tbuckley/cabot-search huggingface dataset:
Neurophysiological changes: Sunitinib fatigue severity.
Authors: David Cunningham, Ela Plow, Didier Allexandre, Brian I. Rini, Mellar P. Davis
Journal: Journal of Clinical Oncology (2016)

e21683 Background: Sunitinib, used to treat renal cancer and GIST, is associated with fatigue. Cause remains unknown. We used transcranial magnetic stimulation (TMS), electromyography (EMG) & peripheral electrical stimulation (M-wave testing) to study fatigue in first cycle of sunitinib (50mg/day, 4/2 cycle). Methods: 9 patients underwent TMS evaluation, & EMG, M-wave & strength testing of first dorsal interosseous (FDI) muscle pre & post sunitinib dose. TMS derived outcomes were excitability of M1, motor map output & area devoted to FDI. Peripheral outcomes were maximum voluntary contraction (MVC), & EMG amplitude (RMS) & mean power frequency (mpf), M-wave amplitude & dispersion, & twitch force (TF) measured at rest, 30% MVC &/or MVC. Post-pre change was analyzed using Wilcoxon or paired t-test & correlated with fatigue change measured by the Brief Fatigue Inventory (BFI). Results: Patients experienced significant increased fatigue (mean BFI score change from 3.0 to 5.5; z = 2.5, p = 0.01). TMS revealed excitability of M1 increased following treatment (z = -2.4, p = 0.02); however, FDI motor output reduced (z = -2.2, p = 0.03) with no change in motor map area (Spearman ρ2= -0.66 BFI; p = 0.01). Despite a reduced MVC force (2.6 to 1.3; p = 0.04) following treatment, EMG amplitude was significantly increased at 30% MVC (p = 0.03) & so is resting M-wave amplitude (p = 0.01). Furthermore, the greater was the increased perceived fatigue following treatment, the greater the change in EMG amplitude and mpf at MVC (ρ2= 0.80, p = 0.01 and ρ2= 0.93, p < 0.001) and 30% MVC (ρ2= 0.47, p = 0.04 and ρ2= 0.74, p < 0.001) & the greater the increased M-wave dispersion (ρ2= 0.85, p < 0.001). Discussion: Findings suggest sunitinib causes peripheral fatigue associated with uncoupling excitation contraction & a reactive reduction in FDI motor map output in M1 cortex. Still, M1 may compensate as evidence by increased excitability. Sunitinib blocks activation of AMP kinase which is vital energy-sensing enzyme responsive to ATP/AMP & phosphocreatine/creative muscle ratios. AMP kinase inhibition would explain the excitation/contraction uncoupling demonstrated by M-wave dispersion with peripheral fatigue. Conclusions: Sunitinib causes peripheral fatigue likely to be caused by AMP kinase inhibitors.
Open-label, dose-escalation, phase 1 study of venetoclax in combination with navitoclax and chemotherapy in patients with relapsed acute lymphoblastic leukemia.
Authors: Thomas Alexander, Seong Lin Khaw, Jeffrey E. Rubnitz, Susan I. Vear, Norman James Lacayo, Michelle Schmidt, Bo Tong, Lindsey Rosenwinkel, Lindsey Bensman, Maria Verdugo, Su Young Kim, Elias Jabbour, Wendy Stock
Journal: Journal of Clinical Oncology (2018)

TPS10575 Background: Acute lymphoblastic leukemia (ALL) relapse in children and adults is associated with poor prognosis. Venetoclax (VEN) is a potent, highly selective BCL-2 inhibitor, and navitoclax (NAV) inhibits various BCL family proteins, including BCL-2, BCL-W, and BCL-XL. VEN and NAV have shown activity in a variety of ALL cell lines and xenografts, and their combination resulted in synergistic antitumor effect in most ALL xenografts (Khaw et al. Blood 2016;128:1382-95). This trial evaluates VEN in combination with NAV and chemotherapy in patients with relapsed ALL. Methods: This is an open-label, multicenter phase 1 dose-escalation trial (NCT03181126) in patients 4‒45 years old with relapsed or refractory ALL. Patients receive daily oral VEN, weight-adjusted to match the adult-equivalent exposure of 400 mg. Daily oral NAV administration starts on day 3. Based on the patients’ weight, up to 3 dose levels (25, 50, and 100 mg) will be explored. Chemotherapy consists of peg-asparaginase (1,250 IU/m2 intravenous [IV] on days 9 and 22), vincristine (1.5 mg/m2 IV on days 9, 15, 22, and 29), and dexamethasone (20 mg/m2/day orally on days 9–13 and 22–26). At the investigator’s discretion, chemotherapy may be delayed, not administered, or repeated for a second cycle. Dose escalation is guided by a Bayesian optimal interval design. For each weight group ( < 45 kg and ≥45 kg), the initial cohort at each dose level enrolls ≥3 dose-limiting toxicity (DLT)-evaluable patients, and additional cohorts ≥2. DLTs are assessed during the first 42 days. In the absence of progressive disease, patients may receive VEN + NAV for up to 9 months; thereafter, therapy may be continued for those with ongoing benefit. Primary endpoints are safety and DLTs of VEN + NAV and chemotherapy, and safety and pharmacokinetics of VEN + NAV. Secondary objectives include assessments of antitumor activity and number of patients who proceed to stem cell transplantation. BH3 profiling and comprehensive genomic analysis will be performed to explore biomarkers of disease response. Approximately 42 patients are planned to be enrolled. As of Jan 5, 2018, 3 patients were enrolled at dose level one. Clinical trial information: NCT03181126.
TCT-140 Long-term Clinical Outcomes After Stent Implantation in Chronic Total Occlusion Lesions: Impact of First-generation Versus Second-generation Drug-eluting Stents
Authors: Hiroyuki Tanaka, Seiji Habara, Takeshi Tada, Yasushi Fuku, Tsuyoshi Goto, Kazushige Kadota
Journal: Journal of the American College of Cardiology (2018)
The importance of recognizing and addressing depression in patients with advanced cancer.
Authors: Risa Wong, Areej El-Jawahri, Kelly Irwin, Sara D'Arpino, Samantha M.C. Moran, Connor Johnson, Daniel Lage, Margaret Ruddy, Brandon Temel, Lara Traeger, Inga Tolin Lennes, Barbara J. Cashavelly, Holly S Martinson, Vicki Jackson, Joseph A. Greer, David P. Ryan, Ephraim P. Hochberg, William F. Pirl, Jennifer S. Temel, Ryan David Nipp
Journal: Journal of Clinical Oncology (2017)

10050 Background: Patients with cancer often experience depression, which is associated with worse outcomes, including longer hospital length of stay (LOS). Although antidepressant medication can improve depressive symptoms in patients with cancer, it is unclear whether their use translates into better outcomes. We sought to clarify the relationship between depressive symptoms, antidepressant medication, and hospital LOS in patients with advanced cancer. Methods: We enrolled hospitalized patients with advanced cancer from 9/2014 to 4/2016 as part of a longitudinal data repository. We examined patients’ medical records to obtain information about documented depressive symptoms in the 3 months prior to admission and use of antidepressant medication at the time of admission. Using descriptive statistics, we compared differences in patient characteristics and hospital LOS across these groups. We used linear regression to examine associations and moderation effects between depressive symptoms, use of antidepressant medication, and hospital LOS. Results: Of 1,036 enrolled patients (89.9% of approached), 126 (12.2%) had documented depressive symptoms in the 3 months prior to admission and 288 (27.8%) were taking an antidepressant medication at the time of admission. Patients with depressive symptoms were more likely to be on antidepressant medication at admission than those without depressive symptoms (48.4% vs 24.9%, p &lt; .001). Patients taking antidepressant medication were younger (62.4 vs 64.4 years, p = .026) and more likely to be female (55.2% vs 47.2%, p = .021). Depressive symptoms were associated with longer hospital LOS (7.3 vs 6.1 days, p = .036), and antidepressant medication was a moderator of this relationship. Among patients not on antidepressant medication, depressive symptoms were associated with longer hospital LOS (7.9 vs 6.1 days, p = .025), but among those on antidepressant medication, depressive symptoms were not associated with hospital LOS (6.6 vs 6.2 days, p = .588). Conclusions: Antidepressant medication moderated the relationship between depressive symptoms and longer hospital LOS. Our results support the need to recognize and address depressive symptoms in patients with advanced cancer.
P04.39 Tenascin-c expression correlates to vasculogenic mimicry formation and predicts a poor prognosis in glioblastoma
Authors: H Cai, Y Chen, X Ni, Z Chen
Journal: Neuro-Oncology (2018)

Glioblastoma is a highly invasive and vascularized primary CNS tumor and the effect of anti-angiogenesis therapy on glioblastoma is not as adequate yet. Vasculogenic mimicry (VM), a vessel-like structure formed by highly invasive tumor cells, has been considered as one of reasons to failure from anti-angiogenesis therapy for GBM patients. Tenascin-c (TNC), an extracellular protein overexpressed in glioblastoma, may stimulate angiogenesis in tumor. However, whether TNC contributes to VM formation remains unclear. Fifty tumor samples from glioblastoma patients were evaluated for VM formation and TNC expression by Immunohistochemistry staining. The results were compared with prognosis of the patients. Tenascin-c expressions were also examined for glioma cell lines, U251, A172, U373, U138 and LN308 by western blotting analysis, and the results were compared with the VM formation ability evaluated by three-dimensional culture assay. The direct effect of TNC on VM formation of glioma cell lines were investigated by exogenous tenascin-c exposure. Tenascin-c positive stainings were found in 54% (27/50) of GBM samples, while VM channels were determined in 34% (17/50) of GBM samples. Tenascin-c expression was significantly higher in VM positive group (15/17) than in the VM negative group (12/33; χ2=12.154, P<0.01). Of glioblastoma samples with TNC overexpression, the levels of microvessel density were 25.55 ± 7.03, which was higher than that in TNC low expression samples (13.22 ± 5.34, p<0.01). The patients with TNC overexpression or VM positive in their tumors exhibited worse survival time (median overall survivalTNC high: 12 months vs. median overall survivalTNC low: 20 months; p=0.011 and median overall survivalVM positive: 12 months vs. median overall survivalVM negative: 17 months; p=0.0041). Glioma cell lines U251 and A172 had high tenascin-c expression (relative expression: 2.01 and 1.38), while U373, LN308 and U138 had low tenascin-c expression (relative expression: 0.05, 0.32 and 0.72). Three-dimensional culture assay showed that U251 and A172 formed more classical vessel-like structures (vessel number: 91.67 ± 2.87 and 76.67 ± 4.99), in contrast with U373, LN308 and U138, which formed open brand-like structures (vessel number: 2.33 ± 0.47, 0.67 ± 0.47 and 2.67 ± 0.94). After stimulated by exogenous tenascin-c (10mg/ml) for six hours in U373, LN308 and U138, the number of closed vessel-like structure increased (vessel number: 24.67 ± 2.05, 6.33 ± 1.25 and 17.67 ± 3.09). Our results indicate that tenascin-c overexpression may contribute to vaccinogenic mimicry formation and relate to poor prognosis of glioblastoma patients. This study was supported by grants from the National Natural Science Funds of China (No. 81372685)
A sensitive and specific assay for the serological diagnosis of antilaminin 332 mucous membrane pemphigoid
Authors: S. Goletz, C. Probst, L. Komorowski, W. Schlumberger, K. Fechner, N. van Beek, M.M. Holtsche, A. Recke, K.B. Yancey, T. Hashimoto, F. Antonicelli, G. Di Zenzo, D. Zillikens, W. Stöcker, E. Schmidt
Journal: British Journal of Dermatology (2018)

Antilaminin 332 mucous membrane pemphigoid (MMP) is an autoimmune subepidermal blistering disease with predominant mucosal involvement and autoantibodies against laminin 332. Malignancies have been associated with this disease; however, no standardized detection system for antilaminin 332 serum antibodies is widely available.Development of a sensitive and specific assay for the detection of antilaminin 332 antibodies.An indirect immunofluorescence (IF) assay using recombinant laminin 332 was developed and probed with a large number of antilaminin 332 MMP patient sera (n = 93), as well as sera from patients with antilaminin 332-negative MMP (n = 153), bullous pemphigoid (n = 20), pemphigus vulgaris (n = 20) and noninflammatory dermatoses (n = 22), and healthy blood donors (n = 100).In the novel IF assay, sensitivities with the laminin 332 heterotrimer and the individual α3, β3 and γ2 chains were 77%, 43%, 41% and 13%, respectively, with specificities of 100% for each substrate. The sensitivity for the heterotrimer increased when an anti-IgG4 enriched antitotal IgG conjugate was applied. Antilaminin 332 reactivity paralleled disease activity and was associated with malignancies in 25% of patients with antilaminin 332 MMP.The novel IF-based assay will facilitate the serological diagnosis of antilaminin 332 MMP and may help to identify patients at risk of a malignancy.
A comprehensive evaluation of breast cancer treatment delays by race among Women's Health Initiative participants.
Authors: Rachel Lynn Yung, Greg S Warnick, Roberta M. Ray, Joshua A. Roth, Lisa Johnson, Di Wang, Rowan T. Chlebowski, Garnet L Anderson, Kerryn Reding
Journal: Journal of Clinical Oncology (2018)

e18579 Background: Breast cancer (BC) mortality is higher in Black vs White women, attributed in some studies to treatment delay. However, prior studies evaluated delay to initial treatment, leaving the role of delay to subsequent therapy uncertain. Therefore, we investigated delays across the treatment spectrum. Methods: We included women from the Women’s Health Initiative (WHI) who were diagnosed with BC (stage I-III) at age 65+ years. In this prospective analysis of 3466 incident BC, we used Medicare claims to characterize treatment. Delays were categorized (yes/no) across surgery, chemotherapy, and radiation as > 8 weeks from diagnosis or prior treatment to initiation of subsequent treatment. Results: Among BC cases, 188 were non-Hispanic black, 3129 were non-Hispanic white; 358 were HER2+, 266 were triple negative. In comparison to white women, a higher percent of black women had delay to chemotherapy (9.0% vs 3.9%; P < 0.001) and a marginally higher percent had surgery delay (13.3% vs 9.1%; P = 0.05), but had similar delays to radiation (12.2% vs 14.0%; P = 0.50). Delay to chemotherapy was associated with an increased risk of BC-specific mortality (HR = 1.7 [1.1-2.6]), but delay to surgery and radiation were not. Treatment delays did not alter the risk of BC-specific mortality associated with race. Conclusions: Our results confirm prior findings that black women with BC are more likely to have chemotherapy delays vs white women, and suggest that black women were more likely to have surgery delays. Our findings suggest that despite the greater risk of mortality associated with chemotherapy delay, this delay did not contribute to the increased risk of BC mortality in black vs white BC cases. N Breast cancer death Mean followup (y) Hazard Ratio* lower CL upper CL Delay to surgery No 3143 199 9.82 1.0 Yes 323 14 8.08 0.80 (0.46, 1.39) Delay to chemotherapy No 3317 184 9.64 1.0 Yes 149 29 9.99 1.70 (1.13, 2.57) Delay to radiation No 2981 177 9.72 1.0 . Yes 485 36 9.27 1.27 (0.89, 1.83) Cumulative delays 0 2584 144 9.87 1.0 1 808 60 9.13 1.24 (0.91, 1.67) 2-3 74 < 11 8.18 1.50 (0.76, 2.98) *Adjusted for a priori confounders: age at diagnosis, tumor size, nodal involvement, ER+, PR+, Her2+, Charlson comorbidity score
Clinical, sociodemographic, and behavioral factors associated with cumulative burden of morbidity (CBM) among testicular cancer survivors (TCS) in the Platinum study.
Authors: Sarah L. Kerns, Chunkit Fung, AnnaLynn Williams, Mohammad Issam Abu Zaid, Howard D. Sesso, Patrick Monahan, Shirin Ardeshirrouhanifard, Darren R. Feldman, Robert James Hamilton, David J. Vaughn, Clair Beard, Robert Anthony Huddart, Jeri Kim, Christian K. Kollmannsberger, Deepak M. Sahasrabudhe, Ashley Amidon Morlang, Ryan Cook, Sophie D. Fossa, Lawrence H. Einhorn, Lois B. Travis
Journal: Journal of Clinical Oncology (2017)

10075 Background: TCS are an important group in which to characterize late effects of cancer and its therapy given their young age at diagnosis and high cure rate. We comprehensively evaluated CBM and identified associated clinical, sociodemographic, and behavioral risk factors among TCS given cisplatin based chemotherapy in a multicenter study. Methods: TCS completed a comprehensive health questionnaire. Responses were grouped into 22 adverse health outcomes (AHO) and graded by severity. A CBM score was calculated based on AHO number and severity, following Geenen et al (JAMA 2007). Multivariable ordinal logistic regression examined the association of clinical, sociodemographic, and behavioral factors with CBM. Variable-based hierarchical clustering identified individual AHOs that co-occurred. Results: Among 1,215 TCS (median age at evaluation 38 y, range 19-68 y; time since chemotherapy 4.6 y), over 20% had a CBM score of high (17%), very high (4%) or severe (0.4%). Most TCS, however, had CBM scores of low (37%), medium (28%), very low (9%) or none (5%). In a multivariable model controlling for time since chemotherapy, older attained age (OR 1.2; 95% CI 1.1 - 1.3), being widowed/divorced/separated (OR 1.8; 95% CI 1.1 - 3.1), having less than college-level education (OR 1.7; 95% CI 1.3 - 2.2), being retired/on disability (OR 2.5; 95% CI 1.2 - 5.3), and receipt of 4 cycles of BEP vs. 4 cycles of EP or 3 cycles of BEP (OR 1.3; 95% CI 1.01 - 1.8) were associated with increased odds of a worse CBM score; vigorous exercise (OR 0.7; 95% CI 0.5 - 0.9) and non-white race (OR 0.6; 95% CI 0.4 - 0.9) were associated with decreased odds. A separate cluster analysis revealed five groups of AHOs: those known to be cisplatin-related (e.g. neuropathy, ototoxicity); metabolic abnormalities (e.g. hypercholesterolemia, diabetes); vascular damage (e.g. stroke); testicular cancer-related (e.g. hypogonadism); and other (e.g. thyroid disease). Conclusions: TCS with factors associated with worse CBM may be candidates for closer monitoring. If confirmed, our cluster analysis showing that groups of conditions tend to co-occur in TCS could provide guidance for survivorship care plans.
Long-term (7-year) outcomes of universal mismatch repair screening (uMMR) of 1156 colorectal (CRC) and endometrial cancers (EC) in an academic setting.
Authors: Michael J. Hall, Yana Chertock, Michelle Savage, Joann Sicilia, Mary Beryl Daly
Journal: Journal of Clinical Oncology (2018)

1513 Background: uMMR of CRC/EC for Lynch syndrome (LS) is recommended to identify the 2-3% of incident CRC/EC with germline MMR mutations in MLH1, MSH2, MSH6, and PMS2. Many US centers use a positive immunohistochemical (IHC+) tumor test to prompt further evaluation such as genetic counseling (GC). Efficacy of uMMR is established, but real-world performance is not. W/recent Blue Ribbon Panel recommendations for broad implementation, we reviewed uMMR effectiveness in an academic cancer center. Methods: Outcomes of all CRC/EC undergoing uMMR from 9/2011 (start of uMMR at Fox Chase Cancer Center) to 12/2017 were reviewed. uMMR results are reported in the surgical pathology report and by email to providers w/a PDF test report meant for pts. Results [IHC, MSI, BRAF, MLH1 promoter methylation, gene testing] and clinical data were extracted from a clinical genetics database and the EMR. Associations were tested by chi-square and T-test (2-sided). Results: From 1156 screened tumors, 278 (24.0%) had +IHC: 112 (40.3%) CRC vs 166 (59.7%) EC. Mean age was 64.7 yrs, and 117/278 (42.4%) reported family history (FamHx) of a LS cancer. After BRAF V600E testing, 91.0% (253/278) warranted GC. Only 98/253 (38.7%) pts warranting GC have to date completed GC (mean follow-up 3.0 yrs)—most common pt-reported reason for non-compliance w/GC was low interest (46.7%). Pts who completed GC were younger (47.9% vs 29.6% were < 60 yrs, p = 0.004), and had stronger FamHx (55.1% vs 34.8%, p = 0.006), while differences in GC uptake by race (40.6% White vs 28.2% non-White, p = 0.14) were not significant. Of the 67 pts who sought counseling and warranted a germline test, 91.8% completed testing. LS was diagnosed in 20.9% (14/67) or 1.1% of the uMMR population—nearly 1 in 4 tested (24.6%, 17/67) were clinically suspicious for LS but test results were inconclusive. Conclusions: uMMR effectiveness is limited by low uptake of GC as well as high rates of non-diagnostic test results. Among uMMR IHC+ pts, low interest is the foremost patient barrier to GC uptake, and is strongly influenced by personal (age) and familial risk factors. Molecular testing alone (IHC+ screen) may be insufficient to achieve desired uMMR outcomes.
Contribution of nationwide genome screening in Japan (LC-SCRUM-Japan) to the development of precision medicine for non-small cell lung cancer.
Authors: Takashi Seto, Shingo Matsumoto, Kiyotaka Yoh, Yutaka Fujiwara, Takuma Yokoyama, Kazumi Nishino, Terufumi Kato, Shunichi Sugawara, Masato Shingoji, Masahiro Kodani, Kadoaki Ohashi, Katsuya Tsuchihara, Koichi Goto
Journal: Journal of Clinical Oncology (2018)

9085 Background: A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of lung cancer precision medicine. Methods: Since 2013, non-squamous non-small lung cancer patients have been screened for ALK/ROS1/RET fusions using RT-PCR and FISH, and since 2015, they have also analyzed for 143 gene alterations using a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. Based on the molecular screening and the monitoring of clinical course and patient survival, a large-scale integrative clinico-genomic database has been established. Results: As of December, 2017, 251 institutions were participating and 4371 patients had been enrolled. The success rates of RT-PCR and NGS were 95% and 92%, respectively. Of 3919 available samples, a total of 1568 actionable gene alterations (382 KRAS mut, 193 ERBB2 mut/amp, 142 ROS1 fus, 100 RET fus, 98 MET skip/amp, 97 BRAF mut, 97 ALK fus, 96 PIK3CA mut, 54 FGFR1 amp, 13 NRAS mut, 6 AKT1 mut, 6 FGFR2/3 fus, 4 NRG1 fus, 2 NTRK3 fus and others) were detected in 1505 samples (38%). The concordance rates of the results in ALK, ROS1 and RET fusion detection between NGS and the corresponding RT-PCR were 0.98, 0.99 and 0.99, respectively. Through this screening, a total of 793 genotype-matched patients to molecular-targeted clinical trials were identified, and 136 of them (17%) were enrolled into the trials. Of the 2345 patients analyzed by NGS, the survival data were available in 1298 (55%). The patients with actionable gene alterations who were treated with targeted agents (n = 136) had significantly longer overall survivals than those not treated with targeted agents (n = 401) or the patients without actionable gene alterations (n = 761) (median survival [95%CI], 4.2 [2.4-8.2.] vs. 3.4 [2.3-5.8] vs. 2.3 [1.9-2.8] years, respectively; p = 0.01). Conclusions: LC-SCRUM-Japan contributes to the development of precision medicine, especially for ROS1, RET, ERBB2, BRAF and MET-positive lung cancers. In addition to the tissue-based molecular screening, a NGS assay with liquid biopsy was started in December 2017 and is now ongoing in the LC-SCRUM-Japan.