Single Antigen–Mismatched Unrelated Hematopoietic Stem Cell Transplantation Using High-Dose Post-Transplantation Cyclophosphamide Is a Suitable Alternative for Patients Lacking HLA-Matched Donors

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is not defined. The use of high-dose post-transplant cyclophosphamide (PTCy) in haploidentical transplantation has proven feasible and effective in overcoming the negative impact of HLA disparity on survival. We hypothesized that PTCy could also be effective in the setting of MMUD transplantation. We retrospectively analyzed 86 consecutive adult recipients of alloHSCT in our institution, comparing 2 contemporaneous groups: PTCy MMUD (n?=?26) versus matched unrelated donor (MUD) (n?=?60). Graft source was primarily peripheral blood (92%). All PTCy MMUD were HLA 7/8 (differences in HLA class I loci in 92% of patients) and received PTCy plus tacrolimus ± mofetil mycophenolate as GVHD prophylaxis. No differences were observed between PTCy MMUD and MUD in the 100-day cumulative incidence of acute GVHD grades II to IV (31% versus 22%, respectively; P?=?.59) and III to IV (8% versus 10%, P?=?.67). There was a trend for a lower incidence of moderate to severe chronic GVHD at 1 year after PTCy MMUD in comparison with MUD (22% versus 41%, P?=?.098). No differences between PTCy MMUD and MUD were found regarding nonrelapse mortality (25% versus 18%, P?=?.52) or relapse rate (11% versus 19%, P?=?.18). Progression-free survival and overall survival at 2 years were similar in both cohorts (67% versus 54% [HR, .84; 95% CI, .38 to 1.88; P?=?.68] and 72% versus 57% [HR, .71; 95% CI, .31 to 1.67; P?=?.44], respectively). The 2-year cumulative incidence of survival free of moderate to severe chronic GVHD and relapse tended to be higher in the PTCy MMUD group (47% versus 24%; HR, .60; 95% CI, .31 to 1.14; P?=?.12). We conclude that HLA 7/8 MMUD transplantation using PTCy plus tacrolimus is a suitable alternative for those patients who lack a MUD.     

MAP2K2 mutation as a cause of cardio‐facio‐cutaneous syndrome in an infant with a severe and fatal course of the disease

Cardio‐facio‐cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.     

Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques

Although the clustering of GFAP immunopositive astrocytes around amyloid-β plaques in Alzheimer’s disease has led to the widespread assumption that plaques attract astrocytes, recent studies suggest that astrocytes stay put in injury. Here we reexamine astrocyte migration to plaques, using quantitative spatial analysis and computer modeling to investigate the topology of astrocytes in 3D images obtained by two-photon microscopy of living APP/PS1 mice and WT littermates. In WT mice, cortical astrocyte topology fits a model in which a liquid of hard spheres exclude each other in a confined space. Plaques do not disturb this arrangement except at very large plaque loads, but, locally, cause subtle outward shifts of the astrocytes located in three tiers around plaques. These data suggest that astrocytes respond to plaque-induced neuropil injury primarily by changing phenotype, and hence function, rather than location.The role of astrocytes in amyloid-β deposition during Alzheimer’s disease—whether they prevent, potentiate, or have no effect on plaque formation—remains unknown. The peer-reviewed literature indicates that it is widely believed that amyloid-β plaques attract astrocytes, with statements such as “astrocytes migrate to amyloid-β plaques,” “amyloid-β plaques recruit astrocytes,” and variations thereof frequently appearing. The idea that astrocytes are attracted to plaques is an extension of the notion that astrocytes migrate to zones of injury (1, 2) and is mostly based on the immunohistochemical observation that amyloid-β deposits are typically surrounded by concentric rings of “reactive astrocytes,” defined by increased GFAP immunoreactivity and hypertrophy. However, recent studies question the capacity of astrocytes to move (3, 4). These suggest instead that astrocytes may be restricted to their birthplace (3), which in the neocortex seems to be within neuronal columns derived from radial glia (5). Recent stereological assessments of astrocytes in Alzheimer’s disease suggest that their most prominent change is phenotypic (i.e., GFAP immunoreactivity and hypertrophy) rather than proliferative (6). Thus, doubts have risen over the recruitment of astrocytes by plaques.Using the APPSwe/PS1dE9 (APP/PS1) double-transgenic mouse model of Alzheimer’s disease, we revisited the idea that astrocytes migrate to plaques. Our approach improved on the traditional GFAP immunohistochemical analysis postmortem in three ways. First, the analyses were performed in 3D reconstructions of images captured in vivo through cranial windows by two-photon microscopy. These materials are superior to sectioned specimens from fixed brains because they preserve true spatial relationships in 3D to great depths (up to 200 μm from the cortical surface), providing accurate positional information for each astrocyte. Second, astrocytes were labeled with sulforhodamine 101 (SR101), a selective fluorescent marker of reactive and nonreactive astrocytes (7), thus avoiding the bias of identifying only a subset of astrocytes as with GFAP. Third, astrocyte and plaque interactions were examined with two mathematical objects: the pair-correlation function g(r) and the characteristic length (L_C) of Voronoi cells. These combine global and plaque-centered perspectives and allow for quantitative comparisons to be made. The g(r) function was used to assess astrocyte topology, and we examined the effect of plaques on several tiers of astrocytes using L_C, a very sensitive approach that reveals changes in object position from the redistribution of astrocyte-associated domains approximated by Voronoi tessellation.Finally, we used simulations to help interpret astrocyte-to-astrocyte and astrocyte-to-plaque interactions and to investigate the effect on astrocyte topology of plaque loads in the upper limit of what could be present in older human patients.Using a statistical physics approach, we found that astrocytes resemble a liquid of objects of different sizes contained in a constant volume. This arrangement is globally unaltered by plaques except at the heaviest plaque loads.     

Expression patterns and prognostic role of transketolase-like 1 in muscle-invasive bladder cancer

Purpose

The pentose phosphate pathway (PPP) has been shown to play an important role in the metabolism of cancer cells. The transketolase-like 1 gene (TKTL1) encodes an enzyme representing an essential component of this pathway. Its expression has been demonstrated to correlate with stage and outcome in various tumors. The aim of the present study was to assess expression patterns and the prognostic role of TKTL1 in muscle-invasive bladder cancer (MIBC).

Patients and methods

The expression of TKTL1 was assessed in a tissue microarray consisting of histopathologically benign and malign tissue of 112 patients who underwent radical cystectomy due to MIBC. Cytoplasmatic and nuclear expression were assessed by immunohistochemistry and compared separately with clinicopathologic parameters and outcome.

Results

Cytoplasmatic expression of TKTL1 was exclusively present in tumor tissue. In contrast, the proportion of nuclei positive for TKTL1 was higher in histopathologically benign tissue compared with malign tissue. No correlation was observed between cytoplasmatic or nuclear TKTL1 expression and tumor stage, grade or the presence of metastases. Patients with lymph node involvement showed a decreased frequency of cytoplasmatic expression compared with node-negative patients (p = 0.01). However, no further correlation was observed between the expression of TKTL1 and clinical outcome of patients.

Conclusions

The present study shows that the cytoplasmatic expression of TKTL1 is specific for MIBC tissue compared with histopathologically benign urothelium. This specific expression is present in a subgroup of MIBC potentially identifying patients with activated PPP suitable for a targeted inhibition of sugar metabolism. In contrast to other malignancies, TKTL1 shows no prognostic significance in MIBC.

     

Three-Dimensional Laparoscopic Sleeve Gastrectomy: Improved Patient Safety and Surgeon Convenience

One of the aims of laparoscopic surgery is to improve upon the results obtained by open surgery. This clearly appears to have been achieved in bariatric surgery. Two-dimensional (2-D) systems have been used to date, though new 3-dimensional (3-D) technologies have been introduced in an attempt to improve surgeon vision and thus increase the safety of the surgical techniques. Sixty obese patients underwent sleeve gastrectomy using a device equipped with 3-D optics allowing surgery to be viewed by the surgeon in 3 dimensions by using a specific monitor and wearing appropriate glasses. The mean patient age was 48.1 years. The mean weight was 114 kg (range, 92–172), with a mean body mass index (BMI) of 44 ± 5.21 kg/m². All surgeries were performed using the 3-D system, with a mean surgical time of 71 ± 49.6 minutes and a mean hospital stay of 3.0 ± 1.2 days. Only 1 intraoperative complication was recorded: retroperitoneal bleeding on insertion of the optical trocar. Over a mean follow-up period of 12 months, the mean body weight of the patients was 88 kg (range, 71–121), with a BMI of 30.56 ± 3.98 kg/m² and a percentage excess weight loss of 68.14% ± 7.89%. There was clear improvement of both the blood pressure and glucose levels. Three-dimensional sleeve gastrectomy is safe, viable, and fully reproducible compared with 2-D surgery, improving visualization of the surgical field, safety, and surgeon convenience. Randomized studies involving larger patient samples are needed for the comparison of results.Key words: 3-D laparoscopy, Bariatric surgery, Metabolic surgeryIn recent years, laparoscopic surgery has become clearly indicated in bariatric and metabolic surgery. This surgical technique has made it possible to reduce morbidity and mortality in comparison with conventional open surgery, and to shorten hospital stay. In addition to the usual 5-trocar technique, laparoscopic surgery has also produced satisfactory results with the single-port approach, which is regarded as less invasive and affords equivalent outcomes and improved aesthetic results.More recently, the possibility of using three-dimensional (3-D) surgery has been considered. The film Avatar (James Cameron, 2006) represented a starting point for a number of multinational medical engineering companies who launched projects that now allow us to use 3-D laparoscopic systems. This new technology offers the perception of depth, which was not previously available.Sleeve gastrectomy is one of the surgical techniques presently used to treat obesity. It was initially regarded as first-step surgery in patients with a high body mass index (BMI), before performing biliopancreatic diversion. Sleeve gastrectomy is currently considered to be a restrictive technique that can be used as a sole option in morbid obesity, even when accompanied by diabetes mellitus, as contemplated by the International Sleeve Gastrectomy Expert Panel Consensus of 2011.Three-dimensional laparoscopic sleeve gastrectomy requires 5 ports, like the two-dimensional (2-D) laparoscopic technique, and one of them must be enlarged to extract the sectioned stomach. However, 3-D visualization is very useful in all the surgical steps, as it improves spatial orientation and can increase the safety of the surgical technique.The present study analyzes the results of 3-D laparoscopic sleeve gastrectomy after a short 1-year follow-up period, with a view to evaluating its safety and feasibility in patients with severe or morbid obesity and type 2 diabetes.     

Energy expenditure,body composition and dietary habits in progressive supranuclear palsy

Journal of Neurology - Little is known about metabolic changes in progressive supranuclear palsy. Goals of the present study are to: (1) investigate whether early progressive supranuclear palsy is...