Circulating cell-free nucleic acids and platelets as a liquid biopsy in the provision of personalized therapy for lung cancer patients.

Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA-ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer. The development of sensitive and accurate techniques such as Next-Generation Sequencing (NGS); Beads, Emulsion, Amplification, and Magnetics (BEAMing); and Digital PCR (dPCR), have made it possible to detect the specific genetic alterations (e.g. EGFR mutations, MET amplifications, and ALK and ROS1 translocations) for which targeted therapies are already available. Moreover, the ability to detect and quantify these tumor mutations has enabled the follow-up of tumor dynamics in real time. Liquid biopsy offers opportunities to detect resistance mechanisms, such as the EGFR T790M mutation in the case of EGFR TKI use, at an early stage. Several studies have already established the predictive and prognostic value of measuring ctNA concentration in the blood. To conclude, using ctNA analysis as a liquid biopsy has many advantages and allows for a variety of clinical and investigational applications.

Dysregulation of the renin-angiotensin system during lung ischemia-reperfusion injury.

UNLABELLED: Aim/Purpose of the Study: Activation of the renin-angiotensin system leading to increased angiotensin-(1-7) (Ang-(1-7)) and decreased angiotensin 2 (Ang 2) levels may be a new therapeutic approach to reduce acute lung injury. Prolylcarboxypeptidase (PRCP) and prolyloligopeptidase (PREP) are capable of hydrolyzing Ang 2 into Ang-(1-7). However, their relation with circulating Ang 2 levels after lung ischemia-reperfusion injury (LIRI) has never been explored. This study determines whether the activity and expression of PRCP and PREP in plasma and lung tissue is related to circulating Ang 2 levels in a murine model of LIRI. MATERIALS AND METHODS: LIRI in Swiss mice (6 animals per group) was induced by temporary left lung hilar clamping (1 h) followed by 0, 1 or 24 h of reperfusion. Animals in the sham group received thoracotomy only. PRCP activity was measured via RP-HPLC, PREP activity using a fluorogenic substrate and plasma Ang 2 levels via ELISA. Western blotting was used to determine the PRCP and PREP protein expression profiles in left lung tissue. RESULTS: Plasma Ang 2 levels significantly rise after lung ischemia and remain increased after 1 h and 24 h of reperfusion compared to the sham group. While a significant decrease in plasma PREP activity was found after 24 h of reperfusion, a transient increase in plasma PRCP activity was observed after ischemia. However, no correlation with plasma Ang 2 levels could be demonstrated. The activity profiles of PRCP and PREP and the protein expression of PRCP in the lung tissues remained unchanged after LIRI. CONCLUSIONS: LIRI causes a dysregulation of circulating Ang 2 levels and plasma PREP activity, although no direct link between both phenomena could be shown. The activity profile of pulmonary PRCP and PREP was not significantly changed after LIRI, which implies a minor role for local PRCP and PREP in the ischemic lung itself.

Emergency endovascular aneurysm repair for ruptured abdominal aortic aneurysms: an institutional experience.

OBJECTIVES: Emergency endovascular aneurysm repair (eEVAR) for ruptured abdominal aortic aneurysms (rAAA) is still under investigation. Since installation of an urgent eEVAR kit in our hospital, all patients with a rAAA or urgent thoracic aortic aneurysm are candidates for eEVAR or eTEVAR (emergency thoracic EVAR), respectively. For this study, we analyzed all rAAA patients treated with eEVAR. METHODS: Data were recorded prospectively. Criteria for an eEVAR were an infrarenal neck > or = 15 mm, acceptable landing zone, angles below 70 degrees and a good femoral approach. We prefer preoperative angio CT-scan but in case of instability, an intra-aortic balloon can stabilize the patient during angiography (in the OR) to decide between open or eEVAR repair. Follow-up was performed on regular intervals by duplex or CT-scan. Thirty-day mortality and overall survival were calculated. RESULTS: Since 2006, nine male rAAA patients with a mean age of 73 years (range : 62-82) had eEVAR repair. Aneurysm diameter was 8 cm (range : 5.8-11). The Hardman index was 1.5 (range : 0-3). In eight patients an aorto-uni-iliac device was placed succesfully followed by a femorofemoral crossover bypass. The 30-day operative mortality was 12.5% (one patient with septic shock). Three patients showed a type 2 endoleak with stable diameter during follow-up but one patient showed expansion 4 years after treatment. CONCLUSIONS: Treating rAAA with eEVAR in selected patients with acceptable anatomy and a kit permanently available in the operating room yielded good results by a surgical team trained for both open and eEVAR repair. The conversion rate was low (11%) and the survival (immediate and 30-days) was excellent (87.5%).

Red blood cell accumulation in a rat model of pulmonary ischemia/reperfusion injury.

AIM: Red blood cell (RBC) accumulation in lung tissue during ischemia/reperfusion has not been studied extensively. A warm lung ischemia/reperfusion-injury model was developed to determine RBC trapping. METHODS: Twenty-four rats were randomized into 5 groups. In 4 groups, the left lung was submitted to 20 minutes of warm ischemia followed by reperfusion for 3, 10, 30 and 60 minutes. Subsequently, both lungs were flushed. Afterwards the heart-lung block was removed and fixed endoluminally. The fifth group was the sham group, in which lungs were flushed after 20 minutes of perfusion without induction of ischemia. RBC were counted in the hilar sectional plane and expressed in area%. RESULTS: In the left reperfused ischemic lung, already 3 minutes after reperfusion, a significant accumulation of RBC was found in the capillaries. This accumulation was accompanied by a significant vascular congestion of these vessels. After in vivo perfusion, almost all RBC were flushed out the blood vessels of the non-ischemic lung (area%=0.082). In ischemic reperfused lungs, capillaries were densely packed with RBC. Significantly more RBC were counted after 3 (area%=1.572; P=0.002) and 10 minutes (area%=1.240; P=0.011) of reperfusion compared to the sham group. After 30 (area%=0.929; P=0.054) and 60 minutes (area%=0.435; P=0.404) no significant increase in RBC was observed compared to the sham group. In the right non-ischemic lungs, no differences in RBC accumulation were observed between the sham group and ischemia-reperfusion groups. CONCLUSIONS: After warm ischemia/reperfusion, a significant early increase in accumulation of RBC was observed.

Asymptomatic pheochromocytoma in the posterior mediastinum.

A 66-year-old female patient was treated for a posterior mediastinal tumour with unknown histology. During thoracotomy, repetitive hypertensive crises had to be treated. The tumour was completely resected. Pathology revealed an extra-adrenal pheochromocytoma. Diagnosis of pheochromocytoma is usually made on the basis of clinical presentation and elevated catecholamine levels in serum or urine. Imaging is used primarily for localizing tumours prior to surgery. Complete surgical excision is the primary treatment. The only absolute indicator of malignancy is the identification of distant metastases to bone, liver, lung or lymph nodes.

Toxicity and efficacy of isolated lung perfusion with gemcitabine in a rat model of pulmonary metastases.

BACKGROUND: Long-term toxicity and efficacy of isolated left lung perfusion (ILuP) with gemcitabine (GCB) were studied in a rat model of metastatic pulmonary adenocarcinoma. TOXICITY: Forty rats were randomized into six groups and administered 160 or 320 mg/kg GCB or buffered starch, received either via intravenous injection (i.v.) or via ILuP. Efficacy experiment: Rats with unilateral metastases had ILuP with 320 mg/kg GCB (maximally tolerated dose administered by ILuP), while rats with bilateral metastases had an i.v. injection of 160 mg/kg GCB (maximally tolerated dose given by i.v.). RESULTS: TOXICITY experiment: After i.v. treatments, all rats receiving 320 mg/kg GCB died within one week, while rats who had received 160 mg/kg GCB had a survival rate of 60%. After ILuP with 160 mg/kg GCB and 320 mg/kg GCB, survival rates were 83% in both groups. A significant increase in collagen deposits was observed for ILuP with 320 mg/kg GCB compared to rats treated i.v. with 160 mg/kg GCB. Efficacy experiment: Median survival of ILuP rats treated with 320 mg/kg (38 +/- 4 days) was significantly longer compared to i.v. rats treated with 160 mg/kg (27 +/- 2 days; p = 0.02). CONCLUSIONS: ILuP with GCB prolongs survival in experimental metastatic adenocarcinoma while no major acute or long term toxicity is observed.

The approach to the surgical management of cancer in four European countries.

Outcome of lung cancer appears poorer in the UK than elsewhere in Europe. This may be due to a less aggressive approach in treatment. This study investigated whether clinicians' perceptions of their approach differed between European countries. A questionnaire was circulated to cancer specialists in four countries (Belgium, Greece, Switzerland and the UK) asking about management. An aggression score was calculated using the proportion of standard cases that would proceed to operation at different ages and levels of pulmonary function. The principle problems suggested by most of the 314 respondents were inoperability before symptoms (particularly in the UK) and confounding effects of comorbidity. Surgeons particularly blamed delay in referral. The aggression scores (Belgium 54%, UK 49%, Switzerland 47% and Greece 37%) did not suggest the UK is an outlier, but the UK was more conservative in its approach to N2 disease and isolated cerebral metastasis. The aggression scores of surgeons were greater than those of the others (51% versus 42%). Lung cancer was felt to present late with potentially confounding symptoms, but delay in the clinical process was thought to be less important. Although the UK was more conservative with special cases, its approach to typical cases could account for differences in patient survival.

Variations in flow, duration, and concentration do not change the final lung concentration of melphalan after isolated lung perfusion in rats.

OBJECTIVE: The influences of flow, perfusion time, and concentration on melphalan (MN) lung levels in a rat model of isolated lung perfusion (ILuP) were studied. METHODS: ILuP was performed in WAG/Rij rats by using a single-pass system with 0.5, 0.05, 0.01, and 0.005 mg of MN. Subsequently ILuP with 0.05 mg MN was performed during 30 min with a flow rate of 0.5 ml/min, during 60 min with a flow rate of 0.5 ml/min, and during 30 min with a flow rate of 1.0 ml/min. RESULTS: The lung MN levels of 0.05 mg were significantly lower as compared with 0.5 mg (p = 0.02). In the second experiment, no significant differences were seen in lung levels of MN between the different groups. CONCLUSION: The final lung MN levels were only determined by the absolute amount administered.