tbuckley/cabot-search huggingface dataset:
Comparison of prognostic models for selecting synchronous mRCC patients who would benefit from upfront cytoreductive nephrectomy followedtargeted therapy.
Authors: Wei Zheng, Jianzhong Shou
Journal: Journal of Clinical Oncology (2018)

e16568 Background: The IMDC model was developed as a prognostic model for mRCC patients on targeted therapy, and earlier report proposed that patients no more than 3 risk factors would be benefited from cytoreductive nephrectomy (CN). In our previous study, we advocated a similar prognostic model based on 74 mRCC patients. In this study, we try to compared the efficiency in the evaluation of prognosis of mRCC patients between our previous model and the IMDC model. And also to evaluate the feasibility in using these two models as an alternative criterion for surgery in mRCC patients in China. Methods: We collected another cohort of mRCC patients who were initially treated with targeted therapy in CHCAMS from January 2006 to January 2016. Patients were stratified in different groups according to the IMDC model and our model. OS was the primary endpoint. We compared these two models with each other by the C-index test and the AUC. Results: There were 102 synchronous mRCC patients enrolled, the total median OS was 26.0 months. A total of 72 patients received CN before targeted therapy. The median OS in CN group and No-CN group was 31.0 and 10.0 months respectively. The C-index for IMDC model and ours was 0.72 and 0.69 respectively. The AUC was 0.68 and 0.65 respectively (P = 0.190). The median OS was 32.0 vs 15.0 months (P = 0.000) in CN and No-CN subset respectively among the patients who had no more than 3 risk factors according to the IMDC model. Similar outcomes were observed when our previous model was used for validation analysis. Thirty patients were divided into CN-negative group according to the IMDC model. Among them, eighteen patients were still belonging to CN-benefit group by using our model. Among these patients, the median OS was 16.0 vs 10.0 months for the ones who received CN and the ones without respectively (P = 0.029). Conclusions: We validated the IMDC model and our prognosis model among synchronous mRCC patients who treated with targeted therapy. All of them showed the similar efficiency in the selection of surgery in Chinese patients with synchronous mRCC. We also proposed a new selection process for the selection of surgery in this population by using both of these two models.
Clinical and radiological features of advanced <i>RET</i>-rearranged lung cancer.
Authors: Masafumi Saiki, Fumiyoshi Ohyanagi, Ryo Ariyasu, Junji Koyama, Tomoaki Sonoda, Yosuke Kawashima, Natsuki Takano, Tomoyo Oguri, Shingo Nishikawa, Satoru Kitazono, Noriko Yanagitani, Atsushi Horiike, Hironori Ninomiya, Kengo Takeuchi, Yuichi Ishikawa, Katsunori Oikado, Makoto Nishio
Journal: Journal of Clinical Oncology (2017)

e23104 Background: RET fusion gene was found in 1–2% of non-small cell lung cancer (NSCLC). Most of the reports published so far investigated only surgical specimens, and details of advanced tumors were unknown. This study explored the clinical and radiological characteristics of RET-rearranged lung cancers in advanced stages. Methods: Among 1,074 advanced NSCLC patients who were treated at The Cancer Institute Hospital, Tokyo, from 2012 to 2016, 14 cases (14/1,074 = 1.3%) were treated as RET- rearranged lung cancer. The cases were identified by FISH and / or by RT-PCR (FISH 3, RT-PCR 2, FISH and RT-PCR 8, unknown 1). The fusion partner genes included KIF5B (n = 10), CCDC6 (n = 1). Three were unknown. The tumor size, location, and shape/margins of the primary tumor as well as lymphadenopathy and site of metastasis were recorded based on computed tomography (CT) images taken right before the initial chemotherapy. Results: The median age of the 14 patients was 64 years (range, 34–79), with 10 patients (71%) over 60 years old. Nine patients (64%) were women, whereas 10 patients (71%) were never smokers. Eight patients were classified as stage IV and 6 underwent recurrence after surgery. We successfully evaluated CT images at the initial chemotherapy of 12 patients. Of the 7 patients whose primary lesions were detectable, all were located peripherally and were of a solid tumor type without ground-glass, air bronchograms, or cavitation. The median size of the primary lesion was 3.0 cm (range, 1.2–6.8), and 3 lesions were less than 3.0 cm. Only 5 patients had lymphadenopathy (4 were of Stage IV, 1 was a recurrence), most of which were isolated with a median size of 1.5 cm (range, 1.2–3.5). The sites of distant metastases included 8 pleural disseminations, 5 lungs, 5 bones, 3 livers, 2 brains, and 0 adrenals. Conclusions: Advanced RET-rearranged lung cancer manifested as a relatively small and peripherally located solid primary lesion with isolated lymphadenopathy. Pleural dissemination was frequently observed, whereas brain metastasis was less frequent. These features differ from EGFR-mutated or ALK-fused lung cancers.
Multiregion gene-expression profiling to reveal heterogeneity in molecular subtypes and immunotherapy response signatures in lung cancer.
Authors: Won-Chul Lee, Lixia Diao, Jing Wang, Jianhua Zhang, Emily Roarty, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tina Cascone, Weiyi Peng, Neda Kalhor, Cesar Moran, Faye M. Johnson, William N. William, Stephen Swisher, John Heymach, Ignacio Ivan Wistuba, Andrew Futreal, Jianjun Zhang
Journal: Journal of Clinical Oncology (2017)

e20077 Background: Intra-tumor heterogeneity (ITH) may be present in all molecular levels. Genomic ITH at the exome level has been reported in many cancer types, but comprehensive gene expression ITH has not been well studied. Methods: We collected 35 samples from 10 NSCLC patients (3 or 4 regions/tumor) including lung adenocarcinoma (n = 6), squamous cell carcinoma (n = 2), large cell carcinoma (n = 1) and pleomorphic carcinoma (n = 1). Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for each sample. Diverse gene expression signatures associated with clinical outcomes were tested for ITH. Results: Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of ITH. The analysis of various clinically relevant gene expression signatures including molecular subtype, EMT and immunotherapy response signatures also revealed heterogeneity between different regions of the same tumor. The gene expression ITH we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Conclusions: Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression ITH.
P04.05 “The Development Tumor Model” used to reproduce and follow glioblastoma evolution in the whole brain and to test and monitor novel therapies
Authors: E Brognaro
Journal: Neuro-Oncology (2018)

“The development tumor model” (TDTM) is currently the only preclinical animal model which can replicate the entire glioblastoma natural history both in the bulk and in the micro-infiltrated brain parenchyma. Furthermore, the model is perfectly suited to test new therapies and continuously monitor subclonal emerging populations after treatment in order to identify molecular predictors of response to innovative therapies. TDTM is a xenogeneic orthotopic transplantation model using glioblastoma-derived cell lines from the pre-hypoxic phase of the founding clone (or of the more ancestral one, inferred after reconstruction of the phylogenetic tree) cultivated in a neurobasal serum-free medium as transplanted material. The model posits the transplantation of the same number of cells into several genetically identical immunocompromised rodents (an inbred strain of mice or rats) at the same time (time zero). Thus, the model creates a pool of twin immunodeficient transplant animals examined under the same conditions. By sacrificing one animal a week (or choosing others intervals as needed) and performing multiple biopsies (from the bulk, ipsilateral hemisphere, corpus callosum, contralateral hemisphere) and stainings on sections during xenograft progression, we can biologically and spatiotemporally (i.e geographically and longitudinally) reproduce and monitor both the entire evolution in the bulk (appreciating the evolving variegated clonal architecture and increasingly more complex intratumor heterogeneity) and the detection of all steps (from the beginning to the end of the natural history) of the brain parenchyma micro-infiltration. TDTM can allow us to identify the CSCs in the brain parenchyma shedding light on the perivascular parenchymal niche where founder CSCs settle quiescent in G0 state until activation. Furthermore, TDTM can enable us to test new therapies. By delivering to all rodents at the same time the identical dose and modality of therapeutic treatments over xenograft progression, the model allows us to follow the dynamics, response and emergence of subclones both in the bulk and in the micro-infiltrated brain parenchyma that occur during and after innovative therapies either as chemotherapy, radiotherapy, immunotherapy or others. TDTM is a very powerful tool to follow the entire glioblastoma evolution and identify appropriate CSC targets. Indeed, glioblastoma progression can be monitored over time as if it were occurring in a single animal both in the bulk and, most importantly, in the micro-infiltrated brain parenchyma. Furthermore, the model is perfectly suitable to test and monitor innovative, targeted and personalized therapies to overcome the two causes of resistance.
Use of clinical factors to predict imaging appearance of bony metastases in colorectal cancer: A retrospective analysis.
Authors: Alpana Mukesh Harisinghani, Marcelo Franciso Zagatti, Sandeep Hedgire, Mukesh Harisinghani
Journal: Journal of Clinical Oncology (2016)

e15152 Background: The purpose of this study was to evaluate imaging features of bony metastases in patients with CRC and to assess if initial tumor stage and serum biomarkers (CEA levels) can predict imaging features and outcome. Methods: 101patients with bony metastases from CRC were enrolled in IRB approved study. Imaging studies were evaluated to record the following features; duration of bony metastases occurrence since primary diagnosis; single vs multiple lesions; size of dominant lesion; location of lesions; and the density of the dominant lesion type (sclerotic, lytic or mixed). The clinical staging and histopathologic features of the CRC and the CEA levels at time of CRC and bone metastases diagnosis were also recorded. The relationship between clinical (CEA, staging, histologic grading) and imaging features of the bony metastases were analyzed using Cox regression analysis. Results: Mean age was 59.5 yrs;66 (65.3%) of 101 patients had T3 stage disease, 17 (16.8%) had T4 stage; 16/101 had poorly differentiated, 79 had moderately differentiated and 6 well differentiated cancer. 11(10.8 %) of the 101 patients had N1disease and 40 (39.6 %) had N2 disease. The average CEA level was 136.93 ng/ml at time of diagnosis, increasing to 529.38 ng/ml at time of bone metastases. Solitary bone metastasis in 40 % and multiple in 60%, dominant lesion size ranging from 0.6 cm to 3.57 cm. The axial skeleton was commonest site of bony metastases with distribution seen in spine, pelvis, bony thorax, long bones and skull(37 %, 33 %, 17%, 8%, 5% respectively). The vertebral body was most common site followed by ribs and iliac bones in the pelvis. Lesions were sclerotic in 50%, lytic in 31 % and mixed in 19 % of patients. Median survival from bone metastases was 23.1 months. Multivariate analysis showed initial high serum CEA level and T stage as independent predictors of short survival (p < 0.03). None of the factors were able to predict imaging features. Conclusions: Commonest site of bony metastases:vertebral body, ribs and iliac bones should be carefully screened at time of primary diagnosis. CEA levels at time of diagnosis and initial T stage can predict survival in patients with osseous metastases but cannot predict imaging features.
Prognostic understanding in acute leukemia: Patient-physician differences.
Authors: Sophia Shimer, Maureen Canavan, Renee Capasso, Steven Gore, Sara Tannenbaum, Tehreem Babar, Nikolai Alexandrovich Podoltsev, Stuart Seropian, Scott F. Huntington, Amer Methqal Zeidan, Gottfried von Keudell, Thomas Prebet, Kerin B. Adelson
Journal: Journal of Clinical Oncology (2018)

e22124 Background: Acute leukemia poses unique challenges for prognostication. In many cases, cure is possible but unlikely and treatment is risky. Little is known about how patients perceive their prognosis. Methods: We surveyed patients admitted with acute leukemia and their treating hematologists. We elicited patient preferences for prognostic information and asked whether goals of care discussions had occurred. We then compared patient vs physician perceptions of treatment goals, chance of cure, expected survival, and chance that treatment would lessen suffering. Concordance was assessed with κ statistics. Results: We enrolled 76.6% (105/137) of eligible patients. We restricted our analysis to the 90 patient-physician dyads in which both parties completed a survey. Although 83.5% of patients wanted to be told their prognosis, only 56.8% recalled their physician disclosing treatment response rates. Most patients (82.2%) and physicians (78.9%) shared a goal of cure. However, they differed significantly in their perceptions of the chance of cure. Both non-relapsed and relapsed patients were more likely than their physicians to report a > 80% chance of cure (57.9% vs 5.2% for non-relapsed, p < 0.001; 38.7% vs 0.0% for relapsed, p < 0.001). Among those willing to estimate survival time, 75.7% of patients vs 28.4% of physicians estimated > 5 years (p < 0.001). Patients were also more likely to report a > 80% chance that treatment would lessen suffering (50.6% vs 21.6%, p < 0.001). Patient-physician concordance was poor for both chance of cure (κ = 0.05) and chance of lessening suffering (κ = 0.02). Conclusions: Most patients overestimate their prognosis compared to their hematologist’s assessment. This finding is significant because, while optimism can help with coping, there is also a risk of unrealistic expectations influencing treatment decisions, especially after relapse. Future work will explore whether prognostic overestimation predisposes patients toward overly aggressive care. Chance of cure (%) Non-relapsed (n = 58) Relapsed (n = 32) Patients (%) Physicians (%) p-value Patients (%) Physicians (%) p-value 0-20 5.3 19.0 < 0.001 16.1 59.4 < 0.001 21-40 3.5 22.4 9.7 25.0 41-60 12.3 32.8 9.7 12.5 61-80 21.1 20.7 25.8 3.1 81-100 57.9 5.2 38.7 0.0
Racial disparities in the surgical treatment of rectal cancer.
Authors: Elliot George Arsoniadis, Yunhua Fan, Stephanie Jarosek, Haitao Chu, Mary R Kwaan
Journal: Journal of Clinical Oncology (2016)

e18080 Background: Rectal adenocarcinoma is a major cause of cancer-related morbidity and mortality, with an estimated 39,610 cases to be diagnosed in 2015. Advances in neoadjuvant chemoradiation therapy have increased the rate of anal-sphincter-preserving surgery, with subsequent increases in quality of life. We hypothesize that despite improvements in multimodality treatment of rectal cancer, African American (AA) patients are still undergoing sphincter-sacrificing operations with the need for permanent colostomy at a higher rate than their non-AA counterparts. Methods: We utilized the US Healthcare Cost and Utilization Project National Inpatient Sample (HCUP NIS) for years 1998-2012. Our cohort was defined by ICD-9 diagnosis codes for rectal cancer and ICD-9 procedure codes for either Low Anterior Resection (LAR) or Abdominoperineal Resection (APR). Patients were separated by race (AA and non-AA) and results were analyzed using Chi-square analysis. Results: We identified 16,881 patients with non-metastatic rectal cancer undergoing either sphincter-preserving or sphincter-sacrificing rectal surgery. Of these, 1,155 (7.3%) were identified as AA. Overall, AA patients were more likely to undergo sphincter-sacrificing rectal surgery compared to their non-AA counterparts (36.7% vs. 28.9%, P<0.0001). When examining rates in men alone, AA male patients were more likely to undergo sphincter-sacrificing surgery compared to non-AA males (37.7% vs. 30.2%, P<0.0001) (Table 1). Conclusions: The reasons for this disparity are unclear, but possibly reflect differences in insurance coverage, stage at diagnosis, use of neoadjuvant chemoradiation, access to high-volume surgeons and hospitals, and higher rates of underlying medical comorbidities at the time of treatment. Further investigation is clearly warranted. This work is an important initial step in understanding reasons for this disparity and in bridging the racial divide in providing optimal rectal cancer care. Anal Sphincter Sacrificed (%) Anal Sphincter Preserved (%) P value AA (total) 424 (37) 731 (63) <0.0001 Non-AA (total) 4538 (29) 11,188 (71) AA (men only) 255 (38) 421 (62) <0.0001 Non-AA (men only) 2797 (30) 6481 (70)
Type II RAF inhibition predicts superior ERK suppression compared to type I RAF inhibition in different BRAF mutant types recurrently found in lung cancer.
Authors: Philippe Giron, Amir Noeparast, Sylvia De Brakeleer, Ulrike De Ridder, Erik Teugels, Jacques De Greve
Journal: Journal of Clinical Oncology (2017)

e23154 Background: Somatic driver BRAF mutations account for 6-8% of lung cancers. As opposed to melanoma in which V600E mutant BRAF predominates, the majority of lung cancer-derived BRAF mutations are non-V600. Yet, the efficacy of RAF-inhibitors and the possible resistance mechanisms in non-V600 BRAF mutant cells remain to be uncovered. Recently, we have shown that non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of type I RAF inhibitor Dabrafenib and a MEK inhibitor Trametinib. As a single agent, Dabrafenib shows only weak suppression of mutant BRAF-induced ERK signaling; moreover it can induce ERK paradoxical activation in CRAF overexpressing cells. Methods: Several recombinant BRAF expression vectors were generated by performing site-directed mutagenesis. We compared the effects of Dabrafenib and a type II RAF inhibitor (AZD-628) at clinically relevant dose as single agents or in combination with MEK inhibitor Trametinib on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants and a non-V600 BRAF mutant lung cancer cell line (H1666). Viability and caspase3/7 activation assays were performed using the H1666 cell line model. Results: In contrast to Dabrafenib, AZD-628 does not induce paradoxical ERK activation in CRAF expressing cells. Increased CRAF expression desensitizes BRAF-mutant expressing cells to Dabrafenib but not to AZD-628. Notably, AZD-628 has superior ERK-inhibitory effect in HEK293T cells co-expressing several different BRAF-mutants with CRAF and in H1666 cells. Combination of Trametinib and AZD-628 has superior MEK-inhibitory and pro-apoptotic effect in H1666 cells compared to combined Trametinib/Dabrafenib. Moreover, upon down titration of the RAF inhibitors with a steady dose of Trametinib, AZD-628 resulted in overall stronger effect on viability compared to Dabrafenib. Conclusions: In our in vitro model, we obtained strong indications that at conventional doses, type II RAF-inhibitor AZD628 is superior to type I RAF-inhibitor Dabrafenib in combination with MEK inhibitor Trametinib for the treatment of non-V600 BRAF mutant lung cancer.
A randomized multicenter phase 3 trial of adjuvant fotemustine versus surveillance in high risk uveal melanoma (UM) patients (FOTEADJ).
Authors: Sophie Piperno-Neumann, Manuel Jorge Rodrigues, Vincent Servois, Gaëlle Pierron, Lauris Gastaud, Sylvie Negrier, Christine Levy-Gabriel, Livia Lumbroso, Nathalie Cassoux, Francois-Clement Bidard, Olivier Michielin, Jean-Philippe Lacour, Xavier Durando, Pascale Mariani, Corine Plancher, Bernard Asselain, Sebastien Armanet, Veronique Mosseri, Laurence Desjardins
Journal: Journal of Clinical Oncology (2017)

9502 Background: Up to 30% of UM patients will develop metastases, with a median survival of 12 months in the metastating setting. Prognostic factors combine clinical features of the primary tumor (diameter, thickness, retinal detachment, extra-scleral extension) and genetic factors (monosomy 3, 8 q gain and class 1 /2 gene expression profiling).The genomic analysis is feasible by fine needle aspiration biopsies before radiotherapy for small UM or on enucleated eyes. Methods: Multicenter randomized phase 3 trial with adjuvant fotemustine, 6 cycles, 100 mg/m2 versus surveillance for 3 years (liver tests/3 months, liver MRI or CT/6 months, whole body CT/12 months) in patients with high risk of recurrence, defined by clinical criteria (diameter &gt; 15 mm with extra scleral extension and/or retinal detachment or diameter &gt; 18 mm) or genomic high risk signature by array-CGH (monosomy 3 or deletion of 3p associated with gain of chromosome 8). The primary objective was 5-year Metastasis Free Survival (MFS). With an expected increase of 5-year MFS from 50 to 70%, 302 patients and 99 events were required to achieve an 95%-power with a 5% type I error rate. Secondary objectives were overall survival (OS), safety (NCI-CTC v3), quality of life (QLQ-C30). Interim analyses were planned for safety and after 50 events, disclosed to an independent safety monitoring board. Results: The trial was stopped for futility after 244 patients had been recruited between June 2009 and January 2016. No unexpected toxicity was found in the chemotherapy group. The study was amended to go on with intensive surveillance in new high risk patients. Ninety-one metastases and 43 deaths were reported, with no treatment-related death. With a median follow-up of 3 years, the 3-year MFS is 60.3% in the chemo group and 60.7% in the surveillance group (HR 0.97 [0.64-1.47]). The 3-year OS is 79.4% [73.2-85.7], with no difference between the 2 groups of patients. Conclusions: FOTEADJ is the first adjuvant randomized phase 3 trial based on genomic analysis in high risk UM patients. Despite negative results, it shows the feasibility of multicenter adjuvant studies in this rare cancer and provides genomic data in small tumors for future trials. Clinical trial information: NCT02843386.