Ex vivo comparison of the tissue effects of six laser wavelengths for potential use in laser supported partial nephrectomy

Laparoscopic/robotic partial nephrectomy (LPN) is increasingly considered for small renal tumors (RT). This demands new compatible surgical tools for RT-resection, such as lasers, to optimize cutting and coagulation. This work aims to characterize ex vivo handling requirements for six medically approved laser devices emitting different light wavelengths (940, 1064, 1318, 1470, 1940, and 2010 nm) amenable for LPN. Incisions were made by laser fibers driven by a computer-controlled stepping motor allowing precise linear movement with a preset velocity at a fixed fiber-tip distance to tissue. Optical parameters were measured on 200 μm tissue slices. Cutting quality depended on power output, fiber velocity and fiber-tip distance to tissue. Contact manner is suitable for cutting while a noncontact manner (5 mm distance) induces coagulation. Ablation threshold differs for each wavelength. Ablation depth is proportional to power output (within limit) while axial and superficial coagulation remains mostly constant. Increased fiber velocity compromises the coagulation quality. Optical parameters of porcine kidney tissue demonstrate that renal absorption coefficient follows water absorption in the 2 μm region while for other spectral regions (900 to 1500 and 1 μm) the tissue effects are influenced by other chromophores and scattering. Tissue color changes demonstrate dependencies on irradiance, scan velocity, and wavelength. Current results clearly demonstrate that surgeons considering laser-assisted RT excisions should be aware of the mentioned technical parameters (power output, fiber velocity and fiber-tip tissue-distance) rather than wavelength only.     

Intestinal polycyclic aromatic hydrocarbon-DNA adducts in a population of beluga whales with high levels of gastrointestinal cancers

Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years (1926–1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (>19-year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH–DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH–DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin-embedded intestine from 51 SLE beluga (0–63 years), 4 Cook Inlet (CI) Alaska beluga (0–26 years), and 20 beluga (0–46 years) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light-to-dark pink color indicating the presence of PAH–DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (P = 0.003). The H-scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH–DNA adducts significantly higher than Arctic and aquarium beluga (P = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH–DNA adducts in four SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. Environ. Mol. Mutagen. 60:29–41, 2019. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.     

A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome

OBJECTIVE: Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1beta (IL-1beta), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS. METHODS: Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values. RESULTS: In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen. CONCLUSION: In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.     

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the “NLRP3 inflammasome,” an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1—blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1—blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient’s disease severity and organ manifestations.     

Monogenic IL-1 mediated autoinflammatory and immunodeficiency syndromes: Finding the right balance in response to danger signals

Introduction

Interleukin-1 was the first cytokine identified and is a powerful inducer of fever and inflammation. The biologically active receptor for IL-1, shares signaling pathways with some pathogen recognition receptors, the Toll-like receptors (TLRs) which early on suggested an important role in innate immune function.

Discussion

The discovery that some intracellular “danger receptors”, the NOD like receptors (NLRs) can assemble to form multimolecular platforms, the inflammasomes, that not only sense intracellular danger but also activate IL-1β, has provided the molecular basis for the integration of IL-1 as an early response mediator in danger recognition. The critical role of balancing IL-1 production and signaling in human disease has recently been demonstrated in rare human monogenic diseases with mutations that affect the meticulous control of IL-1 production, release and signaling by leading to decreased or increased TLR/IL-1 signaling. In diseases of decreased TLR/IL-1 signaling (IRAK-4 and MyD88 deficiencies) patients are at risk for infections with gram positive organisms; and in diseases of increased signaling, patients develop systemic autoinflammatory diseases (cryopyrin-associated periodic syndromes (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA)).

Conclusion

Monogenic defects in a number of rare diseases that affect the balance of TLR/IL-1 signaling have provided us with opportunities to study the systemic effects of IL-1 in human diseases. The molecular defects in CAPS and DIRA provided a therapeutic rationale for targeting IL-1 and the impressive clinical results from IL-1 blocking therapies have undoubtedly confirmed the pivotal role of IL-1 in human disease and spurred the exploration of modifying IL-1 signaling in a number of genetically complex common human diseases.