tbuckley/cabot-search huggingface dataset:
Improving the process for assessing patients (pts) emotional well-being and ensuring appropriate and timely interventions.
Authors: Sirisha Karri, Valorie Harvey, Susanne Evans, Tiffany Williams
Journal: Journal of Clinical Oncology (2018)

e18800 Background: Emotional distress can be a significant problem in oncology pts. Parkland Hospital System (PHHS)serves the underserved pts in Dallas county. Identifying and addressing emotional distress is challenging in these pts due to socio-economic, language and culture barriers. As part of ASCO Quality Training Project we chose QOPI measures 24 and 25. Audit of our new pts’ charts showed distress screening completed for only 50% and interventions documented in only 41% of identified pts. QOPI target for both is ≥ 80%. Methods: Project was implemented in PHHS oncology clinics for 8 months. Our aim was to complete PHQ2 and 9 depression screening in ≥80% of new pts with documented scores and interventions by second visit. Second measure was screening all oncology pt clinic visits at ≥ 80%. Current workflow for distress screening wherein nurses or medical assistants screen pts and inform physicians. Feedback session with staff showed greatest areas of concern were inadequate staff training, time constraints in clinic, lack of standardized process for documenting screening and interventions, and patient trust issues. Eight strategies were implemented 1. Brown bag lectures 2. Self-learning training module 3. Mock screening workshops 4. Real-time observations and feedback 5. Department policy 6. Enhanced EHR with best practice alerts linked to referrals 7. Reassignment of work with nurses required to do screening rather than medical assistants 8. Distress referral work queues and documentation flow sheets. Results: Screening rate increased from 53% to 80% in 5 months, dipped down to 76% for 3 months and then back up to 80%. For pts with scores > 10 chart audit showed our intervention documentation is up to 84%. Conclusions: Focused staff education and reassignment of work helped improve our distress screening rate. In addition we implemented some unique EHR enhancements that made it easier to manage documentation and referrals. Weekly performance monitoring and feedback helped to hardwire the practice. PHQ2-9 SCREENING COMPLETED BY SECOND VISIT 2016/2017 Dec Jan Feb Mar Apr May Jun Jul Aug Sep NO 50% 42% 40% 34% 25% 20% 24% 16% 31% 20% YES 50% 58% 60% 66% 75% 80% 76% 76% 76% 80% Target 80% 80%
Prospective analysis of cancer stem cell drug response assay for glioblastoma patients.
Authors: Tulika Ranjan, Candace M Howard, Jagan Valluri, Alexander Yu, Khaled Aziz, David Jho, Terrence D Julien, Jody Leonardo, Anthony Alberico, Antonio Cortese, Krista L Denning, Pier Paolo Claudio
Journal: Journal of Clinical Oncology (2018)

2057 Background: Over the past 20 years even with the aggressive standard of care (SoC) Stupp treatment protocol the prognosis of glioblastoma (GBM) has only minimally improved from 12 to 14 months. This is due in large part to the presence of chemo- and radiation-resistant GBM cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. We are using ChemoID, a CLIA certified and CAP accredited drug response assay that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. A prospective study was conducted evaluating the use of the ChemoID drug response assay in glioblastoma patients. Methods: Fresh tissue samples were collected for drug sensitivity testing from 61 glioblastoma patients enrolled in IRB approved protocol. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds Ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSCs, bulk tumor and combined assay responses to treatment; sensitivities/specificities, areas under the curve (AUC) were examined. Results: The data suggests that ChemoID guided treatment significantly enhanced tumor response. For every 5% increase in ex-vivo cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2-fold, OR = 2.2 (p = 0.01). Bulk of tumor assay was found not statistically significant. Median recurrence time was 20 months for patients with a positive ( > 40% cell kill) CSCs test versus only 3 months with a negative CSCs test, whereas median recurrence time was 13 months versus 4 months for patients with a positive ( > 55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Conclusions: The ChemoID CSCs drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. Glioblastoma cancer recurrence may occur quickly if the CSC test has a low ex-vivo cell kill rate, even if the bulk tumor test cell kill rate is high.
Genomic testing for HER2 mutation in patients with metastatic lobular carcinoma of the breast.
Authors: Dennis L. Citrin, Arun Kadamkulam Syriac, Vicki Doctor, Bradford A. Tan
Journal: Journal of Clinical Oncology (2018)

e13022 Background: Lobular carcinoma of the breast is classically ER/PR pos and HER2 neg by conventional testing (IHC and FISH). Despite this, genomic alterations in HER2 have been reported in 23% of relapsed CDH1-mutated lobular cancers, compared with only 1.7-2.0% of all breast cancers. (Ross et al. Hum Can Biol 2013) A prior publication describes a single case of HER2 mutated metastatic lobular cancer which responded to lapatinib and capecitabine.(Grellety et al. Ann Oncol 2016). Methods: We identified mutations in HER2 in 4/16 (25%) of pts with metastatic CDH1 mutated lobular carcinoma tested by Next Generation Sequencing (NSG) (Foundation One) . In only one of the four pts was HER2 amplified. Based on the NSG results, we treated all four patients with HER2 directed therapy. Results: All 4 patients achieved durable responses and continue on therapy at the present time. Conclusions: HER2 targeted therapy may produce durable clinical remission in patients with CDH1 and HER2 mutated metastatic lobular carcinoma of breast, even in the presence of negative results of conventional HER2 testing. Patients with metastatic lobular carcinoma should have genomic testing with NSG. If NSG indicates the presence of HER2 mutation, treatment with HER2 directed therapy should be considered. Patient Disease sites Prior systemic treatment Response (by RECIST) Duration of response (mos) 1 Breast, Liver Chemo + hormone PR 4+ 2 Breast, Liver, Bone Chemo + hormone PR 3+ 3 Breast, Liver, Bone Chemo + hormone PR 8, 11, 7+* 4** Chest wall Chemo + hormone CR 34+ * Response to 3 successive lines of HER directed treatment ** HER2 amplified also
Systemic immune-inflammation index to predict survival in Caucasian patients with metastatic urothelial carcinoma.
Authors: Patrik Palacka, Michal Mego, Terezia Mikulova, Michal Chovanec, Katarina Kalavska, Daniela Svetlovska, Jana Obertova, Katarina Rejlekova, Zuzana Sycova-Mila, Karol Kajo, Jozef Mardiak
Journal: Journal of Clinical Oncology (2017)

e16015 Background: The systemic immune-inflammation index (SII) is a prognostic factor in various malignancies that probably reflects a state of immunity. The objective of this retrospective analysis was to explore prognostic value of the SII at baseline and at week 6 during first-line platinum-based chemotherapy in Caucasian population with metastatic urothelial cancer (MUC). Methods: We evaluated 185 consecutive MUC (152 bladder, 72 upper tract) patients (139 men) treated with first-line platinum-based chemotherapy at National Cancer Institute between 2000-2015. Median Karnofsky index was 90% (30–100%), visceral metastases were present in 86 patients. SII was based on platelets (P), neutrophils (N) and lymphocytes (L) counts defined as PxN/L. Progression-free survival (PFS), overall survival (OS) and their 95% CI were estimated by Kaplan-Meier method and compared with logrank test. The study population was dichotomized by median into high SII and low SII groups. Multivariate Cox regression analysis included Karnofski index, status of visceral metastases together with baseline SII and SII at week 6, respectively. Results: At median follow-up 10 months (1-139 months), 170 patients experienced disease progression and 168 of them died.Patients with low SII at baseline had significantly better PFS and OS opposite to those with high SII (HR = 0.62, 95% CI 0.45-0.84 for PFS and HR = 0.52, 95% CI 0.38-0.71 for OS, respectively). Similarly, patients with low SII at 6 weeks had significantly better PFS and OS compared to those with high SII (HR = 0.61, 95% CI 0.45-0.83 for PFS and HR = 0.54, 95% CI 0.40–0.74 for OS, respectively). Multivariate analysis confirmed independent prognostic value of baseline SII and SII at week 6 for PFS and OS. Conclusions: Both, the SII at baseline and at week 6 during treatment with first-line chemotherapy represent independent prognostic factors for Caucasian population with MUC. Based on SII, patients could be stratified into future clinical trials. MUC patients with high SII might be candidates for an experimental first-line treatment.
Regimen-specific costs of chemotherapy for breast cancer (BC).
Authors: Sharon Hermes Giordano, Jiangong Niu, Mariana Chavez-Mac Gregor, Hui Zhao, Daria Zorzi, Ya-Chen T. Shih, Benjamin D. Smith, Chan Shen
Journal: Journal of Clinical Oncology (2016)

6519 Background: Although communicating costs of treatment with patients is important for high-quality care, a lack of data on cost has been a major hindering factor. This is especially concerning for BC in which numerous guideline-concordant BC adjuvant chemotherapy regimens exist. This study’s objective was to generate estimates of costs for such regimens from payers’ and patients’ perspectives in a large insured US population. Methods: Adult women with incident BC (2008-2012) in Marketscan, full coverage 6 mo before to 18 mo after diagnosis, no secondary malignancy within 1 yr of diagnosis, and who received chemotherapy within 3 mo of diagnosis were included (n=14,643). Total and out of pocket (OOP) costs were calculated using all claims within 18 mo of diagnosis and were normalized to 2013 dollars. The extended estimating equations (EEE) method was used to assess cost by regimen adjusting for demographic and clinical factors. Separate analyses were conducted for patients who did and did not receive trastuzumab (Tr). Results: Costs by regimen are shown in the table; statistically significant results are bolded. Other factors significantly impacting total adjusted costs included surgery, radiation, reconstruction, and use of G-CSF. Conclusions: The costs of BC chemotherapy vary widely across regimens and patients bear a substantial OOP burden. These data can help inform discussions regarding the relative value of BC therapies. N Insurance Payment ($) OOP Payment ($) Unadjusted Median Adjusted Mean Difference Unadjusted Median Adjusted Mean Difference Non-Tr Regimens 11,209 TC 5,159 76,200 Ref. 2,569 Ref. AC 519 68,034 -4,080 2,349 -101 AC+P 740 85,282 7,074 2,883 382 AC+T 603 87,604 11,347 3,043 297 CMF 249 62,302 -9,038 2,104 -142 TAC 728 104,197 20,354 3,383 276 ddAC+P 1,322 92,960 8,091 2,983 380 ddAC+wP 752 88,137 6,519 3,071 341 Other 1137 84,945 18,186 2,590 179 Tr Regimens 3,434 TCarboTr 1,956 169,567 Ref. 3,513 Ref. AC+PTr 202 142,937 -20,168 3,811 96 ddAC+PTr 376 165,718 -12,181 3,776 139 TCycloTr 291 146,790 -23,991 3,193 -396 Tr only 158 106,369 -46,936 2,016 -912 PTr 121 141,455 -20,209 1,987 -841 Other 330 147,052 -14,188 3,382 244 T-docetaxel, A-doxorubicin, C-cyclophosphamide, P-paclitaxel, M-methotrexate, F-5FU, dd-dose dense, w-weekly
Open-label, multicenter, randomized phase III trial of pemetrexed/carboplatin doublet vs pemetrexed singlet in chemotherapy-naïve elderly patients aged 70 or more with advanced non-squamous non-small cell lung cancer and good performance status.
Authors: Dae Ho Lee, Eun Kyung Cho, Jin Seok Ahn, Dong-Wan Kim, Byoung Chul Cho, Ki Hyeong Lee, Sang-We Kim
Journal: Journal of Clinical Oncology (2016)

9081 Background: We aimed to compare pemetrexed/carboplatin doublet (PC) versus pemetrexed singlet (P) in chemotherapy-naïve elderly patients aged 70 or more with advanced non-squamous non–small-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Methods: In an open-label multicenter phase III randomized trial, elderly patients aged 70 or more with advanced non-squamous NSCLC, ECOG PS of 0-1, no prior chemotherapy, adequate organ function and measurable disease were assigned to PC doublet (P, 500 mg/m2; C, area under the curve of 5) or P singlet (500 mg/m2) after stratified randomization according to center, gender and Charson Comorbidity Index (CCI). The treatment was given every 3 weeks till disease progression, unacceptable toxicity or withdrawal of consent. However, carboplatin was given only for the first four cycles. The primary end point was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, and safety. Results: A total of 267 eligible patients were enrolled from six centers between March 2012 and October 2015; median age was 74 years (70~86); 95% had PS of 1; 65% were men; and 63% had CCI of 1 or more. The median PFS was 5.5 months for PC doublet and 4.3 months for P singlet, respectively (hazard ratio [HR], 0.85; 95% CI, 0.64 to 1.12; P = 0.246). The median survival time was 12.5 months for PC and 9.3 months for P, respectively (HR, 1.03; 95% CI, 0.70 to 1.52; P = 0.865). There were 13 deaths (4.9%) during the treatment. Conclusions: The addition of carboplatin to pemetrexed did not show the improvement of survival time in elderly patients aged 70 or more with advanced non-squamous NSCLC and ECOG PS of 0-1. Updated data will be presented. Clinical trial information: NCT01593293.
Letter by Koh Regarding Article, “PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)”
Authors: Kwang Kon Koh
Journal: Circulation (2018)

Mefford et al 1 report that that lifelong exposure to low PCSK9 (proprotein convertase subtilisin/kexin type-9) levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.Recent studies showed that low-density lipoprotein (LDL)-cholesterol levels <25 mg/dL or <15 mg/dL on a PCSK9 inhibitor, alirocumab, were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events, although cataract incidence increased 3 times in the group achieving LDLcholesterol levels <25 mg/dL. 2 However, the follow-up period is not enough to be safe.Although evolocumab was not correlated with reduced cognitive function over a median of 19 months, 3 more prolonged exposure to extremely low LDLcholesterol levels could cause neurocognitive dysfunction, cataract, and new-onset diabetes mellitus, because it would impair cellular function, although these studies reported no incidence of diabetes mellitus.Statins are important for preventing adverse cardiovascular events in patients with both a high risk and a low risk of vascular disease by reducing the levels of LDL-cholesterol.However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes mellitus. 4This was previously hypothesized to be attributable to off-target effects, but recent studies have demonstrated that it was attributable to on-target effects. 4Like statins, PCSK9 inhibitors may increase adverse effects and increase the risk of type 2 diabetes mellitus.In the mendelian randomization study, data from cohort studies, randomized controlled trials, case control studies, and genetic consortia were used to estimate associations of PCSK9 genetic variants with LDL-cholesterol, fasting blood glucose, hemoglobin A1c, fasting insulin, etc, and risk of type 2 diabetes mellitus by using a standardized analysis plan, meta-analyses, and weighted gene-centric scores.Combined analyses of 4 independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL-cholesterol showed associations with increased fasting glucose (0.09 mmol/L; 95% CI, 0.02-0.15),bodyweight (1.03 kg; 0.24-1.82),waist-to-hip ratio (0.006; 0.003-0.010),and an odds ratio for type 2 diabetes mellitus of 1.29 (1.11-1.50).PCSK9 variants associated with lower LDL-cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes mellitus. 5In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. 4,5
Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Model for Inorganic Arsenic Exposure Using Data from Two Diverse Human Populations
Authors: Hisham A. El-Masri, Tao Hong, Cara Henning, William Mendez, Edward E. Hudgens, David J. Thomas, Janice S. Lee
Journal: Environmental Health Perspectives (2018)

Multiple epidemiological studies exist for some of the well-studied health endpoints associated with inorganic arsenic (iAs) exposure; however, results are usually expressed in terms of different exposure/dose metrics. Physiologically based pharmacokinetic (PBPK) models may be used to obtain a common exposure metric for application in dose-response meta-analysis.A previously published PBPK model for inorganic arsenic (iAs) was evaluated using data sets for arsenic-exposed populations from Bangladesh and the United States.The first data set was provided by the Health Effects of Arsenic Longitudinal Study cohort in Bangladesh. The second data set was provided by a study conducted in Churchill County, Nevada, USA. The PBPK model consisted of submodels describing the absorption, distribution, metabolism and excretion (ADME) of iAs and its metabolites monomethylarsenic (MMA) and dimethylarsenic (DMA) acids. The model was used to estimate total arsenic levels in urine in response to oral ingestion of iAs. To compare predictions of the PBPK model against observations, urinary arsenic concentration and creatinine-adjusted urinary arsenic concentration were simulated. As part of the evaluation, both water and dietary intakes of arsenic were estimated and used to generate the associated urine concentrations of the chemical in exposed populations.When arsenic intake from water alone was considered, the results of the PBPK model underpredicted urinary arsenic concentrations for individuals with low levels of arsenic in drinking water and slightly overpredicted urinary arsenic concentrations in individuals with higher levels of arsenic in drinking water. When population-specific estimates of dietary intakes of iAs were included in exposures, the predictive value of the PBPK model was markedly improved, particularly at lower levels of arsenic intake.Evaluations of this PBPK model illustrate its adequacy and usefulness for oral exposure reconstructions in human health risk assessment, particularly in individuals who are exposed to relatively low levels of arsenic in water or food. https://doi.org/10.1289/EHP3096.
P05.37 Hypofractionated radiosurgery for benign skull base tumors
Authors: R Daniel, C Hamisch, S Grau, K Jablonska, C Baues, M Kocher, H Treuer, M Ruge
Journal: Neuro-Oncology (2018)

The use of single fraction stereotactic radiosurgery (SRS) is limited by tumour size (>3cm) and/or close proximity to critical structures (e.g. cranial nerves/optical pathway/pituitary gland). Here we present data using hypofractionated SRS (hSRS) for the treatment of benign skull base tumors either > 3 cm and/or neighboring critical structures. In this single center retrospective analysis we consecutively included all patients with benign skull base tumors (meningeomas, nonsecreting pituitary adenomas, schwannomas) who underwent Cyberknife® hSRS using a tumor surface dose of 25 Gy applied in five fractions (isodose level 70–80%) between 2012 and 2016 with a minimum follow-up of 6 months. Patient data were analyzed in terms of tumor control (defined as no further intervention required), symptom control (stable clinical condition) and incidence of early and late treatment related complications (rated by using the Common Terminology Criteria for Adverse Events, CTCAE; v4.03). 33 patients (f:m = 20:13, median age = 58 years) were treated with hSRS. Tumor entities were meningiomas (n=22), pituitary adenomas (n=8), vestibular- (n=1) and trigeminal nerve schwannomas (n=2). 42% underwent surgery prior hSRS. Mean tumor volume was 9.4 ml (0.6–35 ml). Median follow-up was 23 months (6–52 months). The actuarial 1-, 2-, and 4-year tumor control rate was 100%, 94.5% and 94.5%, respectively. Symptoms improved in 38% (n=8) of symptomatic cases (n=21). Transient adverse events (CTCAE grade I and II) were observed in 9% of the cases (headache n=1, arm paresis n=1, partial alopecia n=1). No permanent adverse events were observed. Our treatment results show low rates of mild adverse events and encouraging tumor control rates which are consistent with those reported in literature.
Relationship of acquired resistance of myeloma cells to bortezomib with Lyn and Src induced inhibition of PP2A and effect of treatment with the tyrosine kinase inhibitor dasatinib.
Authors: Barry Paul, Daniel Feinberg, Pasupathi Sundaramoorthy, J. Brice Weinberg, Yubin Kang
Journal: Journal of Clinical Oncology (2018)

8047 Background: Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States. Proteasome inhibitors—especially bortezomib (BTZ)—are a mainstay of treatment in MM, but nearly all patients eventually develop resistance to these agents. We hypothesize that resistant cells are escaping BTZ induced cell killing via dedifferentiation to a more primitive state resulting in inhibition of the tumor suppressive activity of PP2A. Methods: MM cell lines (RPMI-Dox, MM1R, and OPM1) were grown in media with increasing concentrations of BTZ over time to select for resistance, and then treated with dasatinib. MTT assays were conducted to confirm BTZ resistance. Sensitive and resistant cells were harvested for protein and RNA and evaluated through standard qRT-PCR, flow cytometry, and immunoblotting methods to determine levels of PP2A-C, Src, and Lyn, as well as the differentiation markers CD138 and IRF4. Results: MTT assays verified significant resistance in cells grown with BTZ (mean IC50 225.80 ±49.76 nM) compared to parental cells (mean IC50 7.02 ±3.97 nM). Immunoblotting confirmed differential phosphorylation of the Y307 inhibitory site of PP2A-C in the resistant cells. Levels of Src and Lyn RNA and protein were increased in the resistant cells, and treatment with the multikinase inhibitor dasatinib selectively increased cell death in the resistant cells (IC50 1.31 ±0.11 nM). Additionally, expression of the differentiation markers CD138 and IRF4 was absent in the BTZ resistant cells while being appropriately expressed in the parental cells. Conclusions: Our experiments show that inhibition of PP2A plays a significant role in acquired resistance to BTZ and that this process is primarily driven by increased expression of Src and Lyn. Inhibition of Src and Lyn activity with dasatinib was able to overcome this effect and selectively resensitize the resistant cells. Our data also imply that the resistant cells may be dedifferentiating to a more primitive state as evidenced by absent IFR4 and CD138 expression. These data suggest a role for kinase inhibitors in myeloma patients with acquired resistance to BTZ.