High rate of hematological responses to sorafenib in FLT3‐ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3‐ITD‐positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off‐label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post‐transplantation FLT3‐ITD‐positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand‐foot syndrome. None of the patients developed graft‐vs.‐host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T‐cell infusions. Six patients are alive and in remission at the last follow‐up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3‐ITD‐positive post‐transplantation relapses, manageable also in combination with other therapeutic strategies.     

Rituximab‐mediated Raf kinase inhibitor protein induction modulates NF‐κB in Sjögren syndrome

Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by an epithelial injury surrounded by dense lymphocytic infiltrates. The conditions for the long‐term maintenance of human salivary gland epithelial cells from pSS patients and a co‐culture system with pSS lymphocytes were used to assess the effect of Rituximab (RTX) on the inflammatory condition and progression in pSS. Quantitative real‐time PCR, genes and protein array analysis, Western blot, flow cytometry, small interfering RNA transfection and nuclear factor‐κB (NF‐κB) DNA binding assays were used as methods. Supporting the benefits of RTX, this study demonstrates that RTX decreases NF‐κB activity and interrupts the NF‐κB signalling pathway through the up‐regulation of the Raf‐1 kinase inhibitor protein (RKIP). Over‐expression of RKIP down‐regulates interleukins, their receptors and the expression of genes encodes proteins that attracted lymphocytes. Silencing of the RKIP gene leads to significantly increased expression and release of pro‐inflammatory mediators supporting that RKIP expression could be involved in the suppression of NF‐κB activation in pSS salivary gland epithelial cells.     

TAp73 depletion accelerates aging through metabolic dysregulation

Aging is associated with impaired scavenging of reactive oxygen species (ROS). Here, we show that TAp73, a p53 family member, protects against aging by regulating mitochondrial activity and preventing ROS accumulation. TAp73-null mice show more pronounced aging with increased oxidative damage and senescence. TAp73 deletion reduces cellular ATP levels, oxygen consumption, and mitochondrial complex IV activity, with increased ROS production and oxidative stress sensitivity. We show that the mitochondrial complex IV subunit cytochrome C oxidase subunit 4 (Cox4i1) is a direct TAp73 target and that Cox4i1 knockdown phenocopies the cellular senescence of TAp73-null cells. Results indicate that TAp73 affects mitochondrial respiration and ROS homeostasis, thus regulating aging.     

Association between trauma and cancer of the testis: the importance of self-palpation of the testis for the early detection: two case reports

introduction: Cancer of the testis is not always early detected and recognised, both by the physician and by the patient: sometimes physicians do not make an accurate genitals exam while patients often underestimate this problem. Case reports: Case I: 42-year-old man accepted from another hospital's Emergency, because of pain and edema of the right testis after a recent trauma on the gonad. At US, evidence of increased volume of the right testis with a large intraparenchymal hematoma. The markers were higher than normal. We performed a right orchiecthomy. The pathologist noted the presence of a mixed cancer of the testis (95% embryonal, 5% seminoma). Case II: 49-year-old man with hematuria, accepted from Emergency. The abdominal US revealed the presence of a voluminous neoformation (diameter of 12 cm) of the right kidney with neoplastic thrombosis of the right kidney vein. At the general physical exam, we detected the presence of an increased right testis, that at the US appared to be suspicious for cancer. Tumor markers were normal with the exception of αFP. We performed right nephro-adrenalectomy, right orchiectomy and removal of local nodes. The definitive histological examination demonstrated the presence of a seminoma of the testis and papillary carcinoma of the kidney with node metastasis. Discussion: Current studies showed an association between trauma and cancer of the testis, even if some authors did not find this association because they consider that patients with trauma undergo US and in that occasion cancer is incidentally detected. Conclusions: The association between trauma and cancer of the testis is controversial in current studies. Furthermore screening for the cancer of the testis does not seem to be useful, even if the self- and the physician's palpation of the testis seem to be very important because in these two cases they should allow the early detection of the condition, with a resulting better prognosis.