Autopsy Techniques in Patients With History of Radiofrequency Ablation for Atrial Fibrillation.

CONTEXT.­: Esophageal fistula formation is one of the most feared complications of radiofrequency catheter ablation. This procedure and its many variations, such as the "maze," are becoming the mainstream treatment for atrial fibrillation owing to limitations of antiarrhythmic drugs. The incidence of this complication rate has been reported to be from 0.01% to 1%. OBJECTIVE.­: To delineate the importance of using the en bloc Letulle method of dissection for identifying esophageal fistulas for cases with a history of radiofrequency catheter ablation. DESIGN.­: Six autopsy cases with a history of radiofrequency catheter ablation for atrial fibrillation were selected from 1736 autopsies performed between 2009 and 2020. RESULTS.­: The initial presenting symptoms included neurologic symptoms, chest pains, epigastric discomfort, and sepsis. Transesophageal echocardiogram in 4 cases showed no evidence of thrombus or vegetation, however, 2 cases had evidence of atrial esophageal fistula. The autopsy findings included 5 atrial esophageal fistulas and 1 esophagopericardial fistula. Atrial esophageal fistulas were small and could be detected without difficulty when the en bloc Letulle technique was used and would have been easily missed by the Virchow method. The immediate causes of the deaths were myocardial ischemia, septic emboli to brain and heart, hypovolemic shock secondary to exsanguination, stroke, and coagulopathy. CONCLUSIONS.­: To date, this is the largest collection of autopsy cases showing esophageal fistula associated with prior radiofrequency catheter ablation. The Letulle dissection method is preferable in this setting.

Survival Advantage Following TAG-72 Antigen-Directed Cancer Surgery in Patients With Colorectal Carcinoma: Proposed Mechanisms of Action.

Patients with colorectal carcinoma (CRC) continue to have variable clinical outcomes despite undergoing the same surgical procedure with curative intent and having the same pathologic and clinical stage. This problem suggests the need for better techniques to assess the extent of disease during surgery. We began to address this problem 35 years ago by injecting patients with either primary or recurrent CRC with 125I-labeled murine monoclonal antibodies against the tumor-associated glycoprotein-72 (TAG-72) and using a handheld gamma-detecting probe (HGDP) for intraoperative detection and removal of radioactive, i.e., TAG-72-positive, tissue. Data from these studies demonstrated a significant difference in overall survival data (p < 0.005 or better) when no TAG-72-positive tissue remained compared to when TAG-72-positive tissue remained at the completion of surgery. Recent publications indicate that aberrant glycosylation of mucins and their critical role in suppressing tumor-associated immune response help to explain the cellular mechanisms underlying our results. We propose that monoclonal antibodies to TAG-72 recognize and bind to antigenic epitopes on mucins that suppress the tumor-associated immune response in both the tumor and tumor-draining lymph nodes. Complete surgical removal of all TAG-72-positive tissue serves to reverse the escape phase of immunoediting, allowing a resetting of this response that leads to improved overall survival of the patients with either primary or recurrent CRC. Thus, the status of TAG-72 positivity after resection has a significant impact on patient survival.

Linker engineering in anti-TAG-72 antibody fragments optimizes biophysical properties, serum half-life, and high-specificity tumor imaging.

Antibody (Ab) fragments have great clinical potential as cancer therapeutics and diagnostics. Their small size allows for fast clearance from blood, low immunoreactivity, better tumor penetration, and simpler engineering and production. The smallest fragment derived from a full-length IgG that retains binding to its antigen, the single-chain variable fragment (scFV), is engineered by fusing the variable light and variable heavy domains with a peptide linker. Along with switching the domain orientation, altering the length and amino acid sequence of the linker can significantly affect scFV binding, stability, quaternary structure, and other biophysical properties. Comprehensive studies of these attributes in a single scaffold have not been reported, making design and optimization of Ab fragments challenging. Here, we constructed libraries of 3E8, an Ab specific to tumor-associated glycoprotein 72 (TAG-72), a mucinous glycoprotein overexpressed in 80% of adenocarcinomas. We cloned, expressed, and characterized scFVs, diabodies, and higher-order multimer constructs with varying linker compositions, linker lengths, and domain orientations. These constructs dramatically differed in their oligomeric states and stabilities, not only because of linker and orientation but also related to the purification method. For example, protein L-purified constructs tended to have broader distributions and higher oligomeric states than has been reported previously. From this library, we selected an optimal construct, 3E8.G4S, for biodistribution and pharmacokinetic studies and in vivo xenograft mouse PET imaging. These studies revealed significant tumor targeting of 3E8.G4S with a tumor-to-background ratio of 29:1. These analyses validated 3E8.G4S as a fast, accurate, and specific tumor-imaging agent.

Proteomic Signatures of Thymomas.

Based on the histological features and outcome, the current WHO classification separates thymomas into A, AB, B1, B2 and B3 subtypes. It is hypothesized that the type A thymomas are derived from the thymic medulla while the type B thymomas are derived from the cortex. Due to occasional histological overlap between the tumor subtypes creating difficulties in their separation, the aim of this study was to provide their proteomic characterization and identify potential immunohistochemical markers aiding in tissue diagnosis. Pair-wise comparison of neoplastic and normal thymus by liquid chromatography tandem mass spectrometry (LC-MS/MS) of formalin fixed paraffin embedded tissue revealed 61 proteins differentially expressed in thymomas compared to normal tissue. Hierarchical clustering showed distinct segregation of subtypes AB, B1 and B2 from that of A and B3. Most notably, desmoyokin, a protein that is encoded by the AHNAK gene, was associated with type A thymomas and medulla of normal thymus, by LC-MS/MS and immunohistochemistry. In this global proteomic characterization of the thymoma, several proteins unique to different thymic compartments and thymoma subtypes were identified. Among differentially expressed proteins, desmoyokin is a marker specific for thymic medulla and is potentially promising immunohistochemical marker in separation of type A and B3 thymomas.

An obesity paradox: an inverse correlation between body mass index and atherosclerosis of the aorta.

BACKGROUND AND AIMS: Morbid obesity generally has been associated with higher morbidity and mortality for a variety of diseases. However, a number of exceptions to this have been reported and referred to as the "obesity paradox." The purpose of the present study was to obtain objective data on aortic atherosclerosis and its relationship to body mass index (BMI, kg/m2), based on autopsy findings in a large cohort of overweight and obese decedents. METHODS: Decedents were ≥18 years who had autopsies between 2003 and 2014, a subset of whom were morbidly obese (BMI≥40). Autopsy findings were reviewed and compared to a control group (BMI<40) who had consecutive autopsies performed between January 2013 and June 2014. Atherosclerosis was assessed by gross pathologic examination using a semiquantitative grading scale (from 0 to 3), and for statistical analysis, the scores were stratified into two groups: nonsevere (<2) or severe (≥2). RESULTS: There were 304 decedents in the study: 66 were morbidly obese (BMI≥40), 94 were either Class I or II obese (BMI 30-40), 127 were either overweight (BMI 25.0-29.9) or normal weight (BMI 20-24.9), and 17 were underweight (BMI<20). Decedents with mild atherosclerosis were significantly younger than those with severe disease (55.2 vs. 67.3, P<.0001). Decedents were further stratified by age and BMI. Univariate analysis revealed that decedents >60 years were more likely to have severe atherosclerosis than those ≤60 years (61% vs. 30%, P<.0001). There was a highly significant (P=.008) inverse relationship between severe aortic atherosclerosis and BMI. Twenty of 66 decedents (30%) with a BMI≥40 had severe atherosclerosis vs. 122 of 238 decedents (51%) with BMIs<40 (P=.001). As BMI increased, the probability of developing severe disease decreased. Hypertension increased the probability of having severe atherosclerosis (54% vs. 33%, P=.007). After adjusting for other covariates, multivariable analysis revealed that age and hypertension were still positively correlated with the severity of atherosclerosis (P=.014 and 0.028, respectively), and the inverse relationship between BMI and atherosclerosis remained (adjusted relative risk of BMI≥40 vs. <40=0.64, 95% confidence interval: 0.4-1; P=.03). CONCLUSIONS: Our data extend the previously described obesity paradox to another disease entity, atherosclerosis of the aorta. Morbid obesity appeared to have a protective effect for developing severe aortic atherosclerosis, for the reasons for which are yet to be determined. However, the mean age at death of decedents with BMIs≥40 was younger than those with BMIs in the 20-30 range (55.9 vs. 63.2 years, P=.001), confirming that morbid obesity was not associated with increased longevity.

A Wearable Goggle Navigation System for Dual-Mode Optical and Ultrasound Localization of Suspicious Lesions: Validation Studies Using Tissue-Simulating Phantoms and an Ex Vivo Human Breast Tissue Model.

Surgical resection remains the primary curative treatment for many early-stage cancers, including breast cancer. The development of intraoperative guidance systems for identifying all sites of disease and improving the likelihood of complete surgical resection is an area of active ongoing research, as this can lead to a decrease in the need of subsequent additional surgical procedures. We develop a wearable goggle navigation system for dual-mode optical and ultrasound imaging of suspicious lesions. The system consists of a light source module, a monochromatic CCD camera, an ultrasound system, a Google Glass, and a host computer. It is tested in tissue-simulating phantoms and an ex vivo human breast tissue model. Our experiments demonstrate that the surgical navigation system provides useful guidance for localization and core needle biopsy of simulated tumor within the tissue-simulating phantom, as well as a core needle biopsy and subsequent excision of Indocyanine Green (ICG)-fluorescing sentinel lymph nodes. Our experiments support the contention that this wearable goggle navigation system can be potentially very useful and fully integrated by the surgeon for optimizing many aspects of oncologic surgery. Further engineering optimization and additional in vivo clinical validation work is necessary before such a surgical navigation system can be fully realized in the everyday clinical setting.

Extracting Infrared Spectra of Protein Secondary Structures Using a Library of Protein Spectra and the Ramachandran Plot.

Infrared (IR) spectra from 1200 to 1800 cm(-1) of the pure α-helix and ß-sheet secondary structures have been extracted using a covariant least-squares procedure which relates a library of 40 infrared (IR) solution protein spectra from the work of Dong, Carpenter, and Caughey and amino acid fractions of the proteins based on assignments by STRIDE (secondary structure identification) of Eisenhaber and Argos. The excitonic splitting of the ß-sheet structures is determined for this library of solution proteins. The method is extended to find a set of spectral basis functions that analyze IR spectra of protein samples for α-helix and ß-sheet content. A rigorous error analysis including covariance, the correlations between the input library spectra, was used to justify the results and avoid less meaningful results. The utility of the results on α-helix and ß-sheet regions is demonstrated by detecting protein changes due to cancer in imaging Fourier transform IR (FTIR) spectra of liver tissue slices. This work ends with a method to extract IR spectra of less prominent torsional angle distributions.

Cellular localization of protein arginine methyltransferase-5 correlates with grade of lung tumors.

BACKGROUND: Protein arginine methyltransferase-5 (PRMT5) is a chromatin-modifying enzyme capable of methylating histone and non-histone proteins, and is involved in a wide range of cellular processes that range from transcriptional regulation to organelle biosynthesis. As such, its overexpression has been linked to tumor suppressor gene silencing, enhanced tumor cell growth and survival. MATERIAL AND METHODS: Quantitative real-time polymerase chain reaction, Western immunoblot and immunohistochemistry were used to characterize PRMT5 expression in lung cancer cell lines and human tumors. Clinicopathological findings of tissue microarray based samples from 229 patients with non-small cell lung carcinomas (NSCLC) and 133 cases with pulmonary neuroendocrine tumors (NET) were analyzed with regard to nuclear and cytoplasmic PRMT5 expression. RESULTS: There was statistically significant difference in PRMT5 messenger RNA expression between tumors and nonneoplastic lung tissues. Immunoblot experiments showed abundant expression of PRMT5 and its symmetric methylation mark H4R3 in lung carcinoma but not in non-neoplastic human pulmonary alveolar and bronchial epithelial cell lines. More than two thirds of lung tumors expressed PRMT5. High levels of cytoplasmic PRMT5 were detected in 20.5% of NSCLC and in 16.5% of NET; high levels of nuclear PRMT5 were detected in 38.0% of NSCLC and 24.0% of NET. Cytoplasmic PRMT5 was associated with high grade in both NSCLC and pulmonary NET while nuclear PRMT5 was more frequent in carcinoid tumors (p < 0.05). CONCLUSION: The observed findings support the role of PRMT5 in lung tumorigenesis and reflect its functional dichotomy in cellular compartments. VIRTUAL SLIDE: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1611895162102528.

Infrared metrics for fixation-free liver tumor detection.

Infrared (IR) spectroscopic imaging of human liver tissue slices has been used to identify and characterize liver tumors. Liver tissue, containing a liver metastasis of breast origin (mucinous carcinoma), was surgically removed from a consenting patient and frozen without formalin fixation or dehydration procedures, so that lipids and water remained in the tissues. A set of IR metrics (ratios of various IR peaks) was determined for tumors in fixation-free liver tissues. K-means cluster analysis was used to tell tumor from nontumor. In this case, there was a large reduction in lipid content upon going from nontumor to tumor tissue, and a well-resolved IR spectrum of nontumor liver lipid was obtained and analyzed. These IR metrics may someday guide work on IR spectroscopic diagnostics on patients in the operating room. This work also suggests utility for these methods beyond the identification of liver tumors, perhaps in the study of liver lipids.

Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. In organ repair and remodeling, epigenetic events are important. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and can target epigenetic molecules important in DNA methylation. The miR-17~92 miRNA cluster is critical for lung development and lung epithelial cell homeostasis and is predicted to target fibrotic genes and DNA methyltransferase (DNMT)-1 expression. OBJECTIVES: We investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue. METHODS: Expression and DNA methylation patterns of miR-17~92 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-17~92 cluster and DNMT-1 expression was examined in vitro. Using a murine model of pulmonary fibrosis, we examined the therapeutic potential of the demethylating agent, 5'-aza-2'-deoxycytidine. MEASUREMENTS AND MAIN RESULTS: Compared with control samples, miR-17~92 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-17~92 promoter was increased. Several miRNAs from the miR-17~92 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-17~92 expression was reduced in the lungs of bleomycin-treated mice. Treatment with 5'-aza-2'-deoxycytidine in a murine bleomycin-induced pulmonary fibrosis model reduced fibrotic gene and DNMT-1 expression, enhanced miR-17~92 cluster expression, and attenuated pulmonary fibrosis. CONCLUSIONS: This study provides insight into the pathobiology of IPF and identifies a novel epigenetic feedback loop between miR-17~92 and DNMT-1 in lung fibrosis.

Multimodal imaging and detection strategy with 124 I-labeled chimeric monoclonal antibody cG250 for accurate localization and confirmation of extent of disease during laparoscopic and open surgical resection of clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) accounts for approximately 85% to 90% of all primary kidney malignancies, with clear cell RCC (ccRCC) constituting approximately 70% to 85% of all RCCs. This study describes an innovative multimodal imaging and detection strategy that uses (124)I-labeled chimeric monoclonal antibody G250 ((124)I-cG250) for accurate preoperative and intraoperative localization and confirmation of extent of disease for both laparoscopic and open surgical resection of ccRCC. Two cases presented herein highlight how this technology can potentially guide complete surgical resection and confirm complete removal of all diseased tissues. This innovative (124)I-cG250 (ie, (124)I-girentuximab) multimodal imaging and detection approach, which would be clinically very useful to urologic surgeons, urologic medical oncologists, nuclear medicine physicians, radiologists, and pathologists who are involved in the care of ccRCC patients, holds great potential for improving the diagnostic accuracy, operative planning and approach, verification of disease resection, and monitoring for evidence of disease recurrence in ccRCC patients.

Mathematical model of colitis-associated colon cancer.

As a result of chronic inflammation of their colon, patients with ulcerative colitis or Crohn's disease are at risk of developing colon cancer. In this paper, we consider the progression of colitis-associated colon cancer. Unlike normal colon mucosa, the inflammed colon mucosa undergoes genetic mutations, affecting, in particular, tumor suppressors TP53 and adenomatous polyposis coli (APC) gene. We develop a mathematical model that involves these genes, under chronic inflammation, as well as NF-κB, ß-catenin, MUC1 and MUC2. The model demonstrates that increased level of cells with TP53 mutations results in abnormal growth and proliferation of the epithelium; further increase in the epithelium proliferation results from additional APC mutations. The model may serve as a conceptual framework for further data-based study of the early stage of colon cancer.

Isolated cardiac metastasis from plasmacytoid urothelial carcinoma of the bladder.

UNLABELLED: A 57-year-old male with a history of hypertension presented with shortness of breath, intermittent substernal chest pain, subjective fevers, and a 30-pound weight loss. He was found to have a bladder mass four months prior to presentation, for which he underwent cystoscopy and surgical removal. Pathology demonstrated high-grade superficial plasmacytoid urothelial carcinoma extending into the submucosa but not the muscularis propria. Given the superficial nature of his bladder cancer, a cystectomy was deferred. He was subsequently lost to follow-up care. On arrival, physical exam was notable for tachycardia, tachypnea, and distant heart sounds. An ECG showed an incomplete right bundle branch block and sinus tachycardia. Computed tomography pulmonary angiography revealed a three-cm pericardial effusion. Transthoracic echocardiography confirmed this finding and revealed a mass in the right ventricle (RV) extending into the outflow tract and infiltrating the free wall. The RV was dilated with an estimated RV systolic pressure of 37 mmHg. Pericardiocentesis yielded nearly one liter of serosanguinous fluid with non-diagnostic cytology. Partial median sternotomy with biopsy showed pathologic findings consistent with metastatic urothelial carcinoma, plasmacytoid variant. A PET scan showed increased uptake exclusively in the heart. The oncology team discussed options with the patient including chemotherapy and palliative care. The patient decided to withhold further therapy and went home with hospice care. He died two months later. DISCUSSION: Bladder cancer is the fourth most common cancer in men in the United States. Most patients (69%) with metastatic bladder cancer have multiple organs involved; conversely, our patient had a PET scan indicating his disease was localized to the heart. Plasmacytoid urothelial carcinoma is a rare subtype of bladder cancer, and is estimated to make up less than three percent of all invasive bladder carcinomas. At the time of this publication we are aware of only three other reported instances of isolated cardiac metastasis with urothelial bladder origin; none of which were the plasmacytoid variant. CONCLUSION: This case highlights a previously unreported presentation of plasmacytoid urothelial carcinoma. Clinicians must remember that even superficial cancers can have significant metastatic potential.

The cognitive behavior survey: testing for factorial validity and time invariance across two years of medical school.

BACKGROUND: The Cognitive Behavior Survey (CBS) assesses learner behavior in healthcare-related fields. PURPOSE: The study aims were to evaluate the factorial validity of the CBS, which purports to measure three dimensions of learner behavior--conceptualization, reflection, and memorization--and propose and test an alternative model including its time invariance. METHODS: The CBS was administered to 3 cohorts of medical students upon matriculation and at the end of their 1st and 2nd year. RESULTS: Confirmatory factor analysis (CFA) did not support the original CBS model. Exploratory factor analysis (EFA) with an independent sample provided a new model. Retesting the EFA model using CFA with the original sample yielded a model with improved fit and time invariance. CONCLUSIONS: This study provides evidence for the original CBS 3-factor structure but requires alternative scoring for a time-invariant model.

Fusion positron emission/computed tomography underestimates the presence of hilar nodal metastases in patients with resected non-small cell lung cancer.

BACKGROUND: The 5-year survival for patients with resected stage II (N1) non-small cell lung cancer ranges from 40% to 55%. No data exist addressing the benefit of neoadjuvant therapy for patients with stage II disease. This is largely in part due to the lack of a reliable, minimally invasive method to assess hilar nodes. This study is aimed at determining the ability of fusion positron emission/computed tomography (PET/CT) to identify hilar metastases in patients with resected non-small cell lung cancer. METHODS: A retrospective review of surgically resected patients with fusion PET/CT within 30 days of resection was performed. The sensitivity, specificity, positive predictive value, and negative predictive value for PET/CT in detecting hilar nodal metastases was calculated for a range of maximum standardized uptake values (SUVmax). Hilar nodes from patients with falsely positive PET/CT scans were analyzed for the presence of histoplasmosis. Additionally, the impact of hilar node size greater than 1 centimeter on the calculated values was assessed. RESULTS: There were 119 patients evaluated. The number of lymph nodes resected ranged from 1 to 12 (X=2.98). There was decreased sensitivity and increased specificity with higher SUVmax cutoff values. At the standard SUVmax value of 2.5, the sensitivity and specificity were only 48.5% and 80.2%. The addition of size of hilar node by CT led to a modest improvement in sensitivity at all SUVmax cutoff values. CONCLUSIONS: Fusion PET/CT lacks sensitivity and specificity in identifying hilar nodal metastasis in patients with resected non-small cell lung cancer. Further prospective studies assessing the utility of PET/CT versus alternative sampling techniques are warranted.

Antigen-directed cancer surgery for primary colorectal cancer: 15-year survival analysis.

BACKGROUND: Tumor-associated glycoprotein-72 (TAG-72) is a mucin-like high-molecular-weight glycosylated protein complex overexpressed by many adenocarcinomas. Antigen-directed cancer surgery using radiolabeled anti-TAG-72 murine monoclonal antibodies (muMAbs) has been previously investigated for colorectal cancer. Survival analysis of primary colorectal cancer patients with a minimum of 15-year follow-up after antigen-directed cancer surgery was performed to assess the impact of complete surgical resection of all detectable radiolabeled anti-TAG-72 muMAb. METHODS: Survival analysis was performed on 92 patients (study group) with primary colorectal cancer (July 1990 to August 1995) treated with antigen-directed cancer surgery using (125)I-labeled anti-TAG-72 muMAb. The study group was subdivided into those with no detectable TAG-72 antigen-bearing tissues (TAG-72 negative, N=33) and those with persistent detectable TAG-72 antigen-bearing tissues (TAG-72 positive, N=59) at completion of surgery. Comparisons were made with a control group (546 patients) from the same time period. RESULTS: Study group and control group were demographically similar, as were TAG-72-negative subgroup and TAG-72-positive subgroup. TAG-72-negative subgroup had significantly improved median survival (8.8 versus 2.5 years; P=0.005) and time-dependent survival (45.4% versus 22.0% at 10 years; P=0.002 and 39.4% versus 20.3% at 15 years; P=0.003) compared with TAG-72-positive subgroup. TAG-72 positivity was as an independent predictor of long-term mortality risk, when controlled for pathologic stage of disease. CONCLUSIONS: Absence of detectable TAG-72 antigen within the surgical field at completion of antigen-directed cancer surgery for primary colorectal cancer is of significant prognostic value, conferring a long-term survival advantage to those in whom complete surgical removal of all tissues with detectable radiolabeled anti-TAG-72 muMAb was accomplished.

Multimodal imaging and detection approach to 18F-FDG-directed surgery for patients with known or suspected malignancies: a comprehensive description of the specific methodology utilized in a single-institution cumulative retrospective experience.

BACKGROUND: (18)F-FDG PET/CT is widely utilized in the management of cancer patients. The aim of this paper was to comprehensively describe the specific methodology utilized in our single-institution cumulative retrospective experience with a multimodal imaging and detection approach to (18)F-FDG-directed surgery for known/suspected malignancies. METHODS: From June 2005-June 2010, 145 patients were injected with (18)F-FDG in anticipation of surgical exploration, biopsy, and possible resection of known/suspected malignancy. Each patient underwent one or more of the following: (1) same-day preoperative patient diagnostic PET/CT imaging, (2) intraoperative gamma probe assessment, (3) clinical PET/CT specimen scanning of whole surgically resected specimens (WSRS), research designated tissues (RDT), and/or sectioned research designated tissues (SRDT), (4) micro PET/CT specimen scanning of WSRS, RDT, and/or SRDT, (5) total radioactivity counting of each SRDT piece by an automatic gamma well counter, and (6) same-day postoperative patient diagnostic PET/CT imaging. RESULTS: Same-day (18)F-FDG injection dose was 15.1 (± 3.5, 4.6-26.1) mCi. Fifty-five same-day preoperative patient diagnostic PET/CT scans were performed. One hundred forty-two patients were taken to surgery. Three of the same-day preoperative patient diagnostic PET/CT scans led to the cancellation of the anticipated surgical procedure. One hundred forty-one cases utilized intraoperative gamma probe assessment. Sixty-two same-day postoperative patient diagnostic PET/CT scans were performed. WSRS, RDT, and SRDT were scanned by clinical PET/CT imaging and micro PET/CT imaging in 109 and 32 cases, 33 and 22 cases, and 49 and 26 cases, respectively. Time from (18)F-FDG injection to same-day preoperative patient diagnostic PET/CT scan, intraoperative gamma probe assessment, and same-day postoperative patient diagnostic PET/CT scan were 73 (± 9, 53-114), 286 (± 93, 176-532), and 516 (± 134, 178-853) minutes, respectively. Time from (18)F-FDG injection to scanning of WSRS, RDT, and SRDT by clinical PET/CT imaging and micro PET/CT imaging were 389 (± 148, 86-741) and 458 (± 97, 272-656) minutes, 619 (± 119, 253-846) and 661 (± 117, 433-835) minutes, and 674 (± 186, 299-1068) and 752 (± 127, 499-976) minutes, respectively. CONCLUSIONS: Our multimodal imaging and detection approach to (18)F-FDG-directed surgery for known/suspected malignancies is technically and logistically feasible and may allow for real-time intraoperative staging, surgical planning and execution, and determination of completeness of surgical resection.

Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis.

Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α-smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-ß, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.

The future of telepathology for the developing world.

Physician shortages are acute in developing countries, where disease burden is the greatest and resources for health care are very limited. A lack of pathologists in these countries has lead to delays in diagnosis and misdiagnoses that adversely affect patient care and survival. The introduction of telepathology into countries with limited resources for health care is but one of multiple approaches that can be used to alleviate the problem. Telepathology is the electronic transmission of digital images that can be used for education and diagnostic consultation. A basic system consists of a microscope with a mounted digital camera linked to a computer. The ability to produce histologic slides, to repair and maintain equipment, and to provide training are also needed for the successful use of this technology. iPath is a Web-based, open platform, software application which was developed at the University of Basel, Switzerland, for telepathology and which brings together pathologists from around the world to provide telepathology support for diagnostic consultation and provides education to centers with limited resources. The use of virtual-slide technology to provide a digital image of an entire glass slide is another technology for diagnostic consultation and pathology education. This technology requires more costly resources to support it, which may limit its utility in many areas. Telepathology can generate collections of digital images and virtual slides needed for training indigenous pathologists in their countries to become self-sufficient. Thus, the long-term goal of this technology is to improve patient care and survival.