tbuckley/cabot-search huggingface dataset:
Platelts VEGF concentrations in healthy controls volunteers and HCC patients submitted to percutaneously radiofrequency thermal ablation
Authors: G. Ranieri, G. Gadaleta-Caldarola, M. Coviello, M. Quaranta, V. Fazio, V. Mattioli, A. Catino, C. D. Gadaleta
Journal: Journal of Clinical Oncology (2008)

15632 Background: Vascular endothelial growth factor (VEGF) is known to play a central role in tumour angiogenesis. Published data suggest that plasma rather than serum is the more suitable blood fraction for measuring VEGF in human cancer patients. The study aims to assess the plasma (P) P-VEGF levels in 20 healthy controls and 35 hepatocellular cancer (HCC) patients before and after percutaneously radiofrequency thermal ablation (PRFA), respectively. Methods: Enrolled patients showed: single lesion with a maximum diameter of 3.5 cm, no lymphnodal involvement and/or metastatic disease, no main portal vein thrombosis, no ascites, adequate liver functional reserve, A or B status according to Child-Pugh's classification. PRFA procedure was performed by using partially insulated needle electrodes (17.5 gauge; Tyco-Hospital Service, Pomezia Italy) placed under ultrasonographic guidance into the tumour to be ablated that inducing coagulative necrosis. In healthy volunteers and in HCC patients samples of blood were taken before, 2 and 5 days after PRFA respectively. Venous blood was dispensed into a sodium citrate, theophylline, adenosine, dipyridamole tubes for P (Becton Dickinson Hemogard Vacutainer Systems, Plymouth, UK). P samples were centrifuged at 180 × g × 10 min. The supernatant of P was removed obtaining a platelet-rich plasma P-RP. After removing the supernatant, the samples were again centrifuged at 1500 × g × 15 min to obtain a platelet-poor plasma P-PP. P-RP was treated with thrombin (Hemoliance Q.F.A. Thrombin Bovine) (80 μl/ml) obtaining a plasma activated platelet rich P-APR. VEGF levels were examined in all the above P fractions using the Quantikine Human VEGF-ELISA R&D Systems Inc., Minneapolis, MN). Results: A statistical significantly differentiation between healthy controls and HCC patients in P-RP VEGF level per platelet count was found (mean value: 1,6 pg/106 vs 0,3 pg/106 p=0.003 by t-test), while no significant change were found between pre- and post- VEGF levels in HCC patients. Conclusions: We suggest that platelets VEGF my play a role in HCC angiogenesis but it is not useful as early predictive marker of response to PRFA. No significant financial relationships to disclose.
Detection of Cellular Immunity to Tumor Antigens of a Guinea Pig Hepatoma by Inhibition of Macrophage Migration&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Winthrop H. Churchill, Berton Zbar, James A. Belli, John R. David
Journal: JNCI Journal of the National Cancer Institute (1972)

Cellular immunity to a transplantable diethylnitrosamine-induced strain-2 guinea pig hepatoma was detected in vitro by inhibition of macrophage migration. Addition of 10% line-1 tumor cells to peritoneal exudate cells from strain-2 guinea pigs immunized intradermally against line-1 hepatoma inhibited macrophage migration. The average migration index was 41% in comparison to 107% for migration of control peritoneal exudate cells. Inhibition was produced only by the immunizing tumor and not by antigenically unrelated tumor cells or normal spleen cells. Lymphocytes, purified from peritoneal exudate cells harvested from strain-2 guinea pigs, immunized by intradermal injection of living syngeneic tumor cells without any adjuvant, produced migration inhibitory factor (MIF) in response to tumor cell antigens. Tumor cells treated by X radiation, trypsinization, or storage in liquid nitrogen after slow freezing retained their capacity to stimulated MIF production by sensitized lymphocytes.
Prolonged gemcitabine infusion as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM): A phase I study
Authors: C. M. Carapella, A. M. Mirri, A. Felici, A. Vidiri, A. Pace, M. A. Carosi, E. M. Occhipinti, G. Arcangeli, F. Cognetti, A. Fabi
Journal: Journal of Clinical Oncology (2006)

1581 Background: The use of cytotoxic drugs concurrent with RT represents a promising approach in the combined treatment of malignant gliomas. Gemcitabine (dFdCyd) is a drug widely explored for its potential radiomimetic activity in different tumors. The present study was aimed to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of weekly prolonged dFdCyd infusion, administered in combination with RT as first line treatment, in adult pts affected by supratentorial GBM. Methods: Within 6 weeks after surgery, in the presence of measurable residual disease and KPS &gt;70, pts were treated with fractionated RT at a dose of 2.0 Gy/daily fractions, 5 days a week (global dose 60 Gy). From 24 to 72 hours before the first RT application, and afterwards once weekly, pts received concurrent dFdCyd, at fixed dose rate of 10 mg/m 2 /min, over a total period of six weeks. Planned dose levels of dFdCyd started from 200 mg/m 2 /weekly (level 1), with sequential steps of 25 mg/m 2 /w based on toxicity. Results: Ten pts were enrolled into the study: six were male, median age 55.2 years (range 44–75), with a median KPS at baseline of 85 (SD 9.71). The median time from diagnosis to the start of treatment was six weeks (range 4–7). The median RT duration was 6 weeks (range 4–7), all but one pt received the planned dose and all pts received concomitant CT. Four pts entered at Level 1; one pt was excluded from the study, due to rapid progressive disease during the treatment. Two of the three valuable pts presented a relevant neurological worsening; on this basis the dFdCyd dose was reduced to 175 mg/m 2 /w (Level -1). A total of six pts were entered at Level -1, and none of them reported DLT. No hematological grade 3–4 toxicity was reported. Grade 3 non-hematological toxicity was observed in one pt (transaminases increase). After a median follow-up of 13.4 months (range 3–24), the median progression-free survival was 8 months (CI 95% 1–18), and the median overall survival was 14 months (CI 95% 12–17). Conclusions: The recommended dose of prolonged infusion of dFdCyd concomitant with RT is 175 mg/m 2 /w. The observed activity has been considered interesting enough to support a phase II study of this concurrent CT-RT schedule as first line treatment in GBM. [Table: see text]
Results of a prospective clinical trial for VAMP alone without irradiation for pediatric favorable, early-stage Hodgkin lymphoma patients who achieve an early complete response.
Authors: M. Metzger, H. J. Weinstein, M. M. Hudson, A. Billett, E. C. Larsen, A. M. Friedmann, S. S. Donaldson, M. J. Krasin, L. E. Kun, K. C. Marcus, T. I. Yock, N. Tarbell, C. Billups, J. Wu, M. P. Link
Journal: Journal of Clinical Oncology (2011)

9503 Background: To evaluate the efficacy of 4 cycles of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) alone in patients with early-stage, favorable Hodgkin lymphoma (HL) who achieve a complete response after 2 cycles of VAMP. Methods: Multi-institutional phase II trial. Eighty-eight patients with clinical stages I and II, favorable risk (< 3 nodal sites, no B symptoms, no mediastinal bulk and no extranodal extension) HL were treated with four cycles of VAMP chemotherapy with or without involved field radiotherapy (IFRT). Patients who achieved a complete response (CR) (n=46) after 2 cycles of VAMP received no IFRT and those who achieved less than CR (n=42) were given 25.5 Gy IFRT, one patient progressed prior to starting IFRT and another withdrew consent to be treated elsewhere. Results: With a median follow-up of 5.4 years, the 5-year overall survival and event-free survival (EFS) for the whole cohort are 100% and 88% (SE=4.6%) respectively; the EFS for patients who did not get IFRT is 89% (SE=6.5%). IFRT was not a predictor of EFS (P=0.98). Ten patients relapsed and one had progressive disease. One of the irradiated patients developed recurrence as diffuse large B-cell lymphoma. All 5 non-irradiated patients who relapsed were salvaged with intense multi-agent chemotherapy and IFRT without autologous stem cell transplant. No second malignancies have been observed. Therapy was well tolerated with 8 grade 3/4 infections in 6 patients. Neither gender, histology, nor stage were significant predictors of outcome. Conclusions: Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy without radiation for patients achieving a complete response after 2 cycles of VAMP is highly effective and without significant side effects. These results indicate that selected pediatric patients with stages I and II favorable HL can be cured with limited therapy without alkylating agent, bleomycin, etoposide, or radiation therapy. Non-irradiated relapsed patients can be easily salvaged without high dose chemotherapy.
Adaptive Evolution Favoring<i>KLK4</i>Downregulation in East Asians
Authors: Patrícia Isabel Marques, Filipa Fonseca, Tânia Sousa, Paulo Santos, Vânia Camilo, Zélia Ferreira, Victor Quesada, Susana Seixas
Journal: Molecular Biology and Evolution (2015)

The human kallikrein (KLK) cluster, located at chromosome 19q13.3–13.4, encodes 15 serine proteases, including neighboring genes (KLK3, KLK2, KLK4, and KLK5) with key roles in the cascades of semen liquefaction, tooth enamel maturation, and skin desquamation. KLK2 and KLK3 were previously identified as targets of adaptive evolution in primates through different mechanisms linked to reproductive biology and, in humans, genome-wide scans of positive selection captured, a yet unexplored, evidence for KLK neutrality departure in East Asians. We perform a detailed evaluation of KLK3–KLK5 variability in the 1000 Genomes samples from East Asia, Europe, and Africa, which was sustained by our own sequencing. In East Asians, we singled out a 70-kb region surrounding KLK4 that combined unusual low levels of diversity, high frequency variants with significant levels of population differentiation (FST > 0.5) and fairly homogenous haplotypes given the large local recombination rates. Among these variants, rs1654556_G, rs198968_T, and rs17800874_A stand out for their location on putative regulatory regions and predicted functional effects, namely the introduction of several microRNA binding sites and a repressor motif. Our functional assays carried out in different cellular models showed that rs198968_T and rs17800874_A operate synergistically to reduce KLK4 expression and could be further assisted by rs1654556_G. Considering the previous findings that KLK4 inactivation causes enamel malformations in humans and mice, and that this gene is coexpressed in epidermal layers along with several substrates involved in either cell adhesion or keratinocyte differentiation, we propose KLK4 as another target of selection in East Asians correlated to tooth and epidermal morphological traits.
MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in <i>KRAS</i>-mutant advanced non–small cell lung cancer (NSCLC).
Authors: George R. Blumenschein, Egbert F. Smit, David Planchard, Dong-Wan Kim, Jacques Cadranel, Tommaso De Pas, Frank Dunphy, Katalin Udud, Myung-Ju Ahn, Nasser H. Hanna, Joo-Hang Kim, Julien Mazieres, Sang-We Kim, Paul Baas, Erica Rappold, Suman Redhu, Kevin M. Bellew, Michael R. W. Streit, Frank S. Wu, Pasi A. Janne
Journal: Journal of Clinical Oncology (2013)

8029 Background: KRAS mutations are detected in 25% of NSCLC, and there are no approved targeted therapies for this subset of NSCLC. D, an approved second-line treatment for NSCLC, has a response rate of &lt; 10%. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. This phase II trial (NCT01362296) evaluated the efficacy of T vs D in pts with advanced KRAS-mutant NSCLC who had received prior platinum-based chemotherapy. Methods: Pts were randomized 2:1 to T (2 mg QD) or D (75 mg/m 2 IV every 3 weeks) and stratified by type of mutational status and gender. Crossover to the other arm after progressive disease was allowed. Primary endpoint was PFS in pts with KRAS-mutant NSCLC (modified ITT; mITT). Secondary endpoints were OS, ORR, duration of response, and safety. PFS and OS were compared using a stratified log-rank test. The trial was stopped early for futility at a planned interim analysis; 92 PFS events were reported at the time of study termination. Results: Between September 2011 and July 2012, 134 pts were randomized to T (89) or D (45); 129 pts had KRAS-mutant NSCLC. Mean age was 61.4 y and 53% were male. In the mITT, 61/86 pts (71%) on T and 31/43 (72%) on D had a PFS event. HR for PFS was 1.14 (95% CI, 0.75-1.75; P = .5197) with a median PFS of 11.7 vs 11.4 wk for T vs D. ORR was 12% for T (10/86) and for D (5/43). With 27 (31%) deaths on T and 15 (35%) on D, HR for OS was 0.97 (95% CI, 0.52-1.83; P= .934). Five fatal SAEs were reported during treatment with T but none with D; 1 unspecified death was considered related to T. Frequent AEs reported with T were rash (59%), diarrhea (47%), nausea (34%), hypertension (34%), and dyspnea (33%). Grade 3/4 AEs with T were hypertension (16%/0), dyspnea (7%/3%), rash (6%/3%), diarrhea (6%/0), and asthenia (6%/0). Rate of treatment related SAEs was 15% with T and 12% with D. Conclusions: T did not improve PFS in pts with KRAS-mutation–positive NSCLC compared with D. However, an ORR of 12% for T in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted. The safety profile did not favor T, but is, in general, consistent with the overall T safety profile. Clinical trial information: NCT01362296.
DNA copy number changes as diagnostic tools for lung cancer
Authors: Anne M Bowcock
Journal: Thorax (2013)

Lung cancer usually presents as advanced stage disease and there is a need for early diagnosis so that appropriate treatments can be provided prior to tumour progression. Copy number variation is frequently detected in tumours and can contribute to tumour progression. This is because regions harbouring DNA imbalance can contain genes encoding critical proteins whose altered dosage contributes to the neoplastic process. Three copy number variations (CNVs) from chromosomes 3p26-p11.1 (loss), 3q26.2-29 (gain) and 6q25.3-24.3 (loss) have previously been described in individuals presenting with endobronchial squamous metaplasia. These CNVs were predictors of cancer diagnosed within 44 months with 97% accuracy. An evaluation of this CNV-based classifier with an independent set of 12 samples (10 men and 2 women), each with a carcinoma in situ or invasive carcinoma at the same site at follow-up demonstrated 92% prediction accuracy. The negative predictive value of this classifier was 89%. The gain at 3q26.2-q29 contributed the most to the classification, being present in virtually all lesions. This region harbours the PIK3CA gene and evaluation of the number of copies of this gene gave very similar results to those from array comparative genomic hybridisation. This type of test can be performed on sputum or bronchial brushings. Larger cohorts now need to be examined to confirm this finding and to possibly refine the regions of CNV. This type of approach paves the way for future molecular analyses to assist in selecting subjects with endobronchial squamous metaplastic or dysplastic lesions who might benefit from more aggressive therapeutic intervention or surveillance.
OP03ONCOLYTIC HERPES SIMPLEX VIRUS INHIBITS PAEDIATRIC HIGH GRADE GLIOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA MIGRATION AND INVASION; MECHANISM AND POTENTIAL FOR CLINICAL APPLICATION
Authors: Julia V. Cockle, Elizabeth Ilett, Anke Brüning-Richardson, Karen Scott, Susan Picton, Susan Short, Alan Melcher
Journal: Neuro-Oncology (2015)

INTRODUCTION: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumours associated with poor survival, and new treatments that target brain tumour invasion are needed. Oncolytic virotherapy, which uses viruses to selectively infect and destroy cancer cells, while stimulating an anti-tumour immune response, offers a novel approach. Here, we evaluate the effect of oncolytic herpes simplex virus (HSV) 1716 on the migratory behaviour of a panel of pHGG and DIPG cell lines. METHOD: Migratory characteristics were examined using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays. Cell viability was examined by FACS and WST-1 assays. Levels of acetylated tubulin and glycogen synthase kinase-3 (GSK3) were evaluated by Western blot. RESULTS: HSV (multiplicity of infection 10) resulted in blockade of both migration (24h) and invasion (72h) in all cell lines. No significant cytotoxicity was demonstrated at these time points. pHGG cells demonstrated reduced velocity, loss of polarity and altered morphology in the presence of HSV 1716. HSV 1716 treatment of pHGG cells increased expression of acetylated tubulin (associated with stable rather than dynamic microtubules) and substantially reduced expression of GSK3 (a key regulator of cell migration and microtubule Dynamics). CONCLUSION: Our results demonstrate that HSV 1716 can block migration and invasion of pHGG and DIPG cells in vitro, potentially through microtubule stabilisation and inhibition of GSK3. We propose that oncolytic HSV may have therapeutic benefits for pHGG and DIPG, not only as a cytotoxic and immunogenic treatment, but as an anti-invasive agent, improving outcome for this devastating disease.
Does IASLC/ATS/ERS classification of lung adenocarcinoma impacts prognosis?
Authors: Ines Neves, Susana Guimaraes, Conceiçao Souto Moura, Filipa Soares Pires, Ana Paula Vaz, Pedro Bastos, Henrique Queiroga, Venceslau Hespanhol, Gabriela Fernandes
Journal: European Respiratory Journal (2013)

Background:  IASLC/ATS/ERS classification provides a uniform approach to categorize lung adenocarcinoma (AC) subtypes which may have a distinct clinical behavior.   Objective:  To identify clinical characteristics and prognostic impact of the new IASLC/ATS/ERS classification in patients with resected lung AC.   Methods:  IASLC/ATS/ERS classification in resections specimens was reviewed in patients who underwent resection of lung AC between 1999 and 2012. The impact of AC pattern in disease-free (DFS) and overall survival (OS) was determined.   Result:  150 patients were included, 66% male, median age 65 years and 57.3% smokers. Median DFS was 38 months and OS was 76 months. AC patterns were: acinar predominant 44.7%, solid predominant 22.0%, papillary predominant 12.0%, lepidic predominant 3.3%, invasive mucinous 3.3%, two equally predominant patterns 9.4%, no cases of micropapillary predominant and 5.3% were not possible to reclassify. Lepidic predominant was significantly associated to female and non-smoker patients, smaller tumor size (  AC patterns were not associated to DFS. The 5-year OS in lepidic predominant was 100%, acinar predominant 66%, papillary predominant 59%, invasive mucinous 55% and solid predominant 50%. These differences were not statistically independent of the pathological TNM.   Conclusion:  IASLC/ATS/ERS classification of lung AC identifies morphologic patterns seem to be associated with distinct clinical, pathological and prognostic characteristics.
Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results on long-term survival.
Authors: Rudolf Arnold, Michael Wittenberg, Anja Rinke, Carmen Schade-Brittinger, Behnaz Aminossadati, Erdmuthe Ronicke, Thomas Mathias Gress, Hans Helge Mueller
Journal: Journal of Clinical Oncology (2013)

4030 Background: Octreotide LAR (O) compared to placebo (P) lengthens significantly time to tumor progression (TTP) in patients with metastatic midgut neuroendocrine tumors (Rinke et al. 2009). The antiproliferative response was more pronounced in patients with low (≤ 10%) hepatic tumor load (HL). To investigate whether this beneficial effect also affects overall survival (OS), patients included in the PROMID trial were followed until January 2013 at least once a year. Methods: Between July 2001 and January 2008, 42 and 43 patients were randomly assigned to receive O or P. Post study treatment was at the discretion of the local investigator. Data on cause of death and on post study treatment were documented. OS was analyzed using the Kaplan-Meier method. Treatment groups (O vs. P; HL at study entry ≤ 10% vs. &gt;10%) were compared using the log rank test and hazard ratios were estimated with the use of the Cox proportional hazards model. Results: 41 of 85 patients died until January 2013. 19 in the octreotide and 22 in the placebo arm. Median OS for all 85 patients was 85 months, “not reached” in the O arm and 84 months in the P arm (p=0.59, HR=0.85 [CI 0.46; 1.56]). Cause of death was unrelated to the tumor disease in 8 patients. 26 of 64 patients (10 in the O vs. 16 in the P arm) died in the HL ≤ 10% subgroup and 15 of 21 patients (9 in the O vs. 6 in the P arm) in the HL &gt; 10 % (p=0.002, HR=2.7). Median OS in the HL ≤ 10% subgroup was “not reached” (octreotide) vs 80.5 months (placebo) (p=0.14, HR=0.56 [CI 0.25; 1.23]). In the HL &gt; 10% subgroup the respective numbers were 35 vs. 84 months (p=0.14, HR=2.18 [CI 0.75; 6.33]). Post study treatment in the O and P groups included octreotide LAR (29 vs. 38 patients), hepatic CHE (5 vs. 12 patients), PRRT (13 vs. 13 patients) and CHT (4 vs. 5 patients). Conclusions: Octreotide LAR not only prolongs TTP but also extends OS in the subgroup of patients with metastatic midgut NETs and a low HL (≤ 10% at study entry) but not in the high (HL &gt; 10%) subgroup. Almost all patients who were randomized at study entry in the P group received octreotide LAR after disease progression, but these experienced a less favourable OS in the low HL subgroup. Clinical trial information: NCT00171873.
Phase II study of neoadjuvant treatment of rectal cancer with oxaliplatin, raltitrexed and radiotherapy
Authors: E. Casado, J. De Castro, B. Castelo, B. Sanchez, J. Feliu, A. Escribano, D. García-Olmo, A. Redondo, C. Belda M Sereno, M. Gonzalez Baron
Journal: Journal of Clinical Oncology (2004)

3746 Background and objective: Preoperative chemoradiation can improve the outcome of surgery in rectal cancer. The aim of this phase II study was to evaluate the efficacy and toxicity of a preoperative radiochemotherapy combination including oxaliplatin, raltitrexed and radiotherapy in locoregionally advanced rectal cancer. Methods: Between January 2002 and July 2003, 43 consecutive patients (22 women, 21 men; median age 61 years, range 34–74) with stage II and III rectal adenocarcinomas have been enrolled. All patients underwent endorectal ultrasonography (uT2N1= 2, uT3N0= 14, uT3N1= 23, uT4N0= 1, uT4N1= 3), and CT scan for staging purposes. Radiotherapy was delivered with a three-field technique to a dose of 50Gy over 5 weeks with a concomitant boost approach. Chemotherapy was initiated concurrently with RT and consisted of three courses of raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 21 days. Surgery was planned six to eight weeks after RT. Three additional cycles of chemotherapy were given after surgery. Results: 33 patients can be evaluated for response and 43 for toxicity. 25 patients were downstaged (76%), there were 6 pathological complete responses (18%) and sphincter sparing surgery was accomplished in 22 patients (67%). Grade 3 diarrea developed in two patients, and grade 4 in one patient (7%). Grade 3 neutropenia was observed in three patients (7%), including one febrile neutropenia. Other adverse events were mild, including grade 2 hepatotoxicity (transaminases) in 5 patients (11%). Conclusion: The regimen is feasible, has a low toxicity profile and can be administered in a three weeks basis. This treatment achieves significant tumor downstaging with a remarkable rate of conservative surgeries and complete pathological responses. No significant financial relationships to disclose.