bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consistency between K-ras mutation in peripheral blood and matched tumor tissues detected by PCR-RFLP in Chinese patients with advanced NSCLC and its clinical significance analysis
Authors: Shuhang W. , Bai H. , Zhao J. , Duan C. J. , Yang L. , Wu N. M. , Wang J. Z. , Wang Y. Y. , Zhuo L. M. , Zhuo L. M. , Wang J. 
Published: August 2020

8090 Background: To explore the consistency between K-ras mutation in peripheral blood and matched tumor tissues detected by PCR-RFLP and analyze the prognostic effects of K-ras mutation in peripheral blood in Chinese NSCLC patients (pts) treated by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Methods: Plasma free DNA and matched tumor samples were collected from 264 hospitalized pts in Department of Thoracic Oncology, Peking University School of Oncology between Jan 2005 and Feb 2008. K-ras mutations were detected in coden 12 and 13 of exon 1 by PCR-RFLP and then verificated by sequencing. We compared the mutations in plasma samples and matched tumor tissues which determined an association between K-ras mutation status and clinical outcomes. Results: In 264 pts, K-ras mutation rates in codon 12 and 13 of exons 1 in peripheral blood were 11.36% (30/264) and 0.75% (2/264), also 9.84% (26/264) and 1.13% (3/264) in matched tumor tissues, respectively. Consistency of mutation in codon 12 between in tissues and plasma was 94%(248/264) (Kappa=0.686,P<0.001). Among 107 pts who received EGFR-TKIs treatment, the effective rate(RR), progression-free survival (PFS) and median survival time (MST) in pts with K-ras mutation in plasma DNA were 6.7.%, 2.7 months and 20.5 months, respectively, all which were lower than those of pts with wild type K-ras (32.5%, 23.7 months, 31.5 months; P=0.001, P=0.001, P=0.278, respectively). Conclusions: There is a high consistency of K-ras mutation rate between plasma DNA and matched tumor tissues. K-ras mutation in plasma is able to predict both response and PFS of NSCLC pts with EGFR-TKIs treatment. No significant financial relationships to disclose.
Validation study of direct sequencing and PCR-invader for detecting EGFR mutations in non-small cell lung cancer (NSCLC)
Authors: Naito Y. , Goto K. , Kenmotsu H. , Nishiwaki Y. , Kubota K. , Ohmatsu H. , Niho S. , Yoh K. , Nagai K. , Saijo N. 
Published: August 2020

8094 Background: EGFR mutation is both a predictive and prognostic factor for NSCLC treated with EGFR-TKI. Although new, highly sensitive methods for detecting EGFR mutations are currently available, these methods have not been validated. Methods: To validate direct sequencing and PCR-invader for detecting EGFR mutation, we analyzed 124 NSCLC by both methods concomitantly. Tumor tissues were obtained by surgical resection. Formalin-fixed paraffin-embedded specimens were prepared to analyze EGFR mutation. In direct sequencing, Exon 18, 19, and 21 of the EGFR gene were amplified, and PCR amplification products were sequenced directly (Mitsubishi Chemical Medience Corporation). PCR-invader was performed using the invasive cleavage of probe oligonucleotides to detect 10 mutations including Exon 18, 19, 20, 21 (BML incorporation). Results: EGFR mutations were detected in 51 patients (41%) by direct sequencing and 56 (45%) by PCR-invader. Discordance between two methods was found in 12 patients (10%). Exon 19 deletion was detected in 18 and 22 patients respectively. Exon 21 L858R was detected in 30 and 32 patients respectively. Each mutation in exon 19 deletions or L858R detected by direct sequencing could also be identified by PCR-invader. Overall 45 mutations were concordant by both methods. In two patients who received gefitinib, one patient with wild type by both methods did not respond to gefitinib. On the other hand, the other patient expressing Exon 19 deletion by PCR-invader but regarded as wild type by direct sequencing responded to gefitinib monotherapy. Conclusions: Discrepancy between two methods for detecting EGFR mutation was demonstrated and PCR-invader seems to be more sensitive. Further investigation including other highly sensitive methods is currently underway. No significant financial relationships to disclose.
Tanespimycin plus bortezomib in patients with relapsed and refractory multiple myeloma: Final results of a phase I/II study
Authors: Richardson P. G. , Chanan-Khan A. , Lonial S. , Krishnan A. , Carroll M. , Alsina M. , Albitar M. , Berman D. , Kaplita S. , Anderson K. 
Published: August 2020

8503 Background: Tanespimycin (Tan) disrupts HSP90, a key molecular chaperone for signal transduction proteins critical to myeloma (MM) growth, survival and drug resistance. Preclinical data show anti-tumor synergy between Tan and bortezomib (Bz) and suggest Tan may be neuroprotective, including reversibility of Bz-induced peripheral neuropathy (PN). A phase I study of single agent Tan in advanced MM showed favorable tolerability and modest activity. Methods: 72 patients (pts) with relapsed/refractory MM received 0.7 - 1.3 mg/m2 Bz as IVB followed by 1-hr infusion of 100 -340 mg/m2 Tan on days 1, 4, 8,11 q 21d, with 42 pts receiving the highest dose of both drugs as part of a phase II expansion. Toxicities were assessed by CTCAE v3 and response by modified EBMT criteria. Results: Of 72 pts, 72% had IgG subtype with a median age of 60 yo. Median time since MM diagnosis was 50 mos with median of 5 (1–15) prior regimens. Prior treatments included stem cell transplant (69%), thalidomide (74%), Bz (69%), lenalidomide (28%) and Hsp90 inhibitors (13%). 58 pts with measurable disease were treated at 1 or 1.3 mg/m2 Bz. Response rates (≥ MR) were 41%, 20% and 14% in the Bz-naive, -pretreated and -refractory pts respectively. In the subgroup with 1–3 prior therapies and who were Bz-naive, the response rate was 56%. Median duration of response (DOR) for all pts with response (n=14) was 10.7 mos, including 3 Bz-refractory pts who had durable PR through mos 12, 22 and 28. 3 other pts remain in response through 24 mos. Of the 72 pts, the most frequent AEs were diarrhea (60%), nausea (49%), fatigue (49%), thrombocytopenia (40%) and AST elevation (28%), which proved manageable with dose reduction and supportive care. Most frequent G3–4 AEs included thrombocytopenia (25%), diarrhea, anemia and fatigue (7% each), as well as back pain and AST elevation (4% each). Only 21% of pts had G1–2 PN; no G3–4 PN was seen. Conclusions: Tan + Bz is active and well tolerated in relapsed/refractory MM, with durable responses in Bz-naive, -pretreated and -refractory pts. Median DOR for the combination compares favorably to Bz monotherapy. Final PFS data will be presented. No severe PN has been observed, consistent with Tan's neuroprotective effect in pre-clinical models. A phase III study of Tan + Bz vs Bz is ongoing. [Table: see text]
Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: Results of an interim analysis of the German DSMM Xia trial
Authors: Knop S. , Liebisch P. , Wandt H. , Kropff M. , Jung W. , Kroeger N. , Sezer O. , Straka C. , Fingerle-Rowson G. , Einsele H. 
Published: August 2020

8516 Background: Cytoreductive induction followed by HD-MEL and ASCT is considered standard of care for younger patients (pts) with multiple myeloma (MM). The success of this combined procedure partially depends on the efficacy of induction treatment. Bortezomib-containing induction regimens have already been shown to be superior to standard VAD. In order to further improve the efficacy of induction treatment we combined Vel with intravenous (IV) cyclophosphamide (C) and dexamethasone (D). Methods: This trial is an open, prospective, multicenter, uncontrolled phase II/III study with a planned recruitment of 400 pts. The first 30 pts were included in the dose finding study to determine the optimum dose of IV C in conjunction with Vel and D. The following 170 pts up to 60 years of age with untreated MM were enrolled to receive 3 cycles of induction with Vel 1.3 mg/m2 IV d1, 4, 8, 11; D 40 mg/d d1, 2, 4, 5, 8, 9, 11, 12; and C 900mg/m2 IV d1. Primary study objective is response rate (≥ PR) to VelCD according to the EBMT criteria. Results: Data from the first completed 200 pts (mean age: 52 years; 74% stage III) from 36 German centers were analyzed as ITT population. Response rates are given in Table and were documented in 82% of the subjects with 13q-, in 94% with t(4;14) and in 70% with 17p-. SAEs (n=84) occurred in 24.5% of the pts and were related to Vel, C or D in 16%, 14.5% or 9.5% respectively. The mortality rate of 1% is low, 53% of the patients experienced grade 3 + 4 AEs, infections of grade 3 and 4 were reported in 2% and grade 3 paraesthesia occurred in 2%. Conclusions: This interim analysis demonstrates that bortezomib combined with dexamethasone and intravenous cyclophosphamide (VelCD) is a highly effective induction regimen for pts ≤ 60 years with newly diagnosed MM regardless of cytogenetic risk factors. [Table: see text] [Table: see text]
Durable responses with the antiangiogenic metronomic regimen RT-PEPC in elderly patients with recurrent mantle cell lymphoma (MCL)
Authors: Ruan J. , Martin P. , Coleman M. , Furman R. , Glynn P. , Joyce M. , Cheung K. , Shore T. , Schuster M. , Leonard J. 
Published: August 2020

8525 Background: Targeting tumor microenvironment and angiogenesis is a novel therapeutic strategy in lymphoma. Two putative anti-angiogenic regimens, RT (rituximab with thalidomide) and PEPC oral metronomic chemotherapy (prednisone, etoposide, procarbazine and cyclophosphamide) are clinically active. We report phase II safety, activity, and angiogenic profiling data with the novel combination RT-PEPC in elderly patients with recurrent MCL. Methods: RT-PEPC includes an induction phase (mo 1–3) of daily thalidomide (50 mg) and PEPC with weekly rituximab x 4. A maintenance phase (mo 4 until progression) continues with daily thalidomide (100 mg), PEPC dosing titrated to ANC > 1K/ul, and rituximab q 4 months. Endpoints included safety, efficacy, and FACT-G quality of life (QoL) assessment. Translational studies assessed the angiogenic phenotypes of tumor cells, and dynamic levels of circulating endothelial and hematopoietic progenitors in response to treatment. Results: Twenty-five pts (19 males) were enrolled, with 22 evaluable (3 never received rx). At study entry, median age (N=25) was 68 yrs (range 52–81), 24 (96%) had stage ≥ III, 16 (64%) had LDH > nl, and 18 (72%) IPI 3–5. The median number of prior therapies was two (range 1 to 7), and 15 pts (60%) progressed on bortezomib. At a median followup of 30 months, overall response rate was 73% (32% CR/CRu, 41% PR, N=22). Median PFS was 12 months, and median OS 22 months. Four CRs of 4+, 28+, 46+ and 48+ months are ongoing. Toxicities included gr 1–2 fatigue, rash and neuropathy as well as cytopenias (by design) including gr 1–2 thrombocytopenia (56%) and gr 3/4 neutropenia (56%). Two thrombotic events and 5 episodes of gr 3–4 infection were observed. QoL was maintained or improved on treatment. Correlative studies demonstrated pre-therapy autocrine angiogenic loop in tumor cells evidenced by expression of VEGFA and VEGFR1. Circulating levels of hematopoietic and endothelial progenitor cells decreased on rx in responders. Conclusions: RT-PEPC has significant and durable clinical activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity anti-angiogenic approaches warrant further evaluation in MCL and other NHL subtypes, potentially as initial therapy in elderly patients. [Table: see text]
Clinical and biological significance of microRNA profiling in patients with myeloma
Authors: Adamia S. , Avet-Loiseau H. , Amin S. B. , Moreau P. , Minvielle S. S. , Treon S. , Li C. , Anderson K. C. , Munshi N. 
Published: August 2020

8539 MicroRNA, a small endogenous RNA regulating specific expressed gene function has been implicated in normal biological processes as well as in malignant transformation. Here we have investigated the role of microRNAs in multiple myeloma (MM) biology, and their influence on prognosis and clinical outcome. We evaluated profiles of 384 microRNAs in CD138+ MM cells from 79 patients with MM, 11 cell lines and 9 healthy donors using qRT-PCR based microRNA array. We detected significant modulation of expression of 61 microRNAs in myeloma cells compared to normal plasma cells. Unsupervised hierarchical clustering of filtered matured microRNAs, identified two major groups within the MM population (groups A and group B). Group A clustered with MM cell lines, indicating more aggressive course of disease. Within B group, second degree node, group B2, clustered with normal plasma cells indicating indolent course. The unsupervised clustering of all MM samples showed consistent change in miR-146b, -140, -145, -125a, -151, -223, -155, let-7f, indicative of a role of these microRNA in myelomagenesis; while supervised analysis of samples within groups A and B identified modulated expression of different sets of miRNAs. In group A miR585 and let-7f were upregulated 8–12 fold; in group B, all differentially expressed microRNAs were downregulated (p<0.001) compared to normal plasma cells. These modulated miRNAs target critical signaling molecules such as HOX9, c-myc, Bcl-2, SHP1 and SHP2. We further analyzed the effect of microRNA on clinical outcome. We have observed significantly superior event free and overall survival of patients in group B compared to patients ingroup A (2 yr estimated EFS 79% versus 54% respectively; p=0.05; and 2 yr estimated OS 94% versus 70% respectively; p =0.017). Functional analysis by modulating miRNAs 585, 155 and let-7f showed change in levels of predicted genes with consequent biological effect on growth and apoptosis in MM cell line. Taken together, this data identifies miRNAs as critical modulators of gene expression and signaling pathways and provides potential novel targets in MM to both understand biological behavior and for therapeutic application. No significant financial relationships to disclose.
Panobinostat plus lenalidomide and dexamethasone phase I trial in multiple myeloma (MM)
Authors: Spencer A. , Taylor K. , Lonial S. , Mateos M. V. , Jalaluddin M. , Hazell K. , Bourquelot P. M. , San Miguel J. F. 
Published: August 2020

8542 Background: Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), affecting with epigenetic and non-epigenetic pathways of cancer. In vivo experiments demonstrated potent MM cytotoxicity of the triplet panobinostat + lenalidomide + dexamethasone. Methods: Trial started with 5 mg panobinostat (po, TIW) combined with fixed doses of lenalidomide (25 mg po, QD, Days 1–21) and dexamethasone (40 mg po, Days 1–4, 9–12, 17–20, Cycles 1–4), in a 28-day cycle. MTD of panobinostat in this combination for second-line MM will be established based on data from cohorts of ≥6 evaluable patients (pts). Safety, tolerability, PK/PD, and preliminary efficacy will be assessed. Results: Twenty-two pts with relapsed or relapsed refractory MM were treated in three dose levels to date. Dose escalation started at 5 mg panobinostat (po, thrice weekly) combined with fixed doses of 25 mg lenalidomide (po, qd, Days 1–21) and 40 mg of dexamethasone (po, Days 1–4, 9–12, 17–20, Cycles 1–4), in a 28-day cycle. Data from all eight patients in Cohort 1 were evaluated. The median number of prior lines of therapy was two (range 1–3). Six out of eight patients in Cohort 1 remain on therapy. Median follow-up is six cycles (range 4–8+). No DLT was observed. In Cohort 2, eight patients were treated at the dose level of 10 mg of panobinostat, with one single DLT: a Gr 1 increase of QT interval duration was detected on Day 3, persisting on Day 8 with therapy withheld, meeting DLT definition although not deemed clinically relevant. Cohort 3 is enrolling with six patients at 20 mg of panobinostat, thus far. SAEs included fever (two pts), anxious depressive syndrome, respiratory infection, atrial fibrillation, exertional dyspnea, cellulitis, superficial blood clot of thigh, phlebitis, hypokalemia. All, but fever in one patient, were assessed by the investigator as not study drug related. Conclusions: The potential for anti-myeloma activity of this triple combination is strongly supported by in vivo preclinical data. In this first clinical trial assessing this triple oral combination, the 5 and 10 mg dose level of panobinostat appear safe. Updated safety, early efficacy, and subsequent dose-level patient data will be presented. [Table: see text]
Phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma: Final results of JCOG0211
Authors: Yamaguchi M. , Tobinai K. , Oguchi M. , Isobe Y. , Ishizawa K. , Maseki N. , Wasada I. , Ishizuka N. , Hotta T. , Oshimi K. 
Published: August 2020

8549 Background: Nasal NK/T-cell lymphoma is rare and its standard therapy has not been established. Tumor cells express P-glycoprotein concerning multi-drug resistance (MDR). Anthracycline-containing chemotherapy is not effective and %2-yr overall survival (OS) of radiotherapy (RT) alone is only 45%. Methods: To explore a more effective treatment for localized nasal NK/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy consisted of 50 Gy of RT and 3 courses of DeVIC [carboplatin (CBDCA), etoposide (ETP), ifosfamide (IFM), dexamethasone (DMS)]. Patients (Pts) with newly-diagnosed, localized (IE & contiguous IIE with cervical node involvement) diseases, 20–69 years of age and PS 0–2 were eligible. The 3-D conformal RT planning was required to cover adequately target volumes (2 cm margin to gross tumor, entire nasal cavities and nasopharynx) and to minimize doses to organs at risk. Primary endpoint of the phase II portion was 2-yr OS and the enrollment of 24 pts to the phase II portion was planned. Based on the results of the phase I portion (ASH 2005, #2685), 2/3-dose of DeVIC (CBDCA 200mg/m2 d1 IV, ETP 67mg/m2 d1–3 IV, IFM 1.0g/m2 d1–3 IV, DMS 40mg/body d1–3 IV; every 3 wks) was applied for the phase II portion. RT quality assurance review confirmed no protocol violation (ASTRO 2008, #2682). Results: From Sep 2003 to Dec 2006, 33 pts were enrolled in the phase I/II study. 27 pts evaluated in the phase II portion showed the following features: age 21–68 yrs (median 56), M:F=17:10, stage IE 18, stage IIE 9, B symptom (+) 10, elevated serum LDH 5, PS2 2. With a median follow-up of 32 months (range, 24–62), %2-yr OS was 78% (95% CI, 57–89). Of 26 pts evaluable for response, 20 achieved CR, 1 PR, 2SD, and 3PD. %CR and %ORR were 77% (95% CI, 56–91) and 81%, respectively. The most common grade 3 non-hematologic toxicities were mucositis due to RT (30%) and infection (30%). Grade 4 hyponatremia and dermatitis due to RT were observed in each 1 pt. No treatment-related death was observed. Conclusions: Concurrent chemoradiotherapy using MDR-non-related agents and ETP is a safe and effective treatment for localized nasal NK/T-cell lymphoma, providing the basis for subsequent studies. No significant financial relationships to disclose.
Bortezomib, bendamustine, and rituximab in patients (pts) with relapsed (rel) or refractory (ref) follicular lymphoma (FL): Dose-finding results of the VERTICAL study
Authors: Matous J. , Letzer J. , Rosen P. , Noga S. , Fowler N. , Smith S. , Amin B. , Shi H. , Parasuraman S. , Cheson B. 
Published: August 2020

8550 Background: FL is an incurable indolent B-cell non-Hodgkin's lymphoma. Survival has improved in the past decade with the introduction of rituximab (Rituxan, R), but response decreases with repeated exposure. Bortezomib (Velcade, V) plus R was active and generally well tolerated in rel/ref FL [de Vos ASH 2006 Abs694], and bendamustine hydrochloride (Treanda, B) plus R has also shown activity in heavily pretreated FL [Robinson JCO 2008]. The current single-arm, multi-center study evaluates the efficacy and safety of VBR in pts with rel/ref FL. Here we report the safety of dose escalation of B in combination with VR. Methods: Pts with relapsed FL with ≥4 prior doses of R (no prior V or B), ≥1 measurable tumor mass, no active central nervous system lymphoma, KPS ≥50%, adequate hematologic, renal and hepatic function, and no peripheral neuropathy ≥G2 were eligible. Pts received five 35d cycles of V 1.6 mg/m2 (d1, 8, 15, 22), B 50, 70, or 90 mg/m2 (d1, 2) and R 375 mg/m2 (d1, 8, 15, 22, cycle 1; d1, cycles 2–5). B dose escalation continued based on cycle 1 dose-limiting toxicities (DLTs), defined as: treatment-related platelet count <25,000/mm3 for >7 days or any platelet count <10,000/mm3; G4 neutropenia for >7 days; any treatment-related ≥G3 non-hematologic toxicity other than inadequately treated nausea, vomiting, or diarrhea; or any toxicity resulting in >1 week treatment delay. Results: Sixteen pts (4 at B 50 mg/m2, 6 each at B 70 and 90 mg/m2) with a median of 3 prior therapies (range 1–13; 31% prior stem-cell transplantation) have been treated (15 evaluable for DLT); median age was 54.5 (44–80) yrs. There was one DLT at B 70 mg/m2 (severe rash; pt discontinued), and one DLT at 90 mg/m2 (G3 thrombocytopenia requiring cycle 2 d1 delay). Hematologic AEs were manageable and included 4 (25%) ≥G3 neutropenia and 1 (6%) G4 thrombocytopenia. Non-hematologic AEs ≥G3 in >1 pt were diarrhea (31%), fatigue (25%), vomiting (13%), and nausea (13%). Peripheral neuropathy was reported in 6 pts (38%; 1 G3). Evidence of antitumor activity has been observed. Conclusions: Enrollment is continuing in the phase II portion of the study with B 90 mg/m2, the highest planned dose. [Table: see text]
Long-term treatment of CTCL with the oral PNP inhibitor, forodesine
Authors: Duvic M. , Forero-Torres A. , Foss F. , Olsen E. , Pinter-Brown L. , Kim Y. 
Published: August 2020

8552 Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to T-cell selective intracellular accumulation of dGTP, resulting in apoptosis. Methods: An open-label dose escalation study of oral forodesine (40–320 mg/m2 daily) for 4 wks with extended therapy was performed to determine the maximum tolerated and/or optimal biologic dose (OBD). Additional subjects were accrued at an OBD (80 mg/m2) to further assess safety and clinical efficacy. Subjects with refractory CTCL, stages IB-IV were eligible. The primary efficacy endpoint (objective response rate [ORR]) was defined as ≥ 50% improvement by a severity-weighted assessment tool (mSWAT). Results: The overall intent to treat response rate was 17 of 64 (27%) subjects or 14 of 36 (39%) at the OBD. As of October 2008, nine of 64 subjects (14%) have received forodesine treatment for >12 months. This cohort of 9 subjects is further examined. Six discontinued treatment (median time on treatment 440 days): 4 for progressive disease, 1 withdrew consent, and 1 due to an adverse event (Diffuse Large B-cell Lymphoma). Three are continuing on therapy for 416, 710, and 863 days. Median age was 68 years (range 42, 81), and all but one was ≥ stage III. They had received a median of 3 prior systemic therapies including 8 of 9 with prior bexarotene. Five of 9 subjects had a response (2 with complete response, 3 with partial response, and 4 with stable disease). Related AEs were experienced by 7 of 9 subjects. The most frequent were nausea (44%), fatigue, peripheral edema, dyspnea, and urinary casts (all 22%). Grade 3 or higher related AEs were experienced by 2 of 9 subjects (Diffuse Large B-Cell Lymphoma as previously mentioned and peripheral edema). There were no hematologic or infection AEs related to forodesine. Grade 3 lymphopenia and CD4 count < 200 were noted in 8 of 9 and 4 of 9 subjects respectively. The risk of any infection AE regardless of cause in these 9 subjects was 15 per 100 person-months of forodesine exposure compared to 59 in all other subjects (n=55). Conclusions: Forodesine has an acceptable safety profile and efficacy in these CTCL subjects treated for 12 months or longer. [Table: see text]