Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor family. Although Kruppel-like factors are unequivocally implicated in this process, ...experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/Kruppel-like factor element in the TM promoter only partially abolishes statin-induced TM upregulation, whereas simultaneous mutation of relevant heat shock elements and SP1/Kruppel-like factor element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to heat shock elements in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90, nuclear translocation of HSF1, and binding to heat shock elements in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3β. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator, whereas downregulation of thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor was unaffected. Knockdown of 14-3-3β or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tissue plasminogen activator, but did not influence thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.
Small cell carcinoma of the esophagus (SCEC) is a rare subtype of esophageal cancer for which optimal treatment is unknown. We analyzed the impact of treatment factors on outcome in patients with ...nonmetastasized SCEC.
Patients with a histologically confirmed SCEC without distant metastases were analyzed in a nationwide multicenter retrospective cohort. All patients received radiotherapy as part of curative treatment between January 2000 and December 2014. Details on treatment and outcome were retrieved from individual charts. Cox regression analysis was used to determine prognostic factors for survival.
Fifty-eight patients were analyzed. Median survival was 16 months (95% confidence interval, 11-21 mo). Infield recurrences occurred in 25%, distant metastases in 45%, and brain metastases in 12%. In total, 63% of patients developed a recurrence. Most recurrences (67%) occurred within 1 year. In univariable analyses an increased number of chemotherapy cycles (>3) and lower radiotherapy doses (<45 Gy) were associated with improved survival. T-stage, N-stage, treatment period, type of chemotherapy, prophylactic cranial irradiation, and age were not associated with survival. In multivariable analyses, only the number of chemotherapy cycles was associated with better survival (hazard ratio, 0.78; P=0.006).
SCEC recurs frequently at distant sites after definitive chemoradiotherapy and usually within 1 year after curative treatment. With a dose of 45 to 50 Gy, infield recurrence rate was low. We found a relationship between number of received chemotherapy cycles and survival with best results obtained after at least 4 cycles of chemotherapy.
Background
To assess whether extending the observation period in patients with a near clinical complete response (near cCR) after chemoradiation (CRT) leads to an impaired oncological outcome.
...Methods
Patients who had a clinical complete response (cCR) 8–10 weeks after CRT restaging with magnetic resonance imaging and endoscopy were offered a watch-and-wait strategy (W&W1), while patients with a near cCR were offered to undergo local excision or a second restaging 6–12 weeks later. Patients who achieved a cCR at the second restaging were also offered a watch-and-wait strategy (W&W2).
Results
Overall, 102 patients with a cCR at the first restaging immediately entered the W&W1, while the remaining 68 patients had a near cCR: 19 patients underwent transanal endoscopic microsurgery and 49 patients opted for a second restaging. Additionally, 44/49 (90%) patients showed a cCR at the second restaging and entered the W&W2. Patients in the W&W1 group had a 2-year local regrowth-free rate (LRFR) of 84% and 2-year overall survival (OS) of 99%, while patients in the W&W2 group had a 2-year LRFR of 73% and OS of 98% (
p
> 0.05). Multivariable Cox regression analyses showed that late inclusion was not a significant predictive factor for higher risk of LR or lower non-regrowth disease-free survival.
Conclusions
Overall, 90% of patients with a near cCR 8–10 weeks after CRT will proceed to a cCR 6–12 weeks later; therefore, it seems logical to extend the observation period rather than to proceed to surgery. Although there is a non-significant increase in local regrowth rate in these patients, it does not seem to impact the oncological outcome.
The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review ...gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.
•BioXmark® is a novel liquid fiducial marker for image-guided radiotherapy.•The marker remained stable during chemoradiotherapy in 96% of rectal cancer cases.•The fiducial allows for image tracking ...on CT-based imaging modalities.•Marker visibility was good using CT-based imaging without any relevant artifacts.•The marker is easy to inject without marker related adverse events.
Dose-escalation in rectal cancer (RCa) may result in an increased complete response rate and thereby enable omission of surgery and organ preservation. In order to implement dose-escalation, it is crucial to develop a technique that allows for accurate image-guided radiotherapy. The aim of the current study was to determine the performance of a novel liquid fiducial marker (BioXmark®) in RCa patients during the radiotherapy course by assessing its positional stability on daily cone-beam CT (CBCT), technical feasibility, visibility on different imaging modalities and safety.
Prospective, non-randomized, single-arm feasibility trial with inclusion of twenty patients referred for neoadjuvant chemoradiotherapy for locally advanced RCa. Primary study endpoint was positional stability on CBCT. Furthermore, technical aspects, safety and clinical performance of the marker, such as visibility on different imaging modalities, were evaluated.
Seventy-four markers from twenty patients were available for analysis. The marker was stable in 96% of the cases. One marker showed clinically relevant migration, one marker was lost before start of treatment and one marker was lost during treatment. Marker visibility was good on computed tomography (CT) and CBCT, and moderate on electronic portal imaging (EPI). Marker visibility on magnetic resonance imaging (MRI) was poor during response evaluation.
The novel liquid fiducial marker demonstrated positional stability. We provide evidence of the feasibility of the novel fiducial marker for image-guided radiotherapy on daily cone beam CT for RCa patients.
Fu, Q., Berbée, M., Boerma, M., Wang, J., Schmid, H. A. and Hauer-Jensen, M. The Somatostatin Analog SOM230 (Pasireotide) Ameliorates Injury of the Intestinal Mucosa and Increases Survival after ...Total-Body Irradiation by Inhibiting Exocrine Pancreatic Secretion. Radiat. Res. 171, 698–707 (2009). Somatostatin analogs ameliorate intestinal injury after localized irradiation. This study investigated whether SOM230, a novel, metabolically stable analog with broad receptor affinity, reduces intestinal injury and lethality in mice exposed to total-body irradiation (TBI). Male CD2F1 mice were exposed to 7–15 Gy TBI. Twice-daily administration of SOM230 (1, 4 or 10 mg/kg per day) or vehicle was started either 2 days before or 4 h after TBI and continued for either 14 or 21 days. Parameters of intestinal and hematopoietic radiation injury, bacterial translocation, and circulating cytokine levels were assessed. Animal survival was monitored for up to 30 days. SOM230 increased survival (P < 0.001) and prolonged survival time (P < 0.001) whether administration was initiated before or after TBI. There was no benefit from administration for 21 compared to 14 days. The survival benefit of SOM230 was completely reversed by co-administration of pancreatic enzymes (P = 0.009). Consistent with the presumed non-cytoprotective mechanism of action, SOM230 did not influence hematopoietic injury or intestinal crypt lethality. However, SOM230 preserved mucosal surface area (P < 0.001) and reduced bacterial translocation in a dose-dependent manner (P < 0.001). Circulating IL-12 levels were reduced in SOM230-treated mice (P = 0.007). No toxicity from SOM230 was observed. SOM230 enhances animal survival whether administration begins before or after TBI; i.e., it is effective both as a protector and as a mitigator. The mechanism likely involves reduction of intraluminal pancreatic enzymes. Because of its efficacy and favorable safety profile, SOM230 is a promising countermeasure against radiation and should undergo further development.
Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' ...quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease. Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy. The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions, which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy. This drug has shown promising results in several clinical studies when combined with chemotherapy. Therefore, in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer.
A phase I, non-randomized, single-centre, open-label, 3 + 3 trial with repeated hypoxia PET imaging, will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients. Investigated dose levels range from 120 mg/m2 to 340 mg/m2. Evofosfamide will be administered one week before the start of chemoradiotherapy (CROSS-regimen) and repeated weekly up to a total of six doses. PET/CT acquisitions with hypoxia tracer (18)F-HX4 will be made before and after the first administration of evofosfamide, allowing early assessment of changes in hypoxia, accompanied with blood sampling to measure hypoxia blood biomarkers. Oesophagectomy will be performed according to standard clinical practice. Higher grade and uncommon non-haematological, haematological, and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications. Secondary endpoints are reduction in hypoxic fraction based on (18)F-HX4 imaging, pathological complete response, histopathological negative circumferential resection margin (R0) rate, local and distant recurrence rate, and progression free and overall survival.
This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy. The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies. The addition of non-invasive repeated hypoxia imaging ('window-of-opportunity') enables us to identify the biologically effective dose. We believe this approach could also be used for other hypoxia targeted drugs.
ClinicalTrials.gov Identifier: NCT02598687 .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. ...In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC.
This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 × 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 × 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521.
Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval CI, 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio OR = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade ≥3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR = 1.22; 95% CI, 0.35-4.22).
Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC.
The trials within cohorts (TwiCs) design aims to improve recruitment efficiency. We conducted the first TwiCs in radiation oncology and described efficiency of the design and generalizability of the ...results.
In two radiotherapy centers, patients with rectal cancer were asked to participate in a prospective cohort study and to provide broad consent for randomization and patient-reported outcomes (PROs). Consenting patients who met the trial criteria were randomized directly after cohort enrollment. The intervention arm was offered a radiotherapy boost. We evaluated acceptance rate, its impact on sample size, and compared clinical characteristics between trial participants and patients of the Dutch national cancer registry.
128 of the 200 eligible patients (64%) were randomized. Sixty-two patients did not consent (in time) to cohort participation, to broad randomization, or to PROs. Of the 64 patients in the intervention arm, 52 (81%) accepted the intervention. During the trial, the acceptance rate dropped temporarily, after which sample size was adapted. Trial patients were comparable in age, comorbidity, and disease stage to the national rectal cancer population.
The TwiCs design is feasible, allows enrollment of a high proportion of randomizable patients, with positive impact on trial efficiency and generalizability of results in a clinical oncology setting.
•Privacy preserving distributed learning for anal cancer outcome modelling is feasible•A Cox proportional hazards model was developed with data from three institutions•This is one of the largest ...series of anal cancer patients treated with modern RT•Distributed learning is an attractive approach for outcome modelling in rare cancers
Predicting outcomes is challenging in rare cancers. Single-institutional datasets are often small and multi-institutional data sharing is complex. Distributed learning allows machine learning models to use data from multiple institutions without exchanging individual patient-level data. We demonstrate this technique in a proof-of-concept study of anal cancer patients treated with chemoradiotherapy across multiple European countries.
atomCAT is a three-centre collaboration between Leeds Cancer Centre (UK), MAASTRO Clinic (The Netherlands) and Oslo University Hospital (Norway). We trained and validated a Cox proportional hazards regression model in a distributed fashion using data from 281 patients treated with radical, conformal chemoradiotherapy for anal cancer in three institutions. Our primary endpoint was overall survival. We selected disease stage, sex, age, primary tumour size, and planned radiotherapy dose (in EQD2) a priori as predictor variables.
The Cox regression model trained across all three centres found worse overall survival for high risk disease stage (HR = 2.02), male sex (HR = 3.06), older age (HR = 1.33 per 10 years), larger primary tumour volume (HR = 1.05 per 10 cm3) and lower radiotherapy dose (HR = 1.20 per 5 Gy). A mean concordance index of 0.72 was achieved during validation, with limited variation between centres (Leeds = 0.72, MAASTRO = 0.74, Oslo = 0.70). The global model performed well for risk stratification for two out of three centres.
Using distributed learning, we accessed and analysed one of the largest available multi-institutional cohorts of anal cancer patients treated with modern radiotherapy techniques. This demonstrates the value of distributed learning in outcome modelling for rare cancers.
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