In vivo solid phase microextraction for therapeutic monitoring and pharmacometabolomic fingerprinting of lung during in vivo lung perfusion of FOLFOX

In vivo lung perfusion(IVLP)is a novel isolated lung technique developed to enable the local,in situ administration of high-dose chemotherapy to treat metastatic lung cancer.Combination therapy using folinic acid(FOL),5-fluorouracil(F),and oxaliplatin(OX)(FOLFOX)is routinely employed to treat several types of solid tumours in various tissues.However,F is characterized by large interpatient variability with respect to plasma concentration,which necessitates close monitoring during treatments using of this compound.Since plasma drug concentrations often do not reflect tissue drug concentrations,it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs.In this work,in vivo solid-phase microextraction(in vivo SPME)is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous(IV)trials.The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry(LC-HRMS)enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration(IVLP vs.IV)and the therapy itself.This study also shows that the immediate instrumental analysis of metabolomic samples is ideal,as long-term storage at80℃ results in changes in the metabolite content in the sample extracts.

Technetium-99m-labeled macroaggregated albumin lung perfusion scan for diagnosis of hepatopulmonary syndrome: A prospective study comparing brain uptake and whole-body uptake

BACKGROUND Hepatopulmonary syndrome (HPS) is an arterial oxygenation defect induced by intrapulmonary vascular dilatation (IPVD) in the setting of liver disease and/or portal hypertension.This syndrome occurs most often in cirrhotic patients(4%-32%) and has been shown to be detrimental to functional status,quality of life,and survival.The diagnosis of HPS in the setting of liver disease and/or portal hypertension requires the demonstration of IPVD (i.e.,diffuse or localized abnormally dilated pulmonary capillaries and pulmonary and pleural arteriovenous communications) and arterial oxygenation defects,preferably by contrast-enhanced echocardiography and measurement of the alveolar-arterial oxygen gradient,respectively.AIM To compare brain and whole-body uptake of technetium for diagnosing HPS.METHODS Sixty-nine patients with chronic liver disease and/or portal hypertension were prospectively included.Brain uptake and whole-body uptake were calculated using the geometric mean of technetium counts in the brain and lungs and in the entire body and lungs,respectively.RESULTS Thirty-two (46%) patients had IPVD as detected by contrast-enhancedechocardiography.The demographics and clinical characteristics of the patients with and without IPVD were not significantly different with the exception of the creatinine level (0.71±0.18 mg/dL vs 0.83±0.23 mg/dL;P=0.041),alveolararterial oxygen gradient (23.2±13.3 mmHg vs 16.4±14.1 mmHg;P=0.043),and arterial partial pressure of oxygen (81.0±12.1 mmHg vs 90.1±12.8 mmHg;P=0.004).Whole-body uptake was significantly higher in patients with IPVD than in patients without IPVD (48.0%±6.1%vs 40.1%±8.1%;P=0.001).The area under the curve of whole-body uptake for detecting IPVD was significantly higher than that of brain uptake (0.75 vs 0.54;P=0.025).The optimal cut-off values of brain uptake and whole-body uptake for detecting IPVD were 5.7%and 42.5%,respectively,based on Youden’s index.The sensitivity,specificity,and accuracy of brain uptake> 5.7%and whole-body uptake> 42.5%for detecting IPVD were23%,89%,and 59%and 100%,52%,and 74%,respectively.CONCLUSION Whole-body uptake is superior to brain uptake for diagnosing HPS.

Metabolomic fingerprinting of porcine lung tissue during pre-clinical prolonged ex vivo lung perfusion using in vivo SPME coupled with LC-HRMS

Normothermic ex vivo lung perfusion(NEVLP)has emerged as a modernized organ preservation technique that allows for detailed assessment of donor lung function prior to transplantation.The main goal of this study was to identify potential biomarkers of lung function and/or injury during a prolonged(19 h)NEVLP procedure using in vivo solid-phase microextraction(SPME)technology followed by liquid chromatography-high resolution mass spectrometry(LC-HRMS).The use of minimally invasive in vivo SPME fibers for repeated sampling of biological tissue permits the monitoring and evaluation of biochemical changes and alterations in the metabolomic profile of the lung.These in vivo SPME fibers were directly introduced into the lung and were also used to extract metabolites(on-site SPME)from fresh perfusate samples collected alongside lung samplings.A subsequent goal of the study was to assess the feasibility of SPME as an in vivo method in metabolomics studies,in comparison to the traditional inlab metabolomics workflow.Several upregulated biochemical pathways involved in pro-and antiinflammatory responses,as well as lipid metabolism,were observed during extended lung perfusion,especially between the 11th and 12th hours of the procedure,in both lung and perfusate samples.However,several unstable and/or short-lived metabolites,such as neuroprostanes,have been extracted from lung tissue in vivo using SPME fibers.On-site monitoring of the metabolomic profiles of both lung tissues through in vivo SPME and perfusate samples on site throughout the prolonged NEVLP procedure can be effectively performed using in vivo SPME technology.

Correlation between Automated Quantification of Lung Perfusion Blood Volume (PBV) and Pulmonary Artery Pressure

Purpose: Dual-energy CT (DECT) can be used for quantification of lung perfusion blood volume (PBV), allowing objective evaluation. However, no reports have investigated pulmonary perfusion correlating with pulmonary artery pressure (PAP) in patients with chronic pulmonary diseases. The purpose was to evaluate automated quantification of the lung PBV using dual-energy CT, and its correlation with PAP. Methods: 274 patients who underwent echocardiography within two weeks also underwent CT. The population was divided into high (&ge;40 mmHg) and low (<40 mmHg) estimated systolic PAP (sPAP) groups (n = 63 and n = 211, respectively). We retrospectively eva-luated the lung PBV using Syngo software, and correlations between the lung PBV and estimated sPAP. Results: Lung PBV values were 25.0 ± 9.6 and 29.0 ± 9.3 Hounsfield units (HU) in high and low sPAP groups, respectively, with a significant difference between them (p = 0.003). In the high sPAP group with underlying lung diseases (n = 15), chronic thromboembolism (n = 25), pulmonary artery stenosis (n = 12), and left heart failure (n = 11), using the Dana Point classification system, lung PBV values were 18.6 ± 1.6, 25.1 ± 4.5, 25.8 ± 4.5, and 32.7 ± 9.4 HU, respectively. There were significant differences in quantification of the lung PBV among them. The mean sPAP of subjects with left heart failure was significantly higher than in the others. In subjects with left heart failure, a positive correlation between the lung PBV value and sPAP was noted (R = 0.721, p < 0.0001). Conclusions: Automated quantification of the lung PBV may estimate the high sPAP. The lung PBV may contribute to clarifying the etiology of a high PAP due to left heart failure.

Improving lung allograft function in the early post-operative period through the inhibition of pyroptosis

Lung transplantation is the only definitive ther-apy for end-stage pulmonary disease.Less than 20%of offered lungs are successfully transplanted due to a limited ischemic time window and poor donor lung quality man-ifested by pulmonary edema,hypoxia,or trauma.Therefore,poor donor organ recovery and utilization are significant barriers to wider implementation of the life-saving therapy of transplantation.While ischemia reperfusion injury(IRI)is often identified as the underlying molecular insult leading to immediate poor lung function in the post-operative period,this injury encompasses several pathways of cellular injury in addition to the recruitment of the innate immune system to the site of injury to propagate this inflammatory cascade.Pyroptosis is a central molecular inflammatory pathway that is the most significant contributor to injury in this early post-operative phase.Pyroptosis is another form of pro-grammed cell death and is often associated with IRI.The mitigation of pyroptosis in the early post-operative period following lung transplantation is a potential novel way to prevent poor allograft function and improve outcomes for all recipients.Here we detail the pyroptotic pathway,its importance in lung transplantation,and several therapeutic modalities that can mitigate this harmful inflammatory pathway.

Hepatopulmonary syndrome: What we know and what we would like to know

Hepatopulmonary syndrome (HPS) is characterized by abnormalities in blood oxygenation caused by the presence of intrapulmonary vascular dilations (IPVD) in the context of liver disease, generally at a cirrhotic stage. Knowledge about the subject is still only partial. The majority of the information about the etiopathogenesis of HPS has been obtained through experiments on animals. Reported prevalence in patients who are candidates for a liver transplantation (LT) varies between 4% and 32%, with a predominance of mild or moderate cases. Although it is generally asymptomatic it does have an impact on their quality of life and survival. The diagnosis requires taking an arterial blood gas sample of a seated patient with alveolar-arterial oxygen gradient (AaO2) ≥ 15 mm Hg, or ≥ 20 mm Hg in those over 64 years of age. The IPVD are identified through a transthoracic contrast echocardiography or a macroaggregated albumin lung perfusion scan (99mTc-MAA). There is currently no effective medical treatment. LT has been shown to reverse the syndrome and improve survival rates, even in severe cases. Therefore the policy of prioritizing LT would appear to increase survival rates. This paper takes a critical and clinical look at the current understanding of HPS, as well as the controversies surrounding it and possible future research.

PULMONARY BLOOD DISTRIBUTION AFTER TOTAL CAVOPULMONARY CONNECTION OF DIFFERENT TYPES

Objective.To assess the feature of pulmonary blood flow distribution after total cavopulmonary connection(TCPC)of different types,and to provide the selection of the best type.Methods. Thirty-two consecutive survival patients after TCPC underwent radionuclide lung perfusion imaging. According to the radionuclide counts in the left and right lungs,analyses of the distribution of blood flow from superior venous cava(SVC) and inferior venous cava(IVC)and the whole pulmonary blood flow in both lungs were made. All patients were divided into 4 groups by the the anastomosis between IVC and pulmonary artery.Results. GroupⅠ:The flow ratio of the IVC to left lung was greater than that to the right lung,P≤0.01;the flow ratio of the SVC to right lung was greater than that to the left lung,P≤0.01;and the whole pulmonary blood flow went dominantly to the left lung,P≤0.05,which is not in line with physiological distribution. GroupⅡ:the flows from the SVC and IVC were mixed in the middle of the junction and ran evenly into the right and left lungs,the whole pulmonary blood flow went to both lungs,P≥0.05. Group Ⅲ:the flow ratio of the SVC to both lungs were the same,P≥0.05,and major part from IVC went to the right lung,P≤0.01;the pulmonary blood flow go dominantly to the right lung,P≤0.05,which is in accord with physiological distribution. Group Ⅳ:the flows from the right SVC went to right lung by 100%,P≤0.01,and that from the left SVC went to left lung by 100% too,P≤0.01;the flows from IVC went dominantly to the left lung,with little part to the right lung ,P≤0.05.Conclusions. Different types of TCPC can result in different pulmonary blood distributions. The best flow distribution between the left and right lungs can be obtained by an offset of the IVC anastomosis toward the RPA with widening anastomosis for the patients without persist left superior venous cava(PLSVC).

Protection of lung function by introducing single photon emission computed tomography lung perfusion image into radiotherapy plan of lung cancer

Background The lung functional status could be displayed on lung perfusion images. With the images, the radiotherapy plans of lung cancer could be guided to more optimized. This study aimed to assess quantitatively the impact of incorporating functional lung imaging into 3-dimensional conformal radiotherapy （3DCRT） and intensity-modulated radiation therapy （IMRT） planning for non-small cell lung cancer （NSCLC）. Methods Ten patients with NSCLC who had undergone radiotherapy were included in this study. Before radiotherapy, each patient underwent CT simulation and lung perfusion imaging with single photon emission computed tomography （SPECT）. The SPECT images were registered with simulation planning CT and used to contour functional lung （lung-F） and non-functional lung （lung-NF）. Two 3DCRT plans and two IMRT plans were designed and compared in each patient： two anatomic plans using simulation CT alone and two functional plans using SPECT-CT in addition to the simulation CT. Dosimetric parameters of the four types of plans were compared in terms of tumor coverage and avoidance of normal tissues. Total radiation dose was set at 66 Gy （2 Gyx33 fractions）. Results In incorporating perfusion information in 3DCRT and IMRT planning, the reductions on average in the mean doses to the functional lung in the functional plan were 168 cGy and 89 cGy, respectively, compared with those in the anatomic plans. The median reductions in the percentage of volume irradiated with 〉5 Gy, 〉10 Gy, 〉20 Gy, 〉30 Gy and 〉40 Gy for functional lung in the functional plans were 6.50%, 10.21%, 14.02%, 22.30% and 23.46% in 3DCRT planning, respectively, and 3.05%, 15.52%, 14.16%, 4.87%, and 3.33% in IMRT planning, respectively. No greater degree of sparing of the functional lung was achieved in functional IMRT than in 3DCRT. Conclusion Function-guided 3DCRT and IMRT plannings both appear to be effective in preserving functional lung in NSCLC patients.