Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy

Background: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.Patients and methods: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.Results: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors.Conclusions: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.</p

The Promise and Challenge of Therapeutic MicroRNA Silencing in Diabetes and Metabolic Diseases

MicroRNAs (miRNAs) are small, non-coding, RNA molecules that regulate gene expression. They have a long evolutionary history and are found in plants, viruses, and animals. Although initially discovered in 1993 in Caenorhabditis elegans, they were not appreciated as widespread and abundant gene regulators until the early 2000s. Studies in the last decade have found that miRNAs confer phenotypic robustness in the face of environmental perturbation, may serve as diagnostic and prognostic indicators of disease, underlie the pathobiology of a wide array of complex disorders, and represent compelling therapeutic targets. Pre-clinical studies in animal models have demonstrated that pharmacologic manipulation of miRNAs, mostly in the liver, can modulate metabolic phenotypes and even reverse the course of insulin resistance and diabetes. There is cautious optimism in the field about miRNA-based therapies for diabetes, several of which are already in various stages of clinical trials. This review will highlight both the promise and the most pressing challenges of therapeutic miRNA silencing in diabetes and related conditions

Cancers of unknown primary origin: current perspectives and future therapeutic strategies

It is widely accepted that systemic neoplastic spread is a late event in tumour progression. However, sometimes, rapidly invasive cancers are diagnosed because of appearance of metastatic lesions in absence of a clearly detectable primary mass. This kind of disease is referred to as cancer of unknown primary (CUP) origin and accounts for 3-5% of all cancer diagnosis. There is poor consensus on the extent of diagnostic and pathologic evaluations required for these enigmatic cases which still lack effective treatment. Although technology to predict the primary tumour site of origin is improving rapidly, the key issue is concerning the biology which drives early occult metastatic spreading. This review provides the state of the art about clinical and therapeutic management of this malignant syndrome; main interest is addressed to the most recent improvements in CUP molecular biology and pathology, which will lead to successful tailored therapeutic options

On the selection of ground-motion attenuation relations for seismic hazard assessment of the Peninsular Malaysia region due to distant Sumatran subduction intraslab earthquakes

The assessment of seismic hazard from seismicity especially those induced by either subduction interface or intraslab earthquakes requires appropriate ground-motion attenuation relations that are tuned to a suitable magnitude-distance range. The Peninsular Malaysia region could be subject to a remarkable seismic hazard due to the large-magnitude, long-distance earthquakes from the Sumatran subduction zone. The earthquakes from Sumatran subduction intraslab zone have not been taken into special consideration in terms of applying the applicable ground-motion relations in the most previous probabilistic seismic hazard assessment (PSHA) studies for the region. This study has attempted first to derive response spectral ground-motion attenuation relations for distant subduction intraslab earthquakes based on the ground-motion data recorded in Peninsular Malaysia, Japan, and Iran. The response spectra database has been compiled from hundreds of ground motions from subduction intraslab events of moment magnitude (M) 5.0-7.7 recorded at sites with hypocentral distance (Rhyp) of about 120 up to 1400 km. The proposed empirical relations are for peak ground acceleration (PGA), peak ground velocity (PGV), and 5% damped pseudo-acceleration (PSA) for four site classes (i.e., National Earthquake Hazards Reduction Program (NEHRP) site classes B, C, D, and E). Second, an evaluation of the applicability of the present study, the global and overseas regional ground-motion relations to the Sumatran subduction intraslab earthquakes has been presented in order to develop ground-motion logic tree for seismic hazard assessment in the Peninsular Malaysia region

Seismic hazard analysis for east Malaysia; based on a proposed ground motion prediction equation

The seismic hazard analysis requires an estimation of ground motion intensity where the process needs to use a compatible ground motion prediction equation or GMPE, which provides ground acceleration estimates in a function of earthquake magnitude and distance. Hence, the effect of current equation often does not accurately represent the earthquake condition in East Malaysia region. In this study, the characteristics of low-to-moderate databases were used and derived by regression analysis in terms of horizontal peak ground acceleration (PGA). The appropriate GMPE design for East Malaysia is based on the ground motion records compiled from strike slip earthquakes that occurred within 10 to 1,350 km. This earthquake data is based on actual data recorded at a broad range of magnitude levels within a wide range of distances. The new equation is used to predict the PGA value throughout East Malaysia by probabilistic method. PSHA is a method to analyse seismic hazard assessment using probability concept by considering the uncertainties of the size, location and rate of occurrence of earthquake and the variation of ground motion characteristics. The four well-known existing attenuation functions are evaluated with current equation to highlight their limitations in magnitude and distance. With a more complete collection of earthquake databases, GMPE has become more reliable. The GMPE of peak ground acceleration for low-to-moderate earthquake at long distance was found to be logarithmically distributed. The equation provides ease in both implementation and interpretation of physical parameters with a comparable standard deviation

Increased MicroRNA levels in women with polycystic ovarian syndrome but without insulin resistance: a pilot prospective study

Background: Small noncoding microRNA (miRNA) have regulatory functions in polycystic ovary syndrome (PCOS) that differ to those in women without PCOS. However, little is known about miRNA expression in women with PCOS who are not insulin resistant (IR). Methods: Circulating miRNAs were measured using quantitative polymerase chain reaction (qPCR) in 24 non-obese BMI and age matched women with PCOS and 24 control women. A miRNA data set was used to determine miRNA levels. Results: Women with PCOS showed a higher free androgen index (FAI) and anti-mullerian hormone (AMH) but IR did not differ. Four miRNAs (miR-1260a, miR-18b-5p, miR-424-5p, and miR let-7b-3p) differed between control and PCOS women that passed the false discovery rate (FDR) out of a total of 177 circulating miRNAs that were detected. MiRNA let-7b-3p correlated with AMH in PCOS (p < 0.05). When the groups were combined, miR-1260a correlated with FAI and let-7b-3p correlated with body mass index (BMI) (p < 0.05). There was no correlation to androgen levels. Ingenuity pathway analysis showed that nine of the top 10 miRNAs reported were associated with inflammatory pathways. Conclusion: When IR did not differ between PCOS and control women, only four miRNA differed significantly suggesting that IR may be a driver for many of the miRNA changes reported. Let-7b-3p was related to AMH in PCOS, and to BMI as a group, whilst miR-1260a correlated with FAI. Androgen levels, however, had no effect upon circulating miRNA profiles. The expressed miRNAs were associated with the inflammatory pathway involving TNF and IL6

Lithium Storage Properties of Pristine and (Mg, Cu) Codoped ZnFe₂O₄ Nanoparticles

ZnFe₂O₄ and Mg_<i>x</i>Cu_0.2Zn_{0.82–<i>x</i>}Fe_1.98O₄ (where <i>x</i> = 0.20, 0.25, 0.30, 0.35, and 0.40) nanoparticles were synthesized by sol–gel assisted combustion method. X-ray diffraction (XRD), FTIR spectroscopy, Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Brunauer–Emmett–Teller (BET) surface area studies were used to characterize the synthesized compounds. ZnFe₂O₄ and the doped compounds crystallize in <i>Fd</i>3<i>m</i> space group. The lattice parameter of ZnFe₂O₄ is calculated to be <i>a</i> = 8.448(3) Å, while the doped compounds show a slight decrease in the lattice parameter with an increase in the Mg content. The particle size of all the compositions are in the range of ∼50–80 nm, and the surface area of the compounds are in the range of 11–12 m² g^–1. Cyclic voltammetry (CV), galvanostatic cycling, and electrochemical impedance spectroscopy (EIS) studies were used to investigate the electrochemical properties of the different compositions. The as-synthesized samples at 600 °C show large-capacity fading, while the samples reheated at 800 °C show better cycling stability. ZnFe₂O₄ exhibits a high reversible capacity of 575 mAh g^–1 after 60 cycles at a current density of 100 mA g^–1. Mg_0.2Cu_0.2Zn_0.62Fe_1.98O₄ shows a similar capacity of 576 mAh g^–1 after 60 cycles with better capacity retention

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy

Background: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. Patients and methods: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. Results: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. Conclusions: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1