Carboxymethyl Cellulose-Based Hydrogel Film Combined with Umbilical Cord Blood Platelet gel as an Innovative Tool for Chronic Wound Management: A Pilot Clinical Study.

Treatment of chronic leg ulcers remains a major challenge and it is a substantial financial burden on individuals, families, caregivers, and health care system. There is increasing evidence on using of autologous Platelet-rich-plasma in wound repair but limited clinical data are available on the efficacy and safety of the use of umbilical cord blood platelet gel (CBPG). In our pilot study, for the first time, we aimed to evaluated the safety and efficacy of the use of umbilical CBPG combined with a hydrogel dressing in 10 patients with chronic venous ulcers (VU). The protocol consisted of application of umbilical cord blood platelet-rich plasma (PRP) combined with a Carboxymethyl cellulose (CMC)-based hydrogel dressing once a week for 4 weeks. The 80% of patients after 4 weeks of treatment had a significantly decrease in wound size. Moreover, we obtained an improvement in terms of mean Wound Bed Score (WBS), numeric rating scale (NRS) value and the EQ-5D index score. This pilot study showed that the topically therapeutic administration of umbilical CBPG associated with a CMC-based hydrogel dressing has the potential to accelerate the healing of chronic lesions without adverse reaction. However, additional studies with larger sample size and longer follow-up periods are required to confirm our findings.

Clinical and Virological Response to Convalescent Plasma in a Chronic Lymphocytic Leukemia Patient with COVID-19 Pneumonia.

The burden of COVID-19 remains unchanged for immunocompromised patients who do not respond to vaccines. Unfortunately, Omicron sublineages are resistant to monoclonal antibodies authorized in Europe so far, and small chemical antivirals have contraindications and toxicities that have not been studied in these patients. We report here the successful treatment of COVID-19 pneumonia lasting for 4 months after the transfusion of COVID-19 convalescent plasma (CCP) in a patient with severe immunosuppression due to both chronic lymphocytic leukemia and venetoclax treatment. The patient achieved a complete clinical, radiological and virological response after six transfusions (600 mL each) of high-titer CCP collected from triple-vaccinated and convalescent donors. This dramatic case adds to the mounting evidence of CCP efficacy in immunocompromised patients, provided that high-titer and large volumes are infused.

Correlation between Peri-Implant Marginal Bone Loss Progression and Peri-Implant Sulcular Fluid Levels of Metalloproteinase-8.

OBJECTIVES: The aim of this retrospective study was to analyze peri-implant marginal bone loss levels/rates and peri-implant sulcular fluid levels/rates of metalloproteinase-8 in three timeframes (6 months post-surgery-restoration delivery (T0)-and 6 (T6) and 24 (T24)-months post-loading) and to evaluate if there is a correlation between peri-implant sulcular fluid levels of metalloproteinase-8 and peri-implant marginal bone loss progression. MATERIALS AND METHODS: Two cohorts of patients undergoing implant surgery between January 2017 and January 2019 were selected in this retrospective study. A total of 39 patients received 39 implants with a laser-microtextured collar surface, and 41 subjects received 41 implants with a machined/smooth surface. For each patient, periapical radiographs and a software package were used to measure marginal bone loss rates. Implant fluid samples were analyzed by an enzyme-linked immunosorbent assay (ELISA) test. The modified plaque index, probing depth, and bleeding on probing were also recorded. RESULTS: High marginal bone rates at T24 were strongly associated with elevated rates between T0 and T6. The levels of metalloproteinase-8 were significantly more elevated around implants with marginal bone loss, in relation to implants without marginal bone loss. Marginal bone loss (MBL) rates at 24 months were associated with initial bone loss rates and initial levels of metalloproteinase-8. CONCLUSIONS: Peri-implant marginal bone loss progression is statistically correlated to peri-implant sulcular fluid levels of metalloproteinase-8. Moreover, the initial high levels of marginal bone loss and metalloproteinase-8 can be considered as indicators of the subsequent progression of peri-implant MBL: implants with increased marginal bone loss rates and metalloproteinase-8 levels at 6 months after loading are likely to achieve additional marginal bone loss values.

Sulcus fluid volume, IL-6, and Il-1b concentrations in periodontal and peri-implant tissues comparing machined and laser-microtextured collar/abutment surfaces during 12 weeks of healing: A split-mouth RCT.

OBJECTIVES: To compare gingival tissue healing at surgically manipulated periodontal sites and at sites receiving implants and healing abutments with machined (MS) vs laser-microtextured (LMS) surface placed with one-stage protocol. MATERIAL AND METHODS: Twenty-four non-smoking patients each received two implants with one-stage protocol in a split-mouth design on the same jaw. In each patient, one implant with a MS collar and one immediate healing abutment with a MS, and one implant with a LMS collar and one immediate healing abutment with a LMS were used. Soft tissues healing at surgically manipulated periodontal tissues (T+) and at non-surgically manipulated periodontal tissues (T-) at MS implant sites and at LMS implant sites were compared by means of clinical and biochemical parameters at baseline and at 1-2-3-4-6-8 and 12 weeks. RESULTS: PD and BoP mean values were statistically higher in MS than LMS implant sites (p<0.05). During early healing phase (1-4 weeks), MS and LMS peri-implant tissues and periodontal tissues at T(+) showed no statistically significant difference in crevicular fluid volume changes (p>0.05). Between 6 and 12 weeks, compared with T(+), no statistically significant difference in crevicular fluid volume and IL-6 and IL-1ß concentrations was noted in LMS implant sites (p>0.05), while statistically significantly higher mean values were noted in MS implant sites (p<0.05). CONCLUSIONS: Compared with T(+) and T(-), both MS and LMS implant sites presented a higher pro-inflammatory state in the early phase after surgery (1-4 weeks). At 12 weeks, only MS implant sites kept a higher pro-inflammatory state, while at LMS implant sites, it becomes similar to T(+) and T(-).

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. Design, Setting, and Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible. Interventions: Patients in the experimental group received intravenous high-titer CP (≥1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. Main Outcomes and Measures: The primary outcome was a composite of worsening respiratory failure (Pao2/Fio2 ratio <150 mm Hg) or death within 30 days from randomization. Results: Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04). Conclusions and Relevance: In patients with moderate to severe COVID-19 pneumonia, high-titer anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04716556.

Planktonic and Biofilm-Associated Pseudomonas aeruginosa and Staphylococcus epidermidis Elicit Differential Human Peripheral Blood Cell Responses.

Despite the considerable progress made in recent years, our understanding of the human immune response to microbial biofilms is still poor. The aim of the present study was to compare the in vitro response of human peripheral blood mononuclear cells (PBMC) to biofilms and planktonic cells of Pseudomonas aeruginosa and Staphylococcus epidermidis, two bacterial species particularly relevant in patients with cystic fibrosis or undergoing endovascular catheterization, respectively. PBMC isolated from healthy donors were co-cultured with 24 h-old biofilms or with exponentially growing cells of both species. Following 24 h of co-culture, the expression of early activation markers and the levels of cytokines in the culture supernatants were assessed by flow cytometry, while biofilm biomass and architecture were evaluated by crystal violet staining, CFU count, and confocal microscopy. Around 20% of PBMC was activated in response to both biofilms and planktonic cells of P. aeruginosa. In contrast, planktonic cells of S. epidermidis induced a statistically higher degree of activation than their biofilm counterpart (25% versus 15%; p < 0.01). P. aeruginosa biofilms stimulated pro-inflammatory (TNF-α, IL-1ß, IFN-γ, and IL-6) and anti-inflammatory (IL-10) cytokine production at statistically significant levels higher than its planktonic counterpart, while an opposite trend was observed with S. epidermidis. Differences in the architecture of the biofilms and in the number of PBMC infiltrating the biofilms between the two bacterial species may at least partially explain these findings. Collectively, the results obtained highlighted marked differences in the host-cell response depending on the species and the mode of growth (biofilms versus planktonic cultures), allowing speculations on the different strategies adopted by P. aeruginosa and S. epidermidis to persist in the host during the course of chronic infections.

An Update of the Possible Applications of Magnetic Resonance Imaging (MRI) in Dentistry: A Literature Review.

This narrative review aims to evaluate the current evidence for the application of magnetic resonance imaging (MRI), a radiation-free diagnostic exam, in some fields of dentistry. BACKGROUND: Radiographic imaging plays a significant role in current first and second level dental diagnostics and treatment planning. However, the main disadvantage is the high exposure to ionizing radiation for patients. METHODS: A search for articles on dental MRI was performed using the PubMed electronic database, and 37 studies were included. Only some articles about endodontics, conservative dentistry, implantology, and oral and craniofacial surgery that best represented the aim of this study were selected. RESULTS: All the included articles showed that MRI can obtain well-defined images, which can be applied in operative dentistry. CONCLUSIONS: This review highlights the potential of MRI for diagnosis in dental clinical practice, without the risk of biological damage from continuous ionizing radiation exposure.

Nickel-Titanium Rotary Instruments: An In Vitro Comparison (Torsional Resistance of Two Heat-treated Reciprocating Files).

AIM AND OBJECTIVE: The present study aims to evaluate the difference in torsional resistance of two reciprocating nickel-titanium (Ni-Ti) rotary files: WaveOne Gold and EdgeOne Fire. MATERIALS AND METHODS: A total of 40 nickel-titanium rotary instruments (n = 40): 20 WaveOne Gold Small (WOGS) and 20 EdgeOne Fire Small (EOFS) were divided into two groups. Each instrument was tested using a torsional resistance device already validated in previous studies to evaluate and compare torsional resistance. The static torsional test was implemented by blocking each instrument at 3 mm from the tip and rotating it until fracture with a reciprocating motion. Torque to fracture (TtF) and fragment length (FL) were measured and statistically analyzed. RESULTS: Statistical analysis of TtF found significant differences between the two groups (p<0.05). The EOFS showed higher TtF if compared to WOGS, with a mean value and a standard deviation of 3.05 ± 0.07 (N cm) against 2.97 ± 0.08 (N cm). Data for FL showed no significant differences (p>0.05) between the two groups. CONCLUSION: According to the results of this study, it is reasonable to assert that EOFS instruments showed a higher torsional resistance if compared to the WOGS. CLINICAL SIGNIFICANCE: As evidenced by this study, EOFS should be considered as a safer solution, in terms of torsional resistance, if compared to WOGS, reducing the risk of intracanal separation due to excessive torsional load.

Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review.

Background and Objectives: Oral cancer is the 6th most common cancer in the world and oral leukoplakia is an oral potentially malignant disorder that could develop into oral cancer. This systematic review focusses on randomized clinical trials for recombinant adenovirus p-53 (rAD-p53) therapy for the treatment of oral leukoplakia and cancer. Materials and Methods: We searched for research articles on various databases such as Pubmed/Medline, Embase, CNKI (China National Knowledge Infra-structure), Springerlink, cochrane and Web of sciences from 2003 to 2020. MeSH (Medical Subject Headings) terms were used for the search. Inclusion criteria included original research, randomized clinical trials and articles only in English language. Exclusion criteria were any articles that were not research articles, not randomized trials, non-human studies, etc. The articles were further graded on the Jadad scale. Results: 578 articles were assessed from various databases; only 3 articles were found to be appropriate for this review. Thus, meta-analysis was not performed because of heterogeneity and lack of data. In the three studies, whether rAD-p53 was used as a standalone therapy or with other therapies, there was a beneficial effect of the therapy. Furthermore, there were no serious adverse events and the only adverse events reported were fever, pain at the local injection site, flu-like symptoms and lowered WBC count. Conclusions: Thus, we can conclude that this therapy has a potential for beneficial therapeutic effects and further clinical trials with more patients need to be performed to get better understanding of the effect of rAD-p53 therapy, which probably will pave the way to its approval in other parts of the world.

Patient-blood management for COVID19 convalescent plasma therapy: relevance of affinity and donor-recipient differences in concentration of neutralizing antibodies.

BACKGROUND: Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is being extensively investigated as a treatment, with mixed results to date. Overall, there has been a generalized lack of appropriateness in prescriptions, which, in the field of transfusion medicine, is termed patient-blood management. OBJECTIVES: We aimed to separate study design variables that could affect clinical outcome after CCP therapy. We focus here on variables such as pretransfusion antibody testing in recipients, dose adjustments and antibody affinity measurements. SOURCES: We searched PubMed and preprint servers for relevant preclinical and clinical studies discussing each of these variables in the field of CCP therapy. CONTENT: We show evidence that neglecting those variables has affected the outcomes of the vast majority of CCP clinical trials to date. IMPLICATIONS: A better understanding of such variables will improve the design of the next generation of CCP clinical trials. This will likely lead to better clinical outcomes and will minimize risks of immune evasion from subneutralizing doses of neutralizing antibodies.

Laser microgrooved vs. machined healing abutment disconnection/reconnection: a comparative clinical, radiographical and biochemical study with split-mouth design.

BACKGROUND: Repeated removal and replacement of healing abutments result in frequent injuries to the soft tissues. PURPOSE: The purpose of this study was to evaluate the effect of disconnection/reconnection of laser microgrooved vs. machined healing and prosthetic abutments on clinical periodontal parameters, marginal bone levels, and proinflammatory cytokine levels around dental implants. MATERIAL AND METHODS: Twenty-four patients each received 2 implants with one-stage protocol in a split-mouth design on the same jaw. In each patient, one healing and prosthetic abutments with a laser microgrooved surface (LMS group) and one healing and prosthetic abutments with machined surface (MS group) were used. Four months following implant placement (T0), the healing abutments were disconnnected and reconnected three times to carry out the impression procedures and metal framework try-in. Four weeks later (T1), definitive prosthetic abutments were installated with screw-retained crowns. Modified plaque index (mPI), modified gingival index (mGI) bleeding on probing (BOP), and probing depth (PD) were recorded at T0 and T1. At the same time points, samples for immunological analyses were taken from the sulcus around each implant. Peri-implant crevicular fluid (PICF) samples were analyzed for interleukin-1beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-α levels using the ELISA kit. RESULTS: At T0 and T1, mPI and mGI showed no statistical difference between the two groups, while higher PD and BoP values were noted for the MS group (P < 0.05). The mean PICF volume and mean concentrations of IL-1ß, IL-6, and (TNF)-α in the LMS group were statistically less than those in the MS group (P < 0.05). In addition, comparison of IL-6 and IL-1ß mean concentrations at T0 and T1 in the MS group showed a statistically significant increase (p < 0.05) over time, which was not noted for the LMS. CONCLUSION: Disconnection/reconnection of healing and prosthetic abutments with a laser-microgrooved surface resulted in less inflammatory molecular response compared with conventional machined ones. TRIAL REGISTRATION: ClinicalTrials.gov NCT04415801 , registered 03/06/2020.

Assessment of automated high-throughput serological assays for prediction of high-titer SARS-CoV-2 neutralizing antibody.

COVID19 convalescent patient plasma units with high titer neutralizing antibody can be used to treat patients with severe disease. Therefore, in order to select suitable donors, neutralizing antibody titer against SARS CoV-2 needs to be determined. Because the neutralization assay is highly demanding from several points of view, a pre-selection of sera would be desirable to minimize the number of sera to be tested. In this study, a total of 140 serum samples that had been titrated for SARS-CoV-2 neutralizing antibody by microneutralization assay were also tested for the presence of anti-SARS-CoV2 antibody using 5 different tests: Architect® immunoassay (Abbott Diagnostics), detecting IgG against the nucleocapsid protein, LIAISON XL® (Diasorin) detecting IgG against a recombinant form of the S1/S2 subunits of the spike protein, VITROS® (Ortho Clinical Diagnostics), detecting IgG against a recombinant form of the spike protein, and ELISA (Euroimmun AG), detecting IgA or IgG against a recombinant form of the S1 subunit. To determine which immunoassay had the highest chance to detect sera with neutralizing antibodies above a certain threshold, we compared the results obtained from the five immunoassays with the titers obtained by microneutralization assay by linear regression analysis and by using receiver operating characteristic curve and Youden's index. Our results indicate that the most suitable method to predict sera with high Nab titer is Euroimmun® IgG, followed closely by Ortho VITROS® Anti-SARS-CoV-2 IgG.

Fatigue Resistance of Two Nickel-Titanium Rotary Instruments before and after Ex Vivo Root Canal Treatment.

AIM: The aim of the present study is twofold: to evaluate cyclic fatigue resistance differences of two different nickel-titanium rotary instruments, brand new and after an ex vivo instrumentation of single root extracted teeth. MATERIALS AND METHODS: Twenty new S One 20.06 were randomly divided into two groups. The first group (n = 10) was immediately subjected to a cyclic fatigue test (S One Group I). The second group (n = 10) (S one Group II) performed a cyclic fatigue test after three ex vivo root canal treatment with a single-file technique. The same process has been carried out for 20 M-Two 20.06 instruments. RESULTS: Mean time to fracture (TtF) for Group I was 51.14 ± 1.28 for S One and 32.62 ± 0.17 for M-Two 20.06 and for Group II was 46.00 ± 0.99 for S One and 27.75 ± 1.58 for M-Two 20.06. The reduction in TtF values from Group I to Group II was 11% for S One and 15% for M-Two. Statistical analysis found significant differences in all the groups examined (p value < 0.05). Mean fragment length (FL) for Group I was 3.07 ± 0.17 for S One and 3.05 ± 0.14 for M-Two 20.06 and for Group II was 3.05 ± 0.07 for S One and 3.05 ± 0.14 for M-Two 20.06. Statistical analysis was pursued, and no significant difference was found (p value > 0.05). CONCLUSION: The S-One showed significantly more resistance to cyclic fatigue stress than M-Two for both new and used instruments. This validates the hypothesis that the AF H wire enables the S One files to endure more the cyclic fatigue stresses. CLINICAL SIGNIFICANCE: This study demonstrates the cyclic fatigue resistance of a new endodontic instrument after repetitive usage.

Centering Ability of a New Nickel-Titanium Rotary Instruments with a Peculiar Flat-side Design: An In Vitro Study.

AIM: The aim of the present study was to investigate the role of the flat design compared with a non-flat designed instrument on the centering ability in a simulated root canal system. MATERIALS AND METHODS: Two file systems were chosen: the F-One (Fanta Dental, Shanghai, China) and a prototype with the same design but without the flat-side design. A total of 50 simulated L-shaped root canals in resin blocks were shaped with a new instrument each. Pre- and postcanal preparation images were captured and superimposed to measure and compare the canal transportation and evaluate the centering ability of each file. The t test was performed and the level of significance was set at p < 0.05. RESULTS: Prototype files removed significantly less resin from the inner and the outer parts of the canal and showed significantly higher mean transportation values. CONCLUSION: It can be concluded that the F-One file system demonstrated better shaping ability compared with the prototype file system in L-shaped resin-simulated canals. CLINICAL RELEVANCE: The present study showed the safety of the flat-side design, minimizing the risk of iatrogenic errors such as ledging, perforation, or zipping of the root canal.

In vitro human cord blood platelet lysate characterisation with potential application in wound healing.

Platelets contain abundant growth factors and cytokines that have a positive influence on the migration and proliferation of different cell types by modulating its physiopathological processes. As it is known that human umbilical cord blood platelet lysate (UCB-PL) contains a supraphysiological concentration of growth factors, in the present study, we investigated its effectiveness in wound-healing processes. Human UCB-PL was obtained by the freeze/thaw of platelet concentrate (1.1 × 109 platelets/L), and its effect was evaluated on human or mouse endothelial cells, monocytes, fibroblasts, and keratinocytes in different concentrations. Human UCB-PL was observed to have high levels of pro-angiogenic growth factor than peripheral blood platelet-rich plasma. Among the cell lines, different concentrations of human UCB-PL were necessary to influence their viability and proliferation. For L929 cells, 5% of total volume was necessary, while for human umbilical vein endothelial cell, it was 10%. Cell migration on monocytes was increased with respect to the positive control, and scratch closure on keratinocytes was increased with respect to serum-free medium with only 10% of human UCB-PL. We concluded that the human UCB-PL may be useful to produce a large amount of standard platelet concentrates sufficient for several clinical-scale expansions avoiding inter-individual variability, which can also be used as a functional tool for clinical regenerative application for wound healing.

Torsional Resistance of Two New Heat Treated Nickel Titanium Rotary Instruments: An in Vitro Evaluation

Abstract Objective: To evaluate the difference in torsional resistance, angular deflection and fragment length between two new rotary instruments: AF Blue S4 and S-One. These files share all features except cross-sectional design. Material and Methods: A total of 40 new Nickel-Titanium instruments of 25 mm in length were tested in this study and divided in two groups: 20 AF Blue S4, tip 25 and constant 6% taper and 20 AF-Blue S4 tip 25 and constant 6% taper. The torsional test was performed by the use of a torque recording endodontic motor (KaVo, Biberac, Germany). Torque to Fracture (TtF), Angular Deflection (AD) and Fragment Length (FL) was recorded for each instrument. To ensure an immovable block at 3mm of the instrument tip, an auto-polymerizing resin (DuraLay; Reliance Dental Mfg Co, Worth, IL) was used. Each file was rotated clockwise at a speed of 300 rpm until fracture occurred. Results: Group A (AF Blue S4) showed higher TtF and AD than Group B (S-One), and statistical analysis found significant differences between the two instruments (p<0.05). The mean values for FL showed no significant differences (p>0.05) between the two instruments. Conclusion: The AF Blue S4 seems to have a higher resistance to torsional stress in vitro. Clinically, the use of AF Blue S4 could be safer in narrow canals.

Identification of a novel HLA-DPB1, HLA-DPB1*687:01, in an Italian renal transplant candidate.

Two adjacent nucleotide substitutions in exon 2 characterize the novel class II HLA-DPB1*687:01 allele.

Red blood cell exchange as an approach for treating a case of severe tacrolimus overexposure.

Immunosuppressive medication dosing errors are not unfrequent and may present a number of challenges to transplant clinicians. Tacrolimus (TAC) is a widely used immunosuppressant with a narrow therapeutic index and potential severe side effects, including neurotoxicity and kidney injury. We herein report a case of 60-year-old woman who underwent deceased-donor liver transplantation at our center and due to inadvertent TAC overexposure was admitted to the Intensive Care Unit because of severe neurologic impairment, kidney injury and arterial hypotension. This case was challenging because TAC is largely bound to erythrocytes, has a high molecular weight, is highly lipophilic, has a high distribution volume and cannot be removed by hemodialysis or plasmapheresis. Based on these considerations, we decided to replace TAC-saturated erythrocytes with blood-bank red cells with the aim to accelerate its clearance. The treatment was effective in decreasing TAC whole blood trough levels within the therapeutic ranges with a significant improvement of the patient's clinical status. Red-blood cell exchange is a potentially safe and effective means of managing severe and symptomatic TAC toxicity.

Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient.

HBV-DNA integration frequently occurs in HBV-related hepatocellular carcinoma (HCC), but whether HBV antigens are expressed in HCC cells and can be targeted by immune therapeutic strategies remains controversial. Here, we first characterized HBV antigen expression in HCC metastases, occurring in a patient who had undergone liver transplantation for HBV-related HCC. We then deployed for the first time in HCC autologous T cells, genetically modified to express an HBsAg specific T cell receptor, as therapy against chemoresistant extrahepatic metastases. We confirmed that HBV antigens were expressed in HCC metastases (but not in the donor liver) and demonstrated that tumour cells were recognized in vivo by lymphocytes, engineered to express an HBV-specific T cell receptor (TCR). Gene-modified T cells survived, expanded and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Whilst clinical efficacy was not established in this subject with end-stage metastatic disease, we confirm the feasibility of providing autologous TCR-redirected therapy against HCC and advocate this strategy as a novel therapeutic opportunity in hepatitis B-associated malignancies.