Pulmonary artery sarcoma and severe valvular diseases in late-septuagenarian women: was 2-stage surgery an appropriate strategy? A case report.

BACKGROUND: Pulmonary artery sarcomas (PASs) are rare, and complete tumor resection is often difficult at the time of detection. We encountered a case of PAS that was thought to be resectable; however, the patient had severe symptomatic valvular disease. We faced a difficult decision regarding the surgical strategy. CASE PRESENTATION: A 76-year-old female presented with a history of polysurgery for multiple primary cancers. She was referred to our department with a calcified mass in the right pulmonary artery (PA) and severe symptomatic valvular disease. After a discussion with the cardiovascular surgeon, we decided to perform a two-stage surgery. She underwent valvuloplasty through a median sternotomy, resulting in an improvement in her exertional dyspnea. The tumor was removed three months later with a right upper lobectomy and PA patch reconstruction through a posterolateral thoracotomy. When the PA was opened, the edge of the tumor was entrapped by vascular clamp forceps because of insufficient dissection of the adhesions between the superior vena cava and the right main PA resulting from the first operation. The patient underwent proton therapy twice for chest wall metastases which recurred three months after surgery, and local recurrence in the PA was diagnosed five months after surgery. The patient was alive with stable disease 25 months after surgery. CONCLUSION: Two-stage surgery for PAS and valvular disease resulted in incomplete resection of the PAS in the right PA. It is important not to underestimate surgical adhesions due to the initial surgery and to consider and implement measures to prevent adhesions of critical vessels during the second operation.

Relationship between changes in pulmonary function and patient-reported outcomes of lung cancer surgery.

PURPOSE: To investigate the relationship between changes in pulmonary function (PF) and patient-reported outcomes (PROs) of lung cancer surgery. METHODS: We recruited 262 patients who underwent lung resection for lung cancer, to evaluate the PROs, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the Lung Cancer 13-question supplement (LC13). The patients underwent PF tests and PRO assessments preoperatively (Pre) and 1 year after surgery (Y1). Changes were calculated by subtracting the value at Pre from the value at Y1. We set two cohorts: patients under the ongoing protocol (Cohort 1) and patients who were eligible for lobectomy with clinical stage I lung cancer (Cohort 2). RESULTS: Cohorts 1 and 2 comprised 206 and 149 patients, respectively. In addition to dyspnea, changes in PF were also correlated with scores for global health status, physical and role function scores, fatigue, nausea and vomiting, pain, and financial difficulties. Absolute correlation coefficient values ranged from 0.149 to 0.311. Improvement of emotional and social function scores was independent of PF. Sublobar resection preserved PF more than lobectomy did. Wedge resection mitigated dyspnea in both cohorts. CONCLUSION: The correlation between PF and PROs was found to be weak; therefore, further studies are needed to improve the patient's postoperative experience.

Comparison of patient-reported outcomes and clinical outcomes between pleurectomy and pleural covering added to thoracoscopic bullectomy for primary spontaneous pneumothorax.

Background: An optimal surgical procedure for primary spontaneous pneumothorax (PSP) has not yet been established. The study aimed to compare patient-reported outcomes (PROs) and clinical outcomes between parietal pleurectomy (pleurectomy) and visceral pleural covering with absorbable prosthesis (covering) added to thoracoscopic bullectomy in patients with PSP. Methods: From January 2015 to April 2018, PROs were prospectively evaluated using EuroQOL-5 dimensions-5 levels (EQ5D). Questionnaires were administered preoperatively and at 1, 3, and 5 days and 1 month postoperatively. The perioperative outcomes were compared retrospectively. Recurrences and postoperative symptoms in the distant period were investigated cross-sectionally by telephone and mail surveys in February 2020. Results: In total, 26 and 29 patients underwent covering and pleurectomy, respectively. The visual analog scale score of the EQ5D on postoperative day 1 was significantly better in the pleurectomy group than in the covering group. There was no significant difference in the frequency of PROs in the EQ5D including pain. Perioperative outcomes, such as postoperative chest tube placement, and hospital stay, were comparable between the groups, except for the operative time. There was no significant difference in the recurrence rate and frequency of residual symptoms, e.g., chest discomfort in the long-term outcomes. Conclusions: PROs and clinical outcomes were comparable between the two procedures. Further studies are required to determine the optimal treatment procedure.

Mutations in RZF1, a zinc-finger protein, reduce magnesium uptake in roots and translocation to shoots in rice.

Magnesium (Mg) homeostasis is critical for maintaining many biological processes, but little information is available to comprehend the molecular mechanisms regulating Mg concentration in rice (Oryza sativa). To make up for the lack of information, we aimed to identify mutants defective in Mg homeostasis through a forward genetic approach. As a result of the screening of 2,825 M2 seedlings mutated by ion-beam irradiation, we found a rice mutant that showed reduced Mg content in leaves and slightly increased Mg content in roots. Radiotracer 28Mg experiments showed that this mutant, named low-magnesium content 1 (LMGC1), has decreased Mg2+ influx in the root and Mg2+ translocation from root to shoot. Consequently, LMGC1 is sensitive to the low Mg condition and prone to develop chlorosis in the young mature leaf. The MutMap method identified a 7.4-kbp deletion in the LMGC1 genome leading to a loss of two genes. Genome editing using CRISPR-Cas9 further revealed that one of the two lost genes, a gene belonging to the RanBP2-type zinc-finger family that we named RanBP2-TYPE ZINC FINGER1 (OsRZF1), was the causal gene of the low Mg phenotype. OsRZF1 is a nuclear protein and may have a fundamental role in maintaining Mg homeostasis in rice plants.

Trace Metal Impurities Effects on the Formation of [64Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM).

[64Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM) is a radioactive hypoxia-targeting therapeutic agent being investigated in clinical trials for malignant brain tumors. For the quality management of [64Cu]Cu-ATSM, understanding trace metal impurities' effects on the chelate formation of 64Cu and ATSM is important. In this study, we conducted coordination chemistry studies on metal-ATSM complexes. First, the effects of nonradioactive metal ions (Cu2+, Ni2+, Zn2+, and Fe2+) on the formation of [64Cu]Cu-ATSM were evaluated. When the amount of Cu2+ or Ni2+ added was 1.2 mol or 288 mol, equivalent to ATSM, the labeling yield of [64Cu]Cu-ATSM fell below 90%. Little effect was observed even when excess amounts of Zn2+ or Fe2+ were added to the ATSM. Second, these metals were reacted with ATSM, and chelate formation was measured using ultraviolet-visible (UV-Vis) absorption spectra. UV-Vis spectra showed a rapid formation of Cu2+ and the ATSM complex upon mixing. The rate of chelate formation by Ni2+ and ATSM was lower than that by Cu-ATSM. Zn2+ and Fe2+ showed much slower reactions with the ATSM than Ni2+. Trace amounts of Ni2+, Zn2+, and Fe2+ showed little effect on [64Cu]Cu-ATSM' quality, while the concentration of impurity Cu2+ must be controlled. These results can provide process management tools for radiopharmaceuticals.

Preparation of Highly Stable Oil-in-Water Emulsions with High Ethanol Content Using Polyglycerol Monofatty Acid Esters as Emulsifiers.

Oil-in-water (O/W) emulsions containing ethanol have been used in food, cosmetics, paints, and other applications. However, O/W emulsions with long-term stability are difficult to produce at high ethanol concentrations because the adsorption of the emulsifier at the O/W interface is restricted by ethanol. In this study, to resolve this issue, we prepared ethanol-containing O/W emulsions with high dispersion stability using a series of polyglycerol monofatty acid esters (PGFEs) with different fatty acid chain lengths, which are bio-safe nonionic surfactants, as emulsifiers. First, aqueous PGFE solutions containing 0-50 wt% ethanol were prepared and then O/W emulsions were formed using limonene as the oil phase. When decaglycerol stearic acid ester (DGMS, C18) was used as the emulsifier, an O/W emulsion with fine droplets (~30 nm in size) was successfully obtained at an ethanol concentration of 35 wt%. This emulsion remained stable for more than four weeks, during which no phase separation occurred, indicating its high dispersion stability. Furthermore, aqueous DGMS solutions containing 30-40 wt% ethanol were viscous, and a lamellar liquid crystal phase was observed to be dispersed in these solutions. The formation of this lamellar liquid crystal phase at the O/W interface led to an interfacial film with superior viscoelastic properties. The results suggested that the stability of the emulsions was determined by the balance between the decrease in interfacial tension caused by the addition of ethanol and the density (rigidity) of the DGMS film formed at the O/W interface. Finally, to further improve the dispersion stability of the ethanol-containing O/W-type emulsions, O/W emulsions were prepared using a mixture of two PGFEs with different degrees of glycerol polymerization, that is, systems having different hydrophilic-lipophilic balance values.

Whole-body PET tracking of a d-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.

Mutagenesis analysis of GMN motif in Arabidopsis thaliana Mg2+ transporter MRS2-1.

Magnesium is an important nutrient for plants, but much is still unknown about plant Mg2+ transporters. Combining with the structural prediction of AlphaFold2, we used mutagenesis and 28Mg uptake assay to study the highly conserved "GMN" motif of Arabidopsis thaliana MRS2-1 (AtMRS2-1) transporter. We demonstrated that the glycine and methionine in GMN motif are essential for AtMRS2-1 to transport Mg2+.

Risk of stroke even after dissipation of a thrombus in the pulmonary vein stump after lobectomy: A case report.

INTRODUCTION AND IMPORTANCE: Thrombosis in the pulmonary vein stump (PVS) after lung resection has been reported as a cause of cerebral infarction (CI). However, there is limited research focusing on thrombosis in the PVS. Although anticoagulant therapy is performed in clinical settings, the optimal duration of anticoagulant therapy is not established. In addition, no case leading to CI after withdrawal of the anticoagulant therapy has been reported. CASE PRESENTATION: An 81-year-old woman with lung cancer underwent left lower lobectomy. Since a thrombus was detected in the PVS 6 months after the operation, anticoagulant therapy was started. The thrombus disappeared 1 month later, and the medication was discontinued. However, only 23 days after discontinuation, the patient developed CI. CLINICAL DISCUSSION: This case was considered as cardiogenic CI due to a thrombus in the PVS because of the presence of the past thrombus, the distribution of infarction, and the absence of atrial fibrillation. The length of PVS in this case was longer than that reported previously, which could have caused turbulence and congestion leading to thrombogenesis. As long as patients have a long neck PVS, there might be a potential risk of thrombosis. CONCLUSION: We must recognize the risks associated with the discontinuation of anticoagulant therapy for thrombosis in PVS even after thrombus dissipation.

Development of a Stable Peptide-Based PET Tracer for Detecting CD133-Expressing Cancer Cells.

CD133 has been recognized as a prominent biomarker for cancer stem cells (CSCs), which promote tumor relapse and metastasis. Here, we developed a clinically relevant, stable, and peptide-based positron emission tomography (PET) tracer, [64Cu]CM-2, for mapping CD133 protein in several kinds of cancers. Through the incorporation of a 6-aminohexanoic acid (Ahx) into the N terminus of a CM peptide, we constructed a stable peptide tracer [64Cu]CM-2, which exhibited specific binding to CD133-positive CSCs in multiple preclinical tumor models. Both PET imaging and ex vivo biodistribution verified the superb performance of [64Cu]CM-2. Furthermore, the matched physical and biological half-life of [64Cu]CM-2 makes it a state-of-the-art PET tracer for CD133. Therefore, [64Cu]CM-2 PET may not only enable the longitudinal tracking of CD133 dynamics in the cancer stem cell niche but also provide a powerful and noninvasive imaging tool to track down CSCs in refractory cancers.

Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma.

The prognosis of advanced mesothelioma is poor. Podoplanin (PDPN) is highly expressed in most malignant mesothelioma. This study aimed to evaluate the potential alpha-radioimmunotherapy (RIT) with a newly developed anti-PDPN antibody, NZ-16, compared with a previous antibody, NZ-12. METHODS: The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. The absorbed doses were estimated based on biodistribution data. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. Histologic analysis was conducted. RESULTS: The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12, providing higher absorbed doses to tumors. RIT with 225Ac- and 90Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-12. 225Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than 90Y-labeled NZ-16. There is no obvious adverse effect. CONCLUSIONS: Alpha-RIT with the newly developed NZ-16 is a promising therapeutic option for malignant mesothelioma.

Cyclotron production of 225Ac from an electroplated 226Ra target.

PURPOSE: We demonstrate cyclotron production of high-quality 225Ac using an electroplated 226Ra target. METHODS: 226Ra was extracted from legacy Ra sources using a chelating resin. Subsequent ion-exchange purification gave pure 226Ra with a certain amount of carrier Ba. The radium target was prepared by electroplating. We successfully deposited about 37 MBq of 226Ra on a target box. Maximum activation was achieved using 15.6 MeV protons on the target at 20 µA for 5 h. Two functional resins with various concentrations of nitric acid purified 225Ac and recovered 226Ra. Cooling the intermediate 225Ac for 2-3 weeks decayed the major byproduct of 226Ac and increased the radionuclidic purity of 225Ac. Repeating the same separation protocol provided high-quality 225Ac. RESULTS: We obtained 225Ac at a yield of about 2.4 MBq at the end of bombardment (EOB), and the subsequent initial purification gave 1.7 MBq of 225Ac with 226Ac/225Ac ratio of < 3% at 4 days from EOB. Additional cooling time coupled with the separation procedure (secondary purification) effectively increased the 225Ac (4n + 1 series) radionuclidic purity up to 99 + %. The recovered 225Ac had a similar identification to commercially available 225Ac originating from a 229Th/225Ac generator. CONCLUSION: This procedure, which involves the 226Ra(p,2n)225Ac reaction and the appropriate purification, has the potential to be a major alternative pathway for 225Ac production because it can be performed in any facility with a compact cyclotron to address the increasing demand for 225Ac.

Preoperative predictors of restoration in quality of life after surgery for lung cancer.

BACKGROUND: The preoperative predictors of quality of life (QOL) in patients who undergo lung resection for lung cancer are poorly known. Here, we investigated these predictors in such patients using two QOL measures. METHODS: In this single-institutional prospective cohort study, we administered the EQ-5D-5 levels (EQ-5D-5L) from January 2015, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire with 30 items from April 2015 to April 2018 preoperatively (Pre) and at one month postoperatively (M1), and one year postoperatively (Y1). General health status was measured by the EQ-5D visual analogue scale (VAS) and EORTC global health status/QOL (GHS) scores. Multivariable linear regression analyses were used to explore the preoperative predictors of QOL at Y1. RESULTS: A total of 223 patients were included in the study. The EQ-5D VAS and EORTC GHS scores, at Pre, M1, and Y1, were 80 ± 15, 77 ± 15, and 84 ± 11; and 74 ± 19, 65 ± 20, and 78 ± 17, respectively. In the multivariable analyses, the albumin level, preoperative VAS score, and preoperative pain/discomfort and anxiety/depression were identified as predictors by the EQ-5D VAS score. The preoperative EORTC GHS score, absence of diabetes mellitus, preoperative cognitive function score, and preoperative symptom score of pain were identified as predictors by the EORTC GHS score. CONCLUSIONS: The EQ-5D VAS and EORTC GHS scores traced similar trajectories of QOL. In both QOL measures, preoperative pain was found as a common predictor. These predictors may help improve patient/survivor care in the future.

A population-based study of outcomes in patients with surgically resected non-small cell lung cancer with anaplastic lymphoma kinase-rearranged mutations: A matched-pair study.

The present study aimed to evaluate clinical outcomes in patients with surgically resected non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK)-rearranged mutations. A matched-pair analysis in completely resected ALK-rearranged NSLC patients and those with neither ALK nor epidermal growth factor receptor (EGFR) mutations diagnosed at 11 institutes was performed between April 2008 and March 2019. A total of 51 patients with surgically resected ALK-rearranged NSCLC were included. Women constituted 68.6%, and smokers 29.4%. The median age was 65 years. In matched-pair analysis, disease-free survival and overall survival did not differ between patients with ALK-rearranged mutations and those without mutations. Post-recurrence survival in patients with ALK mutations was longer than that of patients with neither ALK nor epidermal growth factor receptor mutations. ALK genetic testing should be performed, even in elderly patients with NSCLC. Favorable prognosis might be expected after appropriate treatment for patients with recurrent ALK-mutated disease.

Delayed postoperative bleeding following lobectomy caused by the sharp tip of a suture: a case report.

BACKGROUND: Postoperative bleeding is a rare but serious complication occasionally caused by hard surgical materials, such as staples. Postoperative hemorrhage caused by sutures is very rare. CASE PRESENTATION: A 75-year-old man with lung cancer underwent right lower lobectomy. Eleven days after surgery, he developed a haemothorax. Emergency thoracotomy revealed arterial bleeding from a pinhole injury in the parietal pleura caused by a monofilament non-absorbable suture tip used during the initial surgery. CONCLUSIONS: Postoperative bleeding is a serious complication, and as sutures are often used in surgery, it is important to be cautious while using this material.

Treatment of Patients With Non-small-cell Lung Cancer With Uncommon EGFR Mutations in Clinical Practice.

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.

Treatment of an Aberrant Arterial Aneurysm with Intralobar Pulmonary Sequestration: A Case Report.

An aberrant arterial aneurysm with pulmonary sequestration is rare. Here, we report about a 35-year-old man who had no symptoms related to pulmonary sequestration. Computed tomography revealed an aberrant arterial aneurysm with an 18 mm in diameter with intralobar pulmonary sequestration, which gradually increased in size to 27 mm over 5 years. The patient underwent thoracic endovascular aortic repair with coil embolization for the aneurysmal distal branches to prevent aneurysm rupture. The postoperative course was unremarkable without a need for lobectomy. During a 1-month follow-up period, the aneurysm shrunk with no endoleaks. Stent-graft placement and coil embolization represent an effective and less invasive treatment option to completely block systemic arterial flow and unexpected retrograde backflow and control the expansion of the aneurysm.

Marriage of black phosphorus and Cu2+ as effective photothermal agents for PET-guided combination cancer therapy.

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu2+-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu2+ into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing 64Cu2+, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.

Structural Characterization of a Cyclodextrin/l-menthol Inclusion Complex in the Solid-state by Solid-state NMR and Vibrational Circular Dichroism.

Hydrophobic and volatile flavor molecules can be encapsulated inside cyclodextrins (CyDs). Inclusion complexes are frequently used in solid or dispersed states in preserved food and cosmetics. In this study, the solid-state structures of spray-dried inclusion complexes of l-menthol in α-CyD and ß-CyD were analyzed using 13C solid-state NMR and vibrational circular dichroism (VCD). The NMR signals of l-menthol and CyDs were identified in the physical mixture and the l-menthol inclusion complex of α- and ß-CyD. The NMR signal of the isopropyl-methyl group of menthol in the α-CyD inclusion complex exhibited a large low-field shift, which suggested a steric hindrance between menthol and α-CyD. VCD exhibited specific changes in the intensity of bands corresponding to C-C vibrations in α-CyD and O-C stretching vibrations in l-menthol. Our results indicated that l-menthol specifically fitted the narrow space within α-CyD. The combined solid-state NMR and VCD analysis provided structural insights into the flavor inclusion complex in the solid-state.

Short-Term Magnesium Deficiency Triggers Nutrient Retranslocation in Arabidopsis thaliana.

Magnesium (Mg) is essential for many biological processes in plant cells, and its deficiency causes yield reduction in crop systems. Low Mg status reportedly affects photosynthesis, sucrose partitioning and biomass allocation. However, earlier physiological responses to Mg deficiency are scarcely described. Here, we report that Mg deficiency in Arabidopsis thaliana first modified the mineral profile in mature leaves within 1 or 2 days, then affected sucrose partitioning after 4 days, and net photosynthesis and biomass production after 6 days. The short-term Mg deficiency reduced the contents of phosphorus (P), potassium, manganese, zinc and molybdenum in mature but not in expanding (young) leaves. While P content decreased in mature leaves, P transport from roots to mature leaves was not affected, indicating that Mg deficiency triggered retranslocation of the mineral nutrients from mature leaves. A global transcriptome analysis revealed that Mg deficiency triggered the expression of genes involved in defence response in young leaves.