tbuckley/cabot-search huggingface dataset:
Accurate detection of circulating tumor cells (CTCs) in patients with metastatic papillary thyroid cancer (MPTC) via an interphase fluorescence in situ hybridization (IFISH) assay.
Authors: Jian Yu Xu, Tanweer M Zaidi, Gilbert J Cote, Mimi I-Nan Hu, Steven G. Waguespack, Maria E. Cabanillas, Anita Kuo Ying, Naifa Lamki Busaidy, Mouhammed Amir Habra, Namita Shanbhag, Duy Truong, Robert K Yu, Sanjay Shete, Ruth L. Katz, Steven I. Sherman
Journal: Journal of Clinical Oncology (2016)

e17550 Background: CTC enumeration in MPTC with EPCAM assays has been unsuccessful. We used an IFISH assay employing simultaneous analysis of 4 DNA probes derived from copy number variations detected in comparative genomic hybridization arrays from non-small cell lung cancers (NSCLC) .We believe that these probes might detect CTCs in MPTC, as both lung and thyroid are foregut derived and differentiate under the influence of TTF1/NKX2-1. Patients and Methods: BCPAP (PTC cell line) and cells in pleural fluid from a MPTC patient were tested to see if NSCLC probes could detect genetic abnormalities. We then analyzed 17 MPTC patients (64.1 ± 14.1 yrs), 9 control PTC patients (49.6 ± 13.9 yrs) who were disease-free for ≥ 5 yrs after total thyroidectomy, and a second control group of 30 healthy subjects without PTC or NSCLC (62.7 ± 7.8 yrs). IFISH analyses were performed on PBMCs with locus-specific identifier probes at 10q22 (surfactant protein A) and 3p22, and centromeric probes, CEP10 and CEP 3. IFISH signals were acquired on 500 cells and classified as: CTCs (aneuploid cells with gains of ≥ 2 probes), cells with single deletions/gains, or normal cells. The percentage of cells in each category was calculated. Results: Aneuploidy was demonstrated in both BCPAP and MPTC pleural fluid cells. Blood from MPTC patients had higher % CTCs (0.91 ± 0.3; P < 0.001) compared with control PTC patients (0.2 ± 0.23) or healthy controls (0.18 ± 0.23). MPTC patients had higher % cells with deletions of CEP 3 (0.76 ± 0.71 vs 0.19 ± 0.53; P = 0.016), CEP10 (1.4 ± 1.14 vs 0.45 ± 0.67; P = 0.003), and gain of 10q22 (0.98 ± 0.95 vs 0.13 ± 0.17; P < 0.001), single deletions and gains (5.98 ± 1.74 vs 2.47 ± 1.27; P < 0.001) and decreased % normal cells (94.02 ± 1.72 vs 97.52 ± 1.24; P < 0.001) compared with healthy controls. Conclusions: Our IFISH assay demonstrated significantly increased numbers of CTCs in MPTC compared with controls. Genomic probes to detect CTCs in NSCLC successfully detected genetic aberrations in MPTC, possibly a result of lineage-specific factors common to both lung and thyroid development. Studies with larger cohorts are needed to confirm the clinical significance of CTCs.
Phase I/II trial of dasatinib and osimertinib in patients with advanced <i>EGFR</i>-mutant non-small cell lung cancer.
Authors: Chul Kim, Stephen V. Liu, Deepa Suresh Subramaniam, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2018)

TPS9113 Background: Epidermal growth factor receptor (EGFR) mutations are one of the most common driver oncogenes in non-small cell lung cancer (NSCLC). While the presence of these mutations predicts sensitivity to tyrosine kinase inhibitors (TKIs), a small but non-negligible subset of patients do not respond to EGFR-TKIs, suggesting intrinsic resistance. Moreover, acquired resistance to EGFR-TKIs is inevitable. In preclinical studies, overexpression of Cripto-1, a member of the EGF–Cripto-1/FRL-1/Cryptic protein family, contributes to the development of intrinsic resistance to EGFR-TKIs through the activation of the Src-tyrosine kinase pathway. In EGFR-mutant mouse models, we demonstrated synergy between erlotinib and Src inhibition. In vitro experiments showed increased synergy when using osimertinib, a third generation EGFR inhibitor with dasatinib, a SRC inhibitor. Based on these data, we initiated a phase I/II trial to explore the feasibility and benefit of combining osimertinib and dasatinib in patients with EGFR-mutant NSCLC. Methods: This is an open-label, single-arm phase I/II trial of osimertinib and dasatinib in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02954523). Patients with sensitizing EGFR mutations as well as those with T790M mutation are eligible. Patients with pleural or pericardial effusions at study entry are excluded. The primary endpoint of the phase I part is to establish a safe and tolerable phase II dose of osimertinib and dasatinib. The endpoint of the phase II part is the reduction of the proportion of patients who progress or have stable disease lasting 4 months or less (definition of intrinsic resistance). For the phase II portion, a two-stage design with a total of 28 patients will be used. The null hypothesis that the proportion of patients with intrinsic resistance is at least 30% will be tested against the alternative hypothesis that the true proportion of patients with intrinsic resistance is at least 10% (alpha one-sided 5%, power 85%). Accrual is underway at Georgetown University and Hackensack University Medical Center. Using tumor and serum samples, the role of Cripto-1 in mediating resistance to osimertinib will be elucidated. Clinical trial information: NCT02954523.
Validation of omics based MSI calling to improve upon traditional methods of MSI detection.
Authors: Andrew Nguyen, J Zachary Sanborn, Charles Joseph Vaske, Shahrooz Rabizadeh, Iain BeeHuat Tan, Stephen Charles Benz
Journal: Journal of Clinical Oncology (2018)

e15663 Background: Detection of microsatellite instability (MSI) status has become a vitally important biomarker for the use of the checkpoint inhibitor immuno-oncology. Traditional MSI detection relies on immunohistochemistry (IHC) images of roughly 4 different biomarkers, MLH1, MSH2, MSH6 and PMS2. These genes participate in DNA mismatch repair and when absent causes aberrations during DNA replication to persist without being repaired. These aberrations are readily detectable in small repeat regions within the human genome known as microsatellites. Methods: Analysis of 2387 loci across the human genome containing short tandem repeats (STR) allows the analysis of whether MSI is present within the tumor sample. Comparisons of tumor DNA against normal DNA will show differences in the number of STR regions. Tumor samples from whole genome sequencing exhibiting a greater than 2.5% difference in STR regions from normal are considered MSI, while tumor samples from exome sequencing exhibiting a greater than 12.05% difference are considered MSI. Results: Analysis of 158 CRC patients for MSI by IHC revealed 38 patients to be MSI with 120 patients being microsatellite stable (MSS). Further analysis by next-generation sequencing of both tumor and normal of 2387 loci, revealed 32 patients to be MSI and 126 patients to be MSS. These 6 discordant samples were sent out for further MSI testing by PCR and were confirmed to be MSS. We further analyzed 1874 clinical grade samples containing a mix of both primary and metastatic diseases and observed a 2% occurrence of MSI. Conclusions: MSI as determined by next-generation sequencing allows a more accurate determination of true MSI status. This method also allows the identification of MSI from patients with Lynch syndrome, which is not easily detectable by IHC. Misdiagnosis of MSI status may lead to erroneous use of checkpoint inhibitors, which would be costly and potentially ineffective.
Lipid-insertion to enable targeting functionalization of paclitaxel loaded erythrocyte membrane nanoparticle by tumor-penetrating bispecific recombinant protein.
Authors: Huizi Sha, Hong Chen, Baorui Liu
Journal: Journal of Clinical Oncology (2017)

e14047 Background: There is a great interest in targeting and penetrating of cancer cells for research or therapeutic purposes. Red blood cells (RBCs) are readily available and fully biocompatible long-circulating intravascular carriers that are amenable to chemical modifications, drug loading and reinjection. The purpose of this study was to design a tumor-targeting biocompatible drug delivery system for delivery of antitumor drugs. Methods: DSPE-PEG-MAL, phospholipid derivatives was used to insert into erythrocyte membrane nanoparticles. To make nanoparticles active targeting to the tumor site, a tumor-penetrating bispecific recombinant protein named anti-EGFR-iRGD was used. The characterization, bio-distribution, tumor targeting ability and antitumor activity of paclitaxel loaded anti-EGFR-iRGD modified erythrocyte membrane nanoparticle were evaluated. Results: In this study, anti-EGFR-iRGD-RBC-PTX nanoparticles was successfully constructed with a size of around 100 nm. A lipid-insertion method is employed to functionalize these nanoparticles without the need for direct chemical conjugation. It showed signifcantly targeted skill and increased cytotoxic effect toward both nontargeted RBC-PTX and combination of anti-EGFR-iRGD and RBC-PTX. The tissue distribution and antitumor assays in mice bearing gastric cancer xenograft confrmed the superior penetration tumor effcacy and antitumor activity of anti-EGFR-iRGD-RBC-PTX. Conclusions: We designed and successfully prepared a novel anti-EGFR-iRGD decorated, erythrocyte membrane sourced nanoparticle for targeted drug delivery, with enhanced tumor targeting and anti-tumor effect. Anti-EGFR-iRGD-RBC-PTX represents a potential effective nanomedicine against gastric cancer.
Identifying determinants of quality of life in patients undergoing systemic therapy for solid tumors.
Authors: Frank Po-Yen Lin, Chloe Martin, Simon Kocbek, Anthony M. Joshua, Rachel Fitz-Gerald Dear, Elgene Lim, Lorraine A. Chantrill, Venessa T. Chin, Richard J Epstein
Journal: Journal of Clinical Oncology (2017)

6596 Background: Knowing which factors compromise quality of life (QoL) in patients undergoing cancer treatments can help oncologists provide more effective care. To identify these factors, we conducted a single-centered cross-sectional study examining the relationships between patient-reported QoL, adverse events (AE), and treatment characteristics. Methods: Consecutive patients attending an outpatient chemotherapy unit completed two questionnaires (EORTC QLQ-C30 and National Cancer Institute PRO-CTCAE) per visit to identify factors contributing to the lowest global QoL score [QLQ-C30 QL2, range 0 (worst)–100 (best)] over a 6-week period. QL2 was correlated to each PRO-CTCAE item and treatment characteristic (tumor type, drug class, number of cycles, and treatment intent) using multiple regression, adjusted for age, sex, and use of concurrent radiotherapy. To determine whether QoL can be reliably modeled by machine learning, ten algorithms were compared for performance in classifying patients into dichotomized QL2 subgroups. Results: One hundred and fifteen of 130 patients (157/244 visits) completed up to 6 sets of questionnaires (median QL2: 67, IQR: 50–83). No difference was found between QL2 and treatment characteristics (at α Bonferroni =5×10 -4 ). However, QL2 was significantly associated with AE in gastrointestinal, respiratory, attention, pain, sleep/wake, and mood categories. Using AE as covariates, support vector machine with radial basis kernel was the best at classifying patients into QoL groups (mean bootstrapped area under ROC curve 0.812, 95% CI 0.700–0.925). Conclusions: Patient-reported QoL is associated with multiple AE, but not with characteristics of systemic therapy. Machine learning analysis suggests that a combined AE analysis may reliably characterize a patient’s QoL. [Table: see text]
Three-dimensional conformal radiotherapy (3D-CRT) for macroscopic vascular invasion (MVI) of advanced hepatocellular carcinoma (HCC).
Authors: Akinori Asagi, Hiroshi Ishii, Kazuhiro Uesugi, Seijin Nadano, Takeshi Kajiwara, Masahito Tanimizu, Atsushi Nishikawa, Takashi Ochi, Yasushi Hamamoto, Masaaki Kataoka
Journal: Journal of Clinical Oncology (2016)

e15626 Background: Although relatively good therapeutic effects have been reported about 3D-CRT for the treatment of HCC with MVI, there is few comparative data between them and those of sorafenib therapy or hepatic arterial infusion chemotherapy (HAIC). Methods: Among 44 consecutive HCC patients with MVI treated with 3D-CRT, we screened them by main inclusion criteria of SHARP trial or phase II trials of HAIC for advanced HCC with portal vein tumor thrombosis, and compared summary statistics of survival data between subgroups in our series and those. Results: The diagnosis of HCC was made either by histologic examination (12 patients, 27%), or distinctive findings on CT, MRI and/or angiography associated with elevated serum levels of alpha-fetoprotein or protein induced by vitamin K antagonist II (32 patients, 73%). Of the 44, 35 had MVI in the portal vein. Of the 44, 14 (32%) had extra hepatic spread of HCC. A total dose of 30-60 gray (Gy) was delivered to MVI with daily fraction size of 1.8-3 Gy. The daily fraction size and the total doses were modified according to location of the tumor and hepatic reserve of each patient. Clinical target volumes covered all HCC lesions in 12 (27%) patients. The remaining 32 (73%) had active HCC lesions outside the planning radiation field to avoid excessive liver damage. Of the 44, 27 and 8 met the inclusion criteria of SHARP trial and the HAIC trials, respectively. The median overall survival months of these cohorts were 8.8 and 7.9, respectively, which was comparable to sorafenib arm in MVI present subgroup of SHARP trial (8.1 months), and the HAIC trial (7.1 months). Conclusions: Therapeutic effect of local radiotherapy to MVI might be comparable to sorafenib therapy or HAIC. 3D-CRT might be an option as an alternative to standard therapy or a part of multidisciplinary treatment for the treatment of HCC with MVI.
Interim analysis of a randomized, open-label phase 2 study of talimogene laherparepvec (T-VEC) neoadjuvant treatment (neotx) plus surgery (surgx) vs surgx for resectable stage IIIB-IVM1a melanoma (MEL).
Authors: Robert Hans Ingemar Andtbacka, Reinhard Dummer, David E. Gyorki, Adam C. Berger, Robert Martin Conry, Lev V. Demidov, Edward Chan, Sheryl Treichel, Mark B. Faries, Merrick I. Ross
Journal: Journal of Clinical Oncology (2018)

9508 Background: There is no approved neotx for resectable stage IIIB-IVM1a MEL. T-VEC, an HSV-1-based oncolytic virus, may reduce the risk of developing visceral and bone metastases in unresectable Stage IIIB-IVM1a MEL (Andtbacka SSO 2015). We conducted a randomized study to evaluate the effect of neotx T-VEC in high risk resectable MEL (NCT02211131). Methods: Patients (pts) with resectable stage IIIB/C/IVM1a MEL, ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm, and no systemic tx 3 mos prior were randomized 1:1 to 6 doses/12 wks of T-VEC followed by surgx (Arm 1) vs upfront surgx (Arm 2). T-VEC was given at standard dosing until surgx, no injectable tumors, or intolerance. This interim analysis was planned for when the 75th pt in Arm 1 completed the safety follow-up visit (30+ days post surgx). Results: 150 pts were randomized (76 Arm 1, 74 Arm 2). Of all pts, ≥ 94% had no prior radio/systemic tx, 91% had prior surgx and 84% had no plans for adjuvant tx. 75% in Arm 1 and 93% in Arm 2 had surgx as planned. Of the 19 pts who did not have surgx in Arm 1, 11 had progressive disease. In Arm 2, 17 pts recurred within 14 wks post-surgx. For pts who had surgx in Arm 1, the pathological complete response (pCR) rate was 21%. Negative margin resection (R0) rates were 56.1% for Arm 1 and 40.6% for Arm 2 (80% CI: 3-28% for the difference). For all randomized pts, pCR rate in Arm 1 was 15.8%; R0 rates were 42.1% (Arm 1) vs 37.8% (Arm 2). Overall response (OR) rate (CR+PR) in Arm 1 was 14.7% (80% CI: 9-22%). In the safety set (73 pts in Arm 1, 69 pts in Arm 2), tx-emergent adverse events (TEAE) was 93% in Arm 1 (1 grade 4 pain, no grade 5) and 45% in Arm 2 (all ≤ grade 3). In Arm 1, preop AE was 89.5% (most common: pyrexia 35%) and intra/postop AE was 29.8% (most common: seroma 5.3%). In Arm 2, intra/postop AE rate was 45% (most common: pain 7.2%). 17.8% (Arm 1) vs 2.9% (Arm 2) pts had an SAE; of these, 5.5% (Arm 1) and 2.9% (Arm 2) were deemed surgx-related. Conclusions: 12 wks of neo T-VEC produced a pCR rate in stage IIIB-IVM1a MEL higher than observed by ORs and may account for the higher R0 margin in Arm 1. No unexpected toxicities were noted. The primary analysis of RFS is ongoing. Clinical trial information: NCT02211131.
Time trends in overall survival (OS) and progression-free survival (PFS) in the first-line treatment of advanced non-small-cell lung cancer (NSCLC).
Authors: Jacek Rutkowski, Everardo D. Saad, Marc E. Buyse, Jacek Jassem
Journal: Journal of Clinical Oncology (2016)

e20580 Background: There is an ongoing debate between the adequacy of OS and PFS as primary endpoints (PEP) in cancer clinical trials. We assessed the frequency of use and gain of OS and PFS, and various time trends in advanced NSCLC. Methods: We searched PubMed for first-line phase III trials published between January 1999 and December 2014 in 13 leading journals. We analyzed trends along 4-year periods. For trials with more than 2 arms (N = 24), the experimental arm with the highest median OS was used for analysis. Results: We retrieved 136 trials that enrolled a total of 64,753 patients in 303 trial arms. Three trials with immature results could not be analyzed for OS, and 16 trials had no data on PFS. Significant trends along the years were the increased number of enrolled patients; increased use of PFS as PEP; increased median OS; and decreased frequency of OS and increased frequency of PFS gain (Table). The ratios of the average median PFS and median OS in the four periods were 0.55, 0.53, 0.44 and 0.39. Conclusions: Significant gains in OS have decreased along recent years, while the reverse trend was observed for gains in PFS. Moreover, median OS increased without a commensurate increase in median PFS, hence OS is due to increasing post-progression survival, with a consequent dilution of the treatment effects on OS. Increasing post-progression survival could be due to benefits from further treatment lines or to enrollment of patients with better prognosis in more recent trials. Trial features Year of publication P- value Statistical test 1999- 2002 2003- 2006 2007- 2010 2011- 2014 N of trials 29 37 36 34 NA - N of patients (average) 340 474 551 514 0.016 Correlation between N and year PEP (% of trials) OS PFS 59% 0% 78% 8% 72% 17% 56% 38% 0.070 < 0.001 Chi-square for trend Median time control arm (average) OS PFS 7.3 m 4.0 m 9.3 m 4.9 m 10.7 m 4.7 m 12.5 m 4.9 m < 0.001 0.057 Correlation between median and year Trials with gain (%) OS PFS 41% 45% 28% 21% 6% 21% 22% 58% 0.006 0.039 Chi-square for trend Median difference (average) OS PFS 1.1 m 1 m 0.3 m 0.3 m 0.2 m 0.3 m 0.4 m 1.3 m 0.34 0.15 Correlation between median difference and year
Health promotion after breast cancer treatment.
Authors: Dharmesh Gopalakrishnan, Shazia Tanvir Goraya, Svetlana Banjac, Courtney Yanda, Jame Abraham, Stephen R. Grobmyer, Holly Jane Pederson
Journal: Journal of Clinical Oncology (2017)

e21586 Background: With significant advances in breast cancer (BC) treatment and improvements in long-term survival, high-quality, coordinated survivorship care is important. Methods: In this retrospective study of patients who were diagnosed with BC (Stages 0 to 3) in 2012 and had &gt; 1 year of follow-up within our network (mean follow-up 3.2 yrs), we analyzed BMI trends and compliance with age appropriate health measures. One-sample t-test was used to compare average BMI at diagnosis and year 3. p &lt; 0.05 was considered as statistically significant. Results: Of 643 patients studied, 99.5% were female, 83% were Caucasian, and 27% were ≤ 50 years of age at diagnosis (mean age 59 yrs). 17% had DCIS and 83% had invasive cancer (Stage I – 40%, II – 33%, III- 10%). 40% had a BMI &gt; 30 Kg/m 2 . BC Surveillance: 89.4% of patients with residual breast tissue or tissue flaps had surveillance mammograms during 3 years of follow-up (Year 1 - 90.0%, 2 - 89.8%, 3 - 88.3%), in compliance with current guidelines. Weight management: There was a statistically significant increase in BMI from diagnosis to year-3. This trend was consistent across different age, race, and baseline BMI groups (See Table). Colon cancer screening: 49% of eligible patients had completed age appropriate screening colonoscopies either prior to diagnosis or during the course of follow-up. Bone health: Among patients who were on aromatase inhibitors, 76% had a documented DEXA scan. Vaccination: Vaccine coverage for eligible patients was low – 63% for pneumococcal, 38% for herpes zoster, and 30% for annual influenza vaccines. Conclusions: While compliance with BC surveillance is high among patients following treatment for BC, adherence to many other important health maintenance practices is low. Renewed focus on these measures, such as weight management, bone health, vaccination and screening for other cancers, represents an important opportunity to improve not only cancer-related outcomes but also the overall health and well-being of BC survivors. [Table: see text]
Sexual function, quality of life, and cancer-related distress among prostate cancer survivors.
Authors: Joanne S Buzaglo, Alexandra K Zaleta, Melissa F Miller, Jamese Johnson, Michael A Diefenbach, Stephen J Lepore, Christian J Nelson, Mark Allen O'Rourke, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2017)

e16587 Background: Prostate cancer (PC) survivors experience long-term disease consequences that can affect quality of life (QoL). This study examined QoL in key areas affected by PC and its association with cancer-related distress. Methods: Of 225 PC survivors enrolled in the Cancer Support Community’s online Cancer Experience Registry, 50 completed questions about cancer-related distress, cancer history, and the Prostate Cancer-Related QoL Scales. Results: Participant median age was 66 years; 21% had surgery, 32% underwent radiation, and 19% reported both. 31% currently and 18% previously received hormone therapy. 38% were diagnosed 5+ years ago; 26% reported recurrence, 30% reported metastatic disease. 76% reported erectile dysfunction (ED) since diagnosis. ED was more common (84%) among those who underwent surgery/radiation than those who had not (44%; chi 2 = 6.1, p &lt; .05) and among those currently (100%) or previously (88%) receiving hormone therapy than those who had not (60%; chi 2 = 9.1, p &lt; .05). 23% reported that incontinence made sexual activity/intimacy difficult. 20% “somewhat to very much” agreed they would choose a different treatment if they could redo their decision. QoL scores (mean±SD; scale range 0-100; higher = better QoL) were: Marital Affection (84.4±26.2); Masculine Self-Esteem (78.4±23.4); PSA Concern (77.2±21.6); Informed Decision (67.8±23.5); Urinary Control (62.1±23.6); Sexual Intimacy (59.1±34.9); Outlook (54.9±38.0); Cancer Control (49.1±31.1); and Sexual Confidence (44.1±33.7). Health Worry and Treatment Regret scores (higher = lower QoL) were 39.5±27.9 and 16.1±19.9, respectively. All QoL scales except Outlook and PSA Concern were correlated with overall cancer-related distress (r = .43 to .77; ps &lt; .05), where lower QoL was associated with greater distress. Conclusions: Some PC survivors report substantial treatment regret, and many also endorse health concerns about uncertainty and disease progression, as well as reduced sexual confidence and intimacy. Lower perceived QoL, including sexual confidence and intimacy, is associated with greater cancer-related distress among survivors. Efforts are needed to address reduced QoL in a variety of life domains among PC survivors.