Donor compatibility and performance status affect outcome of allogeneic haematopoietic stem cell transplant in patients with relapsed or refractory acute myeloid leukaemia

We retrospectively analysed 78 patients with relapsed (n?=?38), primary refractory (n?=?34) or untreated (n?=?6) acute myeloid leukaemia (AML) who underwent allogeneic HSCT at our Institution between 2002 and 2011, to verify outcome and to identify factors that can affect long-term outcome. Myeloablative conditioning regimens were used in 48 patients (24 siblings, 24 matched unrelated donor (MUD)), while 30 patients (18 siblings, 12 MUD) received reduced-intensity conditioning. Acute graft versus host disease (GVHD) developed in 37 (47?%) patients, while chronic GVHD occurred in 19 of the 65 evaluable patients (29?%). With a median follow-up time of 5?years, 13 of 78 patients (17?%) are alive and in complete remission (CR), while 64 have died. Cause of death was disease recurrence in 37 patients (58?%), infection in ten patients (16?%) and GVHD in six (9?%). One-year non-relapse mortality was 35?%. In multivariate analysis, performance status ≥80?% WHO and a full-matched donor were associated with a better outcome: these two variables allowed for risk stratification, identifying three groups with significantly different survival after transplant (P?=?0.0001). Considering post-transplant variables, only CR at recovery and development of cGVHD were correlated with a longer survival. Our data confirm the capacity of allogeneic transplant to prolong survival in a significant proportion of extremely high-risk AML patients.     

Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension

In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 μg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH.     

Multicentre European study for the treatment of advanced emphysema with bronchial valves

This multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bronchial valve therapy using a bilateral upper lobe treatment approach without the goal of lobar atelectasis. Patients with upper lobe predominant severe emphysema were randomised to bronchoscopy with (n = 37) or without (n = 36) IBV Valves for a 3-month blinded phase. A positive responder was defined as having both a ≥ 4-point improvement in St George's Respiratory Questionnaire (SGRQ) and a lobar volume shift as measured by quantitative computed tomography. At 3 months, there were eight (24%) positive responders in the treated group versus none (0%) in the control group (p = 0.002). Also, there was a significant shift in volume in the treated group from the upper lobes (mean ± SD -7.3 ± 9.0%) to the non-treated lobes (6.7 ± 14.5%), with minimal change in the control group (p<0.05). Mean SGRQ total score improved in both groups (treatment: -4.3 ± 16.2; control: -3.6 ± 10.7). The procedure and devices were well tolerated and there were no differences in adverse events reported in the treatment and control groups. Treatment with bronchial valves without complete lobar occlusion in both upper lobes was safe, but not effective in the majority of patients.     

Gender differences in benign renal masses

Purpose

To examine gender-specific differences in benign renal tumors.

Methods

This retrospective study included 135 adult Caucasian patients with 143 benign renal tumors, which were treated surgically at a single institution. Demographics, comorbidity, histology, renal function, and management were compared by gender. A systematic review and meta-analysis of the literature were performed.

Results

A total of 73 women were compared with 62 men. The female-to-male ratio was significantly higher in patients with benign renal tumors than in those with renal cell carcinoma (1.18:1 vs. 0.57:1, p < 0.001). Only 17 % of benign renal tumors were correctly classified by preoperative computed tomography. The most frequently observed histological types were oncocytoma (44 %) and angiomyolipoma (37 %). Angiomyolipoma occurred more than twice as often in women than in men (72 vs. 28 %), while oncocytoma was more frequently found in men (59 vs. 41 %, p = 0.001). Men with benign renal tumors were older (p = 0.002) and had higher body mass indices (p = 0.019), higher comorbidity indices (p < 0.001), lower ECOG performance status (p < 0.001), and smaller tumors (p = 0.045). No differences were seen in pack years, mode of diagnosis, bilaterality, renal function, use of laparoscopic surgery, and the rate of radical nephrectomy. In the meta-analysis of 9,665 renal tumors, women had a 2.55-fold increased chance of benign pathology and a greater chance of angiomyolipoma (OR 4.66) than men.

Conclusions

This study demonstrated several gender-specific differences in benign renal tumors, especially in the histological types. Despite this, clinical–pathological features and management of benign renal tumors in men and women appear more alike than different.     

Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age‐related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well‐characterized model in which outbred, aged, male Long‐Evans rats exhibit a spectrum of individual differences in hippocampal‐dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase‐67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67‐ and somatostatin‐positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN‐immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory‐impaired rats. Age‐related decreases in GAD67‐ and somatostatin‐immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age‐related memory impairment. J. Comp. Neurol. 521:3508‐3523, 2013. © 2013 Wiley Periodicals, Inc.     

Neurogenesis in temporal lobe epilepsy: Relationship between histological findings and changes in dentate gyrus proliferative properties

Objective

The relationship between hippocampal histopathological abnormalities, epileptogenesis and neurogenesis remains rather unclear.

Methods

Tissue samples including the subgranular zone of dentate gyrus (DG) were freshly collected for tissue culture for neurospheres generation in 16 patients who underwent surgery for drug-resistant temporal lobe epilepsy. Remaining tissues were histologically examined to assess the presence of mesial temporal sclerosis (MTS) and focal cortical dysplasia.

Results

MTS was detected in 8 cases. Neurospheres were formed in 10/16 cases. Only three out of these 10 cases exhibited MTS; on the contrary 5/6 cases lacking neurosphere proliferation presented MTS. There was a significant correlation between presence of MTS and absence of proliferation (p = 0.0389). We also observed a correlation between history of febrile seizures (FS) and presence of MTS (p = 0.0004) and among the 6 cases lacking neurosphere proliferation, 4 cases (66.6%) had experienced prolonged FS. Among “proliferating” cases the percentage of granular cells pathology (GCP) was lower (20% vs 50%) compared to “non proliferating” cases.

Conclusion

A decreased potential to generate neurosphere from the SGZ is related to MTS and to alterations of dentate gyrus granule cells, especially in MTS type 1b and GCP type 1. These histological findings may have different prognostic implications, regarding seizure and neuropsychological outcome, compared to patients with other epileptogenic lesions (such as FCD, glioneuronal tumours, vascular lesions).