Central Lung Research Articles

Long-Term Outcomes of Ablative Carbon-Ion Radiotherapy for Central Non-Small Cell Lung Cancer: A Single-Center, Retrospective Study.

The aim of this study is to assess the efficacy and safety of ablative carbon ion radiotherapy (CIRT) for early stage central non-small cell lung cancer (NSCLC). We retrospectively reviewed 30 patients who had received CIRT at 68.4 Gy in 12 fractions for central NSCLC in 2006-2019. The median age was 75 years, and the median Karnofsky Performance Scale score was 90%. All patients had concomitant chronic obstructive pulmonary disease, and 20 patients (67%) were considered inoperable. In DVH analysis, the median lung V5 and V20 were 15.5% and 10.4%, and the median Dmax, D0.5cc, D2cc of proximal bronchial tree was 65.6 Gy, 52.8 Gy, and 10.0 Gy, respectively. At a median follow-up of 43 months, the 3-year overall survival, disease-specific survival, and local control rates were 72.4, 75.8, and 88.7%, respectively. Two patients experienced grade 3 pneumonitis, but no grade ≥3 adverse events involving the mediastinal organs occurred. Ablative CIRT is feasible and effective for central NSCLC and could be considered as a treatment option, especially for patients who are intolerant of other curative treatments.

The bloodstream form of Trypanosoma brucei displays non-canonical gluconeogenesis.

Trypanosoma brucei is a causative agent of the Human and Animal African Trypanosomiases. The mammalian stage parasites infect various tissues and organs including the bloodstream, central nervous system, skin, adipose tissue and lungs. They rely on ATP produced in glycolysis, consuming large amounts of glucose, which is readily available in the mammalian host. In addition to glucose, glycerol can also be used as a source of carbon and ATP and as a substrate for gluconeogenesis. However, the physiological relevance of glycerol-fed gluconeogenesis for the mammalian-infective life cycle forms remains elusive. To demonstrate its (in)dispensability, first we must identify the enzyme(s) of the pathway. Loss of the canonical gluconeogenic enzyme, fructose-1,6-bisphosphatase, does not abolish the process hence at least one other enzyme must participate in gluconeogenesis in trypanosomes. Using a combination of CRISPR/Cas9 gene editing and RNA interference, we generated mutants for four enzymes potentially capable of contributing to gluconeogenesis: fructose-1,6-bisphoshatase, sedoheptulose-1,7-bisphosphatase, phosphofructokinase and transaldolase, alone or in various combinations. Metabolomic analyses revealed that flux through gluconeogenesis was maintained irrespective of which of these genes were lost. Our data render unlikely a previously hypothesised role of a reverse phosphofructokinase reaction in gluconeogenesis and preclude the participation of a novel biochemical pathway involving transaldolase in the process. The sustained metabolic flux in gluconeogenesis in our mutants, including a triple-null strain, indicates the presence of a unique enzyme participating in gluconeogenesis. Additionally, the data provide new insights into gluconeogenesis and the pentose phosphate pathway, and improve the current understanding of carbon metabolism of the mammalian-infective stages of T. brucei.

Stereotactic body radiotherapy of central lung tumours using a 1.5 T MR-linac: First clinical experiences

BackgroundMRI-guidance may aid better discrimination between Organs at Risk (OARs) and target volumes in proximity of the mediastinum. We report the first clinical experiences with Stereotactic Body Radiotherapy (SBRT) of (ultra)central lung tumours on a 1.5 T MR-linac. Materials and MethodsPatients with an (ultra)central lung tumour were selected for MR-linac based SBRT treatment. A T2-weighted 3D sequence MRI acquired during free breathing was used for daily plan adaption. Prior to each fraction, contours of Internal Target Volume (ITV) and OARs were deformably propagated and amended by a radiation oncologist. Inter-fractional changes in volumes and coverage of target volumes as well as doses in OARs were evaluated in offline and online treatment plans. ResultsTen patients were treated and completed 60 Gy in 8 or 12 fractions. In total 104 fractions were delivered. The median time in the treatment room was 41 min with a median beam-on time of 8.9 min. No grade ≥3 acute toxicity was observed. In two patients, the ITV significantly decreased during treatment (58 % and 37 %, respectively) due to tumour shrinkage. In the other patients, 81 % of online ITVs were within ±15 % of the volume of fraction 1. Comparison with the pre-treatment plan showed that ITV coverage of the online plan was similar in 52 % and improved in 34 % of cases. Adaptation to meet OAR constraints, led to decreased ITV coverage in 14 %. ConclusionsWe describe the workflow for MR-guided Radiotherapy and the feasibility of using 1.5 T MR-linac for SBRT of (ultra) central lung tumours.

Minimally invasive surgery role in central squamous lung cancer after neoadjuvant chemoimmunotherapy.

The present body of literature provides restricted evidence concerning the application of video-assisted thoracoscopic surgery (VATS) in individuals diagnosed with centrally located, locally advanced, and initially surgically challenging squamous cell lung carcinoma (SqCLC) following neoadjuvant chemoimmunotherapy (CIT). Further research is warranted to elucidate the role and potential benefits of VATS in this particular patient population. We performed a retrospective analysis on individuals diagnosed with centrally located and locally advanced SqCLC who received preoperative CIT at a single institution. The study evaluated the percentage of VATS performed, conversion rates, and perioperative outcomes. Furthermore, survival outcomes related to the resection extent were compared between patients who underwent standard lobectomy (SL) and extended lobectomy (EL, e.g., sleeve, bilobectomy or pneumonectomy) after neoadjuvant CIT. A total of 27 cases of centrally located SqCLC underwent neoadjuvant CIT followed by VATS, with one case requiring conversion to thoracotomy due to adhesions. Comparison of perioperative outcomes and long-term cancer-specific mortality between the VATS group (N=24) and the thoracotomy group (N=13) did not yield any statistically significant differences. However, the VATS group exhibited a significantly higher frequency of SL (66.7% vs. 30.8%, P=0.046). Notably, within the VATS group, all three patients who experienced tumor relapse or died due to tumor recurrence were from the SL subgroup. This study contributes valuable real-world evidence demonstrating the feasibility and safety of utilizing VATS in the management of patients with centrally located and locally advanced SqCLC following neoadjuvant CIT. However, careful consideration might be given to the extent of resection to optimize patient long-term outcomes.

Cloning of recombinant thyroglobulin

The aim of the study is to clone cDNA fragments of mRNA of the thyroglobulin gene into а vector and introduce it into prokaryotic cell lines for possible use in the diagnosis of autoimmune and oncological diseases of the human thyroid gland. Thyroid hormones are synthesized by thyrocytes of mammalian thyroid tissue from the large protein thyroglobulin having a molecular weight of 330 kDa. The thyroid hormones thyroxine and triiodothyronine are small molecules that have large biological effects. They regulate metabolism in almost all cells, and are important for the development of the central nervous system, musculoskeletal system and lungs. These are also the only hormones that contain iodine and are synthesized partly inside and partly outside of cells. A dimeric glycoprotein is called thyroglobulin.

Single isocenter versus dual isocenter treatment using flattening filter-free and jaw-tracking volumetrically modulated arc therapy for boot-shaped lung cancer: Evaluation of dosimetric and feasibility.

To determine whether a dual-isocenter volumetrically modulated arc therapy (VMAT) technique results in lower normal pulmonary dosage compared to a traditional single isocenter technique for boot-shaped lung cancer. A cohort of 15 patients with advanced peripheral or central lung cancer who had metastases in the mediastinum and supraclavicular lymph nodes was randomly selected for this retrospective study. VMAT plans were generated for each patient using two different beam alignment techniques with the 6-MV flattening filter-free (FFF) photon beam: single-isocenter jaw-tracking VMAT based on the Varian TrueBeam linear accelerator (S-TV), and dual-isocenter VMAT based on both TrueBeam (D-TV) and Halcyon linear accelerator (D-HV). For all 45 treatment plans, planning target volume (PTV) dose coverage, conformity/homogeneity index (CI/HI), mean heart dose (MHD), mean lung dose (MLD) and the total lung tissue receiving 5, 20, 30Gy (V5, V20, V30) were evaluated. The monitor units (MUs), delivery time, and plan quality assurance (QA) results were recorded. The quality of the objectives of the three plans was comparable to each other. In comparison with S-TV, D-TV and D-HV improved the CI and HI of the PTV (p<0.05). The MLD was 13.84±1.44Gy (mean±SD) for D-TV, 14.22±1.30Gy and 14.16±1.42Gy for S-TV and D-HV, respectively. Lungs-V5Gy was 50.78±6.24%, 52.00±7.32% and 53.36±8.48%, Lungs-V20Gy was 23.72±2.27%, 26.18±2.86% and 24.96±3.09%, Lungs-V30Gy was 15.69±1.76%, 17.20±1.72% and 16.52±2.07%. Compared to S-TV, D-TV provided statistically significant better protection for the total lung, with the exception of the lungs-V5. All plans passed QA according the gamma criteria of 3%/3mm. Taking into account the dosimetric results and published clinical data on radiation-induced pulmonary injury, dual-isocenter jaw-tracking VMAT may be the optimal choice for treating boot-shaped lung cancer.

Bronchoscopy in the diagnosis of non-small cell lung cancer

This publication examines the endoscopic semiotics of non-small cell lung cancer. It presents many years of experience in bronchoscopic studies of various forms of central lung cancer growth, the nuances of endoscopic diagnostics, interpretation of the detected changes, and discusses options for performing a biopsy.

Artificial intelligence-based analysis of the spatial distribution of abnormal computed tomography patterns in SARS-CoV-2 pneumonia: association with disease severity

BackgroundThe substantial heterogeneity of clinical presentations in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia still requires robust chest computed tomography analysis to identify high-risk patients. While extension of ground-glass opacity and consolidation from peripheral to central lung fields on chest computed tomography (CT) might be associated with severely ill conditions, quantification of the central-peripheral distribution of ground glass opacity and consolidation in assessments of SARS-CoV-2 pneumonia remains unestablished. This study aimed to examine whether the central-peripheral distributions of ground glass opacity and consolidation were associated with severe outcomes in patients with SARS-CoV-2 pneumonia independent of the whole-lung extents of these abnormal shadows.MethodsThis multicenter retrospective cohort included hospitalized patients with SARS-CoV-2 pneumonia between January 2020 and August 2021. An artificial intelligence-based image analysis technology was used to segment abnormal shadows, including ground glass opacity and consolidation. The area ratio of ground glass opacity and consolidation to the whole lung (GGO%, CON%) and the ratio of ground glass opacity and consolidation areas in the central lungs to those in the peripheral lungs (GGO(C/P)) and (CON(C/P)) were automatically calculated. Severe outcome was defined as in-hospital death or requirement for endotracheal intubation.ResultsOf 512 enrolled patients, the severe outcome was observed in 77 patients. GGO% and CON% were higher in patients with severe outcomes than in those without. Multivariable logistic models showed that GGO(C/P), but not CON(C/P), was associated with the severe outcome independent of age, sex, comorbidities, GGO%, and CON%.ConclusionIn addition to GGO% and CON% in the whole lung, the higher the ratio of ground glass opacity in the central regions to that in the peripheral regions was, the more severe the outcomes in patients with SARS-CoV-2 pneumonia were. The proposed method might be useful to reproducibly quantify the extension of ground glass opacity from peripheral to central lungs and to estimate prognosis.

Temporary Thyroid Dysfunction and Catecholamine Excess Due to Mercury Poisoning in 6 Cases.

Mercury poisoning is a condition with multiple-organ dysfunction that has effects on the central nervous system, gastrointestinal system, cardiovascular system, skin, lungs, and kidneys. It can be fatal or may result in sequelae such as neurological disturbances, if treated late or left untreated. The endocrinological effects of mercury exposure are not well-known. We aimed to evaluate patients with mercury poisoning. A total of 6 cases of mercury poisoning from 3 families were included in the study. Clinical, laboratory, and follow-up data were recorded. Thyroid dysfunction was presented as high thyroid hormones and normal thyrotropin level (unsuppressed) in 5 cases (83.3%). On the other hand, pheochromocytoma-like syndrome was detected in 5 cases (83.3%) with hypertension. The 4 cases were the first to use methimazole for mercury poisoning due to tachycardia and hypertension despite antihypertensive treatment due to catecholamine excess and thyroid dysfunction. Hyponatremia was detected in 3 cases (50%). Mercury poisoning is difficult to diagnose because it is rare and presents with nonspecific physical and laboratory findings. Early diagnosis and providing appropriate treatment are essential in order to prevent sequelae. Mercury poisoning should be considered in patients with unexplained hypertension and tachycardia suggesting the involvement of thyroid hormones and catecholamines.

Evaluation of a New Method for CyberKnife Treatment for Central Lung and Mediastinal Tumors by Tracheobronchial Tracking.

CyberKnife treatment for central lung tumors and mediastinal tumors can be difficult to perform with marker less. We aimed to evaluate a novel tracheobronchial-based method (ie, tracheobronchial tracking) for the purpose of minimally invasive CyberKnife treatment for central lung and mediastinal tumors. Five verification plans were created using an in-house phantom. Each plan included five irradiation sessions. The reference plan irradiated and tracked the simulated tumor (using the target tracking volume, TTV). Trachea plans tracked the simulated tracheo-bronchus and irradiated the simulated tumor and included two types of subplans: correlated plans in which the displacement of the simulated tracheobronchial and the simulated tumor were correlated, and non-correlated plans in which these factors were not correlated. Moreover, 15 mm and 25 mm TTVs were evaluated for each plan. The sin waveform and the patient's respiratory waveform were prepared as the respiratory model. Evaluations were performed by calculating the dose difference between the radiophotoluminescent glass dosimeter (RPLD)-generated mean dose values (generated by the treatment planning system, TPS) and the actual absorbed RPLD dose. Statistical analyses were performed to evaluate findings for each plan. Correlation and prediction errors were calculated for each axis of each plan using log files to evaluate tracking accuracy. Dose differences were statistically significant only in comparisons with the non-correlated plan. When evaluated using the sin waveform, the mean values for correlation and prediction errors in each axis and for all plans were less than 0.6 mm and 0.1 mm, respectively. In the same manner, they were less than 1.1 mm and 0.2 mm when evaluated using the patient's respiratory waveform. Our newly-developed tracheobronchial tracking method would be useful in facilitating minimally invasive CyberKnife treatment in certain cases of central lung and mediastinal tumors.

The experiences and decision making of patients with incurable cancer and health literacy difficulties.

Shared decision making is important when decisions are preference sensitive, as in incurable cancer. A prerequisite for shared decision making is health literacy, which is essential to facilitate good understanding of an individual's current situation, the decision to be made, and the options available to them. This study sought to learn about the challenges for shared decision making faced by patients with incurable cancer and health literacy difficulties. Semi-structured telephone and video interviews were used to collect data on participants' experiences, decision making, and challenges faced. Study procedures followed health literacy principles, with information offered in various formats to suit individuals' preferences, the use of a verbal consent process, and flexibility in whether interviews were conducted over telephone or video call. Data were analysed using Framework Analysis (Ritchie et al. 2003), with initial verbatim transcription of interviews, iterative development of the analysis framework, indexing using Nvivo 12 software and summarising of the data before systematic categorisation and development of final themes. Twenty participants (aged 31-80, of whom 13 male) with a variety of cancers (including breast, central nervous system, gastrointestinal, gynaecological, lung, head and neck, and urological) and experience of a range of treatments were interviewed. Seven themes were identified, including: supportive staff in an imperfect system, additional pressure from COVID-19, in the expert's hands, treatment not so bad, emotional hurdles, accessing information to further understanding and wanting to be a good patient. In order to support patients with incurable cancer and health literacy difficulties to become involved in decisions about their care, we must address the emotional, social and informational challenges they face. Recommendations for achieving this include addressing peoples' emotional needs, facilitating control over information, developing a partnership, involving others, and organisational changes.

Cervicothoracotomy for right upper sleeve lobectomy with carinal resection in the treatment of central lung cancer

We demonstrated successful treatment of patients with complicated central lung cancer, who underwent right upper sleeve lobectomy with carinal resection. We have used the following options for carinal reconstruction: anastomosis of trachea with the left main bronchus and anastomosis of intermediate bronchus with the left main bronchus (clinical case No. 1) or with trachea (clinical case No. 2). Cervicothoracotomy provided correct N-staging and mobilization of trachea with left main bronchus. This approach provided compliance with oncological principles of surgical treatment of lung cancer and significantly reduced tension of anastomosis. These aspects are important for satisfactory immediate functional and oncological results after right upper sleeve lobectomy with carinal resection.

Clinical and Bronchoscopy Assessment in Diagnosing the Histopathology Type of Primary Central Lung Tumors.

The location and type of a tumor influence the prognosis of lung cancer. Primary Central Lung Tumors (PCLTs) are correlated with poor prognoses and certain histologic types. This study aimed to present a comprehensive exploration of clinical and bronchoscopic assessments for diagnosing the histopathology types of PCLTs and identified the factors associated with certain histologic types. This was an observational cross-sectional study of PCLTs, defined as tumors in direct contact with hilar structures or located within the inner two-thirds of the hemithorax. We gathered demographic and clinical data, as well as data on bronchoscopy assessment and histopathology type. Tumor stage, symptoms of superior vena cava syndrome, and enlargement of lymph nodes in the paratracheal and subcarinal regions were also documented. Of the 895 patients, 37.87% had primary lung tumors, with 17.76% classified as PCLTs. Notably, PCLT cases exhibited a higher proportion of stage III (28.9% vs. 18.3%; p = 0.03) and Squamous Cell Carcinoma (SCC) histopathology (37.1% vs. 17.2%; p = 0.00) compared with non-PCLT cases. Bronchoscopic findings in PCLTs revealed a predilection for central airway masses (25.2%) and compressive distal airway stenosis (25.2%). Subgroup analysis of 159 PCLT cases identified 37.10% as SCC. Multivariate analysis underscored that intraluminal masses predict central SCC (odds ratio 2.075, 95% confidence interval 1.07-3.99; p = 0.028). The proportion of stage III, SCC histopathological type, and intraluminal lesions was higher in patients with PCLT than in non-PCLT cases. The presence of intraluminal lesions can predict the histopathological type of SCC in patients with PCLTs.

Application of computer-aided detection for NCCN-based follow-up recommendation in subsolid nodules: Effect on inter-observer agreement.

Computer-aided detection (CAD) of pulmonary nodules reduces the impact of observer variability, improving the reliability and reproducibility of nodule assessments in clinical practice. Therefore, this study aimed to assess the impact of CAD on inter-observer agreement in the follow-up management of subsolid nodules. A dataset comprising 60 subsolid nodule cases was constructed based on the National Cancer Center lung cancer screening data. Five observers independently assessed all low-dose computed tomography scans and assigned follow-up management strategies to each case according to the National Comprehensive Cancer Network (NCCN) guidelines, using both manual measurements and CAD assistance. The linearly weighted Cohen's kappa test was used to measure agreement between paired observers. Agreement among multiple observers was evaluated using the Fleiss kappa statistic. The agreement of the five observers for NCCN follow-up management categorization was moderate when measured manually, with a Fleiss kappa score of 0.437. Utilizing CAD led to a notable enhancement in agreement, achieving a substantial consensus with a Fleiss kappa value of 0.623. After using CAD, the proportion of major and substantial management discrepancies decreased from 27.5% to 15.8% and 4.8% to 1.5%, respectively (p < 0.01). In 23 lung cancer cases presenting as part-solid nodules, CAD significantly elevates the average sensitivity in detecting lung cancer cases presenting as part-solid nodules (overall sensitivity, 82.6% vs. 92.2%; p < 0.05). The application of CAD significantly improves inter-observer agreement in the follow-up management strategy for subsolid nodules. It also demonstrates the potential to reduce substantial management discrepancies and increase detection sensitivity in lung cancer cases presenting as part-solid nodules.

MID­term results of the urgent right lung complex reconstructive tracheobronchial resection in a patient with exacerbated central lung cancer (clinical case)

Introduction. Treatment of patients with central non-small-cell lung cancer (NSCLC) complicated by recurrent hemophtysis is an urgent problem in oncology and thoracic surgery. The aim of this study is to demonstrate the possibility of performing radical organ-preserving surgery (right upper lobectomy with resection of the carina) in a patient with central NSCLC complicated by life-threatening pulmonary hemorrhage. Material and methods. A 64-year-old patient was hospitalized in our thoracic surgery department with grade IB hemophtysis for emergency indications. According to the results of the examination and data from rigid bronchoscopy, an infiltrative peribronchial tumor of the right upper lobe bronchus spreading to the right main bronchus, intermediate bronchus and distal trachea was revealed. According to vital indications, the patient underwent video-assisted mediastinal lymphadenectomy (VAMLA) followed by the right upper lobectomy with carinal resection and circular anastomosis between the trachea and the left main bronchus and reimplantation of intermediate bronchus into the right wall of the trachea proximal to the previous tracheobronchial anastomosis. Results. After a complex tracheo-bronchial resection several “non-surgical” early and delayed complications occured including acute respiratory distress syndrome, non-coronary myocardial infarction type II, thromboembolism of small branches of the pulmonary artery, pneumonia in the lower lobe of the left lung and osteomyelitis of the anterior segment of the 4th rib and perichondritis of the right 4th and 5th rib cartilages after adjuvant chemotherapy. We also demonstrate the methods used to treat complications in order to achieve good mid-term surgical results. Conclusion. Complicated central NSCLC is challenging both for surgical and non-surgical treatment. In carefully selected patients with complicated central NSCLC of the right upper lobe bronchus spreading to the main bronchus and trachea, radical organ-preserving surgery can be performed. Modern advances in thoracic surgery and аnaesthesiology, as well as the collaboration of doctors of various specialties in a multidisciplinary hospital, have made it possible to achieve good oncological and functional results 1.5 years after surgery.

Incidental finding of lung carcinoma invading the left atrium

We report a clinical case of a 64-year-old male with known apical hypertrophic cardiomyopathy, who presented to the hospital with new-onset persistent atrial fibrillation. An electrical cardioversion (ECV) was planned after one month of anticoagulation therapy and transesophageal echocardiogram (TEE) was performed beforehand. During the TEE thrombus in the left atrial appendage was detected, as well as a heterogeneous, hyperechoic, vascularized and non-mobile structure in the left atrium (LA). The ECV was cancelled and the patient was sent for computerized tomography (CT) chest scan. It revealed a big mass in the right lung with macromorphology of central lung carcinoma. There was tumor infiltration of the pericardium and the LA, as well as adrenal and liver metastases. The patient was sent for bronchoscopy with biopsy.

Detection method of viral pneumonia imaging features based on CT scan images in COVID-19 case study

This study aims to automatically analyze and extract abnormalities in the lung field due to Coronavirus Disease 2019 (COVID-19). Types of abnormalities that can be detected are Ground Glass Opacity (GGO) and consolidation. The proposed method can also identify the location of the abnormality in the lung field, that is, the central and peripheral lung area. The location and type of these abnormalities affect the severity and confidence level of a patient suffering from COVID-19. The detection results using the proposed method are compared with the results of manual detection by radiologists. From the experimental results, the proposed system can provide an average error of 0.059 for the severity score and 0.069 for the confidence level. This method has been implemented in a web-based application for general users.•A method to detect the appearance of viral pneumonia imaging features, namely Ground Glass Opacity (GGO) and consolidation on the chest Computed Tomography (CT) scan images.•This method can separate the lung field to the right lung and the left lung, and it also can identify the detected imaging feature's location in the central or peripheral of the lung field.•Severity level and confidence level of the patient's suffering are measured.

A Novel Inverse Algorithm To Solve the Integrated Optimization of Dose, Dose Rate, and Linear Energy Transfer of Proton FLASH Therapy With Sparse Filters

Purpose:The recently proposed Integrated Physical Optimization Intensity Modulated Proton Therapy (IPO-IMPT) framework allows simultaneous optimization of dose, dose rate, and linear energy transfer (LET) for FLASH treatment planning. Finding solutions to IPO-IMPT is difficult due to computational intensiveness. Nevertheless, an inverse solution that simultaneously specifies the geometry of a sparse filter and weights of a proton intensity map is desirable for both clinical and preclinical applications. Such solutions can reduce effective biological dose to organs at risk in cancer patients as well as reduce the number of animal irradiations needed to derive extra biological dose models in preclinical studies. Methods:Unlike the initial forward heuristic, this inverse IPO-IMPT solution includes simultaneous optimization of sparse range compensation, sparse range modulation, and spot intensity. The daunting computational tasks vital to this endeavor were resolved iteratively with a distributed computing framework to enable Simultaneous Intensity and Energy Modulation and Compensation (SIEMAC). SIEMAC was demonstrated on a human central lung cancer patient and a minipig. Results:SIEMAC simultaneously improves maps of spot intensities and patient-field-specific sparse range compensators and range modulators. For the lung cancer patient, at our maximum nozzle current of 300 nA, dose rate coverage above 100 Gy/s increased from 57% to 96% in the lung and from 93% to 100% in the heart, and LET coverage above 4 keV/μm dropped from 68% to 9% in the lung and from 26% to <1% in the heart. For a simple minipig plan, the full-width-half-maximum of the dose, dose rate, and LET distributions decreased by 30%, 1.6%, and 57%, respectively, again with similar target dose coverage, thus reducing uncertainty in these quantities for preclinical studies. Conclusion:The inverse solution to IPO-IMPT demonstrated the capability to simultaneously modulate sub-spot proton energy and intensity distributions for clinical and preclinical studies.

Pneumonectomy with Carinal Sleeve Resection in Patients with Non-Small-Cell Lung Cancer.

Carinal sleeve resection with pneumonectomy is one of the rarest procedures in thoracic surgery, but for locally advanced central lung cancer with infiltration of the carina, it is an option to achieve complete resection. Additionally, it might be the method of choice for patients with stump insufficiency after pneumonectomy or in the cases with anastomosis dehiscence after sleeve lobectomy. The aim of this study was to evaluate the morbidity and long-term survival of patients with non-small-cell lung cancer (NSCLC) who underwent sleeve pneumonectomy, either for curative intent or as an option to treat postoperative complications. All consecutive patients with NSCLC who underwent carinal sleeve pneumonectomy for the aforementioned indications in our department between December 2021 and September 2003 were included in this study. An analysis of demographic characteristics, perioperative variables, and long-term survival was carried out. Data were evaluated retrospectively. Fifty patients underwent pneumonectomy with carina sleeve resection. Thirty-one cases for curative treatment of NSCLC (primary sleeve pneumonectomy [pSP]) and 19 patients were treated because of postpneumonectomy bronchial stump insufficiency or bronchial anastomosis dehiscence (secondary sleeve pneumonectomy [sSP]). Complications occurred in 30 patients (60%) and the 90-day mortality was 18% (n = 9). Patients with pSP had an estimated overall survival of 39.6 months, compared to estimated overall survival for patients after sSP of 24.5 months (p = 0.01). The N status did not appear to affect outcomes. Carinal sleeve resection with pneumonectomy is a feasible procedure with limited morbidity and mortality. This procedure is a reasonable therapeutic option for patients with locally advanced central NSCLC after mandatory patient selection.

NK-2 Homeobox Transcription Factor NKX2-3 Confers Differentiation Block in NPM1-Mutated in Acute Myeloid Leukaemia

Dysregulation of HOX homeobox family transcription factor (TF) gene expression is important in the pathogenesis of AML in particular in NPM1-mutated and MLL rearranged molecular subtypes. However, little is known about the role of NK2-homeobox (NKX2) family TF genes. NKX2 genes have critical roles in normal development of the central nervous system, thyroid, lung and pancreas. We observed high expression of NKX2-3 in patient AML samples and hypothesised the transcription factor might have a functional role in the disease. By qPCR, we found that NKX2-3 is highly expressed in normal HSCs but is rapidly down regulated as cells differentiate. In primary AML samples, it is highly expressed in 21-37% cases, including within the immunophenotypic LSC compartment, in particular in cases with NPM1 and/or FLT3-ITD mutations. Forced expression of NKX2-3 in normal murine KIT + bone marrow (BM) HSPCs transiently enhanced their clonogenic activity and impaired differentiation: NKX2-3-expressing HSPCs expressed higher levels of E2F or MYC target genes, and leukemia stem cell (LSC) maintenance genes. Congenic transplant experiments revealed that forced expression of NKX2-3 in normal BM HSPCs was sufficient to enhance multilineage engraftment across four months of follow up without inducing leukemia. In keeping with this, transplantation of Nkx2-3 -/- knockout BM cells led to significantly inferior engraftment compared with BM cells from litter mate control mice. Thus, while increased expression of Nkx2-3 enhances engraftment of normal stem cells in transplantation assays, loss of Nkx2-3 impairs it. Analysis of NKX2-3 high primary human AML cases demonstrated that HOXA9 was the most highly upregulated transcription factor gene compared with NKX2-3 low cases. We expressed both factors singly and together in murine KIT+ BM HSPCs: Hoxa9/NKX2-3 cells exhibited significantly higher clonogenic activity and reduced morphologic and immunophenotypic differentiation compared with Hoxa9/MTV cells. Congenic BM transplant experiments demonstrated that Hoxa9/NKX2-3 recipients developed leukemias significantly earlier than Hoxa9/MTV recipients (median 82 vs 155 days). BM morphology and immunophenotyping confirmed that Hoxa9/NKX2-3AMLs exhibited a greater degree of differentiation block than Hoxa9/MTV AMLs. Leukemia cells from Hoxa9/NKX2-3 recipients coordinately expressed higher levels of E2F or MYC target genes, and LSC maintenance genes. NKX2-3 KD to ~30% of control values reduced proliferation and induced morphologic and immunophenotypic differentiation in primary patient NPM1-mutated AML cells. NKX2-3 KD led to down regulation of E2F and MYC target genes and normal human CD34 + stem cell genes; and up regulation of myeloid differentiation genes. Using a CRISPR ribonucleofection approach to relocate NPM1c to the nucleus we confirmed that NKX2-3 expression in NPM1-mutant primary AML cells is sustained by mutant NPM1c. ChIPseq in NPM1-mutated primary patient and KO52 AML cells identified NKX2-3 binding peaks. As expected, DNA sequences under peak apices were strongly enriched for NKX2-3 binding motifs; there was also significant enrichment for RUNX and ETS family motifs, but not HOX/MEIS/PBX motifs. To identify genes potentially regulated by NKX2-3, genomic coordinates of strong binding peaks were mapped to the single nearest gene. Remarkably, among genes up regulated following NKX2-3 knockdown in primary human AML cells there was a highly significant enrichment of genes with putative regulatory elements bound by NKX2-3. Likewise, among genes down regulated in NKX2-3-expressing KIT+ murine HSPCs, there was a similar significant enrichment of genes with putative regulatory elements bound by NKX2-3. These data suggest that NKX2-3 functions as a transcription repressor at bound regulatory elements in primary AML cells. In summary, NKX2-3 is highly expressed in NPM1 &amp; FLT3 mutated molecular subtypes of AML and serves to enhance self-renewal and the level of differentiation block through binding to and repressing regulatory elements of myeloid differentiation genes.