Electrocardiographic Abnormalities of Takotsubo Cardiomyopathy in a Patient with Paced Ventricular Rhythm

Takotsubo cardiomyopathy (TCM) is a unique cardiomyopathy characterized by chest pain, ECG, and regional wall motion abnormalities closely mimicking acute myocardial infarction, in the absence of significant coronary artery disease. Classic ECG changes of TCM include ST elevation or T wave inversion. However, ECG abnormalities of TCM in patients with paced ventricular rhythms have not been well characterized. Herein, we report the case of an 85-year-old pacemaker dependant female who was diagnosed with TCM four weeks following the demise of her husband. Abnormal negative T wave concordance in precordial leads and QT interval prolongation were the only new ECG findings and these reverted back to baseline on followup

Chip-Scale, Sub-Hz Fundamental Sub-kHz Integral Linewidth 780 nm Laser through Self-Injection-Locking a Fabry-P\'erot laser to an Ultra-High Q Integrated Resonator

Today's state of the art precision experiments in quantum, gravimetry, navigation, time keeping, and fundamental science have strict requirements on the level and spectral distribution of laser frequency noise. For example, the laser interaction with atoms and qubits requires ultra-low frequency noise at multiple offset frequencies due to hyperfine atomic transitions, motional sidebands, and fast pulse sequencing. Chip-scale integration of lasers that meet these requirements is essential for reliability, low-cost, and weight. Here, we demonstrate a significant advancement in atomic precision light sources by realizing a chip-scale, low-cost, 780 nm laser for rubidium atom applications with record-low 640 mHz (white noise floor at 0.2 Hz$^2$/Hz) fundamental and 732 Hz integral linewidths and a frequency noise that is multiple orders of magnitude lower than previous hybrid and heterogeneous self-injection locked 780 nm lasers and lower noise than bulk microresonator implementations. The laser is a Fabry-P\'erot laser diode self-injection locked to an ultra-high Q photonic integrated silicon nitride resonator. This performance is enabled by a 145 million resonator Q with a 30 dB extinction ratio, the highest Q at 780 nm, to the best of our knowledge. We analyze the impact of our frequency noise on specific atomic applications including atomic frequency references, Rydberg quantum gates, and cold atom gravimeters. The photonic integrated resonator is fabricated using a CMOS foundry-compatible, wafer-scale process, with demonstrated integration of other components showing promise for a full system-on-a-chip. This performance is scalable to other visible atomic wavelengths, opening the door to a variety of transitions across many atomic species and enabling low-power, compact, ultra-low noise lasers impacting applications including quantum sensing, computing, clocks and more

The Utility of Repeat Endoscopic Ultrasound-Guided Fine Needle Aspiration for Suspected Pancreatic Cancer

Background. The utility of repeat EUS in patients with suspicion for pancreatic cancer after non-diagnostic EUS-FNA study is not well established. Aim. Determine the accuracy of repeat EUS-FNA in patients with suspected pancreatic cancer and prior non-diagnostic EUS-FNA. Methods. Retrospective cohort study. Results. From 2002 to 2008 in our institution 28 patients underwent repeat EUS-FNA for suspected pancreatic cancer. Initial EUS showed a pancreatic mass in 24 (85.71%), no mass in 3 (10.71%) and possible mass in 1 (3.58%). FNA was performed and was negative for malignancy in all patients. Repeat EUS showed pancreatic mass in 27 patients (96.42%) and no mass in 1 (3.58%). FNA was performed in all patients and cytology was positive for malignancy in 6 (21.43%). Out of the 28 patients, 17 (60.71%) were eventually confirmed to have cancer. Overall repeat EUS-FNA correctly determined the true final status in 17 out of 28 patients providing sensitivity for the diagnosis of cancer of 35% (95% CI 14%–62%), specificity 100% (95% CI 72%–100%), and overall accuracy of 61%, (95% CI 28%–72%). Conclusion. Repeat EUS-FNA provides reasonable accuracy and may be worthwhile in patients with suspected pancreatic cancer who had had prior negative EUS-FNA

Immune Checkpoint Inhibitors in Neuroendocrine Tumors: A Single Institution Experience With Review of Literature

This unique case series and review of literature suggests that immune checkpoint inhibitors may have clinical activity in neuroendocrine tumors. Objective: Summarize advances of immuno-oncology in neuroendocrine tumors with the help of a case series. Design: Case series and review of literature. Intervention or Exposure: The patients were treated with immune checkpoint inhibitors (pembrolizumab or nivolumab). Main Outcome(s) and Measures(s): Life expectancy, quality of life, disease progression. Results: Maximum durable response of 16 months in one of the patients so far. All patients showed improvement in quality of life before disease progression. Two out of four are still on therapy. None of the patients experienced immune checkpoint inhibitor associated side-effects. All patients had failed standard of care therapy prior to the initiation of immune checkpoint inhibitors and were on the verge of hospice. Conclusions: Immune checkpoint inhibitors have revolutionized cancer management and the last 5 years have seen a rapid expansion in the indications for this class of drug. Neuroendocrine tumors, unfortunately, have been slow to catch on to the immuno-oncology, partly due to difficulties in establishing relevant preclinical neuroendocrine tumors models for immune-oncology studies. In this manuscript, we review the current status of immunotherapy in neuroendocrine tumors

Immune Checkpoint Inhibitors in Large Cell Neuroendocrine Carcinoma: Current Status

Introduction: Large cell neuroendocrine carcinomas (LCNEC) are a group of rare high grade neuroendocrine tumors that often behave clinically like small cell carcinoma (SCLC) and are treated as such. No major advancement in the management of these tumors has occurred in the last 30 years. Methods: We present a case series of three cases from Markey Cancer center along with a review of 13 published cases in the literature wherein immune-checkpoint inhibitors were utilized in the management of LCNEC. Results: Immune-checkpoint inhibitors might have clinical activity in LCNEC. Conclusion: Role of immune-checkpoint inhibitors should be explored in prospective LCNEC clinical trials. We summarize current evidence regarding use of immune checkpoint inhibitors in the treatment of LCNEC

Radiopharmaceutical Validation for Clinical Use

Radiopharmaceuticals are reemerging as attractive anticancer agents, but there are no universally adopted guidelines or standardized procedures for evaluating agent validity before early-phase trial implementation. To validate a radiopharmaceutical, it is desirous for the radiopharmaceutical to be specific, selective, and deliverable against tumors of a given, molecularly defined cancer for which it is intended to treat. In this article, we discuss four levels of evidence—target antigen immunohistochemistry, in vitro and in vivo preclinical experiments, animal biodistribution and dosimetry studies, and first-in-human microdose biodistribution studies—that might be used to justify oncology therapeutic radiopharmaceuticals in a drug-development sequence involving early-phase trials. We discuss common practices for validating radiopharmaceuticals for clinical use, everyday pitfalls, and commonplace operationalizing steps for radiopharmaceutical early-phase trials. We anticipate in the near-term that radiopharmaceutical trials will become a larger proportion of the National Cancer Institute Cancer Therapy Evaluation Program (CTEP) portfolio

Gynecologic Large Cell Neuroendocrine Carcinoma: A Review

Large cell neuroendocrine carcinomas (LCNEC) are rare, aggressive high-grade neuroendocrine neoplasms within the neuroendocrine cell lineage spectrum. This manuscript provides a detailed review of published literature on LCNEC of gynecological origin. We performed a PubMed search for material available on gynecologic LCNEC. We analyzed 104 unique cases of gynecologic LCNECs, of which 45 were cervical primary, 45 were ovarian, 13 were uterine, and 1 was vaginal. A total of 45 cases of cervical LCNEC were identified with a median age of 36 years. Median overall survival was 16 months. We identified 45 ovarian LCNEC cases in the published literature with a median age of 54 years. Median overall survival was 8 months. 13 LCNEC cases of uterine origin were identified; 12 out of 13 were of endometrial origin and the median age was 71 years. The majority of patients presented with Stage III/IV disease (stages I–IV were 31%, 8%, 38%, and 23%, respectively). Gynecologic LCNEC is an aggressive malignancy. Our current understanding of the disease biology is very limited. Efforts are required to better understand the genomic and molecular characterizations of gynecological LCNEC. These efforts will elucidate the underlying oncogenic pathways and driver mutations as potential targets

Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan.

Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed

Synthesis and characterisation of pyrene-labelled polydimethylsiloxane networks: towards the in situ detection of strain in silicone elastomers

Pyrene-substituted polyhydromethylsiloxanes (PHMS-Py-x) were synthesised by the hydrosilylation reaction of prop-3-enyloxymethylpyrene with polyhydromethylsiloxane (M-n = 3700). The ratio of pyrene substituent to Si-H unit was varied to afford a range of pyrene-functionalised polysiloxanes. These copolymers were subsequently incorporated into polydimethylsiloxane (PDMS) elastomers by curing via either Pt(0) catalysed hydrosilylation with divinyl-terminated PDMS (M-n = 186) and tetrakis(dimethylsiloxy) silane, or Sn(II) catalysed condensation with alpha,omega-dihydroxyPDMS (M-n = 26 000) and tetraethoxysilane. An alternative method involving the synthesis and integration of [3-(pyren-1-ylmethoxy)propyl]triethoxysilane (Py-TEOS) into PDMS elastomers was also investigated: a mixture of alpha,omega-dihydroxyPDMS (M-n = 26 000), tetraethoxysilane, and Py-TEOS was cured using an Sn( II) catalyst. Certain of the resulting fluorescent pyrene-labelled elastomers were studied by differential scanning calorimetry and dynamic mechanical analysis. No significant changes were observed in the thermal or mechanical properties of the elastomers containing pyrene when compared to otherwise identical samples not containing pyrene. All of the pyrene-containing elastomers were demonstrated to be fluorescent under suitable excitation in a photoluminescent spectrometer. Two of the elastomers were placed in a photoluminescence spectrometer and subjected to cycles of extension and relaxation (strain = 0-16.7%) while changes in the emission spectra were monitored. The resulting spectra of the elastomer containing the PHMS-Py-50 copolymers were variable and inconsistent. However, the emission peaks of elastomers containing Py-TEOS displayed clear and reproducible changes in fluorescence intensity upon stretching and relaxation. The intensity of the monomer and excimer emission peaks was observed to increase with elongation of the sample and decrease upon relaxation. Furthermore, the ratio of the intensities of the excimer : monomer peak decreased with elongation and increased with relaxation. In neither case was there appreciable hysteresis, suggesting that fluorescent labelling of elastomers is a valid approach for the non-invasive in situ monitoring of stress and strain in such materials

Global Burden of Neuroendocrine Tumors and Changing Incidence in Kentucky

Background: Neuroendocrine tumors (NETs) have a low incidence but relatively high prevalence. Over the last three decades, the incidence of NETs has risen 6-fold in the United States. We conducted an observational study to compare the incidence of NETs reported to the Kentucky Cancer Registry (KCR) versus that reported to Surveillance, Epidemiology, and End Results Program (SEER). We also provide a systematic review of the state of neuroendocrine tumors worldwide, and compare the available global and local published data. Methods: KCR and SEER databases were queried for NET cases between 1995 and 2015. A detailed literature review of epidemiological data for various nations worldwide summarize epidemiological data from various countries. Results: KCR recorded 6179 individuals with newly diagnosed NETs between 1995 and 2015. Between 1995-2012, the incidence of NETs in KCR increased from 3.1 to 7.1 per 100,000 cases, while it increased from 3.96 to 6.61 in the SEER database. The incidence rates in both KCR and SEER databases were linear. 90.57% were Caucasians with 54.74% females. 27.67% of the Kentucky population was from the Appalachian region. Patients aged 50-64 years had the highest prevalence (38%). Lung NET (30.60%) formed the bulk of cases, followed by small intestine (16.82%), rectum/anus (11.35%) and colon (9.71%). Conclusions: NETs incidence between 1995 and 2015 show a linear increase in both KCR and SEER databases. Because of this increased incidence it is imperative for community oncologists to familiarize themselves with this entity, which until recently was under-studied and with few viable treatment options