tbuckley/cabot-search huggingface dataset:
Landscape of kinase rearrangements (kRE) detected in circulating tumor DNA (ctDNA).
Authors: Ben C. Creelan, Daniel S Lieber, Alexa Betzig Schrock, Russell Madison, Jeffrey S. Ross, Jared White, Vincent A. Miller, Samuel Jacob Klempner, Sumanta K. Pal, Sai-Hong Ignatius Ou, Doron Lipson, Jon Chung, Allison W. Welsh, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2018)

12041 Background: kRE are established oncogenic drivers and therapeutic targets across advanced cancers. Increasingly, clinical activity targeting kRE across tumor types has been reported, largely based on tissue analysis. We sought to describe the pan-cancer landscape of predicted driver kRE identified in ctDNA. Methods: Blood samples from 8,567 cancer patients underwent hybrid capture-based genomic profiling of ctDNA. We evaluated rearrangements in 6 genes (ALK, EGFR, FGFR3, PDGFRA, RET, ROS1) for which selected introns are baited, and 7 others (BRAF, ERBB2, FGFR1, FGFR2, MET, PDGFRB, RAF1). Only samples with detectable ctDNA were included in analysis (N = 6,571). Results: kRE were observed in 4.9% of lung cancer (LC) cases (N = 2,709) and 2.4% of non-lung (nLC) (N = 3,862), including 223 unique cases (3.4% overall) with 254 kRE events (Table). The most commonly rearranged kinases were ALK (45%), RET (15%), ROS1 (15%), FGFR3 (8%), FGFR2 (5%), and EGFR (4%). The frequency of kinases altered by kRE varied by anatomic origin, with FGFR2 events identified only outside lung cancer (p < 0.001) (Table 1). Top recurrent kRE were EML4-ALK (61 LC + 7 nLC), FGFR3-TACC3 (7 + 11), KIF5B-RET (9 + 2), CD74-ROS1 (9 + 1), and CCDC6-RET (5 + 3). Comparison with > 70,000 tissue genomic profiles analyzed over the same time period showed ALK, RET, or ROS1 kRE in 4.3% of ctDNA and 4.9% of tissue LC samples, and 1.3% of nLC ctDNA and 0.4% of tissue nLC. 65% of kRE detected in ctDNA were also detected in paired tissue samples (N = 43), including 9 of 11 collected < 30 days apart. Conclusions: Kinase fusions and rearrangements exist across tumor types and can be detected by liquid biopsy. Comparison of genomic profiles of ctDNA to tissue suggest similar frequencies of ALK, RET or ROS1 kRE in lung, but a higher frequency of kRE in non-lung samples by ctDNA vs tissue, perhaps reflecting greater heterogeneity. ctDNA-detected kRE across solid tumors. Cancer Total N N with kRE % ALK RET ROS1 FGFR2 FGFR3 EGFR Lung 2709 134 4.9% 78 20 19 7 4 Non-lung 3862 93 2.4% 20 16 14 12 13 6 Breast 933 16 1.7% 3 4 2 3 2 Unknown primary 618 19 3.1% 4 2 6 4 2 1 Prostate 390 8 2.1% 3 1 2 2 Colorectal 500 18 3.6% 5 3 3 2 1 Pancreas 332 9 2.7% 1 3 1 1 Liver 120 5 4.2% 1 3 Ovarian 181 1 0.6% 1 Bladder 57 3 5.3% 1 2 Esophagus 56 2 3.6% 1 1
Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX).
Authors: Claire N. Harrison, Alessandro M. Vannucchi, Uwe Platzbecker, Francisco Cervantes, Vikas Gupta, David Lavie, Francesco Passamonti, Elliott F. Winton, Hua Dong, Jun Kawashima, Julia D. Maltzman, Jean-Jacques Kiladjian, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2017)

7001 Background: MMB, an oral JAK inhibitor, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion requirements in patients (pts) with MF. This study of previously RUX treated pts with MF tested the superiority of MMB vs BAT in splenic volume reduction, Sx amelioration, and transfusion requirement at 24 weeks. Methods: Eligibility included primary or post-ET/PV MF; DIPSS high risk, Int-2, or symptomatic Int-1; prior RUX ≥4 weeks who either required transfusions or dose reduction to &lt;20 mg BID with at least one of Gr ≥3 thrombocytopenia, anemia, or bleed; palpable spleen ≥5cm; and no Gr ≥2 peripheral neuropathy. Stratification was by transfusion dependency and baseline TSS (modified MPN-SAF Total Sx Score) &lt;18 or ≥18. Pts were randomized 2:1 to 24 weeks of open-label MMB 200 mg QD or BAT. Assessments included spleen volume by MRI, and patient-reported Sx using a daily eDiary for TSS. 1 ° endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline). 2 ° endpoints, evaluated sequentially, were rates of TSS response (TSS RR; ≥50% reduction from baseline), RBC transfusion, RBC transfusion independence (TI) and RBC transfusion dependence (TD). Results: 73 of 104 (70%) and 40 of 52 (77%) pts receiving MMB or BAT, respectively, completed the 24 week randomized treatment phase. BAT for 88% of pts included RUX, and 27% of pts were on RUX in combination with other drugs. Efficacy results are in Table. The most common Gr ≥3 adverse events in MMB pts were anemia (13%) and thrombocytopenia (7%), and in BAT pts, anemia (13%), thrombocytopenia (6%) and abdominal pain (6%); treatment emergent peripheral neuropathy occurred in 11 (11%) of MMB (1 Gr3) and in no BAT pts. Conclusions: In previously RUX-treated patients with MF, 24 weeks of MMB was not superior to BAT for SRR, but significantly better in improving disease related symptoms and transfusion independence. Clinical trial information: NCT02101268. [Table: see text]
Biologic target volume delineation and the application of three-dimensional ultrasound image system in hypofractional radiotherapy for prostate cancer.
Authors: Jie Wang, Jiabao Ma, Jin Yi Lang
Journal: Journal of Clinical Oncology (2017)

e16585 Background: To investigate the value of magnetic resonance spectroscopy (MRS) and positron emission computed tomography (PET-CT) in biological target volume(BTV) delineation of prostate cancer using hypofractional intensity modulated radiotherapy (HF-IMRT) with simultaneously integrated boost(SIB), and the preliminary efficacy and adverse effects of 3D ultrasound (3DUS) guided imaging in the treatment of prostate cancer using HF-IMRT and SIB. Methods: Between August 2015 and May 2016, 13 patients diagnosed with mid-high risk prostate cancer were retrospectively enrolled. All the eligible patients had underwent MRI MRS and PET-CT( 18 F-FDG or 11 C-CHO) examination before radiotherapy. 5 patients had explicit BTV by examinations mentioned above. Radiation oncologists fused 3DUS and CT images and delineated tumor target volume referring to MRS and PET-CT. The target volumes were named as GTV MRI BTV MRS BTV PET-CT respectively and the volume were recorded. 3DUS guided HF-IMRT were applied during the radiotherapy. Results: The volumes of GTV MRI BTV MRS BTV PET-CT among the 5 patients were different. The mean volume of GTV MRI BTV MRS and BTV PET-CT were 3.52±1.69cm 3 , 6.64±2.27cm 3 and 5.47±2.60cm 3 ,respectively. Significant difference was only observed between GTV MRI and BTV MRS ( P = 0.046). Compared to GTV MRI, the average increasing volumes of BTV MRS and BTV PET-CT were 89.07% and 55.52%. The prescription dose and biological effective dose(BED) of BTV MRS were 70.09-73.45Gy and 129.06-135.54Gy. The prescription dose and BED of the whole prostate were 66.02-69.40Gy and 113.32-124.82Gy. The dose of bladder and rectum were within safe control. The prostate specific antigen (PSA) were significantly decreased after radiotherapy. No local recurrence or distant metastasis was observed. Conclusions: MRS and PET-CT can be applied to delineation of the BTV of prostate cancer. With the help of multi-modal image guidance, dose painting for prostate cancer is feasible. 3DUS guided HF-IMRT with SIB is an alternative for radiation oncologists based on BTV MRS . With shortened time and less cost, this technique is safe and non-radioactive compared to CBCT guidance.
Effect of time interval between surgery and radiation therapy initiation in glioblastoma patients on overall survival.
Authors: Mahadev Potharaju, Anugraha Mathavan, Balamurugan Mangaleswaran
Journal: Journal of Clinical Oncology (2018)

e14047 Background: This study evaluated the effect of time interval between surgery to radiotherapy initiation on overall survival in glioblastoma patients. Methods: From January 1998 to June 2016, there were 392 eligible patients. In this retrospective study, only histopathologically confirmed glioblastoma patients were included. All patients were planned for maximal surgical resection, 3D conformal or intensity modulated radiotherapy with 6 cycles of concurrent temozolomide followed by 6 cycles of adjuvant temozolomide. The surgery to radiotherapy interval was evaluated both as a categorical and continuous variable. For categorical variable, the patients were divided into 2 groups based on surgery to starting radiotherapy time interval of ≤ 10 and > 10 days. The association of time interval and other known factors affecting oncological outcomes were analyzed using cox proportional- hazards regression. The primary end point was overall survival. Results: The median time interval between surgery and starting radiotherapy was 15.5 days. The overall median survival in all patients was 14.7 months. The median survival was 19.7 months when surgery to starting radiotherapy time interval was ≤ 10 days and 13.4 months when the time interval was > 10 days (P < 0.001). In univariate analysis, the hazard ratio was 1.78 (95%confidence interval (CI) 1.38 – 2.29; P < 0.001) when compared to the referent group of time interval ≤ 10 days. When adjusted for known prognostic factors like age, performance status and extent for resection in a multivariate analysis, the corresponding hazard ratio was 1.88 (confidence interval, CI 1.45 – 2.43; P < 0.001). This translates to 1.8 times increased risk of death when surgery to radiotherapy time interval is more than 10 days. Surgery to radiotherapy time interval when tested as a continuous variable gave a hazard ratio of 1.015 ( confidence interval, CI 1.003 – 1.026; P = 0.012) translating to 1.5% increased risk of death for every 1 day delay in starting radiotherapy 10 days after surgery. Conclusions: Surgery to radiotherapy time interval of more than 10 days has a detrimental effect on overall survival in glioblastoma patients.
Change of surgical procedure for thyroid tumor after collaboration with Nagasaki (Japan) and Semipalatinsk (Kazakhstan).
Authors: Shigeto Maeda, Tasbolat Adylkhanov
Journal: Journal of Clinical Oncology (2017)

e17590 Background: From 1949 to 1989, 456 nuclear tests were conducted by the former Soviet Union at the Semipalatinsk Nuclear Test Site (SNTS) in Kazakhstan. It is very important to assess the clinical behavior of thyroid cancer which may be affected by SNTS in the control of an accurate diagnosis and standardized surgery. We have collaborated with the Semipalatinsk Oncology Center since 1999, in order to establish an optimal method to diagnose and perform a thyroidectomy and a lymph node dissection for the patients with papillary thyroid cancer that is better suited for the Semipalatinsk environmental effects. Methods: To assess the change of diagnostic accuracy and thyroid surgery from 1999 to 2010 in Semipalatinsk Oncology Center in collaboration with Nagasaki University and Nagasaki Medical Center. Material: A total of 200 patients with thyroid cancer who underwent thyroid surgery at the Semipalatinsk Oncology Center were evaluated. From the 200 patients, 145 patients with papillary thyroid cancer were assessed for surgical procedure. This was a cross-sectional observational study. Results: 1) Before 2001, there were few preoperatively diagnosed thyroid cancers and from 2002, preoperatively diagnosed papillary cancers increased. 2) The partial lobectomies were mainly performed until 2001. From 2002 to 2010, total lobectomies were chosen for the majority of the patients, but total thyroidectomies were rarely performed. 3) Up to 2014, there are no local and distant metastasis were seen in those patients with papillaty cancer. Conclusions: An accurate diagnosis and standardized surgery for thyroid cancer helped to evaluate the biological characteristics of thyroid cancer which may be affected by SNTS in next decade.
Cross sectional survey of male adolescent and young adult (AYA) childhood cancer survivors regarding fertility.
Authors: Douglas James Harrison, Jennifer JG Welch, Katherine Matook, Cindy L. Schwartz
Journal: Journal of Clinical Oncology (2017)

e22019 Background: 30% of male cancer patients receive gonadotoxic therapy that results in infertility. Research exploring male cancer survivors’ attitudes regarding risk of infertility has focused on adults. To understand how AYA survivors perceive their risk of fertility, a cross sectional survey was conducted of male AYA survivors of pediatric cancer. Methods: After IRB approval, the home institution’s database was queried to identify subjects. Eligibility criteria included male survivors between the ages of 15-25 years who had completed treatment in the last 5 years. A self-report survey was designed to assess perspectives of male survivors of pediatric cancer on survivorship with a focus on fertility. Descriptive analysis was performed for all demographic variables collected. To identify whether there was an association between specific demographic variables on survivors’ perspectives regarding their fertility, Fisher’s Exact Test was used (cut-off p-value: 0.05). Results: 33 patients enrolled. Two were deemed ineligible (n = 31). Median age was 20 yrs. Disease and treatment demographics encompassed a wide range of diagnoses and therapy. Subjects were evenly divided as to whether they expected difficulty siring a successful pregnancy. No demographic variable was significantly associated with survivors’ belief that they would have difficulty. A majority recalled being informed during treatment that they may have difficulty siring a pregnancy and having been offered sperm cryopreservation. Of the 22 patients who did not participate in cryopreservation, 12 reported they would have done so to protect their fertility; one would not. Subjects were split as to whether they would have waited to start treatment to allow for cryopreservation. Conclusions: Male survivors of pediatric malignancy are concerned with their future fertility and are informed regarding their risk. Male patients should be counseled regarding their fertility risk and options for fertility preservation. [Table: see text]
Scrambler therapy for established chemotherapy-induced neuropathy: A randomized phase II trial.
Authors: Charles L. Loprinzi, Jennifer Le-Rademacher, Neil Majithia, Ryan McMurray, Markus Bendel, Andreas S. Beutler, Daniel Honore Lachance, Andrea L. Cheville, David Strick, Jon Charles Tilburt, Thomas J. Smith
Journal: Journal of Clinical Oncology (2018)

10016 Background: Pilot data support that Scrambler therapy may benefit patients with Chemotherapy-induced peripheral neuropathy (CIPN). Methods: Patients with CIPN for at least 3 months were eligible if the patient had finished previous neurotoxic chemotherapy. They needed to have CIPN-related tingling or pain of at least 4/10 during the week prior to registration. Patients were randomized to receive Scrambler therapy versus TENS (trans-electrical nerve stimulation), for 2 weeks. Patient- reported outcomes were utilized, including the EORTC CIPN 20 instrument, the Subject Global Impression of Change (GIC) scale, and a number of 0-10 numerical analog scales regarding applicable symptoms. After each treatment day, and weekly for 8 more weeks, patients were asked whether they would recommend their therapy to others. The primary chosen endpoint was the percentage of patients who achieved more than 50% reduction in pain or tingling scores (based on which item was selected most problematic at baseline for each patient), from baseline values, after 2 weeks of therapy. The proportion of patients with ≥50% reduction in symptom scores were estimated and compared using the chi-square test. The areas under the curves (AUC) were compared using the t-test. Results: 50 patients were randomized, 25 per arm. Data are provided in the Table. P values are provided, understanding that this is not a well-powered phase III trial. Conclusions: These results support that Scrambler therapy decreases CIPN symptoms, to a moderate degree. Further exploration of this approach is indicated. Clinical trial information: NCT01290224.Item (higher scores are better) Scrambler TENS P-value ≥50% reduction in selected pain/tingling scores, at 14 days 40% 20% 0.06 ≥50% reduction in pain scores, at 14 days 56% 28% 0.04 ≥50% reduction in tingling scores, 14 days 48% 24% 0.08 14 day AUC pain reduction from baseline 25 16 0.08 14 day AUC tingling reduction from baseline 24 13 0.08 14 day AUC GIC neuropathy symptoms rating 17 5 0.001 14 day AUC GIC pain rating 13 4 0.004 14 day AUC GIC overall QOL rating 14 4 0.006 10 week AUC pain reduction from baseline 11 13 0.72 10 week AUC GIC neuropathy symptoms rating 7 3 0.09 10 week AUC GIC pain rating 5 2 0.16 10 week recommendation of therapy to other patients (mean) 82% 39% 0.0001
Nasopharengeal carcinoma in children: Demographic, clinical, therapeutic characteristics and long term outcome of 97 patients.
Authors: Rejin Kebudi, Musa Altun, Sema Bay Buyukkapu, Omer Gorgun, Rasim Meral, Inci Ayan, Bulent Zulfikar, Fulya Yaman Agaoglu, Emin Darendeliler
Journal: Journal of Clinical Oncology (2018)

10547 Background: The aim of this study is to evaluate the demographic, clinical and therapeutic characteristics and long-term outcome in childhood nasopharyngeal carcinoma (NPC) in a single center. Methods: Data of 97 patients < 18 years with NPC, treated in the Istanbul University Oncology Institute from November 1989 to January 2018 were evaluated retrospectively. All patients received three courses of neoadjuvant chemotherapy (1989-1991; cisplatinum, 5-fluorouracil; 1992-2008: Bleomycin, epirubicin and cisplatinum- BEP; since 2008-EP) followed by radiotherapy given both to the primary tumor and to the metastatic cervical lymph nodes. Results: Sixty-nine boys and 28 girls (M:F = 2.5) with a median age of 14 yrs (6-18), presented mostly with a lump in the neck, headache, and ear and nose problems. Median follow-up was 83 months (3 months-26.6 years). Ninety percent of the biopsies of NPC were WHO type III tumors. Most patients had advanced stage tumors, 5 had distant metastatis. Chemotherapy was followed with radiotherapy 60-66 Gy to the primary tumor and involved lymph nodes, and 50-54Gy to the uninvolved cervical nodal region. The 10-year overall survival (OS) rate was 79%. There was no significant difference in OS in patients who received BEP or EP. Seventeen patients died, 2 due to accident/suicide, 3 with second primary cancer, 12 with recurrent/progressive disease. Seven second malignancies developed in six patients, six in the irradiated field at a median of 12 years (5- 25 years). Late effects included hypothyroidism, neck fibrosis, xerostomia, bony hypoplasia, skin problems and hearing loss. Conclusions: Children with advanced NPC treated with neoadjuvant chemotherapy and radiotherapy have a high locoregional control rate and much higher long-term survival (OS 79 %) than that reported in our center before 1990's when most recieved only radiotherapy (46%) or radiotherapy and adjuvant chemotherapy (58 %) (IJ Radiation Oncology Biol Phys 1996). Neoadjuvant therapy with EP chemotherapy seems to be as effective as BEP. Survivors should be followed for long-term morbidities, including second malignancies.
Systemic effects of cAMP in chemotherapy for Heren’s carcinoma.
Authors: Alla Ivanovna Shikhlyarova, Elena Mikhaylovna Frantsiyants, Galina Vitalyevna Zhukova, Natalia D. Cheryarina, Tatiana Albertovna Barteneva, Tatiana P. Protasova, Elena Alekseevna Shirnina, Tatiana Anatolevna Kurkina, Marina Igorevna Bragina
Journal: Journal of Clinical Oncology (2017)

e14052 Background: Along with tumor itself, mechanisms of regulation of homeostasis are the target for tumor progression inhibition. The brain, various organs and tumor have different resources of energetic and metabolic substrates. Involvement of cyclic adenosine monophosphate (cAMP) into intimate mechanisms of proliferation, hormonal and energetic homeostasis indicates the possibility to use this factor in chemotherapy of tumors to improve the resistance of the organism. The purpose of the study was to analyze levels of endogenous cAMP in tumor and in organs as a criterium of systemic body response to chemotherapy with cAMP application. Methods: The study included 56 male Wistar rats with Heren’s carcinoma receiving peritumoral injections of cyclophosphan (CP) 50 mcg/kg (Baxter Oncology GmbH, Germany) alone and in combination with cAMP (Sigma-Aldrich, USA), P.O. at a concentration of 0.01%. cAMP levels in homogenates of organs and tumors were measured by immunoradiometric assay (Immunotech, Czech Republic) using Arian radiometer (Vitaco, Russia). Data were processed using Statistica 6. Results: cAMP levels in growing tumors in rats without treatment (the control) were maximal (7.03±1.5 nmol/L). CP injections alone during inhibition of carcinoma growth allowed the reduction of tumor cAMP level by 3.3 times. Combination of CP and cAMP resulted in tumor regression, and endogenous cAMP levels in tumor decreased by 10 times compared with the control. Similar dynamics of cAMP reductions was noted in the adrenal glands. The lungs, thymus, lymph nodes and especially the testes and the brain, on the contrary, showed accumulation of cAMP to the normal levels and higher. Conclusions: The range of cAMP levels in organs and tumors of rats receiving combination of CP and cAMP demonstrated the development of adaptive and regenerative processes in organs responsible for the neuroendocrine regulation, suppression of stimulation of stress-realizing systems and metabolic support of the processes of increasing non-specific antitumor resistance along with inhibited proliferative activity of tumors.
Photoacoustic detection of circulating tumor cells in blood samples of stage III melanoma patients.
Authors: John Andrew Viator, Benjamin Goldschmidt, Ahmad A. Tarhini, Cindy Sander, Martin Sanders
Journal: Journal of Clinical Oncology (2016)

9555 Background: Circulating tumor cells have been postulated as indicators of the metastatic spread of cancer via the lymphatic and circulatory systems. We have developed a photoacoustic flow cytometer to target pigmented circulating melanoma cells (CMCs) in which a laser pulse induced ultrasonic signatures in these cells while ignoring healthy blood cells. We tested a pilot group of blood samples from melanoma patients with surgically resected high-risk disease (Stages III) who either remained disease free or relapsed within two years of follow up. The photoacoustic device was used to detect, enumerate, and capture CMCs in this pilot group with the intent of using this data to develop a statistical model for predicting the onset of metastasis well before traditional imaging methods determine it. Methods: We used fourteen archived samples from Stage III melanoma patients collected at the time of diagnosis. Eight of the patients remained disease free within 2 years, while six eventually became metastatic. We used a pulsed Nd:YAG laser to irradiate mononuclear cells in suspension and under flow. Only pigmented cells absorbed the laser light, resulting in photoacoustic waves detected by an acoustic transducer. The flowmeter counted and captured cells that generated photoacoustic waves. The operator of the flowmeter was blinded to the blood samples. Results: Of the eight patients who remained disease free, six showed no CMCs and two showed at least one instance of CMCs. Of the six patients who became metastatic, five showed at least one instance of CMCs, while only one did not. Using a Fisher’s Exact Test, we calculated a p-value of 0.1 between the two groups based solely on the presence or absence of CMCs. Conclusions: This pilot experiment achieved statistical significance with a significance level of 0.1. As we continue to accrue results, we believe that a more sophisticated model that accounts for other relevant factors (age, gender, adjuvant therapy) can be developed and will be an important predictor of metastatic disease. This model, along with the ability to detect CMCs, warrants further testing as it may lead to a powerful prognostic tool for the management of high-risk melanoma.