Fluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved ...near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial.
Intracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection.
In the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (≤ 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (≥24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the "Second Window" of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 ± 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019).
The Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the "Second Window of ICG" may be within this plateau period, thus providing signal uniformity across subjects.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell ...neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.
The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ ...systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.
The median survival of patients with small cell neuroendocrine carcinoma is significantly shorter than that of patients with classic acinar-type adenocarcinoma. Small cell neuroendocrine carcinoma is ...traditionally diagnosed based on histologic features because expression of current immunohistochemical markers is inconsistent. This is a challenging diagnosis even for expert pathologists and particularly so for pathologists who do not specialize in prostate cancer. New biomarkers to aid in the diagnosis of small cell neuroendocrine carcinoma are therefore urgently needed. We discovered that FOXA2, a pioneer transcription factor, is frequently and specifically expressed in small cell neuroendocrine carcinoma compared with prostate adenocarcinoma from published mRNA-sequencing data of a wide range of human prostate cancers. We verified the expression of FOXA2 in human prostate cancer cell lines and xenografts, patient biopsy specimens, tissue microarrays of prostate cancers with lymph node metastasis, primary small cell neuroendocrine carcinoma, and metastatic treatment-related small cell neuroendocrine carcinoma and cases from a rapid autopsy program. FOXA2 expression was present in NCI-H660 and PC3 neuroendocrine cell lines, but not in LNCAP and CWR22 adenocarcinoma cell lines. Of the human prostate cancer specimens, 20 of 235 specimens (8.5%) showed diagnostic histologic features of small cell neuroendocrine carcinoma as judged histologically. Fifteen of 20 small cell neuroendocrine carcinoma tissues (75%) showed strong expression of FOXA2 (staining intensity 2 or 3). FOXA2 expression was also detected in 9 of 215 prostate cancer tissues (4.2%) that were histologically defined as adenocarcinoma. Our findings demonstrate that FOXA2 is a sensitive and specific molecular marker that may be extremely valuable in the pathologic diagnosis of small cell neuroendocrine carcinoma.
Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal ...profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.
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•Weekly metabolome of maternal blood changes dynamically through healthy pregnancy•A metabolic clock of five blood metabolites accurately predicts gestational age•Two to three metabolites identify labor onset within two, four, and eight weeks•Women with metabolic clocks that outpaced ultrasound evaluation tend to deliver earlier
Identification of blood metabolites in pregnant women that can accurately predict gestational age and provide insights into pregnancy variations undetected by ultrasound.
Current tandem mass spectral libraries for lipid annotations in metabolomics are limited in size and diversity. We provide a freely available computer-generated tandem mass spectral library of ...212,516 spectra covering 119,200 compounds from 26 lipid compound classes, including phospholipids, glycerolipids, bacterial lipoglycans and plant glycolipids. We show platform independence by using tandem mass spectra from 40 different mass spectrometer types including low-resolution and high-resolution instruments.
Background & Aims Ulcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced ...remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial. Methods We performed a parallel study of patients with active UC without infectious diarrhea. Participants were examined by flexible sigmoidoscopy when the study began and then were randomly assigned to groups that received FMT (50 mL, via enema, from healthy anonymous donors; n = 38) or placebo (50 mL water enema; n = 37) once weekly for 6 weeks. Patients, clinicians, and investigators were blinded to the groups. The primary outcome was remission of UC, defined as a Mayo score ≤2 with an endoscopic Mayo score of 0, at week 7. Patients provided stool samples when the study began and during each week of FMT for microbiome analysis. The trial was stopped early for futility by the Data Monitoring and Safety Committee, but all patients already enrolled in the trial were allowed to complete the study. Results Seventy patients completed the trial (3 dropped out from the placebo group and 2 from the FMT group). Nine patients who received FMT (24%) and 2 who received placebo (5%) were in remission at 7 weeks (a statistically significant difference in risk of 17%; 95% confidence interval, 2%−33%). There was no significant difference in adverse events between groups. Seven of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with UC ≤1 year entered remission, compared with 6 of 34 of those with UC >1 year ( P = .04, Fisher’s exact test). Stool from patients receiving FMT had greater microbial diversity, compared with baseline, than that of patients given the placebo ( P = .02, Mann-Whitney U test). Conclusions FMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in adverse events. Fecal donor and time of UC appear to affect outcomes. ClinicalTrials.gov Number: NCT01545908.
BACKGROUND:Although real-time localization of gliomas has improved with intraoperative image guidance systems, these tools are limited by brain shift, surgical cavity deformation, and expense.
...OBJECTIVE:To propose a novel method to perform near-infrared (NIR) imaging during glioma resections based on preclinical and clinical investigations, in order to localize tumors and to potentially identify residual disease.
METHODS:Fifteen patients were identified and administered a Food and Drug Administration-approved, NIR contrast agent (Second Window indocyanine green ICG, 5 mg/kg) before surgical resection. An NIR camera was utilized to localize the tumor before resection and to visualize surgical margins following resection. Neuropathology and magnetic resonance imaging data were used to assess the accuracy and precision of NIR fluorescence in identifying tumor tissue.
RESULTS:NIR visualization of 15 gliomas (10 glioblastoma multiforme, 1 anaplastic astrocytoma, 2 low-grade astrocytoma, 1 juvenile pilocytic astrocytoma, and 1 ganglioglioma) was performed 22.7 hours (mean) after intravenous injection of ICG. During surgery, 12 of 15 tumors were visualized with the NIR camera. The mean signal-to-background ratio was 9.5 ± 0.8 and fluorescence was noted through the dura to a maximum parenchymal depth of 13 mm. The best predictor of positive fluorescence was enhancement on T1-weighted imaging; this correlated with signal-to-background ratio (P = .03). Nonenhancing tumors did not demonstrate NIR fluorescence. Using pathology as the gold standard, the technique demonstrated a sensitivity of 98% and specificity of 45% to identify tumor in gadolinium-enhancing specimens (n = 71).
CONCLUSION:With the use of Second Window ICG, gadolinium-enhancing tumors can be localized through brain parenchyma intraoperatively. Its utility for margin detection is promising but limited by lower specificity.
ABBREVIATIONS:5-ALA, 5-aminolevulinic acidEPR, enhanced permeability and retentionFDA, Food and Drug AdministrationGBM, glioblastomaICG, indocyanine greenNIR, near-infraredNPV, negative predictive valuePPV, positive predictive valueROC, receiver operating characteristicROI, region of interestSBR, signal-to-background ratioWHO, World Health Organization
In this study, 20% of patients with Covid-19 had a prolonged activated partial-thromboplastin time. In 90% of these cases, the cause was lupus anticoagulant, with no associated bleeding. Patients ...with Covid-19 are susceptible to thromboses. The presence of a prolonged aPTT should, in general, not be considered a contraindication to anticoagulation.
ABSTRACT
Searches for space–time variations of fundamental constants have entered an era of unprecedented precision. New, high-quality quasar spectra require increasingly refined analytical methods. ...In this paper, a continuation in a series to establish robust and unbiased methodologies, we explore how convergence criteria in non-linear least-squares optimization impact on quasar absorption system measurements of the fine structure constant α. Given previous claims for high-precision constraints, we critically examine the veracity of a so-called blinding approach, in which α is fixed at the terrestrial value during the model building process, releasing it as a free parameter only after the ‘final’ absorption system kinematic structure has been obtained. We show that this approach results in such small consecutive parameter steps during minimization that convergence is unlikely to be reached, even after as many as 1000 iterations. The fix is straightforward: α must be treated as a free parameter from the earliest possible stages of absorption system model building. The implication of the results presented here is that all previous measurements that have used initially fixed α should be reworked.
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