tbuckley/cabot-search huggingface dataset:
Molecular epidemiology of GISTs: Incidence of PDGFRA and KIT exon 9 mutations in the large French population-based study molecGIST
Authors: J. Emile François, S. Brahimi, J. Coindre, G. Monges, J. Y. Scoazec, J. Blay, O. Bouché, P. Aegerter
Journal: Journal of Clinical Oncology (2009)

10535 Background: KIT exon 11, KIT exon 9, and PDGFRA exon 18 mutations are present in 67%, 10% and 5% of gastrointestinal stromal tumors (GIST). However most of these data are based on analyses of patients with overtly metastatic tumors. The MolecGIST study was design to evaluated prospectively the histological, molecular and clinical characteristics of all GISTs diagnosed at all stages. Methods: All patients leaving in France, whose diagnosis of GIST was achieved between June 1, 2006 and May 31, 2008 were includable in the study. MolecGIST was approved by French ethical comities. Samples were collected in 11 reference centers for histology review, immunohistochemistry and detection of mutations within exon 9, 11, 13, and 17 of KIT and 12, 14, and 18 of PDGFRA. Results: In December 2008, 738 patients were referred to MolecGIST, corresponding to 5.95/million/year incidence of GIST en France (62 millions inhabitants). The median age at diagnosis 63.1 years (range [15–96]), and female/male ratio 0.98. GIST originated in the stomach in 56.3% and small bowel in 29.3% of the cases. Tumors were KIT+ in 90,4% of cases. CD34 was expressed by more than 20% of tumor cells in 83.8% of gastric GIST and 39.7% of small bowel GIST respectively (P&lt;0.0001). The risk of metastatic relapse was moderate or high in 62.7% of the patients, according to Fletcher classification, while only in 44% according to Miettinen's. Mutation analyses were achieved in 438 cases (to be updated), and mutations of either KIT or PDGFRA were detected in 66.2% and 12.6% of the patients, and absent in 21.2%. The most frequent mutations were KIT exon 11 (59.1%), PDGFRA exon 18 (9.8%) and KIT exon 9 (4.3%). The incidence of PDGFRA exon 18 and KIT exon 9 were significantly different than the published data (P=0.0008 and P&lt;0.0001 respectively). Among GIST of the small bowel, the mutations were KIT exon 11 (69.1%) and KIT exon 9 (13.1%). Conclusions: The PDGFRAexon18/KITexon9 mutation ratio is 4.5 times higher in our population based study than in patients included in phase III trials. The incidence of GIST with PDGFRA mutations and intestinal GIST exon KIT exon 11 mutations is underestimated in published series as compared to ours, probably because of the better prognosis. [Table: see text]
The effect of silencing luteinizing hormone receptor on prostate cancer cell proliferation.
Authors: S. Xiong, S. V. Liu, Q. Wang, J. K. Pinski
Journal: Journal of Clinical Oncology (2011)

e15057 Background: High intratumoral androgen levels and androgen receptor (AR) activity have been described in prostate cancer (PCA) cells despite the low levels of circulating androgens resulting from androgen deprivation therapy. One potential explanation for these findings is de novo androgen synthesis. We have previously demonstrated that luteinizing hormone (LH) upregulates steroidogenic genes and enzymes, increasing steroid production and cell proliferation in PCA. We now report that knockdown of the LH receptor (LHR) suppresses LH induced proliferation and AR signaling in LNCaP PCA cells. Methods: To knockdown LHR expression, LNCaP cells were transfected with siRNA against human LHR (LHR-siRNA) using scrambled siRNA as a control. Transfection efficiency was calculated by transfection with FITC conjugated-control siRNA and Western blot analysis of LHR expression in transfected cells. The MTS Assay was carried out to examine cell proliferation by using CellTiter 96 AQueous one solution following LH treatment. AR signaling was examined by co-transfection of LNCaP cells with pGL3-PSA-luc/ renilla-luc reporters and a dual-luciferase reporter assay. Results: LHR expression in LNCaP cells was significantly suppressed by LHR-siRNA silencing as evidenced by Western blot analysis. In LHR-silenced LNCaP cells, LH-induced cell proliferation (2 IU/ml, 72 hours) was inhibited by 48.7% (p<0.01) compared to scrambled siRNA-transfected cells. Dual-luciferase reporter assays showed a 51.3% (p<0.01) induction of AR signaling by LH (10 IU/ml, 72 hours) which was prevented by LHR silencing. Conclusions: Our current data strongly support an important role of LH signaling in PCA proliferation and AR signaling and suggest a potential pharmacological target in the treatment of castration-resistant PCA.
Hsp90 Is Critical for the Regulation of Human T Lymphocytes and NK Cell Phenotype and Function.
Authors: Jooeun Bae, Constantine Mitsiades, Rao Prabhala Prabhala, Tai Yu-Tzu, Jeff Martinson, Steven Hartson, Teru Hideshima, Lawrence Catley, Xianfeng Li, Ramesh Babu Batchu, Robert Bertheau, Shammas Masood, Sushima Samala, Jeff Miller, Kenneth Anderson, Nikhil Munshi
Journal: Blood (2005)
Phase II trial of the anti-prostate specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 plus low-dose interleukin-2 (IL-2) in patients (pts) with recurrent prostate cancer (PC)
Authors: S. J. Jeske, M. I. Milowsky, C. R. Smith, K. A. Smith, N. H. Bander, D. M. Nanus
Journal: Journal of Clinical Oncology (2007)

15558 Background: The de-immunized mAb J591 recognizes the extracellular domain of PSMA and was engineered to induce antibody-dependent cellular cytotoxicity (ADCC). Low-dose IL-2 results in the clonal expansion of NK cells and may enhance ADCC. We conducted a phase 2 trial to determine the efficacy and toxicity of mAb J591 plus low-dose subcutaneous (SC) IL-2 in pts with recurrent PC. Methods: 17 pts with recurrent PC (2 groups: 11 with PSA relapse only; and 6 with progressive castrate metastatic disease) received continuous low-dose SC IL-2 (1.2 x 10 6 IU/m2/day) daily for 8 weeks with mAb J591 (25 mg/m 2 IV) weekly on weeks 4, 5 and 6 (1 cycle). Pts could receive a maximum of 3 cycles. Results: 16 evaluable pts received up to 3 cycles of therapy (16 pts, one cycle, 9 two cycles and 2 three cycles). Toxicity was mild and limited to fatigue and injection site reactions. At the end of cycle 1, PSA was stable (-50%&lt;change in PSA&lt;25%) in 9 of 16 patients, with PSA declines up to 34%. No PSA decline &gt;50% was observed. A post-hoc analysis of PSA kinetics showed 5 patients had a reduction in their PSA slope of =25%; 8 of the remaining 11 patients demonstrated PSA stabilization (- 25%&lt;change in PSA slope&lt;25%). PSA response was most commonly observed during weeks 4–6 of the cycle correlating with mAb administration. Flow cytometric analysis of peripheral blood mononuclear cells revealed an average increase in absolute NK cell count of 107% at week 4 and 117% at the end of cycle 1. Conclusions: The combination of mAb J591 with low-dose IL-2 was well tolerated and inhibited PSA kinetics in some patients, however no responses were seen. Repetitive dosed mAb J591 is a viable strategy for use in combination with immune modulatory or other therapies in recurrent prostate cancer. No significant financial relationships to disclose.
Abdominal relapses in irradiated second National Wilms' Tumor Study patients.
Authors: P R Thomas, M Tefft, V T Farewell, P Norkool, B Storer, G J D'Angio
Journal: Journal of Clinical Oncology (1984)

Ten of 259 (3.8%) irradiated patients with group 2 and 3 tumors in the second National Wilms' Tumor Study experienced initial clinical relapse either in the operative site or elsewhere in the abdomen, excluding the liver and opposite kidney. Analysis of factors associated with abdominal recurrences has shown the independent significance of unfavorable histology, field size of the radiotherapy portals, and a postoperative delay of ten or more days before starting irradiation.
Blocking the regulatory T cell molecule LAG-3 augments in vivo anti-tumor immunity in an autochthonous model of prostate cancer
Authors: C. G. Drake, C. Kelleher, T. Bruno, T. Harris, D. Flies, D. Getnet, E. Hipkiss, C. Maris, J. Grosso
Journal: Journal of Clinical Oncology (2006)

2573 Background: LAG-3 is a CD4 homolog expressed on activated T cells, NK cells, tumor infiltrating lymphocytes (TIL), and plasmacytoid dendritic cells. Recently, we showed that LAG-3 was relatively overexpressed in specific T cells rendered unresponsive in vivo by the presence of cognate self-antigen. These anergic T cells display regulatory function both in vitro and in vivo, and blockade of LAG-3 with a non-depleting monoclonal antibody significantly mitigates their regulatory T cell activity. Methods: Using a novel model of prostate cancer in which a tumor-specific antigen is expressed in autochthonous tumors, we tested whether treatment with a non-depleting anti-LAG-3 antibody affected trafficking and function of tumor-specific T cells. Results: LAG-3 blockade significantly augments specific CD8 T cell trafficking to antigen-expressing tumors, but not to normal tissue. Most significantly, LAG-3 blockade functionally reversed CD8 T cell tolerance as assayed by an in vivo cytotoxic T lymphocyte (CTL) assay. Combining LAG-3 blockade with specific anti-tumor vaccination results in a dramatic increase in activated CD8 T cells in the tumor parenchyma. Conclusions: Taken together, these data support the concept that treatment with a LAG-3 blocking antibody may significantly delay disease progression in patients with cancer. We have recently generated a panel of monoclonal antibodies directed against human LAG-3; several of these antibodies significantly augment human T cell responses in vitro. No significant financial relationships to disclose.
Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation–positive metastatic melanoma patients (pts).
Authors: G. A. McArthur, A. Ribas, P. B. Chapman, K. T. Flaherty, K. B. Kim, I. Puzanov, K. L. Nathanson, R. J. Lee, A. Koehler, O. Spleiss, G. Bollag, W. Wu, K. Trunzer, J. A. Sosman
Journal: Journal of Clinical Oncology (2011)

8502 Background: Vemurafenib (PLX4032), an oral, selective inhibitor of oncogenic V600E mutant BRAF, was evaluated for safety and pharmacokinetics in the Phase I dose escalation (DE) study PLX06-02 (Flaherty, et al. NEJM, 2010). Exploratory analyses included the investigation of MOA, pathway inhibition, and primary or acquired drug resistance from pts participating in the DE and melanoma extension phase. Methods: Biopsies were taken at baseline (BL), on vemurafenib therapy Day 15 (D15), and at progressive disease (PD). Protein expression (PTEN, Cyclin D1, p27, and Ki67), phosphorylation (pERK, pMEK and pAKT), apoptosis (TUNEL), gene sequence (MEK1), and mutations in oncogenes and tumour suppressor genes (404 mutations incl. BRAF, H-, K-, N-RAS, and PIK3CA using Sequenom MassArray) were analyzed. Results: Tumor tissue of 5 pts from the DE and 17 pts from the extension cohort was obtained (total samples: 18 BL, 12 D15, 20 PD). In 7/7 pts with paired BL/D15 samples, high levels of pERK were observed at BL followed by a considerable reduction at D15. A similar pattern was observed for pMEK. The percent of cells with nuclear staining for Cyclin D1 and Ki67 was markedly reduced at D15 compared with BL. At PD, a broad distribution of pERK levels was observed across the samples. BRAF V600E mutation was present at both BL and DP in all samples analyzed. Genetic analysis performed on 32 samples (16 BL, 1 D15, 15 DP) revealed 1 MEK P124S mutation (at D15; confirmed in archival tissue) and 1 N-RAS G12R mutation (at PD; no pre-treatment sample available). Conclusions: The strong downregulation of MEK/ERK phosphorylation observed in pts treated with vemurafenib is consistent with preclinical studies and confirms the proposed MOA of vemurafenib (blockade of BRAF V600E-driven signalling). This blockade is associated with reduction in Cyclin D1 expression and downregulation of proliferation. That the BRAF mutation persisted in all PD samples and in some cases ERK phosphorylation was reduced suggests that some patients may continue to respond to inhibition of the BRAF V600E-driven signaling pathway although simultaneously requiring inhibition of other activated signaling pathways.
Characteristics of treatment-related dermatological toxicity in oncology day unit patients.
Authors: A. M. O'Reilly, B. R. Bird, J. O'Keeffe
Journal: Journal of Clinical Oncology (2010)

e19659 Background: This study aimed to determine how increased use of novel targeted therapies (NTT) has changed the profile of dermatological toxicity in oncology day units. Methods: Retrospective analysis was performed in a single institution for all patients presenting over a four week period. Participants were followed up for the remainder of the study period. Patient charts were reviewed for incidences of dermatological toxicity. Toxicity was graded using the CTCv3. Statistical analysis was performed using SPSSv18. Results: A total of 135 patients presented, 116 underwent final analysis. 59 patients received NTT. In total 205 toxicities were evaluated. Patients receiving NTT experienced a higher mean number of toxicities (2.1 (95%CI 1.8-2.5)) then those receiving traditional chemotherapy (1.4 (95%CI 1-1.7)), p<0.01. Those receiving NTT experienced significantly more hand foot syndrome (p<0.01), rash (p<0.01) and nail dystrophy (p=0.02). Those receiving NTT experienced more grade 2 or above dermatological toxicity (p<0.01) and experienced significantly more grade 2 or above HFS (p=0.05), rash (p=0.04) and stomatitis (p=0.01). Those receiving NTT underwent more alterations in chemotherapy then those receiving traditional chemotherapy (p<0.01). Eleven (9%) patients received capecitabine, all in combination with a NTT. Ten of these patients experienced dermatological toxicity, 5 of these were grade 2, one patient experienced a grade 3 toxicity (HFS). HFS affected 25 (22%) participants, 10 (9%) of these were grade 2 or above. Fifty-one (44%) patients experienced rash, 13 (11%) were grade 2 or above. There was 8 instances of acneform rash related to EGFR inhibitors and 1 instance related to temsirolimus. Forty (34%) participants experienced stomatitis, 6 (5 %) were grade 2 or above. Additional toxicities that were evaluated included alopecia (27% participants), nail dystrophy (4% participants), bruising (10% participants) and dry skin (28% participants). Conclusions: Those receiving NTT may be at increased risk of developing dermatological toxicity. Dermatological toxicity in this group may be of higher grade and greater complexity.Treatment of dermatological toxicity in this group may require more dose modifications. No significant financial relationships to disclose.
In newly diagnosed breast cancer, is a contralateral prophylactic mastectomy necessary following a negative MRI?
Authors: J. R. Bernard, L. A. Vallow, R. B. McNeil, S. A. McLaughlin, X. J. Geiger, E. A. Perez
Journal: Journal of Clinical Oncology (2009)

627 Background: With more centers using MRI to aid in initial staging, there is apprehension that the highly sensitive MRI exam may lead to “unnecessary” mastectomies. We evaluated whether a negative contralateral MRI could be used to rule out a synchronous contralateral carcinoma and hence avoid a prophylactic contralateral mastectomy (CPM) at initial breast cancer diagnosis. Methods: Data of women with a new diagnosis of breast cancer (invasive or DCIS) from February 2003-November 2007 at our institution were reviewed. Women who had a negative MRI of the contralateral breast and who subsequently underwent CPM were included. A CPM was one in which there was no histological confirmation of cancer in the contralateral breast before surgery. All mastectomy specimens were analyzed pathologically. True negatives were mastectomy samples which contained no cancer following pathologic examination. False negatives were mastectomy samples which were found to have cancer after pathologic review. Results: 538 women were identified. 51 women met the study criteria. Median patient age was 56 years (range, 33–77). Of the 51 women who underwent a CPM, 2 were found to have pathologic confirmation of cancer. One occult cancer was a 0.3 cm grade 1, invasive lobular carcinoma; the second a 0.5 cm, low grade DCIS. The overall prevalence of synchronous occult contralateral cancer after a negative MRI was 3.9% (95% CI 0.5 - 13.5%). The negative predictive value of MRI was 96.1% (95% CI 86.5 - 99.5%). Conclusions: This study provides pathologic data regarding the utility of a negative contralateral breast MRI in women with newly diagnosed breast cancer. The prevalence of a synchronous occult contralateral cancer after a negative MRI in women with newly diagnosed breast cancer is very low. Physicians and patients can be assured that the risk of occult cancer is low in the setting of a normal contralateral MRI, an important fact when considering CPM after a diagnosis of unilateral breast cancer. No significant financial relationships to disclose.
Phase I study of topotecan (T) with weekly 5-fluorouracil (5FU)/leucorin (LV) in patients with advanced malignancies
Authors: R. S. Axelrod, L. Rose, W. Biermann
Journal: Journal of Clinical Oncology (2007)

13018 Background: Topotecan (T) is a semi-synthetic camptothecin analog with a broad spectrum of activity targeting the nuclear enzyme topoisomerase I. Daily iv schedules (up to 5) can result in dose limiting neutropenia. Reported synergy in vitro between topoisomerase I inhibitor and 5 FU/LV led us to explore a weekly schedule of 5FU, LV, and T in refractory tumors. Methods: Entry criteria: metastatic or locally advanced solid tumors; up to two prior chemotherapy regimens; prior adjuvant regimen admissible; no chemotherapy or radiation therapy within 4 weeks; adequate hepatic, hematologic, renal function. Exclusion: active second malignancy; CNS metastases; prior topotecan; allergy to related agents; active uncontrolled infection or conditions that would interfere with the study. Treatment was administered days 1, 8, 15, 22 of a 42 day cycle as LV 20 mg/meter (m) 2 over 15 minutes intravenously (iv), 5 FU 400mg/m 2 bolus, iv, and T at the specified dose (1.5mg/m 2 , 1.75, 2.0, up to 4 mg) over 30 minutes iv. Cohorts were advanced after at least three pts had completed 42 d. Study is reported through cohort 9: 5 FU 400/m 2 , LV 20/m 2 , topotecan 4 mg/m 2 . Results: Pt characteristics: 19 F, 25 M; ages 29–80, median 62. Tumor types: Pancreas (9), colorectal (6), lung (6), liver (3), salivary gland (5), sinus (2), nasopharynx (2) esophagus (2), and tongue, larynx, ovary granulosa cell tumor (gct), endometrium, mixed mullerian, mesothelioma, sarcoma, gastric (1 each). Related toxicities: gr 3/4 neutropenia 9%/2%, Hb 11%/0, platelets 4.5%/0, fatigue 4.5%/0. Stable disease of ≥ 4 cycles was observed in 18%: pancreas (2), ovarian (1), endometrium (1), salivary gland (3) (2 adenoid cystic, 1 adenocarcinoma). Conclusions: 5 FU, LV and T is well tolerated as a weekly out patient schedule (4 of 6 wks). It achieved minor response in one patient with gct for 8+ cycles and stable disease for ≥ 4 cycles in 6 pts. It is worthy of further exploration for gynecologic, salivary gland and pancreatic cancers. No significant financial relationships to disclose.
Integration of system-level patient-reported outcome measurement into everyday clinical care: Lessons learned from the cancer care Ontario experience.
Authors: Sean Molloy, Jose Pereira, Esther Green, Deborah Jane Dudgeon, Doris Howell, Monika K. Krzyzanowska, Wenonah Mahase, Reena Tabing, Sara Urowitz, Laura Macdougall
Journal: Journal of Clinical Oncology (2014)

159 Background: The goal of the collaborative is to improve the quality and consistency of physical and emotional symptom management across the cancer journey. Objectives are to promote the adoption of electronic symptom assessment using a standardized tool and to increase the clinical use of evidence based guidelines to effectively manage patient identified symptoms. Methods: The actions taken for this initiative are (a) manage cancer symptoms through a patient reported measurement tool; (b) improve the quality of symptom management through the uptake of symptom management guides and algorithms for care; and (c) drive improvement through the adoption of an electronic symptom assessment platform. The following aims were established for this work: (1) aim for symptom screening and assessment (70% of ambulatory cancer clinic patients are screened for symptom severity using ESAS at least once/month); (2) aim for symptom management (evidence from chart audits show intervention as per evidence based guidelines for patients reported symptom scores); (3) aim for patient satisfaction (90% of target population indicates that their health care team took their scores into consideration when developing a care plan); and (4)aim for evidence of use (90% of patients state that their doctor or nurse spoke with them about their symptom screen). Results: 60% of cancer patients are screened each month representing over 28,000 people. Six of fourteen cancer regions are above the provincial target of 70%, with some close to 90%. 92% of patients felt ESAS was important to complete to help health care providers know how they are feeling. Conclusions: Cancer Care Ontario has been able to drive improvements in symptom management through the implementation of system wide electronic symptom assessment. For other jurisdictions interested in adopting this approach, the following areas are critical for success: a) leadership at all levels of the system; b) clinical tools at the point of care; c) engagement of patients in the design of care; d) communications support to spread information to all stakeholders; and e) using to data to drive performance improvement and accountability.