The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.

Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert anti-neoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations. Likewise, givinostat killed primary cells, but not their normal hematopoietic counterparts, from patients carrying CRLF2 rearrangements. At low doses, givinostat downregulated the expression of genes belonging to the JAK/STAT pathway and inhibited STAT5 phosphorylation. In vivo, givinostat significantly reduced engraftment of human blasts in patient-derived xenograft models of CRLF2-positive BCP-ALL. Importantly, givinostat killed ruxolitinib-resistant cells and potentiated the effect of current chemotherapy. Thus, givinostat in combination with conventional chemotherapy may represent an effective therapeutic option for these difficult-to-treat subsets of ALL. Lastly, the selective killing of cancer cells by givinostat may allow the design of reduced intensity regimens in CRLF2-rearranged Down syndrome-associated BCP-ALL patients with an overall benefit in terms of both toxicity and related complications.

Peripheral blood cells from children with RASopathies show enhanced spontaneous colonies growth in vitro and hyperactive RAS signaling.

Germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK pathway are the hallmarks of a newly classified family of autosomal dominant syndromes termed RASopathies. Myeloproliferative disorders (MPDs), in particular, juvenile myelomonocytic leukemia, can lead to potentially severe complications in children with Noonan syndrome (NS). We studied 27 children with NS or other RASopathies and 35 age-matched children as control subjects. Peripheral blood (PB) cells from these patients were studied for in vitro colony-forming units (CFUs) activity, as well as for intracellular phosphosignaling. Higher spontaneous growth of both burst-forming units-erythroid (BFU-E) and CFU-granulocyte/macrophage (CFU-GM) colonies from RAS-mutated patients were observed as compared with control subjects. We also observed a significantly higher amount of GM-colony-stimulating factor-induced p-ERK in children with RASopathies. Our findings demonstrate for the first time that PB cells isolated from children suffering from NS or other RASopathies without MPD display enhanced BFU-E and CFU-GM colony formation in vitro. The biological significance of these findings clearly awaits further studies. Collectively, our data provide a basis for further investigating of only partially characterized hematological alterations present in children suffering from RASopathies, and may provide new markers for progression toward malignant MPD in these patients.

Transient expressive (nonfluent) dysphasia after metrizamide myelography.

Four (3.4%) of 117 patients undergoing metrizamide myelography experienced transient expressive dysphasia 7-8 hr after myelography and lasting up to 36 hr. All four patients had lumbar myelograms obtained with 15 ml of 190 mg l/ml (2850 mg l). Metrizamide was injected via lumbar puncture with a 20 gauge spinal needle under fluoroscopic control. Neurologic complications after metrizamide have been reported, but so far have appeared to be transient. It is likely that the transient expressive dysphasia experienced by the four patients reported here was a neurotoxic reaction, rather than a seizure phenomenon.

Sarcoma metastatic to the central nervous system parenchyma: a review of the literature.

Sarcoma metastatic to cerebral parenchyma, although rare, occurs more frequently than generally recognized. With increased duration of survival due to multi-modal therapy, more CNS metastases are being found. A literature search occasioned by a patient with metastatic sarcoma has produced some interesting results.

Suprascapular nerve entrapment.

Suprascapular nerve compression is a true peripheral entrapment neuropathy that can be cured by lysis of the suprascapular ligament and freeing the suprascapular nerve. It is a rare entity that must be considered in the differential diagnosis of radicular pain, as well as that of the shoulder. Four examples of suprascapular nerve neuropathy in three patients are described, including one case of bilateral entrapment; all were young females. One was diagnosed as systemic lupus erythematosus (case 3); it is now considered that a second patient (case 2) may have the same disorder. The clinical, anatomic, and surgical considerations of the suprascapular nerve are considered in this paper.

Etiology of neck and back pain. An automatic myoneuralgia?

This report presents the theoretical basis and some evidence to support the concept that most back, neck, and shoulder pain is due to a psychophysiological process in muscle and nerve tissue known as tension myositis. Descriptive data on age, past history of associated psychosomatic disorders, mode of onset of pain, patterns of pain location and tenderness, the latter considered the hallmark of tension myositis, and certain neurological correlates, suggest that it is the major cause of back pain rather than structural aberrations of the spine. It is suggested that success or failure in the conventional treatment of back pain is evidence for a psychosomatic process, via the placebo mechanism.

Psychosomatic backache.

It is contended in this report that the majority of pain syndromes involving the neck, shoulders, and low back are the result of a benign, reversible process in the musculature which is psychosomatic in nature and which has been called tension myositis. The natural history of the disorder, findings on physical examination, and diagnostic studies are briefly described. The theoretical basis for the conclusion that it is psychosomatic is discussed, the therapeutic program is described, and long-term results with a group of treated patients are presented. The results suggest that a program of physician counseling and physical therapy is generally successful. The author believes that the psychosomatic nature of the disorder places it within the purview of the behaviorally oriented specialty of family practice.