tbuckley/cabot-search huggingface dataset:
Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
Authors: Kellie N. Smith, Nicolas J. Llosa, Tricia R. Cottrell, Nicholas Siegel, Hongni Fan, Prerna Suri, Hok Yee Chan, Haidan Guo, Teniola Oke, Anas H. Awan, Franco Verde, Ludmila Danilova, Valsamo Anagnostou, Ada J. Tam, Brandon S. Luber, Bjarne R. Bartlett, Laveet K. Aulakh, John-William Sidhom, Qingfeng Zhu, Cynthia L. Sears, Leslie Cope, William H. Sharfman, Elizabeth D. Thompson, Joanne Riemer, Kristen A. Marrone, Jarushka Naidoo, Victor E. Velculescu, Patrick M. Forde, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Jennifer N. Durham, Hao Wang, Dung T. Le, Sune Justesen, Janis M. Taube, Luis A. Diaz, Julie R. Brahmer, Drew M. Pardoll, Robert A. Anders, Franck Housseau
Journal: Journal for ImmunoTherapy of Cancer (2019)

Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently.We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment.These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.
Brachytherapy use for favorable-risk prostate cancer continues to decline in both academic and community centers despite superior survival compared to dose-escalated external beam radiation therapy.
Authors: Kevin H. Nguyen, Sagar Anil Patel, Alan K. Lee, Puja Venkat, Albert Chang
Journal: Journal of Clinical Oncology (2019)

105 Background: Several studies have highlighted the decline in brachytherapy (BT) utilization for localized prostate cancer, possibly due to reduced reimbursement, decreased provider efficiency, and decline in operative training. We sought to evaluate the most contemporary trends in BT versus dose-escalated external beam radiation therapy (DE-EBRT) use, as well as its impact on survival. Methods: We identified 134,713 men in the National Cancer Database with favorable risk prostate cancer (Gleason 6-7, clinical stage T1-2, and PSA &lt; 20 ng/mL) who were treated with BT or DE-EBRT alone from 2004 to 2014. Multivariable logistic regression was used to identify independent determinants of treatment modality. Overall survival (OS) was compared between modalities using Kaplan-Meier and log-rank tests in propensity score-matched cohorts adjusted for age, race, comorbidities, year of diagnosis, and treatment facility. Results: The 10-year OS rate was higher for BT compared to DE-EBRT (BT 74.5%, DE-EBRT 68.2%, P&lt; .0001). However, consistent with prior analyses, BT use decreased significantly from 59.3% in 2004 to 34.7% in 2014 ( P value for trend &lt; .0001), with a corresponding rise in EBRT. The rate of decline was similar in academic and community centers; however, BT was consistently more often utilized in the community (63% in 2004, 61% in 2014). On multivariable analysis, BT was least likely to be used in men who were black (vs. white or Asian), treated at an academic (vs. community) center, and insured by Medicaid (vs. Medicare or private). Conclusions: Nationally, despite its superior survival and cost-effectiveness, prostate brachytherapy continues to be superseded by DE-EBRT in favorable risk prostate cancer, especially in men treated at academic centers and insured by Medicaid, with striking racial disparities. Payment reform, patient/provider education, and more robust resident training in prostate brachytherapy are urgently needed to help reverse this trend and ensure equal access to this efficacious treatment modality.
Correlation of peripheral blood smear review and bone marrow biopsies for benign hematology Outpatient referrals.
Authors: Adrian REYES Bersabe, Michael B. Osswald, Nathan M. Shumway
Journal: Journal of Clinical Oncology (2015)

e17668 Background: Peripheral blood smear (PBS) interpretation is an important diagnostic skill for Hem/Onc clinicians (HOC). We explored practice patterns of PBS utilization and how it may guide the HOC in further testing. Methods: A retrospective review was conducted on 474 consecutive outpatient referrals for benign hematology diagnoses (ICD-9 codes 280-289) from Aug 2011 to May 2012. Patient demographics and diagnostic tests were recorded. In cases with PBS review, we recorded testing based upon the HOC’s findings. Results: 451 records met inclusion criteria. The median age was 55 with males representing 51.9% of the cohort. 44.3% were Caucasian, 22.4% African-American, and 32.2% “Other.” Distribution of disorders were 50.6% (n = 228) erythrocyte (RBC), 25.5% (n = 115) leukocyte (WBC), 11.3% (n = 51) platelet (PLT), and 12.6% (n = 57) “other.” A CBC was ordered in 81.4% cases (367/451). A PBS was ordered in 48% of these cases (176/367, 95% CI, p < 0.001). If a PBS was ordered, it was documented in 44.3% of cases (78/176). Of these, further testing occurred in 46.2% (36/78) representing 8% (36/451) of the cohort. A bone marrow biopsy (BMB) was performed in 7% of cases in which a CBC was ordered (26/367). Of the 36 cases in which PBS review led to testing, additional non-lab tests included one GI consult, an ultrasound, and 10 BMBs (27.8%). Of the 10 BMBs, one was obtained for a RBC disorder showing PMF, 4 for WBC disorders showing 2 cases of CML, one MPD, and one toxin-mediated marrow suppression, 3 were for low PLTs showing aplastic anemia, ITP, and large granular lymphocytic (LGL) leukemia, and 2 were for “other” diagnoses (splenomegaly and MGUS) showing PMF and MGUS. In 16 cases, the HOC obtained a BMB without prior PBS review. A specific diagnosis was found in 43.8% (7/16) of marrows and included a case of CLL, lymphocytic eosinophilia, LGL leukemia, MDS, ITP, metastatic carcinoma, and myeloma. Conclusions: PBS review led to testing in 8% of all benign hematology referrals, and a BMB was ordered in close to a third of these cases. A definitive diagnosis was made in all BMBs obtained after PBS examination, but when a BMB was performed without prior PBS review, definitive marrow findings were seen in less than 50% of cases.
Emergency Department Visits for Sports- and Recreation-Related Traumatic Brain Injuries Among Children — United States, 2010–2016
Authors: Kelly Sarmiento, Karen E. Thomas, Jill Daugherty, Dana Waltzman, Juliet K. Haarbauer-Krupa, Alexis B. Peterson, Tadesse Haileyesus, Matthew J. Breiding
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Traumatic brain injuries (TBIs), including concussions, are at the forefront of public concern about athletic injuries sustained by children. Caused by an impact to the head or body, a TBI can lead to emotional, physiologic, and cognitive sequelae in children (1). Physiologic factors (such as a child's developing nervous system and thinner cranial bones) might place children at increased risk for TBI (2,3). A previous study demonstrated that 70% of emergency department (ED) visits for sports- and recreation-related TBIs (SRR-TBIs) were among children (4). Because surveillance data can help develop prevention efforts, CDC analyzed data from the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP)* by examining SRR-TBI ED visits during 2010-2016. An average of 283,000 children aged <18 years sought care in EDs each year for SRR-TBIs, with overall rates leveling off in recent years. The highest rates were among males and children aged 10-14 and 15-17 years. TBIs sustained in contact sports accounted for approximately 45% of all SRR-TBI ED visits. Activities associated with the highest number of ED visits were football, bicycling, basketball, playground activities, and soccer. Limiting player-to-player contact and rule changes that reduce risk for collisions are critical to preventing TBI in contact and limited-contact sports. If a TBI does occur, effective diagnosis and management can promote positive health outcomes among children.
The tumor immune microenvironment differs between metastatic castrate resistant prostate cancer (CRPC) and hormone sensitive prostate cancer (HSPC).
Authors: Kobe Chi Yung Yuen, Ben Tran, Peter Gibbs, Angelyn Anton, Sanjeev Mariathasan, Shahneen Kaur Sandhu, Edward Ernest Kadel
Journal: Journal of Clinical Oncology (2019)

251 Background: Immune checkpoint inhibitors (CPIs) (anti-CTLA4, anti-PD-1/PD-L1 mAbs) have had limited monotherapy activity in prostate cancer (PC) compared to urothelial cancer (UC). Recent biomarker studies revealed molecular features associated w/ better efficacy/resistance to CPIs in UC. 1 Here we examined the tumor immune microenvironment (iTME) of hormone naïve/sensitive (HSPC) &amp; castrate resistant prostate (CRPC) specimens from primary &amp; metastatic sites, to determine if parallels to UC molecular correlates exist that will allow us to predict subsets of PC pts who are more likely to benefit from rational combination therapies w/ CPIs. Methods: Tumor FFPE archival tissues (HSPC, n = 98; CRPC, n = 46; Unk, n = 6) were sourced from a Royal Melbourne Hospital cohort of PC patients. Tissues were evaluated by H&amp;E for TILs &amp; IHC performed for PD-L1 (clones SP142 &amp; SP263) &amp; CD8. RNAseq was conducted &amp; Lund bladder molecular subtyping performed during bioinformatics analyses. TCGA PRAD dataset was used for further validation. Results: We first applied Lund molecular subtyping to broadly categorize this cohort into luminal/basal subtypes. CRPC tumors were almost entirely luminal, whereas HSPC tumors were mainly basal. Luminal PC tumors enriched for Wnt gene sets (p = 0.026) &amp; enriched for a genomically unstable (GU) subtype w/ higher expression of DNA damage repair (DDR) &amp; cell cycle gene sets (p = 0.082). Compared to CRPC, HSPCs had higher numbers of infiltrating CD8s (p = 4.37e-004), increased expression of T-effector, MHC-I antigen presentation machinery, immune checkpoints, macrophages &amp; activated stromal biology, including the fibroblast TGFβ response signature. PD-L1 on immune cells by SP142 &amp; SP263 was 30% &amp; 17% respectively &amp; was enriched in HSPC samples (SP142: CRPC 18% vs. HSPC 34%, p = 0.08). Within patients w/ CRPC, differences were minimal between primary &amp; metastatic samples. Conclusions: These analyses on the iTME contexture of PC reveal potentially actionable biological nodes for targeted therapies. These findings could inform future clinical strategies to improve CPI responses in CRPC &amp; HSPC w/ rationale combinations.1. Mariathasan et al. Nature 2018.
Abstract P268: Long and Short Sleep and Obesity in the Women’s Health Study
Authors: Eva M Durazo, Tiffany M Powell-Wiley, Susan Redline, Natalie Slopen, Aric Prather, David R Williams, Julie E Buring, Michelle A Albert
Journal: Circulation (2019)

Background: Although evidence suggests that extremes of sleep (i.e. long and short) are associated with cardiovascular disease-related risk factors in the general population, research examining the association between the extremes of sleep and obesity in older women is limited. Methods and Results: We used the Women’s Health Study (WHS) 2012-2013 follow-up cohort of 21,726 older women (mean age = 72.1 ± 6.0 years old) to examine the cross-sectional association between extremes of sleep and obesity. Women with cancer or missing body mass index (BMI) data were excluded. Long sleep was defined as &gt; 9 hours/day, short sleep as &lt; 6 hours/day, and sleep of 6-9 hours/day was the reference. Sleep duration and BMI were self-reported measures. Approximately 23.3% of women were obese (BMI ≥ 30 kg/m 2 ). Overall, women who were obese and had either long or short sleep were less likely to exercise, and more likely to have history of diabetes, depression symptoms, and lower education and income levels. Women who were obese and long sleepers were more likely to use alcohol and have history of hypertension, while short sleepers were more likely to be current smokers. Logistic regression analyses revealed that older women with long sleep and short sleep had 30% higher odds of obesity, respectively, compared to women who slept 6-9 hours, adjusting for age and race/ethnicity. These relationships were attenuated and lost significance when controlling for potential important confounders (Table 1). Conclusion: Older women reporting extremes of sleep had higher odds of obesity compared to women who sleep 6-9 hours, after control for age and race/ethnicity. Further adjustment for traditional cardiovascular risk factors and socioeconomic parameters resulted in loss of significance.
<i>MET</i> Overexpression and Amplification Define a Distinct Molecular Subgroup for Targeted Therapies in Gastric Cancer.
Authors: Jia Wei, Nandie Wu, Jie Shen, Juan Du, Xia Sun, Zihan Lin, Baorui Liu
Journal: Journal of Clinical Oncology (2015)

e15076 Background: Gastric cancer is among the leading causes of cancer deaths. Currently, only trastuzumab, ramucirumab, and lapatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease. Methods: We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied using an in vitro histoculture drug response assay and the patient-derived GC xenograft model in vivo. Gene expression status was also analyzed for association with overall survival. Results: Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed (P= 0.045) in the histoculture drug response assay. Meanwhile, patient-derived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9%) and MET was amplified in 4 (4.1%). ROS1 and ALK overexpression were found in 25 (25.5%) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. There was no significant association found between overall survival and the MET or ROS1 status. We also observed a case that one advanced GC patient with MET-amplification experienced tumor shrinkage (PR by RECIST) after 3 weeks treated with crizotinib at the time of third-line chemotherapy failure. This patient also showed rapid clinical improvement, with decreased pain and improved performance status. Conclusions: Crizotinib may induce clinically relevant anticancer effects in MET-overexpressing or -amplified gastric cancer patients.
An open-label phase II study to evaluate PT2977 for the treatment of von Hippel-Lindau disease-associated renal cell carcinoma.
Authors: Eric Jonasch, Eric Kristopher Park, Sanjay Thamake, Mohammad Hirmand, W. Marston Linehan, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2019)

TPS680 Background: In von Hippel-Lindau (VHL), renal cell carcinomas (RCC) are of clear cell histology (ccRCC). HIF-2α has been established as an oncogenic driver in ccRCC, where VHL deficiency is the underlying genomic alteration. In this setting, HIF-2α accumulates under normoxic conditions, driving the expression of genes associated with progression of ccRCC, including vascular endothelial growth factor A ( VEGFA), cyclin D1 and other factors that contribute to tumor growth and proliferation. Management of VHL-associated renal tumors most often involves active surveillance until surgery is recommended for tumors larger than 3 cm to reduce the risk of metastasis. Repeated surgical procedures, which are often required, can carry significant morbidity. Systemic therapy options that can delay or obviate the need for surgery by reducing tumor size are needed. Methods: This open-label Phase 2 study will evaluate the efficacy and safety of PT2977, a highly selective small molecule inhibitor of HIF-2α, in VHL patients who have at least 1 measurable ccRCC (per RECIST 1.1). PT2977 will be administered orally at 120 mg once daily. Key inclusion criteria include a germline VHL alteration and at least 1 measurable solid ccRCC but no tumor &gt; 3.0 cm requiring immediate surgical intervention. Patients may have VHL-associated tumors in other organ systems. Key exclusion criteria include prior systemic therapy for VHL, evidence of metastatic disease, and history of a non-VHL-associated invasive malignancy in the past 2 years. The primary endpoint is objective response rate (ORR) of ccRCC tumors per RECIST 1.1. Secondary endpoints include duration of response (DOR), time to response (TTR), progression-free survival (PFS), time to surgery (TTS) for ccRCC tumors, and efficacy evaluations for non-ccRCC tumors. Safety and pharmacokinetics of PT2977 will also be evaluated. Patient recruitment is ongoing. Funding: Peloton Therapeutics, Inc. Clinical trial information: NCT03401788.
Three-dimensional lymph node volume and craniocaudal lymph node length as an independent risk factor for recurrence or presence of micrometastatis in clinical stage I non-seminomatous germ cell tumors: A retrospective study.
Authors: Joseph E. Maakaron, Pauley T. Gasparis, Sandra Althouse, Nasser H. Hanna, Lawrence H. Einhorn, Clint Cary, Costantine Albany, Marc Kohli
Journal: Journal of Clinical Oncology (2015)

e15547 Background: Testicular germ cell tumor is the most common malignancy in young adult males in the United States. A prior abstract[1] has studied non-invasive radiographical parameters such as craniocaudal lymph node length (CCNL) and nodal volume (NV) as predictors for the risk of micrometastasis or recurrence in clinical stage I testicular cancer. We aimed at validating that data in non-seminomatous testicular germ cell tumors (NSGCT). Methods: After obtaining the approval of our institutional review board, we reviewed the records of clinical stage I testicular cancer patients seen at our center between years 2000 and 2013. We selected NSGCT patients aged 15 years or older, with at least one year of follow-up, and a computed tomography (CT) scan at time of diagnosis with thin section axial images and coronal reconstructions generated at the time of imaging. The three dimensions of the largest lymph node were measured by our radiologist and the volume calculated. A logistic regression univariate and multivariate analysis was done to look for an association between CCNL or NV and recurrence rate. The multivariate analysis included whether the primary tumor was embryonal predominant or not. Results: 37 patients were identified that met the inclusion criteria. Fifty-one percent (19/37) had either relapsed or had pathologically positive lymph nodes after virgin retroperitoneal lymph node dissection. Logistic univariate analysis revealed a statistically significant correlation between relapse and the CCNL (p=0.01). The correlation between NV and relapse was not significant, but trended towards significance (p=0.09). Conclusions: In our sample of patients with NSGCT, we have shown that CCNL, but not NV, is associated with an increased risk of relapse. This is in agreement with a prior abstract1that suggested a correlation between CCNL and NV in NSGCT but not SGCT. Shortcomings of our study included a small sample size. Validation in a large collaborative cohort is warranted. [1] J Clin Oncol 32, 2014 (suppl 4; abstr 363)
Infusion of NKp30/KIR2DL2 Natural Killer Cell Ratio and Survival Post-Autologous Stem Cell Transplantation in Lymphomas
Authors: Luis Porrata, David J Inwards, Stephen M. Ansell, Ivana N Micallef, Patrick Johnston, Jose C Villasboas, William J. Hogan, Svetomir Markovic
Journal: Blood (2018)
Treatment and characteristics of stage II colon cancer patients residing in CDC Specialized Registry areas.
Authors: Mary Elizabeth O'Neil, Christie Eheman, Frances Babcock, Cyllene Morris, Vivien Chen, Timothy Styles
Journal: Journal of Clinical Oncology (2015)

6554 Background: Some guidelines advise adjuvant chemotherapy be considered after surgical resection for high-risk stage II colon cancer patients; however, high-risk criteria are ill-defined and the long term benefits debated. This study documents patterns of care by selected patient and tumor characteristics using a population-based cohort of stage II colon cancer patients diagnosed in 2011. Methods: We used data from 10 CDC Specialized Cancer Registries participating in the National Program for Cancer Registries’ (NPCR) Enhancing Cancer Registry Data for Comparative Effectiveness Research (CER) project to describe demographic and clinical characteristics of stage II colon cancer patients treated by surgery and adjuvant chemotherapy. We evaluated factors associated with adjuvant chemotherapy by logistic regression. Results: Of a total of 3,999 stage II colon cancer patients, 14.0% were treated with surgery and adjuvant chemotherapy compared to 83.6% by surgery alone. The patients treated with surgery plus adjuvant chemotherapy were more likely to be white (82.3%), non-Hispanic (83.8%), and younger but there were no differences by gender or urban residence. Most patients were insured by Medicare alone (28.2%) or private insurance (includes Medicare with private supplement) (45.9%). Approximately one-third (34.6%) had a T4 extension, 13.4% had < 12 lymph nodes examined, 21.7% had lymphovascular invasion and 21.6% were Grade III. Compared to surgery alone, the four characteristics associated with adjuvant therapy were younger age (median 61 years vs. 71 years; adjusted odds ratio [aOR]: 0.94, P< .01); T4 invasion (aOR: 4.38, P< .01); lymphovascular invasion (aOR 1.83, P< .01) and grade (aOR comparing Grade III to I: 1.78, P< .01). Conclusions: In this population-based cohort, younger stage II colon cancer patients with T4 lesions, lymphovascular invasion and a poorly differentiated tumor were more likely to receive adjuvant chemotherapy in addition to surgery. Ongoing data collection on outcomes, both recurrence and survival, will help clarify the benefits of adjuvant treatments in stage II colon patients. Better tools for risk stratification and predicting treatment benefits are still needed.