tbuckley/cabot-search huggingface dataset:
Characterization of the onset of thyroid function (TF) abnormalities in patients receiving immune checkpoint inhibitor (CPI) therapy.
Authors: Radowan Elnair, Guy vin Chang, Prince Sethi, Hafez Mohammad Abdullah, Jing Zhao, Marcio L Griebeler, Steven Francis Powell
Journal: Journal of Clinical Oncology (2018)

e22082 Background: Nivolumab (N), Pembrolizumab (P) and ipilimumab (I) are active cancer therapies, however; endocrinopathies are common immune-related adverse events (irAEs). The estimated incidence of TF abnormalities in patients receiving these agents is 10%. Methods: We performed a retrospective review of cancer patients who received CPI therapy with N, P, or I between July 2012 and November 2016 – for various indications- through our integrated community-based health system. The primary aim was to characterize the onset of TF abnormalities and the potential predictors of their development. Patients with pre-existing TF abnormalities, prior head and neck radiation, or prior thyroid surgery were excluded. TF abnormalities were classified as thyrotoxicosis (defined as low TSH, or an elevation of FT4 or FT3) or hypothyroidism (defined as an elevation in TSH, or a reduced level of FT4 or FT3). Patient demographics, diagnosis, treatment type, associated symptoms, and number of days before detection (NDBD) of TF abnormality were reviewed. Results: Of 361 eligible patients reviewed, 50 patients (13.85%) developed new onset of TF abnormalities. Among those with TF abnormalities, the median age at the time of receiving immunotherapy was 64. 29 patients (58%) received N, 12 received P (24%), 4 patients received I (8%), and 5 patients received N + I (10%). Thyrotoxicosis was the most commonly noted initial abnormality (n = 27, 54%), compared to hypothyroidism (n = 23,46%). Only 58% of patients had clinically evident symptoms. No significant difference was found between the mean of NDBD of TF abnormality between hypothyroidism and thyrotoxicosis (89 versus 78 days, P = 0.57). The time frame for TF abnormality detection was not significantly different between males and females receiving CPI therapy (71 versus 97 days, P = 0.17). Conclusions: The incidence of CPI related TF abnormalities at our center is similar to clinical trial findings. CPI therapy is associated with different patterns of TF abnormalities. The majority of patients who developed laboratory evidence of abnormal thyroid function were asymptomatic. Ongoing research is exploring the impact of these irAE on patient outcome.
P05.10 Prospective evaluation of cerebrospinal fluid circulating tumor cells (CSF CTC) in patients with HER2 positive cancers and leptomeningeal metastases receiving treatment with intrathecal trastuzumab
Authors: E Pentsova, R Malani, M Fleisher, X Lin, A Omuro, M Groves, N Lin, M Melisko, A Lassman, S Jeyapalan, A Boire, L DeAngelis, J Raizer
Journal: Neuro-Oncology (2018)

The validated CellSearch system (Janssen Diagnostics, LLC), utilizing an immunomagnetic CTC selection method based on EPCAM antibody conjugated ferroparticles, is an FDA-approved methodology for enumerating CTC from blood in pts with breast, prostate and colon cancers. The CellSearch system has been used to evaluate CSF CTC of pts with leptomeningeal metastasis (LM) and has demonstrated potential as a diagnostic marker and response to cancer treatment. We explored the use of CSF CTC enumeration in the follow-up of pts with LM from HER2+ cancers receiving intrathecal (IT) therapy, aimed at characterizing changes over time as a potential biomarker of treatment response. CSF from pts participating in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was evaluated by CellSearch system. 3 ml CSF from a ventricular reservoir was collected for CSF CTC enumeration at pre-treatment Day 1 of each cycle and correlated with CSF cytology from the same sample, and with clinical and radiographic response. LM progression was defined as clinical or radiographic worsening. Fifteen patients with HER2+ LM (14 breast, 1 colon) were enrolled; 14 were women. Six patients had baseline positive CSF cytology; the remaining were diagnosed by MRI. Of the 15 patients, 10 had greater than 1 cycle of treatment to be evaluable; 5 patients progressed during cycle 1. Median CSF CTC at baseline was 22 per 3ml (range 0–200); 2 patients had no detectable CSF CTCs. A decrease in CSF CTC was observed in 5 patients after cycle 1 and remained low (mean =9.5, range 0–92) in 2 patients while disease was stable. 3 patients had a rise in CSF CTCs roughly 1 month prior to progression. In the 10 patients with HER2 analysis, number of CTCs correlated with HER 2 expression. CSF CTC HER2 expression provided further affirmation that CTCs are malignant. Changes in CSF CTC enumeration allow quantitative surveillance of treatment response and should be further investigated.
Lost annual productivity costs due to cervical cancer deaths in the United States in 2014.
Authors: Shelby Corman, Chizoba Nwankwo, Ralph Insinga
Journal: Journal of Clinical Oncology (2018)

e17513 Background: An estimated 4115 women died of cervical cancer in the United States (US) in 2014. Life years lost per cervical cancer death (mean, 26.4 years) are the third highest of any cancer due to relatively young age at diagnosis (median, 49 years). We constructed an economic model to estimate the annual productivity costs associated with cervical cancer death in the US, for the year 2014. Methods: The model calculated the cumulative number of women who would be alive in 2014 if they had not died from cervical cancer between 1935 and 2014, and the lost earnings resulting from early mortality. The model included the age-stratified annual number of deaths attributable to cervical cancer per year, the probability of otherwise surviving to 2014, proportion of patients who are employed, and median annual wage per year, including fringe benefits. All model inputs were collected from publicly available sources including the Centers for Disease Control and Prevention, Social Security Administration, and Bureau of Labor Statistics. Results are reported in 2014 US dollars. Results: The model estimated that 109,286 women would be alive in 2014 had they not died from cervical cancer (Table); of these, 39,959 would have been part of the work force based on age and labor participation rate. The total productivity loss in 2014 due to cervical cancer was estimated at $2.1 billion. Conclusions: Cervical cancer deaths are associated with substantial indirect costs owing to lost earnings. Table. Number of women who would have been alive in 2014 if they had not died of cervical cancer, and resulting productivity loss Age group (2014) Number of women Productivity loss (2014 US$) 15-19 3 $19,047 20-24 35 $725,271 25-29 271 $9,238,425 30-34 765 $26,782,779 35-39 1,643 $67,454,965 40-44 3,285 $138,472,984 45-49 5,583 $234,811,900 50-54 8,691 $370,545,912 55-59 11,473 $438,321,983 60-64 12,825 $374,082,832 65-69 13,295 $205,984,425 70-74 12,053 $101,868,400 75-79 11,253 $38,154,631 80-84 10,704 $36,412,486 85-89 9,467 $32,249,503 90-94 5,728 $19,526,117 95-99 1,860 $6,337,485 100+ 352 $1,205,563 Total 109,286 $2,102,194,708
Prospective randomized phase II study of concurrent chemoradiotherapy versus chemotherapy alone in stage IV esophageal squamous cell carcinoma.
Authors: Tao Li, Jiahua Lv, Fang Li, Peng Diao, Junchao Wang, Rong Chu Li, Long Liang, Lei Sun
Journal: Journal of Clinical Oncology (2016)

4050 Background: Stage IV ESCC carries a poor prognosis with a median survivals of 6-9 months. The standard treatment has traditionally been chemotherapy. Palliative radiotherapy was used for symptom relief. The optimal treatment for stage IV ESCC has not yet been established. The aim of this study was to compare the efficacy and safety of CCRT versus chemotherapy alone in patients with stage IV ESCC. Methods: Stage IV ESCC with a performance status of 0-1 were randomly assigned to the CCRT group and the chemotherapy group. Both groups of patients received at least 2 cycles of chemotherapy with cisplatin and docetaxel every 3 weeks. Patients in CCRT group received 50-60 Gy/25-30 fractions of concurrent radiotherapy to the esophageal primary tumor. The primary end point was overall survival (OS). The secondary end points were progression-free survival (PFS), object response rate (ORR) of primary tumor and toxicity. Results: Between Aug. 2013 and Oct. 2015, 60 patients were enrolled and divided into the CCRT group (n = 30) and the chemotherapy group (n = 30). The baseline clinical characteristics of the 2 groups were similar. Patients in the CCRT group received a mean 54.7 Gy of radiotherapy and a mean 3.6 cycles of chemotherapy, whereas patients in the chemotherapy group received a mean 3.8 cycles. The ORR of the primary tumor was higher in the CCRT group than in the chemotherapy group (83.3% vs. 46.7%, p = 0.001). At a median follow-up of 16 months, median PFS (9.3 vs. 4.7 months, p = 0.021) and median OS (18.3 vs. 10.2 months, p = 0.001) were significantly longer in the CCRT than that in the chemotherapy group. Overall survival rates at 1, 2 years were 73.3%, 43.3% in the CCRT group and 46.6%, 26.7% in chemotherapy group (p = 0.030) Although ≥ grade 3 neutropenia was significantly more frequent in the CCRT group than that in the chemotherapy group (33.3% vs. 20.0 %, p < 0.05), the rates of other toxicities did not differ. Conclusions: CCRT was well tolerated and was associated with longer PFS and OS than chemotherapy alone in patients with stage IV ESCC. Controlled randomized, multi-center trials are required to determine whether CCRT is a primary treatment option for patients with stage IV ESCC.
Comparing cervical cancer stage at diagnosis in immigrant women and long-term residents.
Authors: Teja Voruganti, Rahim Moineddin, Nathaniel Jembere, Lorraine Elit, Eva Grunfeld, Aisha Lofters
Journal: Journal of Clinical Oncology (2016)

e18054 Background: Globally, cervical cancer is the fourth most common cancer in women and seventh most common cancer overall. Cervical cancer is highly preventable with HPV vaccination and screening. Previous work has shown that immigrants are less likely to be screened than non-immigrants. Building on this work, the objective of our study was to examine whether immigrant women are more likely to present with later stage cervical cancer than long-term residents. Methods: We conducted a retrospective cohort study of women with cervical cancer diagnosed from 2010 to 2014 using administrative health data from the Canadian province of Ontario, comparing the odds of late stage diagnosis between immigrants and long-term residents. The outcome of interest was stage of cervical cancer diagnosis, defined as early (stage I) or late (stage II-IV). We compared immigrants and long-term residents on late vs. early stage adjusting for socioeconomic measures, comorbidities and healthcare utilization. We also confirmed results with a cohort from 2007-2012. Results: Complete staging data was available for 218 immigrants and 874 non-immigrants. We found no association between immigrant status and stage at diagnosis (adjusted OR: 0.935, p value = 0.739). Factors that did show significant association with later stage diagnosis were physician characteristics, whether a woman had been previously screened, or having visited a gynecologist in the past 3 years. These results were echoed in the 2007-2012 cohort (immigrants vs. long-term residents OR: 0.942, adjusted p value = 0.6773). Conclusions: Our results show that being an immigrant is not associated with late stage diagnosis of cervical cancer, although getting screened or having visited a gynecologist did reduce the odds of later stage cancer. Our findings support previous studies showing that physician characteristics influence immigrant healthcare utilization. Moreso, it may be that programs broadly aimed immigrants require a targeted approach to address higher-risk subgroups.
Methylation among members of the PI3K/AKT/mTOR pathway in melanoma brain and extracerebral metastases.
Authors: Friedegund Elke Meier, Dana Westphal, Matthias Meinhardt, Konrad Gruetzmann, Daniel Schrimpf, Daniela Ellen Aust, Evelin Schroeck, Gustavo Bruno Baretton, Stefan Beissert, Gabriele Schackert, Andreas von Deimling, Christian Kölsche, Barbara Klink, Michael Muders, Michael Seifert
Journal: Journal of Clinical Oncology (2018)

e21515 Background: Around 75% of stage IV melanoma patients develop brain metastases during the course of their disease. In recent years, effective therapy options became available for treatment of metastatic melanoma. Although these therapies achieve similar initial response rates in brain and extracerebral metastases, the majority of patients eventually progress and die from new brain metastases, indicating brain-specific resistance mechanisms. Uncovering the mechanisms responsible for the different biological behavior of the brain and extracerebral metastases will thus greatly aid in the search for more brain-specific therapeutics. Methods: Initial studies could not detect any significant hotspot mutations or copy number variations distinguishing brain from extracerebral metastases, but observed epigenetic reprogramming of melanoma brain metastases facilitated by the brain microenvironment. We therefore wanted to analyze the methylation and messenger RNA expression differences of brain and extracerebral metastases and performed a methylation array and RNA-Seq on FFPE material of 19 matched pairs. Results: Using integrative bioinformatics approaches, we identified 34 candidates that were differently methylated in the brain and extracerebral metastases and had a corresponding RNA expression level response. Additionally, over 100 candidates from the RNA-Seq data were de-regulated in the brain compared to extracerebral metastases. Conclusions: Many of the candidates belong to signaling pathways shown to be important for survival and metastasis formation of different cancers, such as the cell cycle, various metabolic pathways, TGF-beta, MAPK, PI3K/AKT and mTOR signaling pathways. Notably, recent studies by others and our lab showed a hyperactivation of the PI3K/AKT/mTOR pathway in melanoma brain metastases compared to extracerebral metastases. We will therefore focus on validating the candidate genes from this pathway by immunohistochemistry and functional assays to elucidate their role in the resistance of brain metastases to therapy.
Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo
Authors: Payam A. Gammage, Carlo Viscomi, Marie-Lune Simard, Ana S. H. Costa, Edoardo Gaude, Christopher A. Powell, Lindsey Van Haute, Beverly J. McCann, Pedro Rebelo-Guiomar, Raffaele Cerutti, Lei Zhang, Edward J. Rebar, Massimo Zeviani, Christian Frezza, James B. Stewart, Michal Minczuk
Journal: Nature Medicine (2018)
Alterations in key clear cell renal cell carcinoma (RCC) genes to refine patient prognosis.
Authors: Dominick Bossé, Wanling Xie, Yasser Ged, Andrew W Hahn, Paulo Gustavo Bergerot, Thai Huu Ho, Rana R. McKay, Tracy Lynn Rose, Guillermo de Velasco, Nizar M. Tannir, Pheroze Tamboli, Leonard Joseph Appleman, Kimryn Rathmell, A. Ari Hakimi, Sumanta K. Pal, Neeraj Agarwal, Daniel Yick Chin Heng, Sabina Signoretti, Martin Henner Voss, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2018)

4516 Background: Genomic alterations (GA) in VHL, PBRM1, BAP1, SETD2, TP53 and KDM5C are frequently present in metastatic RCC (mRCC). We investigated the prognostic value of GA resulting in loss of function (LOF) of these genes in mRCC patients stratified by International mRCC Consortium Database (IMDC) risk group. Methods: Patients from 7 US centers and 1 annotated cohort from TCGA who had clear cell mRCC treated with 1st line VEGF tyrosine kinase inhibitor and tumor genomics available were included. Tumors were sequenced using next generation sequencing (institutional and commercial platforms) or whole exome sequencing (TCGA). LOF was defined as presence of pathogenic gene variant or 2 copy deletion. Cox model adjusting for age, IMDC risk group was used to investigate the association between GA and overall survival (OS). The prognostic value of GA was further assessed in IMDC favorable, intermediate and poor risk group. Results: In total, 308 patients were analyzed. IMDC risk group distribution was favorable 21%, intermediate 54%, poor 17% and unknown 8%. Patients had GA in VHL 77%, PBRM1 43%, SETD2 29%, BAP1 19%, TP53 11%, KDM5C 11%. GA in BAP1 was associated with worse IMDC risk group (favorable 8%, intermediate 23% and poor 20%, p = 0.023) and worse OS (aHR 1.7; 95%CI 1.1-2.5, p = 0.01). GA in PBRM1 (aHR = 0.6; 95%CI 0.4-0.8, p = 0.001) and KDM5C (aHR = 0.4; 95%CI 0.2-0.8, p = 0.007) was associated with better OS. SETD2, TP53 and VHL were not associated with prognosis (p > 0.4). Co-occurrence of GA in BAP1 and PBRM1 was 3.8%. Patients with tumors PBRM1 wild type and harboring GA in BAP1 had worse OS [37 vs 50 mos, aHR 1.9 (95%CI 1.2-2.8 p = 0.004]. When stratified by IMDC risk group, this tumor genomic profile was prognostic for patients with intermediate risk disease only (Table). Conclusions: mRCC tumors which are PBRM1 wild type and with LOF in BAP1 have worse survival. Assessment of GA in these key genes can further prognosticate IMDC intermediate risk patients and be useful to stratify patients in clinical trials. IMDC risk group PBRM1 wild type and BAP1 altered N/ N event HR* P-value Good No 61/16 ref Yes 4/1 1.17(0.14-9.85) 0.883 intermediate No 135/66 ref Yes 31/19 1.77(1.05-2.98) 0.032 poor No 45/25 ref Yes 6/5 1.50(0.56-4.06) 0.422 * adjusted for age
Randomized phase II study of adjuvant WT1 vaccine (SLS-001) for malignant pleural mesothelioma (MPM) after multimodality therapy.
Authors: Marjorie Glass Zauderer, Tao Dao, Valerie W. Rusch, Michelle S. Ginsberg, Anne S. Tsao, Katherine Panageas, Angelos M. Stergiou, David A. Scheinberg, Lee M. Krug
Journal: Journal of Clinical Oncology (2016)

8519 Background: WT1 is an ideal candidate for a tumor selective cancer vaccine in malignancies that express WT1, such as MPM. Using native and synthetic WT1 peptide sequences, a multivalent peptide vaccine, SLS-001, was created to stimulate both CD4 and CD8 T cell responses. In a pilot trial including those with previously treated MPM, SLS-001 was well-tolerated and CD4/8 immune responses were generated. Subsequently, we began this trial in WT1 expressing MPM after multimodality therapy. Methods: Within 12 weeks of completing multimodality therapy, patients were randomized to Montanide and GM-CSF with or without SLS-001. Treatment consisted of 6 subcutaneous vaccinations on weeks 0, 2, 4, 6, 8, and 10. Injection sites were prestimulated with GM-CSF on days -2 and 0. Immune responses were evaluated by ELISPOT and T-cell proliferation assays at week 12. Patients were followed with imaging every 3 months with a primary endpoint of 1-year progression-free survival (PFS). Results: 40 patients were randomized (21 placebo, 19 vaccine) from two institutions. Patient characteristics were balanced. There were no serious treatment related adverse events. Based on a prespecified futility analysis of each arm (futility = > 10/20 patients experience progression < 1 year), the control arm was closed in 5/2015; accrual was stopped and the SLS-001 arm was closed in 11/2015. Median PFS from randomization was 11.4 months (95% CI 4.4-24.3) in the SLS-001 arm v. 5.7 months (95% CI 2.7-14.6) in the control arm (HR 0.69, p = 0.3). Similarly, median overall survival (OS) from randomization was 21.4 months (95% CI 8.5-40.4) in the SLS-001 arm v. 16.6 months (95% CI 7.7-24.8) in the control arm (HR 0.52, p = 0.14). In the subgroup with R0 resection, median OS was 39.3 months in the SLS-001 arm and 24.8 in the control arm (p = 0.04). Conclusions: This randomized, controlled phase II trial demonstrated that administration of SLS-001 in MPM was associated with a trend toward improved PFS and OS, though the trial was not originally powered to determine this effect. These results warrant additional better powered, randomized studies to define the optimal use and benefit of SLS-001 in mesothelioma. Clinical trial information: NCT01265433.
Incidence of late effects in long-term childhood cancer survivors.
Authors: Ronica H. Nanda, Rohit Gunan Ganju, Mary M Batcha, Natia Esiashvili
Journal: Journal of Clinical Oncology (2016)

e22009 Background: As therapies for children with cancer have improved, the need for greater attention to adult survivors is becoming more recognized. Our study examined the rates of physician-determined chronic health conditions deemed to be secondary to treatment in a cohort of young survivors cared for at a tertiary healthcare center. Methods: Patients with a history of pediatric malignancies who transition to the adult survivorship clinic at age 21 are offered enrollment in an institutional prospective study, which involves a questionnaire examining their knowledge of their cancer history, as well as consent to collect information from their medical records. For this study, only patients 21-29 years were included. The presence of treatment-related chronic medical comorbidities, as well as the number and degree of these, were determined. If multiple conditions were present, grade was based on the most severe condition; grade was based on Common Terminology Criteria for Adverse Events. Psychosocial outcomes and correlation with questionnaire responses will also be reported separately. Results: A total of 106 patients with complete medical information and who met the above criteria were included in this analysis. The median time from initial diagnosis of malignancy to last follow up was 171 months (14.2 years). The majority of patients (76.4%) had non-solid tumors. Only 10.4% of survivors had no evidence of medical comorbidity to date. Of all survivors, 60.4% had grade 1-2 conditions and 39.6% had grade 3-4 conditions. Of the 89.4% patients with any grade health condition, 72.6% had two or more conditions and 43.2% had at least three conditions. Conclusions: Physician-assessed rates of secondary chronic health conditions in a cohort of long-term survivors of childhood cancers were significant, with the majority of patients suffering from multiple conditions, and an excess number with grade 3-4 effects, despite young age (prior to an age where most de novo health conditions would be expected). This study highlights the need for not only close monitoring of survivors but also early intervention and preventive strategies to reduce the long-term impact of cancer on young adult survivors.