The role of lymph node dissection in kidney cancer surgery for staging and therapy

Background Controversies on the therapeutic efficacy of lymph node dissection (LND) at time of radical nephrectomy (RN) for renal cell carcinoma (RCC) patients have not yet been solved, due to a limited knowledge of nodal dissemination patterns, thus licensing the use of unstandardized LND templates among institutions and causing post-operative patient risk-category misclassification. The aims of the thesis were I) to evaluate if the side and the location of RCC affected the probability of lymph nodal invasion (LNI) and/or nodal progression (NP) at follow-up, II) to describe nodal disease dissemination in clear cell RCC (ccRCC) patients and to assess the effect of the anatomical sites and the number of affected nodal areas on cancer specific mortality (CSM), III) to test the clinical usefulness of performing LND to stratify the risk of patients with RCC and select candidates for adjuvant treatment. Methods Core-data were represented by a prospectively collected database of 3,645 consecutive patients enrolled at a single tertiary Institution and submitted to surgery for RCC with comprehensive clinical, surgical, pathologic and follow-up data of patients. Regional LND consisted of hilar nodes plus, on the right side, pre-retro-caval nodes or, on the left side, para-aortic nodes. Extended LND consisted of regional LND plus interaortocaval nodes. Results Overall, 15% of patients underwent LND and were pN1 at surgery and during follow-up, 2.2% of patients had NP. Higher rates of LNI and NP were observed for patients with primary tumor located in more than one anatomical area relative to patients with tumor in a single area (p<0.01). Neither the RCC side nor the location reached the independent predictor status (all p>0.1). In the second study, among patients with one involved nodal site, 54 and 26% of patients were positive only in side-specific and interaortocaval station, respectively. Interaortocaval nodal positivity (HR 2.3, CI 95%: 1.3–3.9, p<0.01) represented an independent predictor of CSM. In the third study, LNI resulted as the most informative predictor of early progression (OR: 6.39; CI 95%: 3.26-12.54; p<0.0001). The accuracy was higher (p=0.008) for the model to predict early recurrence when implemented with pN (AUC: 0.76; CI95%: 0.71-0.80), as compared to the base model (AUC: 0.72; CI95%: 0.68-0.76). Patients with highrisk disease showed a large difference in the risk of progression according to pN-status (1-year risk: 58% for pN1; 31% for pN0; p<0.001). Conclusions Patients with single-side and more than one anatomical kidney area affected by RCC have higher rate of LNI at surgery and/or NP at follow-up, but this was predicted neither by side nor by location of RCC. When ccRCC patients (about 90% of all RCC) harbour nodal disease, its spreading can occur at any nodal station without involving the others. The presence of interoartocaval positive nodes does affect oncologic outcomes and therefore an extended LND template is advisable, when indicated. Moreover, performing LND at the time of RN improves risk stratification, resulting into clinical advantage for selecting high-risk patients for further treatment after surgery

Unsupervised Burned Area Estimation through Satellite Tiles: A multimodal approach by means of image segmentation over remote sensing imagery

Climate change is increasing the number and the magnitude of wildfires, which become every year more severe. An accurate delineation of burned areas, which is often done through time consuming and inaccurate manual approaches, is of paramount importance to estimate the economic impact of such events. In this paper we introduce Burned Area Estimation through satellite tiles (BAE), an unsupervised algorithm that couples image processing techniques and an unsupervised neural network to automatically delineate the burned areas of wildfires from satellite imagery. We show its capabilities by performing an evaluation over past wildfires across European and non-European countries

Supervised Burned Areas delineation by means of Sentinel-2 imagery and Convolutional Neural Networks

Wildfire events are increasingly threatening our lands, cities, and lives. To contrast this phenomenon and to limit its damages, governments around the globe are trying to find proper counter-measures, identifying prevention and monitoring as two key factors to reduce wildfires impact worldwide. In this work, we propose two deep convolutional neural networks to automatically detect and delineate burned areas from satellite acquisitions, assessing their performances at scale using validated maps of burned areas of historical wildfires. We demonstrate that the proposed networks substantially improve the burned area delineation accuracy over conventional methods

Can local treatment prolong the sensitivity of metastatic prostate cancer to androgen deprivation or even prevent castration resistance?

Purpose A number of observational clinical studies suggest that prior primary tumor treatment favorably influences the course of metastatic prostate cancer (PCa), but its mechanisms of action are still speculative. Here, we describe the long-lasting sensitivity to various forms of androgen deprivation in patients after radical prostatectomy (RP) for locally advanced PCa as one potential mechanism. Methods A consecutive series of 115 radical prostatectomies after inductive therapy for T4 prostate cancer was re-analyzed, and long-term survival, as well as recurrence patterns and responses to different forms of hormonal manipulation, were assessed. Results The estimated biochemical response-free, PCa-specific, and overall survival rates after 200 months were 20%, 65%, and 47% with a median overall survival of 156 months. The majority of patients, although not cured of locally advanced PCa (84/115), showed long-term survival after RP. PCa-specific and overall survival rates of these 84 patients with biochemical recurrence were 61% and 44% at 150 months. Long-term sensitivity to ADT was found to be the main reason for the favorable tumor-specific survival in spite of biochemical recurrence. Conclusions Sensitivity to primary or secondary hormonal manipulation was the main reason for the long-term survival of patients who had not been cured by surgery only. The results suggest that treatment of the primary tumor-bearing prostate delays castration-resistant PCa and enhances the effect of hormonal therapies in a previously unknown manner. The underlying cellular and molecular mechanisms need to be explored in more detailed analyses, which could profoundly impact treatment concepts of locally advanced and metastatic PCa

The Effect of Anatomical Location of Lymph Node Metastases on Cancer Specific Survival in Patients with Clear Cell Renal Cell Carcinoma

Background: Positive nodal status (pN1) is an independent predictor of survival in renal cell carcinoma (RCC) patients. However, no study to date has tested whether the location of lymph node (LN) metastases does affect oncologic outcomes in a population submitted to radical nephrectomy (RN) and extended lymph node dissection (eLND). Objective: To describe nodal disease dissemination in clear cell RCC (ccRCC) patients and to assess the effect of the anatomical sites and the number of nodal areas affected on cancer specific mortality (CSM). Design, setting and partecipants: The study included 415 patients who underwent RN and eLND, defined as the removal of hilar, side-specific (pre/paraaortic or pre/paracaval) and interaortocaval LNs for ccRCC, at two institutions. Outcome measurement and statistical analysis: Descriptive statistics were used to depict nodal dissemination in pN1 patients, stratified according to nodal site and number of involved areas. Multivariable Cox regression analyses and Kaplan-Meier curves were used to explore the relationship between pN1 disease features and survival outcomes. Results and limitations: Median number of removed LN was 14 (IQR 9\u201319); 23% of patients were pN1. Among patients with one involved nodal site, 54 and 26% of patients were positive only in side-specific and interaortocaval station, respectively. The most frequent nodal site was the interaortocaval and side-specific one, for right and left ccRCC, respectively. Interaortocaval nodal positivity (HR 2.3, CI 95%: 1.3\u20133.9, p &lt; 0.01) represented an independent predictor of CSM. Conclusions: When ccRCC patient harbour nodal disease, its spreading can occur at any nodal station without involving the others. The presence of interoartocaval positive nodes does affect oncologic outcomes. Patient summary: Lymph node invasion in patients with clear cell renal cell carcinoma is not following a fixed anatomical pattern. An extended lymph node dissection, during treatment for primary kidney tumour, would aid patient risk stratification and multimodality upfront treatment

Evaluation of HER2 expression in urothelial carcinoma cells as a biomarker for circulating tumor cells

Background Detection of circulating tumor cells (CTC) by techniques based on epithelial cell adhesion molecule (EpCAM) is suboptimal in urothelial carcinoma (UC). As HER2 is thought to be broadly expressed in UC, we explored its utility for CTC detection. Methods HER2 and EpCAM expression was analyzed in 18 UC cell lines (UCCs) by qRT-PCR, western blot and fluorescence-activated cell scanning (FACS) and compared to the strongly HER2-expressing breast cancer cell line SKBR3 and other controls. HER2 expression in UC patient tissues was measured by qRT PCR and correlated with data on survival and risk for metastasis. UCCs with high EpCAM and variable HER2 expression were used for spike-in experiments in the CellSearch system. Twenty-one blood samples from 13 metastatic UC patients were analyzed for HER2-positive CTCs with CellSearch. Results HER2 mRNA and protein were broadly expressed in UCC, with some heterogeneity, but at least 10-fold lower than in the HER-2+ SKBR3 cells. Variations were unrelated to cellular phenotype or clinicopathological characteristics. EpCAM expression was essentially restricted to UCCs with epitheloid phenotypes. Heterogeneity of EpCAM and HER2 expression was observed also in spike-in experiments. The 7 of 21 blood samples from 6 of 13 patients were enumerated as CTC positive via EpCAM, but only one sample stained weakly positive (1+) for HER2. Conclusions Detection rate of CTCs by EpCAM in UC is poor, even in metastatic patients. Because of its widespread expression, particularly in patients with high risk of metastasis, detection of HER2 could improve identification of UC CTCs, which is why combined detection using antibodies for EpCAM and HER2 may be beneficial

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P &lt; 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Tbr2-positive intermediate (basal) neuronal progenitors safeguard cerebral cortex expansion by controlling amplification of pallial glutamatergic neurons and attraction of subpallial GABAergic interneurons

Little is known about how, during its formidable expansion in development and evolution, the cerebral cortex is able to maintain the correct balance between excitatory and inhibitory neurons. In fact, while the former are born within the cortical primordium, the latter originate outward in the ventral pallium. Therefore, it remains to be addressed how these two neuronal populations might coordinate their relative amounts in order to build a functional cortical network. Here, we show that Tbr2-positive cortical intermediate (basal) neuronal progenitors (INPs) dictate the migratory route and control the amount of subpallial GABAergic interneurons in the subventricular zone (SVZ) through a non-cell-autonomous mechanism. In fact, Tbr2 interneuron attractive activity is moderated by Cxcl12 chemokine signaling, whose forced expression in the Tbr2 mutants can rescue, to some extent, SVZ cell migration. We thus propose that INPs are able to control simultaneously the increase of glutamatergic and GABAergic neuronal pools, thereby creating a simple way to intrinsically balance their relative accumulation

The Effect of Anatomical Location of Lymph Node Metastases on Cancer Specific Survival in Patients with Clear Cell Renal Cell Carcinoma

BackgroundPositive nodal status (pN1) is an independent predictor of survival in renal cell carcinoma (RCC) patients. However, no study to date has tested whether the location of lymph node (LN) metastases does affect oncologic outcomes in a population submitted to radical nephrectomy (RN) and extended lymph node dissection (eLND).ObjectiveTo describe nodal disease dissemination in clear cell RCC (ccRCC) patients and to assess the effect of the anatomical sites and the number of nodal areas affected on cancer specific mortality (CSM).Design, setting and partecipantsThe study included 415 patients who underwent RN and eLND, defined as the removal of hilar, side-specific (pre/paraaortic or pre/paracaval) and interaortocaval LNs for ccRCC, at two institutions.Outcome measurement and statistical analysisDescriptive statistics were used to depict nodal dissemination in pN1 patients, stratified according to nodal site and number of involved areas. Multivariable Cox regression analyses and Kaplan-Meier curves were used to explore the relationship between pN1 disease features and survival outcomes.Results and limitationsMedian number of removed LN was 14 (IQR 9–19); 23% of patients were pN1. Among patients with one involved nodal site, 54 and 26% of patients were positive only in side-specific and interaortocaval station, respectively. The most frequent nodal site was the interaortocaval and side-specific one, for right and left ccRCC, respectively. Interaortocaval nodal positivity (HR 2.3, CI 95%: 1.3–3.9, p &lt; 0.01) represented an independent predictor of CSM.ConclusionsWhen ccRCC patient harbour nodal disease, its spreading can occur at any nodal station without involving the others. The presence of interoartocaval positive nodes does affect oncologic outcomes.Patient summaryLymph node invasion in patients with clear cell renal cell carcinoma is not following a fixed anatomical pattern. An extended lymph node dissection, during treatment for primary kidney tumour, would aid patient risk stratification and multimodality upfront treatment

Post-lithiation: a way to control the ionic conductivity of solid-state thin film electrolyte

Ionic conductivity is pivotal for solid-state battery performance. While the garnet oxide electrolyte Li7La3Zr2O12 (LLZO) boasts high ionic conductivity due to its distinct crystal structure and lithium-ion mobility, lithium loss during fabrication hampers its potential. In this study, we introduce a method that merges synthesis optimization with a post-lithiation process, enhancing LLZO's ionic conductivity. This approach compensates lithium loss with a gas-phase diffusion process, which stabilizes the cubic LLZO phase and amplifies its ionic conductivity by more than three orders of magnitude compared to electrolytes without post-lithiation. Through our comprehensive experimental procedure, we have conclusively determined that the film deposited at 700 °C and subsequently annealed at 700 °C with LiOH exhibits the highest conductivity, with a notable value of 1.11 × 10−2 S cm−1 at 200 °C. This is a significant boost compared to the as-deposited film (3.54 × 10−6 S cm−1 at 200 °C). Our findings present an additional approach to boosting lithium ion diffusion. The approach employed in this work has the potential to be applicable to films produced through other deposition methods, as it addresses the prevalent issue of lithium loss, a significant barrier to the utilization of lithium-rich thin films