We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ...ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2-19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4⁺CD25hi⁺Foxp3⁺) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4⁺ and CD8⁺ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8⁺ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69⁺) CD3⁺/CD4⁺ and CD3⁺/CD8⁺ T cells with evidence of induction/potentiation of memory T cells (CD45RO⁺). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The increasing use of renewable energy sources necessitates accurate forecasting models for generation scheduling. Amongst the renewable sources, solar and wind have gained acceptance and are being ...increasingly used in distributed generation. The main problem with these sources is the dependence of their power output on natural environmental parameters at a given point of time. This paper proposes time series models for short-term prediction of solar irradiance from which solar power can be predicted. The predictions are done for 1 day ahead using different time-series models. For each model, these predicted values are compared with the actual values for the next day and graphs are plotted. Basic time-series models such as moving average and exponential smoothing were tested. The decomposition model is proposed, where the measured data is decomposed into seasonal and trend patterns and each of them predicted separately. The model was developed for different durations of data, to identify the best possible set of data. It is observed from the results that the prediction with decomposition model for 2 months data gave the best result with around 9.28% error.
•This paper proposes time series models for short-term prediction of solar irradiance.•The predictions are done for 1 day ahead using different time-series models.•Basic time-series models like moving average and exponential smoothing were tested.•The decomposition model is proposed and each decomposed series is forecasted separately.•Tested with different duration of data viz. 1, 2 and 9 months and errors compared.
Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia ...virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 109 pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.
Pseudomyogenic hemangioendothelioma (PHE) is an uncommon neoplasm with propensity for local recurrence. The tumor mimics epithelioid hemangioendothelioma and epithelioid sarcoma, representing a ...possible diagnostic pitfall. We investigated the clinicopathological, immunohistochemical, and fluorescence in situ hybridization features of PHEs. Eight cases of PHE were retrieved from our pathology archives. The clinical and outcome information was available in 6 patients. In 6 cases, the tumors were located in the lower limb, whereas the upper limb was involved in 2 cases. Three patients had exclusively bone involvement, and 2 patients had cutaneous tumor only. The tumor was multifocal in 5 cases, of which 2 patients had simultaneous bone and soft tissue involvement. Immunohistochemical stains revealed all tumors to be positive for AE1/AE3 (8/8), ERG (7/7), and FLI-1 (7/7) with preserved INI1 (7/7) expression. Most of the tumors were variably positive for CD31 (7/8), CAM5.2 (2/3), and SMA (4/6). t(7;19)(q22;q13) fusion pattern was detected in 3 cases (5 tumors) with cutaneous and multifocal PHE. In 3 cases, a translocation pattern was detected in a few nuclei but did not meet our laboratory cutoff value. MYC amplification was not detected in any of the 5 cases examined, aiding in ruling out the possibility of angiosarcoma. Four patients underwent excision, and 2 with multifocal tumor required below-knee amputation. Six patients with outcome information were alive and free of disease after a median follow-up of 35 months. We conclude that ancillary techniques can be helpful in differentiating this unusual indolent tumor from potentially aggressive epithelioid hemangioendothelioma, epithelioid sarcoma, and epithelioid angiosarcoma. Long-term follow-up is warranted.
•We report a series of PHEs arising in different anatomic sites.•We identify the first 2 cases of cutaneous PHE with t(7;19)(q22;q13) translocation.•Potentially aggressive mimics of PHE can be differentiated by ancillary techniques.•Recurrent and multifocal tumors may require amputation and chemotherapy.•Long-term follow-up is warranted because of its potential to recur and metastasize.
Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). ...E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI.
E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI.
Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio HR, 0.78; 95.6% repeated CI, 0.61 to 0.99;
= .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09;
= .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (
≤ .001).
Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.
This study represents the first attempt to perform a profiling analysis of the intergenerational differences in the microRNAs (miRNAs) of primary cutaneous melanocytic neoplasms in young adult and ...older age groups. The data emphasize the importance of these master regulators in the transcriptional machinery of melanocytic neoplasms and suggest that differential levels of expressions of these miRs may contribute to differences in phenotypic and pathologic presentation of melanocytic neoplasms at different ages.
An exploratory miRNA analysis of 666 miRs by low density microRNA arrays was conducted on formalin fixed and paraffin embedded tissues (FFPE) from 10 older adults and 10 young adults including conventional melanoma and melanocytic neoplasms of uncertain biological significance. Age-matched benign melanocytic nevi were used as controls.
Primary melanoma in patients greater than 60 years old was characterized by the increased expression of miRs regulating TLR-MyD88-NF-kappaB pathway (hsa-miR-199a), RAS/RAB22A pathway (hsa-miR-204); growth differentiation and migration (hsa-miR337), epithelial mesenchymal transition (EMT) (let-7b, hsa-miR-10b/10b*), invasion and metastasis (hsa-miR-10b/10b*), hsa-miR-30a/e*, hsa-miR-29c*; cellular matrix components (hsa-miR-29c*); invasion-cytokinesis (hsa-miR-99b*) compared to melanoma of younger patients. MiR-211 was dramatically downregulated compared to nevi controls, decreased with increasing age and was among the miRs linked to metastatic processes. Melanoma in young adult patients had increased expression of hsa-miR-449a and decreased expression of hsa-miR-146b, hsa-miR-214*. MiR-30a* in clinical stages I-II adult and pediatric melanoma could predict classification of melanoma tissue in the two extremes of age groups. Although the number of cases is small, positive lymph node status in the two age groups was characterized by the statistically significant expression of hsa-miR-30a* and hsa-miR-204 (F-test, p-value < 0.001).
Our findings, although preliminary, support the notion that the differential biology of melanoma at the extremes of age is driven, in part, by deregulation of microRNA expression and by fine tuning of miRs that are already known to regulate cell cycle, inflammation, Epithelial-Mesenchymal Transition (EMT)/stroma and more specifically genes known to be altered in melanoma. Our analysis reveals that miR expression differences create unique patterns of frequently affected biological processes that clearly distinguish old age from young age melanomas. This is a novel characterization of the miRnomes of melanocytic neoplasms at two extremes of age and identifies potential diagnostic and clinico-pathologic biomarkers that may serve as novel miR-based targeted modalities in melanoma diagnosis and treatment.
Childhood maltreatment has been known to produce long-lasting impairments in behavioral, cognitive and social functioning, but their underlying mechanisms are not well-understood. A better ...understanding of their underlying mechanisms will aid in developing effective preventive interventions. Nineteen adolescent volunteers with no personal history of a psychiatric illness, but who were exposed to maltreatment during childhood, and 13 adolescent volunteers with no personal or family history of a psychiatric disorder (controls) underwent diffusion tensor imaging (DTI) studies. The participants were then followed longitudinally at 6-month intervals for up to 5 years to determine the onset of mood and substance use disorders. The associations among fractional anisotropy (FA) values obtained from the DTI scans at baseline and psychopathology at follow-up were examined. At baseline, adolescents exposed to childhood maltreatment had significantly lower FA values in the left and right superior longitudinal fasciculi, right cingulum bundle projecting to the hippocampus, left inferior fronto-occipital fasciculus, and splenium of the corpus callosum compared with controls. Adolescents who developed major depressive disorder at follow-up had significantly lower FA values in the superior longitudinal fasciculi and the right cingulum-hippocampal projection compared with their counterparts who did not develop the illness. Adolescents who developed substance use disorder during follow-up had significantly lower FA values in the right cingulum-hippocampal projection than their counterparts without the disorder. These preliminary results suggest that white matter disruptions observed in adolescents exposed to childhood maltreatment may be associated with increased vulnerability to psychopathology, specifically depressive and substance use disorders.
This study analyzed gene expression patterns and global genomic alterations in hepatocellular carcinomas (HCC), hepatoblastomas (HPBL), tissue adjacent to HCC and normal liver tissue derived from ...normal livers and hepatic resections. We found that HCC and adjacent non‐neoplastic cirrhotic tissue have considerable overlap in gene expression patterns compared to normal liver. Several genes including Glypican 3, spondin‐2, PEG10, EDIL3 and Osteopontin are over‐expressed in HCC vs. adjacent tissue whereas Ficolin 3 is the most consistently under‐expressed gene. HCC can be subdivided into three clusters based on gene expression patterns. HCC and HPBL have clearly different patterns of gene expression, with genes IGF2, Fibronectin, DLK1, TGFb1, MALAT1 and MIG6 being over‐expressed in HPBL versus HCC. In addition, specific areas of the genome appear unstable in HCC, with the same regions undergoing either deletion or increased gene dosage in all HCC. In conclusion, a set of specific genes and areas of genomic instability are found across the board in liver neoplasia. (HEPATOLOGY 2006.)
Global climatic changes and increased carbon footprints provided the main impetus for the decrease in the use of fossil fuels for electricity generation and transportation. Matured manufacturing ...technologies of solar PV panels and on-shore and off-shore windmills have brought down the cost of generation of electricity using solar energy on par with conventional fossil fuel. Initially, solar and wind power generation was envisioned for microgrids, serving small local communities. However, advancements in power electronics have now facilitated large solar and wind farms to be integrated with main power grids. In this context, hosting capacity, which is the amount of distributed energy resources a grid can accommodate, without significant infrastructure up-gradation, has gained importance. In determining the hosting capacity at a particular location, the uncertainties of wind and solar power generation play a role. Effective forecasting models using time-series weather data can be built to predict wind and solar power generation. This forecast is essential to ensure proper grid operation and control when renewable energy sources are already installed. The forecast is also useful in the planning stages for investment decisions and distribution system planning. While long-term forecasts are rarely needed for the operation of integrated grids, accurate short-term predictive models are necessary for scheduling. This paper presents an extensive review of various forecast models available in the literature. The study mainly focuses on the short-term forecast, providing a critical review of the duration of data used in each model and a synoptic comparison of their performance indices.
One of the main protection issues is the possible malfunctioning of protection devices under fault conditions in microgrids with integrated distributed energy resources (DERs). In this paper, a novel ...method of positive-negative sequence (PNS) compensation for grid connected distributed generator (DG) converters with enhanced low voltage ride-through (LVRT) capability in micro grid system is presented. The aim is to maintain the connection of the DGs by injecting the required reactive power considering the limitations imposed by grid codes. In the proposed scheme, a flexibility is provided in terms of active and reactive current injection such that the DGs can stay connected to the grid longer and produce more active power during the fault; while, in previous studies, usually a constant reactive current defined by grid codes was applied. The suitability of the proposed method in terms of utilization of current capacity of the converter is evaluated through comparative study with three other PNS current injection methods. Further, the time taken to disconnect the DGs from the grid in the event of fault is analyzed. The simulation results indicate that DGs can stay connected for longer with 99.98% utilization of converter current capacity compared to other methods.
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