Orthotopic transplantation of the bioengineered lung using a mouse-scale perfusion-based bioreactor and human primary endothelial cells.

Whole lung engineering and the transplantation of its products is an ambitious goal and ultimately a viable solution for alleviating the donor-shortage crisis for lung transplants. There are several limitations currently impeding progress in the field with a major obstacle being efficient revascularization of decellularized scaffolds, which requires an extremely large number of cells when using larger pre-clinical animal models. Here, we developed a simple but effective experimental pulmonary bioengineering platform by utilizing the lung as a scaffold. Revascularization of pulmonary vasculature using human umbilical cord vein endothelial cells was feasible using a novel in-house developed perfusion-based bioreactor. The endothelial lumens formed in the peripheral alveolar area were confirmed using a transmission electron microscope. The quality of engineered lung vasculature was evaluated using box-counting analysis of histological images. The engineered mouse lungs were successfully transplanted into the orthotopic thoracic cavity. The engineered vasculature in the lung scaffold showed blood perfusion after transplantation without significant hemorrhage. The mouse-based lung bioengineering system can be utilized as an efficient ex-vivo screening platform for lung tissue engineering.

Long-term survival and clinical outcomes of delayed chest closure following lung transplantation.

PURPOSES: Delayed chest closure (DCC) is a widely accepted procedure in the context of lung transplantation (LTx); yet there are few reports detailing its long-term survival and clinical outcomes. METHODS: We reviewed the medical records of recipients who underwent deceased-donor lung transplantation (LTx) at Tohoku University Hospital. Long-term survival, including overall survival, freedom from chronic lung allograft dysfunction (CLAD), and CLAD-free survival and the clinical outcomes of graft function and physical performance and constitution were reviewed in recipients with DCC. RESULTS: Between 2009 and 2022, 116 patients underwent LTx, 33 of whom (28.4%) required DCC. The intra-and post-operative courses of the recipients who required DCC were more complicated than those of the recipients who underwent primary chest closure (PCC), with frequent volume reduction surgery and longer periods of invasive mechanical ventilation. Pulmonary vascular disease was considered a risk factor for these complications and DCC. Nonetheless, long-term survival and graft functions were comparable between the DCC and PCC groups. The physical performance and constitution of recipients who required DCC continued to improve, and by 2 years after transplantation, exhibited almost no difference from those who underwent PCC. CONCLUSIONS: In view of the profoundly complicated intra- and post-operative courses, DCC should be performed cautiously and only when clinically indicated, despite which it can result in equivalent long-term survival and acceptable outcomes to PCC.

A Single-Center Analysis of How HLA Mismatch and Donor-Specific Antibodies Affect Short-Term Outcome After Lung Transplantation: A Pilot Study Before a Country-Wide Histocompatibility Study in Japan.

BACKGROUND: Analyzing HLA polymorphism in lung transplantation (LTx) is important, given its impact on LTx recipient survival and graft function. Accordingly, we conducted a retrospective study to examine the influence of HLA mismatch and donor-specific antibodies (DSA) on short-term outcomes and early-phase post-LTx complications. METHOD: HLA antigen or eplet mismatch in LTx patients at Tohoku University Hospital from 2018 to 2023 was determined, and DSA was measured on admission for surgery to identify preformed DSA and at weeks 4 to 12 post-LTx for de novo DSA, respectively. RESULTS: The participants were 45 LTx recipients, HLA-A/B/DR antigen mismatch (5-6 of 6) being identified in 57%, HLA-A/B/Cw/DR/DQ mismatch (8-10 of 10) in 57%, and HLA eplet mismatch (>61) in 46%. The prevalence of preformed DSA was 24%, and persistence (uncleared) was 16%. The incidence of de novo DSA was 16% after LTx. During the study,16 recipients experienced grade 3 primary graft dysfunction (PGD), 8 developed acute rejection, and 5 died. No HLA-related variables were significantly associated with post-LTx mortality and were not risk factors for high-grade PGD or acute rejection. CONCLUSION: Despite limitations in sample size, resulting in tentative findings, the study serves as a crucial pilot study for an ongoing multicenter prospective trial in Japan.

A comparative study of surgical outcomes for secondary spontaneous pneumothorax and the postoperative survival prognostic factor: interstitial vs. non-interstitial pneumonia.

PURPOSE: To investigate the surgical outcomes and postoperative survival prognostic factors of intractable secondary spontaneous pneumothorax. METHODS: A total of 95 patients who underwent thoracoscopic surgery for intractable secondary spontaneous pneumothorax between April 2010 and March 2020 were included in this study. These patients were classified into interstitial pneumonia and non-interstitial pneumonia groups, and a comparative study was performed on surgical outcomes and postoperative survival prognostic factors. RESULTS: There was no difference in the 1-year overall survival rate between the two groups. However, the 3-year overall survival rate was significantly lower in the interstitial pneumonia group than in the non-interstitial pneumonia group. The differences in short-term surgical outcomes (persistent air leakage, postoperative complications, etc.) were not significant between the two groups. Univariate analysis revealed that the drainage period, the development of postoperative complications, and recurrence were significant independent postoperative survival prognostic factors for all cases. Postoperative complications were the only associated postoperative survival prognostic factor for interstitial pneumonia pneumothorax in the multivariate analysis. CONCLUSION: The development of postoperative complications can cause poor postoperative survival prognosis of intractable secondary spontaneous pneumothorax due to interstitial pneumonia.

Single lung transplantation using a lung graft from a donor whose contralateral lung is not suitable for lung transplantation.

OBJECTIVE: This study aims to compare the post-transplant survival of untwinned single lung transplantation (SLT) to twinned SLT. In untwinned SLT, the contralateral lung is judged unsuitable for transplantation and might affect the lung graft within the donor body and recipient survival after SLT. METHODS: A retrospective analysis was conducted on 84 SLT recipients at our center, divided into untwinned SLT and twinned SLT groups. The demographics of donors and recipients, surgical characteristics, complications, mortality, and survival rates were compared. RESULTS: There were no significant differences in recipient and donor demographics between the two groups. Surgical characteristics showed no significant differences. Microbiological findings of the transplanted lungs indicated a low incidence of positive cultures in both groups. 3-month to 1-year mortality and overall survival rates were comparable between the two groups. CONCLUSION: At our institution, both untwinned and twinned SLT procedures exhibited excellent survival rates without significant differences between the two procedures. The favorable outcomes observed may be associated with the strategic advantages of Japan's MC system and the diligent management of marginal donor lungs although this requires further investigation to elucidate the specific contributory factors.

Selective miR-21 detection technology based on photocrosslinkable artificial nucleic acid-modified magnetic particles and hybridization chain reaction.

Recently, microRNA (miRNA) detection in blood has attracted attention as a new early detection technology for cancer. The extraction of target miRNA is a necessary preliminary step for detection; however, currently, most extraction methods extract all RNA from the blood, which limits the detection selectivity. Therefore, a method for the selective extraction and detection of target miRNA from blood is very important. In this study, we utilized photocrosslinkable artificial nucleic acids and the hybridization chain reaction (HCR) in an attempt to improve upon the current standard method RT-qPCR, which is hampered by problems with primer design and enzymatic amplification. By introducing photocrosslinkable artificial nucleic acids to oligonucleotide probes modified with magnetic particles with a sequence complementary to that of the target miRNA and irradiating them with light, covalent bonds were formed between the target miRNA and the oligonucleotide probes. These tight covalent bonds enabled the capture of miRNA in blood, and intensive washing ensured that only the target miRNA were extracted. After extraction, two types of DNA (H1 and H2) modified with fluorescent dyes were added and the fluorescence signals were amplified by the HCR in the presence of the target miRNA bound to the photocrosslinkable artificial nucleic acids, allowing for isothermal and enzyme-free miRNA detection. The novel method is suitable for selective miRNA detection in real blood samples. Because the reaction proceeds isothermally and no specialized equipment is used for washing, this detection technology is simple and selective and suitable for application to point-of-care technology using microfluidic devices.

[Perioperative Management in Lung Transplantation].

Lung transplantation is an established therapy for end-stage lung disease. However, donor shortage remains as a serious issue in Japan. Appropriate brain-dead donor management is the first step toward safe lung transplantation, and the perioperative management begins at the donor hospital. This article overviews the key points of perioperative management in lung transplantation, starting from the donor,the graft, followed by the recipient. Lung transplantation is not just about implanting lungs;it is also about "conditioning" the lungs to be fully functioned after transplantation. In addition to respiratory management, circulatory management, immunosuppressive therapy, and antimicrobial chemotherapy, physiotherapy and nutritional therapy to support them are all indispensable. In other words, it is a treatment including all aspects of surgical managements, which is why it is fascinating.

Systemic-to-pulmonary artery shunt treated with transcatheter arterial embolization and subsequent lung segmentectomy.

BACKGROUND: Systemic-to-pulmonary artery shunt (SPAS) is a rare condition that can occur as a result of congenital heart disease or chronic pulmonary inflammation, occasionally leading to life-threatening hemoptysis. Computed tomography (CT) imaging is crucial in the diagnosis of SPAS, and the optimal management approach for SPAS remains uncertain. This case report presents a novel approach to the treatment of SPAS, consisting of transcatheter arterial embolization of the systemic artery followed by lung segmentectomy. CASE PRESENTATION: A 42-year-old man with abnormal chest findings was referred to us and a diagnosis of SPAS was established based on the CT findings showing a blood flow regurgitation from the dilated left 4th intercostal artery to the Lt. A6. The patient was asymptomatic but we decided to treat him to prevent a risk of future hemoptysis. Transcatheter arterial embolization (TAE) of systemic arteries followed by S6 segmentectomy was successfully performed with minimal blood loss and complete removal of the dilated intra-pulmonary blood vessels. Histological analysis confirmed the diagnosis of SPAS. CONCLUSION: We reported a case of SPAS, who was successfully treated with the combination of TAE and subsequent segmentectomy. The blood loss during surgery was minimal and this strategy appeared to minimize future recanalization and hemoptysis. Further studies and long-term follow-up of SPAS patients are required to establish standardized management guidelines for this rare condition.

A straightforward guide to the swine left upper lobar transplant model: procedures and techniques.

With the rising demand for lung transplants, especially for adults with smaller chest cavities and children, a significant donor-recipient size mismatch challenge exists. A solution is lobar lung transplants from deceased donors with otherwise unsuitable lungs due to local damage. Despite its promise, early post-transplant mortality rates are comparatively high, emphasizing the need for meticulous donor selection and graft evaluation. This video tutorial introduces a detailed methodology for a porcine left upper lobar lung transplant model, from preoperative measures to reperfusion. Steps encompass preoperative measures, donor and recipient preparations, graft procurement and specific anastomosis procedures for the bronchus, pulmonary artery and left atrium. This guidance, derived from rigorous translational research, not only contributes to the knowledge of safe lobar lung transplants in animals but also promises potential implications for clinical practice.

Recurrent Lymphocytic Hypophysitis Presenting as Internal Carotid Artery Stenosis and Oculomotor Nerve Palsy.

A 75-year-old woman presented with nausea and vomiting. Magnetic resonance imaging (MRI) revealed that she had a pituitary mass. A biopsy revealed lymphocytic hypophysitis (LYH). Symptoms were improved by hormone replacement therapy. Although she was asymptomatic, follow-up MRI revealed an increase in the size of the mass. Intravenous methylprednisolone (IVMP) reduced the size of the mass; however, right ophthalmalgia and oculomotor nerve palsy developed. MRI showed that the pituitary mass had enlarged to the right oculomotor nerve in the cavernous sinus and to the right internal carotid artery (ICA), causing stenosis of the ICA. After IVMP administration, the symptoms dramatically improved, but ICA stenosis persisted.

Investigations of Shape Deformation Behaviors of the Ferromagnetic Ni-Mn-Ga Alloy/Porous Silicone Rubber Composite towards Actuator Applications.

Ferromagnetic shape memory alloys (FSMAs), which are potential candidates for future technologies (i.e., actuators in robots), have been paid much attention for their high work per volume and rapid response as external stimulation, such as a magnetic field, is imposed. Among all the FSMAs, the Ni-Mn-Ga-based alloys were considered promising materials due to their appropriate phase transformation temperatures and ferromagnetism. Nevertheless, their intrinsic embrittlement issue and sluggish twin motion due to the inhibition of grain boundaries restrict their practicability. This study took advantage of the single-crystal Ni-Mn-Ga cube/silicone rubber composite materials to solve the two aforementioned difficulties. The single-crystal Ni-Mn-Ga cube was prepared by using a high-temperature alloying procedure and a floating-zone (FZ) method, and the cubes were verified to be the near-{100}p Ni-Mn-Ga alloy. Various room temperature (RT) curing silicone rubbers were utilized as matrix materials. Furthermore, polystyrene foam particles (PFP) were used to provide pores, allowing a porous silicone rubber matrix. It was found that the elastic modulus of the silicone rubber was successfully reduced by introducing the PFP. Additionally, the magnetic field-induced martensite variant reorientation (MVR) was greatly enhanced by introducing a porous structure into the silicone rubber. The single-crystal Ni-Mn-Ga cube/porous silicone rubber composite materials are considered to be promising materials for applications in actuators.

Bilateral lung transplant with pulmonary artery reconstruction using donor aorta for pulmonary hypertension with a giant pulmonary arterial aneurysm.

OBJECTIVES: Standard bilateral lung transplantation (BLT) is not feasible for patients with pulmonary arterial hypertension (PAH) complicated with a giant pulmonary arterial aneurysm (PAA). This study aimed to describe the outcomes of BLT with pulmonary artery reconstruction (PAR) using donor aorta for such patients. METHODS: This is a retrospective single-centre study reviewing PAH patients with a PAA who received BLT with PAR using donor aorta from January 2010 through December 2020. We compared the characteristics and short- and long-term outcomes of recipients receiving PAR (PAR group) with those who had no PAA and received standard BLT (non-PAR group). RESULTS: Nineteen adult PAH patients underwent cadaveric lung transplantation during the study period. Among them, 5 patients with a giant PAA (median pulmonary artery trunk diameter, 69.9 mm) underwent BLT with PAR using donor aorta and the others received standard BLT. Although the operation time tended to be longer in the PAR group compared with the non-PAR group (1239 vs 958 mins, P = 0.087), 90-day mortality (PAR group: 0% vs non-PAR group: 14.3%, P > 0.99), and 5-year survival rate (PAR group: 100% vs non-PAR group: 85.7%, P = 0.74) was comparable between the groups. No dilatation, constriction or infection of the aortic grafts were recorded during the study period with a median follow-up time of 94 months in the PAR group. CONCLUSIONS: Lung transplantation with PAR using donor aorta is a valid surgical option for PAH patients complicated with a giant PAA.

Dosimetric analysis on computed tomography myelography based treatment planning in stereotactic body radiotherapy for spinal metastases.

This study aimed to quantitatively evaluate the influence of enhanced contrast on the CT myelography image of the spinal cord and/or cauda equina in addition to the target volume in spine SBRT treatment planning. In total, 19 patients who had previously undergone spine SBRT were randomly selected. The rigid image registration accuracy of CT myelography that aligned with the treatment planning CT was evaluated by calculating the normalized mutual information (NMI) and Pearson's correlation coefficient for the vertebral landmarks. At postregistration, the contrast-enhanced region of the CT myelography image was replaced with water-mass density, and the original treatment plan was recalculated on this image. For comparison, the dose was also recalculated on the contrast-enhanced CT myelography images. The NMI and Pearson's correlation coefficients for landmarks were 0.39 ± 0.12 and 0.97 ± 0.04, respectively. The mean D0.035cc of the spinal cord and/or cauda equina on the CT myelography image with the contrast-enhanced region replaced by water-mass density showed -0.37% ± 0.64% changes compared with that of the treatment planning CT. Conversely, the mean D0.035cc in contrast-enhanced CT myelography changed by -1.39% ± 0.51%. The percentage change in D98% for the planning target volume was confirmed to be small by replacing the contrast-enhanced region with water-mass density (p < 0.01). The dose calculation of the target volume, spinal cord, and/or cauda equina using the CT myelography image that replaced the contrast-enhanced region with water-mass density could be a more appropriate procedure with less dose calculation uncertainty.

Congenital Hypothyroidism in Two Sudanese Families Harboring a Novel Iodotyrosine Deiodinase Mutation (IYD R279C).

Background: Congenital hypothyroidism due to defects in iodotyrosine deiodinase has variable phenotypes and can present as hypothyroid or with normal thyroid testing. Methods: Whole exome sequencing was performed in individuals from two families originating from different regions of Sudan. Mass spectrometry of urine and serum iodotyrosines was performed on subjects from both families. Results: A novel iodotyrosine deiodinase (IYD) mutation (c.835C>T; R279C) was identified in individuals from two Sudanese families inherited as autosomal recessive. The mutation was identified by multiple in silica analyses to likely be detrimental. Serum and urine monoiodotyrosine (MIT) and diiodotyrosine (DIT) were markedly elevated in the homozygous subjects. Conclusion: Measurement of serum and urine DIT and MIT was more sensitive than that of urine iodine or serum thyroid function tests to determine the effect of the IYD mutation.

Efficacy and safety of mRNA SARS-CoV-2 vaccines in lung transplant recipients.

BACKGROUND: To date, reports addressing the antibody response following mRNA SARS-CoV-2 vaccination in lung transplant (LTX) recipients are limited. Thus, the aim of this clinical study was to investigate the efficacy and safety of the vaccines in LTX recipients compared to controls. METHODS: An open-label, nonrandomized prospective study was conducted at Tohoku University Hospital. LTX recipients and controls who received either the BNT162b2 vaccine or the mRNA-1273 vaccine were recruited, and SARS-CoV-2 IgG was measured before and after vaccination. The adverse events were reviewed. Predictors of negative serology after vaccination were evaluated with logistic regression. RESULTS: Forty-one LTX recipients and 24 controls were analyzed. Although all controls had a positive antibody response to a SARS-CoV-2 mRNA vaccine, antibody response was found in 24.4% of LTX recipients (p < .0001). The amount of SARS-CoV-2 IgG following the 2nd dose significantly climbed to 6557 AU/mL in controls, whereas the increase in IgG in LTX recipients was 8.3 AU/mL (p < .0001). Fewer LTX recipients developed systemic fever than controls (p < .0001) despite equivalent overall adverse event percentages in both groups. A higher plasma concentration of mycophenolate was a significant predictor of negative serology (p = .032). CONCLUSIONS: An impaired antibody response to mRNA vaccines was significantly found in LTX recipients compared to controls and was associated with the plasma concentration of mycophenolate. While repeating mRNA vaccination may be one of the strategies to improve antibody response given the safety of the vaccines, emerging data on humoral immune responses based on immunosuppression regimens in LTX recipients should be studied (jRCT1021210009).

Changes in haemodynamics during single lung transplantation under venovenous extracorporeal membrane oxygenation.

OBJECTIVES: The objective of the present study was to examine the effect of venovenous (VV) extracorporeal membrane oxygenation (ECMO) use on the haemodynamics during single lung transplantation (SLT) and postoperative course. METHODS: Forty-seven patients who underwent SLT for end-stage lung diseases in our lung transplant centre between January 2010 and December 2019 were included in this study. The recipients were divided into 3 groups according to the type of intraoperative ECMO. No type of ECMO was intra-operatively used in the patients of the no use of ECMO (NO ECMO) group. The patients in the venoarterial (VA) and VV ECMO groups were put on VA and VV ECMO during the surgery, respectively. The data were compared among the 3 groups. RESULTS: There were 13 SLT cases in the NO ECMO group, 23 SLT cases in the VA ECMO group and 11 SLT cases in the VV ECMO group. Re-exploration for bleeding was performed in 3 (13.0%) recipients in the VA ECMO group. No recipients required re-exploration in the other groups. In the NO ECMO group, systolic pulmonary arterial pressure (PAP) was significantly elevated during the main pulmonary artery clamp on the SLT side and it was decreased in the VA ECMO group because of the bypass flow. Interestingly, systolic PAP was significantly decreased in the VV ECMO group as well. CONCLUSIONS: VV ECMO decreases the PAP during SLT, which could be a choice for extracorporeal life support during lung transplant surgery for patients, even those with pulmonary hypertension.

Preoperative spirometry and BMI in deep inspiration breath-hold radiotherapy: the early detection of cardiac and lung dose predictors without radiation exposure.

BACKGROUND: This study aimed to investigate preoperative spirometry and BMI as early predictors of the mean heart and lung dose (MHD, MLD) in deep inspiration breath-hold (DIBH) radiotherapy. METHODS: Left-sided breast cancer patients underwent breast-conserving surgery followed by DIBH radiotherapy enrolled. Patients who were not available for preoperative spirometry were excluded. One hundred eligible patients were performed free-breathing (FB-) CT and DIBH-CT for plan comparison. We completed the correlative and multivariate analysis to develop the linear regression models for dose prediction. The residuals were calculated to explore the unpreferable subgroups and compare the prediction accuracy. RESULTS: Among the parameters, vital capacity (VC) and BMI showed the strongest negative correlation with MHD (r = - 0.33) and MLD (r = - 0.34), respectively. They were also significant in multivariate analysis (P < 0.001). Elderly and less VC were independent predictors of increasing absolute residuals (AR). The VC model showed no significant difference in AR compared to the model using the CT parameter of lung volume in FB (LV-FB): median AR of the LV-FB model vs. the VC model was 0.12 vs. 0.11 Gy (P = 0.79). On the other hand, the median AR of the MLD model was 0.38 Gy, showing no specific subgroups of larger AR. CONCLUSION: Preoperative spirometry and BMI are significant predictors of MHD and MLD, respectively. Although elderly and low-VC patients may have larger predictive variations, spirometry might be a substitute for LV-FB as a predictor of MHD.