tbuckley/cabot-search huggingface dataset:
Management of hyperglycemia in patients with metastatic pancreatic cancer receiving UCN-01 and fluorouracil
Authors: J. S. Kortmansky, N. Sauter, E. O'Reilly, M. Shah, G. K. Abou-Alfa, J. Winkelmann, S. Yi, M. Gonen, D. P. Kelsen, G. K. Schwartz
Journal: Journal of Clinical Oncology (2004)

2140 Background: UCN-01 is associated with dose-limiting hyperglycemia (HG). It is postulated that UCN-01-induced HG may be related to inhibition of AKT-mediated pathways, which play an important role in glucose metabolism. Management of HG is an important consideration in the development of UCN-01. Methods: We evaluated relative changes in insulin sensitivity as a function of treatment in patients with pancreatic cancer enrolled in a phase II study of fluorouracil and UCN-01. Fasting plasma samples were collected on days 1 (pre-FU), 2 (pre-UCN-01), 5 (post-UCN-01) and 16 (mid-cycle) in the first cycle and days 1, 2, 3, and 16 in the second cycle of treatment and analyzed for glucose and insulin levels. Insulin sensitivity was evaluated using the simple QUICKI index (1/log10 insulin + log10 glucose). Patients with HgbA1c ≥ 8.0 or fasting glucose ≥ 126 were referred to an endocrinologist. Results: We have enrolled 11 patients (median age 60, range 51–77) to this phase II study: 8 are evaluable for response and 11 are evaluable for insulin sensitivity. We observed grade 3 (n=4) or grade 4 (n=1) HG in 5 of the initial 6 patients; two required hospitalization, one with concurrent gram-negative sepsis. Subsequent patients were seen by an endocrinologist to learn self-administration of insulin, with no further grade 3 or 4 HG observed. Compared to baseline (pre-UCN-01), the mean decrease in QUICKI following UCN-01 infusion was 0.085 ± 0.037, indicating increased insulin resistance following UCN-01. In 7 of 8 patients evaluable for response, insulin sensitivity returned to baseline prior to UCN-01 in the 2nd cycle (day 30); we observed no objective responses. In contrast, 1 patient with persistent increased insulin resistance prior to the 2nd UCN-01 dose had stable disease for 5 months. Two patients await response evaluation. Conclusion: HG from UCN-01 can be controlled with aggressive glucose monitoring and insulin injections in a pancreatic cancer population. The QUICKI index represents a simple method to monitor insulin resistance in patients receiving UCN-01 therapy and may represent a marker of clinical benefit. No significant financial relationships to disclose.
Female sex and standardized mitomycin-c dose are associated with increased risk of neutropenia after hyperthermic intraperitoneal chemotherapy
Authors: L. A. Lambert, T. S. Armstrong, J. J. Lee, M. H. Katz, C. Eng, R. A. Wolff, C. S. Ng, M. L. Smith, S. Gonzalez-Moreno, P. F. Mansfield
Journal: Journal of Clinical Oncology (2007)

15091 Background: Cytoreductive sugery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are being increasingly employed in the managment of peritoneal-based malignancies. Depending on the treatment regimen, neutropenia (NP) is a common and potentially life-threatening early postoperative complication of HIPEC. However, little is known about the incidence or risk factors associated with HIPEC-induced NP. Methods: From January 1993 to October 2006, 120 CRS and HIPEC with mitomycin-c (MMC) were performed in 117 patients with appendiceal neoplasm. NP was defined as an absolute neutrophil count of &lt; 1,000/mm 3 . Variables assessed as potential risk factors for HIPEC-induced NP included: age, sex, weight, BMI, BSA, splenectomy, dose of MMC (standardized for BSA and nonstandardized), percent of perfusate recovered, length of surgery, estimated blood loss, perioperative blood transfusion, and history of prior chemotherapy. Results: Total perfusate MMC doses ranged between 37.25 and 65 mg. The overall incidence of NP was 39.2%. The NP rates in female and male were 57.6% and 21.3%, respectively. Female sex, BMI, BSA, and the standardized dose of MMC were significantly associated with an increased risk of NP by univariable logistic regression. Female sex and standardized dose of MMC remained statistically significant for an increased risk of NP on multivariable logistic regression. The odds ratio (OR) of NP for females was 3.63 (95% CI: 1.54, 8.52); the OR of NP for a 1 mg/m 2 increase in standardized MMC dose was 1.26 (95% CI: 1.11, 1.44). No other variables were identified as independent predictors of increased or decreased risk of NP. Compared to patients without NP, patients with NP had a higher rate of urinary tract infection (42.6% vs. 21.1%, p=0.01) and slightly higher length of stay (median: 24.0 days vs. 18.5 days, p=0.16). Conclusions: NP is a common complication after HIPEC with MMC . Female patients are at significantly increased risk for this complication. Risk of NP also increases with MMC dose standardized for BSA. With increasing interest in the use of CRS and HIPEC, understanding the risk factors for HIPEC-induced NP may facilitate reducing the morbidity associated with this procedure. No significant financial relationships to disclose.
Phase I evaluation of sorafenib (SOR) and bevacizumab (BEV) as first-line therapy in hepatocellular cancer (HCC): North Central Cancer Treatment Group trial N0745.
Authors: J. M. Hubbard, S. R. Alberts, W. S. Loui, M. R. Mahoney, L. R. Roberts, T. C. Smyrk, Z. Gatalica, S. Kumar, S. R. Dakhil, P. J. Flynn, J. M. Lafky, M. J. Bury
Journal: Journal of Clinical Oncology (2011)

4116 Background: HCC tumors are highly vascular and over express VEGF. The monoclonal antibody BEV and the oral multi-kinase inhibitor SOR inhibit VEGF-induced angiogenesis and the associated Ras/Raf/MEK/ERK signaling pathway. It is hypothesized that SOR will complement the mode of action of BEV by more fully blocking VEGF signaling. Methods: Eligibility included measurable locally advanced or metastatic HCC not amenable for surgery or liver transplant (BCLC-C), Child Pugh A or B7, esophageal varices if treated ≥ 6 mos, and acceptable blood chemistries. Patients with mixed cholangiocarcinoma/HCC were ineligible. Treatment doses/schedule appears in the table. The phase I starting dose level (0) was: BEV 1.25 mg/kg d1 and 15 plus SOR 400 mg BID d1-28. Results: 17 patients aged 18-79 (mean 62.4 yrs) were enrolled; 14 were male. A majority of patients presented with ascites (71%). Baseline characteristics included cirrhosis (41% of patients), prior RT (12%), prior chemoembolization (6%), and vascular invasion (20%). Cycle 1 dose limiting toxicities (DLTs) by dose level were: Dose 0 (2 pts with DLTs) – Gr 3 hand/foot skin reaction, fatigue, hypertension; Dose -1 (3 pts) – Gr 3 alanine/aspartate aminotransferase inc, dehydration, hypophosphatemia, creatinine inc, hypoglycemia, nausea vomiting, and Gr 4 hyponatremia; Dose -2 and -2a had 0 DLTs. Conclusions: With an acceptable toxicity profile, dose level -2a (SOR 200 mg BID d1-28, plus BEV 2.5 mg/kg d1 and 15) is currently used in the on-going phase II trial in this population. Supported by NCI Grant ca25224 & Bayer Pharmaceuticals and Bayer’s REACH Program. Dose levels evaluated. Dose 0 Dose -1 Dose -2 Dose -2a S (d1-28) 400 mg BID 400 mg BIDa 200 mg BID 200 mg BID BEV (d1 and 15) 1.25 mg/kg 1.25 mg/kg 1.25 mg/kg 2.5 mg/kg N 3 6 5 3 Had DLT 2 3 0 0 a Days 1-5 of each 7 days, only.
NK cells infiltrate in primary tumor influences response to cetuximab (CTX) in first-line therapy of metastatic colorectal cancer (mCRC)
Authors: R. Maréchal, N. Nagy, A. Verrellen, D. Larsimont, A. Hendlisz, A. Demols, P. Demetter, J. Van Laethem
Journal: Journal of Clinical Oncology (2008)

22008 Background: CTX, a chimeric anti-epidermal growth factor receptor antibody is active in mCRC. It may exert its activity through antibody-dependent-cell-mediated cytotoxicity Methods: Patients with mCRC who underwent resection of the primary tumor in two academic Hospitals and treated with CTX based-chemotherapy in first line (Folfiri or Folfox), have been studied. All surgical primary tumor specimens were analysed with immunohistochimical evaluation of B (LB-CD4+) and T lymphocytes (LT-CD8+), LT regulators (Treg-Foxp3), macrophages (CD68+) and natural killer (NK-CD56+) cells. Immune cells infiltrates were blindly-assessed in the tumor stroma (TS) and along the invasive margin (IM), and correlated with tumor response (TR) and progression free-survival (PFS). Results: 32 patients (median age 59 years) have been analysed. Number of progressive/stable disease/partial/complete response was 13/9/7/3, median PFS: 146,5 days (range: 28–620). Presence of CD56+ cells IM was associated with TR (r=0,62; p< 0,0001) and with a longer PFS (median:338 days; CI: 302–373) than patients without CD56+ cells (median: 56 days; CI: 55–58). Presence of CD56+ cells IM (OR: 6,98 (CI: 2,56–19,05), p<0,0001) and skin rash severity (grade 2 and 3) (OR: 2,63 (CI:1,11–6,23), p=0,027)) were independent prognostic factor for PFS. Macrophages, LB, LT and Treg IM or TS were not correlated with TR nor PFS. We defined 3 groups based on the presence of CD56+ cells IM and skin rash toxicity (grade 2 and 3): group A (median PFS: 338 days): skin rash and presence of CD56+ cells; group B (median PFS: 162 days): presence of CD 56+ cells or skin rash; group C (median survival:56 days): no CD56+ cells and skin rash (grade 0 and 1). The median PFS differed significantly between the 3 groups ( group A vs C: p=0,001, group A vs B: p= 0,013, group B vs C: p=0,022). Conclusions: NK cells infiltrate in primary tumor and skin rash severity are independent prognostic factor for PFS in first-line CTX based-chemotherapy in mCRC. These results could support an in vivo role for NK cells in the mechanism of CTX action in CRC. The role of NK cells should be deeply analysed and explored as a predictive marker in prospective clinical trials. No significant financial relationships to disclose.
Prognostic importance of primary tumor resection in patients with advanced colorectal cancer (CRC): A Canadian province’s experience
Authors: S. Ahmed, R. Shahid, I. Ahmad, R. Alvi, S. Yadav, A. Sami, F. Arnold, D. Popkin, K. Haider
Journal: Journal of Clinical Oncology (2007)

14529 Background: Surgical resection (SR) of primary tumor in patients with newly diagnosed advanced CRC remains controversial. Limited data is available regarding potential benefit of resection in these patients. We performed a population-based study to determine the prognostic value of SR of primary tumor in patients with metastatic CRC. Methods: Medical records of patients with metastatic CRC diagnosed between 1991–2000 in the province of Saskatchewan were reviewed. Patients with unresectable T4M0 disease were excluded. A multivariate analysis was performed using Cox regression model and various clinicopathologic variables were tested for their prognostic significance. Kaplan-Meier curves were used to determine survival. A preliminary analysis of data of 212 eligible patients diagnosed between 1998–2000 is presented here. Results: Patients median age was 71 yrs (33–94) and M:F was 1:0.77. One hundrad thirty one (62%) patients underwent SR for the primary tumor. Among 131 patients, 76 (58%) were operated for tumor related symptoms (36% obstruction, 14% perforation, and 9% bleeding). Six percent patients died of postoperative complications. Of 212 patients, 36% received 5FU-based chemotherapy (46% patients with SR) and 17% received a second line therapy. Median overall survival (OS) of all patients was 6.7 months. Patients who underwent SR of primary tumor had a significantly better median OS of 11 months compared with 3 months in patients who did not have surgery (HR 0.47; 95% CI 0.29–0.76). Patients who underwent SR and had received chemotherapy had a median OS of 14.8 months compared with median OS of 6 months if they did not receive chemotherapy (HR, 0.29; 95% CI 0.15–0.55). In addition to 5FU-based chemotherapy and SR of primary tumor; metastectomy, age &gt;65 yrs, elevated alkaline phosphatase level and thrombocytosis were other important variables that were correlated with survival in patients with advanced CRC. Conclusions: SR of primary tumor has been associated with significant improvement in survival independent of systemic chemotherapy in patients with advanced CRC. Further analysis of data in patients diagnosed between 1991–2000 is planned to confirm these findings in a larger group of patients. No significant financial relationships to disclose.
18F-DOPA PET superior for staging of neuroendocrine tumors
Authors: K. P. Koopmans, E. G. E. de Vries, I. P. Kema, A. N. A. van der Horst-Schrivers, P. H. Elzinga, P. L. Jager
Journal: Journal of Clinical Oncology (2005)

4085 Background: The aim of the study was to assess the value of whole body 18-fluoro-L-DOPA positron emission tomography (F-DOPA PET) for staging and restaging of patients with neuroendocrine tumors, in comparison with the generally used gold standard of abdominal CT in combination with whole body SRS. Methods: Whole body PET was performed after injection of 100 - 200 MBq F-DOPA and oral pretreatment with carbidopa. CT scanning and SRS were performed within a short interval using standard methods. Endpoints were the number of positive patients, positive body regions and individual lesions. Image interpretation of PET was blinded from other studies, but for precise localization PET-CT image fusion was carried out. Newly detected lesions on PET were validated using conventional methods when feasible. Results: In this ongoing study 36 patients (M:F=19:17) were entered. F-DOPA PET was positive in 35 of 36 patients (sensitivity 97%), and detected a mean of 45 lesions per patient (lpp). CT was positive in 31 of 35 patients (sensitivity 88%) with mean of 39 lpp, SRS in 27 of 33 patients (sensitivity 82%) with 27 lpp. In the head/neck region F-DOPA PET/CT/SRS detected 27/15/6 lesions, in the chest 77/26/25. The largest numbers of lesions were observed in the liver, with 1251 for F-DOPA PET, 999 for CT and 541 lesions with SRS. In the extrahepatic abdomen we found 138/23/43, and in the pelvic region 54/20/10 lesions. In 15/26 patients software fusion of F-DOPA PET and CT led to a better localization of lesions. Conclusion: F-DOPA PET was clearly superior to CT and SRS for staging of neuroendocrine tumors. Software based image fusion improved localization of tumor lesions. Support: This study was supported by grant 2003–2936 from the Dutch Cancer Society, Amsterdam, The Netherlands. No significant financial relationships to disclose.
Beta-2 microglobulin (B2M) is an independent prognostic factor for clinical outcomes in patients with CLL treated with frontline fludarabine, cyclophosphamide, and rituximab (FCR) regardless of age, creatinine clearance (CrCl)
Authors: A. M. Tsimberidou, C. Tam, W. Wierda, S. O' Brien, S. Lerner, M. J. Keating
Journal: Journal of Clinical Oncology (2007)

7034 Introduction: High β 2 M levels are a risk factor in CLL. PCR therapy has been reported to be better tolerated than FCR in older or with decrease renal function pts (Shanafelt, Blood 108:15a). We assessed the association between age, CrCl, PS, β 2 M and outcomes in pts treated with FCR. Methods: From 7/99 to 1/04, 300 pts received rituximab 375 mg/m 2 D1; fludarabine 25 mg/m 2 /d D2–3; and cyclophosphamide 250 mg/m 2 /d D2–3. Serum β 2 M levels were measured by radioimmunoassay. CrCl was calculated (Cockcroft-Gault equation). Results: The median age was 57 yrs (≥70, 14%). Age ≥70 was associated with fewer FCR courses (p&lt;.0001); lower rates of CR (p=.001), overall response (OR; p=.04), survival (OS; p&lt;.0001), and FFS (p=.008); and higher rates of G3–4 thrombopenia (p&lt;.0001) or anemia (p=.002) compared with age&lt;70. The median CrCl was 90 mL/min (CrCl &lt;70, 27%). Pts with CrCl &lt;70 had higher rates of G3–4 thrombopenia (p=.006) or anemia (p=.01) than others. There were no differences between the 2 groups in the other outcomes. PS was 0 in 40%, 1 in 57%, and 2 in 3% of pts. Better PS was associated with higher rates of CR (p=.007) and FFS (p=.02) but did not affect OR or OS. The median β 2 M level was 3.7 mg/L (β 2 M ≥ 4, 43%). The rates of CR, survival, and FFS were lower in pts with β 2 M ≥ 4 compared with others (p&lt;.0001 each). High β 2 M levels were associated with older age, lower CrCl levels, poorer PS (p&lt;.0001 each), higher rates of G3–4 neutropenia (p=.005), thrombocytopenia (p=.01), and infections (p=.03), and fewer FCR courses (p=.004). The median follow-up was 5 yrs. The rates of CR, 3-yr OS and 3-yr FFS were 72%, 87% and 76%, respectively. Independent factors predicting response were lower β 2 M (p=.0004) and lower WBC counts (p=.02). Independent factors predicting longer OS were younger age (p=.001), lower β 2 M (p=.003) and lower WBC (p=.03). Independent factors predicting longer FFS were lower β 2 M levels (p=.0006), and lower WBC counts (p=.005). Conclusion: Age ≥70 yrs and poor PS, but not CrCl level were associated with poor clinical outcomes. High β 2 M levels are an independent adverse prognostic factor for CR, OS, and FFS in the context of other prognostic factors. No significant financial relationships to disclose.
Regulatory role of p53 in cancer metabolism through SCO2 and TIGAR in human breast cancer
Authors: S. Choi, J. Song, S. Lim, J. Lee
Journal: Journal of Clinical Oncology (2009)

e22128 Background: Cancer cells showed higher rate of anaerobic respiration than normal cells. The exact mechanisms for this higher rate of glycolysis in cancer cells remain to be elucidated. Recent researches suggest that p53, the most commonly mutated tumor suppressor gene, might play an important roles in the regulation of energy generating metabolic pathways that switch from oxidative phosphorylation to glycolysis through synthesis of cytochrome C oxidase 2 (SCO2) and TP53-induced glycolysis and apoptotic regulator (TIGAR). Methods: We investigated the expression of p53, SCO2, TIGAR and cytochrome C oxidase (COX) in 95 cases of invasive ductal carcinoma using immunohistochemistry. Results: Overexpression of p53, SCO2, TIGAR and COX was observed in 27.4% (26 cases), 82.1% (78 cases), 76.8% (73 cases), and 77.9% (74 cases) respectively. Overexpression of p53 was significantly associated with decreased expression of SCO2 (p=0.009), COX (p=0.001) and TIGAR (p=0.03). Conclusions: These results suggest that p53 can modulate the metabolic pathways via SCO2 and TIGAR in human breast cancer. No significant financial relationships to disclose.
Single-day regimen of palonosetron (PALO) and dexamethasone (DEX) for the prevention of emesis associated with moderately emetogenic chemotherapy (MEC): Subgroup analysis from a randomized phase III trial
Authors: L. Celio, E. Bajetta, A. Denaro, E. Bichisao, S. Frustaci, A. Ardizzoia, E. Piazza, A. Fabi, A. Capobianco, L. Isa
Journal: Journal of Clinical Oncology (2009)

9620 Background: We have recently shown non-inferiority in preventing acute and delayed nausea and vomiting associated with MEC between the PALO plus 1-day DEX and PALO plus 3-day DEX regimens. Planned analysis stratified by type of chemotherapy (anthracycline + cyclophosphamide [AC] group or patients receiving at least one moderately emetogenic agent according to modified Hesketh classification) has been performed. Methods: A total of 332 chemo-naïve patients with solid tumors were randomized to receive a single IV dose of PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (arm A; n=166) or the same regimen followed by DEX 8 mg orally on days 2 and 3 (arm B; n=166). Endpoints included complete response rates (CR: no emetic episodes [EE], no rescue antiemetics; primary endpoint) and proportion of patients with no EE throughout the 5 days after the first cycle of chemotherapy. Subgroups were analyzed by two-sided chi-square test. Results: Per-protocol population included 324 patients (65% women; median age 57.5 years); 35% received AC regimens, and 65% other MEC regimens. There were no significant differences between arms in CR rates according to the type of chemotherapy: 1) CR rates on AC regimens (arm A, 55.8% versus arm B, 60.7%; p=0.599); and 2) CR rates on other MEC regimens (arm A, 68.5% versus arm B, 72%; p=0.576). No significant differences between arms were also observed in the rates of patients with no EE: 1) emesis-free patients on AC regimens (arm A, 78.8% versus arm B, 73.8%; p=0.528); 2) emesis-free patients on other MEC regimens (arm A, 83.8% versus arm B, 90%; p=0.184); 3) nausea-free patients on AC regimens (arm A, 38.5% versus arm B, 44.3%; p=0.533); and 4) nausea-free patients on other MEC regimens (arm A, 58.6% versus arm B, 64%; p=0.418). Conclusions: The single-day regimen of PALO and DEX can provide effective protection against acute and delayed emesis from AC- and MEC-based regimens while avoiding to unnecessarily prolong treatment with DEX. No significant financial relationships to disclose.
Roles and regulations of Rho-kinases in hepatocellular carcinoma
Authors: Carmen Wong, Yick-Pang Ching, Irene Ng
Journal: Cancer Research (2007)

1340  Hepatocellular carcinoma (HCC) is the most common liver cancer and is one of the most prevalent cancers in the human population which causes 500, 000 deaths per annum. However, a complete understanding of the underlying molecular mechanisms involved in HCC is still missing. Since intrahepatic metastasis is the main cause of lethality in HCC patients, study of the molecular mechanisms involved in intrahepatic extension engages a high significance. Rho GTPases (Rho) are responsible for reorganizing actin cytoskeleton in cells and hyperactivation of Rho is implicated in cancer cell metastasis and invasion. Rho-associated serine-threonine protein kinase (ROCK), a downstream effector of Rho, can be activated by the active GTP bound form of Rho, and ROCK is found to be related to the regulations of cell migration. However, the functional roles and regulations of ROCK in HCC still remain to be elusive and hence were investigated herein.  In this study, we demonstrated that ROCK was overexpressed in 59% of primary HCC by at least 2 fold comparing with their corresponding non-tumorous livers in protein level. Besides, ROCK was highly expressed in HCC cell lines especially those with high metastatic potential. Furthermore, ROCK specific inhibitor, Y27632, exhibited substantial inhibitory effect in HCC cell migration via suppressing the formation of stress fibers and focal adhesions in HCC cells.  Rho/ROCK upstream regulators are important in determining the fate of the cell by controlling Rho/ROCK pathway. Members of GTPase Activating Proteins (GAPs) family, well-known negative regulators of Rho, inactivate Rho by promoting Rho to stay in its inactive GDP bound form. Deleted in Liver Cancer 1 (DLC1), encodes a RhoGAP protein, is a potential upstream negative regulator of Rho/ROCK pathway. In this study, we verified the regulatory role of DLC1 in ROCK activity. Ectopic expression of DLC1 inhibited ROCK activity and this inhibitory effect was completely lost in DLC1 RhoGAP deficient mutant, demonstrating that DLC1 negatively regulated ROCK activity via RhoGAP. In conclusion, we showed that ROCK is implicated in HCC cell migration and ROCK activity is negatively regulated by DLC1 in a RhoGAP dependent manner.