BACKGROUND: Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation. METHODS: This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established. RESULTS: Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P = 0.039) were observed in the study cohort. CONCLUSIONS: A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).

• MeSH
• Antilymphocyte Serum * MeSH
• Immunosuppressive Agents adverse effects   MeSH
• Immunosuppression Therapy MeSH
• Infliximab adverse effects   MeSH
• Enzyme Inhibitors MeSH
• Humans MeSH
• Graft Survival MeSH
• Antibodies MeSH
• Graft Rejection prevention & control   MeSH
• Tacrolimus * adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Multicenter Study MeSH

Choice of calcineurin inhibitor may impact the outcome of patients undergoing T-cell replete hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) and mycophenolate mofetil (MMF) for prophylaxis of graft-versus-host disease (GVHD). We retrospectively analyzed 2427 patients with acute myeloid leukemia (AML) in first remission transplanted from a haploidentical (n = 1844) or unrelated donor (UD, n = 583) using cyclosporine A (CSA, 63%) or tacrolimus (TAC, 37%) and PT-Cy/MMF. In univariate analysis, CSA and TAC groups did not differ in 2-year leukemia-free or overall survival, cumulative incidence (CI) of relapse or non-relapse mortality. CI of severe grade III-IV acute GVHD was lower with TAC (6.6% vs. 9.1%, p = 0.02), without difference in grade II-IV acute GVHD or grade III-IV acute GVHD/severe chronic GVHD, relapse-free survival (GRFS). In multivariate analysis, TAC was associated with a lower risk of severe grade III-IV acute GVHD solely with haploidentical donors (HR 0.64 [95% CI, 0.42-0.98], p = 0.04), but not UD (HR 0.49 [95% CI, 0.2-1.21], p = 0.12). There was no significant difference for chronic GVHD. In conclusion, PT-Cy/MMF-based GVHD prophylaxis resulted in favorable OS and GRFS, irrespective of the CNI added. In haploidentical HCT, TAC seemed to prevent severe acute GVHD more effectively than CSA without impact on other outcome parameters.

• MeSH
• Leukemia, Myeloid, Acute * therapy   mortality   MeSH
• Cyclophosphamide * therapeutic use   MeSH
• Cyclosporine * therapeutic use   MeSH
• Child MeSH
• Adult MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Remission Induction MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Graft vs Host Disease * prevention & control   mortality   etiology   MeSH
• Child, Preschool MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Tacrolimus * therapeutic use   MeSH
• Hematopoietic Stem Cell Transplantation * methods   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH

Doba precizní a personalizované onkologie je zde, navzdory tomu dochází při zavádění nových terapeutických postupů a nových léčiv k mnohým dosud nepozorovaným překážkám. V drtivé většině případů jsou to onkologicky nemocní starších věkových skupin s komorbiditami a chronickou medikací, která často komplikuje aplikaci nových léků nebo lékových kombinací. V kazuistice bychom rádi prezentovali průběh nemoci a výzev spojených s protinádorovou terapií u pacienta po jaterní transplantaci s karcinomem prostaty.

The age of precision and personalized oncology is now, but application of new therapeutic possibilities and new pharmaceuticals brings new challenges. In most cases, patients with malignant tumors are of older age with chronic diseases, which complicate usage of new pharmaceuticals or their combination. In this clinical case, we would like to present treatment challenges on a patient with hepatic transplantation, who was diagnosed with prostate carcinoma.

• MeSH
• Precision Medicine * methods   MeSH
• Skeleton diagnostic imaging   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prostatic Neoplasms, Castration-Resistant diagnostic imaging   drug therapy   pathology   therapy   MeSH
• Prostatic Neoplasms * diagnostic imaging   drug therapy   pathology   therapy   MeSH
• Disease Progression MeSH
• Antineoplastic Agents administration & dosage   MeSH
• Radionuclide Imaging MeSH
• Tacrolimus administration & dosage   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Drug Interactions MeSH
• Humans MeSH
• Tacrolimus * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• MeSH
• Immunosuppressive Agents adverse effects   MeSH
• Calcineurin Inhibitors * adverse effects   MeSH
• Humans MeSH
• Prognosis MeSH
• Tacrolimus adverse effects   MeSH
• Kidney Transplantation adverse effects   MeSH
• Thrombotic Microangiopathies * etiology   chemically induced   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Editorial MeSH

Epidermodysplasia verruciformis je extrémně vzácné autozomálně recesivně dědičné kožní onemocnění se známými mutacemi v genech EVER1/TMC6 a EVER2/TMC8, nazývané také Lewandowského-Lutzův syndrom. Onemocnění je asociované s různými typy HPV virů, např. 5 a 8. V klinickém obraze, na místech ozářených sluncem, vznikají generalizované makuly až plaky připomínající kůru stromu, narůstající někdy do gigantických rozměrů. V níže uvedené kazuistice popisujeme případ mladého pacienta s anamnézou získané formy epidermodysplasia verruciformis při imunosupresi.

Epidermodysplasia verruciformis is an extremely rare autosomal recessive inherited skin disease, with known mutations in the EVER1/TMC6 and EVER2/TMC8 genes, also called Lewandowski-Lutz syndrome. The disease is associated with different types of HPV viruses, e.g. 5 and 8. In the clinical picture, generalized macules or plaques sometimes grow to gigantic dimensions, resembling the bark of a tree, in places exposed to the sun. In the case report below, we describe the case of a young patient with a history of acquired epidermodysplasia verruciformis during immunosuppression.

• MeSH
• Warts etiology   pathology   MeSH
• Adult MeSH
• Epidermodysplasia Verruciformis * diagnosis   etiology   pathology   therapy   MeSH
• Immunosuppression Therapy * methods   adverse effects   MeSH
• Humans MeSH
• Drug Substitution MeSH
• Tacrolimus adverse effects   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

BACKGROUND: Nonadherence to immunosuppressives, a risk factor for poor posttransplant outcomes, can be assessed by self-report using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS). Available in written and interview versions, and previously validated on content, the BAASIS is widely used in research and clinical practice. The aim of this study was to investigate its psychometric properties. METHODS: Using a literature search and our BAASIS database, this meta-analysis identified completed studies in adult transplant recipients whose data were usable to examine the BAASIS' reliability and 3 validity aspects: (1) relationships with other variables (electronic monitoring, other self-report scales, tacrolimus blood-level variability, collateral report, depressive symptoms, psycho-behavioral constructs, and interventions); (2) response processes; and (3) internal structure. Testing used random-effects logistic regressions. RESULTS: Our sample included 12 109 graft recipients from 26 studies. Of these 26, a total of 20 provided individual participant data. Evidence of the BAASIS' stability over time supports its reliability. Validity testing of relationships with other variables showed that BAASIS-assessed nonadherence was significantly associated with the selected variables: electronically monitored nonadherence ( P < 0.03), other self- and collaterally-reported nonadherence ( P < 0.001), higher variability in tacrolimus concentrations ( P = 0.02), higher barriers ( P < 0.001), lower self-efficacy ( P < 0.001), lower intention ( P < 0.001), and higher worries ( P = 0.02). Nonadherence also decreased after regimen change interventions ( P = 0.03). Response process evaluation indicated good readability and slightly higher nonadherence with the written version. Structurally, items on taking and timing shared variability. CONCLUSIONS: The BAASIS shows good validity and reliability as a self-report instrument to assess medication nonadherence in transplantation.

• MeSH
• Medication Adherence MeSH
• Adult MeSH
• Immunosuppressive Agents * therapeutic use   MeSH
• Humans MeSH
• Psychometrics MeSH
• Reproducibility of Results MeSH
• Tacrolimus * MeSH
• Self Report MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

• MeSH
• Adult MeSH
• Immunosuppressive Agents adverse effects   MeSH
• Immunosuppression Therapy MeSH
• Quality of Life MeSH
• Humans MeSH
• Graft Rejection diagnosis   prevention & control   MeSH
• Tacrolimus adverse effects   MeSH
• Torque teno virus * MeSH
• Kidney Transplantation * adverse effects   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Acute rejection remains a vexing problem in vascularized composite allotransplantation (VCA). Available immunosuppressive regimens are successful at minimizing alloimmune response and allowing VCA in humans. However, repeated rejection episodes are common, and systemic side effects of the current standard regimen (Tacrolimus, MMF, Prednisone) are dose limiting. Novel immunomodulatory approaches to improve allograft acceptance and minimize systemic toxicity are continuously explored in preclinical models. We aimed to systematically summarize past and current approaches to help guide future research in this complex field. METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed databases. For inclusion, articles had to primarily investigate the effect of a therapeutic approach on prolonging the survival of a skin-containing preclinical VCA model. Non-VCA studies, human trials, anatomical and feasibility studies, and articles written in a language other than English were excluded. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: The search retrieved 980 articles of which 112 articles were ultimately included. The majority of investigations used a rat model. An orthotopic hind limb VCA model was used in 53% of the studies. Cell and drug-based approaches were investigated 58 and 52 times, respectively. We provide a comprehensive review of immunomodulatory strategies used in VCA preclinical research over a timeframe of 44 years. CONCLUSION: We identify a transition from anatomically non-specific to anatomical models mimicking clinical needs. As limb transplants have been most frequently performed, preclinical research focused on using the hind limb model. We also identify a transition from drug-based suppression therapies to cell-based immunomodulation strategies.

• MeSH
• Immunomodulation MeSH
• Immunosuppressive Agents pharmacology   therapeutic use   MeSH
• Rats MeSH
• Skin MeSH
• Humans MeSH
• Graft Rejection prevention & control   MeSH
• Tacrolimus therapeutic use   MeSH
• Vascularized Composite Allotransplantation * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Systematic Review MeSH

S imunoglobulinem IgG4 asociované onemocnění (IgG4-related disease - IgG4-RD) je heterogenní skupina chorob s multiorgánovým poškozením, která byla rozpoznána v posledních 12 letech. Cílem tohoto textu je podat přehled zkušeností s léčbou této choroby. Glukokortikoidy zůstávají stále léčbou první volby, ale dlouhodobé podávání glukokortikoidů v monoterapii je spojeno s četnými nežádoucími účinky a komplikacemi. V případě kombinace glukokortikoidů s některým z léků ze skupiny imunosupresiv je možné podávat nižší dávky glukokortikoidů po kratší čas a počet léčebných odpovědí je vyšší než při použití pouhých glukokortikoidů. Rituximab je možno použít jako monoterapii anebo v kombinaci s glukokortikoidy a imunosupresivními léky. Který z imunosupresivních léků považovat za nejvhodnější, není známo. Pouze jedna studie srovnávala léčbu kombinací glukokortikoidů a mykofenolát mofetilu s léčbou glukokortikoidy a cyklofosfamidem. Počet léčebných odpovědí byl v obou ramenech stejný, ale délka remise byla delší ve skupině pacientů léčených glukokortikoidy a cyklofosfamidem. Rituximab dosahuje vysoký počet léčebných odpovědí (90 %) i v monoterapii, ale je možné jeho účinek dále potencovat glukokortikoidy a imunosupresivy. Rituximab je nyní preferován a doporučován pro udržovací léčbu v dávce 1000 mg 1× za 6 měsíců. U pacientů s multiorgánovým postižením se nám osvědčila kombinace rituximabu, cyklofosfamidu a dexametazonu následovaná aplikací rituximabu s jednorázovou dávku dexametazonu v 6měsíčních intervalech. V klinickém zkoušení jsou dva nové a nadějné léky: abatacept a dupilimab. Základem pro úspěšnou léčbu je podobně jako u jiných chorob časná diagnostika se zahájením léčby před vznikem ireversibilních fibrotických změn v postižených orgánech.

Immunoglobulin IgG4 related disease (IgG4-RD) is a heterogeneous disorder with multi-organ involvement recognised as a separate entity at the beginning of this century only. Evolving therapy is reviewed in this paper. Glucocorticoids are first choice drug but long administration of glucocorticoids is connected with many adverse effects. In case of combination glucocorticoids and immunosuppressive agents lower doses of glucocorticoids are needed, the response rate is higher and therapy is better tolerated. Rituximab is drug, that is possible use as monotherapy or in combination with glucocorticoids and immunosuppressive drugs. Only one study compared two immunosuporessive drugs, mycophenolate mofetil and cyclophosphamide. The response rated was similar but remissions were longer after glucocorticoids with cyclophosphamide then glucocorticoids with mycofenolat mofetil. No other comparative study of combination of various imunossupressive drugs with glucocorticoids was published. Rituximab has high number (90 %) of response rate in monotherapy, but can be used in combination with glucocorticoids and immunosuppressives. Rituximab is now preferred and recommended for maintenance therapy administered in 6-month interval. In case of advanced disease, we prefer therefore combination of rituximab, cyclofosphamide and dexamethasone for initial therapy followed by maintenance with rituximab in 6 months interval. There are two new drugs under investigation abatacept and dupilimab with promising results. Although we have very intensive therapies for good results of therapy early diagnosis before irreversible fibrotic changes in IgG4-RD involved organs is still needed.

• Keywords
• dupilumab,
• MeSH
• Abatacept pharmacology   therapeutic use   MeSH
• Glucocorticoids pharmacology   therapeutic use   MeSH
• Immunoglobulin G4-Related Disease * drug therapy   MeSH
• Immunosuppressive Agents pharmacology   therapeutic use   MeSH
• Humans MeSH
• Rituximab pharmacology   therapeutic use   MeSH
• Sirolimus pharmacology   therapeutic use   MeSH
• Tacrolimus pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH