tbuckley/cabot-search huggingface dataset:
Effect of tumor-specific KRAS mutational status on impact of anti-EGFR therapy in non-small cell lung cancer (NSCLC).
Authors: M. C. Garassino, M. Marabese, M. Broggini, C. Lauricella, I. Floriani, O. Martelli, S. Marsoni, G. Gherardi, G. Farina, A. Scanni
Journal: Journal of Clinical Oncology (2010)

7564 Background: The RAS/RAF/MEK/ERK pathway is a therapeutic target in both colorectal (CRC) and NSCLC cancer, but while mutated KRAS is a negative prognostic marker and a negative predictor for anti-EGFR therapy in CRC, its role in lung cancer is quite ambiguous. KRAS is a pool of mutations mostly occurring in codons 12 and 13 but differing for the replaced basis and for the aminoacid substitution. In CRC the most expressed KRAS mutation is G12D. We hypothesized a different KRAS mutational status in NSCLC patients, bearing a potential different profile in the tumour response to treatment which we tested in vitro. Methods: TAILOR (NCT00637910) is a multicenter Italian phase III trial powered to evaluate a differential effect of all biological markers in selecting patients for erlotinib and docetaxel as second line. Consecutive patients are registered and molecularly profiled centrally. KRAS and EGFR mutations were detected by direct sequencing. Therefore, we identified all KRAS mutations types. The EGFR-wt NCI-H1299 lung cell line was transfected with expression plasmids encoding all different identified KRAS mutations and tested in vitro for the activity of cisplatin, taxanes, erlotinib and pemetrexed. Results: To date, KRAS and EGFR mutational status is available on 161 of 256 patients registered into the trial. We found six types of KRAS mutation in 35 patients (20%): G12C (45.7%) G12D (20%) G12V (20%) G12A (5.7%) G13C (5.7%) G13D (2.8%). Preliminary data, in the NCI- H1299 transfected cell lines, indicate that specific KRAS mutations are associated to different sensitivity or resistance drug profiles. Conclusions: Final results will be presented at the congress and clearly suggest that the specific mutational status of KRAS gene in NSCLC seems to differ from that reported for CRC. This clinical observation, with in vitro results suggesting different patterns of sensitivity/resistance to EGFR inhibition in transfected cell lines, might explain the ambiguous role of KRAS as a predictor to anti-EGFR therapy in NSCLC. Final results of the randomized TAILOR study will definetely allow to verify this suggestive hypothesis. No significant financial relationships to disclose.
A phase III randomized trial of adjuvant biochemotherapy (BC) versus interferon-α-2b (IFN) in patients (pts) with high risk for melanoma recurrence
Authors: K. B. Kim, S. S. Legha, R. Gonzalez, C. Anderson, N. E. Papadopoulos, O. Eton, C. Plager, A. Roe, P. Liu, A. Y. Bedikian
Journal: Journal of Clinical Oncology (2006)

8003 Background: High-dose IFN (HDI) is associated with significant toxicity, and its clinical benefit as an adjuvant therapy for melanoma has been often debated. BC is associated with higher response rates than other regimens, but it has never been tested in an adjuvant setting. Methods: We conducted a prospective randomized phase III study comparing the clinical benefit of IFN and BC in pts who had undergone lymphadenectomy within 56 days for melanoma metastatic to regional lymph nodes. Pts were randomized to receive BC (Cisplatin 20 mg/m 2 IV [d1–4]; Vinblastine 1.5 mg/m 2 IV [d1–4]; DTIC 800 mg/m 2 IV [d1]; IFN 5 MU/m 2 SQ [d1–5]; IL-2 9 MU/m 2 continuous IV infusion [d1–4] every 3 wks for 4 courses) or IFN, and those who were randomized to IFN were further randomized to either HDI (20 MU/m 2 IV for 5 d/week for 4 wks and 10 MU/m 2 SQ 3 times a wk for 48 wks) or intermediate-dose IFN (IDI) (10 MU/m 2 SQ 3 times a wk for 1 year). The primary end points were overall survival (OS) and relapse-free survival (RFS). Using 80% power and 5% significance level, 200 pts would be required to detect the difference in median RFS of 18 vs. 36 months and in OS of 40 vs. 80 months between IFN and BC groups. Results: An interim analysis was performed because of slow accrual. 138 pts were enrolled between 1995 and 2003, with 71, 33 and 33 in the BC, HDI and IDI group, respectively. There were no significant differences in both RFS and OS between HDI and IDI groups. With median follow up of 49.3 months, neither the BC or IFN had reached the median RFS and OS. Log-rank test was used to compare RFS (p=0.96) and OS (p=0.52) between 2 groups. RFS and OS data are presented below. Pts in the BC arm had more grade 3–4 fatigue, nausea, anorexia, capillary leak syndrome, diarrhea and myelosuppression. Conclusions: There were no significant differences in both OS and RFS between the BC and IFN groups. This interim analysis supports terminating this trial before achieving the specified target for patient accrual. Supported in part by Schering-Plough. [Table: see text] [Table: see text]
Patient-reported symptoms obtained through telephonic nursing services in an oncology disease management program.
Authors: Deb Harrison, Melissa Jameson, Janet L. Espirito, Robyn K. Harrell, Matthew Clayton, Mitra Abdullahpour, Jessica McQueen, J. Russell Hoverman
Journal: Journal of Clinical Oncology (2013)

147 Background: Telephonic nursing (RN) outreach was provided as part of an oncology disease management program to provide symptom (sx) management education, assess patient-reported sxs during treatment (tx), and reduce acute care utilization. The Edmonton Symptom Assessment Scale (ESAS) was used to assess sx severity in patients (pts) receiving active chemotherapy. Methods: ESAS scores were obtained at scheduled intervals and documented in the electronic health record for eligible pts receiving chemotherapy between 6/2010-12/2012. Participation was voluntary. Pts were categorized according to cancer diagnosis (dx) and tx setting (early vs. advanced). Repeated measures logistic regression analysis was used to test for differences in ESAS scores between dx and tx settings. Results: 365 pts had 2,198 calls with ESAS scores. Mean age was 53 yrs, 67% female, 33% male. Pts were managed an average of 97 days and received on avg 6 calls/pt. The majority of pts had breast, colon, and non-small cell lung (NSCL) cancer (74%). Of these pts, the most frequent reported sx of any severity other than zero during post-tx calls were for mild/moderate tiredness, appetite, and pain. There was no evidence of a significant difference in the severity of sxs by tx setting in these cohorts; p=NS. One hundred and nine breast, colon, and NSCL pts (40%) received additional unscheduled calls based on sx scores or RN assessment. Outcomes related to acute care utilization are being evaluated. Conclusions: Pt reported sxs obtained through telephonic RN support demonstrated mild/moderate ESAS scores for mainly tiredness, appetite, and pain. This is lower than previously reported in different contexts. Regular RN contact as a supplement to clinic visits may help reduce sx severity. While the ESAS tool is traditionally used for palliative care, in this active tx setting it supported identification of sxs for referrals back to the practice with the goal to reinforce education and avoid acute care utilization. [Table: see text]
Urinary Biomarkers of Brain Diseases
Authors: Manxia An, Youhe Gao
Journal: Genomics Proteomics & Bioinformatics (2015)

Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.
Phase II study of FOLFOX, bevacizumab and erlotinib as initial therapy for patients with metastatic colorectal cancer (MCRC)
Authors: J. A. Meyerhardt, K. Stuart, A. Zhu, C. Fuchs, P. Bhargava, C. Earle, L. Blaszkowsky, C. Lawrence, S. Battu, D. P. Ryan
Journal: Journal of Clinical Oncology (2006)

3545 Background: Cytotoxic chemotherapy with targeted therapy against the vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) has become a standard approach in MCRC, though combining VEGF and EGFR inhibition with chemotherapy as initial treatment is not well established. We conducted a phase II study of the combination of infusional 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX), bevacizumab, and erlotinib in chemotherapy naïve patients with MCRC. Methods: Eligible patients had measurable MCRC, no prior systemic therapy for MCRC or at least one year since completion of adjuvant therapy (only 5-FU and leucovorin acceptable), performance status 0–1. The regimen consisted of 14-day cycles of FOLFOX started on day 1 (oxaliplatin 85 mg/m 2 , bolus 5-FU 400 mg/m 2 , leucovorin 400 mg/m 2 and 46-hour infusion 5-FU 2.4 g/m 2 ), day 1 bevacizumab 5 mg/kg and erlotinib 150 mg daily. This isa single stage trial with goal of 35 patients. The primary endpoint was progression-free survival (PFS). Results: Between Jan and Dec 2005, 31 patients have been enrolled with the following characteristics: male/female, 19/12; PS ECOG 0/1, 15/16; median age 58, range 38–81. Of the 28 patients who completed at least 1 cycle, the most common grade 3/4 adverse events include: 8/28 (29%) diarrhea, 8/28 (29%) neutropenia, 5/28 (18%) rash, 4/28 (14%) fatigue, 3/28 (11%) nausea/vomiting, 3/28 (11%) neuropathy. 22/28 (78%) of patients had at least 1 grade 3/4 toxicity. 14/31 patients remain on trial, 13/31 (42%) came off for toxicity or withdrew consent due to treatment-related toxicities, 4 withdrew consent for other reasons. Efficacy data is not available at time of submission but will be more mature by June 2006. Conclusions: The combination of FOLFOX, bevacizumab and erlotinib appears to have moderate toxicity, with ∼40% of patients coming off trial due to side effects. Further characterization of the tolerability profile will be necessary when interpreting the efficacy of the combination. We expect full accrual as well as reasonable point estimates of PFS by June 2006. Supported by: Sanofi-Synthelabo, a member of the Sanofi-Aventis group, Genentech [Table: see text]
Clinical relevance of angiogenesis and lymphangiogenesis in patients with sex cord-stromal ovarian tumors
Authors: J. Brown, M. T. Deavers, A. M. Nick, L. Milojevic, D. M. Gershenson, A. K. Sood
Journal: Journal of Clinical Oncology (2009)

5575 Background: Distant metastasis is common in patients with sex cord-stromal ovarian tumors (SCSTs), but lymph node involvement is extremely rare. Given the lack of lymphatics in the normal granulosa layer, we examined the clinical relevance of angiogenesis and lymphangiogenesis in patients with SCSTs. Methods: After Institutional Review Board approval, 80 tumor samples (46 primary, 34 recurrent) were obtained from 65 patients and stained for CD31 (microvessel density; MVD), D2–40 (lymphvascular density; LVD), and VEGF. Clinical data were extracted by chart review and correlated with the angiogenesis and lymphatic markers. Results: The median age of the patients was 42.1 years (range, 8.6–78.6 years). At presentation, 53% of patients had stage I disease, 8% had stage II, 16% had stage III, and 23% were unstaged. Although VEGF expression was noted at some level in 99% of samples, VEGF overexpression (upper tertile of overall score) was noted in 35% of samples. On the basis of ROC analysis, vessel density was stratified into high versus low at a mean MVD cutoff of 12.3. High MVD was present in 41% of all tumors. High MVD was significantly associated with shorter disease-specific survival (mean 16.7 versus 32.3 months; p = 0.024), increased risk of recurrence (p &lt; 0.04), and shorter overall survival (median 108.6 versus 388.5 months; p &lt; 0.001). High MVD was strongly related to VEGF overexpression (p = 0.009). While VEGF expression was not related to the pattern of recurrence, high MVD was strongly associated with distant metastasis (abdomen, liver, lung, bone) compared with local recurrence (p &lt; 0.001). Lymph node metastasis was clinically evident in only 3 of the 65 patients. Most tumors had either absent or low LVD. Interestingly, all 3 tumors with nodal metastasis had significantly greater LVD (LVD = 35.8 vessels/hpf) compared to those without nodal metastasis (LVD = 2.7 vessels/hpf; p &lt; 0.001). Conclusions: Increased angiogenesis is a significant predictor of poor clinical outcome in patients with sex-cord stromal tumors. Most of these tumors have poor lymphatic development that might explain the low likelihood of nodal metastasis. These data provide support for further investigation of antiangiogenic biological agents in these patients. No significant financial relationships to disclose.
PPARγ ligands increase antileukemic activity of second- and third-generation tyrosine kinase inhibitors in chronic myeloid leukemia cells
Authors: E Glodkowska-Mrowka, A Manda-Handzlik, A Stelmaszczyk-Emmel, I Seferynska, T Stoklosa, J Przybylski, P Mrowka
Journal: Blood Cancer Journal (2016)

PPARγ ligands increase antileukemic activity of second- and third-generation tyrosine kinase inhibitors in chronic myeloid leukemia cells
Day-and-Night Hybrid Closed-Loop Insulin Delivery in Adolescents With Type 1 Diabetes: A Free-Living, Randomized Clinical Trial
Authors: Martin Tauschmann, Janet M. Allen, Malgorzata E. Wilinska, Hood Thabit, Zoë Stewart, Peiyao Cheng, Craig Kollman, Carlo L. Acerini, David B. Dunger, Roman Hovorka
Journal: Diabetes Care (2015)

OBJECTIVE To evaluate feasibility, safety, and efficacy of day-and-night hybrid closed-loop insulin delivery in adolescents with type 1 diabetes under free-living conditions without remote monitoring or supervision. RESEARCH DESIGN AND METHODS In an open-label, randomized, free-living, crossover study design, 12 adolescents receiving insulin pump therapy (mean [±SD] age 15.4 ± 2.6 years; HbA1c 8.3 ± 0.9%; duration of diabetes 8.2 ± 3.4 years) underwent two 7-day periods of sensor-augmented insulin pump therapy or hybrid closed-loop insulin delivery without supervision or remote monitoring. During the closed-loop insulin delivery, a model predictive algorithm automatically directed insulin delivery between meals and overnight; prandial boluses were administered by participants using a bolus calculator. RESULTS The proportion of time when the sensor glucose level was in the target range (3.9–10 mmol/L) was increased during closed-loop insulin delivery compared with sensor-augmented pump therapy (72 vs. 53%, P &amp;lt; 0.001; primary end point), the mean glucose concentration was lowered (8.7 vs. 10.1 mmol/L, P = 0.028), and the time spent above the target level was reduced (P = 0.005) without changing the total daily insulin amount (P = 0.55). The time spent in the hypoglycemic range was low and comparable between interventions. CONCLUSIONS Unsupervised day-and-night hybrid closed-loop insulin delivery at home is feasible and safe in young people with type 1 diabetes. Compared with sensor-augmented insulin pump therapy, closed-loop insulin delivery may improve glucose control without increasing the risk of hypoglycemia in adolescents with suboptimally controlled type 1 diabetes.
Agreement in Metastatic Spinal Cord Compression
Authors: Estanislao Arana, Francisco M. Kovacs, Ana Royuela, Beatriz Asenjo, Úrsula Pérez-Ramírez, Javier Zamora
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: Metastatic epidural spinal cord compression (ESCC) is a devastating medical emergency. The purpose of this study was to determine the reliability of the 6-point ESCC scoring system and the identification of the spinal level presenting ESCC. Methods: Clinical data and imaging from 90 patients with biopsy-proven spinal metastases were provided to 83 specialists from 44 hospitals. The spinal levels presenting metastases and the ESCC scores for each case were calculated twice by each clinician, with a minimum of 6 weeks' interval. Clinicians were blinded to assessments made by other specialists and their own previous assessment. Fleiss kappa (κ) statistic was used to assess intraobserver and interobserver agreement. Subgroup analyses were performed according to clinicians' specialty (medical oncology, neurosurgery, radiology, orthopedic surgery, and radiation oncology), years of experience, and type of hospital. Results: Intraobserver and interobserver agreement on the location of ESCC was substantial (κ>0.61). Intraobserver agreement on the ESCC score was "excellent" (κ=0.82), whereas interobserver agreement was substantial (κ=0.64). Overall agreement with the tumor board classification was substantial (κ=0.71). Results were similar across specialties, years of experience and hospital category. Conclusions: The ESCC score can help improve communication among clinicians involved in oncology care.
Abstract 12898: Oxidative Stress and Rho-Associated Coiled-Coil Protein Kinase (ROCK)-Mediated Double Phosphorylation of Myosin Light Chain in the Submembranous Region Plays a Key Role in Thrombin-Induced Barrier Dysfunction in Vascular Endothelial Cells
Authors: Mayumi Hirano, Akiko Hanada, Katsuya Hirano
Journal: Circulation (2012)

Endothelial barrier dysfunction plays a fundamental role in the pathogenesis of various vascular diseases such as atherosclerosis. The phosphorylation of the myosin light chain (MLC) is thought to ...
Surgery of residual disease of myxoid liposarcoma (MLS) patients responding to trabectedin.
Authors: R. Sanfilippo, F. Grosso, M. D'Incalci, P. Dileo, S. Pilotti, C. Morosi, M. Fiore, J. C. Tercero, A. Gronchi, P. G. Casali
Journal: Journal of Clinical Oncology (2010)

10056 Background: Our single-institution series, now including 53 metastatic MLS patients (pts) treated with trabectedin (T), was reviewed focusing on the use of surgery of residual disease. Methods: Since September 2002, 53 pts with metastatic pretreated MLS received T. Median age at T start was 48 yrs (range 27-77). T was given as a 24-hr continuous infusion every 21 days, at a dose between 1.0 to 1.5 mg/sqm. Results: 578 courses were delivered (median = 10/pt). RECIST response rate was 50%, the median TTP was 15 months (90% CI = 9-18) and OS was 48 months. Eighteen pts stopped T on their best response (2 CR, 10 PR, 6 MR/SD): 10 remained in follow-up after a median of 11 courses and 8 underwent surgery of residual disease after a median of 12 courses. The decision whether to do surgery was based on resectability and extent of metastatic disease. Surgery was complete in all cases. Median TTP from treatment start was 30 and 25 months, respectively, in surgically and non-surgically treated pts. TTP was 14 months from treatment end in both groups. At a median follow-up of 29 months from treatment end, 13 pts relapsed (7 and 6 in the two subgroups). Twelve of these pts were rechallenged with T, obtaining 2 CR, 5 PR and 5 SD (median PFS = 14 months). Conclusions: T provides prolonged tumor control in MLS. Surgery of residual disease in responding pts is an option. However, in this small series it did not seem to provide any major advantage, in the face of a selection bias favouring in principle operated pts. T rechallenge at progression in pts who stopped their treatment on best response was associated with significant further tumor control. Prospective studies to define optimal management of MLS pts responding to T are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PharmaMar PharmaMar PharmaMar PharmaMar PharmaMar PharmaMar
A phase II trial of oblimersen sodium (G3139) in combination with doxorubicin (DOX) in advanced hepatocellular carcinoma (HCC). NCI protocol # 5798
Authors: J. J. Knox, E. Chen, R. Feld, M. Nematollahi, G. R. Pond, R. Cheiken, S. Gill, J. Zwiebel, M. Moore
Journal: Journal of Clinical Oncology (2006)

14072 Background: Advanced HCC is refractory to most standard forms of chemotherapy, however responses to DOX are seen. The bcl-2 protein confers resistance to apoptosis in cancer cells and is important in tumor progression and resistance to chemotherapy. The bcl-2 antisense oligonucleotide, G3139 (G), has been shown to enhance the activity of DOX in tumor models by blocking bcl-2 synthesis. This argues for evaluating G + DOX in combination in HCC. By decreasing tumor bcl-2 protein levels, HCC may be sensitized to the apoptotic effects of DOX. Methods: We completed a phase II trial evaluating treatment with G at 7 mg/ kg for 7 days cont. i.v. infusion (d1–8) plus DOX at 45 mg/m 2 i.v. bolus d5, every 28 d (as determined from our phase I HCC study). Eligible patients (pts) had path-confirmed, measurable, advanced HCC. Minimal eligibility included Childs-Pugh A cirrhosis, adequate hematological (hem) parameters and ECOG PS &lt;2. Tumor biopsies for correlative studies were obtained at baseline and cycle 1 d 4 in consenting pts. Results: 19 patients were accrued, 1 was ineligible, 18 evaluable for toxicity, 17 evaluable for response; receiving a median (med) of 2 cycles (range 1,10). Risk for HCC was 39% HBV, 22% HCV, 17% alcohol, 22% other. Most common toxicities were hem and could be attributed to both G+DOX and to G alone. Overall grade 3–4 toxicities seen were: ANC- 67% (med nadir d 24–25), lymphopenia - 44%, thrombocytopenia - 6%, transaminitis - 33% and grade 1–2 G-fever - 67%. No responses were seen and the trial was stopped at stage 1. Six patients (35%) had stable disease, with one pt completing 10 cycles as per protocol (pt # 22). Med TTP is 1.8 months (1.7-NA) and 6-month PFS is 17.2% (5.3–56.4). 18 of 19 pts have died with med OS of only 5.4 months (2.7–11.6). Correlative studies on 3 available pts’ paired tumor biopsies showed absent baseline bcl-2 expression but moderate expression of both bcl-xl and BAX protein and with no change after exposure to G (includes pt #22). Conclusions: G + DOX is inactive in HCC at this dose and schedule. The overlap of hem toxicity may have resulted in suboptimal DOX dosing in HCC. Low baseline bcl-2 tumor expression relative to bcl-xl seen may suggest a relative insensitivity to the effects of bcl-2 inhibition in these HCC tumors. [Table: see text]