tbuckley/cabot-search huggingface dataset:
Association of high Gli1 expression with poor survival in head and neck cancer patients treated with radiation therapy (RTOG 9003).
Authors: C. H. Chung, J. Dignam, M. E. Hammond, A. M. Magliocco, R. Jordan, A. Trotti, S. Spencer, J. S. Cooper, Q. Le, K. Ang
Journal: Journal of Clinical Oncology (2010)

5552 Background: Epithelial-to-mesenchymal transition (EMT) in patients with head and cancer (HNC) has been associated with high risk of recurrence and poor survival. To identify a clinically applicable biomarker of EMT, we examined the expression levels of E-cadherin (E-cad), beta-catenin (B-cat), and glioma-associated oncogene homolog 1 (Gli1). They were also examined in context of epidermal growth factor receptor (EGFR) expression. Methods: Cytoplasmic E-cad, nuclear B-cat, and nuclear Gli1 were determined in tumors from patients enrolled in RTOG 9003 (radiation fractionation trial) using automated quantitative analysis. The results were also correlated with previously determined EGFR expression. The expression levels were evaluated in relation to 3 endpoints: time to metastasis (TTM), time to disease progression (TDP), and overall survival (OS). Results: Among 1,068 eligible patients, E-cad, B-cat, Gli1, and EGFR data were available in 326, 236, 339, and 300 patients, respectively. Expression of pairs of E-cad, B-cat, and Gli1 were significantly correlated, but not with expression of EGFR. While E-cad and B-cat expression did not differentiate prognosis, Gli1 was associated with poorer outcomes, adjusted for age, T and N stages, and Karnofsky performance status, and the significant influence persisted in a multivariable analysis. Conclusions: These data suggest that Gli1 may play an important role in HNSCC prognosis, especially in TTM, but its role in EMT process needs further investigation. In addition, risk classification based on this analysis is exploratory and independent validation on other cohorts is necessary. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from the NCI. This abstract's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI. Univariate analysis: HR (95% CI) TTM TDP OS Gli1 (Q4 vs. Q1) 2.7 (1.5-4.9) 1.6 (1.1-2.5) 1.9 (1.4-2.7) Multiple marker models: HR (95% CI) Gli1 (Q4 vs. Q1-3) without EGFR: N=320 2.4 (1.5-3.9) 1.5 (1.0-2.1) 1.4 (1.0-1.8) Gli1 (Q4 vs. Q1-3) with EGFR: N=149 2.9 (1.4-6.1) 1.7 (1.0-2.9) 1.5 (1.0-2.2) EGFR (Q3-4 vs. Q1-2): N=149 1.8 (0.9-3.8) 2.2 (1.3-3.7) 1.7 (1.2-2.5) No significant financial relationships to disclose.
Trends of clinical staging for cancer patients at primary presentation: Have we improved over time?
Authors: Sanjay S. Reddy, Elizabeth Handorf, Marc C. Smaldone, John A. Ridge, Jeffrey M. Farma, Elin R. Sigurdson
Journal: Journal of Clinical Oncology (2015)

737 Background: The efficacy of non-surgical and of neoadjuvant therapy for cancer cannot be determined without appropriate clinical staging. The absence of staging data has been a persistent problem. Methods: Using the National Cancer Database from 1998-2011 we reviewed patients diagnosed with cancers of three disease sites, head and neck (HNC), rectal (RC), and bladder (BC). Rates of clinical staging were assessed by institution type, either community (COM) or academic (ACA). Patients treated with surgery alone were excluded from analysis. Results: 166,670 patients with HNC, 125,699 patients with RC, and 15,433 patients with BC were identified. Prior to induction therapy, 91% and 92% of HNC patients were clinically staged in COM versus ACA, and 73% and 78% of RC patients, respectively (p&lt;0.0001). BC patients were clinically staged 79% of the time in both institutions (p=0.43). Among HNC patients, clinical staging was assigned to 90% in 1998, which increased to 94% in 2011 (p&lt;0.0001). For RC, clinical staging rates increased from 62% in 1998 to 89% in 2011 (p&lt;0.0001). In BC, 74% were staged in 1998, which declined to 66% in 2007. However, the trend reversed, and 92% received a clinical stage by 2011 (p&lt;0.0001). When comparing trends between COM and ACA, in 1998 stage was reported in 90% and 91% for HNC, respectively. By 2011, the proportions rose to 93% and 94%(p&lt;0.0001). In 1998, 60% of RC patients were staged in the COM versus 66% in ACA. By 2011, 88% and 91% had staging reported (p&lt;0.0001). For BC in 1998, 75% of patients were assigned a stage in both center types, which fell until 2007, when a steady increase was observed. By 2011, 92% of patients were staged in both center types (p&lt;0.0001). Conclusions: Clinical staging improved in all classes of patients with time, although a substantial number still lack staging information. Clinical stage reporting varied by type of institution as well as disease sites. Patients with HNC had the highest rate of clinical staging prior to treatment and RC had the lowest. Between 1998 and 2011, RC has seen the most significant upward trend in recording clinical stage. Despite this, thousands of patients have received treatment without documentation of their clinical stage.
Phase II study of dexamethasone, ascorbic acid, thalidomide and arsenic trioxide (DATA) in high risk previously untreated (PU) and relapsed/refractory (RR) multiple myeloma (MM)
Authors: R. C. Baz, M. Kelly, J. Reed, M. Karam, B. Faiman, S. Andresen, M. A. Hussein
Journal: Journal of Clinical Oncology (2006)

17535 Background: The combination of Thalidomide (T) and Dexamethasone (D) is often used first line in patients with MM. Arsenic trioxide (ATO) is active and well tolerated in patients with RR MM. ATO, D and T have non-overlapping toxicity. We therefore initiated a phase II study to assess the efficacy and toxicity of this combination in patients with high risk PU MM (serum B2 microglobulin&gt;5.5, chromosome 13 or 14 abnormalities by FISH or the presence of peripheral plasma cells) and RR MM. Methods: On week 1, ATO was given at a dose of 0.25mg/kg IV on days 1–5. On weeks 2–12, ATO was given at the same dose twice weekly. On weeks 13–16, the patients did not receive treatment. Ascorbic acid 1000mg IV was given after each ATO infusion. D was given at a dose of 20mg orally on days 1–4 of a 28 days cycle, and T was started at a dose of 50mg daily and increased as tolerated to a dose of 100mg daily. A similar 16 weeks consolidation course was given. Maintenance included ATO 0.25mg/kg on days 1,8,15 and 22 every 12 weeks in addition to the above schedule for D, T and Ascorbic acid. Results: Sixteen patients were enrolled (3 with PU and 13 RR), 13 are evaluable for response. The median age was 57 years and 62% were males. The median number of prior chemotherapy regimen is 2 (range 0–6), 7 patients had received a prior T containing regimen, and 2 patients had received an ATO-containing regimen. Seven, seven and two patients had SWOG stages 2, 3 and 4 respectively. The mean serum B2 microglobulin was 7.1-mg/dL (s.d. 4.4). After a median follow up of 9.5 months (range 1–12), 9 patients progressed and 5 died. The median progression free survival was 9.4 months. The median progression free survival for responder has not been reached. Four patients had a PR (31%), 8 had stable disease (62%), and 1 had progressive disease. No patient had a QT&gt;500 or a cardiac arrhythmia. Grade 3 leukopenia, anemia, neuropathy and renal failure occurred in 3, 2, 1 and 1 patients respectively. Three patients had a venous thromboembolic event (2 DVT and 1 PE). Conclusions: The addition of T to the combination of ATO, Ascorbic acid and D is safe, well tolerated and results in 30% PR and 61% stable disease in patients with poor risk MM. [Table: see text]
A phase II first-line study of gemcitabine, carboplatin, and bevacizumab (GCB) in advanced (adv) stage non-squamous non-small cell lung cancer (NSCLC)
Authors: Y. Krupitskaya, K. Ganjoo, P. W. Lavori, A. Kumar, C. Clement-Duchene, G. Zhao, S. Padda, M. San Pedro- Salcedo, H. A. Wakelee
Journal: Journal of Clinical Oncology (2009)

e19024 Background: B adds to 1st-line paclitaxel/carboplatin (PC) for pts with adv NSq-NSCLC. Gemcitabine/carboplatin (GC) has equivalent efficacy to PC with a different toxicity profile. This study was designed to evaluate toxicities (AEs) of GCB and to estimate survival. Methods: Patients (pts) with untreated adv NSq-NSCLC, with no evidence of CNS metastases were eligible. Pts received G 1000 mg/m 2 on d1, 8; C AUC 5 d1; and B 15 mg/kg d1 q21d for up to 6 cycles. B was then continued q21d until disease progression or unacceptable toxicity. Chemo dose reductions were mandated for significant cytopenias. Imaging was every 2 cycles. Results: From 07/06 to 12/08, 48 pts enrolled (accrual complete): 23(48%) men, 19(40%) never smokers, median age 59yo (35–81). One pt died prior to receiving therapy and is not included in the analysis. Median cycle number is 6(0–37). To date, 35 pts (74%) completed ≥ 4 cycles of 3 drugs. Dose reductions occurred in 29(62%) of pts. G3/4 AEs included: neutropenia (47%/17%), thrombocytopenia (11%/15%), and anemia (6%/0%). No pts were hospitalized for neutropenic fever. G3/G4 non-hematologic AEs included dyspnea (6%/2%), bacterial pneumonia (4%/0) hypertension (4%/2%), 1G3 wound dehiscence, 1G4 MI, 1G3 transaminitis and hyperbilirubinemia, 1G3 proteinuria and 1G3 leucocyturia. 1 pt died from hemoptysis with untreated aspergillosis found post-mortem. Other bleeding included 1 case each with G3 epistaxis, hemorrhoidal bleeding and ecchymosis. Common G1/2 AEs included fatigue, hypertension, anemia, constipation, nausea, headaches, transaminitis and epistaxis. In 42 evaluable pts: we saw 7(17%) PRs, and 31(74%) SDs at 1st f/up. 44/47 pts were followed for a median of 10.5mo (3 recently enrolled pts with f/u &lt; 20d - excluded). Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4mo [95%CI 4.6–8.6mo]. 17/44 (38.6%) pts have died with median overall survival (mOS) not reached but preliminarily estimated at 16.7mo [95%CI 13.4mo-inf]. Estimated OS is 73% at 1yr and 32% at 2yrs. Conclusions: Treatment with GCB has an acceptable toxicity profile with promising mOS despite a low RR and frequent dose reductions in a population with a high proportion of non-smokers and women. No significant financial relationships to disclose.
Intratumoral mRNA levels predict clinical outcome in patients with metastatic colorectal cancer treated in a prospective clinical trial with 5-FU and oxaliplatin
Authors: D. Yang, D. Vallböhmer, W. Zhang, S. Iqbal, A. El-Khoueiry, M. Gordon, D. Park, M. Azuma, S. Groshen, K. D. Danenberg, H. Lenz
Journal: Journal of Clinical Oncology (2006)

10010 Background: 5-flurouracil (5-FU) and Oxaliplatin-based therapy is one of the most frequently used combinations in the treatment of advanced colorectal cancer (CRC). There are no validated and established predictive factors for clinical outcome following 5-FU/Oxaliplatin treatment. We had shown an association between intratumoral mRNA levels of TS and ERCC1 involved in 5-FU metabolism and DNA repair, respectively, and survival to 5-FU/Oxaliplatin chemotherapy in advanced CRC in a retrospective study. Now we investigated whether intratumoral mRNA levels of these two genes and others involved in 5-FU metabolism (DPD, TP, dUTPase), DNA repair (ERCC2, XRCC1), angiogenesis (COX-2, EGFR, IL-8, PLA2), and drug detoxification (GSTP-1) predict the clinical outcome of patients with CRC in a prospectively designed biomarker study. Methods: 85 patients with metastatic CRC treated with second-line 5-FU/Oxaliplatin from the prospective trial were included. mRNA levels of 12 genes were assessed from paraffin- embedded tissue samples using laser capture microdissection and quantitative Real-time PCR. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS), response, and toxicity were the secondary endpoints. Results: There were 40 women and 45 men (median age 60 years; range 29–87), median survival of 9.7 ms, median PFS of 4.2 ms, CR in 1 (1%) patient, PR in 15 (18%), SD in 36 (43%) and PD in 32 (38%) patients. High intratumoral mRNA levels of PLA2, TP, GSPTP-1 and low mRNA levels of COX-2 were each significantly associated with shorter OS (P≤0.05, log-rank test). There was a trend in the association between high mRNA levels of PLA2 and shorter PFS (P=0.08). In addition, high mRNA levels of XRCC1 and IL-8 were each significantly associated with high risk of cumulative grade 3+ toxicity (P≤0.05). No significant association was found between mRNA levels and response to 5-FU/Oxaliplatin. Conclusions: This study suggests that mRNA levels of PLA2, TP, GSTP-1, COX-2, XRCC1, and IL-8 may be useful to predict the outcome of patients with metastatic CRC with second-line 5-FU/Oxaliplatin chemotherapy. These findings should be validated with future basic sciences studies and prospective clinical trials. [Table: see text]
Cellular pharmacodynamics and plasma pharmacokinetics of parenterally infused hydroxyurea during a phase I clinical trial in chronic myelogenous leukemia.
Authors: V Gandhi, W Plunkett, H Kantarjian, M Talpaz, L E Robertson, S O'Brien
Journal: Journal of Clinical Oncology (1998)

PURPOSE To determine the maximum-tolerated dose (MTD), toxicities, and antileukemic activity of hydroxyurea (HU) administered intravenously to patients with advanced-phase chronic myelogenous leukemia (CML). Further objectives were to analyze pharmacodynamic effect on deoxynucleotides (dNTPs) and to seek relationships between the decrease in dNTP pools and inhibition of DNA synthesis in CML blasts. PATIENTS AND METHODS HU (8, 12, 18, 27, and 40 g/m2) was administered intravenously by a 24-hour continuous infusion to 19 adults with CML in blastic or accelerated phase. Plasma levels of HU were analyzed in all patients. To determine the role of HU in inhibiting ribonucleotide reductase, dNTP pools in the leukemia cells were quantitated. Correlations were sought with these parameters and DNA synthesis inhibition measured ex vivo by [3H]thymidine incorporation. RESULTS The MTD of HU given as a 24-hour infusion was 27 g/m2. The dose-limiting toxicity was mucositis. There was a significant but transient myelosuppression, with nadir counts generally seen 3 to 4 days after the dose. The steady-state concentration of HU in plasma was achieved by 6 hours, and was proportional to the dose. There was a median 57% decrease in the deoxyadenosine triphosphate (dATP) pool in circulating blasts. In contrast, deoxyguanosine triphosphate (dGTP) and pyrimidine dNTPs were not significantly affected. The extent of DNA synthesis inhibition was related to the residual concentrations of intracellular dATP. CONCLUSION A 24-hour infusion of HU results in significant but transient myelosuppression in advanced-phase CML. The specific decrease of intracellular dATP correlated with the inhibition of DNA synthesis in CML blasts. This pharmacodynamic action of HU provides a rationale for combination with other chemotherapeutic agents, the effects of which could be augmented by the decline in dATP pools.
Phase I trial of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (DEX) in combination with systemic oxaliplatin (OXAL), fluorouracil (FU) + leucovorin (LV) after resection of hepatic metastases from colorectal cancer
Authors: N. E. Kemeny, W. Jarnagin, M. Gonen, D. Haviland, M. D’Angelica, L. Blumgart, R. Dematteo, L. Schwartz, Y. Fong
Journal: Journal of Clinical Oncology (2005)

3579 Background: Our earlier studies using HAI plus SYS chemotherapy after liver resection demonstrated significant decrease in hepatic recurrence. In order to decrease extrahepatic recurrence in resected patients (pts), combinations of HAI and new SYS therapies are needed. We designed a Phase I trial of HAI FUDR + DEX and SYS OXAL, FU + LV. Methods: OXAL was kept constant (85mg/m2) while FU was escalated: 1000–1400 mg/m2 (48-hour infusion). Then OXAL was escalated (100 mg/m2) and FU from 1400–1800 mg/m2. LV was fixed at 400 mg/m2. HAI FUDR dose was fixed at 0.12 mg/kg x pump volume (PV) divided by pump flow rate (PF), and infused Day (D) 1–14 with DEX, heparin and saline. SYS therapy was given on D14 and D28 of a five-week cycle. Results: 21 pts have been enrolled: median age 58 (range 41 -74); margin of resection ≤ 0.3 cm (28%); number of lesions ≥ 2 (71%); synchronous disease (38%); received previous chemotherapy (71%). Dose-limiting toxicity (DLT) was reached when FU was 1800mg/m2 and OXAL 100mg/m2, with Gr 3 diarrhea and fatigue. This dose of OXAL compromised HAI FUDR administration (see table below). Median follow-up is 20.5 months. Three pts [2 lung and 1 liver] progressed at 6, 16, and 7 months; median is not reached. One-year disease-free rate is 88% (95% CI, 73–100). One-year survival is 100%; median is not reached. Conclusion: The MTD of combined HAI + SYS is FUDR 0.12mg/kg x PV/PF, plus systemic OX at 85 mg/m2 and 5FU at 1600 mg/m2. It is too early to determine whether there is a decrease in the occurrence of lung mets, but survival data is encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi
Phase I of high dose (HD) temozolomide (TMZ) with peripheral blood stem cell support (PBSCS) rescue in recurrent high grade glioma (HGG)
Authors: D. Frappaz, J. Pierga, J. Bay, M. Fabbro, L. Djafari, M. Sunyach
Journal: Journal of Clinical Oncology (2007)

12518 Background: Despite improvements obtained with frontline treatments prognosis of recurrent HGG still remains dismal. HD chemotherapy (CT) suggested a dose-effect relationship in lymphoma and germ cell tumors. HD of TMZ could be a promising way to overcome resistance of HGG to standard schedule of CT Methods: This phase I had as principal objective to determine the Maximal Tolerated Dose (MTD) of HD of TMZ with PBSCS rescue in patients with recurrent HGG under 60 year. The MTD was defined as dose level which 50% of patients (pts) treated experienced a DLT (Dose Limiting Toxicity).The dose escalation was planned for eight dose levels from 300 to 650mg/m 2 /day over 5 days with CSP reinfusion at D7 according to the Modified Continual Reassessment Method (MCRM). Treatment was administered for one cycle. Results: Eighteen eligible pts were treated with HD of TMZ, all had received prior radiotherapy, 11 pts previous CT. Overall HD TMZ was well tolerated for the 7 evaluated dose levels. The MTD was not yet reached. Not dose limiting toxicities were reported in 12 pts: grade 2: fatigue (6pts), cephalalgia (3pts), nausea (3pts) , skin eruption (2pts), mucositis, FUO, vomiting, diarrhea, zoster, dental abcess, lung infection, septicemia, hepatic. grade 3 bilirubinemia, grade 4 neutropenia (13pts) and thrombocytopenia (4pts). Dose Limiting Toxicities were reported in 2 pts, gr3 cytolysis at level 3 (400mg/m 2 /day ) 1pt and gr 3 arthritis at level 7 (600mg/m 2 ) 1pt respectively . Main hematological toxicities were gr 4 neutropenia in 13 pts median duration was 8 days, 4 pts had gr4 thrombocytopenia lasting 5 days. All patients were evaluable for tumor response, 2 partial responses were observed at 550 and 600mg/m2 level, 5 pts had a stabilization and a disease progression was reported in 11 patients. Conclusions: This interim analysis demonstrated that HD of TMZ with CSP reinfusion is feasible and well tolerated in patients with recurrent HGG. Nevertheless limited activity reported could be related to a less depletion of O6 alkylguanine transferase with HD than with a protracted schedule. Accrual is still ongoing. No significant financial relationships to disclose.
Peritoneal metastases in breast cancer patients: Differences in survival depending on histological subtype
Authors: Z. Atassi, D. Varga, K. Plotzki, C. Kurzeder, R. Kreienberg
Journal: Journal of Clinical Oncology (2009)

e12024 Background: Distant spread from breast cancer is commonly found in bones, lungs, liver, and central nervous system. Metastatic involvement of peritoneum and retroperitoneum is unusual and unexpected. The aim of the study was to perform a comprehensive analysis of breast cancer patients with peritoneal metastases and to compare survivals depending on biological subtypes. Methods: 44 breast cancer pts with peritoneal metastases were detected out of a database of 2,500 breast cancer patients treated in one institution between 1995 and 2005. Clinical characteristics such as estrogen receptor and progesterone receptor as well as survivals were analized based on breast cancer subtypes. Results: Mean patient age was 54 years, 25 patients (56%) had ductal invasive carcinoma while 19 (44%) were diagnosed lobular invasive carcinoma. 30 (68%) patients had endocrine responsive tumors. A HER-2 percentage is not provided due to the lack of data before the year 2000. Median survival calculated from peritoneal metastases in histologic subgroups was as follows: Median progression free survival was 36.5 months for ductal invasive carcinoma, and 23.5 months for lobular invasive breast cancer. Median overall survival was 46 (Std 38.5) months for ductal invasive breast cancer and 32 (Std 54.5) months for lobular invasive breast cancer. Conclusions: Patients with peritoneal metastases are a heterogenous group with a different outcome. The histologic subtype seems to be an important predictive factor as lobular invasive breast cancer is associated with worsened progression free an overall survival rates. No significant financial relationships to disclose.
Crosstalk between reduced NCX activity and Ca channel inactivation through changes in local Ca in ventricular myocytes of the heterozygous NCX knockout mice.
Authors: Karoly Acsai, Ilse Lenaerts, Patricia Holemans, S Sokolow, S Schurmans, André Herchuelz, Karin Sipido, Gudrun Antoons
Journal: Cardiovascular Research (2010)
Effects of brain irradiation and chemotherapy on myelosuppression in small-cell lung cancer.
Authors: J S Lee, T Umsawasdi, H M Dhingra, H T Barkley, W K Murphy
Journal: Journal of Clinical Oncology (1986)

The effect of brain irradiation on myelosuppression was studied in patients with untreated small-cell lung cancer (SCLC) by comparing 24 patients who received brain irradiation for brain metastasis at presentation (irradiated patients) with 24 control patients who were selected by matching ages and non-CNS metastatic sites with those of irradiated patients. All patients were evaluated during the first three courses of chemotherapy. More irradiated patients than control patients had chemotherapy dose reductions from the starting dose level for the second (nine of 22 v two of 24; P = .03) and the third (nine of 18 v three of 20; P = .05) courses of chemotherapy. Overall, more irradiated patients had chemotherapy dose reductions than did control patients (11 of 22 v three of 24; P = .01). The difference was highly significant even after other variables were considered in a multivariate analysis (P less than .001). Myelosuppression was more severe in irradiated patients for WBCs (P = .01) and for platelets (P = .05). When the second course of chemotherapy was administered at the same dose levels as in the first course, irradiated patients had greater decreases in nadir counts after the second course compared with the first course than did control patients. Irradiated patients had a higher incidence of infectious complications than did control patients (14 of 24 v six of 24; P = .02), particularly after the second course of chemotherapy (seven of 22 v one of 24; P = .04). There were four treatment-related deaths due to sepsis in irradiated patients. Following brain irradiation given concurrently with intensive chemotherapy, close monitoring of myelosuppression and adjustments of chemotherapy doses are advised.