tbuckley/cabot-search huggingface dataset:
Gefitinib (G) plus prednisone (P) versus placebo (pl) plus prednisone in the treatment of hormone-refractory prostate cancer (HRPC): A randomized phase II trial
Authors: F. Boccardo, A. Rubagotti, L. Tacchini, A. Lapini, G. Cruciani, G. De Rubertis, M. Battaglia, G. Conti
Journal: Journal of Clinical Oncology (2007)

5070 Background: In spite of EGF-R overexpression in 40%-80% of pts with HRPC, the results achieved so far with G, a selective EGF-R tyrosine kinase inhibitor have been dismal. This trial was designed to investigate the activity of G when combined with P, a common therapeutic option for HRPC pts. Methods: HRPC pts unresponsive to antiandrogen withdrawal were given P (10 mg/d) plus G (250 mg/d) or pl. On progression, pts initially assigned to pl were offered the possibility to receive G. This was a one-stage trial, and 37 pts per arm were required. Best PSA response (any decrease = 50% in baseline PSA confirmed 4 wks apart) was the primary end-point. Time to disease progression, OS and toxicity were secondary end-points. Results: 82 pts were enrolled (GP: 38; plP: 44). Groups were well balanced in respect to median age (75 vs 74 yrs); WHO PS (0 in both); baseline PSA (52 vs 44 ng/ml); bone disease (87% vs 84%) Gleason score 7 (58% vs 52%); prior treatment. At a median follow-up time of 29 mos (26–32), overall 77 pts progression and 51 died. PSA resp was recorded in 16% and 11% of pts in GP and plP groups. Median time to progression was 4.0 (3.5–4.5) and 4.5 (3.5–5.0) mos, respectively. In both groups, median PSA level increased during the first 8 wks of treatment (GP:13%; plP: 32%) while it decreased thereafter. Median time to death was 26.5 (16–37) and 20.5 (14–27) mos in the GP and plP groups, respectively (HR: 0.69, 0.39–1.23; p=.2). However, OS of pts given either early or delayed treatment with G was significantly longer (26.5 vs 17.5 mos; HR: 0.49, 0.28–0.87, p=.01). This advantage was maintained also after multivariate analysis by Gleason score, baseline PSA, Hb and PAL, WHO PS and pain score. AEs (any grade) occurred in 19 pts in each arm. However diarrhea and skin rash were more common in the GP group (12% vs 0% and 14% vs 2%, respectively). Conclusions: G when combined to P showed a moderate toxicity, achieved PSA control and prolonged pts survival. The efficacy of GP in HRPC warrants to be further investigated. [Table: see text] No significant financial relationships to disclose.
Thrombosis rate is higher with bioresorbable scaffolds than metallic stents, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Patients with coronary artery disease who undergo routine percutaneous coronary intervention (PCI) showed similar rates of target vessel failure but higher incidence of device thrombosis when a bioresorbable vascular scaffold was used instead of a metallic stent, in preliminary results from a randomised trial.1

Drug eluting metallic stents are the standard of care for PCI, but their rigid structure can affect blood flow and lead to atherosclerosis and stent thrombosis. Bioresorbable stents were developed to remove the presence of a permanent implant and to allow normal blood vessel function. …
EGFL7 polymorphism to predict tumor response in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI and bevacizumab (BV).
Authors: Joseph Ethan Li, Wu Zhang, Fotios Loupakis, Dongyun Yang, Takeru Wakatsuki, Yan Ning, Sebastian Stintzing, Rita Elie El-Khoueiry, Nico Benjamin Volz, Federica Marmorino, Marta Schirripa, Lisa Salvatore, Carlotta Antoniotti, Chiara Cremolini, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

3565 Background: Angiogenesis involves endothelial cell (EC) sprouting, proliferation, and differentiation and recruitment of mural cells to stabilize new vessels. The proteins Epidermal Growth Factor Domain-Like 7 (EGFL-7) and Activin Receptor-like Kinase 1 (ALK1) play critical roles. EC-secreted EGFL7 antagonizes Notch to promote EC proliferation, sprouting, and motility. EGFL7 also regulates mural cell recruitment and extracellular matrix deposition. ALK1 is an EC-restricted TGF-β Type 1 receptor with downstream repression of Vascular Endothelial Growth Factor (VEGF) signaling. ALK1 also promotes pericyte-EC adhesion. EGFL7 or ALK1 inhibition enhances antitumor efficacy when combined with BV in murine models. Both are overexpressed in many cancers and may be critical for efficacy of anti-VEGF therapy. We tested whether EGFL7 (rs1051851, rs2297538) and ALK1 polymorphisms (rs2293094, rs11169953, rs706819) will predict efficacy of BV-based therapy in mCRC pts. Methods: Genomic DNA was extracted from peripheral whole blood samples from 455 mCRC pts treated with first-line BV and FOLFIRI. SNPs were analyzed by PCR-based direct DNA sequencing and evaluated for association with tumor response rate (RR), overall survival (OS), and progression free survival (PFS). Results: Male/female: 272/183; median age: 62 (range: 25-81); median PFS and median OS: 10.9 (95%CI: 10.1-11.6) and 29.9 (95%CI: 25.9-34.6) months, respectively; response to therapy: 59% (215 pts); median follow-up:23.6 (range: 1.8-60.4) months. Pts carrying the EGFL7 rs1051851 G/G alleles had a 62% RR versus 56% in pts with A/G and 29% in patients with A/A (p=0.0130, Cochran-Armitage trend test). The result remained significant after adjustment for baseline pt characteristics (p=0.026, Multivariable logistic regression test). There was no statistically significant association between tested polymorphisms and OS or PFS. Conclusions: The EGFL7 SNP rs1051851 may predict tumor response in mCRC pts treated with FOLFIRI and BV. To our knowledge, this is the first study demonstrating predictive significance of genetic variations in EGFL7. Prospective validation of this study is warranted.
Response to tyrosine kinase inhibtors in non-small-cell lung cancer with concomitant c-MET overexpression and driver genes.
Authors: Na-na Lou, Jin-Ji Yang, Xu-Chao Zhang, Qing Zhou, Hua-Jun Chen, Zhen Wang, Jian Su, Zhi Xie, Ben-Yuan Jiang, Zhi-yong Chen, Xiao-Yan Bai, Yi-Long Wu
Journal: Journal of Clinical Oncology (2015)

8089 Background: The common driver genes in non-small-cell lung cancer (NSCLC) include EGFR, ALK and KRAS. We investigate the frequency of MET overexpression coexisting with oncogenic drivers and response to tyrosine kinase inhibitors (TKIs). Methods: We screened 806 consecutive NSCLC patients for the presence of MET overexpression by immunohistochemistry (IHC), in which ≥ 50% tumor cells with moderate to high intensity staining were defined as MET positive. MET amplification and ALK rearrangements were detected by fluorescence in situ hybridization (FISH), and FISH positive was defined as gene focal amplification or high polysomy (at least 15% cells with ≥ 5 copy numbers). Meanwhile, KRAS and EGFRmutations were tested by DNA sequencing or Scorpion amplification refractory mutation system (ARMS). Results: The frequency of MET overexpression was 31.9% (257/806) in NSCLC. Among c-MET positive patients, the frequency of EGFR mutation was 38.1% (98/257) and that of ALK rearrangement was 8.7% (22/257). Response rate (RR) of EGFR-TKIs was 22.2% (8/36) in advanced NSCLC patients with concomitant EGFR mutation and c-MET overexpression, and 56.8% (21/37) in those with only EGFR mutation, P= 0.033. However, there was no significant difference in RR between the patients with concomitant ALK rearrangement and c-MET overexpression and those with only ALK rearrangement, 61.5% (8/13) vs. 75.0% (6/8), P= 0.656. Among 2 cases with concomitant MET amplification and EGFR mutations, one responded to gefitinib, but the other had stable disease. Dramatic response was observed in one with concomitant MET amplification and KRAS mutations. Conclusions: Advanced NSCLC patients with concomitant EGFR mutation and MET overexpression have significantly low RR with EGFR-TKIs, indicating that MET overexpression potentially causes intrinsic resistance to EGFR-TKIs. Similar response was observed in ALK positive patients with or without c-MET overexpression treated with crizotinib.
A retrospective analysis of palliative MRgFUS treatment bone metastases from renal cell carcinoma (RCC).
Authors: Raphael M. Pfeffer, Yael Inbar, Dimitri Iozeffi, Pejman Ghanouni, Alessandro Napoli, Shrinivas B Desai, Joshua E. Meyer, Suzanne D LeBlang, Anne C. Roberts, Sergy Kanaev, Vladimir Turkevich, Junsung Choi, Fiona M. Fennessy, Mark Hurwitz, Clare Mary Tempany, David Gianfelice
Journal: Journal of Clinical Oncology (2014)

e15575 Background: About one third of patients with renal cell carcinoma (RCC) present with or develop bone metastases during their disease. Treatment of metastatic RCC has been revolutionized with targeted therapy. Patients with metastatic RCC may survive several years after diagnosis of metastases. Localized treatment of cancer pain is often required. Historically, RCC has been described as being more resistant to radiotherapy (RT) than other tumor types although subjective pain response has been reported in 58-77%. MR-guided focused ultrasound (MRgFUS) is a non-invasive technique for focal, image guided, temperature-controlled thermal ablation. Several recent studies show the safety and effectiveness of MRgFUS for the palliation of pain from bone metastases. Methods: A retrospective cohort analysis of patients with RCC included in multicenter prospective studies of MRgFUS for palliation of painful bone metastases between 2006 and 2012, Patients had painful bone metastases that was device accessible, MR compatible and whose life expectancy was ≥3 months. Before MRgFUS treatment, pain and analgesic usage were recorded using validated questionnaires. The primary endpoint was a ≥2 point improvement in self-reported pain score without increase of analgesic medication use 3 months post-treatment. Results: 22 patients (15 males/7 females) median age of 69 years (range 32-85 years) were identified. 18 patients (82%) had osteolytic and 3 (14%) had osteoblastic bone lesions. The target tumor was located in the pelvis in 15 (68%), extremities (excluding joints) in 3 (14%), ribs in 3 (14%) and scapula in 1. 13 patients (59%) had persistent or recurrent pain following prior RT and 8 (36%) patients were RT naïve (one status unknown). Overall response rate was 73% (16/22). 5 (23%) patients reported complete pain relief at 3 months. Of the patients that received prior RT, 69% (9/13) were responders and of the patients not previously treated with RT, 88% (7/8) were responders. No serious adverse events were reported. Conclusions: Retrospective analysis of metastatic RCC patients treated for bone pain with MRgFUS suggests that MRgFUS is safe and effective in both RT naïve patients and patients that have not responded to RT. Clinical trial information: NCT00656305.
Renal impairment and late toxicity in germ-cell cancer (GCC) survivors.
Authors: Jakob Lauritsen, Maria Gry Gundgaard, Mette Sakso Mortensen, Ib Jarle Christensen, Niels Vilstrup Holm, Mads Agerbaek, Gedske Daugaard
Journal: Journal of Clinical Oncology (2014)

4555 Background: Treatment with bleomycin-etoposide-cisplatin (BEP) decreases renal glomerular filtration rate (GFR) and confers a risk of later cardiovascular disease (CVD) and death. We investigated the influence of BEP on renal function and looked at associations between renal toxicity and late effects in a large cohort of GCC survivors. Methods: Patients were identified in the Danish DaTeCa database, housing GCC patients diagnosed 1984-2007. All patients (N=1,046) received BEP with measurements of GFR (51Cr-EDTA clearance) before and after treatment. GFR was repeatedly measured at 1, 3, and 5 years of follow-up. Late toxicity was identified by merging with national registers. Influence of covariates on renal toxicity was evaluated by a linear mixed model approach. Risk factors for late toxicity were estimated by a landmark analysis adjusting for covariates and the cohort was compared to the background population with standardized hospitalization/mortality rates (SHR/SMR). Results: After treatment, GFR decreased (ΔGFR) with median 13 ml/min/1.73m2. ΔGFR was inversely associated to GFR pre-treatment (P<0.0001) and associated to number of cycles (P<0.0001). Patients who received 3 or 4 cycles of BEP had significant rebound of renal function during follow-up, whereas patients treated with 5 cycles or more stayed reduced. Compared to the background population all patients, irrespective of renal function, had an increased risk of CVD and death. The risk of CVD and death depended significantly on chronic kidney disease (CKD) stage before treatment but not after treatment (Table). ΔGFR had no influence on risk of late toxicity (CVD: HR 1.08, P=0.34; Death: HR: 0.98, P=0.71). Conclusions: BEP decreases renal function, but the changes in GFR are partly reversible and have no impact on late effects or death. Before treatment After treatment SHR/SMR Outcome CKD P HR (CI) P HR (CI) (CI) Death I II III Total 0.25 0.03 1.00 1.41 (0.78-2.53) 2.60 (1.10-6.16) 0.93 0.24 1.00 1.02 (0.61-1.73) 1.69 (0.71-4.05) 1.81 (1.24-2.56) 2.06 (1.46-2.83) 3.43 (1.48-6.75) 2.03 (1.60-2.53) CVD I II III Total 0.74 0.19 1.00 1.11 (0.62-1.98) 2.00 (0.70-5.68) 0.32 0.47 1.00 0.80 (0.51-1.25) 1.40 (0.56-3.51) 1.96 (1.64-2.28) 1.16 (0.93-1.42) 2.03 (1.22-3.18) 1.57 (1.39-1.78)
The Epitranscriptome of Noncoding RNAs in Cancer
Authors: Manel Esteller, Pier Paolo Pandolfi
Journal: Cancer Discovery (2017)

Abstract The activity of RNA is controlled by different types of post-transcriptional modifications, such as the addition of methyl groups and other chemical and structural changes, that have been recently described in human cells by high-throughput sequencing. Herein, we will discuss how the so-called epitranscriptome is disrupted in cancer and what the contribution of its writers, readers, and erasers to the process of cellular transformation is, particularly focusing on the epigenetic modifications of ncRNAs. Significance: Chemical modifications of RNA play a central role in the control of messenger and ncRNA activity and, thus, are tightly regulated in cells. In this review, we provide insight into how these marks are altered in cancer cells and how this knowledge can be translated to the clinical setting. Cancer Discov; 7(4); 359–68. ©2017 AACR.
Outcomes after second allogeneic hematopoietic stem cell transplantation: A single-center experience.
Authors: Waseem Touma, Sami S. Koro, Pavan Kumar Bhamidipati, Shivaprasad Manjappa, Rizwan Romee, Iskra Pusic, Geoffrey L. Uy, Amanda F. Cashen, Keith Stockerl-Goldstein, Peter Westervelt, Camille N. Abboud, Ravi Vij, John F. DiPersio, Mark A. Schroeder
Journal: Journal of Clinical Oncology (2014)

7018 Background: Relapse and graft failure continue to be major challenges after allogeneic hematopoietic stem cell transplantation (alloHSCT). There is no standard treatment for either condition and a 2nd alloHSCT is often considered. Methods: Here we report outcomes of 77 patients who underwent 2nd alloHSCT at Washington University School of Medicine between 1997 and 2012. Univariate survival analyses (Kaplan–Meier log-rank test) were performed to investigate factors affecting disease–free survival (DFS) and overall survival (OS). Results: The median age was 44 years (19–70). Acute leukemias (ALL and AML) and myelodysplastic syndromes accounted for 82% of the cases. Indications for 2nd alloHSCT were mostly disease relapse (78%) and graft failure (16%). Median time between the two transplants was 330 days (15–3835). 49% of patients underwent 2nd alloHSCT with active disease and 57% underwent myeloablative conditioning. The grafts were mostly from matched unrelated donors and matched siblings (52% and 38%, respectively). The original donor was used in 38% of the 2nd transplants and 34% of the recipient-donor pairs were gender mismatched. OS at 1 and 5 years were 31% and 14%, respectively [median 162 days (5–5966)]. Factors prolonging OS were: acute graft versus host disease (aGVHD) (p=0.007), chronic GVHD (cGVHD) (p=0.027), disease status not active at the time of transplant (p=0.003) [median survival 316 days vs. 129 days], period between the two transplants more than 2 years (p=0.045), and post transplant STR above 95% (p=0.0004). Choosing the same donor as in the 1st transplant improved the OS if that donor was gender mismatched from the recipient (p=0.021). DFS at 1 and 5 years were 46% and 35%, respectively [median 106 days (5–5966)]. Factors prolonging the DFS were cGVHD (p=0.024) and disease remission at the time of 2nd transplant (p=0.0008). The incidences of aGVHD and cGVHD were 39% and 32%, respectively. Conclusions: This single center experience suggests that performing a 2nd alloHSCT on patients with active disease has very poor outcomes. OS is improved when there is long remission following initial alloHSCT. Choosing the same donor can improve OS if the recipient and donor are gender mismatched.
Presentation of late-relapse diffuse large B-cell lymphomas in extranodal sites may represent recurrences of the original disease.
Authors: Rena R Xian, Lode J. Swinnen, Ming-Tseh Lin, Christopher D Gocke, Amy Duffield
Journal: Journal of Clinical Oncology (2014)

e19558 Background: Diffuse large B cell lymphoma (DLBCL) constitutes approximately one-third of non-Hodgkin lymphomas in western countries. About one-third of cases are primary refractory or relapse within 2-3 years after diagnosis. Late relapse (>5 years) is uncommon. The aim of this study is to further characterize the clinical, pathologic and molecular features of late-relapse DLBCL. Methods: A retrospective analysis of all patients with DLBCL seen at Johns Hopkins Hospital between 1984 and 2013 was performed. Patients with biopsy-proven diagnostic and relapse samples were included, and patients with low grade lymphoma at any point were excluded. Molecular studies for IGH gene rearrangements were performed. Results: 163 patients with relapsed DLBCL were identified. 14.1% relapsed 5 years or more after diagnosis (up to 17.9 years). The average age at diagnosis was similar for early-relapse (54.7 years) and late-relapse (57.7 years). 40.0% of early-relapse (<5 years) patients were alive at the time of analysis as compared to 52.2% of late-relapse patients. 67.9% of early-relapse patients presented with extranodal disease at diagnosis vs. 91.3% of late-relapse cases. The most common extranodal site at diagnosis was the gastrointestinal tract (14.3% in early-relapse vs. 26.1% in late-relapse) followed by naso/oropharynx and soft tissue. Most late-relapse patients had extranodal relapse (91.3%), and were more likely to present with disease at a different site from diagnosis. IGH gene rearrangement results on two late-relapse patients show that the same IGHclone was present in both the diagnostic and relapse samples. Conclusions: Late-relapse was seen in a small but significant percentage of patients with DLBCL. Late-relapse was more common in patients who initially presented with extranodal disease. Initial gene rearrangement studies demonstrate that the late-relapses represent recurrence of the original lymphoma rather than a new primary DLBCL. While the mechanism is unclear, it is possible that the tumor environment in extranodal DLBCL may protect neoplastic cells from chemotherapeutic agents thus predisposing to late relapse.
CANCAP02: A study into the pharmacodynamic biomarker effects of vistusertib (AZD2014), an mTORC1/2 inhibitor, given prior to radical prostatectomy (RP).
Authors: Simon Pacey, Javier Garcia Corbacho, Nimish Shah, Ola Bratt, Anne Warren, Richard D. Baird, Vincent Gnanapragasam, Sara Stearn, Susan Ingle, Leanne K Bell, William Dott, Wendi Qian, Wanfeng Zhao, Barry Davies, Elizabeth A. Harrington, Elisabeth Maria Oelmann, Mirela Hategan, Sanjeev Kumar
Journal: Journal of Clinical Oncology (2017)

97 Background: Additional systemic therapy given to unselected patients (pts) around RP has yet to improved pt survival. Further trials should use appropriate pt selection, i.e. men at highest risk of relapse, ideally biomarker stratified. Using novel drugs prior to RP allows direct study of effects in primary prostate cancer (PC) that may guide design of future trials. Altered PI3K/AKT/mTOR pathway signalling is associated with aggressive PC hence we have undertaken a study vistusertib, an oral, dual mTORC1/mTORC2 inhibitor prior to RP. Methods: Primary endpoint was to measure mTOR1/2 inhibition by immunohistochemistry (IHC). Secondary endpoints were feasibility, safety, tolerability and determining plasma concentrations of vistusertib. Exploratory objectives included measurement of anti-cancer effects. Men, due for RP, with high volume or aggressive PC consented and received vistusertib, 50mg bd, for 15 days prior to RP. Diagnostic biopsy and RP tissue were collected for IHC. Adverse events (AE) were graded according to CTCAE v4. Plasma was collected to determine vistusertib concentrations. Results: 21 men, median age 62 (range 50 – 69) included 11 intermediate and 10 high risk PC. 18/21 were evaluable for primary endpoint. On day of RP mean plasma vistusertib concentration at RP was 648 ng/mL (range 386-852) and 6-8 hr post dose 484 ng/mL (range 211-660). Majority of related AEs were Grade (Gr) 1, the most common being rash, thrombocytopenia, oral mucositis, diarrhoea, lymphopenia and fatigue. Six pts experienced Gr3 AEs (3 pt lymphopenia, 1 pt each rash, mucositis and ALT rise). Two pts discontinued due to AEs (mucositis, thrombocytopenia) and one withdrew consent. Surgery was delayed in one pt (Gr 1 thrombocytopenia). IHC confirmed at RP: 4EBP1 was reduced in 100% pt (75% no staining post vistusertib) and pS6 was reduced in 67%, not changed in 25% and increased in 8%. A fall in PSA occurred in 4/18 pts. Conclusions: 2 weeks of AZD2014 can be given prior to RP. Active plasma concentrations were achieved. mTOR pathway inhibition was confirmed on IHC and a PSA fall occurred in 22% of pt. Analysis is ongoing, to be informed by concomitant studies in a PTEN null PC model. Clinical trial information: NCT02064608.