Towards a survival risk prediction model for metastatic NSCLC patients on durvalumab using whole-lung CT radiomics.

Background: Existing criteria for predicting patient survival from immunotherapy are primarily centered on the PD-L1 status of patients. We tested the hypothesis that noninvasively captured baseline whole-lung radiomics features from CT images, baseline clinical parameters, combined with advanced machine learning approaches, can help to build models of patient survival that compare favorably with PD-L1 status for predicting 'less-than-median-survival risk' in the metastatic NSCLC setting for patients on durvalumab. With a total of 1062 patients, inclusive of model training and validation, this is the largest such study yet. Methods: To ensure a sufficient sample size, we combined data from treatment arms of three metastatic NSCLC studies. About 80% of this data was used for model training, and the remainder was held-out for validation. We first trained two independent models; Model-C trained to predict survival using clinical data; and Model-R trained to predict survival using whole-lung radiomics features. Finally, we created Model-C+R which leveraged both clinical and radiomics features. Results: The classification accuracy (for median survival) of Model-C, Model-R, and Model-C+R was 63%, 55%, and 68% respectively. Sensitivity analysis of survival prediction across different training and validation cohorts showed concordance indices ([95 percentile]) of 0.64 ([0.63, 0.65]), 0.60 ([0.59, 0.60]), and 0.66 ([0.65,0.67]), respectively. We additionally evaluated generalization of these models on a comparable cohort of 144 patients from an independent study, demonstrating classification accuracies of 65%, 62%, and 72% respectively. Conclusion: Machine Learning models combining baseline whole-lung CT radiomic and clinical features may be a useful tool for patient selection in immunotherapy. Further validation through prospective studies is needed.

Spatial variations in aromatic hydrocarbon emission in a dust-rich galaxy.

Dust grains absorb half of the radiation emitted by stars throughout the history of the universe, re-emitting this energy at infrared wavelengths1-3. Polycyclic aromatic hydrocarbons (PAHs) are large organic molecules that trace millimetre-size dust grains and regulate the cooling of interstellar gas within galaxies4,5. Observations of PAH features in very distant galaxies have been difficult owing to the limited sensitivity and wavelength coverage of previous infrared telescopes6,7. Here we present James Webb Space Telescope observations that detect the 3.3 µm PAH feature in a galaxy observed less than 1.5 billion years after the Big Bang. The high equivalent width of the PAH feature indicates that star formation, rather than black hole accretion, dominates infrared emission throughout the galaxy. The light from PAH molecules, hot dust and large dust grains and stars are spatially distinct from one another, leading to order-of-magnitude variations in PAH equivalent width and ratio of PAH to total infrared luminosity across the galaxy. The spatial variations we observe suggest either a physical offset between PAHs and large dust grains or wide variations in the local ultraviolet radiation field. Our observations demonstrate that differences in emission from PAH molecules and large dust grains are a complex result of localized processes within early galaxies.

Splenic infarction complicated with abscess after pelvic trauma as the first presentation of patent foramen ovale - A case report.

Hypercoagulability after trauma is a known entity. Following significant trauma, most guidelines advise anticoagulation treatment for venous thromboembolism (VTE) prophylaxis. VTE following minor trauma convoyed with arterial or systemic embolization dictate the need to search for uncommon source of thromboembolic complications. This is a report of an unusual case of pulmonary and systemic emboli complicated by splenic abscess following minor trauma in a patient with Diabetes Mellitus as the first presentation of patent foramen ovale (PFO).

Intravenous immunoglobulin in drug and device refractory patients with the symptoms of gastroparesis-an open-label study.

BACKGROUND: Gastroparesis is a complex clinical entity; many aspects of which remain unknown. Although most patients have idiopathic, diabetic, or postsurgical gastroparesis, many are thought to have measurable neuromuscular abnormalities. Immunotherapy has recently been utilized to treat suspected autoimmune gastrointestinal dysmotility. METHODS: Fourteen patients with symptoms of gastroparesis (Gp) who were refractory to drug/device were selected from 443 Gp patients from 2013 to 2015 who were treated at the University of Louisville motility center. All patients underwent a structural and psychiatric evaluation along with detailed psychological and behavioral examination to rule out eating disorders. We performed detailed neuromuscular evaluation and all 14 patients received at least 12 weeks of intravenous immunoglobulin (400 mg/kg infusion weekly). Response was defined subjectively (symptomatic improvement) using standardized IDIOM score system. KEY RESULTS: All 14 patients had serological evidence and/or tissue evidence of immunological abnormality. Post-IVIG therapy, there was a significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain. CONCLUSIONS AND INFERENCES: Although limited by the absence of placebo group, the data illustrate the role of autoimmunity and neuromuscular evaluation in patients with gastroparesis and support the utility of a diagnostic trial of immunotherapy in an effort to improve therapeutic outcomes for such patients.

Toward Quantitative Assessment of Rheumatoid Arthritis Using Volumetric Ultrasound.

GOAL: Rheumatoid arthritis (RA) is characterized by inflammation within the joint space as well as erosion or destruction of the bone surface. We believe that volumetric (3-D) ultrasound imaging of the joints in conjunction with automated image-analysis tools for segmenting and quantifying the regions of interest can lead to improved RA assessment. METHODS: In this paper, we describe our proposed algorithms for segmenting 1) the 3 -D bone surface and 2) the 3-D joint capsule region. We improve and extend previous 2-D bone extraction methods to 3-D and make our algorithm more robust to the intensity loss due to surface normals facing away from incident acoustic beams. The extracted bone surfaces coupled with a joint-specific anatomical model are used to initialize a coarse localization of the joint capsule region. The joint capsule segmentation is refined iteratively utilizing a probabilistic speckle model. RESULTS: We apply our methods on 51 volumes from 8 subjects, and validate segmentation results with expert annotations. We also provide the quantitative comparison of our bone detection with magnetic resonance imaging. These automated methods have achieved average sensitivity/precision rates of 94%/93% for bone surface detection, and 87%/83% for joint capsule segmentation. Segmentations of normal and inflamed joints are compared to demonstrate the potential of using proposed tools to assess RA pathology at the joint level. CONCLUSION: The proposed image-analysis methods showed encouraging results as compared to expert annotations. SIGNIFICANCE: These computer-assisted tools can be used to help visualize 3-D anatomy in joints and help develop quantitative measurements toward RA assessment.

Mitral valve annulus localization in 3D echocardiography.

The Mitral Valve is a structure on the left side of the human heart that regulates the flow of oxygenated blood into the Left Ventricle and also helps maintain the pressure within the Left Ventricle when the blood gets pumped to the rest of the body from the Left Ventricle. Pathology of the Mitral Valve often manifests through structural changes in the anatomy. Assessment of Mitral Valve pathology as well as determination of specific interventions require quantification of various structures of the Mitral Valve and one of these structures of interest is the Mitral Valve annulus. Three dimensional echocardiography is a popular imaging technique that clinicians use for volumetric quantification of cardiac structures - but manual quantification is cumbersome and subjective. In this paper we describe a semi-automated approach for maximum-a-posteriori estimation of the Mitral Valve annulus from three-dimensional echocardiography images using a simple analytic shape model coupled with a Näive Bayes classifier. We validate our approach against manual annotations on over 15 real patient cases with an average localization error ≤ 2.59 mm.

Gastric dysmotility and low serum vitamin D levels in patients with gastroparesis.

Nutritional abnormalities are common in patients with gastroparesis (Gp), a disorder that may affect gastric motility and may delay emptying. The aim of this work was to identify relationships between serum nutrition markers including 25-OH vitamin D and gastric motility measures in Gp patients. We enrolled 59 consecutive gastric motility clinic patients (48 females, 11 males; mean age 44 years; 42 idiopathic; 17 diabetes mellitus) with Gp symptoms. The 25-OH vitamin D levels, for most patients slightly above the lower limit of normal (96.98 nmol/l ± 60.99), were lowest in diabetic range (DM) (75.68 nmol/l ± 34.22) vs. idiopathic (ID) (105.03 nmol/l ± 67.08) gastroparesis patients. First hour GET: one unit increase in 25-OH vitamin D level was associated 0.11% improvement (95% CI -0.22, 0.01 p=0.056) in gastric motility in all patients; this association, although marked in ID Gp patients, (-0.13, CI -0.25, -0.01 p=0.034), was not seen in DM Gp, (0.2, CI -0.45, 0.87, p=0.525). Fourth hour GET: Every unit increase of 25-OH vitamin D was associated with significant improvement in all patients, ( 0.11% CI -0.23, 0.01, p=0.053), and some weak improvement in ID group, (0.11% -0.24, 0.01, p=0.076) and absent in patients with DM (0.03, CI -0.66, 0.72, p=0.932). It is concluded that 25-OH vitamin D levels may influence gastric emptying. Underlying mechanisms for this observation might include the impact of 25-OH vitamin D on the health of the enteric nervous system. 25-OH vitamin D contributions to enteric nerve functions should be explored, particularly where autonomic nervous system comorbidities exist.

Laryngeal development and anatomy.

Knowledge of laryngeal and tracheobronchial development and anatomy is essential to the pediatric airway endoscopist. Normal and pathologic airway anatomy is discussed in this chapter.

Volumetric ultrasound and computer-assisted analysis at the point-of-care: a musculoskeletal exemplar.

In this paper we motivate the hypothesis that the use of volumetric ultrasound imaging and automated image analysis tools would improve clinical workflows as well as outcomes at the point-of-care. To make our case, this paper presents results from a rheumatoid arthritis (RA) study where several image analysis techniques have been applied to volumetric ultrasound, highlighting anatomy of interest to better understand disease progression. Pathologies related to RA in joints, manifest themselves commonly as changes in the bone (e.g. erosions) and the region enclosed by the joint-capsule (e.g. synovitis). Automated tools for detecting and segmenting such structures would help significantly towards objective and quantitative assessment of RA in joints. Extracted bone coupled with a simple anatomical model of the joint provides a coarse localization of the joint-capsule region. A probabilistic speckle model is then used to iteratively refine the capsule segmentation. We illustrate the performance of proposed algorithms through quantitative comparisons with expert annotations as well as qualitative results on over 30 scans obtained from 11 subjects.

Symmetry and appearance based automated detection of salient anatomical regions in ultrasound.

In this paper we present a method for automated detection of enclosed anatomical regions in ultrasound images by utilizing the coarse shape symmetry as well as relative homogeneity of their sonographic appearance. The proposed method comprises of two steps: First, local phase based filtering [2] is used to detect points in the image which are roughly positioned along the axes of spatial symmetry with respect to structures around them. Secondly, the sonographic 'appearance' and location of these points is used to define a distance-map on the image, which is supplied to a simple fast-marching algorithm in order to provide the final feature detections. The method is robust to ultrasound speckle and works well with or without specialized pre-processing (e.g. speckle-reduction filtering). We illustrate the proposed method with qualitative results on in-vivo Ultrasound images.

Palatal implants for the treatment of snoring and obstructive sleep apnea/hypopnea syndrome.

OBJECTIVE: Randomized, double-blinded, placebo-controlled, clinical trial to determine the effectiveness of palatal implants for treatment of mild/moderate obstructive sleep apnea/hypopnea syndrome (OSAHS). STUDY DESIGN AND SETTING: Sixty-two non-obese adults with history of snoring, daytime sleepiness, and mild/moderate OSAHS, were randomized to receive palatal implants (n = 31) or placebo procedure (n = 31). Complete follow-up including quality of life (QOL, SF-36), snoring visual analog scale (VAS), and Epworth Sleepiness Scale (ESS) data were obtained in 62 patients. Seven patients refused follow-up polysomnography for a total of 55 patients (29 implant and 26 placebo). RESULTS: The treatment group (change in score of -7.9 +/- 7.7) was significantly improved compared with the placebo group (change in score of 0.9 +/- 4.3) for apnea/hypopnea index (AHI) (P < 0.0001), QOL, SF-36 (P < 0.0001), snoring VAS (P < 0.0001), and ESS (P = 0.0002). CONCLUSIONS: Palatal implants improve AHI, QOL, snoring intensity, and daytime sleepiness for selected patients with mild/moderate OSAHS.

Robust foreground detection in video using pixel layers.

A framework for robust foreground detection that works under difficult conditions such as dynamic background and moderately moving camera is presented in this paper. The proposed method includes two main components: coarse scene representation as the union of pixel layers, and foreground detection in video by propagating these layers using a maximum-likelihood assignment. We first cluster into "layers" those pixels that share similar statistics. The entire scene is then modeled as the union of such non-parametric layer-models. An in-coming pixel is detected as foreground if it does not adhere to these adaptive models of the background. A principled way of computing thresholds is used to achieve robust detection performance with a pre-specified number of false alarms. Correlation between pixels in the spatial vicinity is exploited to deal with camera motion without precise registration or optical flow. The proposed technique adapts to changes in the scene, and allows to automatically convert persistent foreground objects to background and re-convert them to foreground when they become interesting. This simple framework addresses the important problem of robust foreground and unusual region detection, at about 10 frames per second on a standard laptop computer. The presentation of the proposed approach is complemented by results on challenging real data and comparisons with other standard techniques.

Wireless upper esophageal monitoring for laryngopharyngeal reflux (LPR).

OBJECTIVES: To confirm feasibility of transnasal placement of a wireless pH-monitoring capsule in the upper esophagus, and to determine the positive predictive value of LPR and GERD signs and symptoms for diagnosis of LPR in patients with OSAHS. STUDY DESIGN: Prospective, nonrandomized, IRB-approved study of 89 OSAHS patients with and without symptoms and signs of LPR. METHODS: After complete history including QOL survey and fiberoptic laryngoscopy, patients underwent transnasal placement of the pH-monitoring capsule and wireless data collection for 24 hours. RESULTS: 77 of 89 consecutive patients underwent successful placement of wireless pH-monitoring capsule (86.5% success rate) and completed the study. 55 (71.4%) OSAHS patients had positive pH studies. 10.4% of these patients reported no symptoms or signs of LPR, indicating occult disease. CONCLUSION: Success rates of placement, tolerability, morbidity, and complications are excellent. Wireless upper esophageal pH monitoring is safe and effective for diagnosing LPR in patients with OSAHS.

Video inpainting under constrained camera motion.

A framework for inpainting missing parts of a video sequence recorded with a moving or stationary camera is presented in this work. The region to be inpainted is general: it may be still or moving, in the background or in the foreground, it may occlude one object and be occluded by some other object. The algorithm consists of a simple preprocessing stage and two steps of video inpainting. In the preprocessing stage, we roughly segment each frame into foreground and background. We use this segmentation to build three image mosaics that help to produce time consistent results and also improve the performance of the algorithm by reducing the search space. In the first video inpainting step, we reconstruct moving objects in the foreground that are "occluded" by the region to be inpainted. To this end, we fill the gap as much as possible by copying information from the moving foreground in other frames, using a priority-based scheme. In the second step, we inpaint the remaining hole with the background. To accomplish this, we first align the frames and directly copy when possible. The remaining pixels are filled in by extending spatial texture synthesis techniques to the spatiotemporal domain. The proposed framework has several advantages over state-of-the-art algorithms that deal with similar types of data and constraints. It permits some camera motion, is simple to implement, fast, does not require statistical models of background nor foreground, works well in the presence of rich and cluttered backgrounds, and the results show that there is no visible blurring or motion artifacts. A number of real examples taken with a consumer hand-held camera are shown supporting these findings.

Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease.

The lack of healthy HLA-identical sibs limits the use of allogeneic hematopoietic cell transplantation in children with high-risk sickle cell disease (SCD). We evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with SCD who had cerebrovascular accidents (CVAs) and did not have HLA-matched sib donors. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. Neutrophil levels above 0.5 x 10(9)/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 x 10(9)/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease (GVHD; two grade II, one grade III), and one developed extensive chronic GVHD. One patient had graft failure and autologous hematopoietic recovery. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD at 40 and 61 months, respectively, after UPBCT. These observations demonstrate the feasibility of UPBCT in children with SCD. Further studies of UPBCT for SCD are needed but, because of risks of procedure-related morbidity and graft rejection, should be restricted to pediatric patients with high-risk manifestations of SCD.

Lymphohistiocytic anaplastic large cell lymphoma stage I: long-term survival after resection alone.

A 17-year-old female presented with axillary lymphoadenopathy, which, on biopsy, demonstrated an anaplastic large cell lymphoma of the lymphohistiocytic type (ALCL-LH). The tumor cells expressed the CD30 antigen and reacted with the ALK1 antibody, suggesting the presence of the nucleophosmin-anaplastic large cell lymphoma kinase (NPM/ALK) fusion protein. No other adenopathy was found. Following a wide excision of the lymph node and without postoperative treatment, the patient remains free of disease 5 years later. This case demonstrates the potential curability of patients with early stages of ALCL by local treatment.

Thalidomide in children undergoing bone marrow transplantation: series at a single institution and review of the literature.

Thalidomide has one of the most notorious drug histories because of its teratogenicity. Its widespread use in the 1960s led to a worldwide epidemic of phocomelia in inborns; this in turn led to its complete ban in most of the world. However, it has now been licensed for selected indications including graft-versus-host-disease (GVHD) after bone marrow transplantation, wasting associated with tuberculosis and human immunodeficiency virus infection, and leprosy. Little is known, however, about its use in children in these settings. Therefore, we report our experience and review the literature on thalidomide in children for GVHD after bone marrow transplantation. We studied 6 patients, 2 with chronic GVHD, 2 with acute GVHD, and 2 with acute GVHD progressing into chronic disease. One patient with chronic GVHD had a complete response, whereas the other had a partial response. Side effects consisted primarily of sedation and constipation, which are reported previously and well known side effects. None had neuropathy. One patient had rash, eosinophilia, and early pancreatitis that began shortly after initiation of thalidomide, persisted, and resolved only after discontinuation of thalidomide. Eosinophilia and pancreatitis are both previously unreported side effects or associated findings of thalidomide treatment. Review of the literature reveals three major studies of thalidomide in GVHD; of these two included children and adults together, and one in which age range of patients was not mentioned. In addition, four series of children receiving only thalidomide are reported. These series contained 1 to 14 patients each. Results show efficacy in at least 50% of children with chronic GVHD and little or no efficacy in children with exclusively acute GVHD. Side effects are similar to those reported in adults and consisted mostly of sedation and constipation, both of which subsided over time and resolved after discontinuing the drug. We speculate on the reasons for which thalidomide is more effective in chronic, compared with acute, GVHD in children, and make recommendations for future study.

Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation.

The pharmacokinetics of tacrolimus have been studied in healthy volunteers and in adults undergoing bone marrow transplantation. However, there is little information on the pharmacokinetics of tacrolimus in children undergoing BMT. We studied pharmacokinetics of tacrolimus in seven patients (age 8-17 years) undergoing allogeneic stem cell transplantation. Four patients received matched unrelated donor (MUD) transplants, two underwent HLA-matched related donor transplants, and one underwent an umbilical cord blood donor transplant. All patients received tacrolimus by continuous infusion at 0.03-0.04 mg/kg/day beginning on the day prior to transplant. Tacrolimus whole blood concentrations were monitored by microparticle enzyme immunoassay. Our goal was to maintain a blood tacrolimus level of 10-20 microg/ml. Once patients were tolerating oral medications, tacrolimus infusion was converted to oral dosing using a 4:1 conversion. Dose of tacrolimus and resulting tacrolimus concentrations were recorded and the total body clearance of tacrolimus was calculated retrospectively. The mean clearance, based on first steady-state tacrolimus concentrations necessary for achieving a therapeutic level (10-20 microg/ml), was 108.1 ml/h/kg (range 79.7-142.0 ml/h/kg), greater than that reported in adult BMT patients (71 +/- 34 ml/h/kg). The average dose required to achieve that therapeutic range was 0.0354 mg/kg/day as an intravenous continuous infusion. Over the entire course of intravenous tacrolimus, mean clearance was 97.0 ml/h/kg (range 33.4-153.3 ml/h/kg). In six of the seven patients, clearance values dropped after 2-4 weeks of therapy by an average of 32.5 ml/h/kg. In two patients, sharp drops in clearance were temporally related to changes in liver function tests. Three of the seven patients died of severe acute GVHD; all these had undergone matched unrelated donor transplantation, and two of these three had initial clearance levels over 120 ml/h/kg. Thus, children appear to have more rapid tacrolimus clearance than adults and may need to begin therapy earlier in order to obtain stable and optimal levels. More studies are needed to confirm these preliminary results.

Medulloblastoma: time-dose relationship based on a 30-year review.

PURPOSE: Time-dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution. METHODS AND MATERIALS: Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (> or =T3b or > or =M1) or low (< or =T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy. RESULTS: At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p=0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p=0.004). Duration of the treatment course was the only radiotherapy-related variable with a significant impact on freedom from relapse and posterior fossa control. For patients whose radiation treatment duration was < or =45 days, posterior fossa control was 89% at 5 years, compared with 68% for those treated for >45 days (p=0.01). Duration of treatment also affected freedom from relapse at 5 years: < or =45 days (76%) compared with >45 days (43%), p=0.004. CONCLUSION: Our study demonstrates that if adequate doses are used, then radiotherapy treatment duration will significantly affect the outcome in terms of control of disease in the posterior fossa and freedom from relapse. Fractions of at least 1.75 Gy given once a day, or a twice-a-day regimen should yield optimal local control results.