tbuckley/cabot-search huggingface dataset:
Unusual metastatic sites in gastrointestinal stromal tumor (GIST)
Authors: R. Bertulli, E. Fumagalli, P. Coco, A. Messina, C. Morosi, P. Dileo, P. G. Casali
Journal: Journal of Clinical Oncology (2009)

10566 Background: Metastases from GIST usually affect liver and peritoneum. Extra-abdominal metastases may occur in a limited proportion of pts. Only anecdotal reports describe rare metastatic sites (MS), to lungs, bone and distant soft tissues. Methods: We reviewed a group of 278 pts with advanced/metastatic GIST treated with tyrosine kinase inhibitors over a 7 years period with a view to unusual MS. Results: Thirteen pts (5%), M/F:10/3, median age 50 yrs (34–68 y), developed uncommon MS in a median time of 42 months from their primary diagnosis (0–120 m). Nine pts showed bone metastases along with peritoneal and/or hepatic lesions. All but four pts had also other unusual sites: 2 had pulmonary lesions, 1 had subcutaneous nodules, 1 had a lesion to parotid gland, and pt had lesions to spleen and lungs. In addition to these 9 pts with bone plus other metastases, other two pts had an histologically confirmed bone recurrence as the only metastatization site. In 4 pts, bone metastases were histologically confirmed. In the others, imaging and evidence of progression elsewhere were used as clinical criteria for diagnosis of bone metastatization. With regard to all pts, the most frequent bone sites were spine and pelvis, while ribs and femurs were rare. In four pts, radiation therapy was done, with pain relief. Nine pts died of disease progression after a median time of 17 months (3–40 m) from bone metastases diagnosis. Two pts with a single bone lesion are alive and still on imatinib treatment. Finally, one pt had mediastinal, retrorbital and brain lesions in addition to abdominal metastases, after therapy with imatinib and PTK787. Sunitinib was started with a partial response in all MS. This pt died due to massive bleeding during treatment. Last pt died in few months after parotid gland and subcutaneous metastases diagnosis. Conclusions: Imatinib has dramatically improved GIST prognosis. This is likely to result in a higher number of unusual MS, as observed in other tumors responding to medical therapies in their advanced stages. Rare MS in our series were bones, lungs, subcutaneous tissues, spleen, parotid gland and brain. These cases did not exceed 5% of all cases. [Table: see text]
Oral administration of PARP inhibitor GPI 18180 increases the anti-tumor activity of temozolomide against intracranial melanoma in mice
Authors: R. G. Lapidus, L. Tentori, G. Graziani, C. Leonetti, M. Scarsella, M. Vergati, A. Muzi, J. Zhang
Journal: Journal of Clinical Oncology (2005)

3136 Background: Poly(ADP-ribose) polymerase-1 (PARP) inhibitors have been investigated as enhancers of chemotherapy. We recently showed that PARP inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) in mice. To select a PARP inhibitor for clinical development, we have characterized several potent inhibitors by determining their pharmacokinetics (PK), oral bioavailability, penetration into brain, maximal tolerated doses (MTD), and ability to enhance TMZ effect. GPI 18180 was identified with superior properties for further development. Methods: Growth inhibition in vitro was evaluated by colony formation assay. For PK analysis, rats were dosed with 40 mg/kg GPI 18180 by iv or po. Plasma and brain samples were analyzed by LC-MS/MS. For MTD, male mice were dosed at 250 to 1000 mg/kg/day x 5 days po and observed for another 5 days. For efficacy testing, B16 melanoma cells were injected ic into male mice. Mice were treated with the MTD of TMZ (100 mg/kg/day x 5 days ip), or TMZ + GPI 18180 (10 - 100 mg/kg po). Median survival times (MST) and increase in lifespan (ILS) were determined. Results: GPI 18180 enhanced tumor growth inhibition by TMZ in vitro by 2 and 3 fold at 1 and 2 uM. In rats, after a single iv or oral administration of 40 mg/kg, the plasma Cmax for GPI 18180 was 4049.7 ± 2541.4 and 485.7 ± 251.6 ng/ml. Oral bioavailability was 34 ± 17%. The brain/plasma AUC ratio was approximately 3. GPI 18180 had an LD50 > 1000 mg/kg/day x 5 days po. In mice bearing B16 melanoma in brain, the MST in the group of TMZ + 10 mg/kg GPI 18180 was 20 days, in comparison to the MST of 15.5 days in the group of TMZ (29% ILS, P = 0.037). The ILS for TMZ + 40 mg/kg and TMZ + 100 mg/kg groups were 38% and 54% (P < 0.001 vs TMZ). Conclusions: Oral administration of GPI 18180 enhances the effect of TMZ against melanoma in mouse brain. The superior physiochemical properties of GPI 18180 warrant its further development towards clinical evaluation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Guilford
Safety and efficacy of bosutinib (SKI-606) in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (IM).
Authors: J. E. Cortes, H. Kantarjian, T. Brümmendorf, H. J. Khoury, D. Kim, A. Turkina, A. Volkert, J. Wang, S. Arkin, C. Gambacorti-Passerini
Journal: Journal of Clinical Oncology (2010)

6502 Background: Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor, with minimal inhibitory activity against PDGFR or c-kit. Methods: A phase I/II study to investigate the efficacy and safety of bosutinib in pts with CP CML who failed treatment with IM is ongoing. Results: We report preliminary data for 299 pts, 72% IM-resistant, 28% IM-intolerant, with a median follow-up from start of bosutinib of 16.5 mos (0.56-43.8). Prior therapy besides IM, included interferon (91 pts) and stem cell transplant (8 pts). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea), usually grade 1-2, manageable, improving spontaneously after 3-4 weeks. Grade 3-4 nonhematologic toxicities (>5% of pts) were rash (9%) and diarrhea (8%). The most common grade 3-4 hematologic abnormalities were: thrombocytopenia (23%), neutropenia (14%), and anemia (9%). Other common grade 3-4 laboratory abnormalities included hypermagnesemia (11%) and increased ALT (10%). 56 (19%) pts were discontinued due to toxicity. Of 132 pts evaluable for hematological response, 103 (78%) had complete response (CHR). 111/192 (58%) evaluable pts achieved a major cytogenetic response (MCyR), 89 (46%) of which were complete. Of 156 pts evaluable for molecular response, 76 (49%) achieved a major molecular response, 47 (30%) of which were complete. 20 different mutations were found at baseline in 45/99 (45%) pts tested. CHR occurred in 78% of pts with mutations and in 89% of pts with no mutations; MCyR occurred in 60% and 54% of pts in these groups, respectively. Conclusions: Bosutinib is an active agent for pts with CP CML who failed prior imatinib, including pts with a wide variety of Bcr-Abl mutations. Bosutinib demonstrated a favorable toxicity profile with minimal hematologic toxicity. IM resistant N (%) IM intolerant N (%) Hematologic response Evaluable* 94 38 Complete 72 (77) 31 (82) Cytogenetic response Evaluable* 144 48 Major 79 (55) 32 (67) Complete 62 (43) 27 (56) Molecular response Evaluable* 113 43 Major 55 (49) 21 (49) Complete 31 (27) 16 (37) * Pts without CHR, CCyR or CMR at baseline, and with ≥1 post-baseline assessment for respective response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Bristol-Myers Squibb, Novartis, Pfizer, Wyeth Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Novartis, Pfizer, Wyeth
Cetuximab in combination with irinotecan in patients after irinotecan failure: An integrated analysis of four studies from different geographic regions
Authors: H. Wilke, A. Buzaid, C. Mathias, R. Lim, R. Esser, A. Loos, E. Van Cutsem, D. Cunningham
Journal: Journal of Clinical Oncology (2008)

4062 Background: The pivotal BOND study (Cunningham et al. N Engl J Med 2004;351:337–45) demonstrated the efficacy of cetuximab alone or in combination with irinotecan in metastatic colorectal cancer (mCRC) after irinotecan failure. As further studies have been performed in heavily pretreated patients who had recently failed irinotecan, this integrated analysis was performed to assess the consistency of cetuximab response across geographic regions. Methods: BOND was an open-label, randomized study conducted in 11 European countries. The single-arm MABEL study assessed cetuximab plus irinotecan in a larger community practice setting in Europe. Smaller versions of this study were conducted in Latin America (LABEL) and Australasia (ELSIE). All patients enrolled in these phase II studies had EGFR-detectable mCRC that had progressed on prior irinotecan therapy. Results: Response rates, disease-control rates, progression-free survival (PFS) time, and overall survival time were similar across the four studies (Table). Conclusions: The addition of cetuximab to irinotecan demonstrated consistent efficacy in studies across Europe, Latin America, and Asia in the second-line treatment of patients with mCRC after irinotecan failure. These results involving over 1,500 patients underline the role of cetuximab and irinotecan as standard treatment for patients after irinotecan failure in the treatment of mCRC. BOND (combination therapy arm) MABEL LABEL ELSIE No. of subjects 218 1147 79 123 Response rate, % (95% CI) 22.9 (17.5–29.1)a 20.1 (17.9–22.6)b 26.6 (17.3–37.7)c 13.8 (8.3–21.2)c Disease-control rate, % (95% CI) 55.5 (48.6–62.2)a 45.2 (42.3–48.2)b 55.7 (44.1–66.9)c 49.6 (40.5–58.8)c Median PFS, weeks (95% CI) 18.0 (12.0–18.9)a 14.1 (13.0–17.1)c 17.4 (11.7–18.9)c 12.1 (9.7–17.7)c PFS rate at 12 weeks, % (95% CI) 56 (3 mo) (48.7–62.6)a 61 (58–64)c 57 (46–68)c 50 (41–59)c Median survival, months (95% CI) 8.6 (7.6–9.6) 9.2 (8.6–9.8) 9.2 (7.9–10.8) 9.5 (7.1–11.7) a WHO criteria –IRC; b Subjective assessment by the investigator; c WHO criteria - Investigator Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck KGaA Merck, Merck KGaA, Merck Serono Merck KGaA Merck KGaA, Merck Serono Merck, Merck Serono
The role of systemic treatment after whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases: Differences depending on biological subtype
Authors: A. Niwinska, M. Murawska, I. Lemanska, J. Milewska
Journal: Journal of Clinical Oncology (2009)

1027 Background: The aim of the study was to analyze the efficacy of systemic treatment (chemotherapy [chth], endocrine therapy, targeted therapy) performed after WBRT in patients (pts) with breast cancer and brain metastases. Methods: The group of 222 consecutive breast cancer pts with brain metastases treated in one institution in the years 2003–2006 was divided into four biological subgroups based on ER, PR, and HER-2 receptors’ expression: HER-2(+++)ER/PR(-); HER-2(+++)ER/PR(+); ER(-)PR(-)HER-2(-); and ER/PR(+)HER-2(-). WBRT was performed in 219 (99%) pts. Systemic therapy after WBRT was continued in 160 (72%) pts. Clinically, patients with triple-negative breast cancer were more often in poor performance status (KPS&lt;60%) than the others (51% vs. 28%, respectively). Survivals from brain metastases without and with systemic treatment were compared in four mentioned biological subgroups. Results: Median survival from brain metastases in the entire group was 7.5 months. In the group of ER/PR(+)HER-2(-) median survival without and with systemic therapy was 3 and 14 months, respectively (p = 0.007). In the group of HER-2(+++)ER/PR(+) median survival without further treatment, after chth and after chth with trastuzumab was 2, 8, and 13 months, respectively (p = 0.000) and in the group of HER-2(+++)ER/PR(-) median survival without further treatment, after chth and after chth with trastuzumab was 4, 8, and 10 months, respectively (p = 0.004). In triple-negative breast cancer patients median survival without and with chemotherapy was 3 and 4 months, respectively (p = 0.75). Conclusions: Systemic treatment (chth, endocrine therapy, targeted therapy) continued after WBRT in breast cancer pts with brain metastases prolongs survival in three of four biological subgroups. In the group of HER-2-positive breast cancer pts, trastuzumab added to chth had independent positive impact on survival. No benefit was observed in the subgroup of triple-negative breast cancer pts; it would be the result of refractory disease and the fact, that more pts were in poor performance status. No significant financial relationships to disclose.
Alternative therapeutic approaches after induction chemotherapy for tonsil squamous cell carcinomas
Authors: F. Huguet, M. Gratacap, J. Ménard, S. Perie, B. Angelard, A. Jafari, F. Pène, F. Torti, E. Touboul, J. Lacau St Guily
Journal: Journal of Clinical Oncology (2009)

e17010 Background: The role of induction chemotherapy (ICT) in the treatment of head and neck squamous cell carcinomas (SCC) remains controversial. This retrospective study aims to evaluate the outcome of patients with tonsil SCC treated with ICT followed by surgery and/or external beam radiotherapy (EBRT). Methods: Between 1997 and 2007, 103 patients (pts) with tonsil SCC received an ICT in Tenon Hospital. Most of pts (88%) received cisplatin (25 mg/m2) and 5-fluorouracil (1,000 mg/m2) for 4 days with a mean of 2.5 cycles. After ICT, 85 pts were operated. After surgery, 69 pts received a dose of 50 to 70 Gy on the primary site depending on pathological findings (Group 1). Sixteen pts with negative margins and no lymph node metastasis didn't receive any EBRT (Group 2). The remaining 17 pts were treated by EBRT without surgery (Group 3). The mean follow-up was 38 months. Results: No significant difference appears between our different groups except for the TNM stage and the tumour pathological response to ICT. After ICT, pathological complete response was observed in 18 pts (25%) for the primary site and 20 pts (34%) for lymph nodes. Clinical and radiological assessment of response after ICT was not predictive of the pathological response. The TNM stage was the only predictive factor for complete response. The 5-year disease-free survival rates were 68% for the whole population, 73% for the Group 1, 43% for the Group 2, 68% for the Group 3 (p = 0.5). A poor pathological response after ICT was the single independent predictive factor of tumour relapse (p = 0.04). In the Group 2, 6 pts had a relapse, among them 4 had EBRT in a second time. The 5-year specific survival rates were 78% for the whole population, 76% for the Group 1, 76% for the Group 2, 39% for the Group 3 (p = 0.03). The radio-clinical evaluation of response, the surgery and the pathological response were predictive factors of specific survival. Conclusions: Pts with a complete pathological response after ICT who were not irradiated had a non significant increase of the relapse rate with a specific survival identical to the group of irradiated pts. This data have to be confirmed by a prospective trial. No significant financial relationships to disclose.
A multi-center phase II study of the cryptophycin analogue LY355703 in patients with platinum-resistant ovarian cancer
Authors: G. D’Agostino, J. Del Campo, B. Mellado, M. A. Izquierdo, T. Minarik, L. Cirri, L. Marini, J. L. Perez-Gracia, G. Scambia
Journal: Journal of Clinical Oncology (2005)

5097 Background: LY355703 is a synthetic product structurally related to the cryptophycin family isolated from the blue-green algae, which exerts a potent destabilization of microtubules during mitosis. This study was performed to determine the activity of LY355703 in patients with platinum-resistant advanced ovarian cancer and to characterize its toxicity profile. Methods: Twenty-six patients were registered into this study. Resistant disease was defined as a platinum-free interval <6 months from primary treatment or re-challenge. Further entry criteria were: radiological evidence of bidimensionally measurable disease as defined by the South Western Oncology Group (SWOG) criteria; age over 18 years; WHO performance status < 2; no more than one prior chemotherapy regimen, (with the exception of patients who remained platinum sensitive after second line therapy); life expectancy >12 weeks; absolute neutrophil count ≥ 1,5 x109/l; platelet count >150 x109/l; bilirubin and creatinine levels less than 1.5 times the upper limit of normality (ULN); liver enzymes (AST, ALT) <2.5 x ULN. Written informed consent was required from all eligible patients prior to enrollment into the study. LY355703 1.5 mg/m2, was administered intravenously on days 1 and 8 every three weeks, infused over two hours. Results: From 24 patients evaluable for response, 3 partial responses (12.5%) and 7 disease stabilizations lasting more than 4 months were registered (29.2%), for an overall clinical benefit of 41.7%. Fourteen patients (58.3%) experienced a progression of the disease during treatment. Among the 25 patients evaluable for toxicity 2 episodes of grade 3 anemia (8%), 1 grade 3 thrombocytopenia (4%), one grade 4 elevation of creatinine (4%) and one grade 3 hyperbilirubinemia (4%)were reported. Conclusions: LY355703 has a modest activity in patients with platinum-resistant advanced ovarian cancer. Nevertheless, the considerable rate of disease stabilization in the absence of serious adverse events in this poor-prognosis study population suggests that this novel cryptophycin may deserve further investigation in this setting. No significant financial relationships to disclose.
Intensive Induction Chemotherapy Followed by Autologous Stem Cell Transplantation (ASCT) In Patients with Enteropathy-Associated T-Cell Lymphoma: a Prospective Study by the Nordic Lymphoma Group (NLG-T-01)
Authors: Esa Jantunen, Thomas Relander, Grete Fossum Lauritzsen, Hans Hagberg, Harald Anderson, Eva Cavallin-Ståhl, Harald Holte, Anders Østerborg, Mats Merup, Peter De Nully Brown, Outi Kuittinen, Martin Erlanson, Bj∅rn Østenstad, Unn-Merete Fagerli, Ole Gadeberg, Christer Sundstrom, Jan Delabie, Elisabeth Ralfkiaer, Martine Vornanen, Francesco d’Amore
Journal: Blood (2010)
Patient obtained medical information used by cancer patients and companions
Authors: D. M. Dilts, E. C. Wang, B. Murphy
Journal: Journal of Clinical Oncology (2005)

6056 Background: Today patients and their companions use self-gathered information, we entitle patient-obtained medical information (POMI), which can impact patient and physician encounter. This study evaluates current and potential POMI sources, the perceived quality of such sources, and the benefits of such information. Methods: Participants, recruited from the Vanderbilt-Ingram Cancer Center, anonymously completed a validated questionnaire that queried 1) socio-demographics, 2) current and future medical information sources and the perceived quality of such sources, 3) medical topics searched for (including Internet web sites), and 4) the perceived benefits of the information acquired. Results: Response rate was 91% (n=424, 166 patient and companion pairs, 91 individual patients and 1 individual companion). Patients were primarily male (54.5%); companions were primarily female (63.5%). Both groups were older (>50, 64%), had a high school education or above (88.0%), and owned a computer (77.2%) with Internet access (76.2%). Both believed that POMI increased their: involvement in decision making (98.3% agreed), satisfaction with treatment choices (95.8%), ability to cope (96.5%), and communication among family members (95.5%). Surprisingly, when compared to these levels, POMI was statistically less likely to reduce anxiety (78.0%, p<.001). The top ranked oncology topics are diagnosis and treatment information both currently (82.2%) and in the future (69.4%), and information concerning drugs and side effects (58.4% current; 55.8% future). Oncologists are the primary source of information (97.2% current; 84.0% future), with the highest perceived quality (6.2 out of 7 current; 6.39 future), with the Internet ranked 7th for current use (46.2%) and 6th for future use (39.9%). Email, while much discussed, at 12th (16.0% current; 14.4% future) ranked well below newspapers/magazines (8th, 37.5%) and TV/radio (9th, 27.1%). Conclusions: POMI has a number of benefits, but it does not necessarily significantly reduce anxiety in either patients or their companions. The Internet can be used as an information supplement but it should not be considered a primary information source even for patients with high levels of Internet access. No significant financial relationships to disclose.
Identification of a novel molecular signature associated with renal carcinoma bone metastasis.
Authors: S. Le Mouel, B. Paule, E. Deslandes, L. Bastien, M. Podgorniak, F. M. Calvo, S. Mourah
Journal: Journal of Clinical Oncology (2010)

e15089 Background: Although recent advancements have been made in the understanding of breast and prostate bone metastasis, there has been less knowledge in the area of metastatic renal cell carcinoma (RCC) to bone, a frequent site of systemic spread of renal cancer. This particular cancer in bone remains relatively resistant to standard forms of treatment such as radiation and chemotherapy. A better understanding of the biology of RCC bone metastasis and the identification of predicting biomarkers of bone metastasis is critically needed and could be useful to identify sub- clinical disease, may improve staging and guide adjuvant therapeutic decisions. Methods: The purpose of this study was to investigate in a multiparametric manner the expression of a panel of biomarkers involved in angiogenesis and tumor invasion, in primary tumors and normal tissues both obtained from clear-cell RCC patients with and without bone metastases. Results: Using a multiplex real-time RT-PCR assay we identified a novel combination of biomarkers involved in angiogenesis and tumor invasion, associated with the risk of bone metastasis. Indeed, among the 25 transcripts of genes studies: VEGF-R1, VEGF-R2, Hif-1α, uPA and PAI-1 overexpression in tumor tissues was significantly associated with the presence of bone metastasis (p = 0.02, 0.02, <10-4, 0.04 and 0.03 respectively). No differences where found of these transcripts expression in corresponding normal tissues. Conclusions: Our results suggest that this novel signature which discriminate the RCC primary cancers with a significantly higher risk of bone metastasis can improve risk stratification independently of known standard clinical variables. A validation in a larger series will help to incorporate this molecular signature with clinical variables to refine prognosis and prediction in metastatic clear-cell RCC patients treated with novel tyrosine kinase-targeted agents. No significant financial relationships to disclose.