tbuckley/cabot-search huggingface dataset:
Missing data in breast cancer: Relationship with survival in national databases.
Authors: Jennifer Kay Plichta, Christel N. Rushing, Holly C. Lewis, Dan G. Blazer, Terry Hyslop, Rachel Adams Greenup
Journal: Journal of Clinical Oncology (2020)

e19114 Background: National cancer registries are valuable tools used to analyze patterns of care and clinical oncology outcomes; yet, patients with missing data may impact the accuracy and generalizability of these data. We sought to evaluate the association between missing data and overall survival (OS). Methods: Using the NCDB and SEER, we compared data missingness among patients diagnosed with invasive breast cancer from 2010-2014. Key variables included: demographic variables (age, race, ethnicity, insurance, education, income), tumor variables (grade, ER, PR, HER2, TNM stage), and treatment variables (surgery in both databases; chemotherapy and radiation in NCDB). OS was compared between those with and without missing data via Cox proportional hazards models. Results: Overall, 775,996 patients in the NCDB and 263,016 in SEER were identified; missingness of at least 1 key variable was 29% and 13%, respectively. Of those, the majority were missing a tumor variable (NCDB 80%; SEER 88%), while demographic and treatment variables were missing less often. When compared to patients with complete data, missingness was associated with a greater risk of death; NCDB 17% vs. 14% (HR 1.23, 99% CI 1.21-1.25) and SEER 27% vs 14% (HR 2.11, 99% CI 2.05-2.18). Rate of death was similar whether the patient was missing 1 or ≥2 variables. When stratified by the type of missing variable, differences in OS between those with and without missing data in the NCDB were small. In SEER, reductions in OS were largest for those missing tumor variables (HR 2.26, 99% CI 2.19-2.33) or surgery data (HR 3.84, 99% CI 3.32-4.45). Among the tumor variables specifically, few clinically meaningful differences in OS were noted in the NCDB, while the most significant differences in SEER were noted in T and N stage (table). Conclusions: Missingness of select variables is associated with a worse OS and is not uncommon within large national cancer registries. Therefore, researchers must use caution when choosing inclusion/exclusion criteria for outcomes studies. Future research is needed to elucidate which patients are most often missing data and why OS differences are observed. [Table: see text]
LENVAGIST - A multicenter, comparative, placebo-controlled, double-blinded, phase II study of the efficacy of lenvatinib in patients with locally advanced or metastatic GIST after failure of imatinib and sunitinib.
Authors: Axel Le Cesne, Claire Cropet, Julien Gautier, Stéphanie Gagne, Katia Francourt, Emilie Remir, Caroline Hernandez, Armelle Dufresne, Isabelle Laure Ray-Coquard, Mélodie Carbonnaux, Benoite Mery, Helene Vanacker, Francois Bertucci, Simon Launay, Delphine Louvel-Perrot, Audrey Monneur, Mehdi Brahmi, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2020)

TPS11568 Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2 nd and 3 rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or &gt; 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .
A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors.
Authors: Filemon S. Dela Cruz, Elizabeth Fox, Jodi Ann Muscal, Ivan Kirov, James I. Geller, Steven G. DuBois, AeRang Kim, James Croop, Theodore Willis Laetsch, Charles G. Minard, Xiaowei Liu, Brenda Weigel, Chinyere E. Okpara, Jie Huang, Lea Dutta, Jagadeesh Aluri, Julia Lynne Glade Bender
Journal: Journal of Clinical Oncology (2020)

10527 Background: Proangiogenic signaling pathways cooperate with mTOR-mediated regulation of cell growth and maintenance to drive development of many pediatric cancers. We report results of the phase 1 dose escalation for LEN + EVE in pediatric patients (pts) with recurrent solid and CNS tumors conducted by Children’s Oncology Group. Methods: Dose escalation was conducted using a rolling-6 design. Pts received LEN + EVE orally once daily in continuous 28-day cycles. Dose determination was based on toxicity (CTCAE v4.03) during cycle 1. Pharmacokinetics (PK) of plasma LEN and EVE were monitored. Results: 17 pts were enrolled (9 male; 8 female). Median (range) age was 10 (3–21) years; 8 pts had CNS tumors. 17 were evaluable for dose-limiting toxicity (DLT). Enrollment started at dose level 1 (DL 1; LEN 11 mg/m 2 + EVE 3 mg/m 2 ) and, after treatment of 3 pts, was initially de-escalated to DL –1 (LEN 8 mg/m 2 + EVE 3 mg/m 2 ) due to DLT of proteinuria in 1 pt and self-resolving headache in another who, on review, did not meet the definition of DLT. No pts enrolled at DL –1 (n = 5) experienced DLT. Overall, DLTs were observed in 2 of the first 6 patients enrolled at DL 1: the initial pt with proteinuria and 1 more pt with hypertriglyceridemia and hypercholesteremia. Because 2 pts had reversible DLT of different categories not related to C max or AUC, the DL 1 cohort was expanded to enroll an additional 6 pts, none of whom had DLT. Thus, 2/12 pts experienced DLT at DL 1. Overall, most common treatment-emergent adverse events (TEAEs; ≥ 50% of pts) were diarrhea, hypertension, hypertriglyceridemia, vomiting, abdominal pain, headache, and hypothyroidism. 47% of pts had ≥ 1 treatment-related TEAE grade ≥ 3; the most frequent was proteinuria (n = 2). On cycle 1 day 15, mean (SD) C max (ng/mL) for LEN at DL –1 and DL 1, respectively, was 314 (150) and 359 (270), and mean (SD) AUC 0-8h (hr•ng/mL) for LEN was 1570 (935) and 1780 (1100). Taking all toxicities and PK into account, no further dose escalation was recommended. Best overall response in pts with measurable disease was 2/11 stable disease, 7/11 progressive disease, and 2/11 not evaluable. Conclusions: The recommended phase 2 dose of LEN + EVE in children with solid and CNS tumors was LEN 11 mg/m 2 + EVE 3 mg/m 2 , with maximum daily doses capped at 18 mg and 5 mg, respectively. The toxicity profile was no more than additive to single-agent therapy. PK exposure was comparable with children on single-agent LEN and to adults receiving LEN + EVE. Enrollment to the phase 2 portion (Ewing sarcoma, high-grade glioma, and rhabdomyosarcoma strata) is ongoing. Clinical trial information: NCT03245151.
Deaths among pancreatic cancer in-hospital, and the utilization of palliative care.
Authors: Anup Kasi, Raed Moh'd Taiseer Al-Rajabi, Anwaar Saeed, Weijing Sun, Saqib Abbasi
Journal: Journal of Clinical Oncology (2020)

e16803 Background: Pancreatic cancer has a dismal 5 year survival of 5-10%. Deaths commonly occur in-hospital as they present with acute complications. The purpose of this study is characterize this population compared to all pancreatic deaths, identify causes for admission, trends in palliative care utilization and its effect on costs and patient stay. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of pancreatic cancer were identified using the National Inpatient Sample. Annual trends in death were compared to overalls deaths using SEER data. Trends in hospital length of stay (LOS) and total charges (TC) were assessed, as well as utilization of palliative care. The effect of palliative care utilization on hospital LOS and TC were also identified. Results: 97,389 (weighted) patient deaths occurred from 2002 to 2014, with 7,634 in 2002, compared to 7,200 in 2014. Compared to total overall deaths of 38,026 and 42,047 respectively. Signifying 25% (2002) to 21% (2014) total patients expiring in an in-patient setting. The most common billed primary diagnosis was sepsis at 15.5%, followed by acute renal failure and fluid disorder (12.5%) and liver failure (5.3%). Overall length of stay trended down from 9.0 days to 7.5 days (p &lt; 0.001). And total charges for admission increased from $36,704 to $88,063 (p &lt; 0.001). Palliative care consults increased from 12% in 2002 to 45% in 2014. In 2014, the TC for deaths among those who received palliative care consults was $52,612 (p &lt; 0.001 when compared to all deaths). LOS among these patients also decreased from 7.5 days to 6.2 days. When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $86,738 to $74,544 (p &lt; 0.001). LOS was not significantly different at 8.8 days compared to 8.5 days (p = 0.15). Conclusions: A quarter of patients with pancreatic cancer die in an in-hospital setting. Palliative involvement decreased health care resource utilization. In reviewing patients who developed sepsis without in-hospital mortality, a palliative care consult decreased total charges of admission.
Serum immunogiobulin A and its clinical role in primary Sjogren's syndrome
Authors: Hui Wang, Jing He, Zhan-guo Li
Journal: BMJ (2008)

Objective To study the relationship between elevated serum level of immunoglobulin A (IgA) and other abnormality in immunological parameters in patients with primary Sjogren's syndrome (pSS)and those with viscera involvement based on determinations of serologic,other laboratory and clinical features.Methods Serum IgA level of 108 patients with pSS,seven males and 101 females with an age of 30～78 years and length of disease course of 0.2～20.0 years,was detected by turbidimetry.Clinical and laboratory parameters in patients were compared between different groups.Remits Elevated serum IgA level was found in 48 (44.4%) of 108 patients with pSS.Elevated erythrocyte sedimentation rate(ESR) was found in 91.7 percent of those with elevated sertum IgA and 63.3 percent in those with normal IgA(P<0.05).Serum positivity of rheumatoid factor(RF) was significantly higher in those with elevated serum IgA (70.8%)than those with normal IgA (48.3%,P<0.05).Pulmonary interstitial fibrosis could be found in 22.9 percent of those with elevated serum IgA,and in 8.3 percent of those with normal IgA(P<0.05).Occurrences of primary biliary cirrhosis and autoimmune hepatitis were higher in those with elevated serum IgA than in those with normal IgA,but not reaching statistical significance.Conclusion Serum IgA level misht play an important role in occurrence and development of pSS,and could be used as an indicator reflecting activity and severity of the disease,as well.

Key words: 
Primary sjogren's syndrome; Immunoglobulin A; Serologic tests
Gitelman综合征合并原发性甲状腺功能减退症一例
Authors: 段宇, 罗兰, 张春玉, 王云, 张小兰, 狄福松, 刘超
Journal: BMJ (2009)

患者女性,29岁.因反复乏力、软瘫12年余,本次发作1周,于2006年11月12 日入院.患者12年前起无明显诱因反复出现发作性四肢软瘫,多在疲劳或情绪紧张时出现,伴明显手足麻木,每次发作时查血钾在1.6～2.8 mmol/L之间,给予补钾治疗后四肢活动好转渐至正常.在此期间无明显头昏或头胀不适,多次测量血压为100/70 mm Hg(1 mm Hg=0.133 kPa)左右。
A phase Ib study of a novel c-MET, AXL and VEGFR-2 inhibitor ningetinib and gefitinib combination therapy in Chinese EGFR-TKI resistant NSCLC with T790M negative.
Authors: Hongyun Zhao, Lianke Liu, Yuxiang Ma, Jian Fang, Wenfeng Fang, Haiqing Ma, Yang Zhang, Guosheng Feng, Shaodong Hong, Shan Zeng, Bo Xie, Jun Ren, Xiaoyan Lin, Yingjun Zhang, Ning Xi, Yingzhi Jiang, Yanjun Wu, Ning Kang, Su Li, Li Zhang
Journal: Journal of Clinical Oncology (2020)

9583 Background: Ningetinib is a novel tyrosine kinase inhibitor, targeted at c-Met, Axl, VEGFR-2, Mer and Flt3. This phase Ib trial (NCT03758287) evaluated the safety, determined the recommended phase II dose (RP2D), and further explored the pharmacokinetic and efficacy of Ningetinib + Gefitinib in EGFR-TKIs acquired resistant NSCLC patients (pts) with T790M negative. Methods: Chinese Pts with advanced or metastatic NSCLC, acquired resistant to at least one EGFR-TKI, T790M negative were enrolled. Pts received Ningetinib 30, 40, 60 mg + Gefitinib 250mg orally once daily in dose-escalation (n = 12) by a Fibonacci 3+3 design. Expansion phase (n = 74, enrollment is ongoing) started at tolerated dosage. Safety, RP2D were primary endpoints; PK, antitumor activity were secondary endpoints. Non-mandatory tumor samples at baseline were collected for exploratory objectives. Results: Totally, 86 eligible pts were enrolled between Nov 2016 and Dec 2019, and received treatment (Ningetinib 30 mg, n = 36; 40 mg, n = 46; 60 mg, n = 4), with median age 56.7 years, 36% with baseline brain metastasis, 66%/33%/1% prior 1/2/3 lines EGFR-TKI treatment, respectively. Treatment-related adverse events (TRAEs) occurred in 82 (95%) pts, grade 3/4 in 32 pts (37%). Most common TRAEs (≥30%) were myocardial enzyme elevation (all grade 74.4%; grade 3-4 0%), transaminase elevation (73.3%; 2.3%), skin rash (60.5%; 3.5%), albuminuria (44.2%; 0%), coagulation abnormalities (mostly asymptomatic Fbp decrease; 37.2%; 15.1%), diarrhea (33.7%; 2.3%) and hypertension (32.6%; 11.6%). Two Dose limited toxicities were observed at 60 mg dosage (both were grade 3 Fbg decrease), RP2D was decided at 40 mg. Of 84 efficacy evaluable pts, ORR was 19.1% (16 PR), DCR was 91.7% (61 SD, 7 PD). Totally, 65 (75.6%) progression events occurred at data cut-off (9 Jan 2020), the median PFS for all pts was 4.4 months (95%CI 3.7-4.6). No PFS differences were found between pts grouped by 3 rd TKIs history or brain metastasis. C-Met gene amplification by FISH was conducted in 72 pts (83.7%). Pts with higher gene copy number (GCN) responded better in treatment, ORR in the GCN ≥6 (n = 11), GCN ≥5 (n = 16) and GCN ≥3 (n = 37) subgroups was 36.4%, 25.0% and 21.6% respectively. Conclusions: Ningetinib was well tolerated at 30 mg and 40 mg dosage with Gefitinib 250 mg, the RP2D for Ningetinb was 40 mg. This combination therapy showed promising anti-tumor activity in prior EGFR-TKIs acquired resistant NSCLC pts with T790M negative. C-Met GCN was the potential efficacy biomarker. Clinical trial information: NCT03758287 .
Meta-analysis of case-control studies to examine the relationship between occupational pesticide exposure and risk of acute myeloid leukemia.
Authors: Nicolas Vallet, Amélie Foucault, Frederic Picou, Emmanuel Gyan, Olivier Herault
Journal: Journal of Clinical Oncology (2020)

7540 Background: Occupational pesticide exposure (OPE) is associated with the risk of developing lymphoid malignancies, but less information is available on large cohorts about the risk of occurrence of acute myeloid leukemia (AML). To answer this question, we performed a meta-analysis including relevant adult case-control studies which reported OPE. Methods: Following PRISMA and MOOSE guidelines, two investigators performed a systematic search in PubMed and Cochrane databases for case-control studies evaluating the association between OPE and AML between 1946 and August 28, 2018. In order to identify the maximum number of studies, keywords related to demographical, pesticides and chemicals data exposures were used. Studies reporting AML diagnosis based only on death certificates, controls from cancer databases and pediatric cases (&lt;15 years-old) were not included. Statistical analyses were performed with R software and the ‘mefafor’ package. Results: Fifteen studies which included 4,068 AML patients and 250,975 control subjects were included. Using a random effects model, the overall analysis showed a significant adverse association between OPE and AML with OR=1.49 (95%CI: 1.10-2.01), and a significant heterogeneity between studies ( I² =0.73, p&lt;0.001). The robustness was checked after sequential exclusion of one study at a time which did not influence the overall OR estimate. A publication bias underestimating the OR was suggested by an asymmetrical funnel plot. Using trim-and-fill method, hypothetical missing studies were added studies in order to adjust the OR (OR=1.76 [95%CI: 1.30-2.38]. A stratified analysis showed that the association was significant in Asian populations (OR=1.74; 95%CI: 1.32-2.30) and upon exposure to insecticides (OR=1.45; 95%CI: 1.16-1.81), yet partly influenced by other factors, since most of the studies reported unadjusted results (n=8, 53%). Data on biological characteristics were unavailable to stratify patients according to AML molecular or cytogenetic characteristics. Conclusions: From this new extensive review and analysis, it clearly appears that AML should be considered as occupational illness in patients with demonstrated OPE. Further studies will have to focus on the biological effects of individual and pesticides cocktails in order to determine the pathogenesis mechanisms involved in leukemogenesis, and to improve individual protection.
Distinct clinical characteristics in young-onset pancreatic neuroendocrine tumor: A propensity-adjusted analysis.
Authors: Suleyman Yasin Goksu, Muhammet Ozer, Syed Mohammad Ali Kazmi, Nina Niu Sanford, Todd Anthony Aguilera, David Hsieh, Aravind Sanjeevaiah, Udit Verma, Leticia Khosama, Mary Claire Maxwell, Jonathan Bleeker, Muslim Atiq, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2020)

e16710 Background: Pancreatic neuroendocrine tumor (PNET) is a rare disease. There is a lack of data on the association of age and sociodemographic characteristics on survival in patients with NET. Our study aimed to evaluate clinical, molecular differences, and survival outcomes in young-onset PNET (YOPNET) and late-onset PNET (LOPNET). Methods: We used the National Cancer Database to identify patients with YOPNET ( &lt; 50 years) and LOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2015. We calculated the survival outcomes using Kaplan Meier and Cox regression methods before and after 1:1 nearest neighbor propensity score matching. We used the AACR Genie cohort to compare mutation frequency with the Benjamini-Hochberg method between YOPNET and LOPNET. Results: A total of 6,259 patients with PNET were selected, of which 27% were YOPNET. Patients with YOPNET were more likely to be female, black, and Hispanic, have private insurance versus LOPNET (all p &lt; .001). Patients with YOPNET had less comorbidity score, but greater tumor size ( &gt; 4 cm) and higher stage (all p &lt; .001). Patients with LOPNET were more likely to be treated in an academic/research facility ( p &lt; .001). Patients with YOPNET were more likely to be located in the head of the pancreas ( p = .004). Patients with YOPNET had better overall survival (OS) as compared to patients with LOPNET which persisted after propensity score matching ( p &lt; .001). This difference continued after adjusting for clinically significant variables (unmatched p = .008; matched p = .01) (Table). For genomic analysis, we identified 177 patients; 27% was YOPNET, and patients with YOPNET had a significantly lower rate of MEN1 mutation than patients with LOPNET (26% vs. 56%, p &lt; .001). Rate of other mutations was not different. Conclusions: Patients with YOPNET who underwent surgery had better OS than LOPNET and were more likely to have higher stage and greater tumor size. YOPNET represents a disease with distinct clinical and molecular features. [Table: see text]
VCAN accumulation and proteolysis as predictors of T lymphocyte-excluded and permissive tumor microenvironments.
Authors: Philip Emmerich, Kristina A. Matkowskyj, Stephanie McGregor, Sean Kraus, Kristen Bischel, Tonela Qyli, Darya Buehler, Cheri Pasch, Christopher Babiarz, Mitchell Depke, Linda Clipson, Kari Braun Wisinski, Mark E. Burkard, Andrew Baschnagel, Nataliya Volodymyrivna Uboha, Fotis Asimakopoulos, Dustin A. Deming
Journal: Journal of Clinical Oncology (2020)

3127 Background: Immune checkpoint inhibitors (ICIs) represent a major advance for treating solid tumors. However, only a minority of patients (pts) benefit from these therapies and markers that predict response have been elusive. Versican (VCAN) is an immunosuppressive proteoglycan in the tumor microenvironment (TME), which releases an immunostimulatory N-terminal fragment versikine (Vkine) when cleaved by ADAMTS proteases. We have demonstrated in colorectal cancers (CRC) that a low VCAN/high Vkine (VCAN proteolytic predominant [VPP]) phenotype correlates with increased tumor-infiltrating CD8 + T lymphocytes (TILs). Here we examine the accumulation of VCAN as a marker of immune exclusion and its proteolysis as a marker of an immune-permissive TME. Methods: Immunohistochemistry for VCAN, Vkine and CD8+ was performed on samples from 1662 pts across breast (BC), CRC, endometrial cancer, pancreatic adenocarcinoma (PDAC), esophageal cancers and neuroendocrine tumors (NETs), across stages of disease (I-IV) and with diverse prior treatments. Stromal intensities of VCAN and Vkine staining quantified in collaboration with blinded surgical pathologists using a 0-3+ scale. 0/1+ were considered “low” for both VCAN and Vkine, whereas 2/3+ were considered “high”. The number of CD8 + TILs were counted using 400x magnification, the equivalent of a high power field (hpf). Results: Across the entire cohort VCAN phenotypes were diverse (VCAN high/Vkine low, 21%; VCAN high/Vkine high, 23%; VCAN low/Vkine low, 29%; VCAN low/Vkine high (VPP), 27%). Consistent with VCAN accumulation as a marker of T cell exclusion, VCAN low cancers had increased TILs compared to VCAN high (4.8 vs 18.3 TILs/hpf, p &lt; 0.001). Low VCAN was identified in 85% esophageal, 79% NET (including small cell lung cancer [SCLC]) 72% endometrial, 47% MSI-H CRCs, 28% triple-negative BC and only 22% MSS CRC, 18% PDAC, 17% ER+ BCs. The VPP subgroup had the highest TILs per hpf across tumors. VPP was identified in 47% of esophageal, 45% endometrial, 41% NETs (including SCLC), 24% MSI-H CRCs, and only 9% MSS CRC, 7% ER+ BCs, 3% triple-negative BCs, and 0% of PDAC (n = 131 PDAC pts). Conclusions: VCAN accumulation correlates with T lymphocyte exclusion, while VCAN proteolysis predicts an immune permissive phenotype. VCAN accumulation and proteolysis are now incorporated into ICI clinical trials as a potential marker of response. Future studies will clarify the role of these biomarkers in predicting benefits of immuno-oncology treatment strategies.