An Ontario Health (Cancer Care Ontario) Clinical Practice Guideline: Surveillance Strategies in Patients with Stage I, II, III or Resectable IV Melanoma Who Were Treated with Curative Intent.

AIMS: To make recommendations on managing the surveillance of patients with stage I, II, III or resectable IV melanoma who are clinically free of disease following treatment with curative intent. MATERIALS AND METHODS: This guideline was developed by Ontario Health's (Cancer Care Ontario's) Program in Evidence-Based Care and the Melanoma Disease Site Group (including seven medical oncologists, four surgical oncologists, three dermatologists, one radiation oncologist and one patient representative). The MEDLINE, EMBASE, Cochrane Library, PROSPERO databases and the main relevant guideline websites were searched. Internal and external reviews were conducted, with final approval by the Program in Evidence-Based Care and the Melanoma Disease Site Group. The Grading of Recommendations, Assessment, Development and Evaluation approach was followed, and the Modified Delphi method was used. RESULTS: Based on the current evidence (eight eligible original study papers and four relevant guidelines) and the clinical opinions of the authors of this guideline, the initial recommendations were made. To reach 75% agreement for each recommendation, the Melanoma Disease Site Group (16 members) voted twice and one recommendation was voted on three times. After a comprehensive internal and external review process (including national and international reviewers), 12 recommendations, three weak recommendations and six qualified statements were ultimately made. CONCLUSIONS: After a systematic review, a comprehensive internal and external review process and a consensus process, the current guideline has been created. The guideline authors believe that this guideline will help clinicians, patients and policymakers make well-informed healthcare decisions that will guide them in clinical melanoma surveillance and ultimately assist in improving patient outcomes.

Mini review: Breast cancer care in individuals with differences of sexual development.

Disorders or differences of sexual development encompasses an important group of conditions that affects up to 1 in 5,000 live births. Many individuals living in the female gender includes Turner syndrome, congenital adrenal hyperplasia and conditions with 46XY karyotype such as gonadal dysgenesis (Swyer syndrome). Individuals are commenced on high dose oestrogen to initiate and maintain development of secondary sexual characteristics such as breasts which is paramount in them identifying in the female gender. We highlight the first case of a patient with Swyer syndrome who was treated with long term oestrogen therapy and later developed breast cancer. In individuals with gonadal dysgenesis, testicular malignancy is a recognised risk and is screened for. Prolonged exposure to exogenous and endogenous hormones can increase the risk of breast cancer however how much this risk increases in those taking high dose hormones is not documented in the literature. We aim to highlight the importance of breast cancer treatment and surgical reconstruction in this group and whether they should be considered for early breast cancer screening. CONCLUSION: It is imperative that triple assessment is undertaken in every patient with a breast lump, regardless of gender identification. Clinicians must not delay investigations in this patient group due to a misunderstanding of their condition. Those on long term hormone supplementation should be entered into the breast screening program at an earlier age with Magnetic Resonance Imaging surveillance. Careful consideration of post treatment endocrine therapy is required and under the care of the multi-disciplinary team.

PLGA-Nano-Encapsulated Disulfiram Inhibits Hypoxia-Induced NF-κB, Cancer Stem Cells, and Targets Glioblastoma In Vitro and In Vivo.

Glioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NF-κB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Disulfiram, an antialcoholism drug, has very strong NF-κB-inhibiting and anti-CSC activity. In this study, the in vitro anti-GSC activity of disulfiram and in vivo anti-GBM efficacy of poly lactic-co-glycolic acid nanoparticle-encapsulated disulfiram (DS-PLGA) were examined. We attempt to elucidate the molecular network between hypoxia and GSCs and also examined the anti-GSC activity of disulfiram in vitro and in vivo. The influence of GSCs and hypoxia on GBM chemoresistance and invasiveness was studied in hypoxic and spheroid cultures. The molecular regulatory roles of NF-κB, hypoxia-inducible factor-1α (HIF1α), and HIF2α were investigated using stably transfected U373MG cell lines. The hypoxia in neurospheres determines the cancer stem cell characteristics of the sphere-cultured GBM cell lines (U87MG, U251MG, U373MG). NF-κB is located at a higher hierarchical position than HIF1α/HIF2α in hypoxic regulatory network and plays a key role in hypoxia-induced GSC characters. DS inhibits NF-κB activity and targets hypoxia-induced GSCs. It showed selective toxicity to GBM cells, eradicates GSCs, and blocks migration and invasion at very low concentrations. DS-PLGA efficaciously inhibits orthotopic and subcutaneous U87MG xenograft in mouse models with no toxicity to vital organs.

Systemic adjuvant therapy for adult patients at high risk for recurrent cutaneous or mucosal melanoma: an Ontario Health (Cancer Care Ontario) clinical practice guideline.

Background: Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma. Methods: The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. Recommendations: For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wild-type disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial.

Transverse-Field Ising Dynamics in a Rydberg-Dressed Atomic Gas.

We report on the realization of long-range Ising interactions in a cold gas of cesium atoms by Rydberg dressing. The interactions are enhanced by coupling to Rydberg states in the vicinity of a Förster resonance. We characterize the interactions by measuring the mean-field shift of the clock transition via Ramsey spectroscopy, observing one-axis twisting dynamics. We furthermore emulate a transverse-field Ising model by periodic application of a microwave field and detect dynamical signatures of the paramagnetic-ferromagnetic phase transition. Our results highlight the power of optical addressing for achieving local and dynamical control of interactions, enabling prospects ranging from investigating Floquet quantum criticality to producing tunable-range spin squeezing.

Isolated diastolic hypertension and its risk factors in semi-rural population of South India.

BACKGROUND: Isolated diastolic hypertension (IDH) has been actively discussed for the last two decades because of its prevalence in a younger population and its association with cardiovascular disease. Furthermore, the association of IDH is significant in South Asian Countries such as India because relatively younger populations are known to have a higher risk of cardiovascular events. OBJECTIVE: The objective of this study is to find prevalence of IDH and its risk correlates in a semiurban population of South Indian state of Andhra Pradesh. METHODS: Data were collected using the modified World Health Organization - STEPwise approach to Surveillance (WHO STEPS) questionnaire for 16,636 individuals from a group of villages under Thavanampalle Mandal. Collated data were analyzed for prevalence and risk factors of IDH. RESULTS: Prevalence of IDH was found to be 4.0% with mean age of 46.0 (±SD 13.6) years and a relatively higher prevalence in men (5.3%) as compared with women (3.2%). The prevalence of IDH peaked in the fifth decade of life (40-49 years of age) and declined thereafter. Among various risk factors that were analyzed for their association with IDH, only age, body weight, and body mass index retained their significance in multivariate binary logistic regression analysis. CONCLUSION: There is a significant prevalence of IDH below 50 years of age in the semiurban population of South India. As IDH in young and middle age is known to be associated with increased risk of cardiovascular events and end organ involvement, it highlights need for study and development of effective IDH management strategies to reduce associated morbidity and mortality.

A High-Efficiency Multispectral Filter Based on Plasmonic Hybridization between Two Cascaded Ultrathin Nanogratings.

Overcoming the disadvantages of low transmission and broad peak bandwidth of previously reported plasmonic color filters, a high-efficiency multispectral plasmonic color filter is theoretically proposed with two cascaded ultrathin metallic nanogratings separated by two heterogeneous dielectric layers, and its optical properties are theoretically investigated using the finite-difference time-domain method. The transmission spectrum presents three near-unity peak bands accompanied with three near-null dip bands adjacent around them. Both transmission efficiencies of above 90% and ultranarrow peak bandwidth of 20 nm are achieved in the visible regime. The peak band positions can be flexibly tailored by varying the structural parameters. The filter selects the visible color with high signal noise ratio at the peak bands. The outstanding spectral properties of this filter indicate significant improvement for the high-accuracy color filtering and multispectral imaging applications. The simulated near-field electromagnetic distributions suggest that the excitation of the hybrid antisymmetric surface plasmon polariton (SPP) leaky mode and metal-insulator-metal waveguide modes are responsible for the peak transmission bands, while the formation of the hybrid SPP bound modes confined on the bottom nanograting makes the dip transmission bands, all of which are the consequence of the plasmonic hybridization between the two neighboring metallic nanogratings.

The Cytotoxicity and Synergistic Potential of Aspirin and Aspirin Analogues Towards Oesophageal and Colorectal Cancer.

BACKGROUND: Oesophageal cancer (OC) is a deadly cancer because of its aggressive nature with survival rates that have barely improved in decades. Epidemiologic studies have shown that low-dose daily intake of aspirin can decrease the incidence of OC. METHODS: The toxicity of aspirin and aspirin derivatives to OC and a CRC cell line were investigated in the presence and absence of platins. RESULTS: The data in this study show the effects of a number of aspirin analogues and aspirin on OC cell lines that originally presented as squamous cell carcinoma (SSC) and adenocarcinoma (ADC). The aspirin analogues fumaryldiaspirin (PN517) and the benzoylsalicylates (PN524, PN528 and PN529), were observed to be more toxic against the OC cell lines than aspirin. Both quantitative and qualitative apoptosis experiments reveal that these compounds largely induce apoptosis, although some necrosis was evident with PN528 and PN529. Failure to recover following the treatment with these analogues emphasized that these drugs are largely cytotoxic in nature. The OE21 (SSC) and OE33 (ADC) cell lines were more sensitive to the aspirin analogues compared to the Flo-1 cell line (ADC). A non-cancerous oesophageal primary cells NOK2101, was used to determine the specificity of the aspirin analogues and cytotoxicity assays revealed that analogues PN528 and PN529 were selectively toxic to cancer cell lines, whereas PN508, PN517 and PN524 also induced cell death in NOK2101. In combination index testing synergistic interactions of the most promising compounds, including aspirin, with cisplatin, oxaliplatin and carboplatin against the OE33 cell line and the SW480 colorectal cancer (CRC) cell line were investigated. Compounds PN517 and PN524, and to a lesser extent PN528, synergised with cisplatin against OE33 cells. Cisplatin and oxaliplatin synergised with aspirin and PN517 when tested against the SW480 cell line. CONCLUSION: These findings indicate the potential and limitations of aspirin and aspirin analogues as chemotherapeutic agents against OC and CRC when combined with platins.

Diagnostic yield in the evaluation of dysphagia: experience at a single tertiary care center.

Evaluation of dysphagia typically starts with esophagogastroduodenoscopy (EGD); further testing is pursued if this is negative. When no mucosal, structural, or motor esophageal disorders are identified with persisting symptoms, functional dysphagia is considered. We evaluated outcomes in patients undergoing EGD for dysphagia, and estimated prevalence of functional dysphagia. The endoscopy database at single tertiary care center was interrogated to identify EGDs performed for an indication of 'dysphagia' over a 12-month period (2008-09). Electronic medical records were reviewed over the next 8 years to assess if an etiology was identified. Data were analyzed to assess the diagnostic yield of endoscopy and subsequent tests in the evaluation of dysphagia. Of 5486 EGDs, 822 (15.0%) were performed for dysphagia in 694 patients (58.4 ± 0.6 year, range: 18-95 year, 55.8% female). Of these, 529 (76.2%) had EGD findings that explained dysphagia; another 22 (3.2%) had findings on histopathology. Of the remainder 143 patients (20.6%) with normal index EGD, 38 (26.6%) patients underwent barium esophagram with 15 (39.5%) having abnormal studies. 19 patients (13.3%) underwent esophageal high resolution manometry with 12 (63.2%) being abnormal, and 7 had a mechanism for dysphagia on alternate testing. A repeat EGD was abnormal in 6 patients, while 45 patients were lost to follow-up. 42 patients had complete resolution of symptoms despite normal endoscopy, of which 30 were treated empirically with a proton pump inhibitor (PPI). Only 16 patients had no findings on evaluation, and had continued dysphagia symptoms, representing true functional dysphagia in 2.3% of all dysphagia patients and 11.2% of patients with normal EGD. Endoscopy remains the test with the highest yield (over 75%) for a diagnosis in patients presenting with dysphagia; secondary tests are useful when endoscopy does not provide a diagnosis. Benign strictures and GERD-related etiologies are leading causes; PPI therapy is useful even when testing is negative. Functional dysphagia is extremely rare, accounting for <2.5% of all dysphagia.

Immuno-detection of cleaved SNAP-25 from differentiated mouse embryonic stem cells provides a sensitive assay for determination of botulinum A toxin and antitoxin potency.

Botulinum toxin type A is a causative agent of human botulism. Due to high toxicity and ease of production it is classified by the Centres for Disease Control and Prevention as a category A bioterrorism agent. The same serotype, BoNT/A, is also the most widely used in pharmaceutical preparations for treatment of a diverse range of neuromuscular disorders. Traditionally, animals are used to confirm the presence and activity of toxin and to establish neutralizing capabilities of countermeasures in toxin neutralization tests. Cell based assays for BoNT/A have been reported as the most viable alternative to animal models, since they are capable of reflecting all key steps (binding, translocation, internalization and cleavage of intracellular substrate) involved in toxin activity. In this paper we report preliminary development of a simple immunochemical method for specifically detecting BoNT/A cleaved intracellular substrate, SNAP-25, in cell lysates of neurons derived from mouse embryonic stem cells. The assay offers sensitivity of better than 0.1LD50/ml (3fM) which is not matched by other functional assays, including the mouse bioassay, and provides serotype specificity for quantitative detection of BoNT/A and anti-BoNT/A antitoxin. Subject to formal validation, the method described here could potentially be used as a substitute for the mouse bioassay to measure potency and consistency of therapeutic products.

Clinical presentation, management, and outcomes in the Indian Heart Rhythm Society-Atrial Fibrillation (IHRS-AF) registry.

AIM: A national atrial fibrillation (AF) registry was conducted under the aegis of the Indian Heart Rhythm Society (IHRS), to capture epidemiological data-type of AF, clinical presentation and comorbidities, current treatment practices, and 1-year follow-up outcomes. METHODS: A total of 1537 patients were enrolled from 24 sites in India in the IHRS-AF registry from July 2011 to August 2012. Their baseline characteristics and follow-up data were recorded in case report forms and subsequently analyzed. RESULTS: The average age of Indian AF patients was 54.7 years. There was a marginal female preponderance - 51.5% females and 48.5% males. At baseline, 20.4% had paroxysmal AF; 33% had persistent AF; 35.1% had permanent AF and 11% had first AF episode. At one-year follow-up, 45.6% patients had permanent AF. Rheumatic valvular heart disease (RHD) was present in 47.6% of patients. Hypertension, heart failure, coronary artery disease, and diabetes were seen in 31.4%, 18.7%, 16.2%, and 16.1%, respectively. Rate control was the strategy used in 75.2% patients, digoxin and beta-blockers being the most frequently prescribed rate-control drugs. Oral anticoagulation (OAC) drugs were used in 70% of patients. The annual mortality was 6.5%, hospitalization 8%, and incidence of stroke 1%. CONCLUSIONS: In India, AF patients are younger and RHD is still the most frequent etiology. Almost two-third of the patients have persistent/permanent AF. At one-year follow-up, there is a significant mortality and morbidity in AF patients in India.

Characteristics of patients who are not resuscitated in out of hospital cardiac arrests and opportunities to improve community response to cardiac arrest.

AIM: This study explores why resuscitation is withheld when emergency medical staff arrive at the scene of a cardiac arrest and identifies modifiable factors associated with this decision. METHODS: This is a secondary analysis of unselected patients who sustained an out of hospital cardiac arrest attended by ambulance vehicles participating in a randomized controlled trial of a mechanical chest compression device (PARAMEDIC trial). Patients were categorized as 'non-resuscitation' patients if there was a do-not-attempt-cardiopulmonary-resuscitation (DNACPR) order, signs unequivocally associated with death or resuscitation was deemed futile (15min had elapsed since collapse with no bystander-CPR and asystole recorded on EMS arrival). RESULTS: Emergency Medical Services attended 11,451 cardiac arrests. Resuscitation was attempted or continued by Emergency Medical Service staff in 4805 (42%) of cases. Resuscitation was withheld in 6646 cases (58%). 711 (6.2%) had a do not attempt resuscitation decision, 4439 (38.8%) had signs unequivocally associated with death and in 1496 cases (13.1%) CPR was considered futile. Those where resuscitation was withheld due to futility were characterised by low bystander CPR rates (7.2%) and by being female. CONCLUSIONS: Resuscitation was withheld by ambulance staff in over one in ten (13.1%) victims of out of hospital cardiac arrest on the basis of futility. These cases were associated with a very low rate of bystander CPR. Future studies should explore strengthening the 'Chain of Survival' to increase the community bystander CPR response and evaluate the effect on the numbers of survivors from out of hospital cardiac arrest.

Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone.

Both term and preterm parturition are characterized by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or co-cultured with PHM1-41 myometrial smooth muscle cells, for 24 h. In a third set of experiments, PHM1-41 myocytes were cultured for 24 h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Co-culture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100 ng/ml). The synergistic secretion of IL-6 and IL-8 from co-cultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from co-cultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from co-cultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS, and can augment myocyte contraction. These effects are all partially inhibited by progesterone.

Inhibition of protein kinase C (PKC) response of voltage-gated calcium (Cav)2.2 channels expressed in Xenopus oocytes by Cavß subunits.

Cav2.2 channels are a substrate for phosphorylation by protein kinase C (PKC) isozymes. The contribution of Cavß, an auxiliary subunit of these channels, in the PKC modulation was studied. Cav2.2 channels were expressed in Xenopus oocytes in various subunit combinations with or without Cavß subunits. Currents were recorded using a two-electrode voltage clamp with barium as the charge carrier (IBa). Acetyl-ß-methylcholine (MCh), an activator of PKCα, potentiated Cav2.2 currents expressed with Cav2.2α1 alone or Cav2.2α1α2/δ. Similarly PKC isozymes α, ßII or ɛ potentiated IBa through Cav2.2α1 subunit channels. In contrast, MCh failed to potentiate currents expressed with Cav2.2α1 and Cavß1b, ß2a, ß3 or ß4 subunits. Similarly, in the presence of Cavß1b subunits, PKC isozymes failed to potentiate these currents; contrarily, PKCs α or ßII decreased the IBa. MCh failed to potentiate Cav2.2α1 subunit currents in the serine/threonine (Ser/Thr)→alanine mutants, T422A, S1757A or S2132A of Cav2.2α1 subunits. Hence Thr-422, Ser-1757 and Ser-2132 may be PKCα isozyme target sites. The action of PKC on these sites was further substantiated by the increased basal IBa along with the loss of MCh potentiation when Ser/Thr was mutated to aspartate. The observation that MCh or PKC isozymes failed to affect Cav2.2 currents in the presence of Cavß subunits suggests that these subunits may have interfered with the interaction between PKC and Ser/Thr sites of Cav2.2α1 subunits. In addition to affecting channel expression and current kinetics, Cavß subunits may also modulate the response of these channels to neurochemicals.