Long-Term Results of Prophylactic Donor Lymphocyte Infusions for Patients with Multiple Myeloma after Allogeneic Stem Cell Transplantation

The major reason for treatment failure after allografting in multiple myeloma (MM) is relapse. Donor lymphocyte infusions (DLIs) are considered a valuable post-transplant strategy mainly for relapsed patients but using them to prevent relapse in MM has been reported rarely. In the present study, we examined the efficacy of prophylactic DLIs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in myeloma patients with a long-term follow-up of more than 5 years. A total of 61 patients with MM who did not relapse or develop disease progression after allo-HSCT were treated with prophylactic DLI in an escalating fashion (overall 132 DLI procedures) to deepen remission status and prevent relapse. Overall response rate to DLI was 77%. Thirty-three patients (54%) upgraded their remission status, 41 patients (67%) achieved or maintained complete remission, and 26% achieved a molecular remission. Incidence of acute graft-versus-host disease (GVHD) grade II to IV was 33% and no DLI-related mortality was noted. After a median follow-up of 68.7 months from first DLI the estimated 8-year progression-free survival (PFS), and overall survival (OS) in a landmark analysis was 43% (95% confidence interval [CI], 28% to 57%) and 67% (95% CI, 53% to 82%), respectively, with best outcome for patients who acquired molecular remission (8-year PFS was 62% and 8-year OS was 83%). Prophylactic escalating DLI in a selected cohort of MM patients to prevent relapse after allograft resulted in a low incidence of severe GVHD and encouraging long-term results, especially if molecular remission is achieved.     

Human ceruminous gland: ultrastructure and histochemical analysis of antimicrobial and cytoskeletal components

The ceruminous glands in the skin of the human external auditory canal are modified apocrine glands, which, together with sebaceous glands, produce the cerumen, the ear wax. Cerumen plays an important role in the protection of the ear canal against physical damage and microbial invasion. We studied the morphology of the glandular cells by light and electronmicroscopy. Antimicrobial and cytoskeletal components of the ceruminous glands were investigated by immunohistochemical methods. Numerous antimicrobial proteins and peptides are present in the ceruminous glandular cells: beta-defensin-1, beta-defensin-2, cathelicidin, lysozyme, lactoferrin, MUC1, secretory component of IgA. These data indicate a crucial role in the innate host defense against diverse pathogens. The apocrine secretion mechanism is a special mode of secretion by which the apical part of the cell cytoplasm surrounded by a membrane is pinched off. We could show that the presence of actin filaments, CK 19 and CK 7, seems to play a role in the pinching-off mechanism. Finally, we showed the secretion of lipid vesicles from the ceruminous gland. We could extend the number of detected antimicrobial peptides and proteins in human ceruminous glandular cells that protect the surface of the external auditory meatus. In addition, we detected proteins involved in the apocrine secretion mode of the ceruminous gland.     

Characterization of hepatocellular tumors: value of mangafodipir-enhanced magnetic resonance imaging

PURPOSE: To assess the value of mangafodipir trisodium-enhanced MR imaging for characterization of hepatocellular lesions. MATERIALS AND METHODS: Magnetic resonance images of 41 patients with 48 histopathologically proven hepatocellular lesions (20 cases of focal nodular hyperplasia [FNH], 4 adenomas, 15 hepatocellular carcinomas [HCCs], 7 regenerative nodules, and 2 others) were retrospectively studied. Magnetic resonance imaging was performed on a 1.5-T unit (Vision, Siemens, Erlangen, Germany; ACS-NT, Philips, Best, The Netherlands) using T2-weighted, fat-saturation, turbo spin echo imaging and T1-weighted gradient echo imaging before and 20 minutes after infusion of 5 micromol/kg mangafodipir (Amersham Health, Oslo, Norway). Qualitative analysis by 4 blinded independent readers included assessment of unenhanced images and, in a second step, assessment of unenhanced and contrast-enhanced images together. Lesions were classified as benign or malignant using a 5-point scale, and readers made a specific diagnosis. RESULTS: For characterization of hepatocellular lesions, mangafodipir-enhanced imaging was significantly superior to unenhanced imaging (P < 0.05). On receiver operating characteristic analysis, the area under the curve was 0.768 (95% confidence interval: 0.633-0.903) for unenhanced images and 0.866 (95% confidence interval: 0.767-0.966) for evaluation of unenhanced and contrast-enhanced images together (P < 0.05). Analysis of enhancement patterns aided in characterization and classification of tumors. CONCLUSION: Administration of mangafodipir improves the differentiation between adenoma or HCC and "nonsurgical" lesions (FNH or regenerative nodules). The accuracy for arriving at a specific diagnosis is higher when unenhanced and mangafodipir-enhanced images are considered together than for unenhanced MR images alone.     

Preemptive treatment of early donor‐specific antibodies with IgA‐ and IgM‐enriched intravenous human immunoglobulins in lung transplantation

This retrospective study presents our 4‐year experience of preemptive treatment of early anti‐HLA donor specific antibodies with IgA‐ and IgM‐enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between March 2013 and November 2017 were reviewed. The treatment protocol included one single 2 g/kg immunoglobulin infusion followed by successive 0.5 g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti‐CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case versus control patients and at 4‐year follow‐up, respectively, graft survival (%) was 79 versus 81 (P = .59), freedom (%) from biopsy‐confirmed rejection 57 versus 53 (P = .34), and from chronic lung allograft dysfunction 82 versus 78 (P = .83). After lung transplantation, patients with early donor‐specific antibodies and treated with IgA‐ and IgM‐enriched immunoglobulins had 4‐year graft survival similar to patients without antibodies and showed high antibody clearance.     

THE PRESSURE-VOLUME CURVE OF THE CEREBROSPINAL FLUID SPACE IN DOGS

The cerebrospinal fluid pressure-volume curve was determined by measuring the pressure response to rapid injection of fluid into the cisterna magna of dogs, by means of a constant flow infusion pump. The shape of the curve is complex, with two plateaus at the levels of the venous and arterial pressures, respectively. The slope dP/dV is referred to as the elastance of the system (mmHg/ml). The elastance has a low value in the normal pressure range and shifts at a fluid pressure of about 15 mmHg to a value approximately 20 times higher, with a relatively minute change in the volume of the system.     

Percutaneous in situ coronary venous arterialization: a catheter-based procedure for coronary artery bypass

Diffuse coronary artery disease is frequently untreatable by coronary artery bypass or angioplasty. Open chest surgical arterialization of the coronary venous system was successfully performed before the widespread use of coronary artery bypass grafting and has been applied in ungraftable patients thereafter. Percutaneous in situ coronary venous arterialization (PICVA) follows this surgical experience, using a series of unique catheter-based devices to arterialize isolated segments of coronary vein, forcing retroperfusion of severely ischemic myocardium. In a series of animals, this procedure had been shown to reduce ischemia and myocardial damage in an infarction model. In the PICVA European Safety trial, the first 11 percutaneous applications of catheter-based coronary bypass in humans revealed feasibility of the technique in highly symptomatic "no-option" patients. Despite two deaths and six failures to create the bypass, we continue to believe that on further development, the catheter-based coronary bypass can become a broad-based interventional application.     

Regional cerebral blood flow and CSF pressures during Cushing response induced by a supratentorial expanding mass

In order to delineate the critical blood flow pattern during the Cushing response in intracranial hypertension, regional cerebral blood flow was measured with radioactive microspheres in 12 anesthetized dogs at respiratory arrest caused either by expansion of an epidural supratentorial balloon or by cisternal infusion. Regional cerebrospinal fluid pressures were recorded and the local cerebral perfusion pressure calculated in various cerebrospinal compartments. In the 8 dogs of the balloon expansion group, the systemic arterial pressure was unmanipulated in 4, while it was kept at a constant low level (48 and 70 mm Hg) in 2 dogs and, in another 2 dogs, at a constant high level (150 and 160 mm Hg) induced by infusion of Aramine. At respiratory arrest, regional cerebral blood flow had a stereotyped pattern and was largely independent of the blood pressure level. In contrast, concomitant pressure gradients between the various cerebrospinal compartments varied markedly in the 3 animal groups, increasing with higher arterial pressure. Flow decreased by 85-100% supratentorially and by 70-100% in the upper brain stem down to the level of the upper pons, while changes in the lower brain stem were minor, on the average 25%. When intracranial pressure was raised by cisternal infusion in 4 dogs, the supratentorial blood flow pattern at respiratory arrest was approximately similar to the flow pattern in the balloon inflation group. However, blood flow decreased markedly (74-85%) also in the lower brain stem. The results constitute another argument in favour of the Cushing response in supratentorial expansion being caused by ischemia in the brain stem. The critical ischemic region seems to be located rostrally to the oblongate medulla, probably in the pons.     

Acute adenoviral infection of a graft by serotype 35 following renal transplantation

Adenoviral infections of immunocompetent patients usually present as self-limiting pharyngitis, gastroenteritis, urocystitis, or conjunctivitis. In immunosuppressed patients, development of the illness can be severe, even life-threatening or fatal, and therapeutical intervention is difficult. Previous case reports of adenoviral infections after kidney transplantation have described a symptomatology of hemorrhagic cystitis, fever, renal dysfunction, and rarely fatal systemic dissemination. Here we report on a 46-year-old female renal transplant recipient suffering from adenoviral serotype 35 nephritis of the donor organ 29 days after transplantation. In this case, the main symptoms of the adenoviral infection were high fever and progressive renal failure of the transplanted organ. At the peak of the clinical symptoms, owing to histological and immunohistochemical evaluations of a kidney biopsy, we were able to establish the diagnosis in time so that adequate therapy could be employed. Immunosuppression was reduced and modified, and a self-limiting course of the infection was observed, followed by significant improvement of graft function. Subsequent to histological diagnosis, adenoviral particles were isolated from urine and identified as adenovirus serotype 35. Adenoviral nephritis of the transplanted organ should be considered in the differential diagnosis of persistent anuria after kidney transplantation. Our case highlights the importance of applying all possible diagnostic techniques, including histological evaluation of renal biopsies.