tbuckley/cabot-search huggingface dataset:
Results of a survey of oncology nurses assessing practice patterns and adherence to antiemetic guidelines.
Authors: Rebecca Anne Clark-Snow, Cynthia N. Rittenberg, Mary Lou Affronti
Journal: Journal of Clinical Oncology (2016)

e21647 Background: Chemotherapy-induced nausea and vomiting (CINV) can be prevented in most patients with use of evidence-based guideline-recommended antiemetic regimens. However, studies suggest that adherence to antiemetic guidelines is suboptimal in both US (Gilmore 2014) and European (Aapro 2012) oncology practices. Oncology nurses, as part of a multidisciplinary team, can help promote appropriate antiemetic prophylaxis. Methods: In Sept 2015, ONS:Edge invited ~8,000 practicing US-based oncology nurses to participate in an online survey; 531 responded. Survey goals were to assess antiemetic guideline awareness and practice patterns of antiemetic use for prevention of CINV in highly (HEC) and moderately emetogenic chemotherapy (MEC) settings, determine adherence to guideline recommendations, and query barriers to adherence. Results: Nurses were most familiar with NCCN (73%) and ASCO (48%) guidelines. Utilization of antiemetics revealed low adherence to guideline recommendations, particularly in the HEC setting. Only 17% of nurses reported most ( > 75%) of their patients having CINV optimally controlled. In HEC there was a significant (p = 0.038) relationship between adherence and estimated CINV control. The predominant barrier interfering with use of guideline-recommended antiemetic prophylaxis was physician preference (reported by 71% respondents). Others included satisfaction with current antiemetics (27%), and product cost/insurance (26%) or formulary coverage (25%). Conclusions: Consistent with prior studies, this nursing survey revealed low adherence to antiemetic guidelines. While awareness of guideline recommendations can be improved, addressing reported barriers interfering with use of guideline-recommended antiemetics is critical to improving CINV control for patients. Setting Guideline1 Recommendation Antiemetics Utilized (% respondents) Calculated Guideline Adherence3 Acute Delayed Acute Delayed Acute Delayed 5HT3 RA + -- 95% 78% 73% 25% HEC DEX + DEX + 93% 71% NK1 RA NK1 RA2 81% 33% 5-HT3 RA + 5-HT3 RA or 95% 80% 85% 91% MEC DEX DEX 89% 61% 1ASCO/MASCC/NCCN; 2Unless fosaprepitant used Day 1; 3Calculated based on actual reported use of guideline-recommended agents
The influence of socioeconomic status, tumor characteristics and patterns of breast cancer care on breast cancer specific survival among elderly women.
Authors: Amanda L. Kong, Ann B Nattinger, Emily L McGinley, Michael Nattinger, Liliana E Pezzin
Journal: Journal of Clinical Oncology (2018)

6557 Background: The purpose of this study was to examine the relationship between patient demographic and socioeconomic status (SES), tumor characteristics, initial and follow-up breast cancer care, and 3-year breast cancer mortality among a population-based cohort of elderly women with incident breast cancer. Methods: We identified women with newly diagnosed breast cancer in 2006-2009 from the Surveillance and Epidemiology End Result study linked with Medicare claims (SEER-Medicare). A Classification and Regression Tree (CART) model was applied to 15 individual indicators of neo-adjuvant and adjuvant breast cancer treatment, tumor characteristics, and patient demographic and SES variables to identify patterns (i.e. combinations of variables) with the greatest discriminant value in predicting 3-year mortality by cause of death (outcome = breast cancer vs. other causes vs. alive) . Results: Nineteen unique patterns were identified as best discriminating 3-year mortality by cause of death. Breast cancer mortality probabilities associated with these patterns ranged from 2.6% to 39.7%. CART identified the number of positive nodes as the best single discriminator between high and lower breast cancer mortality, followed by the use radiation therapy and tumor stage. Patient’s SES was a discriminant factor in four of the ten patterns associated with high ( > 15%) breast cancer mortality while non-use of adjuvant hormonal therapy was a discriminant factor in six of the ten high breast cancer mortality patterns. Receipt of treatment within 50 days from diagnosis was associated with two of the lowest probabilities of breast cancer mortality (3.1% and 7.7%). Conclusions: Greater adoption of certain patterns of care could improve breast cancer survival of elderly women with incident disease overall, and reduce SES disparities therein.
Phase I study of HC-1119, an androgen receptor inhibitor: Results from the dose escalation and expansion cohorts.
Authors: Feng Bi, Li Zheng, Jiyan Liu, Ke Cheng, Peng Chao, Yuwen Zhou, Qiang Wei, Hao Zeng, Pengfei Shen, Zhengqing Shu, Zhongxiu Zhou, Wei Zheng, Yuanwei Chen, Xinghai Li
Journal: Journal of Clinical Oncology (2018)

e17021 Background: HC-1119 is a deuterated form of enzalutamide. Preclinical studies showed that 1) HC-1119 had a 2-fold increase in the plasma drug exposure and anti-tumor activity as compared with enzalutamide; 2) HC-1119 has a lower potential of inducing epilepsy as deuteration decreased the brain exposure of HC-1119 and its metabolite M2 in relative to enzalutamide. Thus, HC-1119 has the potential to be differentiated from enzalutamide through reduced dosages and a higher safety margin. Methods: HC-1119 was escalated in a 3+3 design from 40 mg once daily to 200 mg once daily of oral capsules in a 12-week period study (40 mg, N=3; 80 mg, N=9, 160 mg, N=9; 200 mg, N=3). Key eligibility: progressive mCRPC. PSA changes were dynamically observed. All patients were involved in pharmacokinetics (PK) studies. Results: All patients tolerated treatments well. There were no drug-related grade 3 and above adverse reaction, no withdrawal due to an adverse reaction, and no epilepsy in any patient. The most frequent (≥5%) treatment-related adverse events were fatigue (9%) and dizziness (5%). At week 12, PSA decreases by ≥50% (change over baseline) and ≥90% were observed in 62% patients and 52% patients, respectively. PSA decrease by ≥50% at any time during treatment period was observed in 70% patients. The PSA response rate was not dose-dependent, due to the plasma drug exposures of 40-200 mg in the range of a saturated drug-AR binding capability. Plasma PK profile showed an approximately 2-fold increase in parental drug M0, >80% reduction in M2, and >75% reduction in M1, compared with enzalutamide. Plasma drug exposures were proportionally increased from 40 to 160 mg of a single dose or continuous multiple doses. Two hundred mg PK profile was similar to 160 mg, indicating a dose saturation. The plasma active drug exposure (M0+M2) of 80 mg HC-1119 was similar to that of 160 mg enzalutamide in terms of Cmax, Ctrough, and AUC0-24h. Conclusions: HC-1119 was associated with a favorable safety profile and a good PSA response. Eighty mg HC-1119 once daily dosing schedule has been chosen for the phase III study.
Considerations for tisagenlecleucel dosing rationale.
Authors: Rakesh Awasthi, Karen Thudium Mueller, Gregory A. Yanik, Constantine Si Lun Tam, Susana Rives, Joseph McGuirk, Michael W. Boyer, Ulrich Jäger, Andre Baruchel, Gary Douglas Myers, Peter Borchmann, Samantha Mary Jaglowski, Heather E Stefanski, Michael Russell Bishop, Edward K Waldron, Jason Hamilton, Mariana Cota, Lida Bubuteishvili-Pacaud, Edmund K. Waller
Journal: Journal of Clinical Oncology (2018)

e15056 Background: Analyses supporting a safe and efficacious dose for CAR therapies are not well defined and vary across CAR-T programs. These analyses present key considerations to support tisagenlecleucel dose range. Methods: Data from pivotal phase II studies in relapsed/refractory (r/r) pediatric and young adult acute lymphoblastic leukemia (B-ALL) patients (pts) (ELIANA [NCT02435849, n = 75]; ENSIGN [NCT02228096, n = 29]) and adult diffuse large B cell lymphoma (DLBCL) pts (JULIET [NCT02445248, n = 99]) were used to investigate dose related impact on efficacy, safety, and exposure. Results: Unlike conventional drugs, the dose in T cell therapy is a result of various factors: pt characteristics, manufacturing attributes, indication. Final product attributes (transduction efficiency, %T cells, cell viability, total cell count), exposure (maximal in vivo expansion), efficacy, and safety were evaluated against dose. Dose and exposure were independent. Increased probability of any grade (G) or G 3/4 cytokine release syndrome (CRS) was associated with increase in dose in DLBCL; no impact was observed in B-ALL.CRS is manageable with the CRS management algorithm. Clinically meaningful responses were observed across the dose range. Results are presented in Table 1. The proposed dose range, as CAR positive viable T cells, were based on totality of these analyses considering the benefit-risk ratio (B-ALL: body weight (wt) ≤ 50 kg, 0.2-5.0 × 106/kg, for > 50 kg, 0.1–2.5 × 108; DLBCL: 0.6–6.0×108). Conclusions: Product attributes, efficacy, safety, and exposure of CAR T, as key parameters supported the recommended dose range. Clinical trial information: NCT02435849, NCT02228096, NCT02445248.Table Endpoints Analysis Pediatric ALL Adult DLBCL Product attributes Scatter plots/ regression No impact Exposure No impact Response Logistic regression Slight positive trend at lower end No impact *OR: 1.56 (95% CI: 1.000, 2.424) OR: 1.03 (95% CI: 0.624, 1.685) CRS No impact (any G or G 3/4 CRS); slight positive trend (grade 4 CRS) for wt adjusted dose Increased probability of CRS (G 3/4 or any G) *§OR: 0.79 (95% CI: 0.327, 1.911) §OR: 2.79 (95% CI: 1.394, 5.567) Neurologic events (NE) No impact *OR (for G ≥2 NE): 1.12 (95% CI: 0.736, 1.700) §OR: 0.99 (95% CI: 0.544, 1.801) OR: Odds ratio for 2-fold increase in dose *for total dose; §any grade safety endpoint
P09 Comparison of Liquid Biopsy and Histopathologic Results with Clinical Outcomes in Non–Small Cell Lung Cancer Patients
Authors: S. Zhang, J. Harris, T. Boyle, C. Williams, S. Antonia, A. Chiappori, J. Gray, T. Tanvetyanon, B. Creelan, E. Haura, M. Shafique, J. Fontaine, J. Cox, F. Kaszuba, R. Keenan, V. Nair, E. Toloza
Journal: Journal of Thoracic Oncology (2018)
Circulating PD-L1+ exosomes as potential prognostic and predictive biomarkers in pulmonary lymphoepithelioma-like carcinoma.
Authors: Mian Xie, Yingying Gu, Xiaojun Wu, Xinge Fu
Journal: Journal of Clinical Oncology (2018)

e24081 Background: Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a histologically distinctive subtype of NSCLC. Exosomes isolated from plasma of cancer patients play a role in the regulation of tumor progression. It is not clear whether PD-L1 carried by circulating exosomes correlates with clinical outcome s in pulmonary LELC. Methods: We detected PD-L1 expression from a discovery set and a validation set consisting of locally advanced-stage pulmonary LELC cohorts. Plasma exosomes were isolated using the exosome-specific dual-patterned immunofiltration (ExoDIF) and PD-L1 level in plasma exosome was analyzed by flow cytometry. Plasma exosomes were incubated with activated CD69+ human CD8+ T-cells ± PD-L1 inhibitor. Changes in CD69 expression levels on T cells were measured. PD-L1 expression in tumor tissues were evaluated by immunostaining. Plasma exosome were collected at baseline and at the end of chemotherapy or chemoradiotherapy. Results: 51.8% pulmonary LELC patients harbored PD-L1high exosomes, and 54.2% showed PD-L1 positive tumor cells in tumor tissue with 93% concordance between tissue and plasma exosomes (Sensitivity = 82%; Specificity = 100%). Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression. At the end of treatment, there was a significant correlation (r = 0.87; p = 0.003) between synchronous changes of PD-L1 level in plasma exosome and tumor size. Detection of plasma PD-L1high exosomes at the end of treatment was also a significant prognostic factor of progression-free survival (Hazard ratio = 9.3 [3.6; 24.1], p < 0.001) and overall survival (Hazard ratio = 10.2 [3.9; 26.2], p < 0.001), similar to the effects of PD-L1 expression in matched tumor tissues. Conclusions: Monitoring PD-L1 expression of circulating exosomes is a valuable tool to assess prognosis and tumor response in patients with pulmonary LELC. Pulmonary LELC patients may represent a potential group that will benefit from adjuvant PD-L1 blockade immunotherapy.
Effect of nationwide palliative care education program on lung cancer specialists.
Authors: Akira Inoue, Takuhiro Yamaguchi, Keiko Tanaka, Akihiro Sakashita, Keisuke Aoe, Kenji Eguchi
Journal: Journal of Clinical Oncology (2017)

e21715 Background: Although palliative care has owed an essential part of cancer treatment, palliative care specialists are still insufficient. Thus in Japan, the Palliative care Emphasis program on symptom management and Assessment for Continuous Medical Education (PEACE) was launched in 2008 to provide primary palliative care education for all physicians engaged in cancer treatment. However, the effect of PEACE program on participants was uncertain. Methods: We conducted web-based surveys for physicians belonging to the Japan Lung Cancer Society and assessed outcomes of the PEACE program across three domains: knowledge, practices, and difficulties regarding palliative care by using the palliative care knowledge questionnaire for PEACE (PEACE-Q), Palliative Care self-reported Practice Scale (PCPS), and the Palliative Care Difficulties Scale (PCDS), respectively. All of these instruments were already validated in previous studies. Results: In February 2015, the survey was distributed to 5300 physicians and 923 of those surveyed including 455 respiratory physicians, 345 pulmonary surgeons, and 35 medical oncologist responded to all questionnaires. The result of PEACE-Q, PCPS, and PCDS (low score is better) were significantly superior in physicians who had participated in the PEACE program (n = 519) compared with non-participants (n = 404) (28.0 vs. 24.5, 71.8 vs. 67.1, and 34.4 vs. 36.9, respectively). The PEACE participants made significantly better scores than non-participants in all domains of PEACE-Q (philosophy of palliative care, cancer pain, side effects of opioids, dyspnea, nausea and vomiting, psychological distress, delirium, communication, and community-based palliative care) and PCPS (pain, dyspnea, delirium, dying-phase care, communication, and patient- and family-centered care), and 3 domains of PCDS (alleviation of symptoms, expert support, and communication with the patient and family). Conclusions: The PEACE program improved knowledge and practice of palliative care in lung cancer specialists in Japan.
Dermatophytosis and STAT3 mutation
Authors: J.K. Simpson, P. Fröbel, S.L. Seneviratne, M. Brown, D.M. Lowe, B. Grimbacher, M. Fliegauf, L. Fearfield
Journal: British Journal of Dermatology (2018)

Dermatophytes are fungi that cause skin infections such as ringworm and athlete's foot. They are very unlikely to cause infection deeper inside the body in people with normal immunity. STAT3 (Signal Transducer and Activation of Transcription 3) mutations are genetic defects known to be associated with deep fungal infections. The authors, based in London and Freiburg, present a case report of a 45‐year old man of Indian descent who developed a mass in the groin associated with a widespread itchy rash. CT imaging showed that the groin mass extended into the abdomen. A biopsy of the groin mass showed extensive infiltration by the ringworm fungus Trichophyton interdigitale. Skin biopsy showed areas of ulceration with breakdown of collagen in the skin layer called the dermis, resembling that seen in so‐called perforating disorders, where damaged collagen fibres are spontaneously pushed through the skin. These changes, called pseudoperforation, can be seen with intense scratching. Deletion of the STAT3 gene was found in the patient's blood cells. The rash cleared and the groin mass reduced considerably after three months of oral antifungal treatment. The authors conclude that the unusual deep infection with this skin fungus was caused by the genetic abnormality and that the extensive rash was a reaction to this fungal infection.
Mutational landscape of uterine and ovarian carcinosarcomas.
Authors: Gulden Menderes, Siming Zhao, Carlton Schwab, Salvatore Lopez, Jonathan Black, Stefania Bellone, Dan-Arin Silasi, Elena Ratner, Masoud Azodi, Babak Litkouhi, Peter E. Schwartz, Joseph Schlessinger, Richard P Lifton, Alessandro Santin
Journal: Journal of Clinical Oncology (2016)

5589 Background: Carcinosarcomas (CS) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. While an increasing body of evidence supports the origin of both CS elements from a common epithelial cell that undergoes sarcomatous dedifferentiation, limited information is currently available about the role of somatic mutations (SNV) and copy number variations (CNV) in these rare tumors. The objective of our study was to evaluate the genetic landscape of uterine and ovarian CSs by whole-exome-sequencing (WES). Methods: We analyzed the mutational landscape of 63 fresh frozen CS biopsies and 5 primary CS cell lines by WES, most of which were matched to normal DNA from the same patients. We also performed multi region WES in separate carcinoma and sarcoma areas to resolve the genetic architecture and evolutionary histories of CS. Finally, in transfection experiments we validated somatic histone 2A and 2B mutations as potential drivers of epithelial-mesenchymal transition (EMT). Results: Our results demonstrated the presence of two major genetic types of uterine CSs and provided evidence that both subtypes, as well as ovarian CS, arise from sarcomatous transformation of carcinomas. We found an excess of mutations in histones H2A and H2B. We also found frequent deletions comprising TP53 and MBD3, and frequent amplification of chromosome segments containing PIK3CA, CCNE1, TERT and c-MYC. Amplifications of the histone cluster and TERT were significantly more frequent in CS than their epithelial counterparts. Stable transgenic expression H2A and H2Bin USC cell lines demonstrated that mutant, but not wild type H2A and H2B increased expression of markers of epithelial-mesenchymal transition (EMT), suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages resulting in these two components. Conclusions: Our results provide new insight into the origins and development of uterine and ovarian CS and defined the genetic landscape of this type of malignant tumor. These findings also suggest new therapeutic targets for these highly aggressive neoplasms.
TCT-405 Sex Differences and Outcomes Following Rotational Atherectomy: Do Women Receive Optimal Care?
Authors: Tom Ford, Alice Jackson, Kieran Docherty, Adnan Khan, Rajib Alam, Eric Yii, Hany Eteiba, Mitchell Lindsay, Stuart Watkins, Richard Good, Stuart Hood, Aadil Shaukat, Mark Petrie, Keith Robertson, Keith Oldroyd, Colin Berry, Paul Rocchiccioli, Margaret McEntegart
Journal: Journal of the American College of Cardiology (2018)
HDAC11 as a candidate therapeutic target in multiple myeloma.
Authors: Allison Distler, Jason B. Brayer, Mark Meads, Eva Sahakian, John Joseph Powers, Melissa Alsina, Taiga Nishihori, Rachid C. Baz, Javier Pinilla-Ibarz, Eduardo M. Sotomayor, Kenneth H. Shain
Journal: Journal of Clinical Oncology (2017)

8029 Background: Histone deacetylase (HDAC) inhibitors (HDI) have a therapeutic niche in multiple myeloma (MM) due to their ability to salvage proteasome inhibitor and immunomodulatory drug responsiveness in refractory patients, thus raising interest in this therapeutic class. Selective HDI may further improve therapeutic efficacy. Methods: B cell lymphopoiesis was evaluated using Tg-HDAC11-eGFP mice expressing eGFP regulated by the HDAC11 promoter and congenic mouse strains deficient in HDAC11 expression globally (B6.HDAC11 -/- ) or targeted to the B cell lineage (CD19Cre.HDAC11 -/- ). Molecular and pharmacologic means were used to impair HDAC11 in established MM cell lines. Viability was measured by activated caspase-3, Annexin/PI (A/PI) staining, and CCK-8 viability assay. Subcellular localization changes induced by HDI and identification of the novel binding partner IRF4 were assessed by proximity ligation assay (PLA). Results: Profound eGFP increases in PC of Tg-HDAC11-eGFP mice suggest HDAC11 influences late stage B cell development. In addition, HDAC11 deficiency results in dramatically reduced PC in the bone marrow and periphery. PC depletion in CD19Cre.HDAC11 -/- mice suggests activity inherent in B cells rather than via externally derived signals. Quisinostat (QS), an HDI with enhanced HDAC11 selectivity, showed dose-dependent cytotoxicity in 10 MM cell lines (EC50 1-10nM). This activity was synergistic with bortezomib (BTZ) and carfilzomib (CFZ) in RPMI-8226 cells, while synergism was amplified in the BTZ-resistant RPMI-8226-B25 cell line. Exposure of RPMI-8226 cells to QS decreased detection of nuclear, but not cytosolic, HDAC11. Targeted siRNA–mediated silencing of HDAC11 in RPMI-8226 cells activated caspase-3 and reduced viability by A/PI staining. PLA of MM cell lines showed a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, unmasking a potential mechanism for HDAC11-induced cytotoxicity in MM. This interaction was disrupted by QS. Conclusions: We show that HDAC11 inhibition reduces MM cell survival in vitro. Furthermore, we identify IRF4 as a binding partner for HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and MM survival.