bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies of pemetrexed and gemcitabine, alone and in combinations, in human lung cancer models
Authors: Chan D. C. , Chen V. J. , Zhang Z. , Helfrich B. , Hirsch F. R. , Ma D. , Bunn P. A. 
Published: March 2020

17114 Background: Gemcitabine (GEM) is a deoxycytidine analog that inhibits DNA synthesis. Pemetrexed (ALIMTA, PEM) is a novel antifolate inhibiting multiple enzymes targets, including thymidylate synthase (TS). This study aimed at evaluating the antitumor effects of these antimetabolites against NSCLC and SCLC tumor models. Methods: In vitro growth inhibition (IC50) studies were done by 6-days MTT assays against a panel of 20 NSCLC and 17 SCLC cell lines. In vivo studies used only NSCLC H2122 tumor line, implanted either subcutaneously in athymic nude mice or orthotopically in athymic nude rats. Drugs were given via the ip route at the designated schedules. Results: Against NSCLC and SCLC cell lines, the averaged IC50s of GEM were 0.015 ± 0.008 μM and 0.055 ± 0.04 μM respectively. The corresponding averaged IC50s for PEM were 0.65 ± 0.2 μM and 0.091±0.018 μM respectively. When H2122 tumors reached 50–100mg, mice were treated with 10 daily doses of PEM at 100, 200 and 300 mg/kg, or three doses of GEM every 4 days at 30, 60 and 120 mg/kg. PEM delayed tumor growth by 12 to 18 days, and GEM delayed by 10 to 14 days, relative to vehicle control. Results of three combination regimens with GEM (30 mg/kg) and PEM (100 mg/kg) were: (1) GEM → PEM gave intermediate activities between the two single agents, but was toxic to animals; (2) PEM and GEM given concurrently were more active than single agents alone and delayed tumor growth by 12 days with some toxic side effects; (3) PEM → GEM was better than the single agents alone, and delayed tumor growth by ∼14 days without toxicity. Athymic nude rats bearing orthotopic H2122 tumors given PEM daily at 50, 100 and 200 mg/kg for 21 days had significantly prolonged survival, but not in a dose-dependent manner. PEM at 50 mg/kg was more effective than doses at 100 or 200 mg/kg. GEM was toxic to nude rats due to poor plasma deamination of GEM. Conclusions: In vitro, PEM was more potent against SCLC than NSCLC cell lines, but GEM had similar activities against all lung lines tested. Studies of H2122 xenografts in rodent supported PEM → GEM as the preferred sequence for the combined administration of these two drugs. [Table: see text]
A phase II study of BAY 43–9006 (Sorafenib) in patients with relapsed non-small cell lung cancer (NSCLC)
Authors: Liu B. , Barrett T. , Choyke P. , Maynard K. , Wright J. , Kummar S. , Murgo A. , Doroshow J. , Gutierrez M. 
Published: March 2020

17119 Background: Sorafenib is an inhibitor of multiple kinases including Raf-1 (C-Raf), b-Raf and pro-angiogenic tyrosine kinases (VEGFR-2/3 and PDGFR-β) and showed preclinical activity against NSCLC cell lines. Its anti-tumor activity may be attributable to inhibition of proliferative signaling through the RAS/Raf/MEK/ERK pathway and its anti-angiogenic effects. In NSCLC, the proliferation signaling of the Ras/Raf/MEK/ERK pathway is increased due to the increase in K-ras mutations. We initiated a single agent sorafenib trial in patients (pts) with relapsed NSCLC to assess clinical response and translational endpoints in tumor biopsies. Methods: This phase 2 trial uses a two-stage design targeting an objective response rate (RR) which can rule out 5% in favor of a more desirable 20% RR. Eligibility criteria: Pts with recurrent NSCLC with measurable disease who have received only one prior chemotherapy regimen, ECOG 0–1. Pts receive Sorafenib 400 mg bid continuously on 28-day cycle. Responses were evaluated every 8 weeks (wks) according to RECIST criteria. Dynamic contrast enhanced MRI (DCE-MRI) and tumor biopsy are performed before cycle 1 and at C1D15 to study early changes in tumor vascularity and translational endpoints. Results: 6 pts are evaluable for toxicity and 5 pts are evaluable for response. Best Response: 1PR (41% tumor reduction at wk 8, remained in PR until wk 28), 1 PR (unconfirmed) at wk 3, 2SD (16 and 19 wks respectively) and 1PD after 8 wks of treatment. Skin toxicity: Acne like drug-related rash (5 pts), hand-foot syndrome (6 pts), keratoacanthoma (1pt) and vasculitis (1pt). All skin toxicities are G1 or G2 and have responded to temporary withdrawal of Sorafenib and supportive care. Hypertension occurred in 1 pt (G2). No G4 toxicities have been observed. G3 toxicities include: anemia (1 pt), hyponatremia (2 pts), and nausea (1 pt). DCE-MRI results: 1 pt on C1D15 showed decrease in permibility parameters (ktrans and kep) and tumor size. DCE-MRI from the other 2 pts (1 PD, 1 SD for 16 weeks) showed no decrease in the permeability parameters. Conclusions: Sorafenib appears to be well-tolerated and active against relapsed NSCLC. Preliminary evidence of objective response warranting second stage accrual. No significant financial relationships to disclose.
Curative-intent resection for bronchogenic carcinoma in patients with prior spinal cord injury: The Department of Veterans Affairs experience
Authors: Brunworth L. S. , Dharmasena D. , Virgo K. S. , Johnson F. E. 
Published: March 2020

17127 Background: There are approximately 250,000 people with spinal cord injury (SCI) in the US, and they have a high prevalence of smoking. A literature search yielded no published information concerning the clinical course of SCI patients who subsequently develop bronchogenic carcinoma and undergo pulmonary resection for this condition. We hypothesized that poorer outcomes of surgery would be observed in this population, as compared to neurally-intact patients. Methods: We conducted a study of all veterans at Department of Veterans Affairs (DVA) Medical Centers during fiscal years 1993–2002 who were diagnosed with SCI, subsequently developed non-small cell lung cancer and were then surgically treated with curative intent. Inclusion criteria included American Spinal Injury Association type A injury (complete loss of neural function distal to the injury site) and traumatic etiology. Data were compiled from national DVA datasets and supplemented by operative reports, pathology reports, progress notes, and discharge summaries. Results: Of 12,634 patients who underwent surgery for bronchogenic carcinoma, 55 also had codes for prior SCI; 7 were evaluable. The mean age was 64. Five (71%) had one or more co-morbid conditions in addition to their spinal cord injuries. All 7 underwent pulmonary lobectomy. Post-operative complications occurred in 4 patients (57%). Two patients died post-operatively on days 29 and 499, yielding a 30-day mortality rate of 14% and an in-hospital mortality rate of 29%. Conclusions: We believe this isthe only report in the English language literature on this topic. SCI patients with resectable bronchogenic carcinoma have a high incidence of co-morbid conditions. Those who undergo curative-intent surgery have high morbidity and mortality rates. This evidence suggests that SCI should be considered a risk factor for adverse outcomes of surgery for primary lung cancer, strengthening the case for alternative treatments. No significant financial relationships to disclose.
Preliminary results of second-line chemotherapy with vinorelbine and gemcitabine after docetaxel and carboplatin failure in advanced non small cell lung cancer (NSCLC)
Authors: Abou Yared J. , Chahine G. , Kattan J. , Farhat F. , Moukadem W. , Nasr F. , Younes F. , Ghosn M. 
Published: March 2020

17130 Background: To evaluate the efficacy and safety of a doublet platinum-free therapy based on Vinorelbine and Gemcitabine in the salvage treatment of patients with advanced NSCLC, previously treated with Carboplatin and Docetaxel. Methods: We conducted a phase II study with the combination of vinorelbine 30 mg/m2 and gemcitabine 1000 mg/m2 d1 d8 / 3w. Eligible were patients with histologically proven advanced or metastatic NSCLC who were refractory or progressed after first-line chemotherapy combining Docetaxel and Carboplatin. Results of this first-line therapy were already reported (Proc. Am. Soc. Clin. Oncol. 2005, abstr 7330). Patients must have measurable disease, PS ≤ 2, life-expectancy ≥ 3 months, adequate hematologic, liver and renal functions. Response to therapy was evaluated according to RECIST guidelines. Toxicities were assessed according to the national cancer institute (NCI) common toxicity criteria 3.0. Results: From August 2004 to September 2005, 28 patients were enrolled. Median age was 63 years (range, 44 to 77) with 18 males and 10 females. A total of 109 cycles were delivered with a median of 4 cycles per patient (range, 1 to 9). Mean metastatic sites were lymph nodes in 9 pts, liver in 6 pts and pleura in 5 pts. 26 patients were evaluable for response (1 patient too early and 1 pt lost of follow-up). 6 patients responded partially (23%), one of them was initially resistant to the first-line therapy. 11 patients had stable disease (42%). Mean objective response duration was 7 months (range, 5 to 10+). Main toxicities (grade 3/4) were: anemia in 4 patients, neutropenia in 7 patients, leucopenia in 8 patients and lymphopenia in 4 patients. Neutropenic fever was encountered in only one patient. Non-hematological toxicities grade 3/4 were universally absent. No dose reduction or treatment delay related to toxicity was necessary. Conclusion: The study is still ongoing and more patients are expected to define time to progression and survival. However, these preliminary results were encouraging with low toxicity profile. No significant financial relationships to disclose.
Second line therapy with cetuximab in NSCLC
Authors: Buosi R. , Gatti A. , Carnio S. , Sponghini A. , Olympios C. , Alabiso O. 
Published: March 2020

17145 Background: EGFR is overexpressed in different solid tumors and in 50–80% of NSCLC. The neoplastic growth and metastatic process is correlated with EGFR overexpression, so that it became the target of a new therapeutic approach. The monoclonal antibody (Mab) against the extracellular domain represent the most innovated method of EGFR inaction. Methods: From May to October 2005 10 patients (8 M and 2 F) of median age 62 years with NSCLC in stage IIIB-IV (7 adenocarcinomas and 3 squamocellulars) have been treated with the association of chemotherapy and Cetuximab. All patients presented a strumental PD after a first line of platinum-based chemotherapy. At the basic valuation, 7 presented ECOG 0 and 3 ECOG 1. Before treatment EGFR expression has been valued by immunohistochemical analysis. Carboplatinum AUC6 + Paclitaxel 175 mg/mq D1 every 3 weeks was chosen as schedule in 5 patients, Paclitaxel 80 mg/mq/w (4/6 weeks) administered in 3 patients while Vinorelbine 25 mg/mq D1, 8 every 3 weeks administered in 2 patients with moderated cardiac disease. All patients received Cetuximab 400 mg/mq at first week followed by 250 mg/mq weekly until PD. Results: Till now 7 patients valued for OR after three months of treatment: 1 RC, 3 RP, 1 SD, 2 PD; none presented an ECOG worsening. Gr 4 hematological toxicity with febrile neutropenia registered in 1 patient treated with vinorelbine. Alopecia reported in all patients treated with paclitaxel and Gr 3 neurotoxicity reported in 1 patient. No other Gr > 2 toxicity has been registered. Skin rash has been checked in all patients. Conclusions: according to our experience the administration of Cetuximab seems to be well tolerated and does not modify the chemotherapy toxicity profile. The combination with vinorelbine is the most toxic. At the moment our data do not allow us to express any judgment on the treatment efficacy, but till today all patients are alive and only one of them presents clinical signs of PD. No significant financial relationships to disclose.
Neuropilin-1 expression in adenocarcinoma and squamous cell carcinoma of the lung is differentially regulated by hypoxia
Authors: Pidgeon G. P. , Barr M. P. , Cathcart M. C. , Gray S. , O’Byrne K. J. 
Published: March 2020

17152 Background: Neuropilin-1 (NRP-1) is an isoform-specific receptor for VEGF165 and semaphorin3A, initially discovered on migrating neurons. NRP-1 expression has been reported on a number of tumour cell lines in the absence of the other VEGF receptors, where it mediates survival signals. In this study we examined the regulation of NRP-1 by hypoxia, its effect on survival in a panel of lung cancer cell lines and its potential as a biomarker in retrospective human lung tumours. Methods: A549, SK-MES1, H460 and H647 cells were grown in serum depleted media (0.5%) in normoxic or hypoxic (0.1% O2) conditions and screened for NRP-1 expression by western and immunocytochemistry analysis. Cell survival and apoptosis was determined using BrdU and Annexin-V/PI staining respectively following treatment with an antibody to the extracellular NRP-1 domain. A panel of 100 retrospective resected lung tumours and matched normal samples were stained for NRP-1 expression by immunhistochemistry. Results: A549, SKMES-1 and H647 cell lines all expressed NRP-1 and displayed reduced survival following treatment with NRP-1 antibody (1ug/ml) compared to controls (A549 46%, SKMES-1 61%, H647 53%). H460 did not express NRP-1 and no survival inhibition was seen in the cell line (104%). Reduced survival was accompanied by increased apoptosis in all NRP-1 positive cell lines. Hypoxia strongly increased NRP-1 expression in the A549 adenocarcinoma (AC) cell line, while NRP-1 was decreased in SKMES-1 squamous cell carcinoma (SCC) following hypoxia. Neutralisation of NRP-1 had a greater effect in A549 cells under hypoxia (37%), with a lesser effect in SKMES-1 cells (82%). Western analysis of matched frozen normal and lung cancer biopsies showed NRP-1 overexpression in AC and decreased expression in SCC relative to normal. High NRP-1 expression was confirmed in AC and large cell carcinoma by immunohistochemistry, relative to normal. However, SCCs had a lower level of NRP-1 staining, supporting the results by western analysis and following hypoxia in vitro. Conclusions: These results implicate NRP-1 as an important survival pathway in lung cancer. Hypoxia differentially regulated NRP-1 mediated survival implicating this pathway as a potential therapeutic strategy in AC. No significant financial relationships to disclose.
The influence of HAART on HIV-associated primary cerebral lymphoma: Declining incidence and improving survival
Authors: Bower M. , Mazhar D. , Newsom Davis T. , Powles T. , Mandalia S. , Gazzard B. , Stebbing J. 
Published: March 2020

17512 Background: The risk of primary central nervous system lymphoma (PCL) is increased in individuals infected with the human immunodeficiency virus type-1 (HIV-1). As highly active anti-retroviral therapy (HAART) has reduced morbidity and mortality secondary to HIV, we investigated the effect of HAART on the presentation and outcome of HIV infected individuals with PCL. Methods: From a single centre cohort of 9,621 HIV infected individuals, patients with PCL were identified. We compared pre-HAART and HAART era clinico-pathologic variables and investigated whether exposure to anti-retrovirals with differing CNS penetrations, protected from the development of this AIDS-defining illness. Results: In 61 patients diagnosed with PCL and a median survival of 1.3 months, we observed a decreased incidence of PCL in the HAART era compared to the pre HAART era (χ2 p = 0.0001), and a significantly improved overall survival (Log rank p = 0.032). In the HAART era there were fewer patients with prior AIDS defining illnesses (χ2 p = 0.015) and patients were significantly more likely to have the diagnosis confirmed histologically or by CSF PCR examination (χ2 p < 0.0001). Exposure to specific anti-retrovirals did not protect from the development of PCL, regardless of cerebro-spinal fluid (CSF) penetration. Conclusions: Although the prognosis remains dismal, the HAART era has decreased the incidence and prolonged the survival of individuals with HIV-1 associated PCL. No significant financial relationships to disclose.
Addition of bortezomib to thalidomide, dexamethasone and zoledronic acid (VTD-Z regimen) significantly improves complete remission rates in patients with relapsed/refractory multiple myeloma
Authors: Teoh G. , Tan D. , Hwang W. , Koh L. P. , Chuah C. , Ng H. J. 
Published: March 2020

17537 Background: We previously treated 26 patients with relapsed/refractory multiple myeloma (MM) with thalidomide (Thal), dexamethasone (Dex) and zoledronic acid (Zol); dtZ regimen; and demonstrated an overall response rate of 75.0%. However, the rate immunofixation (IF)-negative complete remissions (CR) was only 7.7%. Recently, the bortezomib (Velcade) has been shown to be effective against MM. In this study, we added bortezomib (Vel) to dtZ (VTD-Z regimen) in a subgroup of patients to determine whether the CR rate can be improved. Methods: A non-randomized, single-arm study was conducted. Consecutive patients (n = 14) who either failed to achieve a partial response (PR) after 3 cycles; or CR after 9 cycles of dtZ were treated with 2 to 11 three-weekly cycles of VTD-Z; comprising: Vel 1.3 mg/m2 on days 1, 4, 8 and 11; Thal 50 mg ON; Dex 20 mg OM on days 1 to 4, 8 to 11, 15 to 18; and Zol 4 mg on day 1. The primary study objective was to determine the maximal response rates (RR). The end-point of the study was maximum response, graded by Bladè’s criteria. Results: Fourteen patients (3 males, 11 females; median age 63.3 years) were studied. Complex karyotypes, including 5 patients with deletion of chromosome 13 (del(13)), were present in 11 patients at diagnosis. The overall RR was 92.9% (13 out of 14), of which 42.9% (6) achieved CR (p < 0.001, chi-squared test). In addition, 21.4% (3) achieved near-CR (nCR), and 28.6% (4) achieved PR. There were no minimal responders (MR) and 1 (7.1%) non-responder (NR). Two patients who achieved CR had del(13). Painful grade 3 peripheral neuropathy was observed in 2 (14.3%) patients. Grade 1 and 2 peripheral neuropathy was observed in another 4 (25.0%) of patients; transient grade 3 thrombocytopenia was observed in 5 (35.7%) patients; and papular rashes were observed in 3 (21.4%) patients. The single NR was the only death that occurred during the period of study. Conclusions: Our study demonstrates that the VTD-Z regimen is exceptionally effective and safe in patients with relapsed/refractory MM. Addition of Vel to dtZ significantly increases the CR rate from 7.7% to 42.9%. These data suggest that combination of these 4 drugs may be at least additive, if not, even synergistic. No significant financial relationships to disclose.
Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin’s lymphoma
Authors: Kim J. , Chae Y. , Kim D. , Baek J. , Yang D. , Lee J. , Kim H. , Shin H. , Jung J. , Bae S. 
Published: March 2020

17544 Background: The current study aimed to evaluate the efficacy and toxicity of the combination of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with non-Hodgkin’s lymphoma (NHL). Methods: Forty patients with relapsed (n = 24) or high-risk (n = 16) lymphoma were enrolled into the study. High-dose chemotherapy consisted of intravenous busulfan (0.8 mg/kg i.v. q 6 hr from day-7 to day-5), cyclophosphamide (50 mg/kg i.v. on day-3 and day-2), and etoposide (400 mg/m2 i.v. on day-5 and day-4). Results: The median age of patients was 34 years (range, 17–63 years), and 21 (52.5%) patients were male. Pathologic subtypes were as follows: diffuse large B cell (n = 20), peripheral T cell, unspecified (n = 8), extranodal NK/T cell (n = 4), angioimmunoblastic T cell (n = 3), anaplastic large cell (n = 4), nodal marginal zone B cell (n = 2), and lymphoblastic (n = 3). The median dose of infused CD34+ cells and MNC was 3.95 (range, 0.7–20.6) × 106 and 8.12 (range, 3.0–13.6) × 108, respectively. WBC and platelet were successfully engrafted after ASCT in all patients, and the median days of engraftment of WBC and platelet was 12 (range, 9–48) and 27 (range, 8–263) days, respectively. After the ASCT, 34 complete responses (CR; 85.0%) and 4 partial responses (PR; 10.0%) were confirmed. Thirty-three (82.5%) patients experienced a fever without documented infection, while 2 patient developed fungal infection. However, there was no treatment-related death. After median follow-up duration of 360 (range, 83–639) days, 33 patients are in continuous complete remission, 4 patients are alive in relapse, and 3 patients died of disease. The estimated event-free and overall survival rate at 1.5-year was 80.9 ± 10.0 % and 92.5 ± 5.7 %, respectively. Conclusions: IV Bu/Cy/VP-16 was found to be well-tolerated and effective as a conditioning regimen in patients with NHL. Accordingly, this regimen can be regarded as an alternative high-dose treatment option in the ASCT for NHL. No significant financial relationships to disclose.
A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma
Authors: Kaufman J. L. , Waller E. K. , Torre C. , McMillan S. , Langston A. , Flowers C. , Lechowicz M. , Tighiouart M. , Lonial S. 
Published: March 2020

17550 High dose chemotherapy and autologous transplant (HDT) clearly benefits most patients with myeloma, but the addition of chemotherapy or TBI to melphalan (M) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor which synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data has shown that B upregulates the anti-apoptotic protein MCL-1, which would suggest that B followed by M is inferior to M followed by B. We designed a randomized phase I trial combining B and Melphalan 200 mg/m2 (Mel200) in order to determine the toxicity, optimal dose and sequence of administration. Patients were randomized to receive either B 24 hours before Mel 200 or B 24 hours after Mel 200. Standard transplant criteria were used with the addition of requiring measurable numbers of plasma cells at the time of transplant. Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for apoptosis, and myeloma cells were sorted for protein analysis. Age range was 48–74 years. Prior therapy has included Velcade (n = 2, both responsive) thalidomide (n = 2) and prior melphalan in 2 (1 HDT). Time to WBC and Plt engraftment were not different from historical cohorts receiving MEL 200 alone. Four patients have been randomized to date with 3 in the B “before“ arm, and 1 in the B “after” arm. Of the 3 patients who received B before M, day 0 bone marrow revealed minimal changes in marrow myeloma cell apoptosis in two patients, and in one patient a >20 fold increase in myeloma cell apoptosis on the day 0 marrow sample when compared to the day - 4 marrow. In the patient enrolled in the B after M arm, there was a 10 fold increase in the day 0 marrow myeloma cell apoptosis. Western blot analysis for DNA repair enzymes and MCL-1 on sorted tumor cells are planned, as is ELISA for secreted cytokines before and after therapy. Toxicity and response data with an update of the molecular correlates will be presented. The combination of B and M as conditioning for HDT is feasible. The optimal dose and sequence of administration remains unknown. Accrual continues. [Table: see text]