tbuckley/cabot-search huggingface dataset:
Circulating tumor cells (CTCs) and association with survival in molecular subtypes (MST) of metastatic breast cancer (MBC).
Authors: M. Graham, N. Fleming, A. Pinto, E. Dropkin
Journal: Journal of Clinical Oncology (2010)

1094 Background: An elevated CTC ≥ 5 predicts worse outcome in MBC patients (pts). We have measured CTCs in all MBC pts in our community practice to determine if recognized MSTs (ER+, HER2 (H2)-; triple-negative [TN]; H2+) of MBC have different patterns of CTC behavior. Methods: CTCs were measured by the CellSearch technology (Veridex , LLC; Warren, NJ), in all pts (111) whether beginning a new therapy with first metastatic recurrence (54), or already under way with treatment (57; 35 of whom later progressed; 22 have not). Pts had CTCs measured from 11/20/06 through 12/31/09, a 37 mo. period. Pts with elevated CTCs were treated with chemotherapy, and when CTCs improved to < 5 for a sustained 3-4 mo. period, we sought less morbid therapies: hormonal if ER+, or single-agent chemotherapy, ± biologics if ER- or hormone refractory. Results: 1,141 tests for CTCs were done in 111 pts; ave. 10.3 tests per pt; range 1-28. The median time of f/u: 20.7 mo. (range 1-35 mo). The distribution of the 111 pts' highest measured CTC over time for the 3 MSTs and the frequency of pts. measuring <5, 5-99, or ≥ 100 CTCs, and the associated death rates for each MST and CTC level are shown in the Table. Each MST has 1/3 or more of pts with low CTCs (0-4) at any time (ER+, H2- 39%; TN 56%; H2+ 47%), even with sustained f/u. Similarly, each MST has a distinct smaller group with very high CTCs ≥ 100, 19% of all the pts (21 of 111). 39% of all deaths (11 of 28) occurred in the 19% of pts with ≥ 100 CTCs; 52% of pts with ≥ 100 CTCs died in the observation period. These are early deaths once pts. develop ≥ 100 CTCs. In contrast only 4 pts (8%) died in the 49 pts with CTCs < 5. (p < 0.01). Conclusions: 1) Each MST of MBC has 1/3 or more of pts with sustained low levels of CTCs, which predict long OS. 2) Very high levels of CTCs ≥ 100 are an oncologic emergency. 3) CTCs should be considered as a stratification factor for phase II/III clinical trials. Distribution of pts and deaths by highest CTC in MSTs of MBC MST/highest CTC < 5 5-99 ≥ 100 ER+, H2- (13/60; 22%) 2/24 (8%) 6/26 (23%) 5/10 (50%) TN (7/16; 44%) 1/9 (11%) 3/3 (100%) 3/4 (75%) H2+ (8/35; 23%) 1/16 (6%) 4/12 (33%) 3/7 (43%) Br Ca deaths (28/111; 25%) 4/49 (8%) 13/41 (32%) 11/21 (52%) Test for trends, association of death rate with CTC level, p < 0.01 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Veridex
ST3GAL1-Associated Transcriptomic Program in Glioblastoma Tumor Growth, Invasion, and Prognosis
Authors: Yuk Kien Chong, Edwin Sandanaraj, Lynnette W. H. Koh, Moogaambikai Thangaveloo, Melanie S. Y. Tan, Geraldene R. H. Koh, Tan Boon Toh, Grace G. Y. Lim, Joanna D. Holbrook, Oi Lian Kon, Mahendran Nadarajah, Ivan Ng, Wai Hoe Ng, Nguan Soon Tan, Kah Leong Lim, Carol Tang, Beng Ti Ang
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:Cell surface sialylation is associated with tumor cell invasiveness in many cancers. Glioblastoma is the most malignant primary brain tumor and is highly infiltrative. ST3GAL1 sialyltransferase gene is amplified in a subclass of glioblastomas, and its role in tumor cell self-renewal remains unexplored.
Clinical proof-of-concept with JX-594, a novel targeted multi-mechanistic oncolytic poxvirus, in patients with refractory liver tumors
Authors: T. Liu, B. Park, T. Hwang, H. Kwon, S. Oh, S. Han, A. Moon, K. Speth, H. M. Pinedo, J. Bell, D. H. Kirn
Journal: Journal of Clinical Oncology (2008)

3573 Background: JX-594 is a first-in-class targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and EGFR/ ras pathway activation. Direct oncolysis plus GM-CSF expression also stimulates tumor vascular shutdown and anti-tumoral immunity. Methods: A Phase I-II dose-escalation trial was carried out with JX-594 administered by intratumoral injection every three weeks in patients with end-stage refractory primary or metastatic tumors within the liver. Standard dose- escalation guidelines were used. Data was collected on safety, efficacy, pharmacokinetics and pharmacodynamics. Results: Fourteen patients were enrolled in four dose cohorts, including hepatocellular (HCC), colorectal, melanoma and lung cancers. Patients were heavily pretreated and had large tumors (median 6 cm.). The mean number of JX-594 treatments was 3.5 (range 1–8). All patients experienced mild to moderate flu-like symptoms and transient dose-related thrombocytopenia. Grade III hyperbilirubinemia was dose-limiting at the highest dose level. JX-594 replication-dependent mechanism-of-action was demonstrated, including dissemination in blood and resultant infection of distant tumor sites, plus GM-CSF expression resulting in significant increases in neutrophil counts. Ten patients were radiographically evaluable. Objective responses of the JX-594-treated tumors were demonstrated by RECIST (30%) and by Choi (80%) criteria; only one patient had progressive disease. PET-CT and serum tumor marker responses were also demonstrated. Non-injected tumors were present in 7 patients, and 6 had responses or stable disease. Conclusions: Intratumoral JX-594 treatment resulted in high level replication, GM-CSF expression, systemic dissemination and reproducible efficacy against a spectrum of refractory carcinomas. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Jennerex Biotherapeutics, Inc Jennerex Biotherapeutics, Inc Jennerex Biotherapeutics, Inc Jennerex Biotherapeutics, Inc
Prognostic factors for progression-free survival (PFS) in CLARINET study of lanreotide depot/autogel (LAN) vs placebo (PBO) in neuroendocrine tumors (NETs).
Authors: Edward M. Wolin, Martyn E. Caplin, Marianne E. Pavel, Jaroslaw B Cwikla, Alexandria T. Phan, Markus Raderer, Eva Sedlackova, Guillaume Cadiot, Jaume Capdevila, Lucy Wall, Guido Rindi, Alison Langley, Edda Gomez-Panzani, Philippe B. Ruszniewski
Journal: Journal of Clinical Oncology (2015)

e15180 Background: CLARINET showed LAN 120 mg significantly increased PFS vs PBO (hazard ratio [HR] for progressive disease [PD]/death 0.47 [95% CI: 0.30, 0.73]) in metastatic intestinal and pancreatic NETs. This was a preplanned exploratory covariate analysis to identify prognostic factors for PFS. Methods: Patients with metastatic grade 1/2 nonfunctioning intestinal/pancreatic NETs received LAN 120 mg (n=101) or PBO (n=103) for 96 wks or until PD/death (NCT00353496). Baseline covariates (as listed in table) were tested with treatment and baseline stratification factors (PD yes/no; prior therapy [PT] yes/no) in separate Cox proportional hazards (PH) models. Factors potentially significant in univariate analysis were included in stepwise multivariate (MV) analysis to obtain a final model. Treatment interaction was investigated. Results: In the final model (Table), risk of PD/death was increased in patients with: hepatic tumor load (HTL) >25%; primary tumor type of pancreas; and below-median BMI. No covariate-by-treatment interaction was significant. Adjusted for covariates, treatment with LAN vs PBO reduced the risk of PD/death by 60% (Table). Conclusions: LAN is effective across patient characteristics; risk of PD/death was lower with no PD at baseline. Exploratory analysis of other covariates identified HTL and primary tumor type as the most important prognostic factors for PFS. Effect of PT was not significant. Clinical trial information: NCT00353496. Term (reference) HR [95% CI)* P value* LAN (PBO) 0.40 [0.25, 0.63] < 0.0001 PD (no PD) 4.57 [1.67, 12.54] 0.0032 PT (no PT) 1.29 [0.72, 2.31] 0.3914 HTL, %(0): 0.0005 >0, ≤10 0.81 [0.42, 1.59] >10, ≤25 1.22 [0.59, 2.52] >25, ≤50 2.82 [1.41, 5.63] >50 2.47 [1.21, 5.03] Primary tumor type (pancreas): 0.0289 Mid gut 0.80 [0.33, 1.94] Hind gut 0.53 [0.32, 0.88] Other / unknown 0.39 [0.17, 0.86] BMI >median# (≤median) 0.64 [0.41, 1.00] 0.0483 Other baseline terms (sex, age, race, US/ex-US, region, time since diagnosis, Ki67, tumor grade, CgA, prior chemotherapy, prior surgery) had no prognostic value (p>0.1) either in individual models or in presence of other terms in final model.*From final MV Cox PH model; #26.2 kg/m2; intent-to-treat population.
Invasive ductal carcinoma (IDC), triple negative (TN) and inflammatory breast cancer (IBC): A Brazilian single institution experience
Authors: S. O. Ramalho, O. Martucci, G. Redi, A. Garcia, J. Oliveira
Journal: Journal of Clinical Oncology (2008)

11548 Background: Breast cancer is the most prevalent solid tumor in our practice, a community-based oncological center in Campinas, SP, Brazil. Our goal was to determine the overall survival (OS) and disease-free survival (DFS) of three subgroups: the ICD, the triple negative (ER negative, PR negative and HER-2 negative) and the IBC. Methods: We retrieved from our database 415 breast cancer patients treated from 1988 to 2006. A total of 318 IDC, 37 TN and 16 IBC cases were reviewed. The log-rank test and Kaplan-Meier analyses were performed. Results: In the IDC subgroup, results of DFS and OS confirmed data from literature and DFS regarding to estrogen receptor and linfonodal status were statistically significant. In 1998 an important improvement was observed in the DFS in the IDC group after the insertion of paclitaxel in the adjuvant chemotherapy regimens at our institution. OS before 1998 was 52% and after 1998 was 74% (p= NS) while DFS was 43% and 70%, respectively (p= 0.01). It was also found that tumor size at the time of the diagnosis had an important decrease after 1998 (p=0.031) probably due to early referral. Triple negative cancer patients had a ten-year follow-up with OS and DFS of 46% and 30%, respectively. There were more relapses after 4 years from the diagnosis. The IBC group had 16% OS in four years, as expected. Conclusions: Changes in adjuvant chemotherapy for breast cancer after 1998 with the insertion of taxanes and decreasing tumor size, especially for IDC, had a deep impact in the OS and DFS. IBC remains the most aggressive histologic type and more effort is needed to improve the systemic control. As for the TN subgroup, it certainly requires the development of more specific therapies to avoid late relapses. No significant financial relationships to disclose.
A phase I, dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930, an oral tyrosine kinase inhibitor (TKI), in patients (pts) with advanced solid tumors
Authors: R. Lal, D. R. Camidge, S. George, G. D. Demetri, S. G. Eckhardt, A. Stephens, J. Chick, R. Boinpally, S. B. Kaye, M. Scurr
Journal: Journal of Clinical Oncology (2008)

3553 Background: OSI-930 is a potent TKI with nanomolar activity against Kit, KDR and PDGFR. Regression and long-term remissions were seen in a broad range of xenograft models. Methods: A phase I study was performed to determine the maximum tolerated dose (MTD) and evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930. Accelerated DE of 100% dose increases in single pt cohorts until grade 2 toxicity was followed by a standard 3+3 design with 50% increments until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. Plasma concentrations of OSI-930 were determined using a validated HPLC-MS/MS method. Phosphorylation status of key signalling pathways and functional imaging was planned during the expansion phase. Results: To date, 27 pts have been treated (10M/17F) with median age 57 years (range 19–83). All pts had ECOG performance status ≤2. OSI-930 was administered at 7 QD and 2 BID dose levels [mg(# pts treated)]; QD- 50(1), 100(1), 200(2), 400(2), 800(2), 1200(1) and 1600(3); BID- 400(7) and 600(8). Median duration of therapy is 46+ days (d) (range 2–455+d). DLT’s in 3/8 pts at 600 mg BID were G3 rash (2 pts) and G4 GGT (3rd pt) that improved after stopping OSI-930. The 2 pts with rash resumed at 400mg BID w/o recurrent toxicity. Common G1/2 toxicities (per pt) were limited to fatigue (7), diarrhea (5), nausea (5), and rash, lymphopenia and anorexia (2). No hypertension has been noted to date. Disease control rate (PR+SD≥12 weeks) is 58% with 1 PR in platinum-resistant ovarian ca (262+d) and 13 SD, including prolonged SD in GIST resistant to other TKIs (248+d) and sarcoma (455+d). MTD was not reached on the QD schedule as quantity of capsules prohibited further DE. Preliminary PK after 22d dosing at 50–1600mg QD suggests Css reached in 15–22d. Data from 400 and 600mg BID indicate Css reached in 8d, median Cmin of 0.95 & 2.83 μM, and AUC(0-last) from 5.31 to 16.9 μg.hr/ml, respectively. Conclusions: OSI-930 is well tolerated with promising antitumor activity in previously treated pts. Exposure from preclinical efficacy models is achievable and 500mg BID is being explored as potential MTD with PD analyses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Oncology Amgen, Bayer, Infinity, Novartis, OSI Oncology, Pfizer Oncology OSI Oncology Novartis, Pfizer Oncology OSI Oncology Infinity, Novartis, Pfizer Oncology
Prognostic factors in advanced ovarian carcinoma.
Authors: J R Redman, G R Petroni, P E Saigo, N L Geller, T B Hakes
Journal: Journal of Clinical Oncology (1986)

Nineteen factors were analyzed for prognostic significance in a series of 89 women with advanced (stage III or IV) ovarian carcinoma treated with chemotherapy after initial debulking surgery. Seventy-eight of these women received cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and cisplatin (CAP) treatment, and 11 received cyclophosphamide initially with Adriamycin and cisplatin administered at the time of recurrence. Median survival and remission duration were 25 and 19 months, respectively. Using survival as an end point, significant prognostic factors in univariate analyses included the total residual mass after debulking (P = .0007), largest residual mass after debulking (P = .0008), and stage (P = .0098). Using remission duration as an end point, significant prognostic factors in univariate analyses included total residual mass after debulking (P = .007) and the largest residual mass after debulking (P = .0020). The prognostic variables were then considered as possible predictors of survival in a multivariate analysis using the Cox proportional hazards model resulting in the following expression: lambda i(t)/lambda o(t) = exp(0.5928 (log TRM - 1.8117) + 0.6450 (stage - 0.3827) + 0.6673 (C4 - 0.4198) - 0.8596 (CAP - 0.8642)), where lambda i(t)/lambda o(t) is the risk of dying for a particular patient compared with the average risk of the entire group; log TRM is the log of the volume of the total residual mass in cm3 plus 1.0; stage = 0 if stage III, 1 if stage IV; C4 = 0 if cytologic grade is 1, 2, or 3 and 1 if grade 4; CAP = 0 if treatment is cyclophosphamide and 1 if CAP. Median survival times of patients with relative risk greater than 1 and less than 1 are 43 and 19 months respectively. If this model is confirmed in a prospective study, then it could be used to assign risk and assess treatment options for similar patients at diagnosis.
Phenoxodiol, a synthetic analog of genistein, generates ceramide and is equipotent in wild-type and multidrug-resistant human tumor cells
Authors: M. C. Cabot, J. Y. Yu, G. E. Kelly, D. M. Brown, K. M. Lucas, K. Tanabe, J. D. Allen
Journal: Journal of Clinical Oncology (2005)

2075 Background: Multidrug resistance (MDR) continues to undermine the success of chemotherapy against cancer. Phenoxodiol (PXD, 2H-1-benzopyran-7–0,1,3-[4-hydroxylphenyl]) is a flavonoid derivative that inhibits growth of ovarian, prostate, breast, leukemia, and other human tumor cell lines. We evaluated the potency of PXD in MDR tumor cell lines and their wild-type isogenic variants. We hypothesized that its cytotoxic effect might be linked to increased intracellular production of ceramide, an agonist of apoptosis, and that its efficacy might be independent of MDR status. Methods: Three sets of wild-type and MDR cells were evaluated: KB-3–1 and KB-V1 head/neck epidermoid cancer; MCF-7 and MCF-7-AdrR breast cancer; and SKOV-3 and SKOVBL1.0 ovarian cancer. Cells were seeded into 96-well plates. After 24 hours, PXD was added and cells were incubated for 5 days. Cell viability was determined by colorimetric assay, and the PDX concentration causing 50% cell kill (EC50) was determined. Separate experiments examined the effects of PXD on accumulation of paclitaxel in a paclitaxel-resistant human ovarian cancer line (Igrov/P200) and an MDR1-transfected mouse fibroblast line (77.1/MDR1); both are rich in P-glycoprotein. Ceramide and paclitaxel levels were measured by radiotracer assay. Results: EC50 values of wild-type and MDR isogenic variants were 2.3 and 2.2 μM in head/neck lines, 2.4 and 3.0 μM in breast cancer lines, and 10.8 and 2.7 μM in ovarian lines, respectively. In Igrov/P200 and 77.1/MDR1 cells, PXD concentrations as high as 64 μM had no influence on taxane accumulation. A 24-hour exposure to 4.6 μM of PXD increased ceramide by 2.3-fold in KB-3–1 cells and by similar levels in other cell lines. Conclusions: PXD, which was developed to be more stable than its chemical cousin genistein, does not interfere with taxane uptake and shows high potency in MDR cancer cells. Increased production of intracellular ceramide indicates that PXD induces death-signaling complexes associated with sphingolipid metabolism. The cytotoxicity of PXD in highly drug-resistant tumor cells suggests its clinical utility in patients with advanced, chemorefractory cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novogen
The role of acculturation in end-of-life outcomes for Latino advanced cancer patients.
Authors: E. T. Loggers, E. Soto, S. Desanto-Madeya, A. A. Wright, H. Stieglitz, M. E. Paulk, H. G. Prigerson
Journal: Journal of Clinical Oncology (2010)

6117 Background: The role of acculturation (AC) in the end-of-life (EOL) outcomes of Latino cancer patients is unknown. Methods: Fifty-eight self-reported Latino, Stage IV cancer patients and their caregivers participated in a U.S. multisite, prospective cohort study from September 2002-August 2008. Adapted from Cuellar's work, AC score (ACS) was measured using Brief AC Scale (5, 5-point items) for patients and United States Acculturation Scale (19, 5-point items, USAS) for caregivers. All participants were interviewed at baseline; caregiver post-mortem interviews provided location and quality of death. Results: Sixty-nine percent of patients were born outside the U.S. (predominantly Mexico), with the majority (89.7%) recruited from Texas. Mean ACS score was 10.2 (SD 6.7, range 5-25); mean USAS score was 44.0 (SD 20.4, range 21-80). The insured (ACS mean [SD]: 9.4 [6.3] vs. 14.2 [7.3], p = 0.04), those with no religious affiliation (F = 5.1, p = 0.01), and patients and caregivers with higher educational attainment (ACS r = 0.40, p = 0.002; USAS r = 0.44, p = 0.001) were more highly acculturated. ACS did not vary by baseline patient health/demographics, therapeutic alliance, EOL care preferences or discussions. More acculturated patients were more likely to die at home or in a hospice facility after controlling for confounders (OR 1.3, p = 0.005). Less acculturated caregivers were more likely to rate the quality of death positively (0.04, p = 0.05), however this was attenuated after controlling for location of death (0.02, p = 0.35). Conclusions: This study suggests level of acculturation may influence the location of death of Latino advanced cancer patients, but not EOL preferences or caregiver perception of death quality. No significant financial relationships to disclose.
Specific inhalation challenges to metal working fluids
Authors: Vicky Moore, Alastair Robertson, Sherwood Burge
Journal: European Respiratory Journal (2012)

Metal working fluid (MWF) is a recognised cause of occupational asthma and is becoming increasingly prevalent. In Birmingham, UK there are a large number of industries using metal working fluid to machine automotive and aircraft parts. The oil in water emulsion can be used at varying ratios generally ranging from 3% oil in water up to 10%.  Methods: 20 workers underwent specific inhalation challenge (SIC) tests to metal working fluid. Challenges were set up to mimic occupational exposures using indirect (into the room) and direct (into breathing zone) methods of nebulisation of new and used MWF. Exposures lasted from 5 minutes up to 70 minutes in total (spread over 3 exposures). Workers were also exposed to metal contaminants of the MWF by nebulisation of cobalt chloride (cobalt exposure can be from carbide tips used for machining) and potassium dichromate (chrome exposure can be from the machining of stainless steel).  Results: Overall, 15 workers had positive SIC tests to either MWF or metal contaminants (cobalt/chrome). The Venn diagram in Figure 1 shows the results. 8 workers had a ≥2 fold change in methacholine reactivity between pre and post challenge.  Conclusion: Specific inhalation challenge tests to MWF did not produce non-specific reactions. Contaminants of the MWF can be the cause of occupational asthma even with a negative challenge to used MWF.
Clinical profile and treatment of elderly patients hospitalized for acute exacerbation of asthma . A comparative study
Authors: Jihen Ben Amar, Bouthaina Ben Safta, Dhahri Besma, Baccar Mohamed Ali, Azzabi Saloua, Aouina Hichem, Bouacha Hend
Journal: European Respiratory Journal (2014)

Introduction:The heterogeneity of clinical and functional presentation of geriatric asthma, including the partial loss of reversibility and of the allergic component, contributes to her misconception.

Aim:The present study was designed to describe the clinical profile of acute exacerbation of asthma in elderly patients and the treatment prescribed in a pulmonary service, compared with the younger age group and to examine if the advanced age increases the frequency,and severity of asthma.

Methods:A total of 97 patients were recruited and divided in two groups; 41≥ 60 years (G1) and 56 <60 years (G2). We compared the differences between the 2 groups and the rest regarding comorbidity, severity of asthma, previous admissions, length of stay and treatment prescribed.

Results:The mean age in G1 was 67, 5 years, 60% of patients were female versus mean age in G2 40,31 years, 56% of patients were female.

The elderly patients had more comorbidity (P =0.02) with greater presence of cardiac antecedent. G2 had more history of severe acute asthma.Symptoms were dominated by attacks of breathlessness, wheezing and spasmodic dry cough in both groups, and length of stay were most important in G1 (P<0,005).

The mean exacerbation of asthma frequency was 2 in G1 versus 3 in G2. Mean duration of each exacerbation was 11 days in G1 versus 5,3 days G2. Pneumonia was the most frequent etiology of exacerbation in G1 while in G2 there was therapeutic malobservance.

Conclusion:The frequent coexistence of comorbid conditions in older patients compared to younger asthmatics, together with age-associated changes of the human lung, may render the management of asthma a complicated task.