tbuckley/cabot-search huggingface dataset:
The genetic variants in interleukin locus at 1q32.1 as markers of melanoma survival.
Authors: Justin Rendleman, Christina Adaniel, Elizabeth Kern, Nathaniel H. Fleming, Michelle Krogsgaard, David Polsky, Russell S. Berman, Richard L. Shapiro, Anna C. Pavlick, Yongzhao Shao, Iman Osman, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2014)

9094 Background: Interleukins play a critical role in immune regulation of tumor development. Because melanoma is a highly immunogenic cancer, and its progression often correlates with immune-related factors, in this study we have tested whether inherited genetic variants in interleukin pathways affect the clinical outcomes of melanoma patients. Methods: We performed a two-stage association analysis of 94 SNPs tagging 32 interleukin genes in 1,200 melanoma patients, ascertained at the New York University Medical Center between 2001-2013. The two stages (discovery and validation) were matched by tumor characteristics, age, and gender. Multivariate Cox regression models tested the associations with recurrence-free and overall survival (RFS and OS, respectively), including age, gender, stage, thickness, ulceration status, anatomic site, and histological subtypes as covariates. Results: A region within 1q32.1 containing IL10, IL19, IL20, IL24 was significantly associated with melanoma OS. Specifically, two SNPs in IL10 (rs3024493 and rs2222202) showed the strongest associations with OS (HR=5.82, 95% CI=2.08-16.3, p=0.0009; HR=0.47, 95% CI=0.28-0.80, p=0.006 respectively). The association between rs3024493 and OS replicated among both stages (stage 1 p=0.028, stage 2 p=0.017). In addition, SNPs tagging IL16 were associated with both RFS and OS in the aggregate analysis of both stage 1 and 2 (p=0.04). Conclusions: The study has identified novel associations of germline genetic risk variants in an interleukin locus at 1q32.1 with melanoma outcomes (rs3024493), and validated the associations from previous smaller studies that showed germline variants in IL10 (rs2222202) associate with worse OS. Pending multi-institutional meta-analysis and further genetic and functional investigations, this study strongly suggests that germline variants in the interleukin locus at 1q32.1 should be considered as novel prognostic markers with potential clinical utility.
Who wins from maintenance chemotherapy (mCT) for metastatic colorectal cancer (mCRC)? Single center experience.
Authors: Mikhail Fedyanin, Alexey Tryakin, Ilya Pokataev, Anna Vyborova, Sergey Gordeev, Vechaslav Aliev, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2014)

e14643 Background: A role of maintenance chemotherapy (mCT) in patients (pts) with metastatic colorectal cancer (mCRC) is still controversial. The purpose of this retrospective study was to investigate the toxicity and efficacy of mCT in pts with mCRC. Methods: There were 97/291 (33%) pts with mCRC completed 18 weeks of first line CT from 2007 to 2013 in our center (XELOX/FOLFOX 87,6% FOLFIRI 12,4%, CT+bevacizumab 16,5%). Then pts who had no disease progression were non-randomly allocated to mCT with capecitabine (n=29), capecitabine+bevacizumab (n=6) or surveillance (n=62). PFS was used as a primary endpoint and was calculated from the date of completion of first line CT. Multivariate Cox stepwise regression analysis was performed to determine independent prognostic factors. Median f.-up time was 15 (range 5 - 60) months. Results: There were no differences between groups (with or without mCT) in terms of main prognostic factors including response rate. The incidence of gr. 3-4 toxicity of first line CT including time of mCT or follow-up was higher in group with mCT: 37.1% vs 19.4%, p=0.09. There were no differences between groups in term of incidence of 3-4 grade toxicity in second line CT: 14.3% vs 17.7%, p=0.9. Median PFS and OS were higher in pts with mCT: seven versus three months (HR 0.5, 95%CI 0.28-0.82, p=0.007) and 29 vs 16 months (HR 0.6, 95%CI 0.3-1.1, p=0.09 - log-rank test and 0.04 - Gehan-Breslow-Wilcoxon test). Following independent negative prognostic factors were significant on multivariate analysis: carcinoembryonic antigen (CEA) level > 2.5 ng/ml before start of first line CT (p=0.02, HR 1.4, 95%CI 1.05-2.0), liver metastases (p=0.03, HR 1.8, 95%CI 1.06-3.2) and number of metastatic zones >2 (p=0.008, HR 2.0, 95%CI 1.2-3.3). MCT had an independent positive impact on PFS (p=0.003, HR 0.5, 95%CI 0.28-0.78). MCT prolonged PFS in pts with at least one negative prognostic factors (seven vs. three months, p=0.001, HR 0.38, 95%CI 0.22-0.68), but not in pts without any of them (nine vs eight months, p=0.4, HR 1.7, 95%CI 0.5-6.2). Conclusions: The mCT with capecitabine +/- bevacizumab was most beneficial in pts with negative prognostic factors: CEA level > 2.5 ng/ml before start of first line CT and/or liver metastases and/or number of metastatic zones >2. The mCT did not affect the tolerability of the second line CT.
A Randomized Clinical Trial of Immediate versus Delayed Glasses for Moderate Hyperopia in 1- and 2-Year-Olds
Authors: Marjean T. Kulp, Jonathan M. Holmes, Trevano W. Dean, Donny W. Suh, Raymond T. Kraker, David K. Wallace, David B. Petersen, Susan A. Cotter, Ruth E. Manny, Rosanne Superstein, Tawna L. Roberts, John M. Avallone, Deborah R. Fishman, S. Ayse Erzurum, David A. Leske, Alex Christoff
Journal: Ophthalmology (2019)
Specific Bone Marrow Mesenchymal Subsets in Patients with Myelodysplastic Syndromes Harbor Molecular Perturbations That Alter the Dynamics of Competition between Pre-Leukemic Clones and Normal Cells
Authors: Youmna Kfoury, Esha Jain, Jason R Myers, Fei Ji, David B Sykes, Francois Mercier, Ani Papazian, Cam Le, Mark A Randolph, David P. Steensma, Omar I Abdel-Wahab, Laura M. Calvi, Ruslan I Sadreyev, Michael W. Becker, David T. Scadden
Journal: Blood (2018)
Safety of rolapitant, a novel NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic chemotherapy (MEC or HEC).
Authors: Laszlo Urban, Allen Poma, Michelle Motta Dardeno, Robert E. Martell
Journal: Journal of Clinical Oncology (2014)

9636 Background: Rolapitant is a highly selective competitive long acting NK-1 receptor antagonist that successfully achieved the primary endpoint of complete response (no emesis and no rescue medication) in the delayed phase of CINV in two phase 3 studies in subjects receiving MEC or HEC. In addition, these studies evaluated the safety and tolerability of rolapitant in these subjects. Methods: Two separate phase 3 double-blind active control studies were conducted. 1369 subjects scheduled to receive MEC (cyclophosphamide, doxorubicin, epirubicin, carboplatin, ifosfamide, irinotecan, daunorubicin or cytarabine), and 555 subjects scheduled to receive HEC (≥60 mg/m2 cisplatin) were randomized 1:1 to either (1) rolapitant 200 mg + granisetron + dexamethasone or (2) placebo + granisetron + dexamethasone. Adverse events (AE) and serious adverse events (SAE) were collected for all subjects. Results: AE rates in cycle 1 were similar across rolapitant and control groups for both the MEC and HEC studies (63.9% vs 66.0%; 64.7% vs 60.2%, respectively). The most frequent AEs observed across both the rolapitant and control groups, respectively, for the MEC study were fatigue (16.3% vs 15.4%), constipation (10.3% vs 14.1%) and alopecia (11.3% vs 12.3%); and for the HEC study were constipation (7.4% vs 10.9%), asthenia (6.6% vs 11.3%) and neutropenia (9.9% vs 6.9%). SAEs rates in cycle 1 were also similar across rolapitant and control groups for both the MEC and HEC studies (6.6% vs 7.1%; 12.5% vs 14.2%, respectively). The most frequent SAEs across both the rolapitant and control groups, respectively, for the MEC study were febrile neutropenia (1.2% vs 2.1%), neutropenia (0.3% vs 0.9%) and neutrophil count decrease (0.3% vs 0.6%); and for the HEC study febrile neutropenia (0.7% vs 1.1%), neutropenia (0.7% vs 1.1%) and thrombocytopenia (1.1% vs 0.7%). No serious, related and unexpected AEs were reported for either study. Conclusions: Rolapitant 200 mg in combination with a 5-HT3 receptor antagonist and dexamethasone was demonstrated to be safe and well tolerated in two global phase 3 studies in subjects receiving HEC or MEC. Clinical trial information: NCT01500226.
Quality of life at baseline in the international open-label early-access program of trifluridine/tipiracil in previously treated metastatic colorectal cancer (phase IIIb).
Authors: Alfredo Falcone, Julien Taieb, Timothy Jay Price, Jean Francois Seitz, Lucjan Wyrwicz, Martin Becquart, Shanti Moreno, Nadjat Mounedji, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2018)

803 Background: Pivotal phase 3 RECOURSE trial evaluated efficacy and safety of trifluridine/tipiracil (FTD/TPI, also known TAS-102) in metastatic colorectal cancer (mCRC) without collecting quality of life (QoL) data (Mayer et al. N Engl J Med 2015;372:1909-19). We set up a phase IIIb open-label, early access program to confirm safety and to assess QoL in mCRC in real-world practice (EudraCT Number: 2016‐002311‐18). First patient (pt) was enrolled in Oct 2016; enrolment is ongoing. Methods: Eligible pts had histologically confirmed mCRC previously treated with, or not considered candidates for, available therapies. Other inclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Pts planned to receive FTD/TPI (35 mg/m 2 bid) orally on days 1–5 and days 8–12 of each 28-day cycle. Pts health-related QoL were measured with the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and the EuroQol 5-dimension, 3-level (EQ-5D) questionnaires and visual analogue scale (VAS). For the EORTC QLQ-C30 global health status, EQ-5D utility values and VAS, scores could range to a maximum of 100 representing a better health-related QoL. EORTC QLQ-C30 and EQ-5D were considered non evaluable when responses were missing for one third or at least one of the dimensions, respectively. QoL was measured at baseline, every 4 weeks on treatment, and at treatment discontinuation. Results: A total of 298 pts from 7 countries had received at least 1 dose of treatment as of 7 March 2017. Among 271 patients, 39.5% and 60.1% had respectively ECOG PS 0 and 1 at baseline except 1 pt was enrolled with ECOG PS 2. Out of these 298 pts, 263, 261 and 258 were evaluable at baseline for EORTC QLQ-C30 global health status, EQ-5D utility values and VAS, respectively. These means were 62.4 (standard deviation [SD] 21.3), 73.6 (SD 20.3) and 66.1 (SD 19.1), respectively. Conclusions: Analysis of pt QoL in the real-world practice shows it may be substantially deteriorated in heavily pretreated pts with advanced mCRC in spite of having an ECOG PS of 0/1. Preliminary safety /efficacy and QoL results are expected in summer 2018. Clinical trial information: 2016-002311-18.
A kinder remedy than excising the “surgeon ego” to accelerate progress in the culture of surgery
Authors: Alasdair D Forrest, Murray A Smith
Journal: BMJ (2019)

Myers and colleagues describe narcissism in surgical specialties and argue that damaging arrogance fills surgical departments.1 As psychiatrists, we should perhaps be cheering an own goal in the derby of the specialties. Yet we are not because narcissism isn’t just a trait but a defence. We lose interest in others’ feelings mostly when overwhelmed …
PROSTVAC, PSA-targeted immunotherapy: New evidence for mechanism of action.
Authors: Stefanie J Mandl, Ryan B Rountree, Rachel B Owen, Tracy dela Cruz, Olivia Hwang, Gayatri Paranjpe, Amanda Enstrom, Alexis J. Franzusoff, Carsten Goessl, James Bradley Breitmeyer
Journal: Journal of Clinical Oncology (2014)

3080 Background: PROSTVAC is being tested for treatment of metastatic castration-resistant prostate cancer in the PROSPECT phase 3 trial. PROSTVAC immunotherapy comprises subcutaneous dosing in a heterologous prime-boost regimen with recombinant vaccinia virus (PROSTVAC-V) for priming plus recombinant fowlpox virus (PROSTVAC-F) for boosting doses. Both products encode transgenes for PSA as the target tumor antigen plus TRICOM (B7-1, ICAM-1 and LFA-3) to enhance immune activation. Data from clinical and nonclinical studies provide evidence for mechanism of action potentially leading to improved overall survival following PROSTVAC immunotherapy. Methods: Subjects from a randomized double-blind placebo controlled Phase 2 study (NCT00078585) received PROSTVAC or empty vector. IFN-γ ELISPOT was performed on archived samples meeting viability requirements. Immune responses in therapeutic prostate cancer mouse studies were evaluated by immunoassays. Results: Subjects demonstrated significant enhancement of PSA-specific T cell responses following PROSTVAC immunotherapy compared to control subjects. T cells against endogenous, non-PSA tumor antigens (antigen spread) were also elevated following PROSTVAC immunotherapy. Treatment with PROSTVAC-V/F in mice amplified the magnitude and quality of activated PSA-specific T cells following heterologous vs. homologous prime-boost dosing regimen. Tumor-infiltrating CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines and amplified cytotoxic T cell activity. In vivo CD4 and CD8 T cell depletion revealed that both subsets contributed to anti-tumor efficacy. PROSTVAC immunotherapy also resulted in reduced Treg suppressor cells among total tumor-infiltrating T cells. Conclusions: PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA directly elicited by active immunotherapy and to endogenous tumor antigens via immune-mediated antigen spreading. These results from clinical and nonclinical studies are predicted to explain improved overall survival following PROSTVAC immunotherapy in a phase 2 trial in advance of evidence from the ongoing phase 3 PROSPECT trial. Clinical trial information: NCT00078585.
The NIH genetic testing registry: Hereditary, pharmacogenetic, and somatic tests for oncology practice.
Authors: Wendy S. Rubinstein, Brandi L. Kattman, Adriana J. Malheiro, Jennifer M. Lee, Donna R. Maglott, Vichet Hem, Michael Ovetsky, Guangfeng Song, Craig Wallin, Kenneth S. Katz, Ricardo Villamarin-Salomon, Baoshan Gu, Cathy Fomous, James M. Ostell
Journal: Journal of Clinical Oncology (2014)

11104 Background: Oncology professionals need to access and gauge information about tests for hereditary cancer predisposition, biomarkers, pharmacogenetic dosing and risk-based chemoprevention. NIH has created the Genetic Testing Registry (GTR; http://www.ncbi.nlm.nih.gov/gtr/), a freely available, web-based resource to enable centralized access to comprehensive information about genetic tests and improve transparency. Methods: GTR was implemented by the National Center for Biotechnology Information (NCBI) with oversight by the NIH Office of the Director, extensive input from diverse stakeholders, and ongoing consultation with two advisory committees and other Federal agencies. Data are voluntarily submitted by laboratory providers (e.g., indications, methods, targets, FDA review status, CPT molecular pathology codes) and supplemented by NCBI (e.g., practice guidelines and informative web links to molecular, literature and other resources). Results: As of February 2014, GTR has 13,878 registered tests for 4,051 conditions offered by 395 labs from 39 countries. Next-generation sequencing (NGS), a component of 10% of molecular tests, is used in 113 tests to evaluate hereditary cancer syndromes, the largest a 107-gene panel. BRCA1 gene testing is a component of 32 clinical tests offered by 11 U.S. labs. Somatic test submission was enabled in late 2013; new test purposes include predictive, prognostic, recurrence, and therapeutic management. Registered tests include several targets used to guide treatment such as BRAF, BCR/ABL1, FLT3, KRAS, JAK2 and complex cytogenetic panels. GTR has 64 pharmacogenetic tests for 18 genetically influenced drug responses (e.g., tamoxifen, irinotecan, thioguanine, fluorouracil). Algorithm-based tests that employ variants discovered in genome-wide association studies to inform chemoprevention decisions are also in scope. Conclusions: GTR reflects trends in the genetic testing landscape such as the clinical use of NGS and the immediate effect of the U.S. Supreme Court patent ruling on the availability of BRCA testing. Growing participation in GTR by oncology test providers and clinicians will improve the utility of this resource to the community.
STAG2 Mutations Alter Cohesin Ring Function and Provide Therapeutic Vulnerabilities in Acute Myeloid Leukemia
Authors: Zuzana Tothova, John M. Krill-Burger, Daniel S. Day, J. Erika Haydu, Brian J. Abraham, Catherine C. Landers, Edyta Malolepsza, Christina R. Hartigan, Amie Holmes, Melanie Donahue, Katerina D. Popova, Sebastian Koochaki, Jeanne Rivera, Michael Seiler, Denes Hnisz, Edwin Chen, Silvia Buonamici, Monica Schenone, Alan D. D'Andrea, Steven A. Carr, Richard A. Young, Benjamin L. Ebert
Journal: Blood (2018)
Interim Results from the First-in-Human Clinical Trial of Adct-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: John Radford, Brad S. Kahl, Mehdi Hamadani, Carmelo Carlo-Stella, Paolo Caimi, Kirit M. Ardeshna, Jay Feingold, Shui He, Erin Reid, Melhem Solh, Ki-Young Chung, Leonard Heffner, David Ungar, Owen A. O'Connor
Journal: Blood (2018)
PET/CT in lymphoma surveillance: A large single-center experience.
Authors: Lourdes M. Mendez, Anish V. Sharda, Kelly A. Bodio, Robin Joyce
Journal: Journal of Clinical Oncology (2014)

8569 Background: The role of FDG PET-CT in the modern management of lymphoma continues to evolve. Current guidelines are largely based on studies with limited numbers of patients. The aim of this study was to define the utility of PET-CTs in identifying asymptomatic relapsed disease during post-treatment follow-up. Methods: We performed a large, retrospective cohort study of all PET-CTs performed for patients with pathologically proven lymphoma at our institution from 2003-2005. 1,085 consecutive PET-CTs from 370 patients with lymphoma and accompanying clinical data were reviewed. 81 patients had Hodgkin lymphoma (HL), 154 aggressive Non-Hodgkin lymphoma (a-NHL) and 135 indolent Non-Hodgkin lymphoma (i-NHL). Most scans were obtained in the post-treatment setting (861: either at completion of therapy or during follow-up); 110 and 114 were performed as part of initial staging and during therapy respectively and were excluded from the following analysis. Results: 44% of all scans were positive of which 75.7% were associated with progressive disease and 24.3% with disease remission. PET-CT had a sensitivity of 97.5%, specificity of 90.3%, PPV of 75.7% and NPV of 99.2% for relapsed disease in our cohort (Table 1 shows sub-group statistics). The false positive rate for PET-CT was 24.3% most often leading to further imaging. In comparison, the presence of symptoms had a sensitivity of 43.6%, specificity of 88.5%, PPV of 53.8% and NPV of 83.7% without significant variation among HL, a-NHL and i-NHL. Notably, 52% of a-NHL patients with relapsed disease documented by PET-CTs were asymptomatic. Conclusions: Our results indicate that PET-CT is highly sensitive for detecting progressive lymphoma in the context of post-treatment follow-up offset by a high rate of false-positives. This highlights the need for algorithms incorporating additional parameters for risk stratification. In this series, a significant portion of a-NHL recurrences detected by PET-CTs were clinically silent. Analysis of how detection of asymptomatic relapse affects patient outcomes is underway. Measures of performance of PET-CT by lymphoma subgroup. Lymphoma Sensitivity (%) Specificity (%) PPV (%) NPV (%) HL 100 94 80.5 100 a-NHL 97.8 76.1 50.9 99.3 i-NHL 96.3 90.2 82.3 98.1
A successful model to decrease early deaths in acute promyelocytic leukemia (APL) through the use of a simplified algorithm and expert support.
Authors: Anand P. Jillella, Ravindra B. Kolhe, Kavita Natrajan, Vamsi Kota
Journal: Journal of Clinical Oncology (2014)

e18018 Background: APL is a curable malignancy with survival >90% in large co-operative studies with early mortality of 5%. The recent GIMEMA trial in non-high risk APL showed an expected survival of 98% in the ATRA/Arsenic trioxide arm. These results are not seen in studies from cancer registry data. US SEER data showed that 1 and 5 year relative survival in APL patients is 71% and 65%. Studies from Swedish registry and Brazil also show that the early mortality is as high as 30%. We report our results showing that early deaths can be decreased with a streamlined treatment algorithm and support from experts. Methods: At Georgia Regents University, between 7/2005 and 6/2009, 19 patients were diagnosed with APL. Seven (37%) died during induction, an unusually high mortality rate. Patients who survived induction are presently in remission. The high early death rate prompted us to develop a simple 1.5 page treatment algorithm that focuses on quick diagnosis, prompt therapy, and proactive management of all the major causes of death during induction. More importantly we made our treatment guidelines available to other leukemia treatment centers. Results: From 11/2010 to 01/2014, we treated 10 patients at GRU and helped manage 31 patients at 10 centers. Age range was 21-73 years. 11 patients were high-risk and 30 low-risk based on presenting white cell counts. There were 2 deaths during induction (4.8%), with 1 death in a patient that refused transfusions. Conclusions: Our experience and recent registry based studies show that early mortality is a significant problem in APL. We show that a streamlined treatment algorithm that we developed independently due to our inferior outcome along with help from experts will lead to better outcomes in this curable disease even outside clinical trials. A similar approach pioneered by investigators in Brazil clearly shows this to be an effective model. We believe our experience warrants large scale implementation of our strategy in an attempt to decrease early mortality in APL. We were awarded a $1.68 million grant by the Leukemia Lymphoma Society to implement this protocol in the states of Georgia and South Carolina over a 3 year period.