tbuckley/cabot-search huggingface dataset:
Association of the quality of psychosocial support and quality of life in patients with chronic oncological pain.
Authors: Juan Francisco Gonzalez-Guerrero, Antonia Gloria Alcorta-Garza, Fernando Alcorta-Nuñez, Emma María Melgoza-Alcorta, Melany Gonzalez-Rodriguez, Celia Beatriz Gonzalez-Alcorta, Adelina Alcorta-Garza
Journal: Journal of Clinical Oncology (2019)

e23113 Background: Most studies report that tumor related pain occurs between 46% and 92%. The prevalence of pain by clinical stage is 15% in initial stages, 30% in middle stages, 74% in metastatic cancer and, 87% in terminal disease. In the face of chronic diseases such as cancer, patient's relationships with their social networks are affected; among them the interpersonal relationships between the patient and his networks and these towards the patient. With this, the patient’s quality of life is affected. Most of the recent studies on health-related quality of life come from pharmaceutical groups, so it is necessary for other groups to be vigorously involved in the study of the effect of medical interventions on the quality of life, as well as on the impact on health and on the social support of patients with chronic diseases. Methods: In order to obtain the data, validated questionnaires were used as instruments to evaluate the quality of life, measuring psychosocial and health variables, as well as for the detection of the type and quality of psychosocial support perceived by the subjects. The instruments were applied to 207 patients of the Oncology Service of the University Center Against Cancer of the University Hospital “Dr. Jose Eleuterio Gonzalez” in Nuevo Leon, Mexico, during a session of 25 to 30 minutes. Results: Data were collected from 207 patients with chronic oncological pain. The satisfaction index with psychosocial support had a high linear correlation ( r = .640) with the quality of life index. On the other hand, the number of caregivers was not correlated with this last index. Fatigue was the symptom most frequently associated with a decrease in the quality of life index. In addition, pain correlated with all variables except the cognitive index. Conclusions: Satisfaction with the perceived social support is a factor associated with the quality of life in patients with chronic oncological pain; however, the number of caregivers is not. There was no relationship between the size of the network and satisfaction with it. Also, the symptoms associated with chronic oncological pain affect quality of life, identity and social functionality and roles, which in turn impact on the quality of life perceived by patients.
Using a multiplexed immunofluorescence approach to compare immune cell populations in subtypes of non-small cell lung cancer.
Authors: Anna Juncker-Jensen, Vivek Reddy, Erinn Parnell, Mate Levente Nagy, Judy Kuo, Eric Leones, Flora Sahafi, Nicholas Hoe, Josette William
Journal: Journal of Clinical Oncology (2019)

e20702 Background: Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, and is characterized by a poor response to chemotherapy and a low survival rate. While immunotherapy has recently emerged as a successful approach in the treatment of NSCLC patients only 20-25% of patients show a positive response to anti-PD/PDL1 therapy, stressing the urgent need for additional immunotherapy options. NSCLC is a very heterogeneous disease with the two most common types being adenocarcinoma (ADCA) and squamous cell carcinoma (SCC). While a study using flow cytometry to analyze NSCLC on protein level reported the immune cell composition to be fundamentally different in ADCA compared with SCC (Daraselia et al. Am J Cancer Res, 2012 2(1):93), to the best of our knowledge this study will be the first of its kind performing an extensive analysis of NSCLS immune cell composition in tissue. Methods: In order to perform this comprehensive immunoprofiling of the NSCLC subtypes ADCA and SCC we will be using MultiOmyx™, an immunofluorescence (IF) multiplexing assay with similar staining characteristics as standard IHC stains but with the significant advantage that up to 60 protein biomarkers can be interrogated from a single FFPE section. Proprietary cell segmentation algorithms generate unique IDs for every cell and deep learning based cell classification algorithms then identify positive cells for each biomarker. Results: Using a 16-marker panel consisting of CD3, CD4, CD8, FoxP3, CD20, CD68, CD163, CD15, PD1, PDL1, ICOS, OX40, LAG-3, TIM-3, and PanCK we will analyze the proportion of B cells, T cell subtypes, M1/M2-type tumor-associated macrophages, as well as the expression of PD1/PDL1, in addition to novel immunotherapy targets LAG3, TIM3, ICOS, and OX40 in 20 samples from patients with NSCLC (10 ADCA and 10 SCC). Finally, from the same FFPE blocks that we will use to profile the immune cell composition on protein level we will also be extracting DNA/RNA in order to perform T cell receptor (TCR) sequencing, which will provide additional information on the diversity of T cells present in these tumors. Conclusions: It is our hope that these data will help provide new insights into the biology of ADCA and SCC that can ultimately be used to explore novel immunotherapeutic interventions for lung cancer treatment.
Prognostic impact of tristetraprolin (TTP) and PTEN loss and assessment of associated immune infiltrates in localized prostate cancer (PrCa).
Authors: Anis Hamid, Lillian Werner, Ying Huang, Cecile Vicier, Katherine Morel, Leigh Ellis, Christopher Sweeney
Journal: Journal of Clinical Oncology (2019)

e16601 Background: We previously showed that loss of PTEN by quantitative multiplex immunofluorescence (qIF) is associated with relapse after prostatectomy. Low expression of TTP, which modulates the NF-kB pathway and inflammation, is prognostic for lethal PrCa after surgery. We also showed, with this assay, that low CD8+ density is a poor prognostic marker. We hypothesized that co-loss of these independent cell signaling regulators leads to poorer outcomes, and low TTP is associated with a modified tumor immune microenvironment. Methods: qIF was performed on tissue microarrays from a cohort treated by radical prostatectomy (N = 128). PTEN and TTP expression intensity was measured continuously at a cell-by-cell level and summarized per patient using binary thresholds. Immune marker (CD3, CD8, PD-L1, PD-1, FOXP3) density (positive cells/area) was evaluated in glands and stroma. Median time to biochemical recurrence (BCR) and metastasis (MFS) was estimated using Kaplan Meier method and log rank test summarized associations between expression and time to event outcomes. Wilcoxon test assessed the association of biomarker status and immune marker density. Results: Of 128 patients with a median follow-up of 14.6 years, 67 (52%) had BCR. 102 had staining for PTEN, 103 for TTP and 86 for both. Key findings are detailed in Table. PTEN and TTP co-loss was associated with the shortest time to BCR and worst MFS. TTP-low tumors had an immune infiltrate deplete of CD8 (p = 0.0004) and PD-1 (p = 0.0001) expressing cells. No significant differences in immune markers were noted by PTEN status. Conclusions: Co-loss of regulators of inflammation and cell cycling is associated with incremental risk of relapse in localized PrCa. Loss of TTP is associated with a diminished effector T cell infiltrate and may be a modifier towards a ‘cold’ PrCa immune microenvironment. Table: Clinical outcomes by biomarker status [Table: see text]
A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).
Authors: Joleen Marie Hubbard, Manish R. Patel, Tanios S. Bekaii-Saab, Gerald Steven Falchook, Bradley L. Freilich, Arvind Dasari, Benjamin T Knisely, Marlisa Anderson, Gary Gene Chiang, Kevin R Webster, Sam Sperry, Jeremy Barton, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2019)

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.
Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM).
Authors: David A. Reardon, Thomas Joseph Kaley, Jorg Dietrich, Jennifer Leigh Clarke, Gavin Dunn, Michael Lim, Timothy Francis Cloughesy, Hui Kong Gan, Andrew J. Park, Paul Schwarzenberger, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph Rudolph Venhaus
Journal: Journal of Clinical Oncology (2019)

2032 Background: Durvalumab (durva), a human IgG1 monoclonal Ab against PD-L1, is FDA-approved for selected patients with bladder and non-small cell lung cancers. PD-L1 is expressed by some GBM tumors, while GBM infiltrating T lymphocytes often express PD-1. Radiation induced cell death releases tumor antigens and could potentiate anti-PD-(L)1 therapy. Methods: This ongoing Phase 2 open-label study (NCT02336165) evaluates the safety and efficacy of durva (10 mg/kg every 2 weeks) in 5 GBM cohorts. Results are presented for Cohort A, which evaluates durva + standard radiotherapy (RT, 60 Gy over 30 fractions) followed by durva monotherapy in patients with new unmeth GBM after maximum safe resection. The primary efficacy endpoint for Cohort A is overall survival at 12 months (OS12); secondary endpoints include safety/tolerability, tumor response rate, and progression-free survival (PFS). Historical benchmarks of median OS and OS12 for patients with new unmeth GBM following standard therapy are 12.7 months and 50%, respectively (EORTC 26981-22981/NCIC CE.3). Results: Median follow-up of 40 enrolled patients is 24.5 months (data cutoff = 05 Nov 2018). Baseline characteristics: male, 70%; median age, 57.0 [22 to 77] years; ECOG PS0, 60.0%; ECOG PS1, 40.0%; measurable disease, 80.0%; and dexamethasone use, 32.5%. Treatment-related adverse events with maximum CTCAE grade ≥ 3 occurred in 14 (35.0%) patients; the most common were asymptomatic increased lipase (n = 6) and increased amylase (n = 2). Twenty-four of 40 patients were alive at 12 months (Kaplan-Meier for OS12, 60.0% [90% CI: 46.1, 71.4]). Median OS was 15.1 (95% CI: 12.0, 18.4) months. As of 05 Nov 2018, 8 (20%) patients remain alive, with ongoing survival ranging from 15.7 to 34.9 months. Tumor immunocorrelative and systemic studies are pending. Conclusions: This is the first study report of anti-PD-L1 for new GBM. Durva was well tolerated when combined with RT and seemed to have efficacy among patients with new unmeth GBM. Further studies may be warranted. Clinical trial information: NCT02336165.
Case 24-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, L.F. Borges, A.E. Rosenberg
Journal: New England Journal of Medicine (1989)

Presentation of CaseA 77-year-old man was admitted to the hospital because of an inability to walk of acute onset.The patient was in a stable state of health until three months earlier, when he began to experience difficulty in swallowing solids, with a sensation that food stuck low in the neck; his appetite decreased, and he consumed less food than usual. Two months before admission, fever and nausea occurred, with a burning pain over the upper dorsal region at about the level of the fourth thoracic vertebra. A physician found that the temperature was 38.9°C and noted a loss . . .
A New Segmented Virus Associated with Human Febrile Illness in China
Authors: Ze-Dong Wang, Bo Wang, Feng Wei, Shu-Zheng Han, Li Zhang, Zheng-Tao Yang, Yan Yan, Xiao-Long Lv, Liang Li, Shu-Chao Wang, Ming-Xin Song, Hao-Ji Zhang, Shu-Jian Huang, Jidang Chen, Fu-Qiang Huang, Shuang Li, Huan-Huan Liu, Jian Hong, Yu-Lan Jin, Wei Wang, Ji-Yong Zhou, Quan Liu
Journal: New England Journal of Medicine (2019)

In 2017, surveillance for tickborne diseases in China led to the identification of a patient who presented to a hospital in Inner Mongolia with a febrile illness that had an unknown cause. The clinical manifestation of the illness was similar to that of tickborne encephalitis virus (TBEV) infection, but neither TBEV RNA nor antibodies against the virus were detected.We obtained a blood specimen from the index patient and attempted to isolate and identify a causative pathogen, using genome sequence analysis and electron microscopy. We also initiated a heightened surveillance program in the same hospital to screen for other patients who presented with fever, headache, and a history of tick bites. We used reverse-transcriptase-polymerase-chain-reaction (RT-PCR) and cell-culture assays to detect the pathogen and immunofluorescence and neutralization assays to determine the levels of virus-specific antibodies in serum specimens from the patients.We found that the index patient was infected with a previously unknown segmented RNA virus, which we designated Alongshan virus (ALSV) and which belongs to the jingmenvirus group of the family Flaviviridae. ALSV infection was confirmed by RT-PCR assay in 86 patients from Inner Mongolia and Heilongjiang who presented with fever, headache, and a history of tick bites. Serologic assays showed that seroconversion had occurred in all 19 patients for whom specimens were available from the acute phase and the convalescent phase of the illness.A newly discovered segmented virus was found to be associated with a febrile illness in northeastern China. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China.).
Checkpoint inhibitors assessment in oropharynx cancer (CIAO): Safety and interim results.
Authors: Renata Ferrarotto, Diana Bell, M. Laura Rubin, J. Jack Lee, Jason Michael Johnson, Ryan Goepfert, Jack Phan, Yasir Elamin, Jeffrey Myers, Amy Clark Hessel, Faye M. Johnson, Maura L. Gillison, Andrew G. Sikora, Bonnie S. Glisson, Neil D. Gross
Journal: Journal of Clinical Oncology (2019)

6008 Background: Anti-PD-1/PD-L1 are active in metastatic oropharynx squamous cell carcinoma (OPC). Durvalumab (durva) and tremelimumab (tremi) target respectively PD-L1 and CTLA-4, which in combination may be synergistic. Here we report the safety and interim results of durva vs. durva+tremi prior to surgery in a window of opportunity trial in OPC. Methods: Pts were randomized 1:1 to durva 1500 mg or durva 1500 mg + tremi 75 mg IV Q4W x 2 cycles. The primary objective was to quantify pre- and post-treatment differences in CD8+ tumor infiltrating lymphocytes for the two arms. Secondary objectives included safety, toxicity, ORR by RECIST, fraction of patients undergoing surgery at 8 wks, and percentage viable tumor cells in the surgical specimen. Serial pre- and post-treatment blood and tumor specimens were collected for ongoing correlative analyses. Results: 28 pts enrolled: median age 64y, 27 (96%) male, 19 (68%) newly diagnosed, most (63%) at stage IVA (AJCC 7 th Ed), 9 (32%) had locoregional recurrence, 24 (86%) p16 positive, and 22 (79%) had ≤ 10 PPY smoking history. Median follow-up was 7.6 months. The most common AEs were fatigue (36%), leukopenia/lymphopenia (25%), transaminitis (25%), and rash (21%). Grade 3 AEs occurred in 4 (14%) pts: 2 elevated lipase, 1 diarrhea, and 1 hepatitis, all were manageable. There were no grade &gt;3 AEs. ORR was 43%: 50% had SD (including 29% tumor shrinkage in 1 pt). Treatment effect in the surgical specimen was observed in 19 (79%) of 24 evaluable pts; 2 pts had major pathologic response (≤ 10% viable tumor) at the primary site. Efficacy was equivalent in both arms. The 2 pts with PD and 1 pt with SD were switched to chemotherapy after durva +/- tremi before resection; interestingly, each achieved a pCR in the primary. Most pts (57%) didn’t receive radiotherapy after surgery. There was a statistically significant association between ORR and treatment effect (p=0.014). The median percentage of viable tumor in the primary was 37.5% in pts with PR, and 82.5% in SD (p=0.003). Conclusions: Durva +/- tremi prior to surgery was well tolerated in OPC pts. Activity is encouraging with treatment effect seen in 79% of pts. The primary endpoint and complete efficacy data will be presented. Clinical trial information: NCT03144778.
Not all HLA loss facilitate immune escape.
Authors: Li Zhang, Ping Peng, Yongtian Zhao, Zhikun Zhao, Yuan Chen
Journal: Journal of Clinical Oncology (2019)

e15540 Background: Evolution of tumor immunogenicity during immune checkpoint blockade therapy affects tumor response. This study is to investigate the potential mechanisms of the evolution by identifying the differences in immunogenetics between primary tumor and various metastaticlesions after immunotherapy. Methods: This study was approved by IRB. Three types of tissues from a patient with advanced squamous esophageal cancer were obtained three months after anti-PD-1 therapy. The primary tumor (E) was obtained from surgery, the metastatic tumor tissues were obtained from biopsy of the testicular (T)and skin (S) lesions. The presence of immune cell infiltrates and the availability of target antigens defined by mutated neoantigens in these 3 different tissues were examined. The genetic changes from these lesions were analyzed by whole-exome sequencing and RNA sequencing.The inter-lesional immunogenetic heterogeneity between responsive and non-responsive tumor lesions is interpreted. Results: The patient was evaluated at 1 and 3 months after anti-PD-1 therapy with image examinations. The skin metastatic lesion showed significantly decrease in size, but the testicular metastatic lesion failed to respond to the therapy. To correlate tumor response with immunogenetic heterogeneity, 3 specific genotypic changes were examined and compared. 1. Phylogenetic analysis of multi-site mutational profiles showed that metastases were more closely related to each other than to the primary tumor. Truncal and shared mutations were generally clonal with high cellular prevalence, whereas private mutations had medium to low cellular prevalence indicating subclonal status. 2. Although human leukocyte antigen (HLA) loss occurred in S, the numbers of high expression mutation that can be recognized and presented by HLA were the highest. Compared to E,S and T, an overall higher expression of HLA genes was observed in the S. 3. The number and state of different kinds of immune cell were evaluated. The analysesrevealed an increase in distinct immune cell subsets and activation of specific transcriptional networks that were more pronounced in S than T.s and activation of specific transcriptional networks that were more pronounced in S than T. Conclusions: Recent work has shown that HLA-LOH may result in reduced antigen presentation and thus facilitate immune evasion. This study analysis of inter-lesional heterogeneity during anti-PD-1 therapy demonstrated differential clonal evolution within tumors and potential impact of HLA-LOH on neoantigen presentation and expression.
Genomics of HER2+ breast cancer in young women before and after exposure to chemotherapy (chemo) plus trastuzumab (H).
Authors: Adrienne Gropper Waks, Esha Jain, Laura C. Collins, Shoshana M. Rosenberg, Kathryn Jean Ruddy, Rulla M Tamimi, Lidia Schapira, Steven E. Come, Jeffrey M. Peppercorn, Virginia F. Borges, Ellen Warner, Craig Snow, Ann H. Partridge, Nikhil Wagle
Journal: Journal of Clinical Oncology (2019)

554 Background: HER2+ breast cancer (BC) is particularly common in young women. Genomic features of HER2+ tumors before and after H-based therapy have not been described in a population of young women and may point to clinically targetable mechanisms of resistance. Methods: From a large prospective cohort of women diagnosed with BC age ≤40 years, we identified those with HER2+ BC and tumor tissue available for sequencing before and after chemo+H. Whole exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. Evolutionary analysis was performed for patients with both pre- and post-treatment (tx) samples. Results: 22 women had successful WES samples from at least one timepoint; 13 of these had paired sequencing results both before and after chemo+H. For the majority of women, post-tx sample was following neoadjuvant chemo + H, though post-tx timepoint for other women represented locoregional or distant metastasis (Table). TP53 was the only gene that was significantly recurrently mutated in both pre- and post-tx samples. Comparison of matched pre-tx and post-tx samples demonstrated that large changes in HER2 CN over the course of tx were uncommon, only 2/13 pts had &gt; 2-fold change in HER2 CN. Other clonal and subclonal genomic alterations were found to be acquired in the post-tx sample compared to the pre-tx sample. One patient acquired a putative activating mutation in ERBB2. Another patient acquired a clonal hotpsot mutation in TP53. MYC gene amplification was observed in 4 post-tx tumors. NOTCH2 alterations were found in post-tx biopsies from 2 different patients, and mutations in STIL were also found in post-tx biopsies from 2 patients, though the function of these mutations is not known. Conclusions: HER2+ breast tumors in young women display genomic evolution following tx with chemo+H. HER2 CN changes are uncommon, but we identified several genes that warrant exploration as potential mechanisms of resistance to therapy in this population.[Table: see text]