tbuckley/cabot-search huggingface dataset:
Association between P53 expression or TP53 codon 72 polymorphism and prognosis in patients with operated invasive breast cancer
Authors: J. Jeong, Y. Chae, J. Kim, S. Sohn, H. Park, J. Park, J. Yang, I. Park, Y. Lee
Journal: Journal of Clinical Oncology (2009)

e22175 Background: The present study analyzed the impact of p53 expression and TP53 codon 72 polymorphism on the prognosis in patients with operated invasive breast cancer. Methods: Two hundred thirty-four patients with ductal breast cancer who underwent surgery with curative intent were enrolled in the present study. The tumor expressions of p53, ER, PR, and HER2 were graded immunohistochemically and TP53 codon 72 polymorphism was determined by a PCR-RFLP assay using genomic DNA extracted from paraffin-embedded tissue. Results: The median age was 49 (range, 24–82) years, and 134 (57.3%) patients were premenopause at the time of diagnosis. Pathologic stages after surgery were as follows: stage I (n=77, 32.9%), stage II (n=110, 47.0%), and stage III (n=47, 20.1%). Tumor overexpression of p53 protein was observed in 59 (25.2%) patients and was associated with an unfavorable relapse-free survival (RFS) in an univariate analysis adjusted to age, stage, and menstrual status. In a multivariate analysis, p53 overexpression was an independent prognostic factor for RFS (HR=2.36; 95% CI=1.09–5.13; p=0.030). However, no associations were observed between the genotype of TP53 codon 72 polymorphism and survival or clinicopathologic characteristics. Conclusions: Overexpression of p53 protein can be considered as a prognostic factor for RFS in the breast cancer patients after surgery. No significant financial relationships to disclose.
Abstract 833: S100A4 interacts with p53 in the nucleus promoting its degradation.
Authors: Lukas Orre, Elena Panizza, Vitaliy Kaminskyy, Torbjörn Gräslund, Boris Zhivotovsky, Janne Lehtiö
Journal: Cancer Research (2013)

Abstract Background. S100A4 is a calcium binding protein which has no known enzymatic activity, but it exerts its function by binding and regulating other molecules, among which have been described Myosin and p53. S100A4 has been shown to be upregulated in several types of cancers, correlating with poor prognosis and metastasis. In a previous study (Orre et al., 2007), S100A4 has been shown to be involved the cellular response to ionizing irradiation in a p53 dependent manner; our aim here was therefore to investigate the cellular interaction partners of S100A4 in response to p53 and then, based on this data, to further elucidate the cellular function of S100A4. Observations. Nutlin-3A is a compound that specifically stabilizes p53 through inhibiting the interaction between p53 and mdm2. We could show an interaction between S100A4 and p53 via immunoprecipitation in the NSCLC cell line A549 (which has a high expression of S100A4 and a wild-type p53), and that this interaction is increased after Nutlin-3A treatment. The interaction has been independently confirmed via Proximity Ligation Assay, showing as well that the protein complexes are localized in the nucleus. Since this interaction increased after inhibition of the mdm2-p53 interaction, we hypothesized that S100A4 could be involved in regulation of p53 degradation; therefore we generated two cell lines from A549, infected with S100A4 shRNA (shS100A4) or an Empty Vector shRNA (shEV) as a control. Knockdown of S100A4 resulted in stabilization of p53 and transactivation of p53 transcriptional targets; it also resulted in higher sensitivity to cisplatin-mediated apoptotic cell death, measured as a drop in mitochondrial membrane potential, caspase-3 activation and AV/PI assay. We confirmed this finding by an independent method using transient S100A4 down regulation via siRNA; this resulted in an increase in p53 level and of p21 and MDM2 level in A549 adenocarcinoma cells. S100A4 siRNA resulted also in p53-dependent growth arrest, that was reversed after co-transfecting p53 siRNA. Conclusions. Our data show that S100A4 interacts with p53 increasing its degradation, resulting in higher cell viability and lower apoptosis after cisplatin treatment. A possible correlation in patients between S100A4 overexpression and cisplatin resistance could be used to drive treatment selection. Citation Format: Lukas Orre, Elena Panizza, Vitaliy Kaminskyy, Torbjörn Gräslund, Boris Zhivotovsky, Janne Lehtiö. S100A4 interacts with p53 in the nucleus promoting its degradation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 833. doi:10.1158/1538-7445.AM2013-833
Phase I/II clinical and pharmacokinetic trial of heptaplatin and 5-FU combination treatment in advanced head and neck cancer
Authors: J.-H. Kang, H.-J. Kuh, J.-H. Lee, J.-Y. Shin, K.-S. Lee, J.-A. Jung, D.-Y. Chang
Journal: Journal of Clinical Oncology (2005)

5550 Background: Heptaplatin (SKI-2053R, Sunpla) is a platinum compound, which has shown equivalent anti-tumor activity and less toxicity compared to cisplatin and was approved for advanced gastric cancers in Korea. We conducted phase I/II clinical trial of heptaplatin and 5-FU combination treatment in head & neck squamous cell carcinoma (HNSCC). In phase I study, maximal tolerated dose (MTD) and dose limiting toxicity (DLT) as well as pharmacokinetics (PK) of heptaplatin and 5-FU were investigated. Methods: Fourteen patients with metastatic or recurrent HNSCC were enrolled. Heptaplatin was administered as 24 hr continuous infusion followed by continuous infusion of 5-FU (1,000 mg/m2/d) for 5 days. The dose of heptaplatin was escalated by 50 mg/m2 from 500 mg/m2 according to modified Fabonacchi method. Peripheral blood was collected until 96hr post-treatment and the conc. of heptaplatin in total plasma, plasma ultrafiltrate and RBC fraction were determined using FAAS. Steady-state plasma conc. (CP, ss) of 5-FU was determined using HPLC-UV. Results: Dose of 5-FU was reduced to 750 mg/m2/d due to severe toxicities and MTD of heptaplatin was 600 mg/m2. The average AUC (last), CL (inf), and Vz.(terminal) of heptaplatin was 208.32 ng.hr/ml, 1.52 ml/hr, and 183.16 ml, respectively. Cmax was observed at the end of infusion and was 4.25 ng/ml, 1.92 ng/ml, 1.11 ng/ml in total plasma, plasma filtrate, and RBC, respectively. No differences of heptaplatin conc. were found in different dose levels of heptaplatin. Seven-fold difference in the average Cp,ss of 5-FU was observed among the fourteen patients, indicating great inter-patient variation in PK of 5-FU. There were no significant changes of average Cp,ss of 5-FU, even though the dose of 5-FU was reduced from 1,000 mg/m2/d to 750 mg/m2/d. Conclusions: The average Cp,ss of 5-FU was significantly increased with dose escalation of heptaplatin from 500 mg/m2 to 600 mg/m2, i.e., Cp,ss 240 ng/ml to 500 ng/ml, suggesting pharmacokinetics interaction between 5-FU and heptaplatin. No significant financial relationships to disclose.
Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients not candidates for optimal primary surgery: Safety and effectivenes.
Authors: Vanessa Costa Miranda, Angelo Bezerra de Sousa Fede, Carlos Henrique Dos Anjos, Juliana Ribeiro da Silva, Fernando Barbosa Sanchez, Lyvia Rodrigues da Silva Bessa, Jesus Paula Carvalho, Dr Elias Abdo Filho, Daniela Freitas, Laryssa Almeida Borges de Barros, Samantha Cabral Severino da Silva, Maria Del Pilar Estevez-Diz
Journal: Journal of Clinical Oncology (2013)

5540 Background: Primary debulking surgery (PDS) has been considered the standard of treatment in advanced ovarian cancer, while neoadjuvant chemotherapy, three cycles followed by interval debulking (ID) surgery, is a valid treatment alternative for patients with non-resectable disease. This study aimed to show the efficacy and safety of six cycles of neoadjuvant chemotherapy (N-CT) followed by cytoreduction, a single institution experience. Methods: Aretrospective analysis was performed of all patients (pts) with advanced ovarian cancer treated with platinum based N-CT, between January/2004 and February/2012. Results: 97 pts underwent N-CT in our institution; 78.1% and 18.8% the patients had extensive stage IIIC or IV disease at diagnosis, respectively. Median age 60 years (36 – 82). Histologic types: serous 84.5%, adenocarcinoma not specified 11.3%, endometrioide 1.0%. A median of six cycles of chemotherapy were performed. Patients did not received chemotherapy after debulking surgery. During the treatment 31.4% had grade 3/4 toxicity, the most commonly observed toxicities were hematologic toxicities and nausea, four (4.1%) patients died during chemotherapy due to disease progression. After N-CT 24.7% achieved clinical complete response, 57.7% partial response and 12.4% disease progression. From this cohort 63.1% underwent a complete resection of all macroscopic and microscopic disease (R0). Median length of hospital stay and postoperative ICU stay was 5 and 0.8 days respectively, surgical complications were not common however five (7.1%) patients needed second surgery due to operatory complications and 19 pts (27.1%) needed blood transfusion after debulking. With a median follow up of 21.8 months (0.5-139.7), median overall survival and chemotherapy-free interval were 57,7 and 9,5 months, respectively. Conclusions: Six cycles of neoadjuvant carboplatin and paclitaxel is safe, effective and does not increase perioperative and postoperative complications for patients with stage IIIC-IV not candidates for optimal/R0 PDS. The overall survival of this cohort is higher than those treated with interval debulking surgery.
Low diagnostic accuracy of the AASLD radiologic criteria for hepatocellular carcinoma in grade I tumors.
Authors: M. Iavarone, A. Sangiovanni, G. Ronchi, M. A. Manini, L. V. Forzenigo, M. Colombo
Journal: Journal of Clinical Oncology (2010)

e14606 Background: Contrast-enhanced ultrasound (CE-US), contrast computerized tomography (CT)-scan and gadolinium dynamic magnetic resonance (MRI), are recommended for the characterization of liver nodules detected during surveillance of cirrhotics with US. In a recent study of 64 patients with 67 liver nodules, a sensitivity of 26%, 44% and 44% for CE-US, CT, and MRI for 1-2 cm hepatocellular carcinoma (HCC), with 100% specificity were demonstrated. Aim: To correlate the vascular pattern on contrast-enhanced imaging techniques with cell differentiation (grade) of HCC. Methods: Seventy-five cirrhotic patients were consecutively examined by CE-US, CT, MRI and a fine-needle biopsy as diagnostic standard. The typical radiological feature of HCC was arterial phase hypervascularization followed by portal/venous phase wash-out. Histopathological diagnoses were made according to the Edmonson grading system. Results: HCC was diagnosed in 52 (66%) nodules (3 < 1 cm, 41 1-2 cm, 8 > 2 cm). Tumor grading was grade I in 14 (27%, median diameter 1.5 cm), grade II in 24 (46%, median diameter 1.5 cm), grade III in 14 (27%, median diameter 1.8 cm), grade IV in none. There was no relationship between tumor differentiation and etiology of liver disease (virus vs alcohol), nodule size and alfafetoprotein levels. At CT scan, the typical vascular pattern was present in 27/52 (52%) HCC: 3 (21%) grade I, 14 (58%) grade II, 10 (71%) grade III (p = 0.02). On CE-US, the typical vascular pattern was present in 17/52 (33%) HCC: 3 grade I (21% of all grade I), 8 grade II (33% of all grade II), 6 grade III (43% of all grade III) (p = 0.48). At MRI, the typical vascular pattern was present in 23/52 (52%) HCC: 3 (21%) grade I, 11 (50%) grade II, 9 (64%) grade III (p = 0.06). The AASLD criteria for radiological diagnosis of HCC were present in 2 grade I HCC (14%), 11 grade II HCC (46%) and 9 grade III HCC (64%) (p = 0.02). Conclusions: The diagnostic accuracy of the AASLD radiological criteria for HCC is low in grade I tumors but appreciably increases in grade II and III HCC. No significant financial relationships to disclose.
Are There Any Causal Relations Between Growth Differentiation Factor 15 and Outcomes in Patients With Acute Coronary Syndrome? : - A Report From the Plato Gwas Study
Authors: Emil Hagström, Niclas Eriksson, Åsa Johansson, Maria Bertilsson, Tomas Axelsson, Bryan J. Barratt, Richard C. Becker, Anders Himmelmann, Stefan K. James, Hugo A. Katus, Agneta Siegbahn, Philippe G. Steg, Robert F. Storey, Ann-Christine Syvänen, Christoph Varenhorst, Axel Åkerblom, Lars Wallentin
Journal: Circulation (2013)

Are There Any Causal Relations Between Growth Differentiation Factor 15 and Outcomes in Patients With Acute Coronary Syndrome? : - A Report From the Plato Gwas Study
Evaluation of drug-related discomfort in patients receiving intravenous dexamethasone
Authors: J. G. Kattan, J. G. Kattan, E. E. Assaf, Y. Greige, S. N. Sadaka
Journal: Journal of Clinical Oncology (2004)

8171 Background: Dexamethasone, as an antiemetic or an antianaphylactic drug, became used as a routine drug in premedicating chemotherapy. Perineal pruritis or hot flashes were occasionally described during Dexamethasone administration in some patients. Methods: In order to define the prevalence, the type, and the intensity of these discomforts, we performed a prospective study based on a questionnaire filled by all treated patients during their chemotherapy administration. Results: During a five months period, from May until September 2003, 37 patients (pts) receiving 114 courses including 3- minutes IV administration of 16 mg of Dexamethasone as premedication, were enrolled. Primary tumors were solid in 30 pts and hematologic in 7 pts. There were 12 males and 25 females. Mean age was 58.6 (extremes 34 to 82 years). 30 pts during 80 courses experienced Dexamethasone - related-discomfort (DRD). The DRD was hot-flash in 5 pts during 6 courses, and perineal discomfort in 25 pts during 70 courses. The perineal discomfort was described as pruritis in 46 courses, as burn in 36 courses, and as tingling in 5 courses. 2 pts experienced both hot flash and perineal pruritis. The intensity of the DRD was described as high in 10 pts during 20 courses, as moderate in 24 pts during 46 courses, and as minimal in 12 pts during 14 courses. The duration of the DRD was limited to the time of Dexamethasone infusion in 26 pts during 75 courses, and it lasted for few minutes (< 10 minutes) after the infusion time in 4 pts during 5 courses. Neither the age, the sex,nor the type of the tumor were related to the DRD occurrence. Conclusion: DRD is an underestimated, but a frequent side-effect. It is encountered in 70 % of chemotherapy administered cycles. 87 % of these DRD are perineal discomfort . It is experienced as highly disturbing in 25 % of the courses. Administration of Dexamethasone in 50 ml 5 % Dextrose during 10 minutes is under investigation as an attempt to circumvent DRD No significant financial relationships to disclose.
Phase I and pharmacokinetics (PK) of combined erbB1 and erbB2 blockade with OSI-774 (erlotinib; E) and trastuzumab (T) in combination with weekly paclitaxel (P) in patients (pts) with advanced solid tumors
Authors: A. Patnaik, M. Beeram, J. S. de Bono, A. Mita, S. C. Chu, E. K. Rowinsky, G. Schwartz, P. O’Rourke, C. H. Takimoto, A. W. Tolcher
Journal: Journal of Clinical Oncology (2005)

2000 Background: Co-expression of erbB1 and erbB2 receptors confers a growth advantage in erbB2 overexpressing (+) cancers. Specifically, co-expression alters the normal rapid internalization and inactivation of erbB1, slows dissociation of the erbB1 ligand-receptor complex and degradation of the active receptor. Co-targeting both receptors together may offer a therapeutic advantage over targeting erbB2 alone, especially in T refractory solid tumors. A phase I and PK study was launched to determine the toxicity and recommended dose of continuous daily oral E in patients with erbB2 + cancers along with weekly P and T, especially since T improves survival in combination with chemotherapy. Methods: Eligible pts were treated with escalating doses of E and weekly T IV (2 mg/kg/wk) along with weekly P (starting at 80 mg/m2). MUGA scans were performed at baseline and every 2 cycles (8 weeks). Two schedules- 3 out of 4 weeks and continuous weekly P and T were explored. Results: To date, 16 pts [Breast (14), Colon (1) and Ovary (1)] have received 54 courses [median 2; range 1–13] in 4 cohorts, with E at doses of 50 (n=3), 100 (n=9) and 150 mg (n=4) PO daily for 28-days and P at doses of 80 - 90 mg/m2 weekly for 3 out of 4 weeks. Pts were women with median age -54 yrs [range- 37–75] and PS 0 (4), PS 1 (11) and PS 2 (1). 9 pts received prior T therapy. Dose limiting grade (gr) 3 diarrhea and gr 3 dermatitis was seen in 1 pt at 100 mg of E and 80 mg/m2of P. Other toxicities included gr 2 diarrhea, skin rash, fatigue, neutropenia and alopecia. Significant asymptomatic drop in LVEF was noted in 1 pt after 3 courses, with rapid recovery upon stopping T. One complete and two partial responses have been seen in pts with breast cancers that have failed prior T therapy. Two breast cancer pts experienced stable disease lasting 13 and 6 courses, respectively. Preliminary PK data does not suggest a clinically relevant interaction between the 3 agents. Conclusions: E combined with T and P provides a well-tolerated, targeted therapy with impressive anti-tumor activity in T-refractory breast carcinoma. Dose escalation continues on the continuous dosing schedule. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI
Efficacy results of cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with advanced or metastatic cholangiocarcinoma: A single centre phase II study
Authors: B. Gruenberger, J. Schueller, K. Kaczirek, M. Bergmann, W. Klose, M. Bischof, G. Schernthaner, T. Gruenberger
Journal: Journal of Clinical Oncology (2008)

4586 Background: Patients with advanced cholangiocarcinoma have a poor prognosis and until now, no standard palliative chemotherapy has been defined. The purpose of this prospective single-centre phase II study was to investigate the therapeutic efficacy and saftey of cetuximab in combination with gemcitabine and oxaliplatin in the palliative first line treatment of these patients. Methods: Patients with locally advanced or metastatic cholangiocarcinoma or gallbladder cancer with no prior palliative chemotherapy were eligible. cetuximab 500 mg/m² on day 1 followed by 1,000mg/m² gemcitabine (day 1) and 100mg/m² oxaliplatin on day 2 were administered every second week. The primary endpoint was response rate; secondary endpoints were toxicity, progression free and overall survival. Results: From October 2006 until December 2007 twenty-two patients (11 male, 11 female) with a median age of 65 were enrolled. The overall response rate of evaluable patients (19) was 58%, including one patient with a complete response. 6 patients (32%) achieved stable disease and only 2 patients (11%) progressed under chemotherapy after a median of 6.5 cycles (SD ± 2.8). The response was significantly correlated with the grade of acne-like rash (p < 0.002). Six initially unresectable patients underwent a curative resection after major response was observed (32%). Any WHO grade 3/4 drug-related adverse events occurred in 7 patients (35%), consisting of skin toxicity in 2 patients, thrombopenia in 1, nausea in 1, diarrhoe in 1 and PNP in 3 patients. The median PFS was 9.0 months (95% CI 3.1–14.9). Four patients are currently without evidence of disease after a median follow-up of 6.3 months post curative liver resection. Conclusions: Cetuximab in combination with gemcitabine and oxaliplatin seems a well tolerated regimen in patients with cholangiocarcinoma. The first results demonstrate promising efficacy for both response rates and progression-free survival. Therefore cetuximab in combination with GEMOX deserves further evaluation in prospective randomized trials. No significant financial relationships to disclose.
Comparison of randomized phase II studies (RP2s) and subsequent randomized controlled studies (RCTs) using identical systemic therapies
Authors: J. C. Bin, G. R. Pond, E. X. Chen
Journal: Journal of Clinical Oncology (2009)

e17515 Background: Previous research has shown that results from single-arm phase 2 studies are poor predictors of results from subsequent RCTs. It has been suggested that RP2s are more efficient in predicting outcomes of RCTs, and RP2s have increasingly been used in evaluating novel agents or therapeutic strategies. We attempted to determine if results from RP2s were concordant with outcomes of RCTs. Methods: We searched Medline and Cancerlit for RP2s evaluating systemic therapies for advanced solid malignancies, published from January 2000 to October 2008. Each publication was reviewed and a search was conducted for RCTs using identical therapies. Results of each RCT were reviewed and determined to be either “positive” or “negative” based on whether the stated primary endpoint of the study was met. Additional data such as year of publication, journal impact factor, number of patients enrolled, whether multiple centers were involved, response rates (RR), and survival data were collected. The rate of concordance between RP2s and RCTs was determined and univariate analyses were performed to determine potential predictors from RP2s of “positive” RCTs as well as concordance. Results: A total of 196 RP2s meeting study criteria were identified. However, only 16 had corresponding RCTs. Among these 16 RCTs, 11 showed concordance with RP2s results, for a rate of 68%. There was a moderately strong association between RRs from RP2s and corresponding RCTs, with a mean difference in RR of -3.8% (95% CI -10.6 to 3.0%). The difference in median survival was 1.0 mo (95% CI -1.0 to 3.2) and for time to progression it was -0.5 mo (95% CI -1.0 to 1.1) between RP2s and RCTs. No characteristics from RP2s could predict positivity or concordance with RCTs. Conclusions: Based on this small size of RP2s and RCTs, results from RP2s have relatively high concordance with results from RCTs. However, there were no significant predictors of concordance. No significant financial relationships to disclose.