CT-based tumour response criteria compared after combined treatment for liver metastases of colorectal cancer

open6noPurpose: The aim of this analysis is to compare different tumour response criteria (TRC) after chemotherapy combined with bevacizumab in liver metastases from colorectal cancer (mCRC) to ascertain the best early prognostic indicator of response. Methods and Materials: 103 target liver metastases from 65 mCRC patients treated with chemoterapy plus bevacizumab were examined at the Istituto Oncologico Veneto IOV-IRCSS (March 2008-January 2013). All patients had baseline CT and at least one follow-up scan. Tumour response was retrospectively analyzed by two radiologists using RECIST1.1, modified Choi, and Chun morphologic criteria. Tumour response, classified as good (complete or partial response) or poor (stable or progressive disease), was compared with progression-free survival (PFS) at first follow-up (t1) and time of best response. Interobserver agreement and concordance between TRC were measured. Results: At t1, 32.31% showed a good response according to RECIST1.1 (median PFS 11.1), 84.62% according to Choi (median PFS 10.8). These percentages rose to 49.23% (median PFS 12.1) and 87.69% (median PFS 10.8), respectively, at the time of best response. According to Chun, 67.69% showed a good response at the time of best response (median PFS 10.8). The Choi criteria detected a higher proportion of good responders at t1, showing a better correlation with PFS; all methods correlated with PFS at the time of best response. Conclusion: The Choi criteria proved more consistent in the early detection of response in mCRC treated with chemotherapy plus bevacizumab, underscoring the importance of using these criteria in the early assessment of response to combined treatment.openopenVarotto, A.; Di Grazia, L.; Aliberti, C.; Bergamo, F.; Nardin, M.; Pomerri, F.Varotto, A.; Di Grazia, L.; Aliberti, C.; Bergamo, F.; Nardin, M.; Pomerri, Fabi

Tumour-induced osteomalacia: 18 months of 2-weekly burosumab treatment

Summary: Tumour-induced osteomalacia (TIO) is due to an overproduction of fibroblast growth factor 23 (FGF23) by mesenchymal tumours, causing hypophosphatemia, osteomalacia and muscle weakness. TIO is usually cured by tumour resection, but neoplasms may be unidentifiable and unresectable or the patient may refuse surgery. In these cases, medical treatment with oral phosphate and calcitriol is mandatory, but it is not fully effective and it is associated with low compliance. Burosumab, a human MAB against FGF23 employed to treat X-linked hypophosphatemia (XLH), has recently been approved for TIO in the USA. Maximum burosumab dose in XLH is 90 mg administered for 2 weeks; there are no data on clinical efficacy and safety of this dose in TIO. We reported the case of a 73 years old male with multiple non-traumatic fractures, low bone mineral density, pain and reduced independence of activities of daily living. Biochemical evaluation showed hypophosphatemia, high alkaline phosphatase (ALP) and C-terminal telopeptide (CTX) and normal albumin-corrected total calcium and parathyroid hormone. Tubular phosphate reabsorption was low (80%), whereas C-terminal tail of FGF23 (cFGF23) was elevated. A 68Ga-DOTATOC PET was performed, identifying a lesion in the first left rib. The patient refused surgery; therefore, burosumab therapy was started. After 18 months of treatment (maximum dose: 60 mg administered for 2 weeks), plasma phosphate normalized and ALP levels improved (138 U/L). Patient clinical symptoms as well as pain severity and fatigue improved. Neither adverse events nor tumour progression was reported during follow-up except for a painless fracture of the second right rib. Learning points: Our case shows efficacy and safety of burosumab treatment administered every 2 weeks in a tumour-induced osteomalacia (TIO) patient. After 18 months of treatment at a maximum dose of 60 mg every 2 weeks, we found plasma phosphate normalization and ALP reduction as well as improvement in clinical symptoms and fatigue. Neither adverse events nor tumour progression was reported during follow-up, except for a painless fracture of the second right rib

A non-linear autoregressive model for indoor air-temperature predictions in smart buildings

In recent years, the contrast against energy waste and pollution has become mandatory and widely endorsed. Among the many actors at stake, the building sector energy management is one of the most critical. Indeed, buildings are responsible for 40% of total energy consumption only in Europe, affecting more than a third of the total pollution produced. Therefore, energy control policies of buildings (for example, forecast-based policies such as Demand Response and Demand Side Management) play a decisive role in reducing energy waste. On these premises, this paper presents an innovative methodology based on Internet-of-Things (IoT) technology for smart building indoor air-temperature forecasting. In detail, our methodology exploits a specialized Non-linear Autoregressive neural network for short-and medium-term predictions, envisioning two different exploitation: (i) on realistic artificial data and (ii) on real data collected by IoT devices deployed in the building. For this purpose, we designed and optimized four neural models, focusing respectively on three characterizing rooms and on the whole building. Experimental results on both a simulated and a real sensors dataset demonstrate the prediction accuracy and robustness of our proposed models

Upper Respiratory Tract Microbiome and Otitis Media Intertalk : Lessons from the Literature

Otitis media (OM) is one of the most common diseases occurring during childhood. Microbiological investigations concerning this topic have been primarily focused on the four classical otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes) mainly because most of the studies have been conducted with culture-dependent methods. In recent years, the introduction of culture-independent techniques has allowed high-throughput investigation of entire bacterial communities, leading to a better comprehension of the role of resident flora in health and disease. The upper respiratory tract (URT) is a region of major interest in otitis media pathogenesis, as it could serve as a source of pathogens for the middle ear (ME). Studies conducted with culture-independent methods in the URT and ME have provided novel insights on the pathogenesis of middle ear diseases through the identification of both possible new causative agents and of potential protective bacteria, showing that imbalances in bacterial communities could influence the natural history of otitis media in children. The aim of this review is to examine available evidence in microbiome research and otitis media in the pediatric age, with a focus on its different phenotypes: acute otitis media, otitis media with effusion and chronic suppurative otitis media

SOCS2-Induced Proteasome-Dependent TRAF6 Degradation: A Common Anti-Inflammatory Pathway for Control of Innate Immune Responses

Pattern recognition receptors and receptors for pro-inflammatory cytokines provide critical signals to drive the development of protective immunity to infection. Therefore, counter-regulatory pathways are required to ensure that overwhelming inflammation harm host tissues. Previously, we showed that lipoxins modulate immune response during infection, restraining inflammation during infectious diseases in an Aryl hydrocarbon receptor (AhR)/suppressors of cytokine signaling (SOCS)2-dependent-manner. Recently, Indoleamine-pyrrole 2,3- dioxygenase (IDO)-derived tryptophan metabolites, including L-kynurenine, were also shown to be involved in several counter-regulatory mechanisms. Herein, we addressed whether the intracellular molecular events induced by lipoxins mediating control of innate immune signaling are part of a common regulatory pathway also shared by L-kynurenine exposure. We demonstrate that Tumor necrosis factor receptor-associated factor (TRAF)6 – member of a family of adapter molecules that couple the TNF receptor and interleukin-1 receptor/Toll-like receptor families to intracellular signaling events essential for the development of immune responses – is targeted by both lipoxins and L-kynurenine via an AhR/SOCS2-dependent pathway. Furthermore, we show that LXA4- and L-kynurenine-induced AhR activation, its subsequent nuclear translocation, leading SOCS2 expression and TRAF6 Lys47-linked poly-ubiquitination and proteosome-mediated degradation of the adapter proteins. The in vitro consequences of such molecular interactions included inhibition of TLR- and cytokine receptor-driven signal transduction and cytokine production. Subsequently, in vivo proteosome inhibition led to unresponsiveness to lipoxins, as well as to uncontrolled pro-inflammatory reactions and elevated mortality during toxoplasmosis. In summary, our results establish proteasome degradation of TRAF6 as a key molecular target for the anti-inflammatory pathway triggered by lipoxins and L-kynurenine, critical counter-regulatory mediators in the innate and adaptive immune systems

Prevalence, risk factors and outcomes of patients coming from the community with sepsis due to multidrug resistant bacteria

Background: Although previous studies showed an increasing prevalence of infections due to multi-drug resistant (MDR) bacteria in the community, specific data on sepsis are lacking. We aimed to assess prevalence, risk factors and outcomes of patients with sepsis due to MDR bacteria. Methods: An observational, retrospective study was conducted on consecutive adult patients coming from the community and admitted to the Policlinico Hospital, Milan, Italy, with a diagnosis of sepsis between January 2011 and December 2015. Primary study outcome was in-hospital mortality. Results: Among 518 patients, at least one MDR bacteria was isolated in 88 (17%). ESBL+ Enterobacteriaceae were the most prevalent MDR bacteria (9.7%) followed by MRSA (3.9%). Independent risk factors for sepsis due to MDR bacteria were septic shock (OR: 2.2; p = 0.002) and hospitalization in the previous 90 days (OR: 2.3; p = 0.003). Independent risk factors for sepsis due to ESBL+ bacteria were hospitalization in the previous 90 days (OR: 2.1; p = 0.02) and stroke (OR: 2.1; p = 0.04). A significantly higher mortality was detected among patients with vs. without MDR bacteria (40.2% vs. 23.1% respectively, p = 0.001). Independent risk factors for mortality among patients with sepsis were coagulation dysfunction (OR: 3.2; p = 0.03), septic shock (OR: 3.2; p = 0.003), and isolation of a MDR bacteria (OR: 4.6; p < 0.001). Conclusion: In light of the prevalence and impact of MDR bacteria causing sepsis in patients coming from the community, physicians should consider ESBL coverage when starting an empiric antibiotic therapy in patients with specific risk factors, especially in the presence of septic shock

Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor–associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses

Helmet CPAP treatment in patients with COVID-19 pneumonia: a multicenter, cohort study

Helmet CPAP treatment fails in up to 44% of patients with moderate-to-severe hypoxemic acute respiratory failure due to COVID-19 pneumoni