Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need.
...Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out.
The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29–7.75 and of progression (HR = 4.10; 95% CI 3.08–5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR.
Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.
•Development of a domestic microgrid and house thermal model.•Model Predictive Control for simultaneous management of power flow and thermal comfort.•Modeling of summer and winter typical ...conditions.•Comparison with standard rule based controller results.•Fuel cell downsizing potential of output is up to 60%.
In this paper a Model Predictive Control (MPC) logic, based on weather forecasts, has been applied to the analysis of power management in a domestic off-grid system. The system is laid out as the integration of renewable energy conversion devices (Photovoltaic, PV), a high efficiency energy conversion programmable system (a Fuel Cell, FC) and an electrochemical energy storage (batteries). The control strategy has the objective of minimizing energy costs, while maintaining the optimal environmental comfort in the house, thus optimizing the use of renewable sources. To that aim, a validated numerical model of the whole system has been developed, and simulations have been carried out for winter and summer periods. Performances attainable with a MPC-based logic have been evaluated in comparison with a standard Rule Based Control logic, by means of costs and efficiency parameters of the micro-grid. Temperature violations have been taken into account to represent the impact of the control on comfort.
Results show an improvement of the house comfort conditions and a lower use (on average 14.5%) of primary fossil energy. This is due both to a reduction of required energy, and to an increased use of renewable energy sources. Moreover, the modulation of the HVAC load and of the FC operation gives a reduction of requested power by approximately 40%. Smoother battery pack charge and discharge processes are also obtained. As a main positive effect, a reduction of the FC powerplant size and an increase of its durability seems feasible, leading to an overall reduction of capital costs.
The conjunction of approximate computing and emerging nanotechnology could lead to very powerful and energy efficient integrated infrastructures in the near future. Research in this field is already ...very active and promising. In this brief, we present the design of approximate binary adders that very effectively exploit the inherent logic and physical behaviors of the Quantum-dot Cellular Automata technology. With respect to state-of-the-art competitors, the 16-bit architecture, designed as proposed here, exhibits an energy-delay-product and an area occupancy up to ~9 and ~3.7 times lower, respectively, with an accuracy more than 10 times higher.
In the last few years, binary comparators have received a great deal of attention as parts of complex computational data-paths. However, while several multi-bit architectures have been demonstrated ...using conventional CMOS technologies, few examples of n-bit comparators, with n higher than 4, can be found in literature for designs based on emerging nanotechnologies, such as the Quantum Dot Cellular Automata, the Nano Magnetic Logic, and many others. This brief proposes a novel approach to design efficient multi-bit binary comparators using the Quantum Dot Cellular Automata nanotechnology. The approach here presented allows improving state-of-the-art competitors in terms of computational complexity and average energy consumption. As an example, in comparison with its direct counterparts, the 32-bit comparator designed as proposed here saves up to 26%, 23% and 11% of the occupied area, the used basic cells and the average energy consumption, respectively. When implemented using the Nano Magnetic Logic, the 4-bit version of the novel comparator uses 1183 magnets and 38 clock phases.
Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients?
Performing COS ...before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS).
COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments.
The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021.
To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale.
A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11).
This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences.
Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy.
Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 × 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.
N/A.
The need to increase renewable energy sources deployment and to reduce consumption of fossil fuels has led to the diffusion of small-scale DG (Distributed Generation) systems, which may be ...effectively integrated in micro-grids. The role of control logic in defining microgrid performances and reliability is predominant and can be improved by using advanced control logics such as the ones based on MPC (Model Predictive Control).
In a previous paper, a MPC logic, based on the use of weather forecasts to improve the performances, has been applied to the analysis of power management in a domestic micro-grid system composed by: PV (Photovoltaic panels), FC (Fuel Cells) and a battery pack; in that case, the system was not affected by real uncertainties. In this paper the same system has been considered for domestic microgrid applications. The system control logic has been implemented by assuming real weather forecast as input data. DMPC and SMPC (Deterministic and Stochastic Model Predictive Control) concepts have been applied to the system and results have been compared to both MPC and to a standard RBC (Rule Based Control) logic. The impact of forecast uncertainties has been evaluated showing the advantages of a stochastic approach. In that case, the SMPC showed encouraging performances compared to standard control logics, primarily in terms of primary energy savings and downsizing potential of the power-delivering sub-systems using programmable energy sources.
•A Model Predictive Controller has been used to optimize the behaviour of a microgrid.•A stochastic approach has been used to model weather forecast uncertainties.•10% savings of HVAC required energy have been demonstrated.•Savings in primary fossil energy range between 10% and 30%.•Power sub-systems using programmable sources can be consistently downsized.
Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to ...uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling.
Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Oncology 500 panel (tumor tissue/cfDNA) from 23 patients consecutively enrolled at our center according to at least one of the following criteria: no available therapeutic options; long responding patients potentially fit for other therapies; rare tumor; suspected hereditary cancer; primary cancer with high metastatic potential; tumor of unknown primary origin. Variants were annotated for OncoKB and AMP/ASCO/CAP classification.
The overall yield of actionable somatic and germline variants was 57% (13/23 patients), and 43.5%, excluding variants previously identified by somatic or germline routine testing. The accuracy of tumor/cfDNA germline-focused analysis was demonstrated by overlapping results of germline testing. Five germline variants in BRCA1, VHL, CHEK1, ATM genes would have been missed without extended genomic profiling. A previously undetected BRAF p.V600E mutation was emblematic of the clinical utility of this approach in a patient with a liver undifferentiated embryonal sarcoma responsive to BRAF/MEK inhibition.
Our study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.
Background
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell ...proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs).
Purpose
In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features.
Methods
Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA,
n
= 12) and functioning (
n
= 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation.
Results
All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (
p
= 0.036), miR-130a-3p (
p
= 0.014), and miR-370-3p (
p
= 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (
p
= 0.031) and between miR-30a-5p and ‘atypical’ morphological features (
p
= 0.038) or cavernous sinus invasion (
p
= 0.049), while 508-5p was inversely correlated with clinical aggressiveness (
p
= 0.043).
Conclusions
In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.
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