Dynamic T(1) mapping predicts outcome of chemoradiation therapy in primary rectal carcinoma: sequence implementation and data analysis

PURPOSE: To describe details about the implementation of a dynamic T(1)-mapping technique and a simple data analysis strategy that can be used to predict therapy outcome in primary rectal carcinoma and to investigate the physiologic meaning of the obtained parameter. MATERIALS AND METHODS: Contrast-enhanced dynamic T(1) mapping was achieved with a snapshot fast low-angle shot (FLASH) T(1) mapping sequence implemented on a 1.5 T MR scanner. This method was applied to 58 patients with primary rectal cancer before onset of chemoradiation therapy. A simple data analysis strategy based on the calculation of the maximum slope of the tissue concentration-time curve divided by the maximum of the arterial input function (AIF) was used as a measure of tumor microcirculation (PI values). RESULTS: The snapshot FLASH (SFL) T(1)-mapping technique is accurate and sensitive enough to detect inhomogeneous uptake kinetics within tumor tissue. Classifying the patients into two groups according to therapy response showed lower mean PI values for responders as compared to nonresponders. PI was found to combine information about permeability surface area product (PS) and blood volume. CONCLUSIONS: The described method based on dynamic T(1) mapping has the potential to be a clinical tool for predicting therapy outcome of preoperative chemoradiation in patients with primary rectal carcinoma.     

Efficacy of Emodepside plus Praziquantel Tablets (Profender? Tablets for Dogs) against Mature and Immature Infections with Toxocara canis and Toxascaris leonina in Dogs

The efficacy of emodepside plus praziquantel tablets (Profender? tablets for dogs) against mature adult, immature adult and larval stages of Toxocara canis and Toxascaris leonina was evaluated in ten randomised, blinded and placebo-controlled dose confirmation studies in naturally or experimentally infected dogs. The tablets were used at the proposed minimum dose of 1 mg emodepside and 5 mg praziquantel per kg body weight. Efficacy was calculated based on worm counts after necropsy. Five studies demonstrated >99% efficacy against mature adult, >92% efficacy against immature adult, >98% efficacy against L4 and >94% efficacy against L3 larval stages of T. canis. Another five studies demonstrated >99% efficacy against mature and immature adult and >95% efficacy against L4 larval stages of T. leonina. No side effects of the treatment were observed. Emodepside plus praziquantel tablets thus provide a comprehensive new treatment option for ascarid infections in the dog.     

Enteric-coated mycophenolate sodium provides higher mycophenolic acid predose levels compared with mycophenolate mofetil: implications for therapeutic drug monitoring

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS) may lead to different MPA predose (C0) levels compared with mycophenolate mofetil (MMF). A post hoc analysis was performed on MPA morning predose values assessed in 88 maintenance renal transplant patients from three studies converted from MMF (1000 mg twice a day) to equimolar EC-MPS (720 mg twice a day) or vice versa, both in combination with cyclosporine. The median MPA predose level was approximately 30% higher when patients received EC-MPS (2.40 microg/mL; range, 0.49-39.30 microg/mL) compared with MMF (1.83 microg/mL; range, <0.1-12.80 microg/mL). Rare cases (3.0%) of high MPA C0 levels 15 microg/mL or greater were observed with EC-MPS consistent with a very prolonged release of MPA from this formulation. Both EC-MPS and MMF exhibited a poor correlation between MPA C0 levels and exposure as assessed by MPA area under the curve. Physicians targeting a certain MPA predose level have to be aware of the higher morning C0 levels with EC-MPS, whereas the overall MPA exposure is not different to MMF.     

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients

Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8⁺ T cell responses were less abundant than their CD4⁺ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.     

Treatment of the wrist in rheumatoid arthritis

Wrist involvement is common in rheumatoid arthritis and affects up to 50% of patients within the first 2 years after the onset of the disease, including bilateral involvement. It is a progressive disease that destroys the articular cartilage and surrounding soft tissues, thus leading to severe deformities. Radiological changes are characteristic and include narrowing of the joint line, cysts, and periarticular osteoporosis. Clinical changes are characterized by different scoring systems, indicating different therapeutic options. Surgical orthopedic treatment options include joint-preserving techniques to prevent further damage (radiosynoviorthesis, synovectomy, or axial correction with tendon transfers in earlier stages) and joint replacing techniques to restore function (arthrodesis, resection arthroplasty or total joint arthroplasty in later stages). This article reviews pathologic changes in the rheumatoid hand and their surgical treatment alternatives.     

Steroid- and calcineurin inhibitor free immunosuppression in kidney transplantation: state of the art and future developments

Owing to the increasing disparity of organ demand and organ supply the search for optimal immunosuppressive strategies has become a central issue in kidney transplantation (KTX). In the focus today are modifications of the use of calcineurin-inhibitors (CNIs, Cyclosporine A/Tacrolimus) and steroids, as they are nephrotoxic and promote cardiovascular risk factors like arterial hypertension, hyperlipidemia and diabetes mellitus. These modifications can either be withdrawal or avoidance of these substances in combination with new and/or established immunosuppressants. Because about half of all KTXs are performed by or with the help of urologists’ knowledge of modern immunosuppressive regimens is crucial also for urologists. We performed a literature research (PubMed, DIMDI, medline) for CNI- and steroid-sparing protocols and studies to elucidate their influence on graft-function and graft- and patient-survival. New substances and actual studies were also evaluated. Several published reports on CNI- and steroid-sparing protocols after KTX exist, including withdrawal, reduction or avoidance. The time of reduction seems to be crucial: an initially increased immune response should be counterbalanced by an initially intensified immunosuppression. Therefore, late steroid withdrawal seems to be safer than early withdrawal especially in Cyclosporine-based immunosuppression. Steroid avoidance also seems feasible on a CNI based regimen, especially in context with induction therapy. Withdrawal or avoidance of CNIs seems feasible with mycophenolate acid and/or induction therapy with IL 2-receptor antibodies as co-immunosuppressants. This is of interest in grafts with deteriorating function or from donors with extended criteria. Also, CNI- and steroid-free immunosuppression can be successfully performed with new immunosuppressants but results are yet premature. CNI- and/or steroid reduction, withdrawal or even avoidance is feasible. As long-term graft function is the goal of KTX and as more kidneys from donors with extended criteria are transplanted “tailored immunosuppression” will replace standards in the future.     

Activity of levofloxacin in a murine model of tuberculosis.

The activity of levofloxacin (LEV) was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 were given intravenously to 4-week-old female outbred mice. In a dose-response study, treatment with LEV at 100, 200, and 400 mg/kg of body weight was started 1 day after infection and was given daily for 28 days. Viable cell counts were determined from homogenates of spleens and lungs. A dose-related reduction in organism cell counts in organs was noted for LEV. The activities of LEV at 100, 200, and 300 mg/kg were compared with those of first-line antituberculosis agents. Both isoniazid and rifampin were more active than LEV. There was no difference in activity between LEV and either ethambutol or pyrazinamide against splenic organisms. The activities of ethambutol and LEV at the two higher doses were comparable against lung organisms. LEV at 300 mg/kg was more active than pyrazinamide against lung organisms. The activity of LEV was compared with those of two other quinolones, ofloxacin and sparfloxacin. LEV at 200 mg/kg had more than twofold greater activity than ofloxacin at the same dose. Sparfloxacin at 100 mg/kg was more active than LEV at 200 mg/kg; however, the activities of sparfloxacin at 50 mg/kg and LEV at 200 mg/kg were comparable. The promising activity of LEV in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent.