PRRX‐NCOA1/2 rearrangement characterizes a distinctive fibroblastic neoplasm

Fibroblastic/myofibroblastic neoplasms represent a broad, and occasionally diagnostically challenging, category of soft tissue neoplasms. A subset of these tumors defy conventional classification. However, with the advent of next‐generation sequencing, the identification of disease‐defining molecular alterations is gradually improving their subclassification. Following identification of two index cases of a distinctive fibroblastic neoplasm with a fusion gene involving PRRX1 and NCOA1, we performed a retrospective review to further characterize this entity. We identified two additional cases, including one with a fusion between PRRX1 and NCOA2. The average patient age was 38 years, and three patients were female. Two tumors occurred on the neck, and the others involved the groin and thigh. Tumors were centered in the subcutis and ranged from 2.3 to 14.0 cm (average 5.8 cm). Morphologically, they were predominantly hypocellular, with focal hypercellularity. They were composed of monomorphic spindle‐stellate cells with a vague fascicular pattern. The nuclei were bland with only rare mitotic activity, and occasional multinucleation. The intervening stroma was typically abundant and ranged from myxoid to collagenous, with frequent rope‐like collagen bundles. Three of the cases had a prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn‐like vessels. Immunohistochemistry was negative for desmin, smooth muscle actin, S100, CD34, keratin, and epithelial membrane antigen. Each of the patients was treated by simple excision and none of the tumors were associated with local recurrence or metastasis. Based on their unique morphological and molecular attributes, we believe this represents a novel fibroblastic tumor for which we have tentatively proposed the name “PRRX‐NCOAx‐rearranged fibroblastic tumor.”     

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

A recent breakthrough in the classification of soft tissue tumors (STT) has been a significant expansion in the number of neoplasms associated with NTRK and other kinase related fusions. This is important not only for diagnostic purposes, but also because it opens new avenues for targeted therapy. Indeed, recent clincal trials have shown significant benefit across multiple tumor‐types, prompting approval of NTRK inhibitors for clinical use in the setting of advanced/metastatic NTRK‐rearranged neoplasms. Despite these therapeutic oportunities, diagnostic challenges have transpired in recognizing these emerging new histologic subtypes of kinase fusions positive‐STT prospectively. This, in part, is attributable to their wide morphologic spectrum, variable risk of malignancy, and non‐specific immunoprofile. As such, recommendations for pathologic criteria and immunohistochemical testing are needed to improve classification and streamline the small subset of potential candidates for further molecular validation. This overview summarizes the key histologic features of various STT associated with NTRK and other kinase fusions, which appear to share a similar morphologic spectrum. Immunohistochemically, many of these tumors, regardless of the kinase fusion type, notably show co‐expression of S100 and CD34; issues related to the utility of pan‐NTRK and NTRK1 immunostaining are therefore summarized. Finally, I discuss the role of confirmatory molecular testing and how, in some instances, this may also be of prognostic value. This review is intended as a critical summary of the current literature to emphasize pathologic criteria for improving recognition of this emerging and complex group of kinase fusion associated STT.     

Allocation to Matched Related or Unrelated Donor Results in Similar Clinical Outcomes without Increased Risk of Failure to Proceed to Transplant among Patients with Acute Myeloid Leukemia: A Retrospective Analysis from the Time of Transplant Approval

Clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-SCT) from unrelated donors (URDs) approach those of matched related donor (MRD) transplants in patients with acute myeloid leukemia (AML). Yet, available data fail to account for differences in pretransplantation outcomes between these donor selection strategies. In this regard, URD allo-HSCT is associated with longer waiting times to transplantation, potentially resulting in higher probabilities of failure to reach transplant. We retrospectively analyzed 108 AML patients accepted for first allo-HSCT from the time of approval to proceed to transplant. Fifty-eight (54%) patients were initially allocated to MRD, while URD search was initiated in 50 (46%) patients. Time to transplant was longer in patients allocated to a URD when compared with patients assigned to an MRD (median 142 days versus 100 days; p < .001). Forty-three of 58 (74%) patients in the MRD group and 35 of 50 (70%) patients in the URD group underwent transplantation (odds ratio [OR], 1.22; p?=?.63). Advanced disease status at the time of allo-HSCT approval was the only predictor of failure to reach transplantation in the multivariate analysis (OR, 4.78; p?=?.001). Disease progression was the most common cause of failure to reach allo-HSCT (66.7%) in both the MRD and URD groups. With a median follow-up from transplantation of 14.5 (interquartile range, 5 to 29) months, the 2-year estimate of overall survival (OS) from allo-HSCT was 46% in the MRD group and 57% in the URD group (p?=?.54). There were no differences in OS according to donor type allocation in the multivariate analysis (hazard ratio, 1.01; p?=?.83). When including patients from the time of transplant approval, 2-year OS was 39% in the MRD group versus 42% in the URD group. Our study suggests that allocation of AML patients to URDs may result in comparable clinical outcomes to MRD assignment without a significant increase in the risk of failure to reach transplant.     

Basic fibroblast growth factor: effects on matrix remodeling, receptor expression, and transduction pathway in human periosteal fibroblasts with FGFR2 gene mutation.

The Crouzon syndrome, which is associated with fibroblast growth factor receptor (FGFR2) mutations, is characterized by premature fusion of cranial sutures. We used an in vitro model of cultured periosteal fibroblasts from normal subjects and from Crouzon patients with FGFR2 mutation. We analyzed the matrix turnover rate and the effects of adding FGF2 by evaluating fibronectin synthesis and the activity of some proteolytic enzymes. To assess the role of some FGF signaling molecules involved in FGFR2 regulation, we studied Grb2 tyrosine phosphorylation and the phosphotyrosine proteins associated with Grb2. The iodinate FGF binding assay was performed to quantify FGFR expression. Compared with normal fibroblasts, fibronectin synthesis was decreased in Crouzon fibroblasts, and protease activities in cells and medium were enhanced, suggesting that excess fibronectin catabolism is present. Differences were more marked when FGF2 was added. Very few phosphoproteins were visible in anti-Grb2 immunoprecipitations from Crouzon fibroblasts, which showed a significant increase in the number of high-affinity and low-affinity FGF2 receptors. These results suggest that the abnormal genotype and the Crouzon cellular phenotype are related. To compensate the low levels of tyrosine phosphorylation, Crouzon cells might increase the numbers of FGFR2, thus increasing the cell surface binding sites for FGF2.     

Factors of high impacts on the life of caregivers of disabled elderly

Elderly caregivers suffer physical and psychological consequences of the act of caring. The objective of this study was to characterize primary caregivers of elderly people in the community and identify the higher impacts of this activity on their life. We interviewed 127 caregivers about sociodemographic characteristics, presence of anxiety/depression (self-reporting questionnaire = SRQ), burden of care (caregiver burden scale = CBS); while their dependents were evaluated using sociodemographic questionnaires, health history, activities of daily living (ADL) scale and geriatric depression scale (GDS-15). The caregivers’ mean age was 55.1 ± 13.3 years; among them most were women and daughters with up to 4 years of education. The mean time as responsible for the elderly was 86.5 ± 96.3 months; 56% divided the caring responsibility and 28.2% had another occupation; 32.3% presented psychoemotional illness. There was a positive correlation between the CBS and the caregiver factors: psychoemotional disorders, time as responsible for the elderly and education level; as well as between the CBS and the elderly: number of activities with dependence, presence of depression and incontinences. The correlation between the elderly's personal income and number of visits received was negative. The identification of high impacts on the caregivers’ life would facilitate the professional approach.     

Distinctive changes in end-diastolic wall thickness and postsystolic thickening in viable and infarcted myocardium.

OBJECTIVES: In this study, we sought to compare the magnitude of changes in end-diastolic wall thickness (WT(ed)) and postsystolic thickening (PST) in a swine model of stunning and reperfused acute myocardial infarction, and to explore the relationship between WT(ed) and PST. METHODS: Twenty-six pigs were subjected to left anterior descending coronary artery occlusion followed by reperfusion to induce stunning (n = 6), nontransmural (n = 8), or transmural (n = 12) myocardial infarction. Myocardial wall thickness was measured using intracardiac echocardiography. Transmural extent of necrosis (TEN) was quantified by triphenyltetrazolium chloride technique. RESULTS: During the first minutes of reperfusion, a marked increase in WT(ed) occurred in the myocardial walls with nontransmural and transmural infarct (42% and 102%, respectively) but less in those with stunning (19%). PST persisted at reperfusion in walls with stunning and nontransmural infarct (23% and 26%, respectively). In transmurally infarcted walls, PST progressively decreased either during occlusion (5/12 pigs) or shortly after reperfusion (7/12 pigs). PST at reperfusion was virtually absent when TEN was >70%. Both PST and the increase in WT(ed) at reperfusion correlated well with TEN (P <.0001 for both). Changes in PST at reperfusion were weakly correlated with changes in WT(ed). CONCLUSIONS: A marked increase in WT(ed) after reperfusion and absence of PST indicate transmural myocardial infarction. Presence of PST at reperfusion indicates viable tissue in more than 30% of wall thickness. The results suggest that amplitude of PST is modulated predominantely by factors related to the severity of ischemia and, to a smaller extent, by changes in wall thickness.