Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives.

The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment

Noise reduction and spatial resolution in CT imaging with the ASIR iterative reconstruction algorithm at different doses and contrasts – a phantom study

Aims and objectives The aim of this study was to quantitatively assess noise reduction and spatial resolution in computed tomography (CT) imaging with the ASIR (Adaptive Statistical Iterative Reconstruction, GE Healthcare) reconstruction algorithm at different kVp, mAs and contrasts. Methods and materials Acquisitions of the Catphan-504 phantom were performed on a PET/CT scanner (Discovery-710, GE Healthcare). CT images were reconstructed using both filtered back projection (FBP) and ASIR with different percentages of reconstruction (20%, 40%, 60%, 80%, 100%). The image noise was estimated for different values of scanning parameters (i.e. tube-load, kilovoltage, pitch, slice thickness). Then, 3D/2D/1D noise power spectrum was estimated. Also, spatial resolution was assessed by obtaining the modulation transfer function (MTF) for a wide range of scanning parameters values and different contrast objects by the circular Edge Spread Function method (using CTP404 modulus) and the Point Spread Function method (using CTP528 modulus). . Results Image noise decreased (up to 50% as compared to FBP) with increasing the percentage of ASIR reconstruction (behaviour more relevant for higher spatial frequencies). Only for low tube load (<56 mAs) and low contrast objects (polistirene with respect to PMMA) acquisitions, MTF analysis showed that ASIR-reconstructed images were characterized by an appreciable reduction in spatial resolution, when compared to FBP-reconstructed images. Conclusion When compared to FBP, ASIR allows a relevant noise reduction without appreciably affecting image quality, except for very low dose and contrast acquisitions

Ultra-High Frequency Ultrasound (Uhfus) Applications in Sjogren Syndrome: Narrative Review and Current Concepts

Primary Sjogren’s syndrome (SS) is a systemic autoimmune chronic inflammatory disease with predominant involvement of the exocrine glands, particularly the salivary glands (SGs). The role of salivary glands ultrasound (SGUS) in the work-up of patients with primary Sjogren syndrome (SS) is progressively increasing due to its useful support in diagnosis and follow-up as a widely available, repeatable, noninvasive and safe technique. Although SGUS is not yet included in the dominant primary SS classification, several studies supported its inclusion in the American College of Rheumatology/European League Against Rheumatism criteria. In this context, a novel imaging technique, ultra-high frequency ultrasound (UHFUS), is being explored. Compared to the frequencies used in conventional ultrasound (US) (up to 22 MHz), UHFUS operates with higher frequencies (30–100 MHz) allowing for outstanding image resolution, up to 30 μm. UHFUS permits the scn of both major and minor SGs, opening new avenues for the integration of tissue and imaging biomarkers. Although further studies are needed to confirm its role, this novel imaging technique might lead to several potential improvements, including earlier diagnosis, reduction of unnecessary and inadequate biopsies and better management and follow-up of patients with primary SS

Average absorbed breast dose (2ABD): an easy radiation dose index for digital breast tomosynthesis

Background: To propose a practical and simple method to individually evaluate the average absorbed dose for digital breast tomosynthesis. Methods: The method is based on the estimate of incident air kerma (ka,i) on the breast surface. An analytical model was developed to calculate the ka,i from the tube voltage, tube load, breast thickness, x-ray tube yield, and anode-filter combination. A homogeneous phantom was employed to simulate the breast in experimental measurements and to assess the dose-depth relationship. The ka,i values were employed to calculate the “average absorbed breast dose” (2ABD) index. Four mammographic units were used to develop and test our method under many conditions close to clinical settings. The average glandular dose (AGD) calculated following the method described by Dance et al., and the 2ABD computed through our method (i.e., from the exposure parameters) were compared in a number of conditions. Results: A good agreement was obtained between the ka,i computed through our model and that measured under different clinical conditions: discrepancies &lt; 6% were found in all conditions. 2ABD matches with a good accuracy the AGD for a 100% glandular-breast: the minimum, maximum, and mean differences were &lt; 0.1%, 7%, and 2.4%, respectively; the discrepancies increase with decreasing breast glandularity. Conclusions: The proposed model, based on only few exposure parameters, represents a simple way to individually calculate an index, 2ABD, which can be interpreted as the average absorbed dose in a homogeneous phantom, approximating a 100% glandular breast. The method could be easily implemented in any mammographic device performing DBT

Multislice computed tomography SYNTAX score for coronary artery disease evaluation prior to transcatheter aortic valve implantation

Background: Coronary computed tomography angiography (CCTA) is a useful tool for the evaluation of coronary anatomy prior to both surgical and transcatheter aortic valve implantation (TAVI). Multislice Computed Tomography (MSCT) SYNTAX score (SXscore) strongly correlates with the traditional angiographic SXscore, and the latter has proven to predict cardiovascular events in patients with coronary artery disease (CAD) referred to TAVI. Purpose: The aim of the study is to evaluate the feasibility and accuracy of the calculation of MSCT SXscore in TAVI patients, compared to the gold standard angiographic SXscore. Materials and methods: We evaluated 65 patients eligible for TAVI who underwent both CCTA and invasive coronary angiography (ICA) prior to valve replacement. CCTA was compared to ICA in terms of sensitivity, specificity, and positive and negative predictive values. CCTA performance was evaluated at 3 levels: patient level, vessellevel and segmentlevel. MSCT SXscore was calculated, when possible (i.e. only in fullyevaluable scans), and compared to the angiographic SXscore. Results: Overall CCTA diagnostic performance was good, with high sensitivity and negative predictive values (97.2% and 96.0%, respectively) and good agreement with ICA (k=0.81). As expected, specificity and positive predictive values were lower (82.8% and 87.5%, respectively). At vessellevel, the circumflex artery (CA) was more often misdiagnosed than the other arteries. We were able to calculate MSCT SXscore in 50/65 scans (76.9%). The correlation between MSCT and angiographic SXscore was excellent (Pearson's R=0.965, P&lt;0.001). Conclusions: MSCT SXscore emerges as an interesting tool with strong agreement with angiographic SXscore, providing a noninvasive ambulatory alternative to assess CAD severity in TAVI patients

Role of perfusion CT in the evaluation of metastatic nodal tumor response after radiochemotherapy in head and neck cancer: preliminary findings

OBJECTIVE: To assess changes of CT perfusion parameters (ΔPCTp) of cervical lymph node metastases from head and neck cancer (HNC) before and after radiochemotherapy (RT-CT) and their association with nodal tumor persistence. PATIENTS AND METHODS: Eligibility criteria included HNC (Stage III-IV) candidates for RT-CT. Patients underwent perfusion CT (PCT) at baseline 3 weeks and 3 months after RT-CT. Blood volume (BV), blood flow (BF), mean transit time (MTT) and permeability surface (PS) were calculated. PET/CT examination was also performed at baseline and 3 months after treatment for metabolic assessment. RESULTS: Between July 2012 and May 2016, 27 patients were evaluated. Overall, only 3 patients (11%) experienced tumor persistence in the largest metastatic lymph node. A significant reduction of all PCTp values (p<0.0001), except MTT (from 6.3 to 5.7 s; p=0.089), was observed at 3 weeks post-RT-CT compared to baseline. All PCTp values including MTT were significantly lower at 3-month follow-up compared to baseline (p<0.05). Moreover, a statistical significant association was observed between nodal tumor persistence and high BF values (p=0.045) at 3 months after treatment that did not occur for the other parameters. CONCLUSIONS: Our preliminary findings show that all PCTp except MTT are significantly reduced after RT-CT. High BF values at 3 months post-RTCT are predictive of nodal tumor persistence

Factors predicting survival in patients with locally advanced pancreatic cancer undergoing pancreatectomy with arterial resection

Pancreatectomy with arterial resection is a treatment option in selected patients with locally advanced pancreatic cancer. This study aimed to identify factors predicting cancer-specific survival in this patient population. A single-Institution prospective database was used. Pre-operative prognostic factors were identified and used to develop a prognostic score. Matching with pathologic parameters was used for internal validation. In a patient population with a median Ca 19.9 level of 19.8&nbsp;U/mL(IQR: 7.1–77), cancer-specific survival was predicted by: metabolic deterioration of diabetes (OR = 0.22, p = 0.0012), platelet count (OR = 1.00; p = 0.0013), serum level of Ca 15.3 (OR = 1.01, p = 0.0018) and Ca 125 (OR = 1.02, p = 0.00000137), neutrophils-to-lymphocytes ratio (OR = 1.16; p = 0.00015), lymphocytes-to-monocytes ratio (OR = 0.88; p = 0.00233), platelets-to-lymphocytes ratio (OR = 0.99; p = 0.00118), and FOLFIRINOX neoadjuvant chemotherapy (OR = 0.57; p = 0.00144). A prognostic score was developed and three risk groups were identified. Harrell’s C-Index was 0.74. Median cancer-specific survival was 16.0&nbsp;months (IQR: 12.3–28.2) for the high-risk group, 24.7&nbsp;months (IQR: 17.6–33.4) for the intermediate-risk group, and 39.0&nbsp;months (IQR: 22.7–NA) for the low-risk group (p = 0.0003). Matching the three risk groups against pathology parameters, N2 rate was 61.9, 42.1, and 23.8% (p = 0.04), median value of lymph-node ratio was 0.07 (IQR: 0.05–0.14), 0.04 (IQR:0.02–0.07), and 0.03 (IQR: 0.01–0.04) (p = 0.008), and mean value of logarithm odds of positive nodes was −&nbsp;1.07 ± 0.5, −&nbsp;1.3 ± 0.4, and −&nbsp;1.4 ± 0.4 (p = 0.03), in the high-risk, intermediate-risk, and low-risk groups, respectively. An online calculator is available at www.survivalcalculator-lapdac-arterialresection.org. The prognostic factors identified in this study predict cancer-specific survival in patients with locally advanced pancreatic cancer and low Ca 19.9 levels undergoing pancreatectomy with arterial resection

Defect calculations in semiconductors through a dielectric-dependent hybrid DFT functional : the case of oxygen vacancies in metal oxides

We investigate the behavior of oxygen vacancies in three different metal-oxide semiconductors (rutile and anatase TiO2, monoclinic WO3, and tetragonal ZrO2) using a recently proposed hybrid density-functional method in which the fraction of exact exchange is material-dependent but obtained ab initio in a self-consistent scheme. In particular, we calculate charge-transition levels relative to the oxygen-vacancy defect and compare computed optical and thermal excitation/emission energies with the available experimental results, shedding light on the underlying excitation mechanisms and related materials properties. We find that this novel approach is able to reproduce not only ground-state properties and band structures of perfect bulk oxide materials but also provides results consistent with the optical and electrical behavior observed in the corresponding substoichiometric defective systems

Baseline computed-tomography (CT)-evaluated sarcopenia predicts toxicity from first-line chemotherapy in metastatic gastric cancer (mGC) patients

Introduction: The impact of sarcopenia as a predictor of poor prognosis and its association with chemotherapy toxicity have been explored in different cancer types but remain controversial in mGC. Our aim was to explore the correlation between sarcopenia, evaluated at baseline CT scan, and toxicity and efficacy of first-line therapy. Methods: We retrospectively analyzed pre-treatment CT scans from 78 mGC patients treated with first-line doublet chemotherapy comprising oxaliplatin and 5-fluorouracil/leucovorin or capecitabine (trastuzumab was administered in case of HER2-positive disease). Sarcopenia was defined according to previously published criteria (Martin L et al. J Clin Oncol 2013) by the use of the skeletal muscle index (SMI) and body mass index (BMI), according to gender-specific cut-off values. SMI was calculated as follows: cross-sectional skeletal muscle area (SMA) measured at the level of the third lumbar vertebra / (height)2 (m2). Toxicities were graded according to NCI CTCAE v.4.0. Association between the presence of sarcopenia and different adverse events was evaluated by Chi-square test. Correlation with response rate (RR, evaluated according to RECIST criteria 1.1), progression-free survival (PFS) and overall survival (OS) was assessed by the use of the log-rank test. Results: Sarcopenia was evident in 34 (44%) patients. We observed a significant association between the presence of sarcopenia at baseline assessment and a higher risk of severe (i.e. grade 3-4) neutropenia (38% versus 18%; p = 0.048) and a higher risk of any grade mucosal toxicities (56% versus 34%; p = 0.045). None of the other investigated clinical factors (comprising age, gender, performance status, sites of metastases and previous surgery on primary tumor) was associated with the risk of toxicity. Neither sarcopenia nor the other evaluated clinical parameters were associated with outcome as measured by RR, PFS, and OS: the only exception was performance status, which was confirmed a major prognostic determinant in terms of PFS and OS. Conclusion: Our experience identified sarcopenia as a potential determinant of the risk of hematologic and mucosal toxicities from first-line platinum plus fluoropyrimidine chemotherapy in mGC patients. Sarcopenia was apparently not associated with benefit from treatment and survival, but larger studies are needed to address this issue. Strategies aiming at improving the nutritional status of mGC patients are warranted to optimize the risk-to-benefit ratio of available treatments