tbuckley/cabot-search huggingface dataset:
The impact of different brain imaging strategies for initial staging and post-treatment surveillance in patients with EGFR-mutant lung adenocarcinomas.
Authors: Chia-I Shen, Hsu-Ching Huang, Chi-Lu Chiang, Yung-Hung Luo, Tsu-Hui Shiao, Chao-Hua Chiu
Journal: Journal of Clinical Oncology (2018)

e21145 Background: According to NCCN guideline, brain MRI is suggested for lung cancer staging; however, brain CT is still commonly used in clinical practice. In addition, the brain surveillance strategy in advanced lung cancer patients during treatment varies from routine follow-up (RFU) to symptom-driven survey (SDS). There’s limited data on the outcome of different brain staging and surveillance strategies in patients under epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. Methods: Clinical data was collected from patients with advanced lung adenocarcinoma bearing EGFR mutation and were treated with first-line EGFR-TKI. Patients’ characteristics and brain imaging strategies were analyzed. RFU was defined as at least one not-for-cause brain imaging per year, and SDS as no brain imaging study until symptoms developed. Results: We collected one hundred advanced lung adenocarcinoma patients diagnosed during 2012 to 2017 in one medical center. Among them, 82% were staged by brain MRI, 14% by brain CT, and 4% were missed. Patients who died within 3 months were excluded. Among 74 patients who received MRI for brain staging, 45.9% received RFU and 54.1% underwent SDS. Comparing with patients receiving brain CT, patients staged with brain MRI had higher RFU rate (45.9% vs. 9.1%; p = 0.023). Clinicians tended to use SDS for elderly-patients (age > 70, OR = 2.56 (1.04 - 6.33); p = 0.042). The overall survival in patients with two surveillance strategies showed no significant difference (p = 0.316). In patients underwent RFU, initial staging modalities had no impact on overall survival. The duration of first-line EGFR-TKI treatment was longer in patients undergo RFU (RFU 13.3 months, SDS 10.3 months; p = 0.049). Conclusions: In this real-world data analysis, there was no significant survival difference between routine and symptom-driven brain imaging strategies in patients with EGFR-mutant advanced lung adenocarcinoma under EGFR-TKI treatment.
A phase II, open label, single arm study of nivolumab for recurrent or progressive IDH mutant gliomas with prior exposure to alkylating agents.
Authors: Laura Donovan, David Cieremans, Lakshmi Nayak, Yazmin Odia, Fabio Massaiti Iwamoto
Journal: Journal of Clinical Oncology (2018)

TPS2073 Background: Gliomas are the most common malignant primary brain tumors in adults. Mutations in Isocitrate dehydrogenonase 1 (IDH1) or IDH2 genes are associated with longer survival. These mutations are found in over 70% of WHO Grade II and III astrocytomas and are now required for the diagnosis of oligodendroglioma. Upfront standard of care treatment for high grade gliomas includes a combination of radiation with alkylating agents including temozolomide or procarbazine and lomustine. Unfortunately, independent of initial grade or IDH mutation status, recurrence after first line therapy is nearly universal. Currently, there is no standard of care therapy for recurrent disease. Trials of PD1 and PD-L1 inhibitors in recurrent high grade gliomas and IDH inhibitors in IDH mutant gliomas have been disappointing. Multiple studies in other solid tumors have shown that high mutational burden is associated with response to immune checkpoint inhibitors. In comparison to other cancers, gliomas have a low mutational burden. However, there is evidence suggesting that IDH mutant gliomas are more prone to develop a hypermutated phenotype after exposure to alkylating agents. This subgroup of patients may be more likely to benefit from treatment with nivolumab, an anti-PD1 agent. Methods: Design This is a Phase 2, open label, single arm study. We will enroll 37 evaluable subjects. The primary endpoint is ORR based on RANO criteria. Secondary endpoints are PFS, OS, and duration of response. Exploratory endpoints include evaluation of mutational burden, 2HG spectroscopy, spatial profiling of PD-1/PD-L1 interaction and NANO scale. Eligibility Adult patients with recurrent or progressive IDH mutant high-grade gliomas who have received prior treatment with alkylating agents with no prior bevacizumab or other immune checkpoint inhibitors. Treatment All subjects will be treated with nivolumab 240mg IV every 2 weeks for 8 cycles. Beginning with cycle 9, nivolumab 480mg IV will be administered every 4 weeks until completion of the study.
Clinical factors and the role of Wnt regulators in racial disparity of metastatic colorectal cancer survival.
Authors: Shin Yin Lee, Umit Tapan, Moshe Shashar, Jamaica Siwak, Qing Zhao, Vijaya B. Kolachalama, Jean M. Francis, Kevan L. Hartshorn, Vipul Chitalia
Journal: Journal of Clinical Oncology (2016)

6551 Background: African American (AA) colorectal cancer (CRC) patients experience lower survival compared to Caucasian Americans (CA). Aberrant Wnt/beta catenin (bcat) signaling is the hallmark of CRC pathogenesis, yet its contribution and that of its regulators to racial disparity remains elusive. Recently, Casitas B-lineage Lymphoma (c-Cbl) was identified as a suppressor of tumorigenic bcat. A negative correlation between them supports effective regulation of bcat by c-Cbl. We examined the contribution of baseline characteristics, treatment, and Wnt regulators on survival disparity in a cohort of metastatic CRC (mCRC) patients at a safety-net hospital (SNH) with a large AA population. Methods: Patients with mCRC between 2004-2014 at the largest SNH in New England were analyzed. Histologic analysis to quantify the amounts of bcat and c-Cbl was performed using a customized, color-based customized image segmentation pipeline. Results: Among 147 subjects with mCRC, 41.5% were AA, and 35.4% CA. Median survival from diagnosis was significantly lower in AA compared to non-AA (20.16 vs 25.68 months, p < 0.05). No significant differences were detected in: age, gender, Charlson Comorbidity index, tumor location, number of metastatic sites, tumor mutations (KRAS/BRAF/MSI), chemotherapy regimen, or use of biologics. There were no significant differences in number of cycles received, response rate, progression rate, or toxicity with 1st line chemotherapy. Although a negative correlation between bcat and c-Cbl was observed in AA, it was stronger in non-AA patients (Pearson correlation coefficient -0.81, 95% CI -0.93 to -0.55 for AA, and -0.87, 95% CI -0.93 to -0.77 for non-AA). Conclusions: Lower survival rates in AA mCRC patients could not simply be accounted by socioeconomic, clinical, mutation, or therapy-related parameters, thus raising the possibility of pathogenic mediators as potential contributors to the racial disparity. These data support a trend towards stronger negative correlation suggesting better control of bcat in non-AA patients. These hypothesis-generating observations may potentially explain lower survival in AA mCRC patients, although validation in a larger cohort is warranted.
National Cancer Database analysis on patterns of care for brain metastases.
Authors: Catherine R. Garcia, Stacey A. Slone, William H. St Clair, Eric B. Durbin, Donita D. Lightner, Thomas A. Pittman, John L. Villano
Journal: Journal of Clinical Oncology (2018)

e14001 Background: Brain metastases (BM) are associated with high morbidity and mortality. The incidence of BM has increased in the last decade and survival has increased due to introduction of novel treatment strategies. Large studies describing patterns of care of BM focus on radiation treatment or predate the extensive use of novel systemic therapies. We describe current patterns of care of patients with BM. Methods: We analyzed the National Cancer Database from 2010-2015, for patients with diagnosis of lung, colorectal, liver, melanoma, and breast cancer with BM to compare patterns of care across the largest cancer database in the United Sates. Results: 82,090 cases of brain metastases were included. Lung cancer accounted for 90% of the patients, of which 74.5% were non-small cell (NSCLC), 17.9% were small cell (SCLC), and 7.6% other types. Breast cancer accounted for 4.35% of the cases, melanoma for 3.5%, and gastrointestinal tumors (liver and colorectal cancer) for 2.26%. The majority of cases were males (50.5%), whites (83.3%), and non-Hispanics (93.2%) with a mean age of 64 years. Comorbidites were low and were higher in patients with lung cancer. Patients were more likely to be treated in community centers and dwelled in metropolitan areas. Overall 54.3% received radiation to the brain, 53.1% of the cases received chemotherapy, and 3.2% received immunotherapy. Stereotactic radiosurgery was performed in 22.37% of those that received radiation. Treatment receipt varied by primary cancer diagnosis. Chemotherapy was used in over 70% of patients with SCLC, and in less than 30% of patients with melanoma. The majority of patients with SCLC, NSCLC, and melanoma received radiation. Immunotherapy was more frequent in patients with melanoma (16.9%), and breast cancer (11.2%). Median survival was 5 months in the overall sample, and was significantly higher in breast cancer (10.5 months) and lower in gastrointestinal cancer (4.5 months). Conclusions: Our study is the largest patterns of care analysis of brain metastases to date. The majority of patients received systemic therapy and radiation. The increased survival in the current era compares favorably to historical RTOG recursive partitioning analysis studies.
Programmed death (PD)-ligand 1 (L1) expression and mismatch repair (MMR) deficiency across tumor types: Candidates for checkpoint inhibitor based immunotherapy.
Authors: Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Su Jin Lee, Kyoung-Mee Kim, Jeeyun Lee
Journal: Journal of Clinical Oncology (2017)

e14622 Background: The identification of biomarkers associated with response to therapeutic agents has changed the paradigm of cancer treatment into the precision medicine by identification of right targets across cancer types. PD-L1 expression and mutational or neoatigen burden (Mismatch repair (MMR) deficiency) have been actively studied as the predictive biomarkers for the response to immune checkpoint inhibitors. Methods: We have conducted the PD-L1 and hMLH1/MSH2 expression (MMR deficiency) as part of a clinical practice for 430 patients with advanced gastrointestinal (GI) cancer, genitourinary (GU) cancer or rare cancers between June 2012 and March 2016. Herein, we evaluated potential candidates who could be targeted to further immune checkpoint inhibitors. Results: In 430 patients, 414 (96.2%) patients were available to evaluate the status of PD-L1 expression by immunohistochemistry (IHC). Irrespective of tumor-types, overall 26.8% (111 of 414) exhibited expression of PD-L1 in tumor tissues. The PD-L1 expression was examined as follows; 33.5% in HCC, 31.0% in CRC, 27.3% in GC, 25.5% in melanoma, 18.8% in BTC, 16.7% in pancreatic cancer, 15.8% in sarcoma and 13.0% in GU cancer. Among the 394 patients available for MLH1/MSH2 expression, only 18 patients (4.5%) had the MMR-deficient tumors with complete loss of MLH1/MSH2 expression. The MMR-deficiency was observed as follows; 7.9% in GC, 6.7% in HCC, 4.0% in CRC, and 2.7% in sarcoma. On 382 patients evaluable for the status of both PD-L1 and MLH1/MSH2 expression, there was no the significant association between the PD-L1 expression and MLH1/MSH2 loss (p = 0.267) Conclusions: These data may provide useful information and background for future research for immune checkpoint inhibitor across tumor-types. As a single selection biomarker for immune checkpoint inhibitor in various tumor-types, neither the PD-L1 expression nor the MMR deficiency is optimal application in clinical trials.
Efficacy and safety of paclitaxel/ramucirumab as the second-line chemotherapy in Japanese patients with advanced gastric cancer.
Authors: Tetsuya Kusumoto, Akinori Egashira, Hideto Sonoda, Kenkichi Hashimoto, Hideo Uehara, Eiji Kusumoto, Chiaki Shinzato, Keita Uchino, Yoshihisa Sakaguchi, Koji Ikejiri, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2017)

e15540 Background: Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer (AGC). Two global randomized phase III trials (REGARD and RAINBOW) showed that survival benefit was significantly observed in patients treated with ramucirumab (RAM) alone and in combination with weekly doses of PTX, compared with placebo, respectively. The purpose of the study is to evaluate the efficacy and safety of weekly dose of PTX combined with RAM practically as the second-line treatment in Japanese patients with AGC refractory to an S-1-containing chemotherapy regimen. Methods: We conducted a retrospective review of the data of 18 patients with AGC who received more than 2 cycles of PTX/RAM combined chemotherapy as the second-line regimen following S-1-based treatment. The objective response rate (ORR), adverse events, progression-free survival (PFS) and overall survival (OS) were analyzed and compared with PTX monotherapy group. Results: Median number of courses were 5 for the PTX/RAM group and the discontinuation of treatment except for disease progression was found in 2 cases (33.3%). The rates of hematological toxicities of higher than grade 3 were 33.3% in the PTX/RAM group, which were higher than those found in the PTX groups. The tumor responses of the PTX/RAM group were 22% for the ORR and 78% for the DCR, compared with 21% and 48% in the PTX group, respectively. The dose intensities of PTX were 72.4% in the former group. The survival data showed that the MST after second-line exposure was 290 days and the median PFS was 131 days in the PTX/RAM group, compared with 159 days and 90 days in the PTX group, which were not significantly different. Conclusions: PTX/RAM might be one of the best regimens for Japanese patients with AGC as the second-line treatment following S-1-containing chemotherapy.
Effect of Kupffer cells depletion on ABC phenomenon induced by Kupffer cells-targeted liposomes
Authors: Chaoyang Lai, Cong Li, Mengyang Liu, Qiujun Qiu, Xiang Luo, Xinrong Liu, Ling Hu, Yihui Deng, Yanzhi Song
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Accelerated blood clearance (ABC) phenomenon is common in many PEGylated nanocarriers, whose mechanism has not been completely elucidated yet. In this study, the correlation between Kupffer cells (KCs) and ABC phenomenon has been studied by KCs-targeted liposomes inducing ABC phenomenon and KCs depletion. In other words, the 4-aminophenyl-α-D-mannopyranoside (APM) lipid derivative DSPE-PEG2000-APM (DPM), and 4-aminophenyl-β-L-fucopyranoside (APF) lipid derivative DSPE-PEG2000-APF (DPF) were conjugated and modified on alendronate sodium (AD) liposomes to specifically target and deplete KCs. The dual-ligand modified PEGylated liposomes (MFPL) showed stronger ability to damage KCs in vitro and in vivo, which also could indirectly illustrate that dual-ligand modification could better target KCs. Besides, the hepatic biodistribution and pharmacokinetics could directly prove that MFPL had a stronger targeting ability to KCs. In addition, in depletion rats, plasma concentration and splenic biodistribution of MFPL and PEGylated liposomes (PL) were significantly elevated and hepatic biodistribution was significantly reduced, which demonstrated that KCs played an important role on elimination of nanoparticles. What's more, ABC phenomenon of the secondary injection of PL was stronger in KCs depletion rats than that in normal rats, which indicated that depletion of KCs prolonged the circulation of PL in the first injection repeatedly stimulating B-cells in the marginal region of the spleen and causing it to secrete more IgM antibodies. This could also illustrate that anti-PEG IgM takes up a major station compared with KCs. Most important of all, KCs-targeted liposomes could induce a stronger ABC phenomenon than PL in normal rats, which declared that based on the same IgM concentration, the more the KCs were stimulated, the stronger ABC phenomenon was induced. However, in depletion rats, this difference of ABC phenomenon between PL and MFPL could no more exist, further demonstrating that KCs could participate and play a certain role in the ABC phenomenon.
Activity of single-agent PD-1 inhibitor (PD-1i) therapy in advanced sarcoma: A single-center retrospective analysis.
Authors: Dionisia Marie Quiroga, David A. Liebner, Jennifer Phillipon, Sarah Hoffman, Jeremy Tan, James Lin Chen, Scott Lenobel, Paul Wakely, Gabriel Tinoco
Journal: Journal of Clinical Oncology (2018)

e23541 Background: Sarcomas constitute a heterogeneous group of mesenchymal tumors with variable responses to traditional chemotherapies. Recent PD-1i immunotherapy studies show promising results with use in certain soft-tissue sarcomas, however, clinical and molecular features which best predict response to PD-1i are unclear. In this study, we explore responses to PD1i in a cohort of patients treated off-trial as stratified by tumor and patient demographics. Methods: Demographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who initiated single-agent nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and March 31st 2017. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST 1.1). Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Results: 29 patients met inclusion criteria for this study; these patients were pretreated with a median number of 2 prior therapies. Representative histologies included liposarcoma (n = 9), leiomyosarcoma (n = 4), synovial sarcoma (n = 2), osteosarcoma (n = 1), spindle cell sarcoma (n = 4) and others (n = 9). Objective radiographic responses were seen in 2 patients; no complete responses were observed (ORR 6.9%). The median PFS of all patients was 16 wk, with 6 mo PFS of 39% and 12 mo PFS of 30%. Median OS was 47 wks, with 6 mo OS of 71% and 12 mo OS of 46%. There was no association between PD-1 expression and PFS, though patients with PD-1 positive tumors trended towards longer OS (p = 0.09). Compared with patients who received < 3 cycles, patients that received ≥3 cycles PD1i had a longer median PFS (35 vs 7 wk, p = 0.0013) and OS (NR vs 17 wk, p = 0.0001). Trends toward increased PFS and OS were also noted in patients of male gender and those aged ≥56 yr. Conclusions: This retrospective study confirms the activity of single-agent PD1i in a pretreated cohort of advanced sarcoma patients. Our results highlight the importance of further research to better identify the optimal target population.
On <i>Bacteroides Fragilis</i> participation in vulvar carcinogenesis.
Authors: Tatiana Zykova, Oleg Ivanovich Kit, Galina Andreevna Nerodo, Victoria A. Ivanova, Vera P. Nikitina, Ekaterina V. Verenikina, Oksana E. Kravtsova, Olga A. Bogomolova
Journal: Journal of Clinical Oncology (2017)

e17026 Background: The purpose of the study was to identify the rate of Bacteroides spp. infection in vulvar cancer tissues. Methods: FFPE samples of tumor and peritumoral area and healthy tissues of 44 patients with vulvar cancer, as well as frozen tumor tissues of 34 cervical cancer and 29 uterine cancer patients were studied. DNAs of Bacteroides spp. were detected by real-time PCR. Results: 18.75% of patients had stage I disease, 75.0% - stage II, 6.25% - stage III. The analysis of tumor histological type showed squamous cell carcinoma: G1 - 31.25%, G2 - 68.75%. B. fragilis were found in all vulvar tissues: tumor tissue – in 87.5%, perifocal area – in 76.9% and healthy tissue – in 71.4% of patients. Bacteroids of other groups were not found. For comparison, B. fragilis DNAs were detected in 20.7% in uterine cancer and in 15.4% in cervical cancer. DNA amount in samples was assessed by the Ct value. This index is inversely proportional to the DNA amount in the sample. Mean Ct level in tumor tissue was 23.2, in peritumoral area – 23.7, and in healthy tissue – 26.1; so, the amount of B. fragilis DNAs was similar in tumor and peritumoral area and was lower in healthy tissues. Differences in bacterial contamination of tumor tissue were found between vulvar cancer, cervical and uterine cancer. The amount of B. fragilis DNAs was maximal in vulvar cancer. We did not establish clear relationships between the rate of B. fragilis infection in tumor and the disease stage, tumor grade and the rate of metastasis. Conclusions: B .fragilis infection was found in tissues of the entire vulva; however, the infection rate and bacterial contamination level were higher in tumor tissue compared to the perifocal area and healthy tissue. Tumor tissues in vulvar cancer were infected more often than in uterine and cervical cancers. Bacterial contamination level in tumor tissue was higher in vulvar cancer than in uterine and cervical cancers which was undoubtedly significant in vulvar cancer pathogenesis.
G<sub>D2</sub> as a circulating tumor biomarker (CTB) for neuroblastoma (NBL).
Authors: Frank M. Balis, Christine Busch, Ami Vijay Desai, Emily Hibbitts, Arlene Naranjo, Rochelle Bagatell, Meredith Irwin, Elizabeth Fox
Journal: Journal of Clinical Oncology (2018)

10538 Background: CTBs that reflect tumor burden or viability can improve the accuracy and sensitivity of assessing tumor response in phase 2 trials and substantially shorten the timeline of phase 3 trials if they are predictive of relapse or survival. GD2 is a ganglioside present in the plasma membrane of NBL tumor cells, is measurable in the serum of patients with high-risk NBL, and could serve as a CTB. Methods: We developed and validated a sensitive and specific high-pressure liquid chromatography/tandem mass spectroscopy assay for GD2 in serum and plasma and quantified its circulating lipoforms that differ in the chain length of the fatty acid moiety (C18 and C20) in the ceramide portion of the molecule. We measured GD2 lipoforms in serum or plasma from 40 normal children (controls) and pretreatment samples from 128 (86 high-risk) children with NBL and 8 to 12 children each with 10 other childhood cancers. Results: The C18 lipoform was the predominant circulating form of GD2 in controls and in patients with NBL. The median concentration of the C18 lipoform in children with high-risk NBL at diagnosis was 156 nM (range, 4-1060 nM), which was > 25-fold higher than the median concentration (5.6 nM) in controls. GD2 was not measurable ( < 2.4 nM) in 16 of 40 controls, and the highest concentration in controls was 15 nM. GD2 was not elevated in children with 10 other childhood cancers except for medulloblastoma (median, 34 nM; range, 6-111 nM). MYCN amplification (p < 0.0001), high-risk disease (p < 0.0001), and INSS stage 4 (p < 0.0001) were associated with higher GD2 concentration. Median GD2 concentration in non-high-risk NBL was 9.9 nM. Conclusions: These preliminary data indicate that GD2 may be a sensitive and specific CTB for high-risk NBL. GD2 will be studied prospectively and longitudinally in new COG frontline, high-risk NBL treatment trials to determine if pretreatment GD2 concentration or change in GD2 concentration post-treatment are predictive of response or survival and if GD2 concentration is predictive of response to GD2-targeted immunotherapy. Although our focus is on developing GD2 as a surrogate clinical trial endpoint, the associations noted above with other prognostic markers also suggest it may also be useful as a diagnostic or prognostic CTB.