Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

<p>Abstract</p> <p>Background</p> <p>In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.</p> <p>Findings</p> <p>Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.</p> <p>Conclusions</p> <p>When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00455351">NCT00455351</a></p

Multi-professional ethical competence in healthcare – an ethical practice model

Introduction The starting point is that ethical competence is the basis for ethical healthcare practices and quality of care. Simultaneously, there is a need for research and development from a holistic multi-professional perspective. Aim The aim is to create a proposed model for multi-professional ethical competence grounded in clarified meanings and dimensions of ethical competence studied from a multi-professional healthcare perspective. The research questions are, what is ethical competence from a multi-professional healthcare perspective and what strengthens a multi-professional ethical healthcare practice? Research design The research has a qualitative approach and hermeneutic application research design. Two groups with six participants from clinical practice and two scientific researchers in each group met four times for dialogue. Thematic analysis was used as an analysis method. Ethical considerations The research is approved by the Declaration of Helsinki, the General Data Protection Regulations, and ethical permission was asked from the Norwegian Centre for Research Data (NSD). Results The proposed model for multi-professional ethical competence encompasses a three-dimensional ethical value base that is underpinned by: Ethical attitude – a personal desire to do good; Ethical basis – the best for the patient as a common goal and Ethical culture – common goals and values in the organization. Multi-professional ethical competence is strengthened by: Reflection – to see with new wondering eyes; Time for talk – interdisciplinary teamwork and Leadership – an ethical role model and support. Discussion Ethical competence has a strong link to the core of caring ethics and a deeper personal value base and attitude. Ethical competence involves the whole culture and is seen as a shared value base and a responsibility to do the best for the patient as a multi-professional team and organization. Ethical competence becomes active in healthcare practice by opening up for meaningful multi-professional talks and reflections.publishedVersio

Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer

Background: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. Methods: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. Results: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3–19.7) and 3.9 months (95% CI, 2.3–5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9–14.7) for control arm patients (N = 31). Conclusions: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases.publishedVersio

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

Background The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Methods Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Results Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Conclusions Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials

Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

BACKGROUND: The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. METHODS: Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. RESULTS: In addition to G(2)/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G(1 )phase cells). In contrast, histone acetylation was associated with complete depletion of the G(1 )population of cells with functional p53 but accumulation of both G(1 )and G(2)/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G(2)/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. CONCLUSION: In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified

Principal component analysis for the comparison of metabolic profiles from human rectal cancer biopsies and colorectal xenografts using high-resolution magic angle spinning 1H magnetic resonance spectroscopy

<p>Abstract</p> <p>Background</p> <p>This study was conducted in order to elucidate metabolic differences between human rectal cancer biopsies and colorectal HT29, HCT116 and SW620 xenografts by using high-resolution magnetic angle spinning (MAS) magnetic resonance spectroscopy (MRS) and for determination of the most appropriate human rectal xenograft model for preclinical MR spectroscopy studies. A further aim was to investigate metabolic changes following irradiation of HT29 xenografts.</p> <p>Methods</p> <p>HR MAS MRS of tissue samples from xenografts and rectal biopsies were obtained with a Bruker Avance DRX600 spectrometer and analyzed using principal component analysis (PCA) and partial least square (PLS) regression analysis.</p> <p>Results and conclusion</p> <p>HR MAS MRS enabled assignment of 27 metabolites. Score plots from PCA of spin-echo and single-pulse spectra revealed separate clusters of the different xenografts and rectal biopsies, reflecting underlying differences in metabolite composition. The loading profile indicated that clustering was mainly based on differences in relative amounts of lipids, lactate and choline-containing compounds, with HT29 exhibiting the metabolic profile most similar to human rectal cancers tissue. Due to high necrotic fractions in the HT29 xenografts, radiation-induced changes were not detected when comparing spectra from untreated and irradiated HT29 xenografts. However, PLS calibration relating spectral data to the necrotic fraction revealed a significant correlation, indicating that necrotic fraction can be assessed from the MR spectra.</p

Low Concordance Between T-Cell Densities in Matched Primary Tumors and Liver Metastases in Microsatellite Stable Colorectal Cancer

Background: The subtype, density and location of tumor infiltrating T-cells are being explored as prognostic and predictive biomarkers in primary colorectal cancer (pCRC) and colorectal liver metastases (CLM). Very limited data exist comparing findings in pCRC and matched CLM. Patients and methods: Fifty-eight patients with available pCRC and matched CLM (57/58 microsatellite stable) were included in this OSLO-COMET substudy. In immunohistochemically stained sections, total (Ttot), helper (TH), cytotoxic (CTL), and regulatory (Treg) T-cells were manually counted in hotspots from the invasive margin (IM), intratumor (IT), and tumor adjacent regions to determine T-cell densities. Results: A striking accumulation of T-cells was found in IM of both pCRC and CLM with much lower densities in the IT region, exemplified by Ttot of 2838 versus 340 cells/mm2, respectively, in CLM. The correlation at the individual level between T-cell densities in pCRC and corresponding CLM was poor for all regions and T-cell subtypes; for instance, the correlation coefficient (R2) for IM Ttot was 0.07. The IT TH : CTL and Treg : TH ratios were 2.94 and 0.44, respectively, in pCRC, and 1.84 and 0.24, respectively, in CLM. Conclusion: The observed accumulation of T-cells in the IM regions of pCRC and CLM with low penetration to the IT regions, combined with high TH : CTL and Treg : TH ratios, point to the presence of an immune suppressive microenvironment. T-cell densities of CLM differed markedly from the matched pCRC, indicating that to evaluate T-cell biomarkers in metastasis, the commonly available pCRC cannot serve as a surrogate for the metastatic tumor

Møtet – å se og bli berørt av pasienten: En grunn for etisk kompetanse hos helsepersonell

The purpose of this caring science study is to deepen the understanding of health personnel’s experiences of challenges and the fundamental basis for maintaining ethical competence in clinical practice. The study has a qualitative design. The methodology is hermeneutic application research. Twelve participants from several professions were divided into two groups for dialogue and reflection about ethical competence. Systematic text condensation was used as an analysis method.   The analysis resulted in four themes, ethics are challenged in complex clinical situations, to create space for reflection, to see the human being, and to be touched by the patient. The results confirm that the encounter between health personnel and the patient is significant and that the encounter itself is immanent ethics. Health personnel work with a tension between a system characterized by busyness and chores and seeing the patient as a human being and being overwhelmed by his or her suffering. In this field of tension, health personnel can be in the movement of becoming and reflecting on what promotes and maintains ethical competence.I denne omsorgsvitenskaplige studien søker vi en dypere forståelse av helsepersonells erfaringer av utfordringer og grunnlag for å opprettholde etisk kompetanse i klinisk praksis. Studien har et kvalitativ design. Metodologien er hermeneutisk applikasjonsforskning. Tolv deltakere fra ulike profesjoner, fordelt på to grupper, deltok i dialoger om etisk kompetanse. Systematisk tekstkondensering er brukt som metode for å analysere dataene. Funnene presenteres i fire temaer: I komplekse kliniske erfaringer blir etikken utfordret, Å skape rom for refleksjon, Å se mennesket og Å bli berørt av pasienten. Resultatet bekrefter at møtet mellom helsepersonell og pasient er betydningsfullt, og at møtet i seg en iboende etikk. Helsepersonell arbeider i en spenning mellom å se mennesket i pasientrollen og å bli overveldet av lidelse i et system preget av travelhet og gjøremål. I dette spenningsfeltet kan helsepersonell være i en danningsprosess, gjennom refleksjon som fremmer og opprettholder etisk kompetanse. Funnene presenteres i fire temaer: I komplekse kliniske erfaringer blir etikken utfordret, Å skape rom for refleksjon, Å se mennesket og Å bli berørt av pasienten. Resultatet bekrefter at møtet mellom helsepersonell og pasient er betydningsfullt, og at møtet i seg en iboende etikk. Helsepersonell arbeider i en spenning mellom å se mennesket i pasientrollen og å bli overveldet av lidelse i et system preget av travelhet og gjøremål. I dette spenningsfeltet kan helsepersonell være i en danningsprosess, gjennom refleksjon som fremmer og opprettholder etisk kompetanse

Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer

Background Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy. Methods In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS). Results In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046). Conclusion In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression