tbuckley/cabot-search huggingface dataset:
Mutation burden and tumor neoantigens in RCC patients (pts) treated with nivolumab.
Authors: Martin Henner Voss, Matthew David Hellmann, Yingbei Chen, Theresa Margaret Gold, Courtney Rose Lambert, Eliezer VanAllen, Toni K. Choueiri, Alexandra Snyder Charen, Robert J. Motzer
Journal: Journal of Clinical Oncology (2016)

514 Background: Durable benefit with CTLA4 or PD1 blockade associates with high somatic mutation burden in melanoma and lung cancer (Snyder, NEJM 2014; Rizvi, Science 2015). The same studies suggest that tumor neoantigens arising from somatic mutations may be mediating this association. For RCC, a disease with a comparatively low mutation burden but good response to PD1 directed therapy, such associations are unknown. To examine these concepts, we used whole exome (WES) and transcriptome (RNAseq) sequencing of RCC samples from pts treated with nivolumab (Nivo). Methods: WES and RNASeq were performed on frozen pre-treatment tumor/normal tissue for 7 pts treated with Nivo and 1 pt treated with ipilimumab/Nivo (Ipi/Nivo) x 4 followed by Nivo. Efficacy was assessed by RECIST. Neoantigen prediction and HLA typing were performed in silico using NetMHC3.2 and ATHLATES, respectively. Expression of predicted neoantigens and putative pathways of resistance/response were investigated using DESeq-normalized reads. Results: Two of 7 Nivo-monotherapy pts achieved durable clinical benefit (DCB, PR &gt; 12 months); 1 pt had a non-durable PR (5 months). For 2 Nivo/DCB pts, the burden of non-synonymous somatic mutations was 113 and 224 compared to a median of 95 in those with no DCB (range 53-124). The ratio of predicted neoantigens/total mutations was higher for pts with DCB/Objective response (all ≥ 0.5) compared to those with progressive disease (all &lt; 0.5). The Ipi/Nivo pt experienced &gt; 95% tumor regression ongoing 2+ years, but harbored the lowest mutation count (29) and lowest neoantigen/mutation ratio ( &lt; 0.2) in the cohort. Across all pts, 80% of predicted neoantigens were expressed. Further, RNASeq findings differed distinctly for DCB vs. non-DCB pts in various genes of interest, including mediators of antigen presentation to T-cells (HLA-A, -B, -C; B2M) and composition of other immune regulators (CSF1R, LGALS1), but not for PDL1. Conclusions: In RCC, somatic mutations, particularly those causing tumor neoantigens, and the counterbalance between molecular immune compartments may be determinants of treatment benefit from Nivo and warrant future study. Their impact might be distinctly different in pts treated with combination immunotherapy.
Distress management in a community oncology center.
Authors: Lori Watts, Nicolas Camilo, Nicole Thurston, Michele Betts, Dan Sayam Zuckerman
Journal: Journal of Clinical Oncology (2012)

107 Background: NCCN and the Institute of Medicine recommend distress screening for all cancer patients. Surveys have found that 20% to 47% of newly diagnosed and recurrent cancer patients experience significant levels of distress. Less than half of distressed patients with cancer are actually identified and referred for psychosocial help. The development of screening tools, processes, appropriate timing, and systems for follow up on concerns is an ongoing challenge for many cancer programs. Mountain States Tumor Institute p,iloted a distress screen process as part of our work with NCCCP. Methods: From October 24, 2011, to April 30, 2012, 133 patients completed distress screens. Most frequently reported concerns included fatigue (50%), sleep changes (32%), and anxiety/worry (31%). 51% of patients reported three or more concerns. 90% of all patients reporting anxiety also reported fatigue or sleep problems. All patients who reported concerns were offered social work and other supports. Screens were reviewed by social workers and discussed at weekly multidisciplinary psychosocial care rounds by social workers, psychiatrist, nurse practitioners, and chaplains. A variety of interventions were used to respond to distress including symptom management, education and referrals to on-site social workers, chaplains, supportive care clinic, integrative medicine and psychiatry. Results: A task was created in Mosaiq Electronic Medical Record to cue Health Information Specialists to schedule patients for distress screening as close as possible to 45 days from first chemotherapy treatment. Patients completed screens before seeing their medical provider. The majority of patients screened received one or more interventions in follow-up. Conclusions: EMRs can be effective tools to cue scheduled screening of patient distress. The use of multidisciplinary psychosocial care rounds can effectively help clinics plan interventions to alleviate patient distress. The use of rounds can ensure staff from different disciplines are not duplicating efforts and can help determine appropriate timing of various psychosocial interventions. Project funded with Federal funds from the NCI, Contract No HHSN261200800001E.
Customization of electronic health record (EHR) to implement meaningful use for quality improvement (QI).
Authors: Laura M. Miller, Bridgette Heard, Kendall Howard, Pankaj Kumar
Journal: Journal of Clinical Oncology (2013)

246 Background: Meaningful Use is a government program that encourages providers to use an electronic health record (EHR) for QI. The goals of MU are to have complete and accurate information in the patient’s electronic record and share that information with other care providers to improve the quality of patient care and avoid duplication of services. The MU program is divided into 3 stages. Providers can earn incentive bonuses for successfully reporting on MU criteria set forth by CMS. There are incentive bonuses for each year until 2015 when penalties for non-reporting are assessed. Stage I has 20 criteria to report on with thresholds for 11 of the criteria. In stage II and III those thresholds will increase. When using an EHR, user efficiency is particularly important. Our goal was to collect MU data by facilitating efficient workflow and taking the documentation burden off the providers. Methods: We identified the MU criteria that required data collection. Some criteria required one time patient data; others involved collecting data at each patient visit. Committees were formed. Processes and responsible staff were identified. We customized features in our EHR to maximize efficiency for the staff collecting the data. We used reports to audit compliance with data collection. Results: We successfully met and reported all 20 Meaningful Use criteria for 16 providers in 2012 and are on track to meet all criteria again in 2013. 11 criteria had measureable thresholds. The average threshold for the 11 measures is 54.5%; our average for the 16 providers for those 11 measures is 86.8%. We collected $288,000 in incentive money for 2013. Since most of the data collection is done by staff, physician documentation is minimal. Conclusions: Customization of EHR allowed us to collect MU data efficiently, obtain the financial incentive in 2012 and helped us get ready for stage II of data collection.
Management tips for the low incidence, of adverse events and well efficacy of regorafenib for metastatic colorectal cancer in Juntendo University Medical Hospital.
Authors: Yoshie Higashihara, Nobuko Serizawa, Junko Kato, Tomohiro Kodani, Taro Osada, Akihito Nagahara, Sumio Watanabe
Journal: Journal of Clinical Oncology (2015)

778 Background: Regorafenib is an oral multi-kinase inhibitor that has demonstrated significant overall survival for metastatic colorectal cancer in CORRECT study. In the Japanese subset of CORRECT study, adverse events (AEs) such as hand-foot skin reaction (HFSR), anorexia, and liver dysfunction occurred at high frequency. Therefore, those AEs were one of the causes for treatment discontinuation. Methods: We retrospectively analyzed the safety and efficacy in 14 patients who received regorafenib monotherapy in our hospital between June 2013 and August 2014. Results: Among the 14 patients, median age was 64.5 years old (range 53-76). Median follows up time was 209 days (range 72-340), median PFS was 64 days (range 19-272), and median TTF was 66.5 days (range 18-280). There was no patient who had complete or partial response. The disease control rate was 36%. Nine patients initiated with 160 mg of regorafenib once daily, 4 patients with 120 mg, and one patient with 80 mg. The most common grade 3 or more AEs were HFSR, AST and ALT elevations and hypertension (2 patients, 14.2%, respectively). The frequency of HFSR was lower in our cohort the Japanese patients of CORRECT study. Treatment discontinuation due to drug related AEs occurred to 5 patients (35.7%). Dose reduction and interruption of regorafenib were required in 10 patients (71.4%) and 8 patients (57.1%), respectively. For prevention of HFSR, more than 90% of the patients were received proactive treatment including heparinoid and strong steroid from the start of the therapy. We carefully monitored their toxicities every week during the first cycle, and chose interruption if patients were had more grade 2 AEs. It is very important, we think to give the patients instructions on possible AEs and how to manage them using an illustrated book. Conclusions: Our cohort had lower HFSR in frequency than and similar efficacy to the Japanese subpopulation in CORRECT study. Enough explanation and instruction to patients might be important to decrease an incidence of AEs and treatment discontinuation due to drug- related AEs. We will increase the number of cases and examine in future.
Comparing overall survival (OS) outcomes in patients with newly diagnosed chronic lymphocytic leukemia (CLL) with normal life expectancy.
Authors: Richard R. Furman, John N Allan, Angela J. Howes, Michelle Mahler, Mark A. Wildgust
Journal: Journal of Clinical Oncology (2016)

7 Background: CLL is an orphan hematologic malignancy but also accounts for the most common adult leukemia in the Western Hemisphere, with a median age at diagnosis of 72 years. Median OS for symptomatic, treatment-naïve, elderly patients with CLL is approximately 5.3 years (CLL5; Eichhorst, et al. Blood 2009), whereas the life expectancy of a 72 year old (yo) is around 12 years (US Life Tables, 2006). Ibrutinib, an oral, first-in-class, covalent Bruton’s tyrosine kinase inhibitor, significantly improves OS. Early results from a phase 1/2 study in treatment-naïve elderly patients with CLL (PCYC-1102; median age, 71 years) suggest that single-agent ibrutinib extends OS, with survival at 3 years of approximately 97% (Byrd, et al. Blood 2015). Here we compare the OS in newly diagnosed patients with CLL treated with single-agent ibrutinib or chlorambucil with the normal life expectancy of a 72 yo adult. Methods: OS outcomes for patients treated with chlorambucil from the CLL5 study conducted in Germany (Eichhorst, et al. Blood 2009) were compared with long-term OS results from PCYC-1102 (Byrd, et al. Blood 2015). Life expectancy data were obtained from US Life Tables. Results: Results from CLL5 suggest that single-agent chlorambucil has a median OS of 5.3 years (median age, 71 years), with approximately 75% of patients alive at 3 years. The median OS for ibrutinib has not been reached (median follow-up, 3 years), with an estimated progression-free survival of 96% and OS of 97% at 3 years. Life expectancy for a 72 yo healthy person at 3 years is approximately 95%. Naïve comparisons suggest that single-agent ibrutinib may be altering the natural history of CLL, providing a longer OS versus chlorambucil and a similar OS as expected in a 72 yo in the general population. Conclusions: Treatment outcomes in CLL are fundamentally changing with the advent of new targeted therapies. This indirect naïve comparison between ibrutinib-treated patients and a general population suggests we may be moving from palliative care for elderly patients with CLL to chronic care management. Implications for chronic care management of patients with CLL will be discussed.
Structural History of Human SRGAP2 Proteins
Authors: Michael Sporny, Julia Guez-Haddad, Annett Kreusch, Sivan Shakartzi, Avi Neznansky, Alice Cross, Michail N. Isupov, Britta Qualmann, Michael M. Kessels, Yarden Opatowsky
Journal: Molecular Biology and Evolution (2017)

In the development of the human brain, human-specific genes are considered to play key roles, conferring its unique advantages and vulnerabilities. At the time of Homo lineage divergence from Australopithecus, SRGAP2C gradually emerged through a process of serial duplications and mutagenesis from ancestral SRGAP2A (3.4-2.4 Ma). Remarkably, ectopic expression of SRGAP2C endows cultured mouse brain cells, with human-like characteristics, specifically, increased dendritic spine length and density. To understand the molecular mechanisms underlying this change in neuronal morphology, we determined the structure of SRGAP2A and studied the interplay between SRGAP2A and SRGAP2C. We found that: 1) SRGAP2A homo-dimerizes through a large interface that includes an F-BAR domain, a newly identified F-BAR extension (Fx), and RhoGAP-SH3 domains. 2) SRGAP2A has an unusual inverse geometry, enabling associations with lamellipodia and dendritic spine heads in vivo, and scaffolding of membrane protrusions in cell culture. 3) As a result of the initial partial duplication event (∼3.4 Ma), SRGAP2C carries a defective Fx-domain that severely compromises its solubility and membrane-scaffolding ability. Consistently, SRGAP2A:SRAGP2C hetero-dimers form, but are insoluble, inhibiting SRGAP2A activity. 4) Inactivation of SRGAP2A is sensitive to the level of hetero-dimerization with SRGAP2C. 5) The primal form of SRGAP2C (P-SRGAP2C, existing between ∼3.4 and 2.4 Ma) is less effective in hetero-dimerizing with SRGAP2A than the modern SRGAP2C, which carries several substitutions (from ∼2.4 Ma). Thus, the genetic mutagenesis phase contributed to modulation of SRGAP2A's inhibition of neuronal expansion, by introducing and improving the formation of inactive SRGAP2A:SRGAP2C hetero-dimers, indicating a stepwise involvement of SRGAP2C in human evolutionary history.
Prognostic role of nitrotyrosines in surgically resected non-small cell lung cancer (NSCLC).
Authors: L. Toschi, P. Colombo, C. Soldani, L. Giordano, G. Finocchiaro, L. Siracusano, L. Gianoncelli, M. Incarbone, A. Destro, M. Alloisio, L. Terracciano, M. Varella-Garcia, F. Cappuzzo, M. Roncalli, A. Viola, A. Santoro
Journal: Journal of Clinical Oncology (2011)

7064 Background: Several immunotherapy approaches are currently under investigation in patients (pts) with human malignancies, including NSCLC, although clinically objective responses are observed only in a minority of cases. Tumoral expression of nitrotyrosines (NT), a marker of peroxynitrite activity in tissues, has been shown to suppress antitumor immune response in prostate cancer by negatively affecting tumor-infiltrating lymphocytes (TILs), and has emerged as a poor prognostic factor in breast cancer and melanomas, leading to the development of inhibitors of key enzymes involved in NT formation (inducible nitric oxide synthase [iNOS] and arginase [ARG] isoforms). The present study aimed to investigate the prognostic impact of NT expression in a formerly published cohort of unselected surgically resected NSCLC pts. Methods: NT expression was assessed by immunohistochemistry (IHC) in TMA sections including 447 surgically resected NSCLCs with known MET gene copy number status by FISH. All cases were assessed in triplicate. IHC results were scored from 0 to 3+ according to staining intensity. Results: NT IHC was successfully performed in 442 pts with the following results (n/%): 0 (17/3.9), 1+ (230/52.0), 2+ (173/39.1), 3+ (22/5.0). Pts were grouped as NT+ (2-3+) and NT- (0-1+). No significant association was observed between NT status and clinicopathological characteristics, including sex, smoking status, stage, histology and grade, although female patients tested more frequently negative than positive (64% vs 36%). Interestingly, MET FISH+ pts had a higher probability of having an NT+ score (p=0.044), when compared with MET FISH- subjects. Overall survival was significantly longer in NT+ vs NT- pts, with a 5-year survival of 51.0 vs 38.1 months (p=0.025, log rank test). Multivariable analysis corrected for stage and MET gene status, previously reported as significant prognostic factors in this cohort, confirmed that NT+ pts had a lower risk of death when compared with the NT- group (HR 0.72, p=0.021, Cox model). Conclusions: NT are frequently overexpressed in NSCLC and represent an independent favourable prognostic factor in surgically resected pts. Assessment of TILs, iNOS and ARG in this cohort is ongoing.
Response Post-First Autologous Stem Cell Transplantation for Multiple Myeloma May Identify Patients Who Will Benefit From Tandem Transplants: A Single Center Prospective Phase II Study- an Update
Authors: Michael T. Byrne, Donya Salmasinia, Helen Leather, Amy Davis, Jack W. Hsu, Laura Wiggins, Christopher R. Cogle, Myron N Chang, John R. Wingard, Jan S Moreb
Journal: Blood (2012)
Clinical and immunologic responses to a novel in situ lymphoma vaccine maneuver: Preliminary results of a phase II trial of intra-tumoral CpG 7909
Authors: J. Brody, W. Z. Ai, D. Czerwinski, R. Advani, S. J. Horning, K. N. Ganjoo, R. Levy
Journal: Journal of Clinical Oncology (2008)

3003 Background: Lymphoma vaccines have shown preliminary clinical success, but their development has been slowed by the difficulties of individualized ex vivo production. An 'off-the-shelf' vaccine which is instead individualized at administration, in situ would greatly facilitate vaccine development. We describe clinical and immunologic responses of an ongoing phase II trial of an intra-tumoral 'CpG-based' vaccine maneuver for recurrent low-grade lymphoma. Historically, T cell immune response assays have been difficult to reproduce and clinically validate. Therefore, our lab has developed and validated a series of immunologic assays to test for both humoral and cell-mediated immune responses in these patients. Methods: The vaccine maneuver consists of combined low dose XRT and intra-tumoral injection of an immune stimulant referred to as 'CpG'. Patients receive 2x2Gy irradiation to a single site of lymphoma and 10 weekly intra- tumoral injections of CpG-7909. Peripheral blood samples from these patients were used to design a method for simultaneous multi-color flow cytometric detection of three independent markers of tumor-specific CD8 T-cell immunity: intracellular IFN-γ, CD137, and CD107. Results: As of January 2008, all of the planned 15 patients have been enrolled, 14 of whom are clinically evaluable. At the treated site, there have been 5 CRs, 5 PRs, 3 SD, and 0 PD. At all other sites, there have been 1 CR, 2 PR, 1 MR, 5 SD, and 4 PD. We have been able to use a panel of B cell lymphoma lines as allo-stimulators to demonstrate that, in our assays, there is excellent correlation of CD8 T cell responsiveness on a single-cell level and cell population levels. Conclusions: This is the first report of an intra-tumoral CpG based vaccine for lymphoma and its feasibility, safety, and evidence of a significant proportion of objective clinical responses is incredibly exciting for the promise of such an approach. Correlation of immunologic findings and clinical responses in this cohort is guiding the development of subsequent iterations of this trials. No significant financial relationships to disclose.
Differences Between Normal and Leukemic Stem Cell-Specific Methylome Indicates Aberrantly Silenced Genes Involved in the Pathogenesis of Malignant Evolution
Authors: Rebecca D Ganetzky, Ying Jiang, Jeffrey Falk, Mingjie Jin, Dongyan Liu, Soledad Negrotto, Yogen Saunthararajah, Jaroslaw P. Maciejewski
Journal: Blood (2008)
Human papillomavirus (HPV)–related head and neck squamous cell carcinoma (HNSCC) and outcome after treatment with epidermal growth factor receptor inhibitors (EGFR inhib) plus radiotherapy (RT) versus conventional chemotherapy (CT) plus RT.
Authors: B. Pajares, J. M. Trigo Perez, M. D. Toledo, M. Alvarez, L. Perez-Villa, C. Gonzalez-Hermoso, A. Rueda, J. A. Medina, B. Jimenez, J. M. Jerez, L. Perez, E. Alba
Journal: Journal of Clinical Oncology (2011)

5528 Background: HPV-related HNSCC has been associated with an improved prognosis in patients treated with RT +/- CT; however, no information is available regarding patients treated with RT + EGFR inhib. Our purpose was to detect differences in outcome in patients treated with RT+EGFR inhib according to p16 tumor status. Methods: We retrospectively determined DNA of HPV 16 and immunohistochemical expression of p16 from formalin-fixed, paraffin-embedded (FFPE) tissue tumors from 78 patients with newly diagnosed locally advanced (LA)-HNSCC treated with RT + CT (37) and RT + EGFR inhib (41), entered in clinical trials. Tumors were classified dichotomously as either p16-positive (strong, diffuse staining) or negative, and DNA of HPV 16 was determined by multiplex polymerase chain reaction (PCR) methods. Disease free survival (DFS) and overall survival (OS) were analysed by Kaplan-Meyer method. Results: DNA of HPV 16 was found in 12 of 78 tumors (15%) and p16 positivity in 11 tumors (14%) with similar rates in both arms. p16 positive patients were less likely to be smokers than p16 negative patients (p < 0.01). After a median follow-up of 22 months (2-108), p16 positive patients showed a trend for better OS compared with p16-negative (median OS 58 vs 39 months; p = 0.4; HR 0.7; 95% CI 0.3 to 1.7). p16 positive patients treated with RT + EGFR inhib showed an improved survival compared with those treated with CT + RT (2-year OS 80% vs 60%; p = 0.03; HR 0.15; 95% CI 0.02 to 0.77 and 2–year DFS 80% vs 20%; p = 0.006; HR 0.11; 95%CI 0.02 to 0.61). However these differences were not observed in p16 negative patients (2-year OS 61% vs 57%; p = 0.9; HR 0.99; 95% CI 0.5 to 1.9 and 2-year DFS 41% vs 44%; p = 0.7; HR 1.07; 95% CI 0.6 to 2.0). Conclusions: This is the first study to report that p16 positive patients may benefit most from RT + EGFR inhibitors than conventional CT + RT. These results are hypothesis-generating and should be confirmed in prospective trials.