tbuckley/cabot-search huggingface dataset:
Twenty-year trends in survival for metastatic kidney cancer.
Authors: Liam Connor Macleod, Sarah Holt, Jonathan L. Wright, Lawrence D. True, Scott S. Tykodi, Daniel W. Lin, John L. Gore
Journal: Journal of Clinical Oncology (2015)

454 Background: Since the 1990s, the therapies for metastatic renal cell carcinoma (mRCC) expanded from immunotherapies to survival-extending targeted therapies. Targeted therapy is most efficacious in clear cell RCC. Trial results likely overestimate population norms. Population-based studies on histologically limited cohorts omit a large proportion of patients, giving an overly optimistic prognosis. To clarify the changing prognosis of mRCC we examine a heterogeneous RCC cohort from the Surveillance Epidemiology and End Results (SEER) registry. Methods: mRCC patients were identified from SEER diagnosed calendar years 1990-2009. Cases were primary renal tumors confirmed by histology/cytology, not diagnosed on autopsy. Survival was analyzed by treatment era (cytokine 1990-2005, targeted 2006-2009) and classified by histology. Multivariate Cox regression identified factors independently associated with overall survival (OS). Results: Of 14,521 mRCC patients identified, clear cell mRCC represented 4,136 (median OS 12 months). Non-clear cell RCC represented 10,385 cases (median OS 4 months) of which 8,860 were designated NOS. For clear cell mRCC unadjusted median OS improved from 11 to 14 months pre/post targeted era (p&lt;0.001). For non-clear cell mRCC there was no improvement pre/post targeted era (p=0.56). However, when RCC NOS was removed, median OS improved slightly from 6 to 7 months pre/post targeted era (p&lt;0.001). On multivariable analysis cases diagnosed 2006-2009 were associated with improved OS compared to 1990-2005 (HR 0.90, 95% CI 0.86, 0.94). Female gender (HR 1.06 95%CI 1.02-1.10), unmarried status (HR 1.12 95%CI 1.08-1.15), non-receipt of surgery (HR 1.46, 95%CI 1.44-1.49), T3/4 primary tumor (HR 1.25, 95%CI 1.18-1.32), and higher grade (HR 1.43, 95%CI 1.25-1.63) were also significantly associated with decreased OS. Conclusions: Median mRCC OS in SEER in the targeted therapy era is lower than survival reported in clinical trials, but has improved. These discrepancies are likely related to variation in the availability of optimal treatment strategies including cytoreductive nephrectomy and biopsy-based implementation of targeted therapies in a heterogeneous health care delivery environment.
A phase III trial (RTOG 0129) of two radiation-cisplatin regimens for head and neck carcinomas (HNC): Impact of radiation and cisplatin intensity on outcome.
Authors: K. Ang, Q. Zhang, R. H. Wheeler, D. I. Rosenthal, F. Nguyen-Tan, H. Kim, C. Lu, R. S. Axelrod, C. I. Silverman, R. S. Weber
Journal: Journal of Clinical Oncology (2010)

5507 Background: Data of patients with stage III-IV HNC accrued in a phase III trial of cisplatin (CDDP) plus an accelerated concomitant boost (AFX-C, 72 Gy/6 W) versus standard fractionation (SFX, 70 Gy//7 W) was analyzed with emphasis on the impact of radiotherapy (RT) and CDDP intensity. Methods: Patients had good status (Zubrod 0-1) and predefined blood chemistry range. Therapies were AFX-C + CDDP x2 or SFX + CDDP x3 (100 mg/m2, q3W). Results: Of 743 enrolled, 721 were analyzable. There was no difference in the primary endpoint (5-Y survival: 59% vs. 56%; HR: 0.90, 0.72-1.13; p=0.18). Other endpoints were assessed in 656 patients (AFX-C: 333; SFX: 323) receiving 64-76 Gy in 35-63 days and 1-3 CDDP doses. Table shows the combined effects of RT and CDDP regimens on outcome and toxicity. As a continuous variable, each day of RT delay compromised OS, PFS, and LRP by 5%, 4%, and 4% (p=0.001, 0.006, and 0.02), respectively. Conclusions: RT duration and CDDP dose affected survival significantly. CDDP improved OS more by reducing LRP but it also increased toxicity. The effect of AFX-C approximated the third CDDP dose, suggesting that CDDP acted, in part, by inhibiting clonogen repopulation. Impact of RT and CDDP intensity on outcome HR for: SFX (7 W) +CDDP × 1* N=16 AFX-C (6 W) +CDDP × 1* N=30 SFX (7 W) +CDDP × 2+ N=76 AFX-C (6 W) +CDDP × 2+ N=303 1SFX (7 W) +CDDP × 3^ N=231 OS 1.52 (0.80-2.90) 2.22 (1.31-3.75) 1.17 (0.78-1.76) 0.98 (0.73-1.30) 1 PFS 1.56 (0.86-2.96) 1.69 (1.02-2.79) 1.31 (0.91-1.90) 1.13 (0.87-1.46) 1 LRP 1.62 (0.72- 3.63) 1.73 (0.88-3.40) 1.57 (0.98-2.53) 1.46 (1.05-2.05) 1 Distant metastasis 1.36 (0.40-4.58) 1.33 (0.52- 3.42) 1.00 (0.51-1.99) 0.84 (0.52-1.34) 1 Acute hematologic toxicity2 0.32 (0.09-1.17) 0.70 (0.32-1.57) 2.08 (1.24-3.52) 0.72 (0.51-1.03) 1 Acute mucositis2 1.11 (0.40-3.08) 0.22 (0.07-0.65) 1.02 (0.60-1.71) 0.82 (0.58-1.17) 1 Late morbidity2 0.77 (0.21-2.78) 0.66 (0.24-1.82) 0.56 (0.28-1.14) 1.20 (0.81-1.79) 1 Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival; LRP, local-regional progression. * Ranges: 40-106 mg/m2 + 113-207 mg/m2 ^ 187-309 mg/m2. 1 Reference group. 2 Odds ratio for grade 3-4. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Lymphocytes and Antibody in Retrovirus-Induced Feline Pure Red Cell Aplasia2
Authors: Janis L. Abkowitz, Richard L. Ott, Richard D. Holly, John W. Adamson
Journal: JNCI Journal of the National Cancer Institute (1987)

The possible role of antibody and T-lymphocytes was investigated in the pure red cell aplasia (PRCA) associated with feline leukemia virus, subgroup C (FeLV-C), infection. In previous studies, erythroid colony-forming cells were undetectable in marrow culture of cats with PRCA. Yet erythroid burst-forming cells (BFU-E) remained, suggesting that BFU-E were able to differentiate in vitro but not in vivo. It was inferred that immunologic suppression may contribute to the pathogenesis of feline PRCA, and the interactions of antibody and T-lymphocytes with erythroid and granulocyte-macrophage progenitors were studied. Incubation of normal or PRCA marrow cells with PRCA serum or IgG concentrated from this serum and then complement (C′) failed to decrease hematopoietic colony growth when compared to the results obtained with cultures of marrow cells incubated with C alone. In crossover coculture studies, T-cells from Safari cats with PRCA had no inhibitory effect on colony growth from normal or autologous PRCA marrow cells. For the determination of whether feline PRCAs were associated with a clonal T-cell process, lymphocytes were obtained periodically from glucose-6-phosphate dehydrogenase (Glc-6-PD) heterozygous cats following FeLV-C infection and were expanded with a crude preparation of interleukin-2. The ratios of Glc-6-PD enzyme types in these samples did not change as cats developed anemia, suggesting that the inhbition of erythropoiesis was not associated with the clonal expansion of T-cells. These studies, therefore, do not support the premise that feline PRCA results from the interaction of antibody or T-cells with erythroid progenitors.
The antitumor effects of OSU-HDAC42, a novel histone deacetylase inhibitor, in HER-2-positive breast cancer
Authors: S. Weng, E. Wu, S. K. Kulp, D. Wang, C. Chen, L. D. Yee
Journal: Journal of Clinical Oncology (2009)

e14587 Background: Elevated HER-2/neu expression in primary breast tumors is associated with frequent relapse and poor prognosis. For this reason, HER-2/neu has been actively pursued as a target for novel therapeutic agents. Histone deacetylase inhibitors (HDACi), a new class of antitumor drugs, can downregulate HER2 through hyperacetylation of heat shock protein 90 (hsp90), an important ATP-dependent chaperone that mediates the stability and maturation of a variety of important oncogenic proteins, including HER2, Akt and ERα. In this study, we assess the effects of OSU-HDAC42, a novel orally bioavailable phenylbutyrate-based HDAC inhibitor, on hsp90 and HER2 downregulation. Methods: OSU-HDAC42 was tested for effects on the human breast cancer cell lines BT474, SKBR3, MDA-MB-231 and MCF-7. Assays of cell viability, cell cycle, apoptosis, HER2 expression, phosphorylation, and hsp90 acetylation were performed. Tumor growth was assessed in an orthotopic HER2+ mammary tumor model, using diets ± OSU-HDAC42. Results: SKBR3 (HER2+, ERα-) was the most susceptible to the antiproliferative effects of OSU-HDAC42 after 72 hours of treatment (IC 50 = 0.025 μmol/L), followed by BT474 (HER2+, ERα+), MCF-7 (HER2-, ERα+) and MDA-MB-231 (HER2-, ERα-) cells with IC 50 values calculated at 0.16, 0.19 and 0.2 μmol/L, respectively, which correlated with the level of inhibition of Hsp90 client protein expression (HER2, Akt). OSU-HDAC42 yields 43- or 65- fold greater cell killing than suberoylanilide hydroxamic acid (SAHA; vorinostat) or MS-275, respectively, and more potently suppresses the levels of Hsp90 client proteins (HER2, ERα and Akt) and induction of apoptosis in HER2+ breast cancer cells. In vivo administration of OSU-HDAC42 resulted in reductions of 76% and 82% in NT5 (HER2+,ER-) tumor mass and volume, respectively, concomitant with tubulin hyperacetylation, increased PARP cleavage, and decreased HER2 levels in OSU-HDAC42 treated mouse tumors. Conclusions: OSU-HDAC42 is a potent inhibitor of HER2+ breast cancer, mediated in part through hsp90 downregulation. As an orally bioavailable HDAC inhibitor with greater potency than other clinically available HDACi agents, OSU- HDAC42 warrants evaluation in clinical trials as a novel therapy for HER2+ breast cancer. [Table: see text]
A Phase II Study of Pemetrexed in Ps 2 Patients with Advanced Egfr Wild-Type Non-Squamous Non-Small Cell Lung Cancer
Authors: Akito Hata, Kosuke Tanaka, Shiro Fujita, Nobuyuki Katakami, Toshihiko Kaneda, Akihiro Nishiyama, Takashi Nishimura, Kojiro Otsuka, Yoshiko Urata, Shunichi Negoro
Journal: Annals of Oncology (2014)
Fibrinogen and α<sub>1</sub>-antitrypsin in COPD exacerbations
Authors: Truls S Ingebrigtsen, Jacob L Marott, Line Rode, Jørgen Vestbo, Peter Lange, Børge G Nordestgaard
Journal: Thorax (2015)

<h3>Background</h3> We tested the hypotheses that fibrinogen and α<sub>1</sub>-antitrypsin are observationally and genetically associated with exacerbations in COPD. <h3>Methods</h3> We studied 13 591 individuals with COPD from the Copenhagen General Population Study (2003–2013), of whom 6857 were genotyped for <i>FGB</i> -455 (rs1800790, G&gt;A) and <i>FGB</i> -448 (rs4220, G&gt;A) and had plasma fibrinogen measured. Furthermore, 13 405 individuals were genotyped for the <i>SERPINA1</i> S-allele (rs17580) and the Z-allele (rs28929474) and had measurements of plasma α<sub>1</sub>-antitrypsin. Exacerbations were defined as hospital admissions or treatments with systemic corticosteroids. We studied observational associations between plasma measurements and exacerbations in Cox regression analyses, associations between genotypes and exacerbations in logistic regression analyses and associations between genetically determined plasma levels and exacerbations in instrumental variable analyses. <h3>Results</h3> Elevated fibrinogen and α<sub>1</sub>-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p&lt;0.001) and 1.18 (1.11 to 1.25, p&lt;0.001), respectively, per SD increase. Presence of the Z-allele was associated with increased odds of exacerbations, OR=1.25 (1.05 to 1.48, p=0.01), as was α<sub>1</sub>-antitrypsin level genetically lowered by the Z-allele, OR=1.07 (1.02 to 1.13, p=0.004), per SD decrease. Fibrinogen elevating genotypes, <i>FGB</i> -455 (AA) and <i>FGB</i> -448 (AA), were not associated with exacerbations, OR=0.96 (0.73 to 1.25, p=0.77) and OR=1.01 (0.75 to 1.33, p=0.90), respectively, and neither was genetically elevated fibrinogen level, OR=1.11 (0.76 to 1.63, p=0.58) per SD increase. <h3>Conclusions</h3> Fibrinogen and α<sub>1</sub>-antitrypsin were observationally associated with increased risk of exacerbations. However, genetically, fibrinogen per se was not associated with exacerbations, while lowered α<sub>1</sub>-antitrypsin was associated with increased odds of exacerbations.
Reciprocal expression of indoleamine-2,3-dioxygenase (IDO) and arginase-I in metastatic melanoma tumors
Authors: T. F. Gajewski, A. C. Peterson, C. Slingluff, M. McKee, H. Harlin
Journal: Journal of Clinical Oncology (2005)

7523 Background: Antigen-specific immunotherapy for advanced melanoma often results in increased frequencies of specific T cells yet infrequently causes clinical regression. This observation has led to a search for mechanisms of resistance to immune effector function in the melanoma tumor microenvironment. One proposed mechanism is through the presence of enzymes such as IDO or arginase-I that deplete the microenvironment of amino acids essential for T cell survival and function. However, a systematic appraisal of these and other immune inhibitory factors in metastatic melanoma has been lacking. Methods: RNA was isolated from 41 metastatic melanoma biopsies, 6 melanoma cell lines, and 3 primary melanocyte cell lines. Gene array analysis was performed using Affymetrix U133A chips. Standard normalization was carried out, and expression of Melan-A and tyrosinase transcripts was required to be considered for analysis. Filtering was performed using dCHIP software, focusing on genes expressed in greater than 20% of the samples and with a standard deviation/mean between 1 and10. The gene set was scanned for putative negative regulatory factors for T cell activation. Results: 14 tumors expressed transcripts for IDO, 8 tumors expressed transcripts for arginase-I, and 19 samples expressed neither. No sample was positive for expression of both IDO and arginase-I. These results are consistent with the reported differential induction of these enzymes by Th1 and Th2 cytokines, respectively. Differential mRNA expression was confirmed by real-time RT-PCR. Expression of additional putative negative immunoregulatory factors, including IL-10, PD-L1, and FoxP3 was also found by RT-PCR in a variable fraction of specimens. Conclusions: IDO and Arginase-I are expressed in mutually exclusive subsets of metastatic melanoma cases, suggesting that immune evasion mechanisms may be distinct in individual patients. Interventions aimed at countering immunosuppressive factors in the melanoma tumor microenvironment should be pursued, and might need to be approached as an individualized targeted therapy. No significant financial relationships to disclose.
Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis
Authors: Claus Bachert, Leda Mannent, Robert M. Naclerio, Joaquim Mullol, Berrylin J. Ferguson, Philippe Gevaert, Peter Hellings, Lixia Jiao, Lin Wang, Robert R. Evans, Gianluca Pirozzi, Neil M. Graham, Brian Swanson, Jennifer D. Hamilton, Allen Radin, Namita A. Gandhi, Neil Stahl, George D. Yancopoulos, E. Rand Sutherland
Journal: JAMA (2016)

IMPORTANCEDupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases.OBJECTIVE To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. DESIGN, SETTING, AND PARTICIPANTSA randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up.INTERVENTIONS Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. MAIN OUTCOMES AND MEASURESChange in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point).Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference Ն8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety.RESULTS Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study.The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001).The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001).Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001)and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001).The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%).CONCLUSIONS AND RELEVANCE Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks.Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.
해설논문 : 진행성 간세포암종에 대한 분자생물학적 표적치료
Authors: 송일한 ( Il Han Song )
Journal: Clinical and Molecular Hepatology (2009)

간세포암종은 발생률에 있어서는 전세계적으로 지역적인 차이를 보이나 암 사망률에 있어서는 폐암종과 위암종에 이어 3위를 차지하는 악성 종양이다. 지난 수십 년 동안 근치적 치료가 불가능한 진행성 간세포암종 환자의 생존율을 향상시킬 수 있는 효과적인 전신항암치료법은 없었다. 그러나 최근 multikinase 억제제인 소라페닙(sorafenib)이 간세포암종 환자의 생존율을 유의하게 향상시키고 암종의 진행을 늦춘다는 연구 결과가 발표되면서 진행성 간세포암종에 대한 분자생물학적 표적치료가 주목을 받고 있다. 소라페닙은 세포 내 신호전달체계 중 Raf-1과 B-Raf serine-threonine kinase를 차단함으로써 암세포 증식을 억제하고, 세포막 수용체 중 혈관내피성장인자 수용체(vascular endothelial growth factor receptor, VEGFR)와 혈소판성장인자 수용체(platelet-derived growth factor receptor, PDGFR)를 차단함으로써 신생혈관형성(angiogenesis)을 막을 수 있는 약물이다. 그러나 지금까지 발표된 소라페닙 연구의 결과들을 보면 임상적으로 만족할 만한 수준에 도달하지는 않았으며, 또한 다양한 약물반응을 보이는 경우가 있어 일정 생물학적 반응과 연관을 보이는 표지자의 발굴을 통해 간세포암종을 분류하려는 시도가 진행되고 있다. 즉 같은 생물학적 동질성을 갖는 간세포암종의 분자생물학적 분류를 통해 궁극적으로 간세포암종 환자들의 개별화된 맞춤형 분자생물학적 표적치료를 최적화할 수 있을 것으로 생각된다.
Subcutaneous Bortezomib, Melphalan and Prednisone in Elderly Newly Diagnosed Multiple Myeloma Patients
Authors: Charles Herbaux, Cristina M. Joao, Alexia Plocque, Valentine Richez, Francesca Gay, Loic Renaud, Laurence Legros, Laurent Garderet, Souhila Ikhlef, Brigitte Pegourie, Martine Escoffre-Barbe, Bruno Royer, Laurent Voillat, Cyrille Hulin, Anne Banos, Eric G. Voog, Lionel Karlin, Anne-Marie Stoppa, Lotfi Benboubker, Sonja Zweegman, Eva De Jongh, Niels Abildgaard, Katell Le Dû, Artur J. Jurczyszyn, Philippe Moreau, Thierry Facon, Denis Caillot, Evangelos Terpos, Xavier Leleu
Journal: Blood (2014)
Changes in respiratory impedance during deep inspiration in healthy newborns
Authors: Bence Radics, Zita Gyurkovits, Hajnalka Szabo, Hajnalka Orvos, Peter Sly, Zoltán Hantos
Journal: European Respiratory Journal (2013)

Introduction:  Deep inspirations (DI) have known effects on respiratory impedance (Zrs), reduce airway resistance (Raw), increase airway diameter and decrease airway responsiveness. The changes in Zrs during a natural sigh have not been studied in newborns.   Methods:  Healthy term newborns (n=42) were measured with the forced oscillation technique during natural sleep within 24 hrs after birth. Within-breath changes in Raw and tissue elastance (E) were estimated from Zrs. In each DI epoch 4 volume (V) points were defined. A: end-expiratory V preceeding the DI (0 ml), B: end-tidal V, C: V at minimum resistance, D: maximum V of DI.   Results:  Raw decreased significantly as V increased (data: median [1st, 3rd interquartile]) (Raw A = 26.4 hPa.s/l [18.5-32.6], Raw D = 18.4 [13.9-34.3]) but the minimum occurred before the peak V of DI (Raw C = 13.7 [10.4-22.4]). E increased with V monotonously. (E A = 502 hPa/l [377-633], E D = 1068 [806-1315]. (p   Discussion:  Changes in Zrs during breathing and DIs can be detected successfully in unsedated newborns. The elevation in E indicates the increasing stiffness of the tissues. The decreasing trend in Raw with increasing V can be attributed to the passive dilatation of intrathoracic airways. The drop in Raw before the peak of DI suggests the involvement of active mechanisms (e.g. maximum opening of the glottis) during sighs.  Supported by Hungarian Scientific Research Fund grant K 105403.
Modulation of Cell Proliferation by Human Recombinant Interleukin-1 and Immune Interferon&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S C Tsai, E V Gaffney
Journal: JNCI Journal of the National Cancer Institute (1987)

The growth-modulating effects of recombinant alpha- and beta-forms of human interleukin-1 (IL-1) and interferon-gamma (IFN-gamma) were examined with several human cell lines. Exposure to combinations of IL-1 and IFN-gamma resulted in three categories of cell response. The first was cell lines in which IL-1 stimulated growth and offset the growth inhibitory effects of IFN-gamma. These lines included the lung carcinoma CALU-1 and the colon carcinoma SW-48. The second was some of the cell lines that were refractory to IL-1 and that were inhibited by IFN-gamma alone. These included the cervical carcinoma HeLa, the transformed milk line HBL-100, and the myelogenous leukemia K562. The third group consisted of cells in which growth inhibition by IL-1 and IFN-gamma was additive. These included the mammary carcinomas MCF-7 and MDA-MB-415. The exception to this latter group was ME-180 in which significant additive inhibitory effects could not be demonstrated. IL-1 alone primarily induced a cytostatic effect in growth-inhibited cell lines. The cytolytic effect induced by IFN-gamma was increased in the presence of IL-1. The data support the conclusion that the effects on growth of IL-1 and IFN-gamma are mediated by different mechanisms.