tbuckley/cabot-search huggingface dataset:
Geographic variation in the incidence of marginal zone lymphoma (MZL) subtypes and infectious risk factors.
Authors: Mengyang Di, Adam J. Olszewski
Journal: Journal of Clinical Oncology (2019)

e13094 Background: Helicobacter pylori is a known etiologic factor for gastric MZL, but data for infectious etiology in other MZL subtypes are controversial. Proposed hypothetical factors include Borrelia burgdorferi for cutaneous MZL (cMZL), Campylobacter (Cmp) for intestinal MZL (iMZL), and hepatitis C (HCV) for splenic (SMZL) or nodal MZL (NMZL). We explored geographic variation in the incidence rate (IR) of MZL and reportable infections in the United States (US) to examine these hypotheses. Methods: Using the National Program of Cancer Registries, we calculated age-adjusted IR (per 100 000 person-years) of MZL subtypes for each US state in 2001-2015. We linked them to the 2010 US census data, data on IR (per 10 000) of Lyme disease (2001-2015) and Cmp infections (2016) from the Center for Disease Control, and to published estimates of HCV prevalence (2013-2016). We examined the hypotheses in multivariable Poisson models adjusting for median age, proportion of men, Black or Asian individuals in each state, reporting adjusted IR ratios (IRR) with 95% confidence intervals (CI). Results: The study included 5,085 cases of cMZL, 3,948 of iMZL, 26,648 of NMZL, and 12,184 of SMZL. Across the US, IR varied between 0.02 and 0.22 for cMZL, 0.04-0.12 for iMZL, 0.33-0.91 for NMZL, and 0.12-0.47 for SMZL. For all subtypes, IR was highest in the Northeast, and lowest in the South ( P&lt;.0001), consistent with general lymphoma epidemiology. However, the IRR for South relative to Northeast was significantly lower for cMZL (0.42; CI, 0.38-0.45) than iMZL (0.65), NMZL (0.65), SMZL (0.67), or aggregate MZL (0.65; CI, 0.64-0.66). In adjusted models, IR of Lyme disease was significantly associated with increased IR of cMZL (IRR=1.11; CI, 1.07-1.16), and Cmp infection was associated with iMZL (IRR=1.19; CI, 1.02-1.38). In contrast, HCV, prevalent in the South, was inversely associated with all MZL subtypes. Conclusions: These results support the putative association between cMZL and Lyme disease, and between iMZL and Cmp infection. Conversely, lack of positive association between any MZL subtype and HCV suggests that it is not a major pathogenic factor in the US. These ecological results do not rule out associations at the individual level, which will require further research.
Survival and recurrence of breast cancer patients with pathologic complete response after neoadjuvant chemotherapy.
Authors: Young Joo Lee, Sei-Hyun Ahn, Byung Ho Sohn, jong Won Lee, Il Yong Chung, Beom Seok Ko, Hee Jeong Kim, Jisun Kim, Sae Byul Lee
Journal: Journal of Clinical Oncology (2019)

e12121 Background: Patients with Pathologic complete response after neoadjuvant chemotherapy is known to have a good prognosis. However, there is a difference depending on how the complete remission is defined. Methods: We analyzed basic characteristics and outcomes of 295 patients who had pathologic complete response defined as ypT0 and ypTis after neoadjuvant chemotherapy for breast cancer at Asan Medical Center in Seoul, Korea. Results: Median follow up period was 66.5 month(6~128 month). Overall survival was 94% at 5-year and 10-year. No difference was shown in preoperative age, grade, HR/HER2 status, Ki-67 level. Clinical stage III showed worst outcome(85.8%). Survival rate between ypT0N0 (98.8%) and ypTis (89.1%, p=0.00) and between ypT0/TisN residual (85.7%, p=0.00) was shown, but no statistical difference between ypTis and ypT0/Tis with residual nodes(p=0.539). Disease free survival also showed no statistical significance between age, HR/Her2 status. But patients with low Ki-67 level(0~20%)(68.2%) at diagnosis had worse DFS compared to high Ki-67 level(&gt;20%)(87.5%)(P=0.013). No difference between intrinsic subtypes was shown. Patients with residual nodal disease had worse DFS(66.1%) than ypN0(89.1%)(p=0.00). DFS of ypT0N0 was 92.7% and ypTisN0(75.5%), ypT0/Tis with residual metastatic nodes(71.4%). There was no significant difference in type of chemotherapy regimen. Conclusions: Overall survival and disease free survival was different in ypT0N0 with ypTis and residual nodal disease. Good prognosis of pathologic complete response should be limited to cases in which the cancer has completely disappeared.
A phase I trial evaluating the safety and efficacy of weekly paclitaxel or cisplatin with electro-hyperthermia in patients with recurrent or persistent epithelial ovarian, fallopian tubal or primary peritoneal carcinoma (KGOG 3030).
Authors: Kidong Kim, Dong-Hoon Suh, Jae Hong No, Yong Beom Kim, Jae Hoon Kim, Seung Cheol Kim, Woong Ju, Yun Hwan Kim
Journal: Journal of Clinical Oncology (2019)

e17032 Background: To evaluate the safety and efficacy of weekly paclitaxel or cisplatin with electro-hyperthermia in patients with recurrent or persistent epithelial ovarian, fallopian tubal or primary peritoneal carcinoma. Methods: This prospective trial employed ‘3+3 design’ with no dose escalation. Initially, patients were randomized to weekly paclitaxel (70mg/m2) or weekly cisplatin (40mg/m2) with electro-hyperthermia until three patients in each arm were evaluable for dose-limiting toxicities (DLTs). A cycle was 4 weeks long and paclitaxel or cisplatin was administered at day 1, 8, 15. Targeting tumor beds, electro-hyperthermia was administered semi-weekly (8 time/cycle) for 1 hour per session. DLT was defined as any adverse event possibly or probably related to therapy, that required intensive care or was not recovered to grade 2 or lower within 3 weeks. If ≤1 patient in an arm experienced DLT, additional 3 patients were enrolled to that arm. Unevaluable patients (n = 4) were replaced. Finally, 12 patients (6 in each arm) were evaluated for toxicities, response rate, progression-free survival (PFS) and overall survival (OS). Results: Nine patients had high grade serous histology. Median number of previous regimen was 2 (range 1- 5) and median treatment-free interval from previous chemotherapy was 6 months (range 0 – 27). Nine patients were platinum resistant or refractory. No DLT was observed. Four grade 3 toxicities were observed (nausea 1, hematologic 3) in cisplatin arm. Overall response rate was 42% (5/12), median PFS was 4.3 months (range 1.7 – 11.8), and median OS was over 13.8 months (range 3.9 – &gt; 38.5). Conclusions: Both weekly paclitaxel and cisplatin with electro-hyperthermia are safe enough to be tested in further studies. Chemotherapy with electro-hyperthermia was seems to be an effective treatment strategy for recurrent or persistent epithelial ovarian, fallopian tubal or primary peritoneal carcinomas. No significant differences in oncologic outcomes and toxicities were observed between paclitaxel and cisplatin arms. Clinical trial information: NCT02344095.
Assessment of enrollment characteristics for Children’s Oncology Group (COG) upfront therapeutic clinical trials 2004-2015.
Authors: Kelly Faulk, Amy Anderson-Mellies, Myles Cockburn, Adam Green
Journal: Journal of Clinical Oncology (2019)

6564 Background: Improvements in pediatric cancer survival are attributed to cooperative clinical trials. Under representation of specific demographic groups has been described in adult and pediatric cancer and poses a threat to the generalizability of trial results. A comprehensive evaluation of data provided by the Children’s Oncology Group (COG) of upfront trial enrollment for US patients 0 to 29 years old between 2004 and 2015 was performed to assess for disparities in participation. Methods: Estimates of cancer cases were calculated using the Surveillance, Epidemiology, and End Results registry and the US Census and compared to observed COG cases. Percent enrollment and Standardized Ratios of enrollment were calculated across various demographic, disease, and socioeconomic groups. The COG website was utilized to quantify available upfront trials during the study period and assess age eligibility criteria. Results: 21.3% of estimated US cancer patients age 0 to 19 years enrolled on COG trials. Younger patients were consistently more represented across disease types and race/ethnicities. Patients with hematologic malignancies were more represented compared to solid and central nervous system (CNS) tumors. Conclusions: COG clinical trial enrollment rates are declining, which may be due to challenges in pediatric drug development, difficulty designing feasible trials for highly curable diseases, and issues in ensuring trial availability for the heterogeneous group of solid and CNS tumors. Though racial/ethnic groups and county-level socioeconomic factors were proportionally represented, under representation of the adolescent/young adult (AYA) population and younger patients with solid and CNS tumors remain significant concerns. Targeted enrollment efforts should focus on the identified subgroups and further research should evaluate AYA enrollment across all available trials to provide continued treatment advances for all patients.
Modeling accrual of older adults to cancer clinical trials: (Alliance A151736).
Authors: Noam Avraham VanderWalde, Daniel Victor Wakefield, Daniel V. Satele, Travis Dockter, Jeff A. Sloan, Reshma Jagsi, Stuart M. Lichtman, Rachel A. Freedman, Jacqueline M. Lafky, Hyman B. Muss, Harvey Jay Cohen, Arti Hurria, Aminah Jatoi, Jennifer Le-Rademacher
Journal: Journal of Clinical Oncology (2019)

e18132 Background: Older adults (65+ years) make up &gt; 50% of cancer patients in the US, 1 yet, older patient enrollment onto trials remains &lt; 30%. 2 This study’s aim was to determine the association between trial level variables and accrual rates of adults 65+ to better design trials that can more improve enrollment of these patients. Methods: We analyzed enrollment percentages of patients age 65+ in non-age specific Alliance trials with &gt; 50 patients, that completed accrual between 1995- 2015. Enrollment percentage by 65+ for each study was compared to cancer incidence percentage by 65+ according to the Surveillance, Epidemiology, and End Results (SEER) Program for the same time periods. Enrollment Disparity Difference (EDD) 3 , defined as the difference between SEER incidence percentage of patients 65+ and the trial percentage enrollment of 65+ was calculated for each trial ( SEER % – trial %). Univariate analyses (UVA) were performed using simple linear regression to determine trial variables associated with larger EDDs (higher disparity). Variables that had an F-test p-value &lt; 0.20 were included in a multivariable fixed-effects linear model for multivariate analysis (MVA). Results: Median age of 66,708 patients across 237 trials with 10 cancer types was 60 years. Average % of 65+ in trials was lower than average SEER comparison % 65+ per trial (37.6% vs. 57.8%). The median trial EDD, was 16.7%. On UVA, cancer type was significantly associated with higher EDD (see Table). Use of fewer modalities (1, 2, vs 3+) was associated with lower estimated EDDs (1 = -11 [+/-3.6], 2 = -8.9 [+/-3.9], F-test p = .012). On MVA, non-genitourinary (GU) cancer type, number of treatment modalities, and the phase (II or III compared to observational/other) were all significantly associated with higher EDD. Conclusions: Older adults were under-represented in this large sample of trials. This information can be used as a platform to better design disease-specific trials to improve older patient accrual, particularly in disease areas which are under-performing. Support: U10CA180821, U10CA180882, UG1CA189823: https://acknowledgments.alliancefound.org . References: 1. Smith BD et al. J Clin Oncol 27:2758-65, 2009; 2. Hurria A, et al. J Geriatr Oncol 1:40-44, 2010; 3. Pang HH, et al. J Clin Oncol, 2016.[Table: see text]
A phase I/II study of nivolumab plus or minus ipilimumab in combination with multifraction stereotactic radiosurgery for recurrent high-grade radiation-relapsed meningioma.
Authors: Jiayi Huang, Jian Li Campian, Feng Gao, Tanner Michael Johanns, Annick Desjardins, Andrea Wang-Gillam, Josh Rubin
Journal: Journal of Clinical Oncology (2019)

TPS2073 Background: There is currently lack of effective therapy for meningiomas that have relapsed despite surgery and radiation therapy (RT). Reirradiation have been used in selected cases, but the long-term clinical outcomes remained poor, especially for high-grade meningiomas. Preclinical data have suggested synergy between hypofractionated radiosurgery with immune checkpoint inhibitors such as PD1 and CTLA4 inhibitors. The purpose of this study is to evaluate feasibility and preliminary clinical efficacy of combining reirradiation using hypofractionated radiosurgery with concurrent nivolumab (PD1 inhibitor) plus or minus ipilimumab (CTLA4 inhibitor) for recurrent high-grade meningiomas. Methods: During the phase I portion, eligible patients will be treated according to treatment-escalation schema following the modified 3+3 design (Table). The maximum tolerated combination (MTC) will be the regimen at which ≤1/6 patients experience dose-limiting toxicity within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. Key eligibility criteria include patients with recurrent grade II-III meningiomas after prior RT; age ≥ 18 years; ECOG score ≤ 2; measurable disease but ≤ 5 cm (or 20 cm 3 ); prior radiation dose ≤ 70 Gy with at least 6 months interval; normal organ function; no active autoimmunity. The primary endpoints are to determine the MTC (phase I) and the objective response rate of the MTC (phase II). Secondary endpoints include safety, duration of response, progression-free survival, overall survival. Exploratory endpoints include developing an immune or molecular signature for predicting treatment response and resistance. The trial is actively enrolling and funded by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI-ETCTN). Treatment Escalation Schema. Clinical trial information: NCT03604978. [Table: see text]
Re-evaluating disease-free survival (DFS) as an endpoint versus overall survival (OS) in adjuvant colon cancer (CC) trials with chemotherapy +/- biologics: An updated surrogacy analysis based on 18,886 patients (pts) from the Accent database.
Authors: Qian Shi, Aimery De Gramont, Jesse G. Dixon, Jun Yin, Eric Van Cutsem, Julien Taieb, Steven R Alberts, Norman Wolmark, Hans-Joachim hans-joachim Schmoll, Leonard B. Saltz, Richard M. Goldberg, Rachel Kerr, Sara Lonardi, Takayuki Yoshino, Greg Yothers, Axel Grothey, Thierry Andre, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2019)

3502 Background: DFS with 3 years median follow-up (3yDFS) was validated as a surrogate for OS with 5 years median follow-up (5yOS) in adjuvant chemotherapy CC trials prior. Recent data showed improved survival after recurrence and OS, over time, in pts who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS, as well as the optimal follow-up of OS to aid its utility in future adjuvant trials is needed. Methods: Individual patient data from 8 randomized adjuvant studies conducted from 1998-2009 were included; 3 trials tested anti-VEGF or anti-EGFR agents. Trial-level surrogacy examining the correlation of treatment effect estimates (i.e. hazard ratios) of 3yDFS and 5y to 8yOS was evaluated using both linear regression (R 2 WLS ) and Copula bivariate (R 2 Copula ) models. For the R 2 , a value closer to 1 indicates a stronger correlation. Prespecified criteria for surrogacy required either R 2 WLS or R 2 Copula ≥ 0.80 and neither &lt; 0.7, with lower-bound 95% Confidence Interval (CI) &gt; 0.60. The rank correlation coefficient (ρ) quantified the individual-level surrogacy. Results: Total of 18,886 pts were analyzed, with median age 60, 54% male, 83% stage III, 59% &gt; 12 nodes examined. Median follow-up for survival ranged from 5 to 10 years across trials. Trial level correlation between 3yDFS and OS remained strong (R 2 WLS ≥0.74; R 2 Copula ≥ 0.89) and increased as the median follow-up of OS extended longer (see table). Analyses limited to stage III pts and/or trials tested biologics showed consistent results. Conclusions: 3yDFS remains a validated surrogate endpoint for 5yOS in adjuvant trials in CC pts per prespecified criteria. The correlation was strengthened with more than 6 years of follow-up for OS. [Table: see text]
The impact of sequential therapy of crizotinib followed by alectinib: Real-world data analysis of 840 ALK-inhibitor naïve patients with NSCLC harboring ALK-rearrangement (WJOG9516L).
Authors: Kentaro Ito, Takeharu Yamanaka, Satomi Watanabe, Yoshihiro Hattori, Kazumi Nishino, Haruki Kobayashi, Yuko Oya, Toshihide Yokoyama, Takashi Seto, Koichi Azuma, Tomoya Fukui, Toshiyuki Kozuki, Atsushi Nakamura, Isamu Okamoto, Katsuya Hirano, Takashi Yokoi, Haruko Daga, Shinya Sakata, Kazuhiko Nakagawa, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2019)

9038 Background: Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1 st -line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1 st -line setting earlier than in other countries. Methods: We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group. Results: Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P= 0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P= 0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P&lt; 0.0001. Conclusions: The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown. Clinical trial information: UMIN000028605.
ARID1A interacts with nonmuscle myosin IIA to regulate cancer cell motility.
Authors: Oloruntoba Ismail Osagie, Zhigui Li, Shijun Mi, Jennifer T Aguilan, Gloria S. Huang
Journal: Journal of Clinical Oncology (2019)

e17036 Background: ARID1A (BAF250A), a member of the SWI/SNF chromatin remodeling complex, is one of the most frequently mutated genes in human cancer. Here we report the discovery of a novel protein-protein interaction between ARID1A and the actin-binding motor protein, non-muscle myosin IIA (NM IIA) encoded by the myosin heavy chain 9 ( MYH9). Methods: The ARID1A immunoprecipitated protein complex was separated by gel electrophoresis followed by analysis of the peptide digested gel bands by C18-Reversed Phase chromatography using an Ultimate 3000 RSLCnano System (Thermo Scientific) equipped with an Acclaim PepMap C18 column (Thermo Scientific) and connected to a TriVersa NanoMate nanoelectrospray source (Advion) and a linear ion trap LTQ-XL mass spectrometer (Thermo Scientific). Protein identification was performed by Mascot search engine v. 2.5.1 (Matrix Science) against NCBI Homo sapiens database. Scaffold software v. 4.5.1 (Proteome Software Inc.) was used to validate the MS/MS peptide and protein identification based on 99% protein and 95% peptide probabilities. Immunoprecipitation and immunoblotting were done to evaluate the protein-protein interaction in ARID1A-wild type cell lines. Isogenic engineered cell lines, ES2 shRNA-control or shRNA- ARID1A stable transfection , and HCT116 control or ARID1A knockout by CRISPR-Cas9 (Horizon Discovery) were used to evaluate the effect of ARID1A loss on NM IIA expression and phosphorylation, and on cell migration by in vitro scratch assay with time lapse imaging. Results: Scaffold analysis of peptide spectra identified NM IIA with &gt; 99% probability in the ARID1A immunopurified protein complex. In the ARID1A wildtype cell lines ES2 and KLE, endogenous NM IIA co-immunoprecipitated with ARID1A and vice versa. ES2 sh ARID1A cells had decreased total and phosphorylated NM IIA expression, and impaired cell migration compared to control cells. Similarly, HCT116 ARID1A homozygous knockout cells had impaired cell migration compared with HCT116 control cells. Conclusions: We report for the first time that ARID1A interacts with NM IIA to regulate cancer cell motility. Further investigation is ongoing to elucidate the significance of this newly identified function of ARID1A.
Optimizing cut-offs for high neutrophil-to-lymphocyte ratio as poor survival prognostic factor in colorectal cancer.
Authors: Fernando Namuche, Jorge Leon, Paola Catherine Montenegro, Claudio J. Flores
Journal: Journal of Clinical Oncology (2019)

e15111 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Needing to use all the possible tools for an accurate diagnosis and early treatment. Neutrophil-to-lymphocyte ratio (NLR) has been associated as poor prognostic factor in OS and PFS in CRC. There is no data that support this statement in Latin America. It is of a special utility in our country the detection of a simple and reproducible prognostic biomarker that guides the use of more advanced tests. Our objective was to explore the factors associated with OS in the local-locally advanced and metastatic settings. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016 Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We divided our population into two groups: Local-locally advanced (L-LA) (516 pts) and debut metastatic- recurrence (M-R) (108 pts). We performed a ROC curve analysis to determine an appropriate cut-off value for NLR in both groups (L-LA:NLR ≥3, M-R:NLR ≥5). A univariate survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: Pts with high NLR had significantly shorter OS in L-LA [HR, 12.1; 95% CI,5.019-29.211; p &lt; 0.001] M-R [HR, 5.382; 95% CI,2.835-10.217; p &lt; 0.001] than pts with low NLR. In the multivariate model, NLR retained a significant association with OS in both groups. Cox regression demonstrated that in L-LA setting sex, histologic grade and lymph node involvement; and in M-R setting sidedness, histologic grade, LVI and metastasectomy performed were independently risk factors for a shorter OS. Conclusions: High NLR is associated with poor prognosis (with our cut-offs L-LA:NLR ≥3, M-R:NLR ≥5). There are other variables to be considered that affect the OS, as: sex, histologic grade and lymph node involvement, sidedness, histologic grade, LVI and metastasectomy performed.