Virtual 4DCT generated from 4DMRI in gated particle therapy: phantom validation and application to lung cancer patients.

Objective. Respiration negatively affects the outcome of a radiation therapy treatment, with potentially severe effects especially in particle therapy (PT). If compensation strategies are not applied, accuracy cannot be achieved. To support the clinical practice based on 4D computed tomography (CT), 4D magnetic resonance imaging (MRI) acquisitions can be exploited. The purpose of this study was to validate a method for virtual 4DCT generation from 4DMRI data for lung cancers on a porcine lung phantom, and to apply it to lung cancer patients in PT.Approach. Deformable image registration was used to register each respiratory phase of the 4DMRI to a reference phase. Then, a static 3DCT was registered to this reference MR image set, and the virtual 4DCT was generated by warping the registered CT according to previously obtained deformation fields. The method was validated on a physical phantom for which a ground truth 4DCT was available and tested on lung tumor patients, treated with gated PT at end-exhale, by comparing the virtual 4DCT with a re-evaluation 4DCT. The geometric and dosimetric evaluation was performed for both proton and carbon ion treatment plans.Main results. The phantom validation exhibited a geometrical accuracy within the maximum resolution of the MRI and mean dose deviations, with respect to the prescription dose, up to 3.2% for targetD95%, with a mean gamma pass rate of 98%. For patients, the virtual and re-evaluation 4DCTs showed good correspondence, with errors on targetD95%up to 2% within the gating window. For one patient, dose variations up to 10% at end-exhale were observed due to relevant inter-fraction anatomo-pathological changes that occurred between the planning and re-evaluation CTs.Significance. Results obtained on phantom data showed that the virtual 4DCT method was accurate, allowing its application on patient data for testing within a clinical scenario.

Metabolic profiling study of shikonin's cytotoxic activity in the Huh7 human hepatoma cell line.

Shikonin and its enantiomer alkannin, which are natural products, have been extensively studied in vitro and in vivo for, among others, their antitumor activity. The investigation of the molecular pathways involved in their action is of interest, since they are not yet clearly defined. Metabolic profiling in cells can provide a picture of a cell's phenotype upon intervention, assisting in the elucidation of the mechanism of action. In this study, the cytotoxic effect of shikonin on a human hepatocarcinoma cell line was studied. Huh7 cells were treated with shikonin at 5 µM, and it was found that shikonin markedly inhibited cell growth. Metabolic profiling indicated alterations in the metabolic content of the cells and the culture media upon treatment, detecting the metabolic response of the cells. This study demonstrates the potential of metabolomics to improve knowledge on the mechanisms involved in shikonin's antitumor action.

Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.

Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

The need for thoracic surgery in adult patients receiving extracorporeal membrane oxygenation: a 16-year experience.

OBJECTIVES: Patients on extracorporeal membrane oxygenation (ECMO) are at risk from thoracic complications such as bleeding or pneumothorax, which may subsequently necessitate thoracic surgical intervention. We aimed to: 1) analyse the indication and nature of thoracic surgical intervention in these patients and 2) analyse the effect of a change in the ECMO circuit from roller pump to centrifugal pump on transfusion requirements pre and post thoracotomy. METHODS: We retrospectively reviewed a prospectively collected database of 569 adults put on ECMO between 1995 and 2011. Patients undergoing thoracotomy were identified and outcomes were statistically analysed. RESULTS: Forty thoracotomies were performed in 18 patients [61% male, median age 31 (14-56) years, one bilateral procedure]. The indications for ECMO included: pneumonia 14/18 (78%), trauma 2/18 (11%) and other 2/18 (11%). Median duration on ECMO was 13 (1-257) days and the time to initial thoracotomy was 10 (1-183) days. The indications for thoracotomy were: excessive bleeding post chest drain insertion (11/19, 58%), uncontrolled air leak (9/19, 47%) and pleural effusion (4/19, 21%). The primary operations were 12/19 (63%) evacuation of haemothorax, 3/19 (16%) lung repair, 2/19 (11%) diagnostic lung biopsy and 2/19 (11%) other. Ten patients needed a further 21 thoracotomies (3 lobectomies); average 2 (1-5) per patient. In total, 30/40 (75%) thoracotomies were performed for bleeding complication. The change from roller to centrifugal pump trended towards a reduction in mean transfusion requirements in these patients following thoracotomy (11.5 versus 4 units, p=0.14). The in-hospital mortality was 7/18 (39%) patients. There were no statistically significant predictors of poor outcome. CONCLUSIONS: The need for thoracotomy whilst on ECMO is 3.2% in this large series. Intervention may be complicated, thus, either ECMO specialists should have thoracic training or thoracic surgeons should be on-site. Potential mortality is high and, although not statistically significant, a difference in transfusion requirements was observed following the change of circuit.

Two synchronous non small cell lung carcinomas with different morphologies in the same lobe.

We report the case of a sixty one year old female diagnosed with two synchronous primary lung cancers located within the same lobe. Surgical resection was performed, followed by adjuvant chemotherapy. The patient developed distant bone and skin metastases one year post-surgical resection. In this report we discuss the multimodality therapy used to treat this patient.

Surgical treatment of combined hepatic and pulmonary colorectal cancer metastases.

AIMS: Surgical resection of combined hepatic and pulmonary metastases remains controversial in light of limited supportive evidence. This study aimed to audit our initial experience with this aggressive surgical strategy. METHODS: Between 1997 and 2006 we assessed 19 patients with colorectal cancer metastases for combined liver and lung metastasectomy, of whom 16 patients underwent surgery. We retrospectively reviewed perioperative and survival data. RESULTS: Synchronous liver metastases were present in three out of 16 patients at time of diagnosis of the primary tumour, and one out of 16 patients had synchronous lung and liver metastases with the primary tumour. Of those 12 patients who developed metachronous metastases five patients developed liver metastases first, one patient developed pulmonary metastases first, and six patients developed synchronous liver and lung metastases. Thirty nine operations were performed on 16 patients. The median hospital stay was 5.5 (2-10) days for the pulmonary and 7 (1-23) days for the hepatic resections. There were no in-hospital deaths. Chemotherapy was given to five patients prior to metastasectomy and nine received adjuvant chemotherapy following metastasectomy. Median survival from diagnosis of metastatic disease was 44 months (8-87 months). Estimated 1-year survival from diagnosis of metastatic disease was 94%, estimated 5-year survival was 20%. CONCLUSION: We believe an aggressive but selective surgical approach to combined hepatic and pulmonary colorectal metastases is justified by limited resource requirements and encouraging survival.

[Surgical repair of distal aortic arch aneurysm with hypothermic retrograde cerebral perfusion through standard left postero-lateral thoracotomy].

Five patients with aneurysm involving distal aortic arch underwent graft replacement of distal aortic arch and, in two patients, reconstruction of left subclavian artery through standard left postero-lateral thoracotomy with hypothermic retrograde cerebral perfusion. Retrograde cerebral perfusion with oxygen saturated venous blood could be performed by simply elevating central venous pressure to 20-23 mmHg in the Trendelenburg position and under controlling venous drainage from PA during deep hypothermic (19 degrees C) perfusion of the lower half of the body with the descending aorta occluded. Cardioplegia was induced by administration of cold blood cardioplegic solution into coronary circulation through Foley balloon catheter wedged in ascending aorta. Retrograde cerebral perfusion time was 30-77 min (mean 55 +/- 17 min), and pump time was 156-193 min (mean 168 +/- 15 min). There were no complications neurologically. In conclusion, this method rendered surgical repair of distal aortic arch aneurysm through left postero-lateral thoracotomy with both cerebral and cardiac protection able. Since any clamping of aortic arch and its branch was not necessary during above surgical procedure, cerebral emboli due to atheroma or luminal thrombus in aortic arch was prevented.

[Reconstruction of the common bile duct with a free venous autograft (experimental work - preliminary communication)]. / Rekonstrukcija duktus holedohusa slobodnim autovenskim graftom (eksperimentalni rad - preliminarno saopstenje).

In seven dogs, the authors performed a resection of the supraduodenal part of the main bile duct, 15-2 cm. in length. The arising defect was bridged over with a free autovenous graft taken from the exterior jugular vein (T-T anastomosis), without using a temporary or permanent prosthesis. The animals were followed-up 60 days and the sacrificed. Three dogs perished: the first one on the third day due to intoxication, the second dog on the thirteenth day because of anastomosis' disruption and consequent biliary peritonitis, and the third one on the eighteenth day of unknown causes. In the immediate postoperative course the values of the bilirubin and alkaline phosphatase were increased while those of transaminase were not significantly altered. These values began to normalize during the third week. An intravenous biliography was made on the sixtieth day showing a normal filling of the gallbladder, with an orderly visualization of hepato-choledochus and its correct transit, but with stenosis at the distal anastomosis. Macroscopically, the graft appeared slightly enlarged in length and diameter due to the mentioned stenosis. Histologically, the graft took on an appearance similar to the main bile duct, while its endothelium was completely replaced by biliary epithelium. An answer about the viability of this autovenous graft to serve as a substituent of a normal common bile duct is to be expected with further experimental work.