Mesenchymal neoplasms with NTRK and other kinase gene alterations

Kinase alterations are increasingly recognised as oncogenic drivers in mesenchymal tumours. Infantile fibrosarcoma and the related renal tumour, congenital mesoblastic nephroma, were among the first solid tumours shown to harbour recurrent tyrosine kinase fusions, with the canonical ETV6::NTRK3 fusion identified more than 20 years ago. Although targeted testing has long been used in diagnosis, the advent of more robust sequencing techniques has driven the discovery of kinase alterations in an array of mesenchymal tumours. As our ability to identify these genetic alterations has improved, as has our recognition and understanding of the tumours that harbour these alterations. Specifically, this study will focus upon mesenchymal tumours harbouring NTRK or other kinase alterations, including tumours with an infantile fibrosarcoma-like appearance, spindle cell tumours resembling lipofibromatosis or peripheral nerve sheath tumours and those occurring in adults with a fibrosarcoma-like appearance. As publications describing the histology of these tumours increase so, too, do the variety kinase alterations reported, now including NTRK1/2/3, RET, MET, RAF1, BRAF, ALK, EGFR and ABL1 fusions or alterations. To date, these tumours appear locally aggressive and rarely metastatic, without a clear link between traditional features used in histological grading (e.g. mitotic activity, necrosis) and outcome. However, most of these tumours are amenable to new targeted therapies, making their recognition of both diagnostic and therapeutic import. The goal of this study is to review the clinicopathological features of tumours with NTRK and other tyrosine kinase alterations, discuss the most common differential diagnoses and provide recommendations for molecular confirmation with associated treatment implications.     

Short-term outcomes of patients with neovascular exudative AMD: the effect of COVID-19 pandemic

Graefe's Archive for Clinical and Experimental Ophthalmology - To estimate the impact of delayed care during the coronavirus disease 2019 (COVID-19) pandemic on the outcomes of patients with...     

Islet Xenotransplantation: Are We Really Ready for Clinical Trials?

Four clinical trials of porcine islet transplantation have been reported, and there are verbal reports that clinical trials on much larger scales are continuing in centers in China and Russia. The four reported trials are briefly reviewed and, in the light of the present status of experimental islet xenotransplantation, consideration is given to whether such trials are currently justified. The Ethics Committee of the International Xenotransplantation Association has (1) emphasized the need for encouraging studies in non-human primates before clinical trials should be undertaken, (2) mandatory monitoring for the transfer of porcine microorganisms, and (3) careful regulation and oversight by recognized bodies. Other aspects of the topic, such as the need for informed consent, are briefly discussed. We conclude that, at the present time, more data documenting convincing efficacy, focused on clinically applicable immunosuppressive regimens, are needed to justify the initiation of closely monitored clinical trials. A clinical trial may then be justified even though the potential risk to the patients, and possibly for society, will not be zero.     

The effect of individual HLA-A and -B mismatches on the generation of cytotoxic T lymphocyte precursors

In order to study the correlation between HLA mismatches and the cytotoxic T lymphocyte precursor frequency, we used a limiting dilution analysis to determine the CTLp frequencies against individual mismatched HLA-A and -B alloantigens in 21 patients waiting for a renal transplant. Altogether, thirty-three mismatched HLA-A antigens and 55 HLA-B antigens were tested. The CTLp frequencies against mismatches of HLA-B locus antigens were found to be significantly higher than those against HLA-A antigens (P less than 0.002). This may explain why matching for HLA-B antigens is more important for a good renal allograft survival than matching for HLA-A antigens.     

Magnesium hydroxide: new insights into the mechanism of its laxative effect and the potential involvement of prostaglandin E2.

The mechanism by which Mg(OH)2 acts as a laxative is unknown. To explore the mechanism, six volunteers more than 55 years old, with normal bowel habits, were enrolled in a dose-response, randomized, placebo-controlled, double-blind, crossover design study. Each subject was studied for four inpatient periods of 5 days each on a metabolic ward with 9 days off of all medication between studies. In the hospital, all patients were on a diet fixed in calories, fluid volume, Na+, fiber, and Ca2+. At 8 p.m. on each study day, each subject took 45 ml containing either placebo or 1,200, 2,400, or 3,600 mg of Mg(OH)2 plus 240 ml of water. On the fourth and fifth hospital days of each period, 24-h stool output was quantified and analyses performed. Compared to placebo, Mg(OH)2 caused the following dose-dependent results: (a) increased number of bowel movements; (b) increased percentage of stool water; (c) increased stool volume; (d) increased stool Mg2+; and (e) increased total stool 24-h prostaglandin E2 (PGE2), with mean 24-h excretions as follow: placebo, 95 +/- 18 pg/24 h; 1,200 mg Mg(OH)2, 260 +/- 100; 2,400 mg Mg(OH)2, 357 +/- 117; and 3,600 mg Mg(OH)2, 525 +/- 196. There was a significant correlation between stool PGE2 excretion and stool water consistent with a causative relationship. However, the concentration of stool prostaglandin was lower than the concentration found to alter intestinal electrolyte transport in vitro. In summary, the laxative effect of Mg(OH)2 is associated with increased output of stool PGE2. The contribution of the stool PGE2 to the laxative effect of Mg(OH)2 is unknown.     

Human Tattoo

Ultrathin serial sections of human biopsy specimens, taken at 24 hours, 1 month, and 1, 3, and 40 years post-tattooing were examined under the electron microscope. The ink particles found in cells were measured and compared with control ink particles embedded in agar. Freshly tattooed skin showed an inflammatory reaction followed by ultrastructural necrosis. The time of healing, about 1 month from introduction of ink to complete healing, has been divided into three phases: inflammatory reaction and necrosis, formation of basement membrane, and normal epidermis and dermis. Once the skin showed normal ultrastructure, ink particles were found only in dermal fibroblasts.     

Drug-Induced Antibodies: Interaction of the Drug with a Polymorphic Platelet-Antigen

Preincubation of donor platelets with ticarcillin will prevent the reactivity of a platelet antibody against these platelets, whereas no influence was observed on antisera against HLA, 5A, 5b and ZWa. The implications for the mechanism of drug-induced antibodies with restricted specificity will be discussed.