tbuckley/cabot-search huggingface dataset:
Comparison of weekly cisplatin-epirubicin-paclitaxel (PET) with triweekly epirubicin-paclitaxel (ET) in locally advanced breast cancer (LABC). SICOG 9908 phase III tria
Authors: G. Comella, None D'Aiuto, P. Comella, R. Thomas, I. Capasso, P. Silvestro, A. Russo, A. Petrillo, L. Lapenta, G. Frasci
Journal: Journal of Clinical Oncology (2004)

511 Background: The present study aimed at evaluating whether this new regimen could be more effective than standard triweekly epirubicin/taxol in LABC patients. Patients and Methods: Previously untreated LABC pts (T4 and/or N3), aging ≤ 70 years were eligible. Women were randomised to receive 12 PET (cisplatin 30 mg/m2/week + epirubicin 50 mg/m2/week + paclitaxel 120 mg/m2/week + G-CSF) weekly cycles or 4 triweekly ET (epirubicin 90 mg/m2/ + paclitaxel 175 mg/m2 ) cycles. The pathological Complete Response was the primary endpoint. Results: As of December the 1st 2003, overall 160 patients have been recruited (PET = 78; ET= 82). 140 patients are evaluable for clinical response (PET=69; ET=71), the remaining 20 patients being too early (17) or refusal (3). 20 complete (29%) and 41 partial (59%) responses were recorded in the PET arm, giving a 88% ORR. 11 complete (15%) and 44 partial (62%) responses were observed in the ET arm, giving a 77% ORR. The difference between the two arms was significant as regards the CRR (29% vs. 15%; p=0.05), while there was a trend in favor of the PET arm as regargs the ORR (88% vs 77%; p=0.09) To date, 130 pts have been submitted to surgery. Absence of invasive tumor in the breast (pT0+pTis) was observed in 14 and 10 patients in PET and ET arm, respectively (p=n.s.). Negative axillary nodes (pN0) were found in 17 PET and 14 ET patients (p=n.s.). However, a complete regression of the tumor in both breast and axilla (pT0+pTis+N0) was observed in 11 PET (16%) and only 3 ET (4%) patients (p=0.03). No differences in terms of severe neutropenia and thrombocytopenia were observed between the two arms. However, severe anemia, mucositis, peripheral neuropathy, and gastrointestinal toxicity were substantially more frequent in the PET arm. Conclusions: According to these preliminary data, the PET weekly regimen can significantly improve both the clinical and pathological complete response rate in LABC patients when compared with a standard epirubicin/taxol q3wk administration. The accrual still proceeds until the planned sample size of 120 per arm. No significant financial relationships to disclose.
Intraperitoneal therapy for ovarian cancer: Impact on survival and recurrence—The result of multi-institutional studies
Authors: S. Takeuchi, H. Tsubamoto, S. Adachi, K. Ito, Y. Itani, T. Miyamoto, Y. Terai, J. Kigawa, T. Sugiyama
Journal: Journal of Clinical Oncology (2007)

16068 Background: For optimal debulked mullerian cancer (MC), the Intraperitoneal (IP) therapy has become the effective modality of chemotherapy to obtain better prognosis. We have reported KCOG9811study: IP CDDP + Paclitaxel (PTX) intravenous (IV) 2 cycles followed by 3 cycles of usual PTX-Carboplatin (abstr.1970, ASCO2002). And we have also reported the feasibility study and satisfactory response rate of the weekly IP-PTX with IV Carboplatin therapy (IP-PIVC, abstr. 5120, ASCO2005). Objectives: We have conducted two types of IP therapy for optimal debulked MC to improve the progression free survival (PFS) and overall survival (OS). Here are the prognosis and recurrent fashion after these IP therapies. Methods: Twenty patients (pts) with optimal debulked ovarian cancer were enrolled for KCOG9811, and eleven pts with optimal debulked MC newly/recurrent diagnosed disease were enrolled for IP-PIVC. The regimen of each therapy consisted of as follows: KCOG9811:50mg/ m 2 of CDDP was administered via IP port at operation, after 2 weeks (wks) of operation, PTX was administered at a dose of 175mg/ m 2 IV for 3hrs on day 1, CDDP was administered at 75mg/ m 2 IP on day 2, every 3wks for 2 cycles, followed by PTX 175mg/ m 2 IV and Carboplatin AUC5 IV on day1 every 3wks for 3 cycles. The IP-PIVC therapy consisted of IP-PTX, on days 1, 8, 15 at a dose of 45 mg/m 2 (3pts) and 60 mg/m 2 (8pts). Carboplatin was administered monthly at a dose of AUC 5 on day 1 only. 2–6 cycles were performed. Results: The mean observation time was 72.6 months (m) and 32.6m for KCOG9811 and IP-PIVC, respectively. As for the median PFS was 1308+ days and 678+ days, and the median OS was 2180+ days and 978+ days, respectively. The five years survival rate showed 59.3% on KCOG9811, and the three years survival rate showed 75.8% on IP-PIVC. As for recurrent fashion, liver metastases and proximal lymphnodes metastases, and retroperitoneal metastases were detected. Few cases recurred Intraperitoneal lesion with small ascites Conclusions: There are some differences in the recurrent fashion of IP treatment from that of IV treatment. IP treatment prevented ascitic recurrence. Further improvement of chemotherapy is necessary for liver metastasis and proximal lymphnodes. [Table: see text]
A Comprehensive Map of CNS Transduction by Eight Recombinant Adeno-associated Virus Serotypes Upon Cerebrospinal Fluid Administration in Pigs
Authors: Nicolina Cristina Sorrentino, Veronica Maffia, Sandra Strollo, Vincenzo Cacace, Noemi Romagnoli, Anna Manfredi, Domenico Ventrella, Francesco Dondi, Francesca Barone, Massimo Giunti, Anne-Renee Graham, Yan Huang, Susan L Kalled, Alberto Auricchio, Maria Laura Bacci, Enrico Maria Surace, Alessandro Fraldi
Journal: Molecular Therapy (2015)

Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases.
Chimaeric polymersomes based on poly(ethylene glycol)- b -poly( l -leucine)- b -poly( l -glutamic acid) for efficient delivery of doxorubicin hydrochloride into drug-resistant cancer cells
Authors: Peipei Chen, Chao Deng, Fenghua Meng, Jian Zhang, Ru Cheng, Zhiyuan Zhong
Journal: Journal of Controlled Release (2015)
Randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line chemotherapy in advanced non-small cell lung cancer.
Authors: S. Nagel, A. Groeschel, M. Sebastian, S. Andreas, T. Mueller, F. Schneller, S. Guetz, M. I. Leschinger, H. Buettner, M. Reck
Journal: Journal of Clinical Oncology (2010)

7628 Background: Pemetrexed (P) combined with cisplatin (C) was approved in 1st-line treatment (Tx) of non-small cell lung cancer (NSCLC) in pts with other than predominantly squamous histology. For pts unable to tolerate C, P + carboplatin (Car) might offer an alternative. Methods: Multicenter, open-label phase II trial in pts with stage IIIb/IV NSCLC. 133 pts were randomized to P (500 mg/m2)+C (75 mg/m2) or P (500 mg/m2) + Car (AUC6) d1 q3 wks, for 6 cycles. Primary outcome was 6-mo progression-free survival (PFS) rate, estimate based on exponential distribution, independently for each arm. Secondary outcomes included overall survival (OS) (Kaplan-Meier estimate), objective response rate (ORR), and tolerability. Results: Treatment groups were balanced. The Table shows the results. Conclusions: Both regimens showed efficacy according to study hypothesis. The observed trend in favor of P+C regarding PFS and OS related to histology is consistent with the results of larger phase III trials. N= 133 random/130 treated Median age (yrs) P+C (N = 65) 64 (42-78) P+Car (N = 65) 63 (45-80) n % n % Sex male 42 64.6 46 70.8 Histopathology Squamous 12 18.5 13 20.0 Nonsquamous 53 81.5 52 80.0 Stagea IIIb 5 7.6 9 13.4 IV 61 92.4 58 86.6 6 month PFS rate % [95% CI]b 52.8 [40.3; 65.3] 39.3 [27.8; 50.8] Squamous hist. 34.9 [9.4; 60.4] 42.0 [16.8; 67.3] Nonsquamous hist. 57.6 [43.7; 71.5] 38.5 [25.6; 51.5] Median OS, months [95% CI] 11.7 [9.2; 14.9] 8.9 [6.0; 12.2] Squamous hist. 7.4 [3.5; - ] 9.8 [4.4; 25.7] Nonsquamous hist. 11.9 [9.4;15.2] 8.5 [6.0,13.3] 12-month OS rate (%) [95% CI] 47.5 [34.5; 59.4] 39.2 [27.2; 51.1] ORR, n responders (all PR, %) 21 (32.3) 13 (20.0) Exposure Cycles completed, median 4 6 Cycle delays 40 61.5 41 63.1 Dose reductionsc 3 4.6 16 24.6 Median dose intensity % [25th, 75th percentile] P 98.2 [92.0;100.0] 98.6 [91.6;99.7] C 97.8 [91.6;99.8] – Car – 96.3 [83.1; 99.5] Discontinuationsa Tx complete 28 42.4 32 47.8 AE 11 16.7 4 6.0 Progression 13 19.7 20 29.9 Pt/physician decision 10 15.2 6 9.0 Tolerability Pts ≥ 1 related G 3/4 TEAEd 29 44.6 36 55.4 Pts ≥ 1 related TE SAEd,e 11 16.9 15 23.1 Abbreviations: n, pts; N, pt population. a All pts random. b H0 6 mo PFS rate ≤ 25%. c All compounds. d Possibly related, e 13 deaths [C/Car] (3/10); 1/2 study drug tox. 0/3 unrelated AE. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly
Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma.
Authors: D E Wazer, T DiPetrillo, R Schmidt-Ullrich, L Weld, T J Smith, D J Marchant, N J Robert
Journal: Journal of Clinical Oncology (1992)

The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma.Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored.Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03).Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.
Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group.
Authors: R Seshadri, F A Firgaira, D J Horsfall, K McCaul, V Setlur, P Kitchen
Journal: Journal of Clinical Oncology (1993)

PURPOSE To determine prospectively the prognostic significance of HER-2/neu oncogene amplification in the primary tumors of breast cancer patients. METHODS HER-2/neu amplification in tumor DNA was determined by the slot-blot technique in 1,056 patients with breast cancer (stage I to III) diagnosed between 1987 and 1990. Parameters such as estrogen receptor (ER) and progesterone receptor (PgR) levels, tumor size, axillary nodal involvement, tumor grade, and time to relapse were prospectively obtained. RESULTS HER-2/neu oncogene amplification, &gt; or = 2, &gt; or = 3, and &gt; or = 5 copy number, was detected in 21%, 11%, and 7% of patients, respectively. In a test set of 529 patients, Cox multivariate analysis showed HER-2/neu copy number &gt; or = 3 or &gt; or = 5 was associated with shorter disease-free survival (DFS) duration. HER-2/neu copy number &gt; or = 3 correlated significantly with pathologic stage of disease, number of axillary nodes with tumor, histologic type, and absence of ER and PgR. For all patients, after a median follow-up duration of 39 months, Kaplan-Meier univariate analysis indicated that tumor oncogene copy number &gt; or = 3 correlated with shorter DFS in both node-negative and node-positive patients. In Cox multivariate analysis, HER-2/neu copy number &gt; or = 3 was associated with shorter DFS, independent of nodal status, ER level, and tumor size. CONCLUSION Although the follow-up duration of this study is relatively short, we conclude that HER-2/neu amplification is an independent predictor of shorter DFS in both node-negative and node-positive patients.
Engineered protein coatings to improve the osseointegration of dental and orthopaedic implants
Authors: Jordan Raphel, Johan Karlsson, Silvia Galli, Ann Wennerberg, Christopher Lindsay, Matthew G. Haugh, Jukka Pajarinen, Stuart B. Goodman, Ryo Jimbo, Martin Andersson, Sarah C. Heilshorn
Journal: Biomaterials (2016)
New onset or exacerbation of psoriatic skin lesions in patients with definite rheumatoid arthritis receiving tumour necrosis factor antagonists
Authors: S Kary
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Blockage of tumour necrosis factor α (TNFα) is highly effective in rheumatic diseases, especially in rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. Furthermore, TNFα antagonists have also been shown to significantly reduce psoriatic skin lesions. <b>Case reports:</b> A series of nine patients with RA who were treated with different types of TNFα antagonists and who unexpectedly developed either a new onset or an exacerbation of psoriatic skin lesions are reported
Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM
Authors: A. T. Van Oosterom, H. Dumez, J. Desai, S. Stroobants, A. D. Van Den Abbeele, P. Clement, N. Shand, J. Kovarik, A. Tsyrlova, G. D. Demetri
Journal: Journal of Clinical Oncology (2004)

3002 Background: Primary resistance to IM in advanced GIST pts occurs rarely (<15%), but eventually pts may develop secondary resistance, possibly due to other mutations of KIT, genomic amplification of KIT, as well as activation of alternative oncogenic signaling mechanisms. Signal-profiling studies of GIST lesions with initial response to IM and subsequent clonal evolution of IM-resistant disease demonstrate close association between KIT and AKT/mTOR activity. Synergism has been shown in-vitro between IM and E, slowing proliferation and inducing apoptosis in primary GIST cell lines resistant to IM. Methods: We have initiated a phase I/II clinical study to test feasibility of the combination of E + IM, and also to assess the effect of E+IM in combination in GIST pts refractory to IM. Pts with metastatic GIST are eligible if progressing after ≥4 months' IM therapy at optimal doses, including at least 2 months at ≥600mg/d. Initially, PK interaction was assessed by measuring drug levels of IM alone (600mg/d), then E alone (20mg once weekly), and then of the combination. Serial assessments include FDG-PET and CT or MRI. Tumor biopsies are performed before and on therapy to evaluate changes in intratumoral signaling. Results: In 12 patients evaluated for PK interaction, IM increased levels of E (mean AUC by 3.7 fold, Cmax by 2.2 fold) but E did not effect levels of IM or its main metabolite. Tolerability was good overall. PET demonstrated dramatically increased tumoral FDG-avidity on interruption of IM, and then reduced FDG-avidity with the combination. One patient maintains objectively stable disease after 10 months on study. Conclusions: The increase in E bioavailability could be via competition with IM for CYP3A4 and/or P-glycoprotein. The initial increase in tumor FDG uptake on PET demonstrates residual suppression of GIST clones by IM and their reactivation upon IM interruption. To achieve more consistent exposure to E, this study is ongoing with subsequent intercohort dose escalation testing daily E (2.5–10mg/d) with 600mg/d IM. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis; Amgen; Aventis; Roche; Schering-Plough; PharmaMar; Pfizer
Effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone
Authors: S. Goel, G. Goldberg, L. C. Iacono, M. Cohen, T. Griffin, R. Gollamudi, K. K. Desai, I. Chaudhary, S. Mani
Journal: Journal of Clinical Oncology (2006)

2005 Background: Ixabepilone (Ixa) is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixa has shown clinical activity in a broad range of tumors. Oxidative metabolism by CYP3A4/5 appears to be a prominent route of Ixa biotransformation in vitro. As a single agent, the recommended dose is 40 mg/m 2 over 3 hours once every three weeks. Methods: This was an open-label, sequential study to assess the effect of CYP3A4/5 inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of Ixa. Ketoconazole (K) was used as a model inhibitor of CYP3A4/5. Patients were administered a single 10 (n=4), 20 (n=12), 25 (n=7) or 30 (n=4) mg/m 2 intravenous (iv) infusion of Ixa with K (400 mg/d orally x 6 days) during cycle 1, and a single 40 mg/m 2 iv infusion of Ixa during Cycle 2. Cycles were repeated every 21 days. Detailed PK and PD analysis was performed in cycles 1 and 2. Results: The observed adjusted geometric mean of Ixa AUC for subjects with K was 2892 vs. 1628 ng/mL*hr in subjects without K. The ratio of the geometric means of normalized Ixa AUC and Cmax in Cycle 1/Cycle 2 were 1.78 and 1.07, respectively. The percent of peripheral blood mononuclear cells with tubulin bundle formation after administration of 20 mg/m 2 Ixa with K was similar to that observed with single agent Ixa at a dose of 40 mg/ m 2 . The maximum tolerated dose of Ixa with K was 20 mg/m 2 . Dose limiting toxicities of Ixa with K were similar to those observed in previous Phase 1 studies of single agent Ixa and included prolonged neutropenia, febrile neutropenia, mucositis, elevated liver function enzymes, and fatigue. Conclusions: Oxidative metabolism by CYP3A4/5 appears to be a clinically important route of Ixa biotransformation. Inhibition of CYP3A4/5 by K affects the Ixa tolerable dose, increases the AUC and results in similar PD effects at half the recommended dose. [Table: see text]
Potential non-synonymous single nucleotide polymorphisms (nsSNPs) associated with toxicity in metastatic clear cell renal cell carcinoma (MCCRCC) patients (pts) treated with sunitinib
Authors: P. W. Faber, S. A. Vaziri, L. Wood, C. Nemec, P. Elson, J. A. Garcia, B. I. Rini, R. M. Bukowski, M. K. Ganapathi, R. Ganapathi
Journal: Journal of Clinical Oncology (2008)

5009 Background: Sunitinib has clinical efficacy in the treatment for MCCRCC and can be associated with grade (Gr) 3/4 toxicity requiring dose reduction. There is limited information on clinical or genotypic variations affecting the toxicity. Since nsSNPs in the coding region can affect protein structure/function, and thus impact on drug metabolism/toxic effects on end organs, we examined differences in nsSNPs in MCCRCC pts treated with sunitinib. Methods: In 42 patients with MCCRCC receiving single agent sunitinib (50 mg/d 4/2 wks), genomic DNA from peripheral blood lymphocytes was isolated and analyzed for nsSNPs using the Illumina HumanNS-12 BeadChip® which represents >11,000 nsSNPs. Patients were classified into the following 2 groups: “without significant toxicity” (maximum toxicity during treatment ≤ Gr 2) or “with significant toxicity” (maximum toxicity during treatment ≥ Gr 3 and requiring dose reduction within 6 cycles). Genotypic differences in potentially informative nsSNPs between the 2 patient groups were investigated using Fisher’s exact test. The functions of and relations between the genes containing the informative nsSNPs were analyzed using the Ingenuity Pathways Analysis 5.5 software. Results: A total of 38 pts were analyzed with 19 pts in each of the groups with or without significant toxicity. A total of 31 nsSNPs were found to be significantly different (p≤0.02) between the 2 groups. Analysis of the nsSNPs using the Ingenuity Pathway Analysis identified networks clustering around interferon gamma, tumor necrosis factor, transforming growth factor beta1 and amino acid metabolism molecular pathways. Interestingly, no difference in the 3 nsSNPs for cytochrome P450 3A4 involved in sunitinib metabolism was observed between the two groups. Conclusion: This is the first report describing nsSNPs that may be associated with the severity of sunitinib-induced toxicity. Since all patients in our cohort had MCCRCC, analysis for differences in nsSNPs in patients with other malignancies receiving treatment with sunitinib maybe warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology Pfizer Oncology
Molecular characterization of triple-negative breast cancers using gene expression profiling
Authors: Cornelia Liedtke, Kai Yan, Jing Wang, Bailiang Wang, Jiexing Zhang, Attila Tordai, William Symmans, Jaime Mejia, Vicente Valero, Gabriel Hortobagyi, Lajos Pusztai
Journal: Cancer Research (2008)

5491  Background. Breast cancers lacking expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 are referred to as triple-negative breast cancers (TNBC). They carry an unfavorable prognosis compared to receptor expressing cases, which is in part due to limited therapeutic options. Method. Gene expression profiling of 294 fine needle aspiration samples of breast cancer patients was performed using Affymetrix U133A GeneChips. TNBC was defined based on mRNA expression values for ESR1 and HER2/neu receptor probesets, and immunohistochemistry for PR. Unsupervised Hierarchical Clustering (UHC), Principal Component Analysis (PCA), bootstrapping, unequivocal variance t-test, Geneset Enrichment Analysis (GSEA) and pathway analysis were carried out to (i) compare TNBC to receptor expressing cases (non-TNBC) and (ii) to identify subgroups within TNBC. Results. 1,871 probesets were overexpressed among TNBC (n=73) compared to non-TNBC (n=221, P-value, FDR