Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

Risk and protective factors for secondary procedures after endoscopic dilatation of primary obstructive megaureters.

PURPOSE: High-pressure balloon dilatation (HPBD) of the ureterovesical junction with double-J stenting is a minimally invasive alternative to ureteral reimplantation or cutaneous ureterostomy for first-line surgical treatment of primary obstructive megaureter (POM). The aim of our study was to identify the risk factors associated with the need for secondary procedures due to HPBD failure. METHODS: Prospective data were collected from patients who underwent HPBD for POM between 2007 and 2021 at a single institution. The collected data included patient demographics, diagnostic modalities, surgical details, results, and follow-up. Multivariate logistic regression analysis was performed. RESULTS: Fifty-five ureters underwent HPBD for POM in 50 children, with a median age of 6.4 months (IQR: 4.5-13.8). Nineteen patients (37.25%) underwent secondary ureteric reimplantation, with a median of 9.8 months after primary HBPD (95% CI 6.2-9.9). The median follow-up was 29.4 months (IQR: 17.4-71). Independent risk factors for redo-surgery in a multivariate logistic regression model were: progressive ureterohydronephrosis (OR = 7.8; 95% CI 0.77-78.6) and early removal of the double-J stent. A risk reduction of 7% (95% CI 2.2%-11.4%) was observed per extra-day of catheter maintenance. The optimal cut-off point is 55 days, ROC curve area: 0.77 (95% CI 0.62-0.92). Gender, distal ureteral diameter, pelvis diameter, dilatation balloon diameter and preoperative differential renal function did not affect the need for reimplantation. CONCLUSIONS: The use of a double-J stent for at least 55 days seems to avoid the need for a secondary procedure. Therefore, we recommend removing the double-J catheter at least 2 months after the HBPD.

Long-term outcome of randomized clinical trial between polyacrylate-polyalcohol copolymer (PPC) and dextranomer-hyaluronic acid copolymer (Dx/HA) as bulking agents for endoscopic treatment of primary vesicoureteral reflux (VUR).

OBJECTIVE: The aim of our study is to compare long-term outcome of endoscopic treatment of VUR using PPC or Dx/HA. PATIENTS AND METHODS: From October 2014 to April 2017 patients with VUR grades from 3 to 5 that needed endoscopic treatment were eligible for this RCT. Patients were randomized in two groups: PPC and Dx/HA. A VCUG was performed at 6 months; if VUR > 3 was still present a second ET was performed. We included for this long-term follow-up study those patients that were successfully treated at short-term follow-up. At 36 months postoperative VCUG was performed to assess outcome. Success was considered if postoperative VUR grade was 0 at 36 months, and there was no ureteral obstruction. RESULTS: In the previous study, 60/73 ureters were successfully treated in 36/44 patients, and then we have analyzed 60 ureters in 36 patients. Three patients were lost in long-term follow-up, and then we analyzed 57 ureters in 33 patients divided. PPC group 18 patients (28 ureters); and Dx/HA group 15 patients (29 ureters). After 3 years of follow-up the VCUG showed a success rate of 26/28 of RU in PPC and 26/29 of DX/HA. Two RU in PPC group had ureteral obstruction, and then the successful rate for PPC group dropped to 24/28. The overall successful rate at long-term was 72.7% of the RU in PPC group and 70.3% in Dx/HA group. CONCLUSION: PPC and Dx/HA has similar long-term outcome in VUR resolution, but ureteral obstruction could be present at long-term follow-up in PPC group.

Are weight or age limits for pediatric laparoscopic pyeloplasty? Results of a multicentric study.

INTRODUCTION: Anderson-Hynes pyeloplasty is the technique of choice for the treatment of pyeloureteral junction obstruction (PUJO) with an excellent success rate. Minimally invasive surgery has become the standard of care for the management of PUJO in children. Although it has been comparable to the open approach at all levels, its diffusion or employment in younger children has not been widely adopted. Our aim is to evaluate laparoscopic pyeloplasty outcomes from international academic centers in children under 1 year of age, focusing on feasibility and outcomes including possible complications. MATERIALS AND METHODS: This is review of consecutive infants under 1 year of age who underwent laparoscopic pyeloplasty between 2009 and 2018 with more than 12 months of follow-up. Seven different training centers with different backgrounds participated in this study. Evaluation was carried out with ultrasound and renogram before and after surgery. Demographic data, perioperative characteristics, complications, and results are described and analyzed. RESULTS: Over 9 years, 124 transperitoneal laparoscopic Anderson-Hynes pyeloplasties were performed on 123 children under 1 year of age; 88 males and 35 females, with 1 case of bilateral PUJO. Of the 124 renal units, 86 were left-sided. Mean age at surgery was 6.6 months (1 week-12 months), with 56% (n = 70) done before 6 months of age. Mean weight at surgery was 6.8 kg (3-12 kg), with 59% (n = 73) weighing less than 8 kg. Mean operative time (skin-to-skin) was 150 min (75-330 min). After a mean follow-up of 46 months (12-84 months), 12 (9%) patients developed complications, with only 1 needing a redo pyeloplasty also done laparoscopically. One child, with deterioration in renal function, underwent nephrectomy. CONCLUSION: Laparoscopic pyeloplasty under 1 year of age and/or less than 12 kilos is feasible with lower complication rate. Furthermore, age younger than 6 months and weight less than 8 kg are no longer limiting factors for a successful pyeloplasty as shown by this multicentre study.

Comprehensive Generation of Historical Construction CAD Models from Data Provided by a Wearable Mobile Mapping System: A Case Study of the Church of Adanero (Ávila, Spain).

This paper presents the results of a complex three-dimensional reconstruction of the church of Nuestra Señora de la Asunción (Ávila, Spain) as an example of a successful process of verticalization from point clouds to a comprehensive computer-aided design (CAD) model. The reconstruction was carried out using the novel and advanced wearable mobile mapping system ZEB-REVO in combination with a lifting pole, in order to cover the whole geometry of the temple and, also, to model the different constructive elements. To this end, a set of good practices was followed, which allowed for passing from reality to the CAD model, such as the use of closed loops or even the use of different parametric and non-parametric strategies to capture the real geometry of the elements. As a result, this paper outlines the main guidelines for passing from point clouds to comprehensive CAD models, the former being useful for the application of smart preventive conservation processes, heritage building information models or even advanced numerical simulations.

Selective improvement by rifaximin of changes in the immunophenotype in patients who improve minimal hepatic encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) in cirrhotic patients is associated with specific changes in parameters of the immune system reflecting a more pro-inflammatory environment than in patients without MHE. The aims of this work were to assess the effects of rifaximin treatment of cirrhotic patients with MHE on: (1) MHE; (2) intermediate (CD14++CD16+) pro-inflammatory monocytes; (3) expression of early activation marker CD69 in T lymphocytes; (4) autoreactive CD4+CD28- T lymphocytes; (5) differentiation of CD4+ T lymphocytes to Th follicular and Th22; (6) serum IgG levels; and (7) levels of some pro-inflammatory cytokines. METHODS: These parameters were measured by immunophenotyping and cytokine profile analysis in 30 controls without liver disease, 30 cirrhotic patients without MHE and 22 patients with MHE. Patients with MHE were treated with rifaximin and the same parameters were measured at 3 and 6 months of treatment. We assessed if changes in these parameters are different in patients who improve MHE (responders) and those who remain in MHE (non-responders). RESULTS: Rifaximin improved MHE in 59% of patients with MHE. In these responder patients rifaximin normalized all alterations in the immune system measured while in non-responders it normalizes only IL-6, CCL20, and differentiation of T lymphocytes to Th22. Non-responder patients do not show increased expression of CD69 before treatment. CONCLUSIONS: Rifaximin normalizes changes in the immune system in patients who improve MHE but not in non-responders. Some alterations before treatment are different in responders and non-responders. Understanding these differences may identify predictors of the response of MHE to rifaximin.

The 2019 mathematical oncology roadmap.

Whether the nom de guerre is Mathematical Oncology, Computational or Systems Biology, Theoretical Biology, Evolutionary Oncology, Bioinformatics, or simply Basic Science, there is no denying that mathematics continues to play an increasingly prominent role in cancer research. Mathematical Oncology-defined here simply as the use of mathematics in cancer research-complements and overlaps with a number of other fields that rely on mathematics as a core methodology. As a result, Mathematical Oncology has a broad scope, ranging from theoretical studies to clinical trials designed with mathematical models. This Roadmap differentiates Mathematical Oncology from related fields and demonstrates specific areas of focus within this unique field of research. The dominant theme of this Roadmap is the personalization of medicine through mathematics, modelling, and simulation. This is achieved through the use of patient-specific clinical data to: develop individualized screening strategies to detect cancer earlier; make predictions of response to therapy; design adaptive, patient-specific treatment plans to overcome therapy resistance; and establish domain-specific standards to share model predictions and to make models and simulations reproducible. The cover art for this Roadmap was chosen as an apt metaphor for the beautiful, strange, and evolving relationship between mathematics and cancer.

Value of supranormal function on 99m Tc-mercaptoacetyltriglycine renal scan in paediatric patients with obstructive hydronephrosis.

OBJECTIVES: To study related factors and clinical significance of supranormal function in paediatric patients with pelvi-ureteric junction obstruction, and to predict which factors cause renal function overestimation. PATIENTS AND METHODS: Patients who underwent pyeloplasty from 2012 to 2017 were prospectively collected. Variables were compared between patients with and without supranormal function on 99m Tc-mercaptoacetyltriglycine renal scan (supranormal defined as differential renal function [DRF] ≥55%). Univariate, multivariate logistic and linear regressions analyses were performed. RESULTS: Of 100 patients, 18 were excluded because of comorbidities. Nine patients (11.5%) showed preoperative supranormal function. The preoperative anteroposterior pelvic diameter (APD; 24 mm vs 35 mm, P = 0.026) and the ratio between preoperative pelvic and kidney volumes (0.2 vs 0.6, P = 0.003) were higher in supranormal kidneys. For each unit increase in the preoperative ratio between pelvic and kidney volumes, the risk of supranormal function rose 3.23-times (95% confidence interval [CI] 1.051-9.955). A preoperative APD ≥30 mm was a reliable predictor of supranormal function (area under the curve 0.804, 95% CI 0.707-0.902), with 88.9% sensitivity. Patients with either preoperative supranormal function or preoperative APD ≥30 mm had a greater reduction in renal function after pyeloplasty. CONCLUSION: Supranormal function is related to large hydronephrosis where geometrical features are modified. A preoperative APD ≥30 mm is a reliable predictive factor of supranormal function. Preoperative renal function is overestimated either in supranormal patients or severe hydronephrotic kidneys. DRF should be interpreted with caution in kidneys with large hydronephrosis with or without supranormal function. Surgical indication should not entirely rely upon DRF.

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

BACKGROUND: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. METHODS: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. RESULTS: Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6%) patients were male, 64 (48.1%) had pancreatic NET, 23 (17.3%) had ECOG PS ≥ 2, 41 (30.8%) had functioning tumours, 63 (47.7%) underwent surgery of the primary tumour, 45 (33.8%) had received prior chemotherapy, and 115 (86.5%) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5% (6 months), 68.6% (12 months) and 57.0% (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3% (6 months), 73.0% (12 months), and 67.4% (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95% CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. CONCLUSIONS: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.