tbuckley/cabot-search huggingface dataset:
Absorption, metabolism, and excretion of <sup>14</sup>C gimatecan (LBQ707) after oral administration in patients with advanced cancer
Authors: M. M. Woo, L. Rodriguez, H. Gu, K. Crenshaw-Williams, F. Rocha, S. Freestone, J. Dickson, D. Jodrell, J. B. Mangold
Journal: Journal of Clinical Oncology (2007)

2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [ 14 C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) T max for Gim was 1 h (0.5 to 3 h) and mean t 1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]
The Use of Secox (Sorafenib, Oxaliplatin, Capcitabine) as the Treatment of advanced Hepatocellular Carcinoma (HCC) - A Single Center Retrospective Study
Authors: J. Chiu, V. Tang, P. Chan, R. Leung, H. Wong, R. Poon, S.T. Fan, T. Yau
Journal: Annals of Oncology (2012)
Schedule modifications and treatment outcomes for sunitinib-related adverse events.
Authors: B. J. Atkinson, J. Perpich, N. M. Tannir, E. Jonasch
Journal: Journal of Clinical Oncology (2010)

e15115 Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 4 wk on, 2 wk off (4/2) schedule. Sunitinib is associated with several adverse events (AEs). An ideal dose modification algorithm is not known. We sought to identify 1) commonly occurring AEs, 2) schedule modifications (SM) that maintained dose intensity while decreasing AEs, and 3) the impact of SM on 6 mo follow-up (f/u). Methods: Retrospective review of mRCC pts in an outpatient clinic was performed from 1/1/08 to 5/31/09. Pts ≥ 18 years of age with clear cell mRCC on sunitinib therapy with ≥ 6 mo f/u were eligible. At first intolerable AE, pts were switched from a 4/2 schedule to a 2/1 schedule, or further adjusted to a 7 day on/3 day off or other schedule. Pt characteristics including demographics, disease status, laboratory data, AEs, SMs and treatment outcomes were analyzed. Results: 74 eligible pts were identified; preliminary data from 31 pts are presented. Median age was 66 yrs; 23% had prior systemic therapy; 32% were good, 48% intermediate and 20% poor prognosis by MSKCC criteria. Pts had median 2 visceral mets and 49% had primary tumor in place. At baseline, all pts received sunitinib 50 mg daily on schedules shown in the Table. AEs included fatigue (51%), diarrhea (35%), hand-foot syndrome (32%), and mucositis (29%). Dose intensity was maintained in 81% of pts at 6 mo f/u. SM were common (Table). For the 25 pts initiated on a 4/2 schedule, 7 discontinued for PD and 3 for toxicity at 6 mo. All 6 pts initiated on a 2/1 schedule continued on sunitinib at 6 mo at the original dose intensity and schedule, whereas 13 of 15 remaining pts initiated on a 4/2 schedule had switched to an alternate schedule (p=0.0005, 95% CI 0.0752-0.830). Median treatment duration (MTD) was 10 mo for all pts. At last available f/u, 29% of pts continue on sunitinib therapy with MTD of 15.3 mo, and 89% of pts are on an alternate dosing schedule. Conclusions: In this group of pts, sunitinib SM maintained high dose intensity and did not appear to adversely impact outcome. Prospective investigations of alternate sunitinib dosing schemas may be warranted. (%) Sunitinib Schedule 4/2 2/1 7/3 alt 7/4 Other Baseline 100 77 19 3 1 6-mo follow-up 68 10 48 29 13 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Pfizer Bayer, Genentech, Pfizer
Spontaneous pneumothorax in children with osteosarcoma
Authors: R. Kebudi, M. Fayda, I. Ayan, Ö. Görgün, Y. Dizdar, G. Aksu, F. Gün
Journal: Journal of Clinical Oncology (2006)

9070 Background: Spontaneous pneumothorax (SPx) is an emergency situation and early diagnosis and management is very important. SPx may sometimes be seen as a complication of malignancy or its treatment. SPx have been reported in some osteosarcoma patients, mostly in adults. The incidence of SPx in children with osteosarcoma is not well documented. The aim of this paper is to investigate the incidence, treatment and outcome of children with osteosarcoma in a single institution and to review the literature. Methods: Files of all children with osteosarcoma diagnosed and treated in a single institute during September 1989 and December 2002 and followed up until September 2005 were investigated retrospectively for the development of SPx and its outcome. Results: Three of the 81 children (3.7%) developed pneumothorax during their follow-up. Two cases had lung metastases and one case had a broncho-pleural fistula but no metastatic foci at the time pneumotorax was detected. He subsequently developed lung metastasis. Retrospectively, it was suspected that the bronchopleural fistula might have been a manifestation of an undetected micrometastasis. The incidence of developing spontaneous pneumotorax in children with osteosarcoma was 3.7% (3/81) in this single institution survey. We have also reviewed the 45 osteosarcoma cases with pneumothorax in the literature. Including the three cases reported in this paper, 39 of the 48 (81%) were metastatic. Conclusions: Although spontaneous pneumothorax is a rare event in the cancer patient, it should be kept in mind if there is worsening of pulmonary symptoms or shoulder pain. SPx is encountered mostly in metastatic patients, although it may occur in non-metastatic cases. No significant financial relationships to disclose.
Novel human cancer biomarkers identified by blood cells gene expression
Authors: I. Osman, D. Bajorin, T.-T. Sun, M. Mikhail, H. Zhong, R. Zheng, M. Han, W. Marshall, C.-C. Liew
Journal: Journal of Clinical Oncology (2005)

4530 Background: Gene signatures from malignant tumors have prognostic and diagnostic importance. Little is known, however, about the gene expression profiles of blood cells that circulate throughout the body coming in close contact with host tissues and cells. We hypothesized that such a blood analysis may provide diagnostic clues for different types and stages of cancer. Methods: Total RNA’s from blood of 34 patients (pts) with genitourinary cancers (10 testicular, 9 renal, 10 superficial bladder and 5 metastatic bladder) and of 10 healthy subjects were profiled on Affymetrix U133Plus2.0 GeneChips. Differentially expressed genes were identified using the non-parametric, Wilcoxon-Mann-Whitney test, some confirmed by real time RT-PCR, and analyzed by Hierarchical Clustering to assess the correlation between samples. Logistic regression and two-gene ratios were used to assess the ability of linear combinations of specific transcripts to appropriately group the samples. The diagnostic power for each combination was evaluated by the Receiver Operating Characteristic curves. Results: Comparison of the blood gene expression profiles from testicular, renal and bladder cancer pts with those of the controls identified significant differences in the expression of 544, 362 and 309 genes, respectively (p<0.01); 322 genes could distinguish superficial bladder cancer from the controls (p<0.01); and 682 genes could differentiate between superficial and metastatic bladder cancer samples (p<0.001). A two-gene ratio was identified that could rigorously discriminate the bladder cancer from the normal control with 95% sensitivity (CI,76–99%)and 93% (CI, 66–99%)specificity. Conclusions: Our data support the hypothesis that gene expression signatures of circulating blood appear to differentiate between control subjects and pts with different genitourinary cancers, as well as between different stages of bladder cancer. Additional studies are being conducted using larger number of cases to test this hypothesis in blinded samples. This approach may provide a new paradigm for the identification of novel blood markers for various cancers and to distinguish early versus more advanced stages of specific tumors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chondrogene Chondrogene Chondrogene
The activity of CKD601, telomerase inhibitor, against gastric cancer cell lines and resistance mechanism, which is associated with hTERT expression and ALT
Authors: J. Jung, Y. Park, H. Jong, S. Im, Y. Song, W. Kim, Y. Bang
Journal: Journal of Clinical Oncology (2006)

13126 Background: CKD601, a newly developed telomerase inhibitor, shows an anti-cancer effect through its inhibitory effect on telomerase, by intercalation of the drug into the structures of the G-quadruplex. No study has been conducted to assess the anti-cancer effects of CKD601 in regards to gastric cancer. We attempted to confirm the anti-cancer effect of CKD601 in the gastric cancer cell line, and to investigate the mechanisms of the anti-cancer effect and resistance in some cell lines. Methods: After long-term drug exposure, we performed Southern analysis, TRAP, and β-Gal staining about the extracted DNA, RNA, and protein from the gastric cancer cell lines and the U2OS cell line to confirm the anti-cancer effect of CKD601. We attempted to investigate the change in the hTERT expression of cancer cells as a result of exposure to CKD601 by RT-PCR and real-time PCR, and to confirm the presence of the ALT (alternate lengthening of telomere) mechanism by metaphase telomere FISH and IF. Results: The anticancer effect of CKD601, including the shortening of telomere, inhibition of telomerase activity, cellular aging, and decreased growth rates, was observed in some gastric cancer cell lines (SNU-1 and SNU-601). SNU-484 and SNU-668 cell lines showed no anti-cancer effect of CKD601. The resistance mechanism of SNU-484 was the significant overexpression of hTERT following exposure to CKD601. ALT, another mechanism that functions in the maintenance of telomere length, was detected in SNU-668 following exposure to CKD601, and it is the resistance mechanism against CKD601. Conclusions: CKD601 is active in gastric cancer by the inhibition of telomerase activity. The resistance mechanisms of gastric cancer cell lines against CKD601 are the induction of the overexpression of hTERT and the ALT mechanism. [Table: see text] No significant financial relationships to disclose.
Preclinical studies of MDX-12C, a selective membrane androgen receptor ligand with activity in prostate cancer
Authors: K. Alevizopoulos, N. Bacopoulos, N. Papadopoulou, K. Dambaki, C. Stournaras
Journal: Journal of Clinical Oncology (2008)

14549 Background: Membrane Androgen Receptor (mAR) is a novel, yet unknown GPCR functionally distinct from the classical intracellular Androgen Receptor (iAR). mAR is frequently over-expressed in aggressive prostate cancer and initiates rapid non-genomic signaling resulting to tumor cell death by apoptosis in both iAR-positive and iAR-negative cell lines. Methods: MDX-12C is a novel mAR binding ligand comprising a male androgen derivative conjugated to Human Serum albumin (HSA). MDX-12C was evaluated for its potency in vitro against various androgen dependent (LNCaP) and independent (PC-3, DU145) cell lines and in DU145-derived mouse xenografts co-treated with paclitaxel. Fluorescent MDX-12C derivatives were used to assess mAR expression in prostate, breast and colon tumor tissue. Finally, mAR-dependent signaling events and pathways activated by MDX-12C treatment were analyzed. Results: MDX-12C induced potent apoptotic regression of prostate cancer cell lines in vitro. This effect was independent of iAR expression or co-treatment with iAR antagonists. MDX-12C activates two distinct pathways resulting in actin cytoskeleton re-organization and apoptosis: (I) a FAK/PI-3/Rac/cdc-42 pathway in iAR+ cell lines and (II) a RhoA/ROCK/LimK2 pathway in iAR- cell lines. In both cases, apoptotic cell death was marked by caspase-3 activation and FasL over-expression. In vivo, MDX-12C synergizes with paclitaxel resulting in significant tumor growth delay and prolongation of overall survival. Finally, analysis of mAR expression in xenograft tissue isolated from tumor-bearing mice indicated strong mAR expression not only in prostate, but also in breast and colon tissue. Conclusions: The findings support development of MDX-12C as a molecular targeted therapy in mAR-positive prostate tumors independently of their iAR status. Further development for breast and colon cancer is also indicated. No significant financial relationships to disclose.
Nordic MCL3 Study: Zevalin Combined with High-Dose Chemotherapy Followed by Autologous Stem Cell Support As Late Intensification for Mantle Cell Lymphoma (MCL) Patients &lt; 66 Years Not in CR After Induction Chemoimmunotherapy: No Benefit of Zevalin
Authors: Kolstad Arne, Anna Laurell, Mats Jerkeman, Kirsten Grønbæk, Erkki Elonen, Riikka Räty, Lone Bredo Pedersen, Annika Loft, Trond Velde Bogsrud, Marie Nordstrøm, Per Boye Hansen, Unn-Merete Fagerli, Herman Nilsson-Ehle, Grete Fossum Lauritzsen, Anne Kristine Lehmann, Christer Sundstrom, Marja-Liisa Karjalainen-Lindsberg, Elisabeth Ralfkiaer, Mats Ehinger, Jan Delabie, Hans Bentzen, Jukka Schildt, Kamelia Kostova-Aherdan, Henrik Frederiksen, Peter de Nully Brown, Christian H. Geisler
Journal: Blood (2012)
Prospective study of predictive factors of docetaxel (DCX)-induced febrile neutropenia (FN): Relevance of in vivo cytochrome 3A (CYP3A) phenotyping
Authors: J. Alexandre, E. Rey, V. Dieras, S. Grabar, A. Tran, V. Montheil, F. Rabillon, G. Pons, J.-M. Treluyer, F. Goldwasser
Journal: Journal of Clinical Oncology (2005)

2046 Background: FN is a rare but severe side effect of DCX, remaining unpredictable. DCX is metabolised by CYP3A which displays high inter-individual variability. We studied the respective role of baseline characteristics of the patient and CYP3A phenotype on the risk of DCX-induced FN. We hypothesized that inflammation and/or denutrition might affect CYP3A activity and the risk of FN. Methods: Eligibility criteria included cancer for which DCX was indicated, normal liver function, performance status (PS) < 3. CYP3A activity was estimated by a single determination of midazolam plasma concentration (MPC), 4 H after 0.015 mg/kg IV bolus. Ferritine plasma concentration and nutritional and inflammatory status (NIS) ratio, defined as (C-reactive protein x alpha-1 acid glycoprotein)/(albumin x prealbumin) were evaluated at baseline. DCX 75–100 mg/m2 was administered. Occurrence of FN evaluated after the first cycle, was defined as fever ≥ 38.5°C associated to neutropenia <1.0x109/L. Kruskal-Wallis test and exact logistic regression were used for univariate and multivariate analysis, respectively. Results: 58 patients (F/M: 29/29; 31% breast, 29% prostate, 20% lung and 20% other cancers) with median age 61 years (47–75) were included.; FN occurred in 7 patients (12%). In univariate analysis, variables associated to increased risk of FN were: high MPC, poor PS, low lymphocytes count baseline values (p<.05). Statistical association reached border-line significance for high baseline ferritine plasma concentration and NIS ratio (p=0.06 and 0.08, respectively). Age, dose of DCX and site of primary tumor were not associated to increased risk of FN. In multivariate analysis, only MPC remained significantly associated to increased risk of FN. High MPC was correlated with high ferritine level (r=0.32, p=0.02). Conclusion: In vivo CYP3A phenotyping using the dosage of MPC may be a potent and useful predictive factor for DCX-induced FN. This parameter should be further evaluated in larger patient populations. No significant financial relationships to disclose.
Preoperative gemcitabine (gem) and bevacizumab (bev)-based chemoradiation for resectable pancreatic adenocarcinoma
Authors: G. R. Varadhachary, R. A. Wolff, C. H. Crane, J. E. Lee, E. K. Abdalla, J. H. Lee, P. W. Pisters, L. Ho, J. L. Abbruzzese, D. B. Evans
Journal: Journal of Clinical Oncology (2008)

4630 Background: Over 80% of pts who undergo potentially curative pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PC) develop local or distant recurrence. Preoperative therapy maximizes the no. of pts who receive multimodality therapy and undergo a complete (R0) resection. Our phase I study using bev and capecitabine based chemoradiation for locally advanced PC was well tolerated. We hypothesized that gem and bev with RT in pts with resectable PC may allow more pts to undergo PD and improve the rate of R0 resections. Methods: Pts with biopsy proven, stage I/II adenoca of the pancreatic head or uncinate process received 6 wkly infusions of gem (400 mg/m2) and 3 infusions of bev (10 mg/kg, every 2 wks) with concomitant RT, 50.4 Gy at 1.8 Gy/fr. Pts were restaged 4–6 wks after the last dose of radiation. Those without disease progression and with good PS underwent surgery. Pts with adequate recuperation received bev (10mg/kg) every 2 weeks for 3 months starting ∼ 6 wks after surgery. Results: This study has enrolled 11 pts. Median age is 64 yrs; all pts had ECOG-PS 0–1. Median CA19–9 was 52. Of the 11 pts who finished chemoradiation, 10 underwent restaging and 1 pt died from cardiac arrest before restaging. At restaging, 1 pt. had metastatic disease, and 9 (90 %) went to surgery and underwent a successful (R0) PD. Pathologic PR rate (>50 % tumor kill) was 56 %. Preoperative grade 3–4 toxicities were infrequent and included stent related cholangitis (1), gastrointestinal toxicity (1), neutropenia (4), hypertension (1), and PE (1). Major postop complications occurred in 5 of the 9 pts (56%) who underwent PD including wound dehiscence (3) requiring reoperation, large ventral hernia related to fascial dehiscence (1) and biliary anastomotic leak (1). Conclusions: This study was planned to build on our previous gem-based preop chemoradiation program with an estimated accrual of 31 pts. However, interim analysis after accrual of 11 pts suggests that the rate of major postop complications was unforeseen and significant. The combined use of bevacizumab with radiation or gemcitabine (or both) may have contributed to poor wound healing. Optimal use of anti-VEGF therapy in the preop setting requires further refinement. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology
Percutaneous Endoscopic Gastrostomy in Cetuximab-Combined Radiotherapy for Locally Advanced Head and Neck Cancer
Authors: Tomoya Yokota, Tsuyoshi Onoe, Hirofumi Ogawa, Satoshi Hamauchi, Tomomi Hikosaka, Yoshiyuki Iida, Tomoyuki Kamijo, Toshihito Suda, Tomohito Fuke, Tetsuro Onitsuka
Journal: Annals of Oncology (2014)
Concordance and clinical value of the <i>MGMT</i> promoter methylation pattern in tissue with paired serum and MGMT protein expression in a series of glioblastoma (GB) patients
Authors: C. Balañá, C. Carrato, J. Ramírez, M. Berdiel, D. Kaen, J. Sánchez, M. Tarón, C. Hostalot, A. Ariza, R. Rosell
Journal: Journal of Clinical Oncology (2008)

2037 Background: MGMT (O6-methyl-DNA-methyltransferase) gene promoter methylation and MGMT tissue expression predict benefit from alkylating chemotherapy in GB. Tumoral MGMT promoter methylation can be detected in patients’ serum. We studied the concordance of tissue MGMT methylation pattern (t-MGMT+ or -) with paired MSP (methylation specific polymerase-chain reaction) in serum DNA (s-MGMT+ or -) and with the expression of MGMT protein measured by quantitative immunohistochemistry (q-IHC) in a series of GBs with complete clinical follow-up. Methods: MSP was performed in 70 patient samples and 37 paired patient's serums. Sixty-three patients were assessed for tissue nuclear q-IHC expression (2 tissue microarrays) giving 3 values per patient: minimum (min-q-IHC), maximum (max-q-IHC) and average (ave-q-IHC) of positive cells. Clinical factors were age (≥ 50, < 50), surgery (biopsy, resection), KPS (< 70, ≥ 70%), radiotherapy (< 40Gy, 60 Gy), base chemotherapy (BCNU, TMZ), chemotherapy benefit (P, SD+PR+CR), progression-free survival (PFS) and overall survival (OS). Results: t- MGMT+ patients (38.6%) had longer PSF (P=0.03), OS (P=0.04) and benefited from chemotherapy (P=0.09) compared with t-MGMT- patients. Multivariate analysis disclosed t-MGMT+ status and radiotherapy as independent factors for better OS and longer PFS (where age <50 was also significant). An s-MGMT+ status (27% of patients) was an independent factor of better survival and longer PFS in multivariate analysis. A high concordance between t-MGMT and s-MGMT was found (P<0.0001, Cohen's Kappa = 0.586). The sensibility to detect t-MGMT- of MSP in serum was 95.4% with a specificity of 60%. There were not significant differences between max-IHC, min-IHC and ave-IHC (Long-test P=0.65). Max-IHC had the best sensibility to predict t-MGMT- status. The cut off point was >12 positive cells for a sensibility of 97.4 % but a specificity of only 8.9% (ROC ((0,70; (0,56–0.84) P=0.007)). Conclusions: t-MGMT is the gold standard to identify patients who benefit from alkylating therapy. In the case of no tissue available, s-MGMT MSP assay has a good sensibility to detect t-MGMT- patients. MGMT q-IHC is not a good surrogate of t- MGMT status. No significant financial relationships to disclose.