Plasma Cytokine Analysis in Patients with Advanced Extremity Melanoma Undergoing Isolated Limb Infusion

Background

Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in-transit extremity melanoma.

Methods

Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1α, IL-1Rα, IP-10, IL-1β, IL-1α, MCP-1, IL-6, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated.

Results

Of 180 ILIs performed, 28 % (95 % confidence interval 22–35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1α, IL-1Rα, IL-1β, IL-1α, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients.

Conclusions

Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune-targeted therapies and immune monitoring in patients with regionally advanced melanoma.     

Vertebral Strength and Estimated Fracture Risk Across the BMI Spectrum in Women

Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor‐of‐risk (Φ), the ratio of applied load to bone strength, is a biomechanically based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength (linear combination of integral volumetric bone mineral density [Int.vBMD] and cross‐sectional area from quantitative computed tomography [QCT]), vertebral compressive loads, and Φ at L₄ in 176 women (65 anorexia nervosa, 45 lean controls, and 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from dual‐energy X‐ray absorptiometry [DXA]) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared with controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p < 0.0001) but were highest in anorexia nervosa for bending (p < 0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p < 0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p < 0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R = 0.28 to 0.45, p ≤ 0.0001) in all groups combined and negatively with VAT (R = –[0.36 to 0.38], p < 0.003) within the obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending because of inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting because of higher applied loads from higher body weight. Examining the load‐to‐strength ratio helps explain increased fracture risk in both low‐weight and obese women. © 2015 American Society for Bone and Mineral Research.     

Tarlov cysts: long-term follow-up after microsurgical inverted plication and sacroplasty

Purpose

Surgical treatment of Tarlov cysts is still a matter of debate. Published literature thus far includes mainly small case series with retrospective evaluation and short-term follow-up. We present a novel microsurgical technique that combines the decompression of the nerve fibers with the prevention of recurrence. The long-term follow-up is provided.

Methods

The indication for surgery was incapacitating pain refractory to medical therapy for at least 6 months. The surgical technique consisted in microsurgical opening of the cyst, relief of CSF followed by secured inverted plication of the cyst wall, packing of remnant space with fat graft, and sacroplasty. Pain and neurological deficits were evaluated according to a modified Barrow National Institute score (BNI score, 0–5) and the Departmental Neuro Score (DNS score, 0–20).

Results

A total of 13 patients (9 women, 4 men) were operated and followed up to 14 years (mean FU 5.3 years). Mean age at surgery was 51.8 (±14) years. Pain and neurological deficits improved significantly in 11/13 patients (BNI score pre-OP 5 vs 3.1 ± 1.2 at 1-year-FU, and 2.8 ± 1.2 at last follow-up visit; DNS score pre-OP 5.5 ± 1.5 vs 2.8 ± 2.1 at 1-year follow-up, and 2.6 ± 2.2 at last follow-up visit. Two patients needed revision surgery due to reoccurrence of the cyst. One patient suffered deterioration of preexisting neurological deficit.

Conclusions

The inverted plication technique combined with sacroplasty is a promising technique. It improves pain and neurological deficits on the long term in the majority of patients with symptomatic Tarlov cysts.

     

Sensitivity and reproducibility of chemical tests for fecal occult blood with an emphasis on false-positive reactions

In 20 healthy volunteers ingesting 5 to 50 ml of⁵¹Cr-red cells, reaction intensities obtained with four chemical methods for fecal occult blood were compared with the “true” blood loss simultaneously determined by radioassay of each stool. Dilute tincture of guaiac reagent was found to have the same sensitivity and high frequency of false-positive reactions as the saturated guaiac reagent, but was more reproducible. Hematest^TM was slightly less sensitive but was poorly reproducible and yielded frequent false-negative as well as false-positive reactions. False-positive reactions by both methods were not eliminated by a meat-free diet; they were increased with guaiac reagents if stools were stored for 3 or more days. A new guaiac method (Hemoccult^TM) was found to be one-fourth as sensitive as the older tests, but was virtually free from false-positive reactions, even on an unrestricted diet and after storage of the stool specimens. It is recommended that the use of Hematest be abandoned and that Hemoccult be used preferentially if future studies confirm that its sensitivity is sufficient to detect most gastrointestinal lesions which are yielding occult blood.     

Lateral spread response monitoring during microvascular decompression for hemifacial spasm

Aim

The aim of the present study was to determine (1) whether successful intraoperative electromyography monitoring for lateral spread response (LSR) is possible with partial neuromuscular blockade (NMB) in subjects undergoing microvascular decompression (MVD) for hemifacial spasm and (2) the adequate level of NMB to achieve that goal.

Material and methods

A total of 61 patients in whom LSR was monitored during MVD were enrolled in the study. Patients were randomly allocated to two groups: group TOF in which the NMB target was maintenance of two train-of-four (TOF) counts and group T1 in which the NMB target was maintenance of a T₁/Tc ratio of 50?% (T₁: first twitch height of TOF and Tc: control twitch height). The adductor pollicis brevis muscle was used to monitor TOF responses. The frequency of successful LSR monitoring, defined as successful baseline establishment and maintenance of LSR until surgical decompression, was compared between the two groups.

Results

Of the 61 patients 2 were excluded from the study so that 30 patients in group TOF and 29 patients in group T1 were analyzed. The success rate of LSR monitoring was clinically acceptable and significantly higher in group T1 than in group TOF, i.e. n?=?15 (50.0?%) in group TOF versus n?=?24 (82.8?%) in group T1 (P?=?0.008), corresponding to a 32.8?% higher success rate in group T1 than group TOF (95?% CI: 13.9–51.7?%). Mean vecuronium infusion dose was smaller and mean TOF count was higher in group T1 than group TOF with a TOF count =?2 (1) in group TOF versus 3 (1) in group T1 (P?=?0.003). Mean sevoflurane and remifentanil infusion doses were not different between groups. There was no incidence of spontaneous movement during microscopy in either group.

Conclusion

Maintenance of partial NMB with a target T₁/Tc ratio of 50?% resulted in a clinically acceptable success rate of LSR monitoring and surgical condition during MVD. Maintenance of partial NMB with a target T₁/Tc ratio of 50?% rather than TOF count of two during LSR monitoring for MVD can therefore be recommended.     

Sol-Gel-Derived Fibers Based on Amorphous α-Hydroxy-Carboxylate-Modified Titanium(IV) Oxide as a 3-Dimensional Scaffold

The development of novel fibrous biomaterials and further processing of medical devices is still challenging. For instance, titanium(IV) oxide is a well-established biocompatible material, and the synthesis of TiO_x particles and coatings via the sol-gel process has frequently been published. However, synthesis protocols of sol-gel-derived TiO_x fibers are hardly known. In this publication, the authors present a synthesis and fabrication of purely sol-gel-derived TiO_x fiber fleeces starting from the liquid sol-gel precursor titanium ethylate (TEOT). Here, the α-hydroxy-carboxylic acid lactic acid (LA) was used as a chelating ligand to reduce the reactivity towards hydrolysis of TEOT enabling a spinnable sol. The resulting fibers were processed into a non-woven fleece, characterized with FTIR, ¹³C-MAS-NMR, XRD, and screened with regard to their stability in physiological solution. They revealed an unexpected dependency between the LA content and the dissolution behavior. Finally, in vitro cell culture experiments proved their potential suitability as an open-mesh structured scaffold material, even for challenging applications such as therapeutic medicinal products (ATMPs).