Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Results: Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. Conclusion: The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

Thoracoscopic mesh implantation as a definitive treatment approach for peritoneal dialysis-associated hydrothorax.

Pleuroperitoneal leakage with the formation of hydrothorax is a rare complication of peritoneal dialysis, usually necessitating termination of peritoneal dialysis. We hypothesized that implantation of a polypropylene mesh on the diaphragm using video-assisted thoracoscopic surgery might induce permanent closure of pleuroperitoneal leakage. We report a case series of n = 12 peritoneal dialysis patients with pleuroperitoneal leakage and right-sided hydrothorax who underwent video-assisted thoracoscopy with mesh implantation from 2011 to 2020. Pleuroperitoneal leakage had been confirmed before surgery by intraperitoneal administration of toluidine blue, contrast-enhanced computer tomography or glucose determination from the pleural effusion. Median time from the start of peritoneal dialysis to manifestation of pleuroperitoneal leakage was 52 days. Video-assisted thoracoscopic surgery revealed multiple penetration points in the tendinous part of the diaphragm in all patients, which appeared as blebs. These were closed by covering the whole diaphragm with a polypropylene mesh. In all patients, peritoneal dialysis was paused for three months and bridged by hemodialysis. After restarting peritoneal dialysis and a median follow-up time of 1.9 years, none of the patients experienced a recurrence of pleuroperitoneal leakage. This case series demonstrates that pleuroperitoneal leakage in peritoneal dialysis patients can be permanently closed using thoracoscopic mesh implantation and allows peritoneal dialysis to be continued as renal replacement therapy.

Intraperitoneal extension of the peritoneal dialysis catheter-a new technique for catheter implantation in patients with obesity.

BACKGROUND: In patients with obesity and end-stage kidney disease, implantation of the peritoneal dialysis (PD) catheter may be complicated by increased abdominal circumference or skin folds. Relocation of the implantation site to the upper abdomen could solve this problem. However, this would require an extended catheter. METHODS: We developed an extended PD catheter based on a swan neck Missouri PD catheter with the help of two adaptors and a straight intraperitoneal extension segment. The extended catheter was assembled intraoperatively, and its length was adjusted individually to ensure correct positioning. After the operation, PD was commenced and handled as usual. RESULTS: In the period from 2011 to 2021, we implanted 31 extended PD catheters in 29 patients (38% men) with end-stage renal failure and obesity. Median age was 53 (range 28-77) years and body mass index was 35.5 (range 26.4-46.9) kg/m2. The postoperative course was unremarkable except for seroma formation in one patient and dialysate leakage in another. Continuous ambulatory peritoneal dialysis (CAPD) was initiated in 20 and APD in 9 patients. The achieved median Kt/V was 2.10 (range 1.50-3.10). During the follow-up period lasting up to 51 months, there was one case of intraperitoneal catheter disconnection due to an avoidable handling error. The peritonitis rate was 1:40 months. The 1- and 2-year catheter survival was 92% and 67%, respectively, and paralleled patient survival. CONCLUSIONS: When using a PD catheter with an intraperitoneal extension, PD catheter implantation can be relocated to the upper abdomen in patients with obesity, thus providing optimal position and easy surgical access.

Clinical Implications of Combinatorial Pharmacogenomic Tests Based on Cytochrome P450 Variant Selection.

Despite the potential to improve patient outcomes, the application of pharmacogenomics (PGx) is yet to be routine. A growing number of PGx implementers are leaning toward using combinatorial PGx (CPGx) tests (i.e., multigene tests) that are reusable over patients' lifetimes. However, selecting a single best available CPGx test is challenging owing to many patient- and population-specific factors, including variant frequency differences across ethnic groups. The primary objective of this study was to evaluate the detection rate of currently available CPGx tests based on the cytochrome P450 (CYP) gene variants they target. The detection rate was defined as the percentage of a given population with an "altered metabolizer" genotype predicted phenotype, where a CPGx test targeted both gene variants a prospective diplotypes. A potential genotype predicted phenotype was considered an altered metabolizer when it resulted in medication therapy modification based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Targeted variant CPGx tests found in the Genetic Testing Registry (GTR), gene selection information, and diplotype frequency data from the Pharmacogenomics Knowledge Base (PharmGKB) were used to determine the detection rate of each CPGx test. Our results indicated that the detection rate of CPGx tests covering CYP2C19, CYP2C9, CYP2D6, and CYP2B6 show significant variation across ethnic groups. Specifically, the Sub-Saharan Africans have 63.9% and 77.9% average detection rates for CYP2B6 and CYP2C19 assays analyzed, respectively. In addition, East Asians (EAs) have an average detection rate of 55.1% for CYP2C9 assays. Therefore, the patient's ethnic background should be carefully considered in selecting CPGx tests.

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets.

BACKGROUND: The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are  now available, effective treatment options are still out of reach. RESULTS: To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < - 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. CONCLUSIONS: Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients' expression profiles of BALF cells.

Implementation of Urgent Start Peritoneal Dialysis Reduces Hemodialysis Catheter Use and Hospital Stay in Patients with Unplanned Dialysis Start.

BACKGROUND: Unplanned start of renal replacement therapy is common in patients with end-stage renal disease and often accomplished by hemodialysis (HD) using a central venous catheter (CVC). Urgent start using peritoneal dialysis (PD) could be an alternative for some of the patients; however, this requires a hospital-based PD center that offers a structured urgent start PD (usPD) program. METHODS: In this prospective study, we describe the implementation of an usPD program at our university hospital by structuring the process from presentation to PD catheter implantation and start of PD within a few days. For clinical validation, we compared the patient flow before (2013-2015) and after (2016-2018) availability of usPD. RESULTS: In the 3 years before the availability of usPD, 14% (n = 12) of incident PD patients (n = 87) presented in an unplanned situation and were initially treated with HD using a CVC. In the 3 years after implementation of the usPD program, 18% (n = 18) of all incident PD patients (n = 103) presented in an unplanned situation of whom n = 12 (12%) were treated with usPD and n = 6 (6%) with initial HD. usPD significantly reduced the use of HD by 57% (p = 0.0005). Hospital stay was similar in patients treated with usPD (median 9 days) compared to those with elective PD (8 days), and significantly lower than in patients with initial HD (26 days, p = 0.0056). CONCLUSIONS: Implementation of an usPD program reduces HD catheter use and hospital stay in the unplanned situation.

Routine Monitoring of Sodium and Phosphorus Removal in Peritoneal Dialysis (PD) Patients Treated with Continuous Ambulatory PD (CAPD), Automated PD (APD) or Combined CAPD+APD.

BACKGROUND: Adequate removal of sodium (Na) and phosphorus (P) is of paramount importance for patients with dialysis-dependent kidney disease can easily quantified in peritoneal dialysis (PD) patients. Some studies suggest that automated PD (APD) results in lower Na and P removal. METHODS: In this study we retrospectively analysed our data on Na and P removal in PD patients after implementation of a routine monitoring in 2011. Patients were stratified in those treated with continuous ambulatory PD (CAPD, n=24), automated PD (APD, n=23) and APD with one bag change (CAPD+APD, n=10). Until 2015 we collected time-varying data on Na and P removal from each patient (median 5 [interquartile range 4-8] values). RESULTS: Peritoneal Na and P removal (mmol per 24h ± standard deviation) was 102 ± 48 and 8 ± 2 in the CAPD, 90 ± 46 and 9 ± 3 in the APD and 126 ± 39 and 13 ± 2 in the CAPD+APD group (ANOVA P=0.141 and <0.001). Taking renal excretion into account total Na and P removal (mmol per 24h) was 221 ± 65 and 16 ± 5 in the CAPD, 189 ± 58 and 17 ± 6 in the APD and 183 ± 38 and 16 ± 6 in the CAPD+APD group (P=0.107 and 0.764). Over time, peritoneal removal of Na but not that of P increased in all groups. In patients with modifications of PD treatment, Na but not P removal was significantly increased over-time. CONCLUSIONS: Overall Na and P removal were similar with different PD modalities. Individualized adjustments of PD prescription including icodextrin use or higher glucose concentration can improve Na removal while P removal is mainly determined by the dialysate volume.

[Progredient dyspnea and poor drainage in a peritoneal dialysis patient - case 2/2012]. / Zunehmende Dyspnoe und geringes Auslaufvolumen bei einem Peritonealdialysepatienten - Fall 2/2012.

HISTORY AND ADMISSION FINDINGS: We report on a peritoneal dialysis patients who presented with dyspnea, poor drainage and weight gain. INVESTIGATIONS: A chest x-ray showed a large pleural effusion on the right side. Thoracocentesis revealed a clear protein-devoid fluid with a glucose concentration greater than that of plasma. By intraperitoneal administration of toluidine blue, a pleuroperitoneal leakage was proven. DIAGNOSIS, TREATMENT AND COURSE: The patient underwent video-assisted thoracoscopy revealing a total of four spots of pleuroperitoneal leakage on the diaphragm after intraperitoneal administration of toluidine blue. Closure was attempted with the aid of a prolene patch which was stiched onto the diaphragm inducing adhesion to the lung. After three months bridging with hemodialysis, the peritoneal dialysis was commenced again without a recurrence of the leakage. CONCLUSIONS: Pleuroperitoneal leakage can occur during the course of peritoneal dialysis treatment leading to hydrothorax. Video-assisted thoracoscopy and patching of the diaphragm with a prolene mesh can be used to treat these patients.

[Heart and kidney--only together they are strong. On the cardiorenal and renocardiac syndrome. Case 5/2011]. / Herz und Nieren--nur gemeinsam sind sie stark. Über das kardiorenale und renokardiale Syndrom. Fall 5/2011.

HISTORY AND ADMISSION FINDINGS: We report on two patients with cardiorenal and renocardiac syndrome, respectively, who were treated with peritoneal dialysis. INVESTIGATIONS: Patient 1 suffered from dilated cardiomyopathy with an ejection fraction of 20%. There was no hint for an intrinsic renal disease, urinalysis showed microalbuminuria at the most. Due to progressive cardiac forward failure kidney dysfunction and diuretic-refractory volume retention developed. Patient 2 was admitted with an uremic syndrome and newly developed atrial fibrillation. Echocardiography revealed a hitherto unknown dilated cardiomyopathy. DIAGNOSIS, TREATMENT AND COURSE: Both patients were treated with continuous ambulatory peritoneal dialysis. This led to regression of the uremic complications. Sinus rhythm was restored in patient 2 after two weeks and cardiomyopathy was reversed after another 9 months. CONCLUSIONS: End-stage heart failure results in kidney dysfunction which can progress to a dialysis-dependent state. End-stage renal failure is often accompanied by cardiac dysfunction and failure.

Dissolution and re-crystallization processes in multiphase silicon stabilized tricalcium phosphate.

Ultrasonically accelerated dissolution of multiphase silicon stabilized tricalcium phosphate powders in water or Earle's balanced salt solution transforms the powders into needle-like calcium deficient apatite crystals with the c-axis (001) oriented along the needle. Ion exchange with the solution occurs primarily in the first hours of immersion. The transformation is driven by an interaction between the crystal surface and adsorbed water leading to the growth of crystallites which have the most stable surface configuration. First principles calculations of the surface energies of various hydroxyapatite surfaces with and without adsorbed water shows that depending on the ion concentrations in the fluid that determine the chemical potential of tricalcium phosphate, either Ca-rich (010) or stoichiometric (001) layers are the dominant surfaces. The higher the chemical potential, the more elongated in the (001) direction the crystallites become to minimize the total surface energy. The loss of a calcium Ca(2+) compensated by the addition of two H(+) is strongly favoured energetically on the (001) and Ca-rich (010) surfaces. A high concentration of excess Si at grain boundaries may be partly responsible for the rapid transformation of multiphase Si-TCP.

Silicon substitution in the calcium phosphate bioceramics.

Silicon (Si) substitution in the crystal structures of calcium phosphate (CaP) ceramics such as hydroxyapatite (HA) and tricalcium phosphate (TCP) generates materials with superior biological performance to stoichiometric counterparts. Si, an essential trace element required for healthy bone and connective tissues, influences the biological activity of CaP materials by modifying material properties and by direct effects on the physiological processes in skeletal tissue. The synthesis of Si substituted HA (Si-HA), Si substituted alpha-TCP (Si-alpha-TCP), and multiphase systems are reviewed. The biological performance of these Si substituted CaP materials in comparison to stoichiometric counterparts is discussed. Si substitution promotes biological activity by the transformation of the material surface to a biologically equivalent apatite by increasing the solubility of the material, by generating a more electronegative surface and by creating a finer microstructure. When Si is included in the TCP structure, recrystallization to a carbonated HA is mediated by serum proteins and osteoblast-like cells. Release of Si complexes to the extracellular media and the presence of Si at the material surface may induce additional dose-dependent stimulatory effects on cells of the bone and cartilage tissue systems.

Fabrication of PZT sol gel composite ultrasonic transducers using batch fabrication micromolding.

A new micromolding technique for fabricating high-frequency (>20 MHz) ultrasound transducers has been developed. The technique combines sol gel processing with an epoxy-based, photo-resist Su-8 micromold to form miniature PZT structures. An advantage of this technique as compared to more traditional lithographic galvanforming and abforming (LIGA) processing is that the intermediate step of producing a nickel-plated mold is avoided. Instead, the PZT is formed directly using a photo-resist. The resulting structures can be fabricated with aspect ratios up to 3:1 and thicknesses up to 50 micro. We have successfully fabricated 50-micro-thick linear array elements with 23-micro-wide elements separated by 15 kerfs. A 50-micro thick, 2.5-mm diameter, five-element annular array structure with 20-micro kerfs also has been fabricated. The micromolded PZT composite has a density of 5.7-5.8 micro 0.4 g/cm3 and a thickness coupling coefficient as high as 0.32.

Synthesis and characterization of single-phase silicon-substituted alpha-tricalcium phosphate.

Silicon-substituted calcium phosphate (CaP) powders with a Ca/(P+Si) ratio of 1.50 have been prepared by a wet chemical method, with silicon contents up to 2.16 weight percent (wt%). Sintering for 2 h at 1250 degrees C yields single-phase silicon-substituted alpha tricalcium phosphate (Si-alpha-TCP) for compositions between 0.59 and 1.14 wt% silicon. The sintered powders have been characterized with X-ray fluorescence (XRF) spectrometry, X-ray diffraction (XRD), attenuated total reflection infrared spectroscopy (ATR-IR) and transmission electron microscopy (TEM). Compositions with less than 0.59 wt% silicon result in mixtures of Si-alpha-TCP, beta-TCP, and calcium hydroxyapatite (HA), while compositions with more than 1.14 wt% silicon result in mixtures of Si-alpha-TCP and HA. The lattice parameters of single-phase Si-alpha-TCP prepared with 0.87 wt% silicon are a=12.874(1)A, b = 27.372(2) A, c = 15.225(1) A, and beta = 126.38(1) degrees .

Functional atomic force microscopy investigation of osteopontin affinity for silicon stabilized tricalcium phosphate bioceramic surfaces.

Resorbable silicon stabilized tricalcium phosphate (Si-TCP)-based bioceramics are characterized from a biological perspective by measuring the intermolecular interaction force between osteopontin (OPN) protein and the material surface using atomic force microscopy (AFM). OPN protein was covalently bound to silicon nitride AFM tips and adsorption and adhesion forces were measured in an electrolyte with a composition similar to that of physiological fluids. A strong relationship exists between the adhesion force of OPN on the material surface, the number of adherent osteoclasts (OC) and the resorption of the material. OPN adhesion is strongest on hydroxyapatite (HA) surfaces, or in samples that induce a HA-like surface through a precipitation reaction in electrolytic media. It is proposed that the increased biological response of the Si-TCP phase can be attributed in part to its reactivity in a physiological electrolyte, which involves a rapid conversion to a calcium deficient HA phase with a corresponding increase in the adhesion strength of OPN to the material, with a consequentially higher OC resorption response.

Electron spin resonance in silicon substituted apatite and tricalcium phosphate.

Impurity centers associated with silicon have been observed in the phase mixture of silicon substituted apatite (Si-Ap) and silicon stabilized tricalcium phosphate (Si-TCP) using electron spin resonance (ESR). Two unique centers occur upon addition of SiO2 to the calcium phosphate system: an orthorhombic center with g-values 2.0072+/-0.0001, 2.0024+/-0.0001 and 2.0003+/-0.0001 (Si-h1) and a center with tetrahedral symmetry having g-values components 2.0054+/-0.0001 and 1.9992+/-0.0003 (Si-h2). Both centers are hypothesized to be characteristic of defects associated with silicon in the Si-Ap phase. Through comparison of the intensity of F-OH centers in undoped calcium hydroxyapatite (HA) prepared with various levels of OH occupancy, a relationship is demonstrated between the ESR intensity of an F-center signal with g = 2.0019+0.0004 (F-OH) and the OH occupation of HA. Relative changes in the intensity of ESR signals Si-h1 and F-OH are consistent with a chemical model describing the substitution of SiO4(4-) for PO4(3-) in HA with the creation of OH- vacancies as charge compensation, resulting in a mixed phase composition of Si-Ap and Si-TCP that results when a hydroxyapatite precipitate (HA) is heated in the presence of added SiO2.