tbuckley/cabot-search huggingface dataset:
Phase I dose escalation study of SR271425 administered as 24-hour intravenous continuous infusion in patients with refractory solid tumors
Authors: F. de Braud, C. Sessa, E. Gallerani, G. Curigliano, C. Cipolla, A. Columbo, A. Gallino, G. Schackleton, C. Zilocchi, M. Chadjaa
Journal: Journal of Clinical Oncology (2005)

3116 Background: SR271425 is a DNA-binding agent from a new class of cytotoxics. This clinical trial aims to determine dose-limiting toxicities (DLTs), maximal tolerable dose (MTD) and PK profile of SR271425 given as 24-hour (h) IV infusion every 3 weeks. Methods: An accelerated dose escalation schema has been used similar to the 2b method (Eisenhauer EA, et al, JCO 2000). SR271425 was administered intravenously over 24 hr every 3 wks. Bloud samples were obtained during the infusion and up to 24 h post-infusion for the determination of SR271425 in plasma using a validated LC-MS/MS Method: Since a predecessor thioxanthone agent has been shown to prolong QTc and caused Torsade de pointes, careful monitoring of QTc was done including central reading of ECGs. Results: 31 patients have been enrolled; 20 men, 11 women, median (med) age 54 range 31–72, med ECOG performance status: 0 range 0–1. Tumor types: 7 colorectal, 5 pancreas, 4 sarcoma, 4 melanoma, 3 renal, 3 prostate, 1 lung, 4 others, eleven dose-levels from 128 mg/m2to 2920 mg/m2, med number of cycles was 2 (1–8). Grade (Gr) 1–2 toxicities included QTc prolongation, nausea/vomiting, venous inflammation at injection site and yellow skin discoloration. Two pts experienced DLT’s (Gr 3 QTc prolongation as defined using CTCv3) with no clinical symptom at 1524 and 2432 mg/m2. Gr 3 neutropenia occurred in 2 pts at the highest dose-levels tested: 2432 and 2920 mg/m2; in 1 pt concomitant Gr 3 anemia and Gr 1 thrombocytopenia were observed. PK data is available in 24 patients; steady state plasma drug concentrations appeared to be reached by the end of infusion, consistent with the drugs elimination half-life of around 8 h. Both Cend and AUC increased in a dose related manner. Mean (± SD) Cl and Vss were 28.0 ± 10.7 L/h and 303 ± 149 L, respectively, and independent of dose. One biological response (PSA decrease in prostatic cancer) and 3 stable disease were observed. Conclusions: Preliminary data show that the 24 h schedule allows increase in the total dose administered by reducing the peak plasma which appears to be correlated with QTc prolongation DLT. At these higher doses tested so far hematological toxicity is observed. The study is ongoing to define the MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis
The prognostic significance of lymphatic invasion in primary melanoma
Authors: X. Xu, L. Chen, W. Hwang, P. Dawson, D. Guerry, P. VanBelle, D. Elder, L. Schuchter, P. Gimotty
Journal: Journal of Clinical Oncology (2009)

9050 Background: Lymphatic invasion (LI) is an under-observed phenomenon in primary malignancies that can be better detected by immunostaining and that may associate with prognosis. In this study we sought to test the hypothesis that LI was associated with melanoma-specific survival (MSS) and was an independent prognostic factor. Methods: This study included 277 patients with stage I/II melanomas in vertical growth phase (VGP) who had at least 10 years of follow up. The log-rank test was used to test the study hypothesis - 72 melanoma-specific deaths were needed for 80% power to detect an odds ratio of 2.1. Paraffin sections were stained with antibodies to podoplanin (lymphatic vessels) and S-100 (melanoma cells) to identify LI. Univariate and multivariate Cox models were used to evaluate the prognostic significance of LI. An independent cohort of 106 similar patients was used for validation of the 10-year MSS rates. Results: LI was observed in 44.5% (95% CI: 38.6% - 50.4%) of the melanomas and its presence was significantly associated with thickness, mitotic rate, gender, age, and ulceration (U). The Kaplan-Meier survival curves for those with and without LI were significantly different (log-rank test p=0.022). The final multivariate model for time to MSD identified 4 independent prognostic factors: thickness (HR=1.5, p&lt;0.001), U (HR=2.2 p=0.013), site (HR=3.9, p&lt;0.001) and LI (HR=1.9, p=0.015). These factors were used to define a prognostic tree with 5 risk groups defined by melanomas that were thin (≤1.0mm) with no LI or U; thin with LI but no U; 1–3mm with no U; 1–3mm with U; and &gt;3mm. Respectively, MSS rates were 100%, 88.6%, 77%, 48% and 42%. In the validation set, observed 10-year MSS rates in each risk group were not significantly different from those predicted from the survival curves for the tree-based risk groups. Conclusions: LI is an independent prognostic factor for MSS. Among patients with thin melanomas without U the 10-year MSS was lower for those patients with LI (89%, 95% CI=78% - 99%; n=41) compared to those without (100%, n=78). LI is an important prognostic factor that needs further validation in a population of patients from the sentinel node biopsy era. No significant financial relationships to disclose.
Variables with time-varying effects and the Cox model: Illustration with the role of estrogen receptor status in breast cancer
Authors: C. A. Bellera, G. MacGrogan, M. Debled, C. Tunon de Lara, V. Brouste, S. Mathoulin-Pélissier
Journal: Journal of Clinical Oncology (2008)

6584 Background: The Cox proportional hazards model allows one to estimate the effect of factors influencing a time-to- event or survival time. This model, however, relies on a fundamental assumption, the proportionality of the hazards (PH): given two individuals with distinct values for a specific factor, the ratio of the estimated hazards is constant over time. A typical example in the genral population is the effect of age on the survival time following surgery. If age is more likely to impact the survival immediately after surgery than weeks or months later, then the PH hypothesis would not hold, and thus misleading effect estimates could be derived. Altman et al. showed that the majority of cancer publications do not report verifying this crucial assumption. Methods: We emphasize the importance of the assumption of the Cox model, and the misleading conclusions that can be inferred if it is violated. We recall that the hazard ratio (HR) provided by the Cox model is a time-averaged hazard ratio. If the HR changes over time, this time-averaged HR might not be representative of the true effect. Results: We illustrate our discussion by analyzing time to metastases in 855 women treated with surgery for a primary breast cancer, with the following prognostic factors: age, tumor size, SBR grade, vascular emboli, lymph node involvement, estrogen (ER) and progesterone receptor status, Her2 status, Mib1 proliferation index. The median follow-up time was 11 years, and there were 216 relapses. While ER was not significantly associated with the time to metastases in the initial Cox model, further analyses showed that ER effect was not constant over time. On average over the study follow-up, ER is not associated with time to metastases, but given the non constant HR, ER may have an impact over some specific periods of time. Conclusion : Our example illustrates that misleading conclusions can be inferred when one ignores the PH assumption. We provide statistical elements the reader should look for when reviewing clinical publications relying on a Cox model; this is particularly important when the follow-up period is long. No significant financial relationships to disclose.
Sorafenib targets BRAF and VEGFR in metastatic thyroid carcinoma
Authors: V. Gupta, K. Puttaswamy, W. Lassoued, M. Redlinger, K. Ransone, K. Gold, W. Lee, V. LiVolsi, D. Fraker, S. Mandel, M. S. Brose
Journal: Journal of Clinical Oncology (2007)

6019 Background. There is no effective therapy for patients with metastatic thyroid cancer not cured by surgery or treatment with I 131 . Sorafenib is a promising multi-tyrosine kinase inhibitor for patients with metastatic PTC (mPTC). Although the primary targets of sorafenib are thought to include BRAF and VEGFR, this has been the subject of debate. Whether sorafenib primarily acts on the tumor cells (TC) or endothelial cells (EC) and how BRAF mutation status (45% of PTC harbor V600E) relates to response is also unknown. Methods. Responses of patients with metastatic, iodine-refractory PTC, enrolled into our phase II study of sorafenib were monitored by PET at 4 wks and CTs every 2 mos. Sorafenib activity was studied using immunohistochemistry (IHC) for pERK, pAKT, and pVEGFR-2, while Ki-67 showed proliferating cells in tumor tissue pre- and on treatment. BRAF mutation status was determined by DNA sequencing. Results. Of 15 patients, five patients achieved a PR, three are stable (SD), two progressed, and three patients with SD withdrew due to toxicity. Target lesions decreased on average 31%. Eight of 10 PET scans showed decreased activity at 4 weeks. IHC on tissue from 2 patients (at 1 and 2 wks, both BRAF wt ) showed 50% decrease in pERK (downstream of VEGFR2 and BRAF) and 30% decrease in pAKT (downstream of VEGFR2). p-ERK and p-AKT were altered in both the TC and EC. Ki-67 decreased from 10% to &lt;1%. No change in VEGFR-2 was seen; but, pVEGFR-2 completely disappeared in one sample while the other showed a small decrease. Quantitative analysis using a multispectral imaging system confirmed the changes observed by IHC. In tissue from a patient at 17 months on sorafenib, the decrease in pERK and pAKT appeared to be the same or reversed, suggesting compensatory changes in these pathways in resistant but stable disease. Conclusions. Our study shows the early clinical and biologic activity of sorafenib in patients with mPTC and the targets of early suppression. Importantly, it also reveals compensatory changes in target molecules in cells resistant to therapy. These cells are the likely source of tumor resistance that has been seen to develop to other similar targeted agents. Sorafenib is the first viable treatment option for patients with mPTC, and these results provide key insights into the mechanisms of action and resistance of this drug. No significant financial relationships to disclose.
Impact of insulin-like growth factor gene polymorphisms on survival of patients with colorectal cancer.
Authors: B. Kang, J. Kim, Y. Chae, S. Sohn, S. Kim, S. Lee, J. Jeong, J. Baek
Journal: Journal of Clinical Oncology (2010)

e14076 Background: Insulin-like growth factors (IGF) regulate a wide range of biological functions including cell proliferation, differentiation, and apoptosis through paracrine and autocrine mechanisms. Accordingly, the present study analyzed polymorphisms of IGF genes and their impact on the prognosis for patients with colorectal cancer. Methods: Four hundred and thirty-five consecutive patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 8 polymorphisms of IGF genes (IGF1 −16540A >G, IGF1 +1830C>T, IGF1 −177G>C, IGF1 − 533C>T, IGF1 −2995C>A, IGF2 +1280A>G, IGF2 −69C>T, IGF2 −233C>T) determined using a real-time PCR genotyping assay. Results: The median age of the patients was 64 years (range, 21–85), and 252 (56.6%) patients had colon cancer and 193 (43.4%) patients rectal cancer. Pathologic stages after surgery were as follows: stage 0/I (n = 85, 19.1%), stage II (n = 149, 33.5%), stage III (n = 148, 33.3%), and stage IV (n = 63, 14.2%). Multivariate survival analysis including stage, age, site of disease, and CEA level showed that the progression-free survival for the patients with the combined IGF2 +1280 AA and AG genotype was better than for the patients with the IGF2 +1280 GG genotype (hazard ratio [HR] = 0.666, 95% Confidential Interval [CI], 0.459-0.967, p = 0.033), although there was no significant difference in the overall survival. However, the other polymorphisms were not associated with survival. Conclusions: The +1280A>G polymorphism of IGF2 may be associated with progression-free survival for patients with colorectal cancer. However, further studies are warranted to clarify the role of IGF gene polymorphisms as a prognostic biomarker for colorectal cancer patients. No significant financial relationships to disclose.
Clinical outcomes in 66 patients with advanced gastric cancer treated in phase I trials: The NCCHE experience.
Authors: Akihito Kawazoe, Kohei Shitara, Shota Fukuoka, Yasutoshi Kuboki, Hideaki Bando, Wataru Okamoto, Takashi Kojima, Takayuki Yoshino, Toshihiko Doi, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2015)

213 Background: Patients with advanced gastric cancer (AGC) have a poor prognosis once standard therapies fail. Phase I trial of investigational drugs might be one of the treatment options for patients with sufficient general status. But, the clinical outcome of patients with AGC treated in phase I trials has not yet been reported in detail. Methods: We retrospectively reviewed the clinical outcomes in 66 consecutive patients with AGC who were treated in phase I trials after standard chemotherapies between March 2008 and July 2014. Results: Median age was 66 years (range, 28-78 years) and all had performance status ECOG 0 or 1. The median number of previous systemic chemotherapy was 3 (range, 1-6) with the median interval from beginning of first-line chemotherapy to enrollment for phase I trials of 18 months. Twenty-three patients were enrolled for two or more phase I trials. Objective response was observed in 5 patients (8%) and additional 8 patients (12%) achieved stable disease &gt;3 months. Although the median time to treatment failure (TTF) of the best phase I treatment was shorter than those of the last line of systemic chemotherapy (1.5 vs. 2.3 months; HR 1.80; P=0.002), the median TTF of best phase I trial was longer than the last line of systemic chemotherapy in 21 patients (32%). Severe adverse events and grade &gt;3 toxicities were reported in 8 patients (12%) and 12 patients (18%), respectively. No treatment related death was observed. Median survival time after enrollment for phase I trials was 7.5 months and 4 death (6%) within 30 days after last administration was observed. Conclusions: The clinical outcome for patients with AGC treated in phase I trials was comparable to that of other malignancies previously reported. These results of our study suggest phase I trial might be one treatment option for patients with AGC after failure of standard chemotherapy.
Clinical significance of CXC chemokine receptor-4 (CXCR4) and c-Met in childhood rhabdomyosarcoma (RMS) tumors
Authors: F. Diomedi Camassei, H. P. McDowell, M. A. De Ioris, P. Altavista, R. Cozza, A. Donfrancesco, A. Inserra, F. Callea, C. Dominici
Journal: Journal of Clinical Oncology (2007)

9510 Background: Both CXCR4/SDF-1 and c-Met/HGF axes promote invasive growth of RMS cells in experimental models, but no data are available on their expression and significance in RMS tumors. Expression for CXCR4 and c-Met (and their ligands) was evaluated in primary RMS tumors and correlated with clinical features, marrow involvement at diagnosis, overall (OS) and progression-free survival (PFS). Methods: Forty newly diagnosed pts, aged 2–180 months (median 58), with embryonal (n. 20) or alveolar (n. 20) RMS admitted between 1994 and 2004 were retrospectively enrolled. The only selection criterion was availability of data on marrow involvement at diagnosis as assessed by cytomorphology and immunocytochemistry for MyoD1 and myogenin. Primary site was favorable (orbit, paratesticular, uterus/vagina) in 7 pts and unfavorable (all the others) in 33. Pts were entered as group I/II (n. 5), III (n. 28) or IV (n. 7) (IRS grouping system). Marrow was infiltrated at diagnosis in 16 pts. Treatment was according to Italian RMS protocols. Expression for CXCR4, SDF-1, c-Met and HGF proteins was investigated by immunohistochemistry. Three separate counts (each &gt;5,000 tumor cells) were performed without knowledge of clinical features and outcome; results expressed as mean percentage of immunostained tumor cells. Student t test, log-rank test, Kaplan-Meier survival analysis were applied. Institutional informed consent and ethical approval were obtained. Results: As of December 2006, median follow-up was 60 months, with 25 pts DF, 1 AWD and 14 DOD. CXCR4 and c-Met were expressed in =5% of tumor cells in all cases, but 14/40 tumors showed =50% tumor cell positivity (high expression) for either markers. High CXCR4 expression correlated with alveolar histology (p=0.006), unfavorable primary site (p=0.009), advanced group (p&lt;0.001), marrow involvement (p=0.007), shorter OS and PFS (p&lt;0.001). High c- Met expression with alveolar histology (p=0.005), advanced group (p=0.04), marrow involvement (p=0.02). SDF-1 and HGF were expressed by a lower percentage of tumor cells (1–95% of cells positive for the correspondent receptor). Conclusions: CXCR4/SDF-1 and c-Met/HGF pathways are clinically relevant in children with RMS and represent novel targets for disease-directed therapy. No significant financial relationships to disclose.
A clinical phase I, pharmacokinetic (PK), and pharmacodynamic study of twice daily BIBF 1120 in advanced cancer patients
Authors: K. B. Mross, D. Gmehling, A. Frost, F. Baas, R. Strecker, J. Hennig, P. Stopfer, M. Stefanic, G. Stehle, L. de Rossi
Journal: Journal of Clinical Oncology (2005)

3031 Background: BIBF 1120 is a potent, orally available triple angiokinase inhibitor (VEGFRs, PDGFRs, FGFRs) that suppresses tumor growth by angiogenesis inhibition. After an initial study with once daily dosing in advanced cancer patients, twice daily (bid) dosing was performed in order to increase drug exposure without increasing toxicity. Methods: Treatment cycles consisted of 28 days continuous administration of BIBF 1120 bid followed by 7 days off. The dose was escalated until dose limiting toxicity (DLT) was observed. Further treatment cycles were allowed in the absence of progressive disease and persistent toxicity. PK profiles were obtained at the beginning and at end of the 1st cycle. Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) was performed at baseline, day 3, day 30, and after each further cycle. Results: 36 patients (5 female, 31 male) were included, 33 completed treatment cycle 1, and 3 patients were excluded due to unrelated adverse events (AE) or DLT. The dose was escalated according to the following scheme: 150 mg bid, 150+200 mg, 200 mg bid, 250 mg bid and 300 mg bid. Main drug-related AEs (mostly ≤CTC°2) were nausea, vomiting, and diarrhoea. Elevations of hepatic enzymes (LFT) were dose limiting (≥CTC°3) in 2/5 patients at 300 mg bid. 23/36 patients (64%) were treated for more than two cycles. 3 patients showed a partial tumor response at ≥200 mg bid (RECIST). In DCE-MRI, blood flow and permeability (IAUC60) in target lesions were reduced by ≥40% in 10/34 evaluable patients. BIBF 1120 exposure (AUC) displayed moderate to high variability. Maximum plasma concentrations were reached ∼3 hours after drug intake. BIBF 1120 was extensively distributed out of the blood and showed a high clearance with a mean terminal half-life of ∼15 h. Conclusions: As compared to once daily dosing, bid administration of BIBF 1120 allowed increased drug exposure to cancer patients without additional toxicity. AEs largely consisted of mild/moderate gastrointestinal toxicity. Reversible LFT elevations constituted DLT at 300 mg bid. Based on these results, 250 mg bid is considered the maximum tolerated dose of BIBF 1120. Encouraging signs of anti-tumor activity have been observed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Boehringer Ingelheim Boehringer-Ingelheim
Phase II study of CC-5013 in patients (pts) with metastatic renal cell cancer (MRCC)
Authors: A. Rawat, M. N. Needle, B. Miles, R. J. Amato
Journal: Journal of Clinical Oncology (2005)

4604 Background: Immunomodulatory drugs are compounds that originated via the deliberate structural modification of thalidomide. CC-5013 a derivative with enhanced immunological and anti-angiogenic properties lacking toxicities associated with Thalidomide. Objectives were to determine response rate, time to progression, one-year survival, and toxicity in patients with progressive MRCC. Methods: Eligibility included: metastatic measurable disease, normal organ/marrow function, Zubrod Performance Status (ZPS) ≤ 2, life expectancy ≥ 3 months, ≤ 1 prior therapy, and no CNS involvement. CC-5013 was administered orally at a dose of 25mg daily for 21 days with 7 days rest (28-day cycle), with dose modifications for toxicity. Re-evaluation is done every three cycles (12 weeks). RECIST criteria is utilized to determine response rate. Time to progression is determined from entry into study. Results: Forty pts enrolled. 30 male/10 female, range 38–73 (median 63) years. All pts had histologically confirmed progressive MRCC; 385 pts had clear cell carcinoma, 3 pts with clear cell plus a granular component; 2 pts with papillary. 24 pts received prior immunotherapy and/or chemotherapy. All pts had a ZPS of 0. Sites of disease included: lung, nodal, bone, adrenal, kidney, and liver. Seventeen pts had 1 metastatic site, 13 pts had 2 metastatic sites, and 10 pts had 3 or more metastatic sites. Ten pts continue to receive CC-5013 therapy. Thirty-six pts completed at least 12 weeks of therapy. Three Four pts had early progressive disease. Three pts had partial responses, 13 patients are were stable for 6+ months. Median duration of therapy is 5.6+ months (range <1–12+). Conclusion: CC-5013 was well tolerated. Antitumor activity has been demonstrated by a 7.5% partial response rate in MRCC pts. Antitumor activity was suggested by prolonged time to progression ≥ 6 months, for 327.5% of pts. The tumor effect was also demonstrated as a second-line therapy following cytokine failure. CC-5013 continues to be investigated for the treatment of MRCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Celgene
Evolution of SUMO Function and Chain Formation in Insects
Authors: Enric Ureña, Lucia Pirone, Silvia Chafino, Coralia Pérez, James D. Sutherland, Valérie Lang, Manuel S. Rodriguez, Fernando Lopitz-Otsoa, Francisco J. Blanco, Rosa Barrio, David Martín
Journal: Molecular Biology and Evolution (2015)

SUMOylation, the covalent binding of Small Ubiquitin-like Modifier (SUMO) to target proteins, is a posttranslational modification that regulates critical cellular processes in eukaryotes. In insects, SUMOylation has been studied in holometabolous species, particularly in the dipteran Drosophila melanogaster, which contains a single SUMO gene (smt3). This has led to the assumption that insects contain a single SUMO gene. However, the analysis of insect genomes shows that basal insects contain two SUMO genes, orthologous to vertebrate SUMO1 and SUMO2/3. Our phylogenetical analysis reveals that the SUMO gene has been duplicated giving rise to SUMO1 and SUMO2/3 families early in Metazoan evolution, and that later in insect evolution the SUMO1 gene has been lost after the Hymenoptera divergence. To explore the consequences of this loss, we have examined the characteristics and different biological functions of the two SUMO genes (SUMO1 and SUMO3) in the hemimetabolous cockroach Blattella germanica and compared them with those of Drosophila Smt3. Here, we show that the metamorphic role of the SUMO genes is evolutionary conserved in insects, although there has been a regulatory switch from SUMO1 in basal insects to SUMO3 in more derived ones. We also show that, unlike vertebrates, insect SUMO3 proteins cannot form polySUMO chains due to the loss of critical lysine residues within the N-terminal part of the protein. Furthermore, the formation of polySUMO chains by expression of ectopic human SUMO3 has a deleterious effect in Drosophila. These findings contribute to the understanding of the functional consequences of the evolution of SUMO genes.