Advances in CAR T Cell Therapy for Non-Small Cell Lung Cancer.

Since its first approval by the FDA in 2017, tremendous progress has been made in chimeric antigen receptor (CAR) T cell therapy, the adoptive transfer of engineered, CAR-expressing T lymphocyte. CAR T cells are all composed of three main elements: an extracellular antigen-binding domain, an intracellular signaling domain responsible for T cell activation, and a hinge that joins these two domains. Continuous improvement has been made in CARs, now in their fifth generation, particularly in the intracellular signaling domain responsible for T cell activation. CAR T cell therapy has revolutionized the treatment of hematologic malignancies. Nonetheless, the use of CAR T cell therapy for solid tumors has not attained comparable levels of success. Here we review the challenges in achieving effective CAR T cell therapy in solid tumors, and emerging CAR T cells that have shown great promise for non-small cell lung cancer (NSCLC). A growing number of clinical trials have been conducted to study the effect of CAR T cell therapy on NSCLC, targeting different types of surface antigens. They include epidermal growth factor receptor (EGFR), mesothelin (MSLN), prostate stem cell antigen (PSCA), and mucin 1 (MUC1). Potential new targets such as erythropoietin-producing hepatocellular carcinoma A2 (EphA2), tissue factor (TF), and protein tyrosine kinase 7 (PTK7) are currently under investigation in clinical trials. The challenges in developing CAR T for NSCLC therapy and other approaches for enhancing CAR T efficacy are discussed. Finally, we provide our perspective on imaging CAR T cell action by reviewing the two main radionuclide-based CAR T cell imaging techniques, the direct labeling of CAR T cells or indirect labeling via a reporter gene.

Comparing postoperative complication of LigaSure Small Jaw instrument with clamp and tie method in thyroidectomy patients: a randomized controlled trial [IRCT2014010516077N1].

BACKGROUND: LigaSure® Small Jaw (LSJ) has been recently introduced as an energy-based vessel sealing device, which has provided better intraoperative and postoperative outcomes in thyroidectomies, compared to conventional technique. In the current study, we aimed to examine the efficiency of hand-sewn and LSJ thyroidectomy, based on operation time and perioperative complications. METHODS: All patients with the diagnosis of multinodular goiter, thyroid cancers, retrosternal goiter and other indications for thyroid surgeries, enrolled. Of 550 patients, 261 patients randomly assigned to the conventional group (A) and 274 patients to LigaSure Small Jaw group (B). Study groups compared concerning operative time, recurrent laryngeal nerve (RLN) injury, hypocalcemia, and postoperative complications. RESULTS: There was no significant difference regarding demographic data between groups A and B. During total thyroidectomy, intraoperative blood loss was 64.42 ± 20.72 ml and 49.64 ± 17.92 ml in groups A and B, respectively (P 0.043). Operative time was significantly lower in LSJ group compared to the conventional group in total and subtotal thyroidectomy (P 0.002; P 0.001). Three patients who underwent conventional total thyroidectomy had RLN palsy. However, there was no significant difference between techniques regarding RLN injury (P 0.134). Postoperative total and ionized serum calcium levels decreased compared to preoperative levels in both conventional and LSJ technique; however, changes in total and ionized serum calcium were more severe in patients with conventional thyroidectomy (total calcium, P < 0.0001) (ionized calcium, P 0.005). CONCLUSION: The LigaSure Small Jaw device decreases operative time and intraoperative bleeding compared to conventional technique. Besides, changes in total and ionized calcium levels in patients with LSJ thyroidectomy are subtle compared to HS technique. TRIAL REGISTRATION: Registered in Iranian Registry of Clinical Trials ( www.irct.com ), trial registration: IRCT2014010516077N1, Registered: 23 May 2014).

Do Rib-Based Anchors Impair Chest Wall Motion in Early Onset Scoliosis (EOS)?

Purpose: There is a concern in pediatric surgery practice that rib-based fixation may limit chest wall motion in early onset scoliosis (EOS). The purpose of this study is to address the above concern by assessing the contribution of chest wall excursion to respiration before and after surgery. Methods: Quantitative dynamic magnetic resonance imaging (QdMRI) is performed on EOS patients (before and after surgery) and normal children in this retrospective study. QdMRI is purely an image-based approach and allows free breathing image acquisition. Tidal volume parameters for chest walls (CWtv) and hemi-diaphragms (Dtv) were analyzed on concave and convex sides of the spinal curve. EOS patients (1-14 years) and normal children (5-18 years) were enrolled, with an average interval of two years for dMRI acquisition before and after surgery. Results: CWtv significantly increased after surgery in the global comparison including all EOS patients (p < 0.05). For main thoracic curve (MTC) EOS patients, CWtv significantly improved by 50.24% (concave side) and 35.17% (convex side) after age correction (p < 0.05) after surgery. The average ratio of Dtv to CWtv on the convex side in MTC EOS patients was not significantly different from that in normal children (p=0.78), although the concave side showed the difference to be significant. Conclusion: Chest wall component tidal volumes in EOS patients measured via QdMRI did not decrease after rib-based surgery, suggesting that rib-based fixation does not impair chest wall motion in pediatric patients with EOS.

Assessment of 3D hemi-diaphragmatic motion via free-breathing dynamic MRI in pediatric thoracic insufficiency syndrome.

Purpose: Thoracic insufficiency syndrome (TIS) affects ventilatory function due to spinal and thoracic deformities limiting lung space and diaphragmatic motion. Corrective orthopedic surgery can be used to help normalize skeletal anatomy, restoring lung space and diaphragmatic motion. This study employs free-breathing dynamic MRI (dMRI) and quantifies the 3D motion of each hemi-diaphragm surface in normal and TIS patients, and evaluates effects of surgical intervention. Materials and Methods: In a retrospective study of 149 pediatric patients with TIS and 190 healthy children, we constructed 4D images from free-breathing dMRI and manually delineated the diaphragm at end-expiration (EE) and end-inspiration (EI) time points. We automatically selected 25 points uniformly on each hemi-diaphragm surface, calculated their relative velocities between EE and EI, and derived mean velocities in 13 homologous regions for each hemi-diaphragm to provide measures of regional 3D hemi-diaphragm motion. T-testing was used to compare velocity changes before and after surgery, and to velocities in healthy controls. Results: The posterior-central region of the right hemi-diaphragm exhibited the highest average velocity post-operatively. Posterior regions showed greater velocity changes after surgery in both right and left hemi-diaphragms. Surgical reduction of thoracic Cobb angle displayed a stronger correlation with changes in diaphragm velocity than reduction in lumbar Cobb angle. Following surgery, the anterior regions of the left hemi-diaphragm tended to approach a more normal state. Conclusion: Quantification of regional motion of the 3D diaphragm surface in normal subjects and TIS patients via free-breathing dMRI is feasible. Derived measurements can be assessed in comparison to normal subjects to study TIS and the effects of surgery.

Auto-segmentation of thoraco-abdominal organs in pediatric dynamic MRI.

Purpose: Analysis of the abnormal motion of thoraco-abdominal organs in respiratory disorders such as the Thoracic Insufficiency Syndrome (TIS) and scoliosis such as adolescent idiopathic scoliosis (AIS) or early onset scoliosis (EOS) can lead to better surgical plans. We can use healthy subjects to find out the normal architecture and motion of a rib cage and associated organs and attempt to modify the patient's deformed anatomy to match to it. Dynamic magnetic resonance imaging (dMRI) is a practical and preferred imaging modality for capturing dynamic images of healthy pediatric subjects. In this paper, we propose an auto-segmentation set-up for the lungs, kidneys, liver, spleen, and thoraco-abdominal skin in these dMRI images which have their own challenges such as poor contrast, image non-standardness, and similarity in texture amongst gas, bone, and connective tissue at several inter-object interfaces. Methods: The segmentation set-up has been implemented in two steps: recognition and delineation using two deep neural network (DL) architectures (say DL-R and DL-D) for the recognition step and delineation step, respectively. The encoder-decoder framework in DL-D utilizes features at four different resolution levels to counter the challenges involved in the segmentation. We have evaluated on dMRI sagittal acquisitions of 189 (near-)normal subjects. The spatial resolution in all dMRI acquisitions is 1.46 mm in a sagittal slice and 6.00 mm between sagittal slices. We utilized images of 89 (10) subjects at end inspiration for training (validation). For testing we experimented with three scenarios: utilizing (1) the images of 90 (=189-89-10) different (remaining) subjects at end inspiration for testing, (2) the images of the aforementioned 90 subjects at end expiration for testing, and (3) the images of the aforesaid 99 (=89+10) subjects but at end expiration for testing. In some situations, we can take advantage of already available ground truth (GT) of a subject at a particular respiratory phase to automatically segment the object in the image of the same subject at a different respiratory phase and then refining the segmentation to create the final GT. We anticipate that this process of creating GT would require minimal post hoc correction. In this spirit, we conducted separate experiments where we assume to have the ground truth of the test subjects at end expiration for scenario (1), end inspiration for (2), and end inspiration for (3). Results: Amongst these three scenarios of testing, for the DL-R, we achieve a best average location error (LE) of about 1 voxel for the lungs, kidneys, and spleen and 1.5 voxels for the liver and the thoraco- abdominal skin. The standard deviation (SD) of LE is about 1 or 2 voxels. For the delineation approach, we achieve an average Dice coefficient (DC) of about 0.92 to 0.94 for the lungs, 0.82 for the kidneys, 0.90 for the liver, 0.81 for the spleen, and 0.93 for the thoraco-abdominal skin. The SD of DC is lower for the lungs, liver, and the thoraco-abdominal skin, and slightly higher for the spleen and kidneys. Conclusions: Motivated by applications in surgical planning for disorders such as TIS, AIS, and EOS, we have shown an auto-segmentation system for thoraco-abdominal organs in dMRI acquisitions. This proposed setup copes with the challenges posed by low resolution, motion blur, inadequate contrast, and image intensity non-standardness quite well. We are in the process of testing its effectiveness on TIS patient dMRI data.

Is pulmonary fibrosis a precancerous disease?

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease (ILD) characterized by a histopathological pattern of usual interstitial pneumonia with progressive fibrosis of the pulmonary epithelium. The incidence of IPF is increasing worldwide as the population ages and with that, there is a concomitant increase in the incidence of lung cancer in these patients who are living longer with the disease. The average length of time for lung cancer development following an IPF diagnosis is 3 years. Given the high prevalence of lung cancer among patients with pulmonary fibrosis, we wondered if pulmonary fibrosis could be classified as a precancerous disease. We provided support from the Pubmed published literature to investigate whether pulmonary fibrosis meets the five criteria of the National Cancer Institute's definition of premalignant conditions for classification as a precancerous disease. We found out pulmonary fibrosis meets the five criteria of the National Cancer Institute's definition of a premalignant condition and can be considered a precancerous disease. To identify early lung cancer in patients with pulmonary fibrosis, regular screening with HRCT and PET-CT scans is highly recommended for these patients.

Unfolding the direct connectivity of the occipital cortex with the hypothalamic, septal and BNST nuclei of the human brain.

The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei and the bed nucleus of stria terminalis (BNST) are also known to be involved in control of autonomic, motivational, learning, emotional and associative processes in the human brain. Multiple animal dissection studies have revealed direct connectivity between central limbic gray matter nuclei and occipital cortex, particularly from the hypothalamic, septal and BNST nuclei. However, the detailed anatomy of this connectivity in the human brain has yet to be determined. The primary objective of this study was to explore the utility of high spatial and high angular resolution diffusion weighted tractography techniques for mapping the connectivity pathways between the occipital cortex and central limbic gray matter nuclei in the human brain. We studied 30 healthy adult human brains, delineated, and reconstructed the trajectory of the occipito-hypothalamic/septal/BNST for the first time in the human brain.

Can magnetic resonance imaging differentiate muscle invasion (T2) and lamina propria invasion (T1) urothelial carcinoma of the bladder? A systematic review and meta-analysis of Vesical Imaging-Reporting and Data System accuracy.

Background: Vesical Imaging-Reporting and Data System (VI-RADS) was developed as a structured reporting tool to anticipate the possibility of muscle invasion. This study is aimed to investigate the diagnostic accuracy of VI-RADS for discriminating T2 from T1 bladder cancer. Materials and methods: Scopus, Web of Science, PubMed, and Embase were searched on October 4, 2021, for studies with the following characteristics: (1) bladder cancer patient population, (2) VI-RADS as an index test, (3) retransurethral resection of bladder tumor/cystectomy as a reference, and (4) adequate VI-RADS score data for T1 and T2 lesions. The analyses were performed using the binary regression model of MIDAS in Stata. Results: Six studies with 624 magnetic resonance imaging reports were included. The receiver operating characteristics curve for differentiation of T2 from T1 bladder cancer showed an area under the curve of 0.93 (95% confidence interval [CI], 0.91-0.95) for a VI-RADS ≥3 and 0.75 (95% CI, 0.71-0.79) for a VI-RADS ≥4. A VI-RADS ≥3 showed high sensitivity of 93% (95% CI, 85%-97%), specificity of 61% (95% CI, 30%-86%), positive likelihood ratio of 2.4 (95% CI, 1.1-5.3), and negative likelihood ratio of 0.11 (95% CI, 0.05-0.24). A total of 10.4% of T2 lesions were scored as VI-RADS 2, while 10% of T1 lesions were scored as VI-RADS 4 or 5. Conclusions: The VI-RADS ≥3 has high accuracy and sensitivity for detecting muscle invasion in borderline populations of T1 or T2 bladder cancer. Thus, the VI-RADS could be a good non-invasive screening test for the detection of T2 urothelial lesions.

ALK-positive histiocytosis involving the cavernous sinus: A deceptive radiologic mimic of meningioma.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is an uncommon condition, recently considered a separate condition from other histiocytosis by WHO 5th edition. It can involve intracranial structures. This manuscript describes a case of ALK-positive histiocytosis of the cavernous sinus, focusing on the radiologic and pathologic presentation of the entity. Our case had MRI manifestations mimicking meningioma, metastasis, and Langerhans histiocytosis. On CT imaging, benign osseous remodeling of the cavernous sinus was detected, which can be helpful in differentiating it from more common meningioma.

The health care utilisation and out-of-pocket expenditure associated with Australian stroke survivors aged 55 and over.

OBJECTIVE: Stroke is a major cause of mortality and disability worldwide. People with stroke have a number of options available to treat post-stroke related symptoms and challenges. The aim of this study was to assess the use of healthcare services, self-care practices and out-of-pocket expenses associated with post-stroke healthcare. METHODS: We retrospectively analysed data collected between April and October 2017 from a survey of 576 participants aged 55 to 96 from the 45 and Up Study, NSW (Australia), who had earlier reported a clinical diagnosis of stroke. Participants were asked about their use of health care services, including conventional medicine practitioners and medications, complementary medicine practitioners, practices and products and the respective associated out-of-pocket expenditure for each. RESULTS: Amongst the total of 576 individuals who participated in the study, 39% consulted a doctor, 18% consulted an allied health practitioner, and 8% consulted a complementary medicine practitioner in the previous year for their stroke. Participants' average combined out-of-pocket expenditure for post-stroke related healthcare was AU$386.4 per annum. Extrapolated to all Australians with stroke, aged 55 years and over, the total out-of-pocket expenditure for post-stroke related healthcare is estimated to be AU$42 million per annum. CONCLUSIONS: Post-stroke individuals used a wide range of health services and various self-care practices for stroke rehabilitation. Such healthcare utilisation is associated with significant annual out-of-pocket expenditure. Given the socioeconomic burden of stroke, further research is required to identify the barriers and facilitators of self-care among patients with stroke and explore the cost-effectiveness of the wide range of treatments(s) utilised for post-stroke care.