tbuckley/cabot-search huggingface dataset:
Combined immuno-chemotherapy (R-FCM) results in superior remission rates and overall survival in recurrent follicular and mantle cell lymphoma: Follow-up of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)
Authors: M. H. Dreyling, R. Forstpointner, W.-D. Ludwig, M. Gramatzki, H.-P. Boeck, M. Haenel, H. Wandt, R. Parwaresch, M. Unterhalt, W. Hiddemann
Journal: Journal of Clinical Oncology (2005)

6528 Background: Rituximab monotherapy has shown a high activity in relapsed follicular lymphomas. Recently, phase III studies indicated that its addition to chemotherapy may further improve the progression-free survival substantially. Methods: In 1998 the GLSG embarked on a multicenter national trial in patients with relapsed or refractory follicular and mantle cell lymphoma. As most patients had received CHOP for first line treatment, a fludarabine-containing regimen (FCM) was chosen for salvage therapy followed by an optional Rituximab maintenance. A total of 4 courses were given. After the statistical analysis confirmed the significantly improved response rate of the combined study arm (R-FCM), 111 subsequent patients were designated to immuno-chemotherapy. Results: 122 of 244 currently evaluable patients (50%) had follicular, 95 patients (39%) mantle cell and 24 patients (10%) other indolent lymphomas. In 67 randomized patients with follicular lymphoma, complete (39% vs. 23%, p=0.013) as well as overall response rate (96% vs. 71%, p=0.011), progression-free survival (median: 3.9 vs. 1.7 years, p=0,029) and overall survival (74% at 4 years vs. median of 3.8 years, p=0,033) was significantly improved after combined immuno-chemotherapy. 55 patients subsequently designated to the combined study arm (R-FCM) confirmed the superior remission rates (36%/96%), progression-free and overall survival. Similarly, in 50 randomized MCL patients, R-FCM achieved higher complete (29% vs. 0%, p0.004) and overall response (58% vs. 46%, p= 282) as well as overall survival (median: 2.5 vs 0.9 years, p=0,031). Again, the improved remission rates (20%/75%) and overall survival was confirmed by 45 patients subsequently designated to combined immunotherapy. Conclusions: In summary, this is the first prospective randomized trial which demonstrates the superiority of a combined immuno-chemotherapy in patients with relapsed follicular and mantle cell lymphoma, both in terms of response rates but most importantly also in terms of overall survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche
NGRhTNF, a new vascular targeting agent with a dual mechanism of action: preliminary clinical results
Authors: C. Bordignon, F. Caligaris Capio, S. Toma, L. Manenti, P. Rizzardi, F. Curnis, C. Gallo Stampino, A. Corti
Journal: Journal of Clinical Oncology (2006)

13052 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding solid tumor (lung, renal, and colorectal) neovasculature. NGRhTNF specific binding relies on dynamic interactions with TNF-receptors, aminopeptidase N (CD13) and a specific integrin: a combination of receptors expressed by the tumor neovasculature endothelium, but not on normal vessels. This combination provides NGRhTNF with unique biological properties: at low dose, increased tumor vascular permeability, and massive tumor necrosis at high dose. Mouse preclinical data confirmed these properties, revealing also strong synergy between low dose NGRhTNF and cytotoxic agents (antracyclines, platinum based compounds, etc.). Methods: Based on these data, a series of studies were designed. A multicentre phase I study with NGRhTNF as single agent -still in progress- aims at defining MTD and preliminary anticancer activity, within the EORTC network (EORTC 16041). A single center phase I study exploiting the low dose range (0.2–1.6 μg/m 2 ) aims at defining safety and NGRhTNF activity on the tumor vascular permeability using DCE MRI (HSR NGR002). Results: Twelve advanced neoplastic patients were enrolled in the HSR NGR002 study. Up to the dose of 1.6 μg/m 2 , the only common toxicity was represented by constitutional symptoms such as infusion-associated chills (40%) of mild to moderate intensity. At the tested doses, NGRhTNF increased vascular permeability, as shown by changes in DCE MRI parameters (K trans and K ep ), and modulated the expression of chemokines possessing antiangiogenic activity. NGRhTNF achieved stable disease in about 45% of highly refractory treated patients, and still ongoing long lasting disease control in 2 cases (7 and 9 months along with sharp decline of CA125 and VEGF). Conclusions: NGR-hTNF, a VTA with a unique mechanism of action, combines activity on tumor vascular permeability and direct anti-cancer effect. Preliminary data in humans confirm its favourable safety profile along with remarkable anticancer activity, thus rendering the agent suitable for a development program alone or in combination with chemotherapeutics. Phase II low dose combination studies will begin in 2006. [Table: see text]
HtrA1 expression as a predictive factor of response to cisplatin-based regimen in patients with advanced gastric cancer
Authors: V. Catalano, A. Baldi, V. Shridhar, M. P. Staccioli, J. Chien, P. Giordani, D. Rossi, A. M. Baldelli, P. Alessandroni, P. Muretto, G. Catalano
Journal: Journal of Clinical Oncology (2006)

4077 Background: Human HtrA1 is a member of the HtrA (High temperature requirement) family of serine proteases. Recent reports suggest that htrA1 plays a protective role in varous malignancies due to its tumour suppressive properties. This study was performed to estimate HtrA1 expression as a predictor of the response to chemotherapy of patients with gastric cancer. Methods: HtrA1 was measured immunohistochemically on archival specimens of primary gastric cancer from 51 patients treated consecutively at our institution with a weekly chemotherapy including cisplatin 40 mg/m 2 , epirubicin 35 mg/m 2 , 6S-leucovorin 100 mg/m 2 , 5-fluorouracil 500 mg/m 2 , with the support of filgrastim 5 μg/Kg from the day 2 to 7 (PELF regimen), or cisplatin 40 mg/m 2 , epirubicin 35 mg/m 2 , 6S-leucovorin 100 mg/m 2 , 5-fluorouracil 500 mg/m 2 (PLF regimen). Response to chemotherapy was assessed after 8 weekly treatments according to the WHO criteria. Results: our population consisted of M/F 32/19; median age 64 years (range, 46–79). The prevalent metastatic sites were liver (17 pts), peritoneum (13 pts), lymph nodes (21 pts), locoregional disease (16 pts); 31/16/4 pts had 1/2/3 or more sites of disease. 23 pts had a low expression of HtrA1 (0/1+) versus 28 patients with higher expression (2+). Of the total 51 patients, there were 28 responders: 8 showing complete response (CR) and 20, partial response (PR). Of the 28 responders, 20 were in the higher HtrA1 staining group (2+), while of the 23 non-responders, 15 were in the higher HtrA1 staining group (0/1+). A statistically significant correlation between HtrA1 expression (HtrA1 2+ versus HtrA1 0/1+) and the clinical response was observed (response rate in patients with 2+ and 0/1+: 71.4% versus 34.8%, P &lt; 0.01, respectively). Interestingly, among 16 pts with locoregional disease (stomach, gastric bed, anastomosis), 1/6 pts had HtrA1 1+ expression compared to 8/10 pts with HtrA1 2+ (17% versus 80%, respectively; p = 0.025). Conclusions: The immunohistochemical identification of HtrA1 on the primary gastric cancer prior to chemotherapy may be a useful predictor for choice of potentially responders to a cisplatin-based chemotherapy. No significant financial relationships to disclose.
Phase II trial of cladribine (2-CdA) and rituximab in patients with CLL and SLL: Preliminary report of a single institution
Authors: P. Bertazzoni, D. Laszlo, F. Gigli, S. Bassi, L. Calabrese, L. Saronni, J. Quarna, A. Alietti, E. Cocorocchio, G. Martinelli
Journal: Journal of Clinical Oncology (2007)

7093 Background: Byrd et al (Blood 2003) confirmed the synergistic effect of Rituximab and Fludarabine in the treatment of CLL patients (pts). The choice of purine analogue still remains controversial. We evaluated feasibility, efficacy, and toxicity of 2-CdA-Rituximab combination in the treatment of CLL and SLL pts requiring treatment. Methods: The combination therapy consisted of intravenous Rituximab at a dose of 375 mg/m 2 on Day 1 and 2-CdA at a dose of 0.1 mg/kg (sc injection) per day on Days 2 through 6. The course was repeated at 4-week intervals for 4 times. 31 pts (21 CLL and 10 SLL) was enrolled in the study and the median age was 59 years (31–73); 42% of pts were pre-treated. A CT scan was abnormal in 95% of CLL pts. Immunophenotypic evaluation by ZAP-70 was positive in 70% of pts while no evaluable pts showed an adverse prognostic cytogenetic features by FISH. Minimal residual disease (MRD) assessment was performed by flow-cytometry and PCR methods. Results: 2 pts had to discontinue therapy after 2 cycle: one due to herpes zoster reactivation and the other one to the progression disease (PD). We observed grade 3 and 4 neutropenia in 4 pts (12%), major infections in 4 pts (12%) and no episodes of grade 3–4 thrombocytopenia. 24 pts were evaluable for response with an ORR of 96%. At the end of therapy 10 pts (42%), 7 CLL and 3 SLL, achieved a CR, with negative MRD (by PCR) in 4 pts (3 untreated); 13 pts (54%) obtained a PR and 1 patient had no response. With a median follow-up of 12 months (range 3–34) 7 pts (2 pts with MRD+CR and 5 pts with PR after treatment) experimented a PD; 5 of these pts were pre-treated and 2 died because of PD. Conclusions: The combination of 2- CDA and Rituximab seems to be tolerable and active principally for untreated pts and able to induce a molecular clearance also in pre-treated pts. The achieving of a CR with negative MRD seems to be the most important issue to improve the outcome. No significant financial relationships to disclose.
Prognostic significance of WT-1 levels in patients with myelodysplastic syndrome and leukemia after reduced-intensity allogeneic transplantation
Authors: L. C. Michaelis, D. Sher, M. Myers, M. Siddiqui, D. Collins-Jones, J. Ulaszek, D. Huo, A. Wickrema, K. Van Besien, W. Stock
Journal: Journal of Clinical Oncology (2006)

6524 Background: Expression of WT-1, a zinc-finger transcription factor, is elevated at diagnosis in many kinds of leukemia. The prognostic significance of the WT-1 transcript level before and after stem cell transplant is controversial. We performed real-time quantitative PCR (RQ-PCR) on samples from pts with leukemia and MDS undergoing allo stem-cell transplant (SCT) to determine if WT-1 expression correlates with survival (OS) and/or disease-free survival (DFS). Methods: Pts were conditioned with fludarabine, melphalan and alemtuzumab. cDNA was synthesized for RQ-PCR, which was performed on bone marrow (BM) and peripheral blood (PB) samples drawn prior to transplant admission and at day 28 (D28) post transplantation. All samples were analyzed using LightCycler technology and reported as a normalized ratio of WT-1 copy number to ABL copy number. Results: Data on 48 patients who underwent allo SCT are reported here. During a median follow up of 17 months, 24 patients died and the OS rate at one year was 52%. The DFS rate at one year was 34%. There was a statistically significant association between pretransplant WT-1 levels measured in PB and OS, with increase in risk of death by 36% for every 10 fold increase in WT-1 levels (p=0.048). Pretransplant WT-1 levels in both PB and BM also predicted DFS: the risk of relapse or death was increased by 44% (PB) and 71% (BM) for every 10 fold increase in WT-1 levels (p=0.012; p=0.048). However, after controlling for disease status at transplantation using a Cox model, pretransplant WT-1 levels were no longer a significant predictor because these levels were highly correlated with disease status at transplantation. We did not find any significant correlation between WT-1 levels 28 days post-transplantation and outcome. Conclusions: Our preliminary results differ from several published studies demonstrating prognostic significance of WT-1 RQ-PCR after allo SCT. Although elevated WT-1 levels prior to transplantation correlate with higher risk of post-transplant relapse and death from any cause, these preliminary data fail to establish an independent prognostic role for WT-1 RQ-PCR in the setting of reduced intensity allo SCT. Analysis of additional post-transplant time points is proceeding. No significant financial relationships to disclose.
Fatal hematologic toxicity with prolonged continuous administration of temozolomide (TMZ) during radiation therapy (RT) in the treatment of newly-diagnosed glioblastoma multiforme (GBM): Report of a Phase II trial
Authors: T. J. Doyle, T. Mikkelsen, D. Croteau, H. Ali, J. Anderson, R. Beasse, L. Rogers, M. Rosenblum, S. Ryu
Journal: Journal of Clinical Oncology (2005)

1546 Background: A Phase III trial demonstrated superior survival in GBM patients (pts) treated with postoperative RT and concomitant and adjuvant TMZ. Hematologic toxicity was acceptable; only 7% of pts experienced grade 3/4 toxicity (Stupp et al, ASCO Proc 2004, No. 2). The current phase II trial studied the same regimen. Methods: Pts age ≥ 18 with newly diagnosed histologically-proven GBM and KPS ≥ 60 with normal hematologic, hepatic and renal function were enrolled from 1/2001–10/2002. RT (60 Gy in 30 daily fractions of 2 Gy) and concomitant TMZ 75mg/m2 for up to 42 days were administered. Adjuvant TMZ 200mg/m2 day 1–5 every 28 days for up to 12 cycles was given following RT. Survival and toxicity were primary endpoints. Prophylactic trimethoprim-sulfamethoxazole (TMP-SMZ) 160mg/800mg 3 times weekly was given to those taking dexamethasone. Results: 16 pts were registered and all included in the analysis. The table describes survival and hematologic toxicity of all 16 pts. 3 (3/16, 19%) died from toxicity of TMZ given with RT. These are detailed in the lower part of the table. 1 pt had bone marrow (BM) biopsies (day 46 and 67) showing aplasia. Another pts day 38 BM biopsy showed 5% cellularity. Grade 3/4 thrombocytopenia preceded grade 3/4 neutropenia. Conclusions: 3/16 pts experienced fatal hematologic toxicity following daily TMZ 75mg/m2 during RT. 2 pts had BM examinations; 1 had aplastic anemia, the other only 5% cellularity. Due to routine use of TMP-SMZ prophylaxis, a drug interaction with TMZ cannot be excluded as a cause of hematologic toxicity. Further investigation is warranted. Caution is advised when using this regimen. N (pts) 16 Age, median/range 56/35–72 KPS 90–100/60–80 7/9 Survival, median (days)/1 yr/2 yr 393/38%/19% Grade 4 neutropenia 3/16 Grade 4 thrombocytopenia 3/16 Grade 5 hematologic toxicity 3/16 Aplastic BM 2/16 Patients with fatal toxicity: Age 57 61 63 Days of TMZ during RT 33 22 29 Days† to grade 3/4 neutropenia ANC nadir 35/39 0 -/27 0 35/36 0 Days† to grade 3/4 thrombocytopenia Platlet nadir k/uL 28/31 5* 24/-28* 32/34 13* Survival (days) 155 103 51 * pt given platelet transfusion-true nadir unknown † from day 1 TMZ Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering Schering
Serum cathepsin B (CB) levels are prognostic in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2
Authors: J. W. Singer, F. B. Oldham, B. Bandstra, L. Sandalic, J. Bianco, P. Bonomi, H. Ross
Journal: Journal of Clinical Oncology (2007)

18036 Background: CB is an estrogen-influenced lysosomal cysteine protease produced by tumor cells and tumor-associated macrophages; tumor tissue CB protein levels and proteolytic activity are prognostic in NSCLC (Anticancer Res. 2004; 24:4147–61). The prognostic value of serum CB has not previously been evaluated in NSCLC. Here we evaluate the impact of pretreatment CB levels on survival in pts from 2 phase III trials in advanced NSCLC, STELLAR 3 and 4. These trials compared paclitaxel poliglumex (PPX) against commonly used regimens. As the intratumoral metabolic pathway of PPX is characterized by the CB-mediated release of paclitaxel (P) from a polymeric backbone (Ca Chemother Pharm. 2006. Epub ahead of print), correlation of CB levels with PPX efficacy was assessed as well. Methods: Pretreatment serum samples from 450 chemo-naive pts with advanced NSCLC and PS 2 enrolled in STELLAR 3 (P + carboplatin (C) v. PPX + C) (N=315) and STELLAR 4 (vinorelbine or gemcitabine v. PPX) (N=135) were assayed for CB by ELISA (ICON Labs). Values were assessed by quartiles and there was a clear breakpoint at the median. Pts were categorized as high or low CB based on values above or below the median (64 ng/ml). The effect of CB levels on survival was evaluated by log rank for pooled pts from the studies. Results: As detailed in the table , median survival for non-PPX-treated pts was worse if CB was high; in contrast, median survival for PPX-treated pts did not differ by CB level. Pts with high CB receiving PPX showed a trend towards better survival compared to those receiving control regimens. Conclusions: The data suggest that serum CB may be prognostic biomarker for NSCLC. Retrospective analysis suggests a trend towards improved survival in patients with high CB receiving PPX; prospective studies are required to confirm this observation. [Table: see text] No significant financial relationships to disclose.
A first-in-human phase I study of U3-1287 (AMG 888), a HER3 inhibitor, in patients (pts) with advanced solid tumors.
Authors: J. Berlin, V. L. Keedy, P. A. Janne, L. Yee, N. A. Rizvi, X. Jin, C. Copigneaux, T. Hettmann, D. M. Beaupre, P. LoRusso
Journal: Journal of Clinical Oncology (2011)

3026 Background: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for the HER family and activates oncogenic signaling pathways. Its overexpression in many solid tumors has been linked to poor prognosis. U3-1287 (AMG 888) is a fully human anti-HER3 monoclonal antibody with demonstrated anticancer activity in preclinical models. This study had 2 parts: based on the observed tolerability of ≤20 mg/kg and pharmacokinetics (PK) study from the dose-escalation phase (part 1), 9, 14, and 20 mg/kg Q2W dosages were given in the dose-expansion phase (part 2). Methods: Pts with non–small cell lung cancer (NSCLC) and other refractory solid tumors thought to express HER3 were eligible. Study assessments included adverse event (AE) rates, PK, and tumor response (per modified RECIST and overall metabolic tumor response by EORTC). Human antihuman antibody (HAHA) responses were measured to assess immunogenicity. Results: Part 2 data (as of 9/24/10) are reported. Pts (N=31) with head and neck (1 pt), breast (1), ovary (1), cecum/appendix (1), colorectal cancer (CRC, 10), and NSCLC (17) tumor types were given 9 (n=10), 14 (n=2), and 20 mg/kg (n=19) of U3-1287 (AMG 888). Pts had a median (range) of 5 (2–10) prior chemotherapy regimens. 11 serious AEs were reported in 10 pts; none were attributable to U3-1287 (AMG 888). 16 pts (51.6%) experienced AEs ≥ grade (Gr) 3, with 1 Gr 5 dyspnea and 1 Gr 4 hypoglycemia. Two AEs ≥ Gr 3 were considered drug-related: Gr 3 anemia and Gr 3 rash. Gr 1/2 drug-related AEs in ≥10% of pts were fatigue, diarrhea, and nausea. Of 21 pts assessed, no HAHA responses were observed (by 21 days postdose). PK analysis (n=15) showed that steady state is reached after 3 dosing cycles for pts receiving 9, 14, or 20 mg/kg. Mean steady state Cmin was >10-fold greater than the threshold concentration required for 90% HER3 inhibition in xenograft models. Eight pts (6 NSCLC, 2 CRC) had a best response of stable disease at or beyond day-70 visit. One pt (NSCLC, 20 mg/kg) had significant tumor shrinkage (26.3%) and partial metabolic response by FDG-PET scan. Conclusions: U3-1287 (AMG 888) is well tolerated, with an absence of detectable HAHA responses. Part 2 data support 9–20 mg/kg Q2W dosage for future studies.
Flecainide
Authors: Dan M. Roden, Raymond L. Woosley
Journal: New England Journal of Medicine (1986)

FLECAINIDE acetate (Tambocor, Riker Laboratories) has recently become available in this country for the management of ventricular arrhythmias. The synthesis of flecainide in 1972 was the culmination of a systematic search for fluorinated local anesthetic analogues of procainamide (Fig. 1).1 Early screening experiments showed that this structure, N-(2-Piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy) benzamide, was active in a variety of animal models of arrhythmia.2 Clinical testing of the agent began in 1975. Only oral flecainide is currently available, although an intravenous form is under investigation.Flecainide is the first of a number of agents with similar electrophysiologic properties to be approved in the United . . .
ErbB/HER pathway profiling in formalin-fixed paraffin embedded tissues using multiplexed proximity-based assays
Authors: R. Dua
Journal: Journal of Clinical Oncology (2005)

645 Background: The EGFR, ErbB2, ErbB3 and ErbB4 are members of the Type I receptor tyrosine receptor kinase family (also known as the HER or ErbB family). Overexpression of these receptors in a number of cancer types (e.g. breast, colon, ovarian, and lung) results in an aggressive phenotype with poor prognosis. However, clinical trial data has shown that overexpression of ErbB receptors alone is not sufficient to predict patient response. A thorough analysis of the activation status of the ErbB pathway will likely achieve better prognosis. Methods: We report the development of a novel proximity-based, multiplexed assay to detect and quantify the levels of EGFR/EGFR, EGFR/HER2, HER2/HER2, HER2/HER3, and EGFR/HER3 homo- and hetero-dimers in formalin-fixed, paraffin embedded (FFPE) samples of tumor tissues including breast, lung, ovarian, head and neck, and colon cancers. The eTag assay is performed on samples that are deparaffinized, rehydrated and processed by standard protocols. Cytokeratin is used as an internal reference control for the total epithelial content. Upon completion of the assay the reporter eTags are released and separated by capillary gel electrophoresis and quantified by eTag-Informer software. Results: The data demonstrated the simultaneous detection and quantification of HER receptor expression, dimerization and phosphorylation in a single tissue section. The validity of the detection and quantification of HER dimers in FFPE tissue samples was independently confirmed by immunoprecipitation/Western blot and eTag assays in total cell lysates from the same tissues. Conclusion: We conclude that the eTag assays provide sensitive, quantitative assessment of various HER dimers from the same sample. They can be used to determine the activation status of ErbB/HER receptor in clinical sample for the correlation with disease prognosis or response to targeted therapies. No significant financial relationships to disclose.
Abstract 12537: Effect of Statin on Long-term Outcomes of Percutaneous Transluminal Renal Angioplasty in the Patients with Atherosclerotic Renal Artery Stenosis
Authors: Hideaki Aihara, Yoshimitsu Soga
Journal: Circulation (2012)

Introduction: Percutaneous transluminal renal angioplasty (PTRA) has become popular for treating atherosclerotic renal artery stenosis. However, effect of statin treatment after PTRA is uncertain. ...