Current concepts in the diagnosis and management of cytokine release syndrome

and it can severely reduce a patient’s quality of life. It consumes approximately 2% of the National Health Service budget in the United Kingdom, and in the United States, the total annual cost of treatment for heart failure is approximately $28 billion. Moreover, the financial burden of heart failure will increase in coming decades because of the aging population and the improved treatments of its causes. Over the past 20 years, there has been considerable progress in the treatment of chronic heart failure with angiotensin-converting–enzyme (ACE) inhibitors, 4,5 aldosterone antagonists, 6 beta-receptor blockers, 7,8 and resynchronization therapy. 9,10 Even with the very best of modern therapy, however, heart failure is still associated with an annual mortality rate of 10%. 10 The search for better treatments is one of the major challenges in cardiology. Chronic heart failure is multifactorial. There are many reasons why a human heart can fail, 11 but the available evidence suggests that the failing heart is an engine out of fuel — that is, altered energetics play an important role in the mechanisms of heart failure. For this reason, the modulation of cardiac metabolism has promise as a new approach to the treatment of heart failure. This review describes cardiac energy metabolism, appraises the methods used for its assessment, evaluates the role of impaired energy metabolism in heart failure, and gives options for metabolic therapy.

/pdf/the-failing-heart-an-engine-out-of-fuel-3m3ohmvi7b.pdf

The failing heart--an engine out of fuel.

Papillary and follicular thyroid carcinomas are among the most curable of all cancers. However, some patients are at high risk of recurrence or even death from their cancer. Most of these patients can be identified at the time of diagnosis using well-established prognostic indicators. The extent of initial treatment and follow-up should therefore be individualized. The early discovery of persistent and recurrent disease is based on the combined use of serum thyroglobulin determination and of total body scanning with 131I. The recent availability of recombinant human thyroid stimulating hormone has greatly improved the quality of the patient's life during follow-up. Treatment of recurrences is based mainly on surgery and 131I treatment.

Papillary and follicular thyroid carcinoma.

Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer.

/pdf/the-functional-role-of-long-non-coding-rna-in-human-z2g4vnspj4.pdf

The functional role of long non-coding RNA in human carcinomas

Thyroid papillary cancers (PTCs) are associated with activating mutations of genes coding for RET or TRK tyrosine kinase receptors, as well as of RAS genes. Activating mutations of BRAF were reported recently in most melanomas and a small proportion of colorectal tumors. Here we show that a somatic mutation of BRAF, V599E, is the most common genetic change in PTCs (28 of 78; 35.8%). BRAF(V599E) mutations were unique to PTCs, and not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). Moreover, there was no overlap between PTC with RET/PTC, BRAF, or RAS mutations, which altogether were present in 66% of cases. The lack of concordance for these mutations was highly unlikely to be a chance occurrence. Because these signaling proteins function along the same pathway in thyroid cells, this represents a unique paradigm of human tumorigenesis through mutation of three signaling effectors lying in tandem.

/pdf/high-prevalence-of-braf-mutations-in-thyroid-cancer-genetic-28r3o4s5ga.pdf

High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.

In this study, we compare the morphological and genetic characteristics of 38 post-Chernobyl thyroid papillary carcinomas from Belarussian children 5-18 years old with those of 23 sporadic papillary carcinomas from the same age children without history of radiation exposure from Los Angeles and Cincinnati. Among radiation-induced tumors, solid variant of papillary carcinoma was found in 37%, follicular in 29%, typical papillary in 18%, and mixed and diffuse sclerosing variants in 8% each. In the sporadic group, a typical papillary pattern was prevalent in 70%, follicular in 17%, diffuse sclerosing variant in 9%, and solid in 4%. In both groups, the prevalence of ret rearrangements was high, but the frequency of specific types of rearrangement was significantly different. Among radiation-induced tumors, ret/PTC3 was found in 58%, ret/PTC1 in 16%, and ret/PTC2 in 3%, whereas among sporadic tumors, ret/PTC1 was found in 47% (P < 0.05), and ret/PTC3 was found in 18% (P = 0.01). The morphological variants of papillary carcinoma showed different prevalence of the specific types of ret rearrangement. Seventy-nine % of solid variant tumors had ret/PTC3, whereas only 7% had ret/PTC1 (P = 0.0007). Among typical papillary tumors, ret/PTC1 was found in 38%, ret/PTC3 in 19%, and ret/PTC2 in 5%. Thus, ret rearrangements are highly prevalent in pediatric papillary carcinomas from children exposed to radiation and in those occurring sporadically. However, the types of ret/PTC vary between these two populations, with ret/PTC3 present more commonly in post-Chernobyl tumors. Furthermore, solid variants have a high prevalence of ret/PTC3, whereas typical papillary carcinomas do not, suggesting that the different types of ret rearrangement confer neoplastic thyroid cells with distinct phenotypic properties.

https://cancerres.aacrjournals.org/content/canres/57/9/1690.full.pdf

Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.

We studied serum vitamin E levels and the ratio of serum vitamin E to serum lipid levels in 11 children with chronic cholestasis complicated by vitamin E deficiency, as defined by characteristic neurologic signs or sural-nerve histopathology in addition to impaired intestinal absorption of vitamin E. Eight of the children had low levels of serum vitamin E, as well as low ratios of serum vitamin E to total lipids and to cholesterol. However, three patients had normal serum vitamin E levels but low ratios of serum vitamin E to total lipids (two of the three had normal ratios of vitamin E to cholesterol). In four patients who were not vitamin E-deficient, all three values were normal. We conclude that vitamin E deficiency may exist in a child with a normal serum vitamin E concentration and that the ratio of serum vitamin E to total serum lipids is the most reliable biochemical index of vitamin E status during chronic childhood cholestasis.

https://www.nejm.org/doi/pdf/10.1056/NEJM198405103101901?listPDF=true

Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis.

Since Reye's syndrome is associated with hyperammonemia, we measured the urea-cycle enzymes in hepatic tissue of 13 patients. Expressed as nanomoles of citrulline per milligram of hepatic protein per minute, mean activity of carbamyl phosphate synthetase (6.27 +/- 2.45 S.D.) and ornithine transcarbamylase (136.19 +/- 41.83) in Reye's syndrome was reduced significantly (P less than 0.005) when compared with that of 25 "normal" controls (11.54 +/- 4.24 and 307.49 +/- 94.15, respectively). Activity was maximally reduced during the first days of clinical symptoms; it returned toward normal during the following week regardless of whether the disease ended in death or recovery. The activity of the two enzymes was normal in patients with salicylate intoxication or heritable argininosuccinic acid synthetase deficiency. The apparent Km of hepatic ornithine transcarbamylase for ornithine was in the normal range in patients with Reye's syndrome (mean 0.24 mM). These observations indicate that Reye's syndrome is associated with acquired and transient dysfunction of hepatic mitochondrial urea-cycle enzymes.

Transiently reduced activity of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of children with Reye's syndrome.

Macrophage activation syndrome (MAS), a recognized complication of systemic juvenile rheumatoid arthritis (sJRA), has been associated with significant morbidity and mortality. Dysregulation of macrophage-lymphocyte interactions leading to uncontrolled proliferation of highly activated macrophages and massive release of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) appears to be central to the pathogenesis of this syndrome. Until now the mainstay of therapy has been corticosteroids and cyclosporin A. We describe a patient with MAS and sJRA successfully treated with the anti-TNF agent etanercept. The outcome in this patient suggests etanercept might be an effective therapeutic agent in MAS.

https://www.jrheum.org/content/jrheum/28/9/2120.full.pdf

Etanercept in the treatment of macrophage activation syndrome.

IN adults, deficiency of carnitine palmitoyltransferase (CPT) II is a genetic disorder characterized by exercise intolerance and myoglobinuria.1 , 2 In newborns, it is a generalized, lethal disease with reduced CPT II activity in multiple organs, reduced concentrations of total and free carnitine, and increased concentrations of lipids and long-chain acylcarnitines.3 The clinical severity of CPT II deficiency is not determined by the degree of the reduction in CPT II activity, since this reduction is of similar magnitude in adults, young children, and newborns.1 2 3 4 5 However, lethal CPT II deficiency is associated with an accumulation of arrhythmogenic long-chain acylcarnitines,6 , 7 as in the patient . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199112263252607

Kevin E. Bove

Papers

Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.

Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis.

Transiently reduced activity of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of children with Reye's syndrome.

Etanercept in the treatment of macrophage activation syndrome.

Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II.