administration costs, inconvenience, burden for the patient, and hypersensitivity reactions to the solubilizing agent Cremophor EL. HM30181A is an intestinal P-gp pump blocker that, when administered orally with paclitaxel capsules (Oraxol), enhances paclitaxel absorption. Interim data from a phase I crossover study showed Oraxol (15-mg HM30181A + 205 mg/m 2 ) 3 days/week had similar AUC 0-∞ to IV paclitaxel 80 mg/m 2 over 1 hour (Oraxol 5078 ng*hr/mL vs. IV paclitaxel 5652 ng*hr/mL), however the Cmax was substantially lower with Oraxol which may result in lower incidence of neuropathy. In a phase II single arm study of Oraxol in MBC 45.8% and 41.7% of subjects had PR or SD according to RECIST 1.1. Methods: KX-ORAX-001 is a, multi-national open-label, randomized (2:1 Oraxol to IV paclitaxel) phase III registration study comparing Oraxol (15-mg HM30181A + paclitaxel 205 mg/m 2 daily x 3 days QW) to IV paclitaxel 175 mg/m 2 over 3 hours every third week, in female patients with histologically- or cytologically-confirmed MBC for whom treatment with IV paclitaxel monotherapy has been recommended. The study is powered to demonstrate the superiority of Oraxol on confirmed tumor response rate vs IV Paclitaxel 175mg/m 2 q3weeks. The primary efficacy endpoint is confirmed tumor response according to a blinded central radiologist using RECIST 1.1 criteria. The study is designed to enroll approximately 360 evaluable subjects. Two interim DSMB reviews were conducted at approximately 90 and 180 evaluable subjects for safety, futility, and efficacy. Enrollment was initiated Dec 2015 at 45 sites in Central and South America and enrollment has been completed. At final analysis, if there is an approximate difference of ≥10% favoring Oraxol, a p-value of 0.045 [2-tailed] will be achieved. Secondary endpoints are PFS and OS. Clinical trial information: NCT02594371.
Clinical benefit of breakthrough cancer drugs approved by the United States Food and Drug Administration.
Authors: Consolacion Molto, Thomas J. Hwang, Marta Andres, Maria Borrell, Ignasi J. Gich Saladich, Agust Barnadas, Eitan Amir, Aaron S. Kesselheim, Ariadna Tibau Martorell
Journal: Journal of Clinical Oncology (2019)

6513 Background: The Breakthrough Therapy program was established in July 2012 to expedite drug development and approval by the FDA. We compared the characteristics of clinical trials leading to FDA approval as well as the magnitude of clinical benefit and value framework scores of breakthrough-designated and non-breakthrough-designated cancer drugs. Methods: We searched the Drugs@FDA website for cancer drug approvals from July 2012 and December 2017. For each indication, we applied the value frameworks and used thresholds of high clinical benefit developed by American Society of Clinical Oncology Value Framework version 2 (ASCO VF v2; scores ≥45), the ASCO Cancer Research Committee (OS gains ≥2.5 months PFS gains ≥3 months), the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1; grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks (scores of 4 and 5). Trial characteristics and value framework scores were compared using Chi squared or Mann Whitney U tests. Results: We identified 106 pivotal trials supporting the approval of 52 individual drugs for 96 indications. Of these indications, 38 (40%) received breakthrough designation. Compared with trials for non-breakthrough drugs (n = 62), trials for breakthrough drugs (n = 44) had smaller sample size (median 373 vs 612, P= .03), were less often randomized (57% vs 86%; P= .001) and more likely to be open-label (84% vs 53%, P= .001). Trials for breakthrough drugs were more likely to demonstrate high clinical benefit using ASCO VF (68% vs 31%, P= .002) and NCCN Evidence Blocks (86% vs 56%, P= .002). A similar proportion of trials supporting breakthrough and non-breakthrough drugs demonstrated high clinical benefit using the ASCO Cancer Research Committee (82% vs 68%, P= .25) and ESMO-MCBS (35% vs 33%; P= .87) frameworks. Conclusions: In patients with advanced solid tumors, cancer drugs approved under breakthrough therapy designation were more likely to demonstrate high clinical benefit as defined by the ASCO VF and NCCN value frameworks. A similar proportion of approved breakthrough and non-breakthrough therapy drugs met the high benefit thresholds using the ASCO Cancer Research Committee and ESMO-MCBS frameworks.
Exosomal markers (CD63 and CD9) expression using immunohistochemistry (IHC) in patients with right-sided and left-sided colon cancer.
Authors: Pranitha Prodduturvar, Ben McCormick, Wadad Mneimneh, Valeria Dal Zotto, Leander Grimm, Paul Rider, John Hunter, Greire Iliff, Clayton Smith, Girijesh K. Patel, Lewis Pannell, Seema Singh, Ajay Singh, Josiah Perry, Moh'd M. Khushman
Journal: Journal of Clinical Oncology (2019)

e15119 Background: Embryologically, the right colon (cecum, ascending colon, hepatic flexure and proximal two-thirds of the transverse colon) is derived from the midgut, whereas the left colon (sigmoid colon, descending colon, splenic flexure and distal third of the transverse colon) is derived from the hindgut. There are clinical, pathological and molecular differences between patients with right-sided colon cancer (RSCC) and left-sided colon cancer (LSCC). Exosomes mediate intercellular communications and interactions and have pivotal roles in cancer behavior. CD63 and CD9 are widely accepted exosomal markers. Here we explored CD63 and CD9 expression using immunohistochemistry (IHC) in patients with RSCC and LSCC. Methods: Between 2015 and 2018, 63 patients underwent colon surgical resection for whom we had available tissues for CD63 and CD9 IHC staining. Two pathologists independently scored CD63 and CD9 expression in the tumor and adjacent normal mucosa (ANM). Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean quick-score (Q-score) was calculated (intensity x percentage). Unpaired t test was used for statistical analysis. Results: Median age was 64 (range 33-78). Females represented 60% of our cohort. Caucasians, African Americans and other Ethnicities represented 55%, 40% and 5% respectively. The sidedness was designated as RSCC in 52% and as LSCC in 48%. The ANM and Tumor CD63 Q scores were 225 vs 191 (p = 0.009) in RSCC and 224 vs 154 (p = 0.0001) in LSCC respectively. The ANM and Tumor CD9 Q scores are 134 vs 152 (p = 0.142) in RSCC and 135 vs 154 (p = 0.137) in LSCC respectively. In patients with RSCC and LSCC, the mean Tumor CD63 Q score is 191 vs 154 (p = 0.024), while the mean ANM CD63 Q score is 225 vs 224 (p = 0.920). The mean Tumor CD9 Q score is 152 and 154 (p = 0.883) and the mean ANM CD9 Q score is 134 vs 135 (p = 0.926). Conclusions: In our cohort of patients with RSCC and LSCC, the exosomal marker CD63 expression is lower in the tumor compared to the ANM. While ANM CD63 expression was similar between RSCC and LSCC, tumor CD63 expression was higher in RSCC compared to LSCC. The exosomal marker CD9 was not found to have significant differential expression between ANM and tumor and between RSCC and LSCC. To our knowledge, this is the first study to explore exosomal markers expression using IHC in patients with RSCC and LSCC.
Pulmonary Infective Endocarditis
Authors: Raquel Prieto-Arévalo, Patricia Muñoz, Gregorio Cuerpo, Amaia Marí-Hualde, Laura Castelo-Corral, Enrique Navas-Elorza, Carmen Cifuentes-Luna, Maria del Mar Alonso-Socas, Lucía Boix-Palop, Manuel Martínez-Sellés
Journal: Journal of the American College of Cardiology (2019)
Effect of concurrent TP53 mutation in EGFR/ALK/ROS1 positive non-small cell lung cancer treated with first-line TKI therapy: A Single Institution Retrospective Study.
Authors: Sandhya Sharma, Emily Miao, Joanna Stein Fishbein, Chung-Shien Lee, Kevin M. Sullivan, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2019)

e20592 Background: Tyrosine Kinase Inhibitors (TKI) are the mainstay of therapy for patients (pts) with EGFR/ALK/ROS1 positive (pos) non-small cell lung cancer (NSCLC), however resistance to these drugs is inevitable and remains a clinical challenge. The cause for early resistance leading to progression has not been fully understood, but several mechanisms have been reported. We conducted a retrospective study to determine the impact of concurrent TP53 mutation (TP53m) in this population. Methods: NSCLC pts treated with first line TKI from 01/2014 to 06/2017 were studied. Descriptive statistics were computed. Progression was equated with TKI resistance (TKIr). We compared time to TKIr among pts with TP53m to those without. Standard survival analysis methods (i.e., Kaplan-Meier curves and multivariable Cox proportional hazards regression) were used. Results: Forty-two subjects on first line treatment TKI were included. The mean (SD) age was 67.2 (14.7) years. 37 (88%) were EGFR, 4 (10%) were ALK and 1 (2%) were ROS pos. 76% were female, 50% White, 74% non-smokers and 50% had a TP53m. The estimated median time to TKIr was 19.4 months. At 24 months from start of therapy, the predicted probability of not reaching TKIr was 46% (95% CI: 26-64%). The estimated median time to TKIr among those without TP53m is 19.4 months vs 14.4 months in those with TP53m (p = 0.13). The predicted probability of no TKIr at 12 months from start of therapy among those with and without TP53m were 59% and 80%, respectively. In multivariable analysis, TP53 status remained nonsignificant (p = 0.08) after adjusting for line of therapy. Conclusions: TP53m has been associated with worse prognosis in various cancers. The results from the studies looking at association between TP53m and NSCLC with targetable mutation have been mixed, with few studies demonstrating the association of TP53m with poor survival and earlier treatment resistance. In our study, although there was a tendency towards improved survival and delayed TKIr in the cohort without TP53m, it was not statistically significant, which may be due to small sample size. Further studies looking at concurrent TP53m and targetable mutation are required, which may help clinicians deciding how to direct therapy in this population.