tbuckley/cabot-search huggingface dataset:
Time trend in treatment-related deaths of patients with advanced non-small cell lung cancer enrolled into phase III trials of systemic treatment.
Authors: Y. Fujiwara, K. Hotta, M. Di Maio, K. Kiura, N. Takigawa, M. Tabata, M. Tanimoto
Journal: Journal of Clinical Oncology (2010)

7623 Background: Despite recent improvements in the supportive care, treatment-related death (TRD) remains a serious problem for lung cancer patients undergoing systemic chemotherapy. However, few studies have assessed formally whether the TRD proportion has changed over the years. Here, we investigated these issues in patients with advanced NSCLC through the literature search. Methods: We searched phase III trials addressing the role of systemic chemotherapy in the treatment of advanced non-small cell lung cancer. Time trend was assessed by the linear regression analysis. Data for the calculation of overall incidence of TRDs were available from 119 trials with 263 treatment arms (46,477 patients), while the information about causes of deaths was provided in 197 arms (75%; 30,147 patients). Results: Cisplatin-based regimens were the most frequently investigated. Crude TRD proportion in the overall cohort was 1.26%. Notably, the overall TRD proportion was stable during the observed period with a regression coefficient of -0.010 (p = 0.762), corresponding to a decrease in TRDs by 0.01% per year. The commonest cause of deaths was febrile neutropenia and there was no significant change in its incidence over the years (p = 0.139). Contrary, deaths due to renal toxicity decreased significantly (p = 0.042) while deaths due to pulmonary disorder increased significantly (p = 0.007). Additionally, among the pulmonary disorders, the TRD by interstitial lung disease similarly increased over the years (p = 0.011). TRDs due to febrile neutropenia were similarly observed across all regimens other than single agent therapies, whilst non-platinum regimens never induced deaths from the renal failure. Both docetaxel and EGFR-TKIs were associated with highly led to deaths from pulmonary disorder although EGFR-TKIs never induced any other type of TRDs. Conclusions: The overall TRD proportion was low, but not still negligible in phase III trials for advanced lung cancer, because it has been consistently observed over the past 19 years, and notably the incidence and pattern of TRD stratified by its causes have been clearly changing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Roche
Evaluating a prognostic factor in advanced adenocarcinoma of the lung who have treated with gefinitib
Authors: K. Matsuura, S. Kudoh, S. Mitsuoka, N. Yoshimura, H. Kanazawa, K. Hirata, J. Yoshikawa
Journal: Journal of Clinical Oncology (2004)

7334 Background: Gefinitib is an orally active, selective epidermal growth factor receptor thyrosine kinase inhibitor, which has shown efficacy in non-small cell lung cancer patients in phaseI and IIstudies. The result of phaseII trials (IDEALI and IDEALII) showed a response rate of 10–20% and overall disease-related symptom improvement rate of approx,40%. Significant factor for response were female gender and histological adenocarcinoma. Factors associated with efficacy of gefinitib were retrospectively analyzed in patients with lung adenocarcinoma who treated with gefinitib in our institute. Methods: Patients were received gefinitib from October 1998 to March 2003. They were categorized by age, gender, clinical stage, tumor differentiation, performance status (PS), number and response of prior chemotherapy, smoking history, and disease control. We examined whether there are the relationship between categories and, disease control and overall survival. Results: A total of 47 patients (median age, 63 years; range 24–85) were reviewed. The patients included 28 males and 19 females, and two patients had stage IIIB disease, 45 patients had stage IV disease. Tumor differentiation included 20 poor differentiations, 13 moderate differentiations, 5 well differentiations and 9 unknowns. Overall response rate and disease control rate was 14.8% and 31.9% respectively (CR 0 PR 7 SD 8). Estimated median survival time was 8.5 months. Significant correlation was found between gender and disease control. Significant predictive factors for improved survival included better PS (p=<0.01), disease controlled by gefinitib (p=<0.01) and well or moderately differentiation (p=0.04). Conclusions: To evaluate the furthermore, we conducted not only clinical characteristics but also biomarker that is EGFR, p-EGFR, p-AKT, p-ERK and HER2. These peptides are now evaluated by using IHC, and we will present the result of this study at 2004 ASCO meeting. No significant financial relationships to disclose.
Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: A randomized, double-blind study
Authors: J. A. Boice, H. Schmoll, C. Brown, A. Taylor
Journal: Journal of Clinical Oncology (2009)

9626 Background: Aprepitant (A) has been shown in a previous trial to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving cyclophosphamide and anthracycline. This study assessed A in patients with a variety of tumors receiving a broad range of MEC regimens. Methods: This Phase III, randomized, gender-stratified, double-blind, trial enrolled female and male patients ≥18 years old with confirmed malignancies naïve to MEC or highly emetogenic chemotherapy and scheduled to receive a single dose of 1 or more MEC agent. Patients received A triple-therapy regimen (A 125 mg, ondansetron [O] 8 mg b.i.d., and dexamethasone [D] 12 mg on Day 1 of chemotherapy, A 80 mg q.d. on Days 2–3) or a control regimen (O 8 mg b.i.d. and D 20 mg on Day 1, and O 8 mg q12h on Days 2–3) all administered orally. Episodes of vomiting, nausea, and rescue medication use were recorded in a patient diary. Tolerability was assessed by physical and lab examinations, and adverse event (AE) reporting. Primary and key secondary efficacy endpoints were proportions of patients with No Vomiting and Complete Response (no vomiting and no rescue medication use), respectively, during the 120 hours postchemotherapy. Results: Among 848 randomized patients, 77% were female while 52, 20, 13, and 5% of patients had breast, colorectal, lung, or ovarian cancer, respectively. Significantly more patients in the A group achieved No Vomiting and Complete Response (a difference of 14.1 &amp;12.4 percentage points vs. control, respectively). The incidences of AEs were generally similar in the aprepitant (61.9%) and control groups (66.5%). Conclusions: The aprepitant regimen provided superior efficacy over the control regimen in the treatment of CINV in a broad range of patients receiving MEC in both No Vomiting and Complete Response endpoints. Aprepitant was generally well tolerated. [Table: see text] [Table: see text]
Prognostic value of pre-operative serum MUC4 levels for predicting recurrence of pancreatic cancer
Authors: M. H. Villanueva, J. Stoner, A. Sasson, S. K. Batra, R. J. Hauke
Journal: Journal of Clinical Oncology (2007)

15160 Background: The human transmembrane mucin MUC4 is aberrantly expressed in approximately 75% of pancreatic ductal adenocarcinomas, but not in normal pancreatic tissue. Preliminary data suggests serum MUC4 levels may have a diagnostic utility. Hence, we sought to determine if pre-operative MUC4 levels have a prognostic value in pancreatic adenocarcinoma. Methods: A database of MUC4 samples collected under an IRB-approved protocol was queried for subjects with pre-operative MUC4 levels. MUC4 assays were performed using RT-PCR. Descriptive statistics were used to summarize the disease and treatment characteristics of the patients. A level of 0.01 (median) was used to divide patients into high and low MUC4 groups. Kaplan-Meier method was used to summarize the time to event distributions for groups defined by MUC4 levels. Log-rank test was used to compare the time to event distributions between two groups. Results: Seventeen patients (eleven males - 65%) were identified, with a mean age of 65.8 yrs (range: 46 - 76 years) were identified. Pathologic staging was T2/T3 in 95%, 9 pts (53%) had N1 disease, while 15 patients (88%) had stage II disease. All but one received adjuvant therapy with chemotherapy (5FU ± gemcitabine) ± radiation. Patient, disease and treatment characteristics were similar in patients with low MUC4 levels (n=9) and high MUC4 levels (n=8). At a median follow-up of 1.8 years, 13 (77%) experienced disease recurrence and 14 (82%) died. There was no significant association between MUC4 levels and the risk of disease recurrence or death (p&gt;0.9; p = 0.1, respectively). The one- year probabilities for relapse free survival (RFS) and overall (OS) were 0.9 (95% CI: 0.68 - 1.00) and 1 (95% CI: 1 - 1) for patients with low levels and 0.5 (95% CI: 0.15 to 0.85) and 0.63 (95% CI: 0.29 to 0.96) respectively, for subjects with high levels. Conclusions: Although these differences were not statistically significant, the group with high MUC4 levels appears to have higher risk features such as higher stage, regional lymph node disease and older age. Patients with high MUC4 levels had a trend towards higher risk of relapse or death. No significant financial relationships to disclose.
Effects of immunotherapy on survival and progression-free survival in patients with splenic marginal zone lymphoma or marginal zone leukemia/lymphoma
Authors: A. M. Tsimberidou, S. O’Brien, W. G. Wierda, G. Garcia-Manero, S. Lerner, M. J. Keating
Journal: Journal of Clinical Oncology (2005)

6583 Background: The optimal management of patients with splenic marginal-zone lymphoma (SMZL) or marginal-zone leukemia/lymphoma (MZL) is controversial. There is interest in eliminating cytotoxic chemotherapy. We therefore explored the role of immunotherapy in patients with SMZL or MZL. The aim of this study was to retrospectively assess the complete remission (CR), progression-free survival (PFS) and overall survival rates in patients treated with immunotherapy. Methods: A total of 35 patients with SMZL or MZL, referred to the Leukemia Service between May 1995 and October 2004, were treated with standard-dose rituximab (n=34) or alemtuzumab (n=1), as previously described (Keating et al, Hematology 2003:153). The indications for therapeutic intervention in SMZL patients were those used for chronic lymphocytic leukemia. Outcomes were compared with those of patients treated during the same time period with immuno-chemotherapy, chemotherapy, splenectomy, or the “watch and wait” approach. Results: Response rates were comparable between the immunotherapy, immuno-chemotherapy and chemotherapy groups (p=0.11). Of particular note, PFS and overall survival rates were higher (p=0.04 and p=0.004, respectively, log rank test) in patients treated with immunotherapy compared with those treated with immuno-chemotherapy or chemotherapy. Differences in PFS and overall survival rates remained statistically significant when the analysis was limited to SMZL patients alone (p=0.001 and p=0.009, respectively). Conclusions: These results demonstrate that immunotherapy induces durable responses and prolongs survival in patients with SMZL or MZL. In particular, rituximab should be considered the therapy of choice in patients with SMZL, if treatment other than splenectomy is needed. No significant financial relationships to disclose.
Bone sialoprotein is predictive of bone metastases in resectable non-small cell lung cancer: A case-control study and prevalence data
Authors: G. Scagliotti, T. Kalebic, M. Volante, S. Cappia, S. Novello, E. Bacillo, P. Borasio, L. Chiusa, M. Papotti
Journal: Journal of Clinical Oncology (2006)

7049 Background: Bone metastases (BM) in non small cell lung cancer (NSCLC) may be present at diagnosis or develop in the follow up, are associated with a worse prognosis, and currently there are no chemical or biological markers predicting their clinical onset. Methods: Thirty cases of resected NSCLC which subsequently develop BM (group A - mean follow up time 27.2 months) were matched for several clinico-pathological parameters (including age, sex, stage of the disease, histology, differentiation grade, adjuvant therapy) to 30 cases of resected NSCLC without any metastases (group B - mean follow up time 75.1 months) and 26 resected NSCLC with non-bone metastatic (group C - mean follow up 21.1 months). Primary tumor samples were investigated by immunohistochemistry for 10 markers previously recognized to be involved in bone resorption or metastatization process (cathepsin K, bone sialoprotein [BSP], VEGF, MMP-2, p53, RECK, TIMP-1, CD-117, Ki-67 and TRAcP). For statistical analysis the intensity of the staining was assessed by a semi-quantitative score (0, &lt;10%, 10–50%, &gt;50% +ve tumor cells). Differences among groups were estimated by X-square test, whereas the prognostic impact of clinico-pathological parameters and markers expression was evaluated by univariate and multivariate analyses. Results: Among the different markers investigated, BSP was strongly associated to bone dissemination (p &lt; 0.001) and, independently, to poor outcome (p = 0.02 by Mantel-Cox test). None of the other markers was differentially expressed within the groups or demonstrated a prognostic impact, both in terms of overall survival and of time interval to metastases. Based on these findings, the prevalence of BSP in NSCLC was further estimated in a large series of 120 resected lung carcinomas (M:F ratio 3:1; mean age 67 years; adenocarcinomas 55%, squamous cell carcinoma 39%, others 6%; stages: I 54%, II 17%, III 29%). BSP prevalence reached 40%, without any statistically significant difference according to histotype or other clinico-pathological parameters. Conclusions: BSP protein expression in resected NSCLC strongly predicts bone dissemination, and may therefore be useful in selecting patients for treatments targeted to inhibit bone metastatic spread. [Table: see text]
Phase II results of Study PX-171–007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasome inhibitor, in patients with selected advanced metastatic solid tumors
Authors: P. J. Rosen, M. Gordon, P. N. Lee, E. Sausville, K. P. Papadopoulos, A. F. Wong, M. Vallone, L. Kunkel, J. Infante, H. A. Burris
Journal: Journal of Clinical Oncology (2009)

3515 Background: CFZ is a novel proteasome inhibitor of the peptide epoxyketone class that exhibits a high level of selectivity for proteasome active sites. This phase 1/2 study assessed the maximum tolerated dose (MTD), safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of CFZ in patients (pts) with advanced metastatic solid tumors. Methods: Pts failing ≥ 2 prior treatments were enrolled in the phase 1 3+3 dose escalation study. Pts received CFZ IV Day (D) 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C) Cycle 1 D1, D2 dosing in all cohorts was at 20 mg/m 2 . Subsequent doses remained at 20 mg/m 2 or were escalated to 27 or 36 mg/m 2 in a stepped up regimen on D8. At 20/36 mg/m 2 , 1 pt had a DLT (Grade 3 fatigue) and established the phase 2 dose. Phase 2 is designed as a Simon 2 stage of 70 pts split into 5 subgroups (small cell lung [SCLC], non-small cell lung [NSCLC], ovarian, renal, and other cancer). Tumor response was measured every 2 C. ORR, defined as CR+PR+SD, to 16 wks of CFZ. Stage 2 will open if a 1 PR or better at 16 wks occurs in a selected subgroup. Results: 14 pts in phase 1 and 51 pts in phase 2 (23M/28F, mean age 61 yrs) received a total of 154.5 cycles of CFZ. Median cycles administered was 1.7 (range 1 to 12). To date, there were 6 SCLC, 10 NSCLC, 11 ovarian, 6 renal, and 18 other cancer patients enrolled to the Simon stage 1. Efficacy of SD or better is detailed in the table. The most common AEs included fatigue headache, diarrhea, nausea and constipation. Notable was the absence of grade &gt; 1 peripheral neuropathy and severe hematologic toxicities. Final results of the PK and PD will be reported. Conclusions: CFZ is active as a single agent in relapsed solid tumors demonstrating PR in both renal and SCLC; and SD &gt;16 wks in mesothelioma, ovarian, renal and NSCLC. The 20/36 mg/m 2 QDx2 dose schedule was well tolerated and lacks severe myelosuppression, hepatotoxicity and neuropathy which make CFZ an attractive agent to combine with traditional or novel targeted agents. [Table: see text] [Table: see text]
NSP4 is an elastase-related protease with arginine specificity that is released by activated human neutrophils as an active endoprotease
Authors: Natascha Perera, Walter Back, Karl-Heinz Wiesmüller, Maria Torp-Larsen, Niels Borregaard, Dieter Jenne
Journal: European Respiratory Journal (2014)

Serine proteases stored in neutrophil granules, namely neutrophil elastase, cathepsin G and proteinase 3, have been intensely investigated for several decades. They are known for their role in intracellular killing of pathogens, but are also implicated in the pathobiology of lung diseases, such as emphysema, pulmonary fibrosis or cystic fibrosis. Recently we identified NSP4, the fourth serine protease in neutrophils which has been completely overlooked so far.

For a better understanding of the role of NSP4 during neutrophil immune responses, our objective was to analyze NSP4 with regard to its biosynthesis, storage and extended substrate specificity.

We performed Western blot analyses of subcellular fractions of neutrophils as well as RT-PCR analyses of neutrophil precursors from human bone marrow. To determine the extended specificity of recombinant NSP4, we used a FRET-based optimization strategy. A tailor-made, NSP4-targeting alpha-1-antitrypsin variant was then generated to detect active NSP4.

We identified NSP4 as a novel azurophil granule protein of neutrophils. We further specified the extended NSP4 substrate specificity. Replacing the reactive center loop of α1-antitrypsin by the preferred NSP4 target sequence resulted in an irreversible NSP4-specific inhibitor. This serpin variant was shown to form covalent complexes with all NSP4 of neutrophil lysates and supernatants of activated neutrophils.

NSP4 is stored as an already activated enzyme in azurophil granules like the other neutrophil serine proteases. As a secreted and active protease, it potentially also contributes to neutrophil-mediated inflammation and tissue damage in lung diseases.
Novel Flushing Provoked by Volatile Anesthetics in &lt;italic&gt;Mastomys natalensis&lt;/italic&gt; Bearing a Transplantable Substrain of Gastric Carcinoid That Predominantly Secretes Serotonin&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Hosoda, Syun, Suyama, Motokazu, Saito, Toshiko, Kohmura, Yuji, Hosoda, Renko
Journal: JNCI Journal of the National Cancer Institute (1984)

A tumor substrain secreting a large amount of serotonin [5-hydroxytryptamine (5-HT); CAS: 50-67-9; 3-(2-amino-ethyl)indol-5-ol] and a minute amount of histamine (CAS: 51-45-6) has been isolated from the previously established strain of transplantable gastric carcinoid of Mastomys (Praomys) natalensis secreting both histamine and 5-HT. Mastomys bearing a large growing transplant and excreting a large amount of 5-hydroxy-indoleacetic acid [(5-HIAA) CAS: 54-16-0] were associated often with reddening of the nose, lower lip, auricles, hands, and feet. Soon after the animals were anesthetized by ether or other volatile anesthetics, the tinges of red of the above-mentioned exposed parts abruptly turned bright red and rapidly spread over the neck, upper chest, and epigastric area. The reddening was transient, lasting 1.5-5 minutes, thereby fulfilling the criteria of flushing. The severity of ether-provoked flushing in tumor-bearing Mastomys paralleled the urinary excretion levels of 5-HIAA. The ether-provoked flushing was prevented completely by sc injection of either ketanserin (150 micrograms) or somatostatin (20 micrograms). The same ether-provoked flushing as found in tumor-bearing Mastomys could be reproduced in normal ones by constant infusion of 20 mg 5-HT/kg/24 hours (i.e., doses comparable to those released from a transplanted tumor) through an osmotic minipump implanted subcutaneously.
Tumoral response in breast cancer (BC) after neoadjuvant (NEO) trastuzumab (T) plus chemotherapy (CT): Experience of a single reference center in Brazil.
Authors: M. Costa, C. S. Gomes, D. Herchenhorn, L. P. Branco
Journal: Journal of Clinical Oncology (2010)

e13162 Background: In Brazil, the National Cancer Institute estimates 49.240 new cases of BC for 2010 and almost 50% are locally advanced. NEO CT improves ressection rates and breast preservation surgeries. Adding trastuzumab in large HER2+ tumors is not well studied in this setting. Methods: Retrospective observational study to analyze response after NEO T associated to cytotoxic CT (doxorubicin and taxane-based) between 2007 and 2009 in a single institution in Brazil. Results: Were analyzed 84 patients, 55 (65.5%) went to surgery and 29 (34.5%) not, 10 (12%) due to nonresponse, 12 wait surgery, 5 refused and 2 disappeared. Median age was 53 years (27-63) and tumors mean size, 8 cm (5-17). All patients completed the scheduled treatment, with no cardiotoxicity reported cases and no grade 3-5 toxicities. Mean time between treatment completion and surgery was 60 days (30-125). Mean pathologic size of lesions was 1.8 cm after treatment, with eight pathological complete response (14.5%), 37 (67.3%) partial responses, and 10 (18.2%) stable disease. Conclusions: Adding trastuzumab is a valid option in the NEO treatment of HER2+ tumors, with high responses even in large locally advanced and unresectable breast tumors. No significant financial relationships to disclose.
161. Antigen Signaling Enhances Proliferation and Cytotoxic Capacity of CD19-Targeting CD28/4-1BB CAR T Cells During Expansion Without Inducing Exhaustion
Journal: Molecular Therapy (2014)

Antigen Signaling Enhances Proliferation and Cytotoxic Capacity of CD19-Targeting CD28/4-1BB CAR T Cells During Expansion Without Inducing Exhaustion