Horizontal GBR with anorganic equine bone combined with a customized titanium mesh.

This case report describes the fixed rehabilitation of the lower left arch in a patient following an horizontal GBR procedure by means of a customized titanium mesh and a new slow resorption bone substitute of equine origin.

Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification. SIGNIFICANCE: Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384.

Implants Placed with the All-On-4 Technique: A Radiographic Retrospective Study on 156 Implants with a 5- to 14-Year Follow-up.

The aim of this retrospective study was to evaluate the performance of implants placed with the All-on-4 technique after a mean time in function of 9 years. A total of 34 patients with 156 implants were selected for this study: 18 patients underwent tooth extraction on the day of implant placement (Group D), and 16 patients were already edentulous (Group E). A periapical radiograph was taken at a mean follow-up of 9 years (range: 5 to 14 years). Success and survival rates and the prevalence of peri-implantitis were calculated. Statistical analysis was used to assess comparisons between groups. After a mean follow-up of 9 years, the cumulative survival rate was 97.4% and the success rate was 77.4%. The difference between the initial and final radiographs resulted in a mean marginal bone loss (MBL) of 1.3 ± 1.06 mm (range: 0.1 to 5.3 mm). No differences were seen between Groups D and E. Peri-implantitis affected 15 implants (9.6%) in 9 patients (26.5%). This study shows that the All-on-4 technique is a reliable treatment method for both edentulous patients and patients requiring tooth extractions, with results maintained over a long follow-up period. The present MBL results are similar to those around implants in other rehabilitation types.

A comparison between anorganic bone and collagen-preserving bone xenografts for alveolar ridge preservation: systematic review and future perspectives.

After tooth extraction, dimensional changes affect the alveolar socket, leading to loss in alveolar bone height and width. Histological modifications also occur, with initial formation of a blood clot that is replaced with granulation tissue and subsequently with a provisional connective tissue matrix. Spontaneous healing ends with socket filling with woven bone, which is gradually replaced with lamellar bone and bone marrow. Adequate alveolar ridge dimensions and bone quality are required to assure optimal stability and osseointegration following dental implant placement. When a tooth is extracted, alveolar ridge preservation (ARP) procedures are an effective method to prevent collapse of the post-extraction socket. Heterologous bone is widely chosen by clinicians for ARP, and anorganic bone xenografts (ABXs) made bioinert by heat treatment represents the most used biomaterial in clinical applications. Collagen-preserving bone xenografts (CBXs) made of porcine or equine bone are fabricated by less invasive chemical or enzymatic treatments to remove xenogenic antigens, and these are also effective in preserving post-extraction sites. Clinical differences between anorganic bone substitutes and collagen-preserving materials are not well documented in the literature but understanding these differences could clarify how processing protocols influence biomaterial behavior in situ. This systematic review of the literature compares the dimensional changes and histological features of ABXs versus CBXs in ridge preservation procedures to promote awareness of different bone xenograft efficacies in stimulating the healing of post-extraction sockets.

Liver Resection for Type IV Perihilar Cholangiocarcinoma: Left or Right Trisectionectomy?

How the side of an extended liver resection impacts the postoperative prognosis of advanced perihilar cholangiocarcinoma (PHC) is still controversial. We compared the outcomes of right (RTS) and left trisectionectomies (LTS) in Bismuth-Corlette (BC) type IV PHC resection. All patients undergoing RTS or LTS for BC type IV PHC in a single tertiary center between January 2012 and December 2019 were compared retrospectively. The endpoints were perioperative outcomes, long-term overall (OS), and disease-free survival (DFS). Among 67 hepatic resections for BC type IV PHC, 25 (37.3%) were LTS and 42 (63.7%) were RTS. Portal vein and artery resection rates were 40% and 52.4% (p = 0.29), and 24% and 0% (p < 0.001) in the LTS and RTS groups, respectively. The severe complication (Clavien−Dindo > IIIa) rate was comparable (36% vs. 21.5%, p = 0.357) while the postoperative liver failure (POLF) rate was lower in the LTS group (16% vs. 38%, p = 0.048). The R0 resection rate was similar between groups (81% vs. 92%; p = 0.154). The five-year OS rate was higher in the LTS group (66% vs. 30%, p = 0.009) while DFS was comparable (43% vs. 18%, p = 0.11). Based on multivariable analysis, the side of the trisectionectomy was an independent predictor of OS. Compared with RTS, LTS is associated with lower POLF and higher overall survival despite more frequent arterial reconstructions in type IV PHC. Although technically more demanding, LTS may be preferred in the treatment of advanced PHC.

Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay.

Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA.

Normothermic regional perfusion in liver transplantation from donation after cardiocirculatory death: Technical, biochemical, and regulatory aspects and review of literature.

BACKGROUND: Organs from donation after circulatory death (DCD) are increasingly used for liver transplantation, due to the persisting organ shortage and waiting list mortality. However, the use of DCD grafts is still limited by the inferior graft survival rate and the increased risk of primary non-function and biliary complications when compared to brain death donors' grafts. METHODS: Abdominal normothermic regional perfusion with extracorporeal membrane oxygenation (ECMO) is an in situ preservation strategy. which may mitigate ischemia-reperfusion injuries. and has been proposed to restore blood perfusion after the determination of death thus optimizing liver function before implantation. RESULTS: In this systematic review, we highlighted the clinical evidence supporting the use of normothermic regional perfusion in DCD liver underlying the pathophysiological mechanisms, and technical, logistic, and regulatory aspects. CONCLUSIONS: Despite the lack of properly designed, prospective, randomized trials, the current available data suggest beneficial effects of normothermic regional perfusion on clinical outcomes after liver transplantation.

Comparison of alternative arterial anastomosis site during liver transplantation when the recipient's hepatic artery is unusable.

Background: Few studies have analyzed outcomes of liver transplantation (LT) when the recipient hepatic artery (HA) was not usable. Methods: We retrospectively evaluated the outcomes of LT performed using the different alternative sites to HA. Results: Between 2002 and 2017, 1,677 LT were performed in our institution among which 141 (8.4%) with unusable recipient HA were analyzed. Four groups were defined according to the site of anastomosis: the splenic artery (SA group, n=26), coeliac trunk (CT group, n=12), aorta using or not the donor's vessel (Ao group, n=91) and aorta using a vascular prosthesis (Ao-P group, n=12) as conduit. The median number of intraoperative red blood cell transfusions was significantly increased in the Ao and Ao-P groups (5, 5, 8.5 and 16 for SA, CT, Ao and Ao-P group respectively, P=0.002), as well as fresh frozen plasma (4.5, 2.5, 10, 17 for the SA, CT, Ao and Ao-P groups respectively, P=0.001). Hospitalization duration was also significantly increased in the Ao and Ao-P groups (15, 16, 24, 26.5 days for the SA, CT, Ao and Ao-P groups respectively, P<0.001). The occurrence of early allograft dysfunction (EAD) (P=0.07) or arterial complications (P=0.26) was not statistically different. Level of factor V, INR, bilirubin and creatinine during the 7th postoperative days (POD) was significantly improved in the SA group. No difference was observed regarding graft (P=0.18) and patient (P=0.16) survival. Conclusions: In case of unusable HA, intraoperative and postoperative outcomes are improved when using the SA or CT compared to aorta.

Cortical Thickness, Bone Density, and the Insertion Torque/Depth Integral: A Study Using Polyurethane Foam Blocks.

PURPOSE: Bone density and implant primary stability parameters have been introduced that are based on calculating (1) the average of the instantaneous torque needed to keep the rotation speed of a bone density probe constant while it descends into bone or (2) the integral of the instantaneous torque-depth curve at implant insertion (I), a quantity that is equal to the insertion energy multiplied by a constant. This study aimed to determine how these two quantities are affected by the presence and thickness of a cortical bone layer. MATERIALS AND METHODS: An instantaneous torque-measuring micromotor was used to measure the density of six double-layer polyurethane foam blocks mimicking different cortical/cancellous bone combinations. Twenty measurements per block were collected, averaged, and compared. The insertion torque and the integral (I) of the instantaneous torque-depth curve at implant insertion were recorded when 20 3.75 × 12-mm cylindrical implants were inserted in each of nine blocks, including three single-layer blocks simulating the absence of a cortical layer, under three final cortical (countersink) preparations: 4.0, 3.7, and 3.5 mm. The relationship between the insertion torque, the integral of the instantaneous torque-depth curve at implant insertion (I), cortical thickness, and the final diameter preparation were investigated with regression and best-fit slope analyses. RESULTS: Bone density measurements showed that the average of the instantaneous torque at probing allowed differentiation of five of six different bone classes (hard-hard, hard-normal, hard-soft, normal-normal, normal-soft, soft-soft); the post hoc analysis of variance (ANOVA) comparisons were all statistically significant except for the hard-soft-normal-soft pair. The insertion torque and the integral (I) of the instantaneous torque-depth curve at implant insertion increased proportionally with cortical bone thickness (Pearson's r > 0.96 in all cases). CONCLUSION: When the final preparation varied from 3.7 mm to 3.5 mm, the insertion torque-thickness plot slope did not change significantly, while that of the instantaneous torquedepth curve integral (I)-thickness plot did change, suggesting that the torque-depth curve at implant insertion integral (I) may detect the increase in implant stability consequent to slight anatomical changes or changes in the site preparation protocol better than the insertion torque when measuring the cortical bone layer stress while undergoing insertion. These findings concerning bone density and primary stability should be investigated further using different experimental settings. If confirmed, they might generate improvements in the predictability of implant and prosthetic rehabilitation outcomes.

Favorable Outcomes of Liver Transplantation from Controlled Circulatory Death Donors Using Normothermic Regional Perfusion Compared to Brain Death Donors.

BACKGROUND: Liver transplantation (LT) from controlled donation after circulatory death (cDCD) was initiated in France in 2015 under a protocol based on the use of normothermic regional perfusion (NRP) before organ procurement. The aim was to compare outcomes following cDCD LT with NRP and donation after brain death (DBD) LT. METHODS: This is a multicenter retrospective study comparing cDCD LT with NRP and DBD LT. A case-matched study (1:2) was performed using the variables such as recipient and donor age, indication of LT. RESULTS: A total of 50 patients from the cDCD group were matched to 100 patients from the DBD group. From postoperative days 1-4, serum transaminase release was significantly lower in the cDCD group compared to the DBD group (P < 0.05). Early allograft dysfunction (cDCD: 18% versus DBD: 32%; P = 0.11), acute kidney injury (26% versus 33%; P = 0.49), 90-d graft loss (2% versus 5%; P = 0.66), and arterial (4% versus 12%; P = 0.19) and biliary (16% versus 17%; P = 0.94) complications were similar between the 2 groups. The 2-y graft survival was 88% for cDCD group and 85% for DBD group (P = 0.91). The 2-y patient survival was 90% for cDCD group and 88% for DBD group (P = 0.68). CONCLUSIONS: This study provides evidence that cDCD LT following postmortem NRP can be safely and effectively performed in selected recipients with similar graft and patient survival outcomes, without increased rates of biliary complications and early graft dysfunction compared to DBD LT.

Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer.

Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.

ABEMUS: platform-specific and data-informed detection of somatic SNVs in cfDNA.

MOTIVATION: The use of liquid biopsies for cancer patients enables the non-invasive tracking of treatment response and tumor dynamics through single or serial blood drawn tests. Next-generation sequencing assays allow for the simultaneous interrogation of extended sets of somatic single-nucleotide variants (SNVs) in circulating cell-free DNA (cfDNA), a mixture of DNA molecules originating both from normal and tumor tissue cells. However, low circulating tumor DNA (ctDNA) fractions together with sequencing background noise and potential tumor heterogeneity challenge the ability to confidently call SNVs. RESULTS: We present a computational methodology, called Adaptive Base Error Model in Ultra-deep Sequencing data (ABEMUS), which combines platform-specific genetic knowledge and empirical signal to readily detect and quantify somatic SNVs in cfDNA. We tested the capability of our method to analyze data generated using different platforms with distinct sequencing error properties and we compared ABEMUS performances with other popular SNV callers on both synthetic and real cancer patients sequencing data. Results show that ABEMUS performs better in most of the tested conditions proving its reliability in calling low variant allele frequencies somatic SNVs in low ctDNA levels plasma samples. AVAILABILITY AND IMPLEMENTATION: ABEMUS is cross-platform and can be installed as R package. The source code is maintained on Github at http://github.com/cibiobcg/abemus, and it is also available at CRAN official R repository. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Bone Density and Implant Primary Stability. A Study on Equine Bone Blocks.

Previous results on synthetic blocks mimicking bone indicate that bone density can be measured by the friction encountered by a rotating probe while it descends into bone, and that primary implant stability may be measured through the integral (I) of the torque-depth curve at implant insertion. This study aims to repeat those tests on collagen-preserving equine bone blocks as they better reproduce the mechanical properties of natural bone. Fifteen cancellous equine blocks had their density measured using a measuring probe. This was compared to their known physical density through linear regression analysis. Implant placement was carried out into six cancellous equine blocks and primary stability was measured using (I), as well as the insertion torque (IT), the implant stability quotient (ISQ), and the reverse torque (RT). The relation between (I), (IT), (ISQ), and (RT) was investigated by correlation analysis. Bone density measured using the probe correlated significantly with actual density, both with (r = 0.764) and without irrigation (r = 0.977). (I) correlated significantly with IT and RT under all irrigation conditions, and with ISQ only without irrigation (r = 0.886). The results suggest that the probe provides actual bone density measurements. They also indicate that (I) measures primary implant stability and is more sensitive to density variations than IT, RT, and ISQ. Results are consistent with those obtained on synthetic blocks but suggest that equine bone blocks may better reproduce the mechanical properties of human cancellous alveolar bone. This should be the subject of additional studies.

Outcome of medical and surgical therapy of GERD: predictive role of quality of life scores and instrumental evaluation.

INTRODUCTION: Aim of this study is to determine whether quality of life (QoL) assessment in association with instrumental evaluation can help to identify factors predictive of outcome both in surgically and medically treated GERD patients. METHODS: Between January 2005 and June 2010, 301 patients affected with GERD were included in the study. QoL was evaluated by means of GERD-HRQL and SF-36 questionnaires administered before treatment, at 6 months, at 1 year follow-up and at the end of the study. The multivariate analysis was used to detect if variables such as sex, age, heartburn, acid regurgitation, dysphagia, presence of esophagitis, percentage of total time at pH < 4, symptom index score (SI), the SF-36 and HRQL scores before treatment, at 6 months and 1 year could affect the QoL questionnaires scores at the end of the study. RESULTS: One hundred forty-seven patients were included in the surgical group and 154 in the medical group. No differences with regard to gender, age, mean SF-36 and HRQL scores before treatment were documented. At the end of the study, quality of life was significantly improved for SF-36 and HRQL scores, either for surgical or medical group. The multivariate analysis showed no factors individually affected the SF-36 and the HRQL scores, but symptom index score (SI) and QoL questionnaires scores at 6 months and 1 year follow-up. CONCLUSIONS: The combined use of pHmetry with evaluation of SI and QoL questionnaires can predict the outcome of GERD patients managed either by medical or surgical therapy.

Definition, incidence and etiology: what's new in the 21st century?

Actually, achalasia can be defined as a primary esophageal motor disorder characterized by esophageal aperistalsis and abnormal post-deglutitive lower esophageal sphincter (LES) relaxation. Its incidence varies from 0.03 to 1.63 cases per 100,000 people per year and increases with age, while the prevalence is almost 10/100,000 with no difference between the sexes. Regarding etiology, the most frequent histologic alteration is represented by the loss of the myenteric nerve fibers regulating inhibitory nitrergic neurotransmission in the LES, with the presence of a lymphocytic infiltrate and collagen deposition. The cause of this loss remains unclear. Among the theories proposed, the infectious, hereditary and autoimmune etiologies have been widely investigated. The only infectious agent identified as a cause of achalasia is Trypanosoma Cruzi, responsible of Chagas' disease. Regarding hereditary component, in rare cases achalasia presents as part of a genetic syndrome such as Down syndrome, Allgrove syndrome and familial visceral neuropathy. Although, no disease-specific gene has been identified. The autoimmune hypothesis has focused on the association of specific HLA classes with achalasia. However, no consistent association has been observed across studies. Despite increasing understanding of the physiopathology of achalasia, its etiology remains largely unknown. The onset of the disease is characterized by chronic inflammation of the myenteric plexus of the esophagus secondary to an environmental insult. Probably, genetic factors are involved in the development of achalasia, although the precise molecular basis of the disease has not been identified.

Osteopathic manipulation as a complementary treatment for the prevention of cardiac complications: 12-Months follow-up of intima media and blood pressure on a cohort affected by hypertension.

BACKGROUND: Aim of the present study was to investigate the association between osteopathic treatment and hypertension. METHODS: The design was a non-randomized trial including consecutive subjects affected by hypertension and vascular alterations, using pre-post differences in intima-media thickness, systolic and diastolic blood pressure as primary endpoints. Statistical analysis was based on univariate t tests and multivariate linear regression. RESULTS: A total of N = 31 out of N = 63 eligible subjects followed by a single cardiologist received osteopathic treatment in addition to routine care. Clinical measurements were recorded at baseline and after 12 months. Univariate analysis found that osteopathic treatment was significantly associated to an improvement in all primary endpoints. Multivariate linear regression showed that, after adjusting for all potential confounders, osteopathic treatment was performing significantly better for intima-media thickness (delta between pre-post differences in treated and control groups: -0.517; 95% c.i.: -0.680, -0.353) and systolic blood pressure (-4.523; -6.291, -2.755), but not for diastolic blood pressure. CONCLUSION: Our study shows that, among patients affected by cardiovascular disorders, osteopathic treatment is significantly associated to an improvement in intima-media and systolic blood pressure after one year. Multicentric randomized trials of adequate sample size are needed to evaluate the efficacy of OMT in the treatment of hypertension.