tbuckley/cabot-search huggingface dataset:
Microwave ablation plus recombinant human endostatin (endostar) versus microwave ablation alone in inoperable stage I non small cell lung cancer.
Authors: Min Meng, Guanghui Huang, Xin Ye, Xia Yang, Wenhong Li, Xiaoying Han, Jiao Wang, Zhigang Wei, Yang Ni
Journal: Journal of Clinical Oncology (2018)

8551 Background: Previous studies showed that inoperable stage I non small cell lung cancer (NSCLC) benefited from microwave ablation (MWA) alone. This prospective, randomized, control, single-center clinical trial aimed to determining the survival benefit of MWA plus recombinant human endostatin (endostar) compared with MWA alone. Methods: Patients with untreated, inoperable, stage I NSCLC were recruited. They were divided into MWA/ endostar group and MWA group, the former received MWA in the primary tumor sites, followed by 2 to 4 cycles of endostar and the latter treated with MWA only. The primary endpoint was overall survival (OS), the second endpoint included disease-free survival (DFS) , and adverse events (AE). Results: A total of 183 patients were enrolled, involved 92 cases in the MWA/ endostar group and 91 cases in the MWA group. Up to the latest follow-up , there were 24 cases of disease progression and 6 deaths in the MWA/ endostar group, versus 49 cases of disease progression and 9 deaths in the MWA group. DFS in the MWA/ endostar group (30.0 months, 95% CI, 27.1-32.9) was significantly better than MWA group (21.3 months, 95% CI, 19.5-23.1, p = 0.000). But there was no significant difference (p = 0.471) in OS between the MWA/ endostar group (31.6 months ,95% CI, 28.3-35.0) and MWA group (30.0 months, 95% CI, 27.2-36.5). The 1, 2 and 3 year survival rates in the MWA/ endostar group were 94%, 82% and 82%, respectively, while those in the MWA group were 94%, 89% and 89%, respectively. There was no significant difference between the two groups (p = 0.982, p = 0.924, p = 0.924). AEs of MWA were observed in 63.7 % patients. Endostar -associated AEs were not observed in the MWA/ endostar group. Conclusions: MWA was a safe and effective alternative treatment for patients with inoperable stage I non small cell lung cancer. MWA combined with endostar significantly improved DFS compared to MWA alone, while not increased the MWA-related complications.
First-line FOLFOX-4 plus panitumumab followed by 5-FU/LV plus panitumumab or single-agent panitumumab as maintenance therapy in patients (pts) with RAS wild-type, metastatic colorectal cancer (mCRC): The VALENTINO study.
Authors: Filippo Pietrantonio, Marta Caporale, Rosa Berenato, Sara Lonardi, Roberto Murialdo, Emanuela Paterno, Marco Tampellini, Alessandro Stefano Bertolini, Lorenza Rimassa, Chiara Cremolini, Elisa Giommoni, Gianluca Tomasello, Raffaella Longarini, Fausto Petrelli, Alberto Zaniboni, Enrico Cortesi, Andrea Sartore Bianchi, Ilaria Bossi, Maria Di Bartolomeo, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2016)

TPS3634 Background: First-line FOLFOX-4 plus panitumumab is a standard treatment of RAS wild-type mCRC. Trials with first-line oxaliplatin-based chemotherapy showed that a deintensification-reintroduction strategy has no inferior outcomes when compared to treatment until progression. In the biologics era, the continuation of fluoropyrimidines and bevacizumab in the maintenance setting showed an increase of progression-free survival (PFS) as compared to treatment holiday. Few data are available at present for the optimal maintenance strategy with anti-EGFR monoclonal antibodies when used in association with first-line chemotherapy. This study aims to evaluate the efficacy of maintenance with panitumumab alone as compared to panitumumab with 5-FU/LV following FOLFOX-4 and panitumumab in pts with RAS wild-type mCRC. Methods: This is an open label, multicenter, randomized phase II study. Up to 224 pts will be enrolled and treated with induction FOLFOX-4 and panitumumab for 8 cycles. Then, in presence of disease control, they will receive at 1:1 ratio maintenance treatment panitumumab alone or 5-FU/LV plus panitumumab until progression or unacceptable toxicity. Tumor assessment is planned every 8 weeks. Primary objective is PFS: the sample size is calculated on the basis of a non-inferiority hypothesis of median PFS with panitumumab alone as compared to 5-FU/LV and panitumumab, taking into account a median PFS of 10 months observed in the PRIME trial. An overall sample size of 224 pts achieves 90% power to detect a probability of 50% in the control group and a maximum difference of 15% in the study group, with a significant level of 0.1. The drop-out rate is 15%. Secondary objectives are safety, quality of life, response rate, duration of response, time to progression, time to treatment failure, overall survival. Exploratory objectives: identification of potential biomarkers of primary resistance by Next-generation sequencing (NGS) and in-situ hybridization techniques on archival tissues; evaluation of changes in plasma biomarkers by digital PCR or NGS; pharmacogenetic studies. Clinical trial information: NCT02476045.
Evaluation of BRCA1, STAT-1 and STAT-3 expression in non familial breast cancer from North India: An interim analysis.
Authors: Sameer Gupta, Preeti Agarwal, Arun Chaturvedi, Vijay Kumar, Naseem Akhtar
Journal: Journal of Clinical Oncology (2018)

e13010 Background: Triple negative breast cancer (TNBC) is reported as most common breast cancer subtype in Indian population with incidence nearly double of that reported in West. Optimal targeted therapeutic options for TNBC are elusive. Molecular testing for BRCA1 is difficult, mainly due to prohibitive cost and lack of wide availability. We evaluated the immunohistochemical (IHC) expression of BRCA-1 and downstream molecular targets (STAT 1 and 3) in non-familial breast cancer patients and their correlation with clinico-pathological variables Methods: 222 cases of biopsy proven sporadic breast cancer were classified based on IHC expression of ER/PR/Her-2neu/Ki-67/CK5/6. Further, IHC expression of BRCA-1, STAT1, STAT3 and pSTAT3 studied with appropriate positive and negative controls to study inter marker co-relation and correlation with clinic-pathological variables and clinical outcomes Results: TNBC was most frequent subtype (37%) followed by near equal distribution of HER2 and Luminal B (22% each) and Luminal A (19%). BRCA1 nuclear loss was observed in 52% (115/222) and STAT1-loss in 62.6% (59/86). BRCA1 nuclear loss and STAT1-loss was associated with larger tumor size, higher grade, axillary nodal metastasis (pN2, pN3), high Ki67 and poor clinical outcome. Amongst TNBC, 59% (47/82) had loss of nuclear BRCA1 expression associated with higher Nottingham grade and high mean Ki67 (p = .043). STAT3 upregulation was seen in 48% (28/60) of TNBC and may be potential therapeutic target. On multivariate analysis BRCA1, STAT1 and STAT3 were found to be independent variables governing outcomes in breast cancer. Conclusions: In contrast to published Western data, TNBC is most common breast cancer subtype in Indian population; age of presentation younger, mean tumor size larger. BRCA1 nuclear loss reported in more than 50% of sporadic TNBC, therapeutic targeting with Cisplatin based regimens +/- PARP inhibitor might be useful. Thus BRCA1 loss must be evaluated in all TNBCs. Also IHC evaluation is cheap, reliable and reproducible method and could be viable alternative to more expensive molecular tests. Development of Targeted agents against BRCA 1 and STAT 3 may be especially relevant for TNBC population
P01.163 Impact of absolute postoperative tumor volume on survival in glioblastoma and significance of MGMT-methylation status for benefit of increasing surgical resection
Authors: C Leijonmarck, F Latini, S Libard, E M Larsson, G Hesselager
Journal: Neuro-Oncology (2018)

Previous studies have demonstrated a survival benefit with increasing extent of resection (EOR) for patients with glioblastoma. However, EOR is a relative measurement making it difficult to determine the significance of residual tumor size in clinical practice. Our aim is to determine whether absolute postoperative volume affects survival similarly. Moreover, despite that methylation of the enzyme MGMT is associated with a better prognosis in glioblastoma, it is still unknown whether the survival benefit of increasing surgical resection differs between patients with different MGMT-methylation status. In total 286 patients with newly diagnosed supratentorial glioblastoma that underwent cytoreductive surgery between 2010 and 2016 were identified in a regional cancer registry. Pre- and postoperative 3D volumetric measurements were performed retrospectively. Information about age at surgery, pre- and postoperative WHO performance status, oncological treatment and histopathological data including result of MGMT-methylation status analysis were collected. The median age of patients was 65 years. The median postoperative volume was 0.513 cm3 and median EOR was 98,7%. Median overall survival time was 13 months and for patients with gross total resection 15.3 months. Age, pre- and postoperative performance status and oncological treatment were included in a multivariate Cox proportional hazards analysis. Postoperative volume and EOR were both predictive of survival at p=0.0090 with a concordance index of 0.71. In a separate multivariate interaction analysis including the 151 patients with known MGMT-methylation status the p-value for interaction between MGMT-methylation and EOR was 0.60 and respectively for postoperative volume 0.54. Postoperative volume affects survival in patients with newly diagnosed glioblastoma with similar descriptive abilities as EOR. In considering risk of neurological morbidity no significant differences in postoperative performance status were seen between patients with different EOR or postoperative volume. MGMT-methylation status seems to not significantly affect survival in relation to EOR or postoperative volume, although a slight trend was observed towards a greater benefit for patients with methylated MGMT. Further studies will clarify whether MGMT or other molecular pathological properties in glioblastoma affects benefit of EOR.
The etiology of Balkan endemic nephropathy: still more questions than answers.
Authors: C A Tatu, W H Orem, R B Finkelman, G L Feder
Journal: Environmental Health Perspectives (1998)

Balkan endemic nephropathy (BEN) has attracted increasing attention as a possible environmental disease, and a significant amount of research from complementary scientific fields has been dedicated to its etiology. There are two actual competing theories attempting to explain the cause of this kidney disease: 1) the mycotoxin hypothesis, which considers that BEN is produced by ochratoxin A ingested intermittently in small amounts by the individuals in the endemic regions, and 2) the Pliocene lignite hypothesis, which proposes that the disease is caused by long-term exposure to polycyclic aromatic hydrocarbons and other toxic organic compounds leaching into the well drinking water from low rank coals underlying or proximal to the endemic settlements. We outline the current developments and future prospects in the study of BEN and differentiate possible factors and cofactors in disease etiology.
First-line treatment with panitumumab plus FOLFIRI in elderly patients with <i>RAS/BRAF</i> wild-type unresectable metastatic colorectal cancer and good performance status: OPALO trial.
Authors: Jaime Feliu, Antonieta Salud, Estela Pineda Losada, Vicente Alonso, Antonio Cubillo, Gemma Soler, Alberto Carmona, Ana Ruíz Casado, Brenzo Martinez-Amores, Monica Guillot Morales, Cristina Llorca, Carmen Castañon Lopez, Gemma Soler Gonzalez, Pilar Escudero, Ismael Macias Declara, Jorge Aparicio
Journal: Journal of Clinical Oncology (2018)

TPS3618 Background: Approximately 60% of colorectal cancer (CRC) patients are ≥ 70 years, of whom 50-60% already have metastasis at the time of diagnosis. Available data indicate that elderly patients with good performance status may, like younger patients, benefit from intensive treatment approaches. The objective of this trial is to assess the efficacy and safety of first-line therapy with panitumumab + FOLFIRI in elderly patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer and good performance status. Methods: OPALO is a phase II, single-arm, multicentre clinical trial. Primary objective: progression-free survival (PFS) at one year. Main eligibility criteria: 1. Patients ≥70 years; 2. colorectal carcinoma with unresectable metastatic disease; 3. RAS/BRAF wild-type status; 4. Independence in activities of daily living (ADL) based on the Katz Index and in instrumental activities of daily living (IAL) based on the Lawton Index; 5. To have one or no comorbidity according to the Charlson Comorbidity Index; 6. Patients starting therapy with FOLFIRI + panitumumab with a treatment aim other than achieving potential resectability of the disease. Treatment: all patients are receiving panitumumab (6 mg/kg) plus FOLFIRI every two weeks. Tumour response is evaluated every 8 weeks till disease progression. A blood sample is taken at baseline and at the time of disease progression to determine the RAS/BRAF mutation status. Statistical design: a sample size of 80 patients is deemed appropriate (assuming a precision of 11.45%, a two-sided confidence interval of 95%, a proportion of interest of 60% and a loss to follow-up rate of 10%). The recruitment of patients has begun in October 2017.
Identification of very rare clinically actionable KRAS variants in colorectal cancer patients using a comprehensive large gene panel.
Authors: Shyamal Dilhan Weeraratne, Julie Y Tse, Angeliki Pantazi, Jane Jiang, Maria Lvova, Jennifer E. Ring, Dana Vuzman, Stephen Lyle, Meaghan Russell
Journal: Journal of Clinical Oncology (2018)

e15632 Background: While commercially available hotspot testing detects over 99% of the activating mutations in KRAS located at codons 12, 13, 61, and 146, rare oncogenic variants beyond these regions can significantly impact treatment decisions in colorectal cancer (CRC). Herein we showcase the utility of comprehensive gene panel testing in identifying low frequency yet clinically relevant KRAS alterations to enable informed clinical treatment decisions. Methods: 575 CRC specimens were analyzed using CANCERPLEX over a three-year period (KEW, Inc; Cambridge, MA). CANCERPLEX is a comprehensive large gene panel comprising 435 cancer associated genes. A rare KRAS alteration was defined as a variant with a frequency > 0.02% in COSMIC. Variants with clinical actionability in CRC were defined as activating mutations with inferred therapeutic resistance to anti-EGFR antibody therapy. The analytical sensitivity and specificity for single nucleotide polymorphisms (SNPs) in CANCERPLEXwas 99.2% and > 99.9%, respectively. Results: KRAS Q22K, L19F, and G60D were identified as rare oncogenic variants in our analysis of 575 CRC cases. Q22K, L19F, and G60D has been previously reported in 0.009% (7/73000), 0.017% (13/73000), 0.003% (2/73000), respectively, in CRC cases (COSMIC). All three variants have been reported to have transforming potential in vitro and in vivo and trigger activation of downstream oncogenic pathways [PMID:11095964;26284123; 17150185; 20949621]. As activating mutations in KRAS predict lack of response to EGFR antibody therapies, cetuximab and panitumumab were reported as contraindications in all three cases. While not a rare variant, we detected activating mutations in codon 146 in 3% (17/575) of our cohort; strikingly, 5 of the KRAS A146 variants were not identified by prior less comprehensive modes of RAS testing. Conclusions: Low frequency, clinically relevant KRAS variants in CRC may be overlooked using commercially available RAS hotspot assays. In this study we demonstrate that a comprehensive gene panel may detect clinically consequential rare KRAS mutations that may define patients’ treatment and clinical course.
Exploring the form of change: A latent growth curve model of distress in oncologic patients undergoing specific cancer-related psychological intervention—A preliminary study.
Authors: Alessandro Rossi, Maria Marconi, Giuseppe Di Lucca, Raffaella Morena, Claudia Pogliani, Maria Chiara Parati, Chiara Rossini, Claudio Verusio
Journal: Journal of Clinical Oncology (2017)

e21556 Background: Psychological distress is one of the most important indexes of suffering in oncological patients – due to its severe negative impacts on medical treatments. Thus, the attention to this topic has increased constantly – focusing on the observed outcomes of (psychological) cares. However, very few studies investigated the (latent) pattern ( form) of change in distress within oncological patients receiving psychological intervention. The aim of the study was to test a Latent Growth Curve Model to explore the form of change in distress. Methods: A longitudinal research design was used. Patients ( N= 122, mean age: 68.3, SD= 12.3, 63 female-59 male) were enrolled at the Department of Medical Oncology at Presidio Ospedaliero of Saronno, ASST Valle Olona, Italy, and assessed for the presence of distress with Psychological Distress Inventory (PDI). As clinical routine, all patients received a specific cancer-related psychological intervention (CBT, mainly; mean of sessions: 27.4, SD= 13.5) and were tested at the beginning (T1; α= .88) and at the end of treatment (T2; α= .86) and at timed-balanced follow-up (T3; α= .87). Results: First, longitudinal invariance of measurement was performed to test whether (A) factor structure of PDI and (B) factor loadings of indicators were constant across time. PDI showed metric measurement invariance: Δχ 2 = 20.4; Δχ 2 df = 24; p(Δχ 2 ) = 0.67. Afterward, a LGCM was performed testing different trends of growth (no growth vs. linear vs. free) – controlling for age, number of sessions received, type and localization of tumor. The comparison of growth curves reveal that the linear trends of change had the best model fit to the data: χ 2 = 4.124, p= .248; RMSEA = .055(.000–.171), p(RMSEA &lt; .05) = .372, CFI = .990, SRMR = .027. Conclusions: These findings highlight that the (latent) linear growth better explain true change of distress – among oncological patients receiving a specific cancer-related psychological intervention. These results outline the possibility to improve the structure of psychological and medical treatments for oncological settings, to reduce psychological suffering and increase quality of life.
Inhaled corticosteroid containing combinations and mortality in COPD
Authors: Jørgen Vestbo, Leonardo Fabbri, Alberto Papi, Stefano Petruzzelli, Mario Scuri, Alessandro Guasconi, Stefano Vezzoli, Dave Singh
Journal: European Respiratory Journal (2018)

There is no solid evidence that any pharmacological treatment reduces mortality in chronic obstructive pulmonary disease (COPD). Two large trials with mortality as an efficacy outcome have been carried out testing a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) and in both, the reduction in mortality failed to reach statistical significance [1, 2]. This could be seen as proof of absence of effect, but given that the TORCH trial [1] resulted in a hazard ratio (HR) of 0.825 (95% CI 0.681–1.002; p=0.052) for the comparison of combined fluticasone propionate and salmeterol with placebo, the interpretation may not be that simple. The other negative trial, the SUMMIT trial [2], only included patients with moderate COPD and increased risk of cardiovascular comorbidity. Combinations containing inhaled corticosteroids may reduce mortality in patients with COPD <http://ow.ly/6UCy30lpwEi>
The safety and efficacy of hepatic arterial infusion chemotherapy with cisplatin.
Authors: Kazuhiro Matsumoto, Atsushi Hagihara, Akira Yamamoto, Ritsuzou Kotsuka, Hiroyuki Motoyama, Hiroyasu Morikawa, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori, Masao Hamuro, Shoji Kubo, Shigekazu Takemura, Norifumi Kawada
Journal: Journal of Clinical Oncology (2018)

e16116 Background: The aim of this study was to assess the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) using cisplatin for patients with advanced hepatocellular carcinoma (HCC). Methods: We retrospectively examined the data of 245 patients who underwent HAIC with cisplatin from June 2004 to November 2016. Cisplatin was administered into the feeding artery of HCCs. The treatment was repeated until there were signs of tumor progression or of unacceptable toxicity. Results: The median age of the patients was 72 (40-91) years old. The numbers of patients with hepatitis B virus, hepatitis C virus, and others were 40(16.4%), 158 (64.4%) and 46(18.7%). A total of 152 patients were classified as Child Pugh A, and 92 patients were Child Pugh B. Alpha fetoprotein (AFP) (ng/dl) was 261.2(2 < -974700) and protein induced by vitamin K absence/antagonist-II (mAU/ml) was 1443(2-112870). In total, 127 (51.8%) portal vein tumors were detected. The median overall survival (OS) and median progression-free survival in the entire subject population were 6.0 months and 3.6 months, respectively. The median OS of patients in AFP < 400 (ng/dl) group was longer than that in AFP > 400 (ng/dl) (7.2 months / 4.6 months, p = 0.001). The median OS of patients in Child A group was longer than that in Child B group (7.6 months / 3.8 months, p = 0.001). Major grade 3 or 4 adverse events included blood bilirubin/alanine aminotransferase increased in 8 patients (3.2%) and acute kidney injury in one (0.4%). The gastrointestinal toxicities were mild and reversible. Post-treatment was performed on 59 patients (sorafenib in 27 patients, radiation in 18 patients, transarterial chemoembolization by other agents in 14 patients) Conclusions: HAIC using cisplatin appears to have only modest activity, although toxicity was also mild, in patients with advanced HCC.
Response Gene to Complement 32 Maintains Blood Pressure Homeostasis by Regulating α-Adrenergic Receptor Expression
Authors: Jun-Ming Tang, Ning Shi, Kun Dong, Scott A. Brown, Amanda E. Coleman, Matthew A. Boegehold, Shi-You Chen
Journal: Circulation Research (2018)

Hypertension prevalence is much higher among children and adolescents with low birth weight and greater postnatal weight gain than in individuals with normal birth weight. However, the cause and molecular mechanisms underlying this complication remain largely unknown. Our previous studies have shown that RGC-32 (response gene to complement 32)-deficient (RGC-32-/-) mice are born significantly smaller but grow faster than their WT (wild type) controls, which allows adult RGC-32-/- mice to attain body weights similar to those of control mice.The objective of this study is to determine whether RGC-32-/- mice develop hypertension, and if so, to elucidate the underlying mechanisms.By using a radiotelemetry system, we found that RGC-32-/- mice exhibit higher mean arterial pressure than WT mice (101±4 versus 119±5 mm Hg), which enabled us to use RGC-32-/- mice to study the mechanisms underlying low birth weight-related hypertension. The increased blood pressure in RGC-32-/- mice was associated with increased vascular tone and decreased distensibility of small resistance arteries. The increased vascular tone was because of an increase in the relative contribution of sympathetic versus parasympathetic activity and was linked to increased expression of AT1R (angiotensin II type I receptor) and α1-AdR (α1-adrenergic receptor) in arterial smooth muscles. Mechanistically, RGC-32 regulated AT1R gene transcription by interacting with Sp1 (specificity protein 1) transcription factor and further blocking its binding to the AT1R promoter, leading to suppression of AT1R expression. The attenuation of AT1R leads to reduction in α1-AdR expression, which was critical for the balance of sympathetic versus parasympathetic control of vascular tone. Of importance, downregulation of RGC-32 in arterial smooth muscles was also associated with low birth weight and hypertension in humans.Our results indicate that RGC-32 is a novel protein factor vital for maintaining blood pressure homeostasis, especially in individuals with low birth weight.