A potential biomarker of radiosensitivity in metastatic hormone sensitive prostate cancer patients treated with combination external beam radiotherapy and radium-223.

PURPOSE: The ADRRAD trial reported the safety and feasibility of the combination of external beam radiotherapy and radium-223 in the treatment of de novo bone metastatic prostate. This study aimed to determine if any biomarkers predictive of response to these treatments could be identified. EXPERIMENTAL DESIGN: 30 patients with newly diagnosed bone metastatic hormone sensitive prostate cancer were recruited to the ADRRAD trial. Blood samples were taken pre-treatment, before cycles 2 to 6 of radium-223, and 8 weeks and 6 months after treatment. Mononuclear cells were isolated and DNA damage was assessed at all timepoints. RESULTS: DNA damage was increased in all patients during treatment, with bigger increases in foci observed in patients who relapsed late compared to those who relapsed early. Increases in DNA damage during the radium-223 only cycles of treatment were specifically related to response in these patients. Analysis of hematology counts also showed bigger decreases in red blood cell and hemoglobin counts in patients who experienced later biochemical relapse. CONCLUSIONS: While some patients responded to this combination treatment, others relapsed within one year of treatment initiation. This study identifies a biomarker based approach that may be useful in predicting which patients will respond to treatment, by monitoring both increases in DNA damage above baseline levels in circulating lymphocytes and decreases in red blood cell and hemoglobin counts during treatment.

[Place of 3D custom-made implants after failure of modeling steno-chondro-plasties]. / Place des implants sur mesure 3D après échec des sterno-chondro-plasties modelantes.

Most common congenital malformation of the thorax, Pectus Excavatum affects about one in 500 people. Several surgical or medical techniques have been proposed. Some are followed by complications or insufficient results even though their constant functional value is highly controversial. Secondary surgery with a deep customized 3D elastomer implant, may be an elegant effective and safe solution compared to others; it allows a good aesthetic result expected by patients in the absence of any respiratory or cardio-vascular functional context.

Outcomes and toxicities in oligometastatic patients treated with stereotactic body radiotherapy for adrenal gland metastases: A multi-institutional retrospective study.

BACKGROUND: Studies reporting SBRT outcomes in oligometastatic patients with adrenal gland metastases (AGM) are limited. Herein, we present a multi-institutional analysis of oligometastatic patients treated with SBRT for AGM. MATERIAL/METHODS: The Consortium for Oligometastases Research (CORE) is among the largest retrospective series of patients with oligometastases. Among CORE patients, those treated with SBRT for AGM were included. Clinical and dosimetric data were collected. Adrenal metastatic burden (AMB) was defined as the sum of all adrenal GTV if more than one oligometastases is present.Competing risk analysis was used to estimate actuarial cumulative local recurrence (LR) and widespread progression (WP). Kaplan-Meier method was used to report overall survival (OS), local recurrence-free survival (LRFS), and progression-free survival (PFS). Treatment related toxicities were also reported. RESULTS: The analysis included 47 patients with 57 adrenal lesions. Median follow-up was 18.2 months. Median LRFS, PFS, and OS were 15.3, 5.3, and 19.1 months, respectively. A minimum PTV dose BED10 > 46 Gy was associated with an improved OS and LRFS. A prescribed BED10 > 70 Gy was an independent predictor of a lower LR probability. AMB>10 cc was an independent predictor of a lower risk for WP. Only one patient developed an acute Grade 3 toxicity consisting of abdominal pain. CONCLUSION: SBRT to AGM achieved a satisfactory local control and OS in oligometastatic patients. High minimum PTV dose and BED10 prescription doses were predictive of improved LR and OS, respectively. Prospective studies are needed to determine comprehensive criteria for patients SBRT eligibility and dosimetric planning.

Traumatic thoracoabdominal hernia repair using a novel chest-wall reconstruction technique: a case report.

Thoracoabdominal hernia following blunt trauma is extremely rare. Abdominal viscera are more likely to herniate into the thorax if there is traumatic diaphragmatic rupture. We report the case of a patient presenting with a traumatic thoracoabdominal hernia containing part of the right lobe of the liver and the hepatic flexure of the colon. The hernia migrated cranially, to protrude through a seventh intercostal defect despite the diaphragm remaining fully intact. The need for early multispecialty (thoracic and hepatobiliary) surgical repair is highlighted, with improvements in surgical outcome for a complex trauma case by using a novel chest-wall reconstruction technique.

Isolated Unilateral Pulmonary Artery Agenesis complicated by Symptomatic Aspergilloma.

Isolated unilateral pulmonary artery agenesis is a rare diagnosis. Poor blood flow to the lung parenchyma renders the tissue susceptible to opportunistic infections. We present the unusual case of isolated unilateral pulmonary artery agenesis complicated by aspergilloma. Management options and considerations are discussed.

Acute Respiratory Failure Post Single Lung Transplantation: An Unusual Cause.

Vascular complications of pulmonary vessels post-transplant are rare but are associated with high morbidity and mortality. We describe the first published case of surgical management of pulmonary vein stenosis complicated by early thrombosis post single lung transplantation. This report describes early diagnostic techniques and subsequent management options in such patients where pulmonary vascular complications are a potential.

Isolated anterior mediastinal tuberculosis in an immunocompetent patient.

BACKGROUND: The differential diagnosis of a mediastinal mass is a common challenge in clinical practice, with a wide range of differential diagnosis to be considered. One of the rarer causes is tuberculosis. Atypical presentations of tuberculosis are well documented in immunocompromised patients, but should also be considered in the immunocompetent. CASE PRESENTATION: This case outlines a previously healthy 22 year-old immunocompetent male presenting with worsening chest pain, positional dyspnea, dry cough and dysphagia. Chest x-ray showed evidence of an isolated anterior mediastinal mass, which was confirmed on computed tomography. A mediastinoscopy was diagnostic as histology revealed necrotizing granulomatous inflammation and the presence of acid-fast bacilli, indicating mediastinal tuberculosis. CONCLUSION: Typically the underlying presentation of mediastinal tuberculosis is mediastinal lymphadenitis. This case was unusual in that we detected an isolated large anterior mediastinal mass accompanied by a relatively small burden of mediastinal lymphadenitis. Cases similar to this have been documented in immunosuppressed patients however in our case no evidence of immunosuppression was found. This case report emphasizes the importance that a detailed and logical pathway of investigation is pursued when encountering a mediastinal mass.

First bilateral lobar lung transplant in Ireland: advanced operative strategies in lung transplantation.

Lobar lung transplantation is an option that provides the possibility of transplantation of small size recipients with size-mismatch donor lungs by surgically reducing the size of donor lungs. We report our first experience of bilateral lobar lung transplantation of big donor lungs, in a small size urgently listed recipient, after size reduction. A 24 years old girl with end stage cystic fibrosis received the bilateral lobar lung transplant. She made very good recovery postoperatively and was discharged home two weeks following surgery.

Differential affinity of FLIP and procaspase 8 for FADD's DED binding surfaces regulates DISC assembly.

Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages the DEDs of procaspase 8 and its inhibitor FLIP to form death-inducing signalling complexes (DISCs). The DEDs of FADD, FLIP and procaspase 8 interact with one another using two binding surfaces defined by α1/α4 and α2/α5 helices, respectively. Here we report that FLIP has preferential affinity for the α1/α4 surface of FADD, whereas procaspase 8 has preferential affinity for FADD's α2/α5 surface. These relative affinities contribute to FLIP being recruited to the DISC at comparable levels to procaspase 8 despite lower cellular expression. Additional studies, including assessment of DISC stoichiometry and functional assays, suggest that following death receptor recruitment, the FADD DED preferentially engages FLIP using its α1/α4 surface and procaspase 8 using its α2/α5 surface; these tripartite intermediates then interact via the α1/α4 surface of FLIP DED1 and the α2/α5 surface of procaspase 8 DED2.

Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy.

OBJECTIVE: The aim of this study was to investigate the effect of pre-treatment verification imaging with megavoltage X-rays on cancer and normal cell survival in vitro and to compare the findings with theoretically modelled data. Since the dose received from pre-treatment imaging can be significant, the incorporation of this dose at the planning stage of treatment has been suggested. METHODS: The impact of imaging dose incorporation on cell survival was investigated by clonogenic assay of irradiated DU-145 prostate cancer, H460 non-small-cell lung cancer and AGO-1522b normal tissue fibroblast cells. Clinically relevant imaging-to-treatment times of 7.5 and 15 min were chosen for this study. The theoretical magnitude of the loss of radiobiological efficacy due to sublethal damage repair was investigated using the Lea-Catcheside dose protraction factor model. RESULTS: For the cell lines investigated, the experimental data showed that imaging dose incorporation had no significant impact on cell survival. These findings were in close agreement with theoretical results. CONCLUSION: For the conditions investigated, the results suggest that allowance for the imaging dose at the planning stage of treatment should not adversely affect treatment efficacy. ADVANCES IN KNOWLEDGE: There is a paucity of data in the literature on imaging effects in radiotherapy. This article presents a systematic study of imaging dose effects on cancer and normal cell survival, providing both theoretical and experimental evidence for clinically relevant imaging doses and imaging-to-treatment times. The data provide a firm foundation for further study into this highly relevant area of research.

An in vitro study of the radiobiological effects of flattening filter free radiotherapy treatments.

Flattening filter free (FFF) linear accelerators allow for an increase in instantaneous dose-rate of the x-ray pulses by a factor of 2-6 over the conventional flattened output. As a result, radiobiological investigations are being carried out to determine the effect of these higher dose-rates on cell response. The studies reported thus far have presented conflicting results, highlighting the need for further investigation. To determine the radiobiological impact of the increased dose-rates from FFF exposures a Varian Truebeam medical linear accelerator was used to irradiate two human cancer cell lines in vitro, DU-145 prostate and H460 non-small cell lung, with both flattened and FFF 6 MV beams. The fluence profile of the FFF beam was modified using a custom-designed Nylon compensator to produce a similar dose profile to the flattened beam (6X) at the cell surface but at a higher instantaneous dose-rate. For both cell lines there appeared to be no significant change in cell survival. Curve fitting coefficients for DU145 cells irradiated with constant average dose-rates were 6X: α = 0.09 ± 0.03, ß = 0.03 ± 0.01 and 6FFF: α = 0.14 ± 0.13, ß = 0.03 ± 0.02 with a significance of p = 0.75. For H460 cells irradiated with the same instantaneous dose-rate but different average dose-rate the fit coefficients were 6FFF (low dose-rate): α = 0.21 ± 0.11, 0.07 ± 0.02 and 6FFF (high dose-rate): α = 0.21 ± 0.16, 0.07 ± 0.03, with p = 0.79. The results indicate that collective damage behaviour does not occur at the instantaneous dose-rates investigated here and that the use of either modality should result in the same clinical outcome, however this will require further validation in vivo.

Body site matters: an evaluation and application of a novel histological methodology on the quantification of mucous cells in the skin of Atlantic salmon, Salmo salar L.

Mucous cell size and distribution were investigated in the skin of five salmon using a novel stereology-based methodology: one (48 cm) fish to test 15 tissue treatment combinations on measures of cell area and density on the dorsolateral region and, using the most suitable treatment, we mapped mucous cell differences between body regions on four (52 cm) salmon, comprising a male and a female on each of two diets. The section site, decalcification, embedding medium and plane of sectioning all impacted significantly on mucous cell size, whereas mucous cell density is more robust. There were highly significant differences in both mucosal density and mean mucous cell size depending on body site: the dorsolateral skin of the four salmon had significantly denser (about 8% of skin area) and larger (mean about 160 µm(2)) mucous cells, whereas the lowest mean density (about 4%) and smallest mean area (115 µm(2)) were found on the head. We found that 100 random measurements may be sufficient to distinguish differences >7 µm(2) in mean mucous cell areas. The results further suggest that salmon exhibit a dynamic repeatable pattern of mucous cell development influenced by sex, diet and possibly strain and season.

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis.

FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-specific inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as efficient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as 'FLIP inhibitors'.

Ex vivo evaluation of lungs from donation after cardiac death after recent cardiac surgery with cardiopulmonary bypass.

Lack of suitable donor lungs is still a major limitation of lung transplantation. Extended donor acceptance criteria combined with innovative assessment tools can be used to expand the number of suitable organs. We describe a successful transplantation of lungs retrieved from a donor who had undergone aortic root replacement 9 days before donation after cardiac death. The lungs were assessed using ex-vivo lung perfusion.

Pulmonary resection for airway complication after lung transplantation in a patient with cystic fibrosis: a case report.

We report a case of the interdisciplinary management of recurring bronchial stenosis after bilateral sequential single-lung transplantation (BSSLT) in a 35-year-old female with cystic fibrosis. Initial bronchoscopic therapy including balloon dilatation, stenting, and cryotherapy for granulation tissue overgrowth was unsuccessful in maintaining airway patency. In view of the persistent left lower lobe (LLL) atelectasis and fibrosis predisposing to recurrent infections, she was submitted for left lower lobectomy.