tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients: Preliminary results
Authors: A. Hamada, I. Okamoto, Y. Matsunaga, J. Sasaki, E. Moriyama, H. Kishi, M. Matsumoto, H. Saito
Journal: Journal of Clinical Oncology (2005)

2086 Background: Amrubicin was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The pharmacokinetics (PK) of amrubicin have remained uncharacterized, however. Methods: We evaluated the PK of amrubicin and its active metabolite amrubicinol with the use of a high performance liquid chromatography based assay in 16 patients with advanced lung cancer. Amrubicin at a dose of 30 to 45 mg/m2 was administered to patients in a bolus intravenous injection once every 24 h for three consecutive days. Blood samples were collected from 0 to 72 hours at cycle 1. Plasma specimens were stored at − 80°C until analysis. Results: The plasma concentration of amrubicin peaked immediately after a bolus intravenous injection of the drug and declined in a biexponential mode thereafter, whereas that of amrubicinol also peaked right after amrubicin injection but decreased more gradually compared with that of amrubicin. The area-under-the curve ratios of amrubicinol to amrubicin were 19.1±4.1% (mean±SD) and 14.9±1.2% at amrubicin doses of 45 and 30 mg/m2 per day, respectively. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. The area under the curve of amrubicin and amrubicinol were correlated with the severity of leukocytopenia. Conclusions: The AUCs of amrubicin and amrubicinol predict patients with highest risk of hematological toxicity. Monitoring of the plasma concentrations of amrubicin and amrubicinol might provide an efficient tool for optimal dosage adjustment of amrubicin. No significant financial relationships to disclose.
Investigation and management of patients with differentiated thyroid cancer (DTC) with raised thyroglobulin (TG) and negative Iodine scans
Authors: C. H. Charalambous, U. K. Mallick
Journal: Journal of Clinical Oncology (2004)

5611 Background: A prospective protocol was set up specifying the use of neck US/MRI and CT thorax followed by PET scanning in the investigation of patients with DTC with raised TG and negative I131 scans. Subsequent treatment included TSH suppression, high dose I131 treatment, surgery and radiotherapy. Methods: 124 patients underwent I131 scans as follow-up for DTC between 1999 and 2001.41 patients had raised TG and negative I131 scans. 15 males / 26 females: median age 61 years (17–79). Histological type: papillary 25, follicular variant of papillary 6, follicular 8, Hurthe cell 2. TG range 1.01 - 1500(median 24.6) Results: 10 patients had disease on conventional imaging ( US/MRI neck,CT chest). 11 patients with negative conventional imaging underwent PET scanning. 3 patients underwent neck US/MRI and CT thorax but no PET, 1 patient underwent neck US, but no CT thorax or PET, 3 patients only had CXR and 13 patients underwent no investigations at all. Reasons for non-adherence to the protocol included: other comorbidity (1), patient refused PET (1), and TG normalization on TSH suppression (11). Diagnostic yield: neck US/MRI 4/22 (18%), CXR 1 /4, CT thorax 9/22 (41%), PET 2/11 (18%).Regarding management: TSH suppression resulted in normalisation of TG in 16 patients. 7 patients had surgery with normalisation of TG in 3 and local control in another 3. 20 patients had high dose I131 treatment with 8 positive scans and stabilisation of TG in 11 patients. Radiotherapy was only given to 3 patients. Conclusions: A significant proportion of patients (24%) had metastatic disease on conventional imaging. For patients with negative conventional imaging, the sensitivity and impact on clinical management of PET scanning was low. The use of surgery proved beneficial in patients with localised disease. Treament with radioactive I131 resulted in disease stabilisation in about half the patients it was used. Overall about 40% of these patients normalise their TG on TSH suppression. The clinical significance of raised TG only on TSH stimulation is currently uncertain and careful follow-up is needed in the future. (Updated results to 2003 to be presented) No significant financial relationships to disclose.
EMMPRIN up-regulates VEGFR-2 through HIF-2alpha mediated mechanism: Consequences on angiogenesis and tumor progression.
Authors: F. Bougatef, S. Menashi, C. Quemener, B. Naimi, M. Podgorniak, C. Dosquet, F. M. Calvo, C. Lebbé, S. Mourah
Journal: Journal of Clinical Oncology (2010)

10629 Background: EMMPRIN is frequently over-expressed in cancer tissues and is thought to play an important role in tumor progression and angiogenesis, mainly through its protease inducing function and more recently by its ability to increase tumor cell expression of VEGF. Here we demonstrate that EMMPRIN can up-regulate VEGF receptor-2 (VEGFR-2) in both endothelial cells and melanoma cells, thus promoting both angiogenesis and tumorigenicity. Methods: The role of EMMPRIN on endothelial cells (HUVEC and HMEC-1) and primary melanoma cells (WM278 and M10) was demonstrated by silencing its expression with siRNA and by treatment with exogenously added EMMPRIN-enriched membrane vesicles and the resultant effect on VEGFR-2 was observed at the RNA and protein level and using functional in vitro assays and in vivo studies. Results: Treatment with EMMPRIN increased expression of the VEGF/VEGFR-2 system and increased migration and proliferation of both these cell types while inhibiting their apoptosis. It also increased tube formation capacity of endothelial cells in an in vitro angiogenesis assay. Inhibition of VEGFR-2 expression abrogated all these EMMPRIN's effects. EMMPRIN up-regulation of VEGFR-2 and its biological consequences were shown to be mediated through the over-expression of HIF-2α and its translocation to the nucleus. These results which demonstrate a novel mechanism by which EMMPRIN promote angiogenesis and tumor progression were supported by in vivo studies; both VEGFR-2 and HIF-2α were increased in human melanoma tissues as well as in a mouse model of xenograph tumors overexpressing EMMPRIN. Conclusions: The inhibition of EMMPRIN in cancer may thus simultaneously target both the VEGFR-2/VEGF system and the matrix degrading proteases to block tumor angiogenesis and invasion. No significant financial relationships to disclose.
A multicenter phase II study of thalidomide in combination with interleukin-2 (IL-2) in patients with previously untreated metastatic renal cell carcinoma (MRCC)
Authors: D. Farray, J. I. Clark, T. Kuzel, J. P. Dutcher
Journal: Journal of Clinical Oncology (2006)

14636 Background: Thalidomide, a drug with immune modulating and anti-angiogenic properties has shown activity in relapsed/refractory MRCC; furthermore, early phase I data of oral thalidomide with subcutaneous low-dose IL-2 showed the combination to be safe. The potential anti-tumor activity of this combination formed the basis of this study. Methods: The aim of this multi-center, open label, phase II study was to determine the efficacy and safety of thalidomide and IL-2 given in combination. Patients (pts) with untreated clear cell MRCC with measurable disease and previous nephrectomy were eligible. Two 6-week cycles of thalidomide and IL-2 were planned. Each cycle consisted of thalidomide started at 200 mg orally daily and titrated to 400 mg daily on the 4 th day for 6 weeks; IL-2 was started one week post initiation of thalidomide at a dose of 7mIU/m 2 subcutaneously days 1–5 for 4 weeks, followed by 2 weeks off therapy. Therapy was to be continued until progression, if there was at least stable disease (SD). Planned accrual was 53 patients. Results: 11 pts were enrolled. The trial was terminated early due to lack of responses. Median age was 57 years (51–66). All pts had an Eastern Cooperative Oncology Group performance status of 2 or better. The only grade 3 toxicities were fatigue (3 pts), neuropathy (1 pt), anorexia (1 pt), dyspnea (1 pt), edema (1 pt); these required dose reductions as per protocol. There were no objective responses: 3 pts had SD, 8 pts had progressive disease (PD). The 3 pts with SD completed 4, 4, and 6 cycles of therapy respectively; of the 8 pts with PD, 3 completed two cycles, and 5 completed one cycle of therapy. Conclusions: The combination of thalidomide and low-dose IL-2 was well tolerated, but in this trial did not show anti-tumor activity in patients with clear cell MRCC. We thank Celgene for support of this trial. No significant financial relationships to disclose.
Oral anticancer medication: Does the patient understand?
Authors: Donna M. Graham, Alan O'Shea, Jeffri R. M. Ismail, Richard Martin Bambury, Margaret O'Keefe, Catherine Drake, Eugene J. Moylan, Derek Gerard Power, Seamus O'Reilly
Journal: Journal of Clinical Oncology (2013)

219 Background: Oral anti-cancer medication (OAM) prescribing is increasing. Safety and adherence issues surrounding OAM are causing a shift in the traditional roles and responsibilities of oncologists, nurses and pharmacists. This study aims to investigate patients’ perception of education and safety surrounding OAM use. Methods: Over a 6-month period an anonymous cross-sectional survey was offered to all patients (pts) attending for cancer treatment with OAM at Irish hospitals with cancer services in the South-West region. Data was prospectively analysed using standard statistical tools for non-parametric data. Results: A total of 172 surveys were distributed and 101 pts responded (59%). Of these, 53 (54%) were female. Median age was 62 (range 29-80 yrs). Diagnosis was colorectal cancer in 49 pts (48%), breast cancer in 13 (13%) and brain tumour in 12 (12%). Of treatments used, 85% were oral chemotherapy and 15% oral biological therapy. The most commonly used agent was capecitabine (61%). When commencing OAM, 17% of respondents felt they did not understand it. Understanding was improved by pt education by a doctor (p=0.03) or hospital-based nurse (p=0.04) and provision of information booklets (p=0.04). Pts were unaware of interactions in 30% of cases and 20% were not aware of any safety issues. Pts who had been given information leaflets were significantly more aware of safety including careful handling (p&lt;0.001), storage conditions (p=0.02) and safe disposal (p&lt;0.001). Pts attending nurse-led oral chemotherapy clinics (NOCC) were significantly more aware of safety issues (p=0.04). Of respondents, 1% reported taking too many tablets and 15% had forgotten to take OAM on ≥1 occasion. NOCC improved adherence (p=0.03). Conclusions: OAM, when indicated, is an option for selected pts who are compliant and educated about complications. This study highlights issues with pt education and safety awareness. To our knowledge the factors influencing this have not been previously explored. A significant proportion of our pts were sub-optimally educated regarding medication interactions, storage needs, handling and disposal precautions. Educational tools to aid healthcare professionals in pt instruction and NOCC significantly improve patient understanding.
Impact of 12 months of androgen-deprivation therapy (ADT) on cognitive function in men with nonmetastatic prostate cancer (PC): A matched cohort study.
Authors: S. M. Alibhai, S. Marzouk, G. Naglie, I. Tannock, G. A. Tomlinson, N. Timilshina, D. Stewart, N. Fleshner, P. R. Warde, S. Duff Canning
Journal: Journal of Clinical Oncology (2010)

9027 Background: ADT is used to treat almost 50% of current PC patients. Despite slowing disease progression and prolonging survival, ADT is associated with numerous side effects. However, the impact of ADT on cognitive function remains uncertain, limited by small published studies and inconsistent findings. Methods: Men age 50 or older with non-metastatic prostate cancer (PC) were included. Three separate groups matched on age and education were tested longitudinally for cognitive function; PC patients starting continuous ADT (n = 79), PC patients not receiving ADT (PC controls, n = 83), and healthy controls (n = 82). A battery of 12 neuropsychological tests, examining 8 cognitive domains, was administered at baseline (prior to ADT treatment), 6 months, and 12 months later. Mean scores at baseline were compared using ANCOVA, and change scores between baseline and both 6 months and 12 months were analyzed using multivariable linear regression models. In an alternate analysis, the proportion of subjects per group with 1-SD or greater cognitive changes were compared. Results: The mean age and education level of the patients overall was 69.2 years (range 50-87) and 15.4 years (range 8-24), respectively. All 3 cohorts had similar adjusted cognitive scores at baseline other than in 1 test of working memory. Adjusted for age and education, ADT use was not associated with significant changes in the domains of Attention and Processing Speed, Verbal Fluency, Verbal Memory, Visual Memory, or Executive Functions of Cognitive Flexibility from baseline to either 6 months (all p<0.05) or 12 months (all p<0.05). 1 test of Immediate Memory (p = 0.033), 1 test of Working Memory (p = 0.037), and 1 test of Visuo-Spatial Ability (p = 0.029) were worse among ADT users than controls at 12 months, but these findings were not confirmed by other domain-specific cognitive tests or in analyses of 1-SD change per group. Conclusions: In the largest study to date, there is no consistent evidence of decline in cognitive function with ADT use for 12 months across 8 cognitive domains compared with controls. No significant financial relationships to disclose.
Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.
Authors: C A Hudis, A D Seidman, J P Crown, C Balmaceda, R Freilich, T A Gilewski, T B Hakes, V Currie, D E Lebwohl, J Baselga, G Raptis, M Gollub, M Robles, R Bruno, L Norton
Journal: Journal of Clinical Oncology (1996)

PURPOSE Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed &gt; or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.
Effect of preoperative chemotherapy on the rate of breast conserving surgery in Korean patients with advanced breast cancer
Authors: S. Lee, K. Min, S. Kim, S. Kim, K. Lee, E. A. Kim, Y. Kwon, H. Kang, J. Ro, E. Lee
Journal: Journal of Clinical Oncology (2008)

11599 Background: Preoperative chemotherapy has been used to increase rate of breast conserving surgery (BCS) in westernized countries. But whether it would also increase the rate of BCS in relatively small Asian breast was not verified. Methods: From August 2002 to April 2005, 209 patients with stage II or III were enrolled in phase III randomized trial of preoperative chemotherapy (AC vs TX) and 204 patients underwent surgery. Either modified radical mastectomy (MRM) or BCS with axillary lymph node dissection was performed. Surgeon decided which type of surgery was adequate at initial diagnosis. By randomization, 101 patients received 4 cycles of preoperative AC and 103 patients received 4 cycles of preoperative TX. Operation followed within 3 weeks after the fourth cycle. Postoperative chemotherapy was given as follows: 4 cycles AC for patients with preoperative TX; 4 cycles TX for patients with preoperative AC. Patients with positive hormone receptor received hormone therapy and radiation therapy was applied to all who underwent BCS and some patients who underwent MRM. They have been followed until November 2007. Results: Median age was 44.0 years (range, 21–67 years), and mean tumor size was 3.29 cm (range 0.9- 12 cm) at initial presentation, 1.71 cm (range 0.0–8.0 cm) after 4 cycles of preoperative chemotherapy. Mean reduction of tumor size was 1.58 cm. After preoperative chemotherapy, clinical response was shown in 76.0% (CR: 4.5% and PR: 71.5%) by the RECIST criteria. BCS was performed in 70.1% (143/204) and MRM was done in 29.9% (61/204). Of the 70 patients planned MRM at initial presentation, 27 patients underwent BCS (38%). Clinical T stage after preoperative chemotherapy (p=0.042), pathologic T size (p=0.002) and lymphatic invasion (p<0.001) were associated with conversion to BCS. In multivariate analysis, only lymphatic invasion showed statistical significance. Mean follow-up time was 41.3 months (range 5–61 months). Disease-free survival was not statistically different between BCS and MRM (p=0.1827). Conclusions: This study showed preoperative chemotherapy would be also effective to raise the rate of BCS in Korean patients with advanced breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration National Cancer Center, Korea
Immunocytoma: A Retrospective Analysis From St Bartholomew's Hospital—1972 to 1996
Authors: D. Papamichael, A. J. Norton, J. M. Foran, C. Mulatero, J. Mathews, J. A.L Amess, M. Bradburn, T. A. Lister, A. Z.S. Rohatiner
Journal: Journal of Clinical Oncology (1999)

To analyze the presentation features and outcome for patients with immunocytoma (IMC) managed at St Bartholomew's Hospital (SBH), London, United Kingdom, between 1972 and 1996. Outcome was compared with that of patients with small lymphocytic lymphoma (SLL)/B-cell chronic lymphocytic leukemia (B-CLL) treated at SBH during the same period.One hundred twenty-six patients with newly diagnosed IMC were identified. Patients were subclassified (using the Kiel classification) as having lymphoplasmacytoid (n =92), lymphoplasmacytic (n = 24), polymorphous (n = 9), or undetermined (n = 1) IMC. Six patients (5%) had stage I to IIE disease; the rest had advanced disease. Treatment was given according to disease stage. Seven patients were managed expectantly.Eighty-two (69%) of 119 patients responded to treatment, but complete remission was seen in only 15 (13%) of 119. Treatment failed in 29 (24%) of 119 patients. There were three treatment-related deaths; five patients were not assessable for response. When survival of patients with IMC was compared with that of patients with B-CLL/SLL, a significant difference was found (P <. 01); this difference was maintained when only patients in whom the diagnosis was based on lymph node biopsy were considered (P =.01). A comparison of the three IMC subgroups showed that there was a trend (P =.06) toward a difference between B-CLL/SLL and the lymphoplasmacytoid subtype.Patients diagnosed with IMC are generally older and present with advanced disease. Conventional therapies usually result in incomplete responses of short duration. Overall, these results support the proposed World Health Organization reclassification of IMC to include lymphoplasmacytoid lymphoma (Kiel classification) as a variant of B-CLL/SLL.
Identification of targetable cellular subsets within melanoma tumors
Authors: A. Sekulic, A. Miller, M. Barrett, S. Ejadi, A. Mengos, B. Pockaj, S. Markovic
Journal: Journal of Clinical Oncology (2009)

9082 Background: Human tumors, including melanoma, are complex mixtures of individual, molecularly distinct subpopulations, or clones of cancer cells. Effective cancer therapy will likely require targeting of all tumor subsets within a given cancer. Understanding the tumor complexity and the ability to identify points of therapeutic vulnerability within the individual tumor subsets will be essential for development of effective personalized cancer therapies. Methods: We have developed an approach that combines identification of individual tumor subsets using a multiparameter nuclear flow cytometry coupled with a high-resolution genomic analysis using the array-based comparative genomic hybridization (aCGH). Melanoma nuclei were isolated from tumor tissues and subjected to flow cytomery using melanocyte-specific antibodies (to separate melanoma cells from stroma) and DNA content, to separate individual tumor subpopulations. DNA extracted from isolated nuclear subpopulations was extracted and analyzed by aCGH. This approach was adopted for both fresh-frozen and paraffin-embedded clinical specimens. Results: We initially demonstrate the feasibility of the outlined approach by successful separation of melanoma from stromal nuclei and separation of individual melanoma nuclear subpopulations by DNA content. aCGH analysis of the DNA derived from isolated tumor subpopulations allowed successful identification of potentially targetable molecular aberrations in individual subsets of tumor cells. Notably, such aberrations were often not detected in unsorted, bulk tumors analyzed by the same high-resolution aCGH approach. Conclusions: We demonstrate a feasible approach to in-depth molecular analysis of tumor subpopulations within a clinical cancer tissue. This approach allows identification of potentially targetable molecular aberrations within individual tumor subsets, thus opening a possibility for a broad tumor targeting through design of individually-tailored therapeutic approaches. No significant financial relationships to disclose.
Comparison of two different mouthpieces for the measurement of Pimax and Pemax in normal and weak subjects
Authors: N Koulouris, DA Mulvey, CM Laroche, M Green, J Moxham
Journal: European Respiratory Journal (1988)

We investigated the effect of mouthpiece design on maximum static expiratory (PEmax) and inspiratory (PImax) mouth pressures. We measured PEmax from total lung capacity (TLC) and PImax from residual volume (RV) in 21 healthy volunteers, and in 40 patients referred for respiratory muscle testing. We compared two different mouthpieces, a semi-rigid plastic flanged type fitting inside the lips, and a 4 cm diameter rubber tube held against the lips. The tube mouthpiece gave significantly higher values for PEmax (p less than 0.02) in all subjects. PImax was also significantly higher (p less than 0.005) with the tube mouthpiece in subjects who recorded normal pressures. We conclude that maximum pressures are obtained in all normal subjects with the rubber tube mouthpiece, and that differences in quoted normal ranges of maximum static respiratory pressures reflect in part the design of the mouthpiece and the way in which it was used.