tbuckley/cabot-search huggingface dataset:
Human papillomavirus (HPV) vaccination among survivors of childhood cancer: Predictors of non-initiation and population comparisons.
Authors: James L. Klosky, Melissa M. Hudson, Yanjun Chen, James A. Connelly, Karen Wasilewski-Masker, Can-Lan Sun, Liton Francisco, Laura Gustafson, Kathryn M. Russell, Gina M. Sabbatini, Jessica L. Simmons, Jocelyn M York, John A. Zaia, Anna R. Giuliano, Leslie L. Robison, F. Lennie Wong, Smita Bhatia, Wendy Landier
Journal: Journal of Clinical Oncology (2016)

10573 Background: The growing population of AYA cancer survivors is at high risk for HPV exposure, increasing risk for HPV-related cancers. Vaccination should protect survivors from HPV-related cancers, and per Healthy People 2020 the completion target is 80%, yet the prevalence of vaccine initiation and predictors of non-initiation are unknown. Methods: We administered a survey in 2013-14 to a cohort of 13-26-y-old cancer survivors 1-5y post-treatment. Multivariable logistic regression was used to compare Odds Ratio (OR) of vaccine initiation in survivors vs age and sex-matched US population and to determine predictors of vaccine non-initiation in survivors. Results: Of 679 survivors (Mean age = 18.8y, Mean time off tx = 2.7y) 55% were male, 64% were non-Hispanic white, 58% had leukemia/lymphoma, and 49% had household income < $50K/yr. Comparison with general population (stratified by age: 13-17y; 18-26y): Vaccine initiation rate in adolescent survivors (age 13-17) was 22%, significantly lower than matched population peers (43%, p < 0.0001). After controlling for sex, race, US region, household income, education, and year of data collection, adolescent survivors were 2.4-fold (p < .0001) more likely to be non-initiated compared with peers (males OR 3.0, p < .0001; females OR 2.1, p = .0004). Vaccine initiation rates in young adult survivors (18-26y) and peers were low (26.2% vs 24.5%, respectively) with no significant differences between groups (OR 1.1, p = 0.4). Within cancer survivor analysis (entire cohort):Predictors of vaccine non-initiation included lack of physician recommendation (OR = 13.5, p < .0001), learning about the vaccine from a friend (OR = 7.5, p = 0.0002), male sex (OR 3.3, p = 0.0001), never sexually active (OR = 2.3, p = 0.02) and not associating receipt of the HPV vaccine with being a responsible person (OR = 1.9, p = 0.0004). Conclusions: Vaccine initiation rates for survivors are low. Adolescent survivors are particularly vulnerable to HPV vaccine non-initiation compared to peers. Lack of physician recommendation is strongly associated with vaccine non-initiation among cancer survivors (irrespective of age), and should be targeted in vaccine promotion efforts. Clinical trial information: NCT01492582.
Longitudinal assessment of performance using the QOPI measure in Brazilian oncology care.
Authors: Cristiane Decat Bergerot, Errol Philip, Paulo Gustavo Bergerot, Edvane Birelo Lopes De Domenico, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2017)

e18184 Background: The Quality Oncology Practice Initiative (QOPI) provides a standardized approach to assessing performance on a series of evidence- and consensus-based process measures in oncology. In 2015, the QOPI was utilized in a large oncology practice in Brazil to provide a baseline assessment, identify practice deficiencies and guide improvements. Feedback was provided to the oncology team and specific actions identified. This study reports the results of the follow-up QOPI assessment 2 years after the initial baseline was recorded. Methods: From data obtained in 2015 instructions were established for the documentation of physical and psychological symptoms, and of diagnosis and treatment discussions with patient, side effects and infertility risk, informed consent, and genetic services. No significant differences were found in the sociodemographic and clinical characteristics of the patient cohorts. Results: There was an overall increase in performance (60.6% to 77.1%; p &lt; .01). Elements of medical care and of cancer management still consistently and appropriately documented (e.g., pathology, stage, and treatment). There were a significant improvement in performance on measures related to pain assessment (59.5% to 84.5%), and symptom/toxicity management (62.3% to 91.2%). Relatively poor performance persisted however, most notably in the assessment of patients’ psychosocial status (26.5%), discussion of treatment goals (45.6%) and fertility risks (7.4%). Informal feedback was garnered from team concerning areas of ongoing deficiency. Conclusions: There was a significant improvement in adherence to QOPI indicators. Performance in a number of domains remained relatively poor, despite clinical efforts. The reasons are likely multifactorial; and may include a lack of specific resources in a public service (e.g., absence of a fertility service), clinician-based factors that can be culturally driven (e.g., discomfort discussing prognosis), and inconsistent chart documentation. The QOPI provides important guidance in improving oncology care, with the current study suggesting a need for training on psychosocial assessment, as well as the role of an EMR system in ensuring appropriate documentation.
An open-label, randomized phase III study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation-positive acute myeloid leukemia.
Authors: Alexander E. Perl, Jorge E. Cortes, Stephen Anthony Strickland, Ellen K. Ritchie, Andreas Neubauer, Giovanni Martinelli, Tomoki Naoe, Arnaud Pigneux, Philippe H. Rousselot, Christoph Röllig, Maria R. Baer, Richard A. Larson, Angela Joubert James, Caroline Chen, Lei Shu, Nahla Hasabou, Erkut Bahceci
Journal: Journal of Clinical Oncology (2017)

TPS7067 Background: FLT3 mutations occur in 30% of patients with acute myeloid leukemia (AML), most often as internal tandem duplications (FLT3-ITD) or point mutations at codon D835. FLT3-ITDs are associated with high relapse rates, short remission duration, and poor overall survival (OS); FLT3-D835 can confer resistance to other tyrosine kinase inhibitors (TKIs). Gilteritinib is a highly selective FLT3/AXL TKI with activity against both FLT3-ITD and FLT3-D835 mutations. A recent phase 1/2 study of gilteritinib (20–450 mg/d) in relapsed/refractory (R/R) AML showed favorable tolerability at doses ≤300 mg/d, and consistent, potent FLT3 inhibition at doses ≥80 mg/d. Patients with FLT3 mutation-positive (FLT3 mut+ ) AML receiving doses ≥80 mg/d had an ORR of 52% (CR/CRp/CRi = 41%, PR = 11%) and longer OS than historic experience in R/R AML with combination cytotoxic chemotherapy or other FLT3 TKIs as monotherapy. Given these results, we initiated a phase 3 trial of once-daily (QD) 120 mg gilteritinib. Methods: This randomized, open-label phase 3 study (NCT02421939) will enroll 369 adults with FLT3 mut+ AML in first relapse or refractory to front-line therapy. Patients who have not previously received FLT3 inhibitors, except sorafenib and midostaurin, will be randomized 2:1 to either 120 mg gilteritinib QD or the investigator’s pre-randomization specified salvage chemotherapy choice (LoDAC, Aza, MEC, FLAG-IDA), and stratified by prior chemotherapy response and salvage chemotherapy intensity. Gilteritinib or low-intensity chemotherapy cohorts will receive continuous 28-day treatment cycles until a discontinuation event occurs; the high-intensity chemotherapy cohort will receive ≤2 treatment cycles before response measurement. Primary objective is OS; key secondary objectives are event-free survival and CR rate. Other secondary objectives: leukemia-free survival, remission duration, composite CR rate, subsequent transplantation rate, patient-reported fatigue, and safety. A formal interim analysis is planned when ~50% of planned death events have occurred. Study enrollment began on Oct 23, 2015; as of Jan 20, 2017, 167 subjects have been randomized. Clinical trial information: NCT02421939.
Nivolumab (nivo) vs investigator’s choice (IC) in patients (pts) with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Analysis of CheckMate 141 by age.
Authors: Nabil F. Saba, George R. Blumenschein, Joel Guigay, Lisa F. Licitra, Jerome Fayette, Kevin J. Harrington, Naomi Kiyota, Maura L. Gillison, Robert L. Ferris, Vijayvel Jayaprakash, Mark John Lynch, Li Li, Peter Brossart
Journal: Journal of Clinical Oncology (2018)

6028 Background: Nivo is the only immunotherapy to significantly improve overall survival (OS) in pts with platinum (plt)–refractory R/M SCCHN. In the randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), nivo significantly improved OS vs IC (HR [95% CI] = 0.68 [0.54, 0.86]) in pts with R/M SCCHN who had progressed on or within 6 mo of plt-based therapy. The safety profile of nivo in the overall pt population was favorable compared with IC. With conventional treatments, there has been concern regarding efficacy and tolerability in elderly patients owing to age-related factors and comorbidities. Here we describe efficacy and safety of nivo compared with IC, by age. Methods: Eligible pts were randomized 2:1 to nivo 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab, n = 121). The primary endpoint was OS. Outcomes were analyzed by age < 65 and ≥65 yrs. Data cut: September 2017 (minimum follow-up: 24.2 mo). Results: At baseline, 68 pts (28.3%) in the nivo arm and 45 pts (37.2%) in the IC arm were ≥65 yrs old. Baseline characteristics and relative nivo dose intensity were generally similar across age groups. OS and tumor response benefits with nivo vs IC were maintained regardless of age (Table). The 30-mo OS rates of 11.2% ( < 65 yrs) and 13.0% (≥65 yrs) with nivo were more than tripled vs corresponding IC rates of 1.4% and 3.3%, respectively. As in the overall pt population, the nivo arm had a lower rate of treatment-related adverse events (TRAEs) vs IC (Table). Conclusions: Nivo improved OS and objective response rate (ORR) vs IC in pts < 65 yrs and ≥65 yrs in CheckMate 141, with a manageable safety profile in both age groups. OS benefit with nivo was maintained through 2 yrs of follow-up for both groups. These data support the use of nivo, regardless of age, in pts with R/M SCCHN who progress within 6 mo of plt therapy. Clinical trial information: NCT02105636. < 65 yrs ≥65 yrs Nivo (n = 172) IC (n = 76) Nivo (n = 68) IC (n = 45) Median OS (95% CI), mo 8.2 (6.1, 9.1) 4.9 (3.9, 5.8) 6.9 (4.0, 9.7) 6.0 (4.0, 7.5) HR (95% CI) 0.63 (0.47, 0.84) 0.75 (0.51, 1.12) ORR (95% CI), % 12.8 (8.2, 18.7) 6.6 (2.2, 14.7) 14.7 (7.3, 25.4) 4.4 (0.5, 15.1) TRAEs, any grade, % 64 77 57 83 TRAEs, grade 3/4, % 16 31 13 48
The effect of a lay health worker-led symptom assessment intervention for patients on patient-reported outcomes, healthcare use, and total costs.
Authors: Manali I. Patel, David Ramirez, Richy Agajanian, Jay Bhattacharya, Arnold Milstein, Kate Bundorf
Journal: Journal of Clinical Oncology (2018)

6502 Background: Rising cancer costs demand models that safely lower expenditures and improve patients’ experiences and outcomes. In response, we developed a risk-stratified proactive symptom assessment intervention which consisted of a lay health worker, supervised by a nurse practitioner, who telephonically assessed symptoms weekly for high-risk patients and monthly for low-risk patients. We implemented the intervention in an oncology group with collaboration from a health plan to test the effect on patient-reported outcomes, healthcare use and cost. Methods: We enrolled all newly diagnosed health plan beneficiaries with Stage 3 and 4 cancer from 11/2014 through 9/2015. We evaluated patient-reported satisfaction, emotional and mental health with validated assessments at enrollment and 5-months post-enrollment. We compared healthcare use and costs to all patients with Stage 3 and 4 cancer diagnosed from 11/1/2013-10/31/2014 (control). We assessed differences in demographic and clinical factors using chi-square and t-tests. To evaluate differences in healthcare use and costs we used generalized linear models adjusted for age, stage, co-morbidity, cancer diagnosis, and length of follow-up. Results: There were 186 patients in the intervention and 102 in the control. In both arms, median age was 78 years, 55% were female, and gastrointestinal malignancies were the highest proportion of diagnoses. There were statistically significant improvements in mental and emotional health (p < 0.05) and satisfaction with care (p < 0.05) at 5-months follow-up compared with baseline. Patients in the intervention had significantly lower mean number of inpatient admissions per quarter (0.72 vs. 1.02, p = 0.03); mean number of emergency department visits per quarter (0.61 vs. 0.92, p = 0.04), and lower median total healthcare costs ($22344 vs $28414, p = 0.03) as compared to the control. Conclusions: A lay health worker-led symptom assessment intervention significantly improved patient satisfaction and reduced healthcare use and costs and may represent one solution to improve care for patients.
Alternative splicing links histone modifications to stem cell fate decision
Authors: Yungang Xu, Weiling Zhao, Scott D. Olson, Karthik S. Prabhakara, Xiaobo Zhou
Journal: Genome biology (2018)

Understanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-messenger RNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear. We analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended datasets from Roadmap/ENCODE projects, we exemplify this mechanism by a cell-cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1. We reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.
International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature
Authors: Thomas Günther, Giovanni Tulipano, Pascal Dournaud, Corinne Bousquet, Zsolt Csaba, Hans-Jürgen Kreienkamp, Amelie Lupp, Márta Korbonits, Justo P Castaño, Hans-Jürgen Wester, Michael Culler, Shlomo Melmed, Stefan Schulz
Journal: Pharmacological Reviews (2018)

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.
The prognostic value of the immune profile of breast cancer stage I in Russian and Dutch women.
Authors: Irina Vladimirovna Kolyadina, Irina Poddubnaya, Cornelis J. H. Van De Velde, Peter JK Kuppen, Esther Bastiaannet, Mikhail Davydov, Dmitrii Komov, Georgii Frank
Journal: Journal of Clinical Oncology (2016)

e23108 Background: to study the prognostic value of immune profile in breast cancer Methods: We analyzed of immune marker expression (HLA-E,-G, HC10, HCA2 and Foxp3) in tumor blocks of Russian (n = 315) and Dutch (n = 203) women with breast cancer stage I, treated in Russia (RCRC, RMAPE, Moscow) and the Netherlands (LUMC; Leiden) 1985-2009. A Tissue Micro Array taken from tumor blocks was constructed in LUMC; were immunohistochemically stained for immune markers and analyzed by International HLA and Immunogenetics Workshop recommendations. We studied of prognostic value of immune profile for relapses-free (RFS) and cancer-specific (CSS) survival. Results: has been allocated 3 types of immune profiles of tumors: High Immune Response (HIR) tumor phenotype associated with high activity of CD8+ T- killer cells (HC10(+) HCA2(+) Foxp3(-) HLA-E(-)G(-)), or with high activity NK-cells (HC10(-) HCA2(-) Foxp3(-) HLA-E(-)G(-)). The second type - Moderate Immune Response (MIR) was submitted incomplete expression (HC10(+)HCA2(-) or HC10(-) HCA2(+) with any combination of Foxp3,HLAE and G, as well as tumors with co-expression HC10(+)HCA2(+) Foxp3(+). The third type - Low Immune Response (LIR) was characterized by the loss of HC10 and HCA2 in combination with expression HLAE+G+ or Foxp3+. In Russian cohort the rate of HIR tumors was seen in 14%, MIR- in 76% and LIR in 10% cases; in Dutch cohort – in 31,1%, 56,3% and 12,3%, respectively, p < 0,01. But in both cohort the tumor immune profile was a significant prognostic factor: in Russian cohort HIR tumor phenotype was associated with significantly higher 5- and 10-years RFS (80,8 and 77,5%) and CSS (97,6% and 90,5%, respectively). In Russian women with LIR tumors the rate of RFS was only 61% up to 5-year follow-up, and 5 - 10 years CSS was only 87 and 50%, respectively, p = 0.015. In Dutch patients HIR phenotype associated with highest rate of 5- and 10-years RFS (97,6 and 89,8%) and CSS (97,6 и 95,1%), in contrast to women with LIR tumor phenotype (RFS- 80,7 and 67,2%; CSS - 92,3 и 73,3%, respectively), p = 0,023. Conclusions: Russian and Dutch women with breast cancer have the different immune profile of carcinomas, but immune response tumor phenotype is the independent prognostic factor for both populations.
Real-world utilization of multiple myeloma treatments in the era of novel therapies: What is the current standard of care?
Authors: David Singer, Ellen Thiel, Debra E. Irwin, Meghan Moynihan, Caroline McKay, Eric Maiese
Journal: Journal of Clinical Oncology (2018)

e20019 Background: Historically, few FDA approved treatments for multiple myeloma (MM) were available, with bortezomib and lenalidomide considered the standard of care. Recently, several new treatments for MM have been approved by FDA. With only a short time on the market, little is known about the how the new MM treatments are being utilized in routine clinical practice and how the standard of care may be evolving. To address this gap in understanding, this real-world study described the characteristics of patients initiating a new line of therapy (LOT) and characteristics of the new LOTs. Methods: This retrospective study utilized data from IBM Explorys Research Database to identify MM patients with no record of stem cell transplant and ≥1 record for MM treatment between 11/2015 - 9/2017 (study period). An algorithm was used to identify new LOTs based on MM therapies (excluding corticosteroids) initiated during the study period. Descriptive analyses characterized utilization of all MM therapies and combinations. Results: A total of 2615 patients started a new LOT during the study period. 1753 (67.0%) patients who started a new LOT were ≥65 years and 1169 (44.7%) were female. 1629 (62.3%) patients started 1st LOT, 426 (16.3%) started 2nd LOT, 235 (9.0%) started 3rd LOT, and 325 (12.4%) started 4th or more LOT. Among the new LOTs, the most common regimens were lenalidomide (n = 733 (28.0%)), bortezomib (n = 463 (17.7%)), bortezomib+lenalidomide (n = 345 (13.2%)), daratumumab (n = 219 (8.4%)), and bortezomib+cyclophasomide (n = 187 (7.2%)). Less common regimens included pomalidomide (n = 75 (2.8%)) and carfilzomib (n = 44 (1.7%)). Conclusions: This real-world study suggests that the MM treatment paradigm is evolving to include newer therapies, however, bortezomib and lenalidomide remain common regimens. As disease recurrence is often more aggressive and survival shorter with each subsequent LOT, critical research is in progress to understand the real-world effectiveness of new treatments and how use in earlier LOTs vs. later LOTs may impact effectiveness.
Development of personalized cancer immunotherapy by integrated genomics.
Authors: Yataro Daigo, Atsushi Takano, Koji Teramoto
Journal: Journal of Clinical Oncology (2016)

e23223 Background: Oncoantigens are oncogenic and high immunogenicity proteins specifically expressed in cancers, and are promising targets for the development of new personalized immunotherapy. Methods: To develop new immunotherapeutics for various type of cancers, we have screened HLA-restricted epitope peptides from oncoantigens through cancer genomics-based approach; 1) selection of genes/proteins specifically overexpressed in clinical solid cancers using our original gene expression profile database and tissue microarrays covering thousands of cancer tissues, 2) characterization of their function in the growth and/or invasion of cancer cells by siRNAs and transfection assays, 3) screening of the epitope peptides recognized by human HLA-restricted cytotoxic T lymphocyte (CTL) by ELISPOT assay. Results: We identified 50 oncoantigens whose overexpression is associated with poor clinical outcome of various solid cancers and that some of their 10-amino-acid epitope peptides can strongly induce antigen-specific CTLs. We are screening predictive and monitoring biomarkers for cancer vaccine therapy through genomics/proteomics approach by analyzing pattern of genomic/proteomic profiles of clinical materials including cancer tissues and serum from clinical studies using a combination of these peptides to investigate the safety, immunogenicity, and anti-tumor effect of vaccine treatment for lung cancer patients who failed standard therapy. To date, we have identified several serum candidate biomarkers. Conclusions: Current data of the cancer vaccine therapy coupled with screening of companion diagnostics warrants further clinical studies to develop more personalized and effective immunotherapy. We introduce our current progress using this systematic approach and discuss future prospective to develop personalized cancer vaccine therapy. Clinical trial information: NCT01069575.