tbuckley/cabot-search huggingface dataset:
Clonality of T cell repertoire in the tumor (TME) and peripheral blood of regionally advanced melanoma patients (pts) treated with neoadjuvant ipilimumab (ipi) and high dose interferon-α (HDI).
Authors: Priyanka Vallabhaneni, Tala Achkar, Marissa Vignali, Sharon Benzeno, Julie Rytlewski, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2017)

9585 Background: Pts with regionally advanced melanoma were treated with neoadjuvant ipi and HDI in a reported study ( Tarhini. J Clin Oncol suppl, 2016; abstr 9585). Pathologic complete response (pCR) was found in 32% of pts. Clonality of T cell repertoire was investigated in TME and peripheral blood mononuclear cells (PBMC). Methods: Pts were randomized to neoadjuvant ipi 3 or 10 mg/kg combined with HDI. Tumor biopsies were evaluable for testing at pretreatment (N = 20 pts) and definitive surgery (week 6-8; N = 25). When available, primary (N = 24) and relapse tumors (N = 6) were tested. PBMC: pretreatment (N = 29), 6 weeks (wk) (N = 24), then 3 (N = 23), 6 (N = 21), 12 (N = 14) months. T cell receptor beta chain (TCRB) repertoire was immunosequenced in PBMC and TME to determine repertoire clonality and T cell fraction in blood and TME (TIL; fraction of all nucleated cells identified as T cells). Results: PBMC T cell fraction when measured early on-treatment (6 wks) was significantly higher in pts who had pCR or microscopic residual disease vs. gross disease at the 6-8 wks surgery (p = 0.047). PBMC clonality was significantly lower at 12 wks (p = 0.025) for pts who continued to be relapse free (NED) long term vs. those who eventually relapsed. In TME, except for trends no significant difference in clonality was seen, but in pts with pCR TIL fraction was significantly higher when measured in primary tumors (p = 0.033). The number of tumor-associated clones that were expanded in blood post-treatment was strongly correlated with both TIL fraction (Rho 0.7299, p = 0.0003) and TIL clone diversity (Rho 0.882, p = 2.7 -7 ). Conclusions: Higher T cell fraction and lower clonality in PBMC when measured early on-treatment, and higher TIL fraction in primary tumor constituted promising biomarkers of response. Pts with higher TIL fractions were more likely to have tumor-associated clones detectable in blood, suggesting these may be useful for tracking the immune response. These findings warrant validation in an independent cohort and exploration with other immunotherapeutics. Clinical trial information: NCT01608594.
A multicenter analysis of temporal trends in the treatment complexity of colorectal cancer.
Authors: Leo Chen, Winson Y. Cheung, John Joseph Spinelli, Hagen F. Kennecke
Journal: Journal of Clinical Oncology (2016)

6529 Background: In 2016, there will be an estimated 134,490 new cases of colorectal cancer (CRC) in the US alone. Treatments for CRC include radiotherapy, and chemotherapy; options for which have increased since the year 2000. This study measures how treatment complexity experienced by newly diagnosed CRC patients have changed as a result of these developments. Methods: The BC Cancer Agency (BCCA), a network of British Columbia oncology centers, maintains electronic records of patient appointments. Data from this database were linked at the individual level with disease, radiotherapy and prescription data to assess treatment complexity: this was defined as the per patient number of clinic visits (CV), mean duration of visits in minutes (DV), fractions of radiotherapy (NR), and chemo prescriptions (CP). Trends in treatment complexity were examined using Poisson regression (CV, NR, CP) and linear regression (DV) models. All models were adjusted for stage at diagnosis. Results: From 2000 to 2012, 15,923 patients were treated at the BCCA for CRC; 48.8% of those diagnosed in the province. Of these patients, 12.8%, 27.7%, 33.9%, and 25.6% were referred for stage I, II, III, and IV disease respectively. Averaged across the study population for all years, patients visited their medical oncologist 8.75 times, spent 124 minutes per visit, received 29.8 fractions of radiotherapy, received 31.9 chemo prescriptions, and were treated for 2.32 years. Patients referred in 2012 are estimated to have 12.3% more CV (p < 0.001), 28.7% longer DV (p < 0.001), and 13.3% more CP (p < 0.001) than patients referred in 2000 over the course of their treatment and adjusted for stage at diagnosis. Conclusions: Results from this study suggest that medical oncology treatments for CRC have become more complex and patients see their medical oncologists more times and for longer periods of times, while radiotherapy remains comparable. New CRC patients appear to receive more treatment events on average, underscoring the need for modern oncology centers to help patients coordinate increasingly complex treatments. Measure Annual Relative Change 95% CI P-Value NR -0.2% -0.8% to 0.4% 0.455 CV +0.6% 0.5% to 0.8% < 0.001 DV +2.1% 1.9% to 2.4% < 0.001 CP +1.0% 0.9% to 1.1% < 0.001
Policy influence on 30 years of radical prostatectomies.
Authors: Mark Finkelstein, Khawaja Bilal, Michael Palese
Journal: Journal of Clinical Oncology (2016)

5072 Background: The prostate-specific-antigen (PSA) test was originally approved by the FDA in 1986 to monitor progression of prostate cancer in previously diagnosed males. In 1994, the test in conjunction with a digital rectal exam was approved for testing asymptomatic men for prostate cancer. In 2008, the US Preventive Services Task Force recommended against the screening of men over 75 and in early 2012 recommended against all screening use. In this study we looked into the effects of these policy changes over a 30 year period from 1983 to 2013 on radical prostatectomy (RP) cases stratified by demographic measures to understand their efficacy and how their effects are distributed. Methods: The New York Statewide Planning and Research Cooperative System, which collects information on all inpatient encounters in New York State, was used to identify all RP cases (ICD9 60.5) from 1983 to 2013. Socioeconomic data including age, payment source, and hospital location were compared between 1983 as well us before and after the previously mentioned dates of policy changes (1986,1994,2008,2012). Age was considered in groups (18-40,40-55,55-65,65-75,75-95). Results: A total of 90,068 RP cases were identified, rising 2,196% over the period of interest. RP cases peaked in 2007 with 2.8/1000 per capita cases (N = 5445) in one year followed by decline. Each decision was associated with substantial changes in the number of cases. The 1986 decision was followed by a 767% rise in caseload, the 1994 decision by a 175% increase, the 2008 decision by a 25% increase, and the 2012 decision by a 20% decrease. Over the period of interest, there was a significant shift to urban hospitals (81% to 86%, p = 0.001) The 1994 decision saw the most substantial change in age, witnessing significant increases in the 40-55 age group (5.8% to 19.5%, p < 0.001). The age group 75-95 rose after the 2008 decision (1.0% to 1.6%, p = 0.03). The 1994 is seen with a significant shift payment for PSA with insurance companies involved in a larger portion (56% to 90%, p < 0.001) as compared to medicare (44% to 24%, p < 0.001). Conclusions: Radical Prostatectomy cases rose quickly, but have been slow to fall following changes in policy. Overarching trends, such as urbanization of cases, appear independently of policy.
A phase IIB pre-surgical trial of oral tamoxifen (TAM) versus transdermal 4-hydroxytamoxifen (4-OHT) in women with DCIS of the breast.
Authors: Kelly A. Benante, Yanfei Xu, Mary Beth Tull, Adrian J. Segura, Katrina M. Alber, Kiril Kalinichenko, Lifang Hou, Borko Jovanovic, Marjorie Perloff, Brandy M. Heckman-Stoddard, Eileen P. Dimond, Seema Ahsan Khan
Journal: Journal of Clinical Oncology (2018)

TPS1595 Background: Ductal carcinoma in situ (DCIS) is diagnosed in 60,000 women annually in the US. TAM is proven to reduce risk of local recurrence and new primary breast cancer in women with estrogen receptor (ER) positive DCIS. However, acceptance of TAM has been low, primarily because of toxicity related to systemic exposure. Local delivery to the breast is an attractive alternative as low systemic levels could minimize toxicity. 4-OHT is an active metabolite of TAM. When formulated as a gel and applied to the breast, it is well tolerated, and results in 4-OHT breast tissue drug levels comparable to oral TAM. In small pilot studies, its anti-proliferative effects on invasive breast tumors and DCIS are also similar to oral TAM [Lee O, et al. PMID 25028506]. The goal of our study is to validate these results in preparation for a Phase III trial of 4-OHT gel compared to oral TAM. Methods: We are conducting a randomized, double-blinded, placebo-controlled, Phase IIB pre-surgical trial to demonstrate that daily application of 4-OHT gel will result in a reduction in the Ki-67 labeling index of DCIS lesions that is not inferior to that seen in women receiving daily oral TAM. Ki-67 of the base-line diagnostic core needle biopsy will be compared to that of the therapeutic surgical excision sample after oral TAM or 4-OHT gel for 8 ± 2 weeks. Secondary endpoints include changes in Oncotype DCIS-Score, IHC markers, hormone levels, coagulation markers, drug concentration in the plasma and breast, and experienced symptoms. 100 women (assuming 20% non-evaluable samples or non-compliance) with DCIS (10% ER-positive) will be enrolled across 6 institutions into two intervention arms: oral TAM 20mg daily, placebo gel and 4-OHT gel 4mg daily (2mg/breast), placebo capsule. All participants will be evaluable for toxicity from first dose. To date 8 of 100 participants have been enrolled. Since study open, 39 potential participants have been contacted, 28 did not consent for screening, 9 consented, 2 are pending consent, and 9 have started study intervention. The most common reason potential participants chose not to consent is wanting to schedule surgery as soon as possible. Funding Source: NCI Contract # HHSN2612201200035I. Clinical trial information: NCT02993159.
Screening for Syphilis Infection in Pregnant Women
Authors: Susan J. Curry, Alex H. Krist, Douglas K. Owens, Michael J. Barry, Aaron B. Caughey, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Martha Kubik, Ann E. Kurth, C. Seth Landefeld, Carol M. Mangione, Maureen G. Phipps, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2018)

Untreated syphilis infection in pregnant women can be transmitted to the fetus (congenital syphilis) at any time during pregnancy or at birth. Congenital syphilis is associated with stillbirth, neonatal death, and significant morbidity in infants (eg, bone deformities and neurologic impairment). After a steady decline from 2008 to 2012, cases of congenital syphilis markedly increased from 2012 to 2106, from 8.4 to 15.7 cases per 100 000 live births (an increase of 87%). At the same time, national rates of syphilis increased among women of reproductive age. To update the US Preventive Services Task Force (USPSTF) 2009 recommendation on screening for syphilis infection in pregnant women. The USPSTF commissioned a reaffirmation evidence update to identify new and substantial evidence sufficient enough to change its prior recommendation. Given the established benefits and practice of screening for syphilis in pregnant women, the USPSTF targeted its evidence review on the direct benefits of screening on the prevention of congenital syphilis morbidity and mortality and the harms of screening for and treatment of syphilis infection in pregnant women. Using a reaffirmation process, the USPSTF found that accurate screening algorithms are available to identify syphilis infection. Effective treatment with antibiotics can prevent congenital syphilis and significantly decrease adverse pregnancy outcomes, with small associated harms, providing an overall substantial health benefit. Therefore, the USPSTF reaffirms its previous conclusion that there is convincing evidence that screening for syphilis infection in pregnant women provides substantial benefit. The USPSTF recommends early screening for syphilis infection in all pregnant women. (A recommendation).
Tolerability and antitumor activity of ASP8273 in TKI-naive Japanese subjects with EGFR mutation–positive non-small cell lung cancer.
Authors: Shunichi Sugawara, Koichi Azuma, Makoto Nishio, Hidetoshi Hayashi, Katsuyuki Kiura, Miyako Satouchi, Toyoaki Hida, Atsushi Nakamura, Yasuo Iwamoto, Akira Inoue, Koji Takeda, Satoshi Ikeda, Tomoki Nakagawa, Seitaro Asahina, Kanji Komatsu, Satoshi Morita, Masahiro Fukuoka, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2017)

9037 Background: EGFR-activating mutations (eg, exon 19 deletions [ex19del], L858R) occur in ~50% of East Asian patients with non-small cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitor (TKI) treatment. ASP8273, an orally administered EGFR TKI that inhibits EGFR-activating mutations, has demonstrated clinical activity in subjects with EGFR mutation-positive (EGFR mut+ ) NSCLC. Methods: EGFR TKI-naïve adult subjects (≥20 yr) with EGFR mut+ NSCLC were enrolled in this single arm Phase 2 study conducted in Japan (NCT02500927). Subjects received open-label ASP8273 300 mg once daily until discontinuation criteria were met. Primary endpoint was tolerability; secondary endpoint was antitumor activity defined by RECIST v1.1. Results: A total of 31 Japanese subjects (12 M/19 F; median age 64 years [range: 31–82]) were enrolled. Based on local testing, 27 subjects had an ex19del (n = 13, 42%) or a L858R (n = 14, 45%) EGFR activating mutation; 4 subjects (13%) had other EGFR activating mutations (L861Q [n = 2], G719X [n = 2]). ASP8273 300 mg had tolerable adverse events with diarrhea and peripheral neuropathy being most common; no interstitial lung disease events were reported (Table). Across all 31 subjects, based on investigator assessment, treatment with 300 mg ASP8273 was associated with an overall response rate (ORR) of 52%, disease control rate (DCR) of 94%, and a median duration of progression-free survival (PFS) of 11.3 months (95% CI: 7.2, 15.5). In subjects with ex19del, ASP8273 300 mg was associated with an ORR of 46% and DCR of 85%; median PFS was 8.3 months (95% CI: 2.9, -). In subjects with the L858R, ASP8273 300 mg was associated with an ORR of 57% and DCR of 100%; median PFS was 15.5 months (95% CI: 7.2, 15.5). Conclusions: Once-daily ASP8273 300 mg was tolerable in TKI-naïve Japanese subjects with EGFR mut+ NSCLC and demonstrated antitumor activity. Clinical trial information: NCT02500927. [Table: see text]
Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells
Authors: Yohan Kim, Kyojin Kang, Seung Bum Lee, Daekwan Seo, Sangtae Yoon, Sung Joo Kim, Kiseok Jang, Yun Kyung Jung, Kyeong Geun Lee, Valentina M. Factor, Jaemin Jeong, Dongho Choi
Journal: Journal of Hepatology (2018)
From microarray to RT-qPCR for a multigene panel to predict the risk of breast cancer recurrence.
Authors: Skye Hung-Chun Cheng, Tzu-Ting Huang, Nei-Min Chu
Journal: Journal of Clinical Oncology (2018)

e24249 Background: A new 28-gene panel is composed of three parts (1) an 18-gene classifier, which has proven as an independent prognostic factor of local/regional recurrence (LRR) and distant recurrence (DR) in breast cancer, (2) IHC4 genes and (3) 6 nodal metastasis-related genes. This study aims to examine the performance of this new multigene panel using formalin-fixed paraffin embedded (FFPE) tumor tissues on a reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) system. Methods: Correlation in gene expression levels was determined between the Affymetrix microarray and the RT-qPCR systems for a cohort of 112 patients. LRR genetic model (LGM) and DR genetic model (DGM) were developed by the least absolute shrinkage and selection operator (LASSO) regression method to select a subset of provided covariates. These genetic models were subsequently validated in a separate batch consisting of 56 patients. Results: All the genes of interest have at least one probe that correlated well between the Affymetrix microarray and RT-qPCR systems. Among the training dataset (n = 112), the 5-year rates of distant metastasis-free probability (DMFP) of low-risk (n = 30, 26.8%) and high-risk (n = 82, 73.2%) patients by DGM were 100% and 71.2% (59.8% - 79.8%), respectively. The 5-year rates of local/regional control probability (LRCP) of LGM for patients classified as low-risk (n = 41, 36.6%) and high-risk (n = 71, 63.4%) were 95.1% (81.9% - 98.8%) and 71% (58.7% - 80.3%), respectively. The performance of the genetic models in validation group (n = 56) is similar: 0% DR in low-risk group and 38.3% in high risk group (p = 0.04); 0% LRR in low-risk group and 14% in high-risk group (p = 0.32). Conclusions: This 28-gene panel was successfully transferred from the microarray to RT-qPCR system and performed well in predicting LRR and distant recurrence risk of breast cancer. This RT-PCR-based multi-gene panel may be a useful tool in managing breast cancer after surgery.
AB1118 Procalcitonin differentiates infection from active disease in patients with juvenile idiopathic arthritis (JIA)
Authors: R. Trachtman, E.T. Murray, N. Pan, S.S. Toussi, M.E. Nellis, J. Szymonifka, S.F. Taber, A.B. Adams, K.B. Onel, L.A. Mandl
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Patients with JIA often present with signs and symptoms suggestive of infection. However, differentiation of infectious from non-infectious presentation in routine clinical care is challenging. Procalcitonin (PCT) is a serum biomarker elevated in the setting of bacterial infection, but whether it can reliably differentiate infection from disease flare in patients with JIA is unknown.[<sup>1</sup> <h3>Objectives</h3> To test the hypothesis that PCT levels will differ between active JIA, quiescent JIA, bacteremic patients and healthy controls. <h3>Methods</h3> From 10/16–4/17, consecutive children 6 months – 18 years with a) active untreated JIA b) quiescent JIA and c) healthy pre-surgical candidates were recruited from a musculoskeletal specialty hospital. JIA was defined according to ILAR criteria. Patients with active JIA despite treatment were excluded, to avoid confounding by treatment. Consecutive bacteremic patients were identified from an associated paediatric intensive care unit over the same period. Descriptive statistics and univariate logistic analyses were performed as appropriate. <h3>Results</h3> Patient characteristics are summarised in Table 1; bacteremic patients were younger. PCT was elevated in bacteremic patients, and was undetectable in all other subjects (Table 2). There were trends towards higher ESR and CRP in bacteremic patients, but these were not statistically significant. <h3>Conclusions</h3> Serum PCT levels appear to be a reliable biomarker to distinguish infection vs. active JIA at presentation, and can aid in directing therapy. However, PCT does not appear useful to assess disease activity in JIA. Further studies are needed to assess utility of serum PCT measurement in differentiating JIA flares from less severe infections. <h3>Reference</h3> [1] Milcent K, et al., "Use of Procalcitonin Assays to Predict Serious Bacterial Infection in Young Febrile Infants,"JAMA Pediatrics170, no. 1 (2016): 62–69; Mohsen A, et al., "Predictive Values for Procalcitonin in the Diagnosis of Neonatal Sepsis," Electronic Physician 7, no. 4 (2015): 1190–95. <h3>Disclosure of Interest</h3> None declared
Oncogenes and cancer-associated thrombosis: Is there a rationale for using molecular findings to assess thromboembolic risk in cancer patients?
Authors: L. Provenzano, M. Platania
Journal: Annals of Oncology (2018)

Background: Cancer-associated thrombosis (CAT) is one of the most threatening complications of cancer. Many questions are as yet unsolved in this field, from pathogenesis to clinical management. One of the most interesting issues is the role of oncogenes and oncosuppressors as link between carcinogenesis and CAT. There is much evidence on in vitro capacity of some oncogenes to enhance the clotting system, but less clinical evidence of association between cancer mutational status and risk of thromboembolic events. The aim of this study was to explore the relationship between mutational status of genes commonly analysed and risk of CAT. Methods: We retrospectively evaluated molecular cancer features of all consecutive patients admitted to the National Cancer Institute's Department in Milan between October 2016 and November 2017. Patients with previous thrombotic events and patients under anticoagulant therapy at cancer diagnosis were excluded. All molecular investigations requested by clinicians were recorded. Due to death as competing risk, the Fine and Gray proportional regression model was used to detect statistical association and estimate relative risk. Results: The resulting cohort consisted of 484 patients with solid tumors (most of all gastrointestinal - 47% -, lung - 18% - and breast - 15% - cancers). Molecular investigations were available for 375 (77%) patients, in particular Next Generation Sequencing (NGS) analysis for 148 (31%) patients. After a median follow up of 17 months, 118 patients (24%) exhibited clinical manifestations of thrombosis (i.e. deep vein thrombosis, pulmonary thromboembolism, splanchnic thrombosis, disseminated intravascular coagulation, arterial thrombosis) and 117 (24%) patients deceased without thrombotic events. Statistically relevant data were observed for TP53, KIT and SMAD4 mutational status (respectively, HR = 0.50, 4.30, 3.19; p = 0.04, 0.04 and 0.03). Conclusions: This is the first study using large molecular panel gene analysis for thrombosis risk prediction. Mutational status of some genes was statistically associated to the risk of thrombosis. Due to methodological limits and low prevalence of mutations, prospective and controlled studies are required. Legal entity responsible for the study: Fondazione IRCCS "Istituto Nazionale Tumori" - Milan. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.