| 1. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
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Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
- 2014
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:20, s. 9609-18
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Tidskriftsartikel (refereegranskat)abstract
- The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.
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| 2. |
- Fredriksson, Nils Johan, 1979-, et al.
(författare)
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Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:12, s. 1258-1263
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations in noncoding sequences are poorly explored in cancer, a rare exception being the recent identification of activating mutations in TERT regulatory DNA. Although this finding is suggestive of a general mechanism for oncogene activation, this hypothesis remains untested. Here we map somatic mutations in 505 tumor genomes across 14 cancer types and systematically screen for associations between mutations in regulatory regions and RNA-level changes. We identify recurrent promoter mutations in several genes but find that TERT mutations are exceptional in showing a strong and genome-wide significant association with increased expression. Detailed analysis of TERT across cancers shows that the strength of this association is highly variable and is strongest in copy number stable cancers such as thyroid carcinoma. We additionally propose that TERT promoter mutations control expression of the nearby gene CLPTM1L. Our analysis provides a detailed pan-cancer view of TERT transcriptional activation but finds no clear evidence for frequent oncogenic promoter mutations beyond TERT.
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| 3. |
- Krarup, Anne L., et al.
(författare)
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Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain.
- 2011
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Ingår i: Alimentary pharmacology & therapeutics. - : Wiley. - 1365-2036 .- 0269-2813. ; 33:10, s. 1113-22
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Tidskriftsartikel (refereegranskat)abstract
- Background Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor ‘transient receptor potential vanilloid 1’(TRPV1) are a potential drug class for GERD treatment. Aim To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. Methods Twenty-two healthy men (20–31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. Data analysis: intention-to-treat. Results A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10–38%] and 28%, respectively (CI: 14–43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1–3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0–5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported ‘feeling cold’ and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4 ± 0.3 °C and 0.7 ± 0.3 °C, respectively, P < 0.05). Conclusions AZD1386 increased oesophageal and skin heat pain thresholds and had a safe adverse-event profile. This drug class may have a potential for treatment of GERD (ClinicalTrials.gov identifier: NCT00711048).
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| 4. |
- Krarup, Anne L., et al.
(författare)
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Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain.
- 2013
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Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 48:3, s. 274-84
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhibitors (PPIs). Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 (TRPV1) antagonists. Aim. To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients. Material and methods. Enrolled patients had NERD and a partial PPI response (moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks' PPI therapy). Fourteen patients (21-69 years, 9 women) were block-randomized into this placebo-controlled, double-blinded, crossover study examining efficacy of a single dose (95 mg) of AZD1386. On treatment days, each participant's esophagus was stimulated with heat, distension, and electrical current at teaching hospitals in Denmark and Sweden. Heat and pressure pain served as somatic control stimuli. Per protocol results were analyzed. Results. Of 14 randomized patients, 12 were treated with AZD1386. In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [-3%, 95% confidence interval (CI), -22;20%], distension (-11%, 95% CI, -28;10%), or electrical current (6%, 95% CI, -10;25%). Mean cutaneous heat tolerance increased by 4.9°C (95% CI, 3.7;6.2°C). AZD1386 increased the maximum body temperature by a mean of 0.59°C (95% CI, 0.40-0.79°C), normalizing within 4 h. Conclusions. AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response, whereas it increased cutaneous heat tolerance. TRPV1 does not play a major role in heat-, mechanically and electrically evoked esophageal pain in these patients. ClinicalTrials.gov identifier: D9127C00002.
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| 5. |
- Lund, M, et al.
(författare)
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Nitric oxide and endothelin-1 release after one-lung ventilation during thoracoabdominal esophagectomy.
- 2013
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Ingår i: Diseases of the esophagus. - : Oxford University Press (OUP). - 1120-8694. ; 26:8, s. 853-858
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Tidskriftsartikel (refereegranskat)abstract
- One-lung ventilation (OLV) is applied during esophagectomy to improve exposure during the thoracic part of the operation. Collapse of lung tissue, shunting of pulmonary blood flow, and changes in alveolar oxygenation during and after OLV may possibly induce an ischemia-reperfusion response in the lung, which may affect the pulmonary endothelium. Such a reaction might thereby contribute to the frequently occurring respiratory complications among these patients. In this small trial, 30 patients were randomized to either OLV (n= 16) or two-lung ventilation (TLV, n= 14) during esophagectomy. Central venous and arterial plasma samples were taken before and after OLV/TLV for analysis of nitrite and a metabolite of nitric oxide (NO), and also during the 1st, 2nd, 3rd, and 10th postoperative day for analysis of endothelin, another endothelium-derived vasoactive mediator. Lung biopsies were taken before and after OLV or TLV, and analyzed regarding immunofluorescence for isoform of NO synthase, a protein upregulated during inflammatory response and also vascular congestion. No changes in lung isoform of NO synthase immunofluorescence or vascular congestion were registered after neither OLV nor TLV. Plasma nitrite and endothelin levels were similar in the two study groups. We conclude that OLV does not seem to have any influence on key regulators of pulmonary vascular tone and inflammation, i.e. NO and endothelin. From this perspective, OLV seems to be a safe method, which defends its clinical position to facilitate surgical exposure during thoracoabdominal esophagectomy.
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| 6. |
- Norder Grusell, E., et al.
(författare)
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Bacterial flora of the human oral cavity, and the upper and lower esophagus.
- 2013
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Ingår i: Diseases of the esophagus. - : Oxford University Press (OUP). - 1120-8694. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- This reference study aims to survey the bacterial flora of the healthy lower human esophagus and to compare it with that of the upper esophagus and oral mucosa. The use of biopsies, in addition to brush samples, allows inclusion of not only transient bacteria present on the surface but also bacteria residing in the epithelia, and the yield of the two methods can be compared. Forty patients scheduled for surgery for reasons with no known influence on esophageal flora and with no symptoms or endoscopic signs of esophageal disease were included. Samples were collected from the oral, upper esophageal, and lower esophageal mucosa using sealed brushes and biopsy forceps. Colonies cultivated on agar plates were classified and semiquantified. Twenty-three different bacterial species were identified, with similar strains present at the three sites. The most common group of bacteria was viridans streptococci, with an occurrence rate in brush samples and biopsies of 98% and 95%, respectively. The median number of species occurring in the oral cavity, upper esophagus, and lower esophagus was between 3 and 4 (range 0-7). The total number of species in the oral cavity was significantly higher when compared with either level in the esophagus, while the yields obtained by brush and biopsy sampling were highly correlated. Hence, the normal human esophagus is colonized with a resident bacterial flora of its own, which has similarities to that of the oral mucosa. There are diverse species that make up this flora, although in relatively low amounts. The most frequent inhabitants of the esophagus are streptococci, with an occurrence rate in brush samples and biopsies of 95-98%. Comparative studies of patients with eosinophilic esophagitis and gastroesophageal reflux disease are warranted.
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| 7. |
- Olofsson, Roger, 1978, et al.
(författare)
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Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial) : study protocol for a randomized controlled trial
- 2014
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 15, s. 317-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). Methods/Design: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Discussion: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.
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