tbuckley/cabot-search huggingface dataset:
PD-L1/L2 tumor profile and long-term survival in mRCC patients after intratumoral administration of a cell-based allogeneic immune enhancer.
Authors: Alex Karlsson-Parra, Maria Lonnemark, Anna Laurell, Einar Brekkan, Anders Magnusson
Journal: Journal of Clinical Oncology (2016)

e14531 Background: Initial data from a Phase I/II study in patients (pts) with recently diagnosed metastatic renal cell carcinoma (mRCC) demonstrated that intratumoral administration of a cell-based immune enhancer (proinflammatory allogeneic DCs aimed to recruit and activate endogenous ”bystander” DCs) before nephrectomy was associated with a prominent intratumoral infiltration of CD8+ T cells in a majority of pts. Methods: Long-term survival as well as data on PD-L1/L2 tumor profile and tumor response after subsequent sunitinib treatment has been studied. Results: All evaluated clear-cell tumor samples (n = 8) exhibited a positive and usually general expression of PD-L2 that correlated positively in intensity with degree of CD8+ T cell infiltration while PD-L1 expression was absent in all tumor samples. Two out of 3 pts who to date have received subsequent treatment with sunitinib have experienced an objective tumor response. One patient exhibited a sarcomatoid tumor histology and another patient with 4 brain metastases responded with a complete disappearance of all 4 brain lesions and is still free from CNS-lesions 28 months after initiation of Sunitinib. Median OS for MSKCC intermediate risk (n = 5) or high risk pts (n = 6) is still not reached but is currently (01FEB2016) 37.5 and 28.2 months, respectively. Conclusions: The current mOS has by far surpassed reported mOS of 15.2 and 9.0 months in comparable intermediate and high-risk pts with recently diagnosed mRCC receiving upfront mono-therapy with sunitinib. The objective tumor responses seen in two pts after addition of sunitinib is surprising since historical data indicate that brain metastases as well as sarcomatoid transformation are higly resistant to sunitinib treatment. Taken together, our findings indicate that intratumoral administration of an off-the-shelf immune enhancer consisting of proinflammatory allogeneic DCs induces a CTL-mediated anti-tumor response that may prolong survival in mRCC-patients. Data on patients who have received additional treatment with sunitinib (known to downregulate myeloid-derived suppresor cell number and function) indicate a synergistic anti-tumoral effect. Clinical trial information: NCT01525017.
Second interim analysis of RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC).
Authors: Marcia S. Brose, Fabian Pitoia, Johannes WA Smit, Chia-Chi Lin, Marc Mardoche Fellous, Inga Bayh, Iwao Sugitani, Martin Schlumberger
Journal: Journal of Clinical Oncology (2018)

6081 Background: Sorafenib and lenvatinib are oral MKIs approved for the treatment of RAI-R DTC; however, there is no consensus on when patients with asymptomatic RAI-R DTC should start treatment with a MKI. Methods: RIFTOS MKI is an ongoing, global, non-interventional study, enrolling patients with asymptomatic RAI-R DTC, designed to compare the time to symptomatic progression from study entry in the real-life setting between two cohorts. The classification into one of the two cohorts is based on the treating physician’s decision to initiate a MKI at study entry (yes or no). Here, we report the results from a planned second interim analysis; no comparisons between cohorts were made. Results: Of 551 patients enrolled, and valid for analysis, 44% were male and the median age was 68 years; the median duration of observation was 9.0 months. Most patients had an ECOG performance status of 0 or 1 (95%) and distant metastases (87%) at study entry, and the most frequent histology was papillary (74%). The median time from initial diagnosis of DTC to study entry was 7 years, and RAI refractoriness was mainly due to a lack of RAI uptake (65%). The average dose per RAI treatment and median cumulative activity of RAI were 4.63 GBq and 8.51 GBq, respectively. A total of 28% of patients were treated with sorafenib at any time during the study. The median duration of sorafenib exposure was 6.7 months, and most patients (66%) received an initial dose of 800 mg/day. Of 113 patients included in the sorafenib safety analysis, 106 (94%) had ≥1 adverse event (AE), and 28 (25%) had ≥1 serious AE; hand–foot skin reaction (HFSR) was reported in 54 patients (48%), and grade ≥3 HSFR in 11 patients (10%). Conclusions: The RIFTOS MKI study is the largest non-interventional study in RAI-R DTC. Safety data from patients treated with sorafenib is consistent with the known safety profile of sorafenib. Of note, HFSR appears to be reported less frequently in real-life practice compared with phase 3 clinical studies. Clinical trial information: NCT02303444.
The relationship between IL-33 and monocyte-macrophages in esophageal squamous cell carcinoma.
Authors: Shijie MAI, Kaican Cai, Di Lu, Siyang Feng, Xiaoying Dong, Xiguang Liu
Journal: Journal of Clinical Oncology (2018)

e24056 Background: IL-33 was involved in the recruitment and polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment. However, there was no data about the relationship between IL-33 and monocyte-macrophages in esophageal squamous cell carcinoma (ESCC) patients. Methods: Flow cytometry was used to detect the levels of circulating monocytes subsets in 48 ESCC patients and 33 healthy control. The expression of IL-33 and M2-like TAMs were determined in pathological tissues by immunohistochemistry, western blot and qPCR. THP-1 cell was stimulated with phorbol myristate acetate (PMA), IL-13 and IL-33, or in combination of them for 24h. The expression of CD206 in THP-1 cells and induced macrophages was analyzed using flow cytometer. The differences in the relative mRNA expression levels of IL-10, TGF-β1, IL-12, and IL-23 were detected by qPCR. Then, we used the ESCC cell lines ECA109 cultured in conditioned medium from IL-33 amplified M2-like macrophages (M2-CM) to investigate the migration potential of ESCC cells and epithelial mesenchymal transition (EMT) associated molecular genetics. Results: Our data showed that circulating M2-like monocytes were increased in patients with ESCC and IL-33 and M2-like macrophages were up-regulated in esophagus cancer tissue. Meanwhile, IL-33 amplified IL-13-induced polarization of THP-1 toward a M2 phenotype in vitro. Furthermore, IL-33 amplified M2 macrophages conditioned medium promoted the migration and EMT of ESCC cells. Conclusions: These results suggest that M2-like monocyte-macrophage and IL-33 could be the novel biomarkers of ESCC. Meanwhile, manipulation of IL-33-mediated signal might be a potential therapeutic approach for ESCC.
Pharmacokinetics and pharmacodynamics of gilteritinib in patients with relapsed or refractory acute myeloid leukemia.
Authors: Catherine Choy Smith, Mark J. Levis, Mark Robert Litzow, Alexander E. Perl, Jessica K. Altman, Stan Gill, Geoffrey Yuen, Peter Bonate, Takeshi Kadokura, Angela Joubert James, Charles Liu, Itsuro Nagase, Ogert Fisniku, Erkut Bahceci
Journal: Journal of Clinical Oncology (2016)

7026 Background: Gilteritinib, also known as ASP2215, is a selective FLT3 inhibitor in development for the treatment of acute myeloid leukemia (AML). In ongoing trials, gilteritinib has demonstrated antileukemic activity and has been well tolerated in FLT3-mutation positive subjects with relapsed/refractory (R/R) AML. Methods: Gilteritinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in adult subjects ( ≥ 18 years) with R/R AML in an ongoing phase 1/2 dose-escalation/dose-expansion study (NCT02014558). Gilteritinib was administered once daily (20-450 mg) and blood samples were collected for safety, PK, and PK/PD assessments. Results: As of October 31, 2015, data were available from 252 subjects (n = 23, dose escalation; n = 229, dose expansion) for preliminary PK and PK/PD analyses. Gilteritinib PK was generally dose proportional from 20-450 mg with a median time to maximal concentration of 2–6 hr and a median half-life ~45–159 hr. Increased efficacy was observed in subjects with gilteritinib steady-state trough concentrations ≥ 100 ng/mL, exposure levels that can be achieved in patients dosed at 120 mg gilteritinib once daily. Although ΔQTcF is positively correlated to gilteritinib concentration, the preliminary model-averaged predicted median maximal ΔQTcF (5.8 msec) and 1-sided upper 95% CI (8.7 msec) were less than 10 msec at the mean exposure associated with the 120 mg therapeutic dose. Furthermore, a low incidence of subjects (4.1%) had a maximum post-baseline QTcF interval > 500 msec. While concentration-related increases in ΔCK and ΔAST were observed, < 10% of subjects experienced a ≥ Grade 3 increase in ΔCK or ΔAST. Conclusions: The gilteritinib PK and safety profile support QD oral administration. At 120 mg QD, gilteritinib concentrations associated with increased efficacy are readily achieved and substantial QTc prolongation is not anticipated. Concentration-related increases in ΔCK and ΔAST did not translate to high frequency of incidences ≥ Grade 3 and are clinically manageable. Clinical trial information: NCT02014558.
Predictors of prognosis and assessment of effectiveness of treatment for recurrent cervical cancer.
Authors: Ekaterina Guskova, Oleg Ivanovich Kit, Nailya Guskova, Irina Aleksandrovna Goroshinskaya, Galina Andreevna Nerodo, Natalia V. Chernikova, Yuriy A. Poryvaev, Vera Nikitina
Journal: Journal of Clinical Oncology (2016)

e17024 Background: The purpose of the study was to assess nitric oxide-derived peroxynitrite (P) and nitrosylhemoglobin (N) in prognosis and evaluation of effectiveness of treatment of patients with recurrent cervical cancer (CC). Methods: Levels of peroxynitrite (ONOO−) at λ = 302 nm and nitrosylhemoglobin at λ = 545 nm were studied by spectrofluorimetric method. The data were compared to the results of treatment of patients with recurrent CC with standard CAP regimen chemotherapy. The data on tumor regression were analyzed according to the initial (before chemotherapy) levels of P and N. The control group included 26 women of similar age without oncopathologies. Association between the studied indices and regression effect was evaluated by the analysis of variance, and significance of differences – by Student's t-test. Results: The treatment resulted in 50-80% tumor regression in 15 (55.6%) patients with high P level (166±19.5 nmol/mg, 94% higher than the norm) and low N level (16.77±1.58 nmol/mg, 24% lower than the norm) (p = 0.0001). These patients showed decrease in P content by 2 times (79.5±3.74 nmol/mg) (p = 0.0046), while N content increased (29.84±3.59 nmol/mg) (p = 0.0061). Stabilization was observed in 12 (44.4%) patients with initially low P level (23.8±1.13 nmol/mg, 72% lower than the norm) (p = 0.0003) and high N level (73.24±4.08 nmol/mg, 234% higher than the norm) (p = 0.0000). Absence of positive dynamics was accompanied by an increased post-treatment level of P (141.0±6.88 nmol/mg) and considerably decreased N content (23.87±2.75 nmol/mg) (p = 0.0000). The results demonstrated the association between the studied parameters and the degree of tumor regression. Conclusions: Levels of peroxynitrite and nitrosylhemoglobin can be used as highly informative predictors of prognosis and assessment of effectiveness of treatment for recurrent cervical cancer. Initially sharply decreased peroxynitrite and increased nitrosylhemoglobin levels involve low treatment effectiveness or its absence, while increased or normal content of peroxynitrite and no increase in nitrosylhemoglobin level allow predicting marked tumor regression.
The natural course of hypermutator gliomas.
Authors: Carlos Kamiya-Matsuoka, Nicholas Robert Metrus, Kenna Rael Shaw, Marta Penas-Prado, Shiao-Pei S. Weathers, Monica Elena Loghin, Kristin Alfaro-Munoz, Ying Yuan, Barbara Jane O'Brien, Rebecca A. Harrison, W. K. Alfred Yung, Funda Meric-Bernstam, John Frederick De Groot
Journal: Journal of Clinical Oncology (2018)

2014 Background: Hypermutator genotype (HMGen) is seen in glioblastoma (GB) and lower-grade gliomas. It may be induced by temozolomide (TMZ) and leads to TMZ resistance. We describe demographics, mutational features, treatments and outcomes of HMGen gliomas. Methods: Retrospective review at MD Anderson between 02/2006-02/2017 identified 309 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HMGen was defined as tumor mutation burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes. Results: 38 (12.3%) patients had HMGen. 25 (66%) were men. 19 (50%) had TMB-30, 10 (26%) had mut in Pol gene, 6 (16%) in MMR (1 had mut in both MLH and MSH6 genes), 1 had mut in both MMR and Pol genes and only 2 met all three criteria. GB (N = 26, 68%) was the most common tumor (N = 6, 23.1% IDH1-mut), followed by WHO grade III oligodendroglioma (N = 8, 21%), grade II astrocytoma (N = 3, 8%) and grade II oligodendroglioma (N = 1, 3%). HMGen was found as initial genotype in 17 (45%) cases, the rest after treatment with alkylating agents. Of those patients with de novo HMGen, Pol gene mut was most common (N = 9, 53%), followed by MMR mut (N = 4, 23.5%) and TMB-30 (N = 4, 23.5%). Of those 17, 15 (88%) were GB followed by WHO grade II gliomas: 1 oligodendroglioma with MMR mut (MSH6) and 1 astrocytoma with TMB-30. For post-treatment HMGen, the most common alterations was TMB-30. The mean cumulative TMZ dose at HMGen diagnosis for GB, WHO grade II/III astrocytoma and grade II/III oligodendroglioma was 16g, 24.6g/28g, and 41g/29.6g, respectively with a mean monthly dose of 1.5-1.8g. Only 1 patient received CCNU (0.4g). For de novo and post-treatment HMGen GB IDH1-wild-type, the OS and PFS from HMGen diagnosis was 19.6/15 and 23.7/3.9 months (m) respectively. The latency interval from histopathologic GB to HMGen was 17.5 m and the total OS was 43.6 m. Most of this subgroup (65%) are still alive with a time from initial diagnosis to last follow-up of 35.7 m. Conclusions: HMGen gliomas may occur spontaneously at initial diagnosis before treatment and may be associated with longer survival than historical controls. Further investigation is needed to determine whether HMGen can be predicted due to potential clinical implications.
Two phase I/II open label clinical trials evaluating the safety and efficacy of autologous T cells expressing enhanced TCRs specific for NY-ESO-1 or MAGE-A10 in subjects with stage IIIb or stage IV non-small cell lung cancer (NCT02588612/NCT02592577).
Authors: Ben C. Creelan, Justin F. Gainor, Ramaswamy Govindan, Nancy M. Hardy, John Heymach, Raja Mudad, Karen L. Reckamp, William Bardwell, Tom Holdich, Arundathy N. Bartlett-Pandite, Rafael G. Amado
Journal: Journal of Clinical Oncology (2017)

TPS3096 Background: Non-small cell lung cancer (NSCLC) accounts for 84% of lung cancer. Survival has recently been impacted by molecularly targeted therapies and checkpoint inhibitors (CPI), and the promising CPI results implicate a role for the immune system in NSCLC. 10-40% of NSCLC express NY-ESO-1 or MAGE-A10 cancer/testis antigens. These studies will evaluate the safety and antitumor activity of genetically engineered affinity enhanced TCRs (NY-ESO-1 c259 T or MAGE-A10 c796 T) directed towards a NYESO-1 or MAGE-A10 derived peptides complexed with HLA-A*02. In addition, correlative studies to evaluate persistence, phenotype, functionality of engineered T cells, mechanisms of resistance and antigen spreading will be performed. Methods: Patients (pt) are screened (NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression. For entry into either treatment protocol, pt must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness. Following apheresis, T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1 c259 T or MAGE-A10 c795 TCR, and infused into the pt following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The NY-ESO-1 c259 T study is a 10 pt study utilizing a dose of 1-6 x 10 9 transduced T cells. The MAGE-A10 c796 T first-in-human study is a modified 3+3 design in up to 28 pt with escalating doses of 0.1, 1.0 and 1-6 x 10 9 transduced T cells, with staggered treatments to allow for safety review; dose escalation will be guided by the DLT observed and by safety review committee guidance. Response to treatment will be assessed by RECIST v1.1 at weeks 4, 8, 16, 24, every 3 months (for 2 yr) and every 6 months until disease progression. Clinical trial information: NCT02588612/NCT02592577.
Circulating tumor cell (CTC) as a significant prognostic factor in resected primary lung cancer.
Authors: Kazue Yoneda, Masaki Hashimoto, Teruhisa Takuwa, Seiji Matsumoto, Yoshitomo Okumura, Seiki Hasegawa, Fumihiro Tanaka
Journal: Journal of Clinical Oncology (2017)

e23044 Background: Circulating tumor cell (CTC) is a potentially useful marker in early diagnosis and monitoring therapeutic effects for patients with malignant tumors, but clinical significance of CTC in primary lung cancer remains unclear. We previously showed that CTC was a useful surrogate marker of distant metastasis in primary lung cancer (Clin Cancer Res 2009). In this study, we evaluated the prognostic value among completely resected patients after long-term follow-up. Methods: A total of 94 patients (median age, 68 years; 30 females and 64 males) who underwent complete resection for primary lung cancer (4 with small cell and 90 with non-small cell) were prospectively evaluated. At the time of enrollment into the study, 7.5mL of peripheral blood was sampled from each patient, and an EpCAM-based detection system (CellSearch) was used for detection of CTC. CTC was detected in 16 patients (CTC-positive, 14.9%). Results: CTC-positivity was significantly associated with a poor recurrence-free survival (5-year recurrence-free survival rate, 40% versus 72%; p&lt;0.01) (Table 1), which was confirmed by a multivariate analysis (hazard ratio, 2.57 [95% CI, 1.26-5.26]; P=0.010). CTC-positivity was also associated with a poor overall survival (5-year recurrence-free survival rate, 62% versus 84%; p&lt;0.05) (Table 1), which was confirmed by a multivariate analysis (hazard ratio, 2.76 [95% CI, 1.14-6.71]; P=0.025). Conclusions: CTC-positivity was associated with poor recurrence-free survival and poor overall survival in resected lung cancer. [Table: see text]
Population assessment of head and neck cancer outcomes by race and HPV status in chance.
Authors: Siddharth Sheth, Doug Farquhar, Angela Mazul, David N. Hayes, Jose Zevallos, Andrew F Olshan
Journal: Journal of Clinical Oncology (2017)

6045 Background: Growing literature suggests that racial disparities exist in patients with head and neck squamous cell carcinoma (HNSCC). Currently, there are many hospital-based cohorts assessing racial disparities, however only a limited number of population-based cohorts exist. This study aims to explore the association between clinical characteristics and patient demographics with overall survival by race and HPV status. Methods: Patients were identified from the Carolina Head and Neck Cancer Study (CHANCE), a population based case-control study with enrollment from 2001-2006 in North Carolina. Vital status was determined by linkage with the National Death Index. Survival was considered at 5 years after diagnosis or study enrollment. We used Kaplan-Meyer analyses and Cox proportional hazards regression modeling to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 1361 HNSCC patients with no baseline metastasis and adequate survival time were identified. Of these, 1010 patients were white while 351 patients were black. Black patients were statistically more likely to be younger at age of diagnosis, have a history of tobacco or alcohol use, be uninsured, and not have completed high school (p-value &lt; 0.001). In an unadjusted cox regression analysis, blacks had 1.50 times (95% CI 1.01-1.57) decreased overall survival than whites. Adjusting for gender, stage of disease, age, treatment, and smoking status, this relationship remained (HR 1.30, CI 1.1-1.6). In a subset analysis of male patients by disease site, there was decreased overall survival in black patients in oral cavity cases (p &lt; 0.01). This relationship trended towards significant in pharynx cancer (p = 0.054) and was not found in laryngeal cancer. In pharyngeal cases only, there was decreased overall survival in black patients with HPV+ disease (p = 0.03) but not in HPV- cases (p = 0.33). Conclusions: This is the first population-based study that confirms racial disparities in HPV+ HNSCC. We also found worse overall survival prognosis for black patients with oral cavity cancer and a similar trend in pharynx cancer. Further studies are needed to evaluate if this difference is driven by either biological or socioeconomic factors.
Lobectomy with mediastinal nodal dissection versus partial lobectomy in patients with bronchial carcinoid tumors: A NCDB analysis.
Authors: Gustavo Figueiredo Marcondes Westin, Samer Alsidawi, Konstantinos Leventakos, Thorvardur Ragnar Halfdanarson, Julian R. Molina
Journal: Journal of Clinical Oncology (2017)

8549 Background: Bronchial carcinoid tumors are a rare group of neoplasms that usually have an indolent clinical behavior. Surgical resection is the main treatment modality for patients with early stage disease, however it is unclear if lobectomy with mediastinal lymph node dissection (L) is superior compared to partial lobectomy (PL). Methods: Utilizing the National Cancer Database from 2004-2012, 1551 patients diagnosed with T1N0 or T2N0 typical carcinoid tumors (CT), and 167 atypical carcinoid tumors (ACT), who underwent L or PL (segmental or wedge resection) as initial treatment strategy, and did not receive chemotherapy or radiation were identified. All patients had pathologically confirmed diagnosis, negative surgical margins, and complete follow up data. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used for statistical comparisons. Cox proportional hazards were performed to control for age, sex, race, grade, year of diagnosis, Charlson/Deyo Score, insurance, income, and facility type. T-test was used to compare post-surgical hospital stay. Results: The entire cohort median age was 61 years (range 18-90), and male to female ratio was 0.43. 75% of patients with CT and 78% of ATC underwent L. The 90 day mortality following surgery was &lt; 1 % in both surgical groups. Patients who underwent L had longer post-operative hospitalization stay (mean 5.3 vs. 4.3 days; p &lt; 0.001). The 5 year survival for patients with CT was 95% in the L versus 93% in the PL group (p = 0.62), and for ACT 89% in the L versus 81% PL group (p = 0.28). In a multivariate analysis increasing age was the only prognostic factor, and was associated with inferior survival. The HR for death comparing PL to L was 1.09 (95% CI: 0.65-1.78; p = 0.71) for CT and 1.25 (95% CI: 0.45-3.23; p = 0.65) for ACT. Conclusions: Patients with localized node-negative CT and ACT have excellent 5 year survival. Performing a lobectomy with mediastinal node dissection may not provide additional benefit compared to partial lobectomy, but this may increase the length of hospital stay.