Reoperative Experience with Papillary Thyroid Cancer

Background

Intense postoperative monitoring has resulted in increasing detection of patients with recurrent papillary thyroid cancer (PTC). Our goals included quantifying successful reoperation, and analyzing surgical complications and reasons for relapse.

Methods

From 1999 to 2008, a total of 410 patients underwent reoperation for PTC relapse. We analyzed post-reoperative disease outcomes, reasons for relapse, and complications.

Results

Bilateral reoperative thyroidectomy was performed in 13 (3 %) patients; lobectomy, 34 (8 %); central neck (VI) soft tissue local recurrence excision, 47 (11.5 %); bilateral VI node dissection, 107 (26 %); unilateral VI dissection, 112 (27 %); levels II–V dissection, 93 (23 %); levels III–V, 86 (21 %); lateral single- or two-compartment dissection, 51 (12 %); and node picking, 20 (5 %) of level VI and 53 (13 %) lateral neck. Complications occurred in 6 %; including hypoparathyroidism, 3 %; unintentional recurrent laryngeal nerve (RLN) paralysis, 3 %; phrenic nerve injury, 0.5 %; spinal accessory nerve injury, 0.5 %; and chyle leak in 1.6 %. Of 380 (93 %) patients with follow-up (mean 5.2 years); 274 (72 %) patients are alive with no structural evidence of disease, 38 % developed disease relapse (mean 2.1 years), 42 (11 %) died from PTC, and 55 (14 %) are alive with disease. The reason for relapse was a false negative pre-reoperative ultrasound (US) in 18 (5 %), nodal recurrence in the operative field in 37 (10 %), a combination of these two reasons in 10 (3 %), and disease virulence (local or systemic recurrence) in 81 (21 %).

Conclusions

Although 72 % of patients were rendered structurally disease free after reoperation, nearly 40 % suffered additional relapse. Improved surgical technique or preoperative localization might positively affect 15–20 %; at least 20 % reflect the biologic aggressiveness of the disease.     

Identification of the 11-cis-specific retinyl-ester synthase in retinal Müller cells as multifunctional O-acyltransferase (MFAT)

Absorption of a photon by a rhodopsin or cone-opsin pigment isomerizes its 11-cis-retinaldehyde (11-cis-RAL) chromophore to all-trans-retinaldehyde (all-trans-RAL), which dissociates after a brief period of activation. Light sensitivity is restored to the resulting apo-opsin when it recombines with another 11-cis-RAL. Conversion of all-trans-RAL to 11-cis-RAL is carried out by an enzyme pathway called the visual cycle in cells of the retinal pigment epithelium. A second visual cycle is present in Müller cells of the retina. The retinol isomerase for this noncanonical pathway is dihydroceramide desaturase (DES1), which catalyzes equilibrium isomerization of retinol. Because 11-cis-retinol (11-cis-ROL) constitutes only a small fraction of total retinols in an equilibrium mixture, a subsequent step involving selective removal of 11-cis-ROL is required to drive synthesis of 11-cis-retinoids for production of visual chromophore. Selective esterification of 11-cis-ROL is one possibility. Crude homogenates of chicken retinas rapidly convert all-trans-ROL to 11-cis-retinyl esters (11-cis-REs) with minimal formation of other retinyl-ester isomers. This enzymatic activity implies the existence of an 11-cis-specific retinyl-ester synthase in Müller cells. Here, we evaluated multifunctional O-acyltransferase (MFAT) as a candidate for this 11-cis-RE-synthase. MFAT exhibited much higher catalytic efficiency as a synthase of 11-cis-REs versus other retinyl-ester isomers. Further, we show that MFAT is expressed in Müller cells. Finally, homogenates of cells coexpressing DES1 and MFAT catalyzed the conversion of all-trans-ROL to 11-cis-RP, similar to what we observed with chicken-retina homogenates. MFAT is therefore an excellent candidate for the retinyl-ester synthase that cooperates with DES1 to drive synthesis of 11-cis-retinoids by mass action.Light perception begins with the absorption of a photon by an opsin pigment in the membranous outer segment (OS) of a rod or cone photoreceptor cell. The light-absorbing chromophore in most vertebrate opsins is 11-cis-retinaldehyde (11-cis-RAL). Photon capture isomerizes the 11-cis-RAL to all-trans-retinaldehyde (all-trans-RAL), inducing conformational changes in the protein that lead to its active meta-II state. After a brief period of signaling through the transduction cascade, meta II decays to yield apo-opsin and free all-trans-RAL. Light sensitivity is restored to the apo-opsin when it combines with 11-cis-RAL to regenerate the pigment. Conversion of all-trans-RAL to 11-cis-RAL is carried out by a multistep enzyme pathway called the visual cycle, located in cells of the retinal pigment epithelium (RPE) (1, 2). The retinoid isomerase in this pathway is Rpe65, which converts an all-trans-retinyl ester (all-trans-RE), such as all-trans-retinyl palmitate (all-trans-RP), to 11-cis-retinol (11-cis-ROL) and a free fatty acid (3–5). Retinyl esters are synthesized in RPE cells by lecithin:retinol acyl transferase (LRAT), which transfers a fatty acid from phosphatidylcholine to retinol (6, 7). LRAT converts both all-trans-ROL and 11-cis-ROL to their cognate esters with similar catalytic efficiency (8).A second visual cycle is present in Müller cells of the retina, providing 11-cis-ROL to cones (9–11). Cones, but not rods, can use 11-cis-ROL as a chromophore precursor to regenerate bleached opsin pigments (10, 12, 13). The isomerase in the noncanonical pathway is dihydroceramide desaturase (DES1) (11). DES1 catalyzes rapid equilibrium isomerization of retinol (11). At equilibrium, 11-cis-ROL is much less abundant than all-trans-ROL, due to the 4.1 kcal/mole difference in free energy between these isomers (14). Accordingly, a secondary source of energy is required to drive the conversion of all-trans-ROL to 11-cis-ROL by DES1. Retinas from cone-dominant species contain 11-cis-retinyl esters (11-cis-REs), whereas retinyl esters are much less abundant in retinas from rod-dominant species (11, 13, 15). Homogenates from cone-dominant chicken and ground-squirrel retinas convert all-trans-ROL predominantly to 11-cis-REs in the presence of palmitoyl CoA (palm CoA) (13, 16, 17). These observations suggest that selective esterification of 11-cis-ROL may be the driving force for 11-cis-retinoid formation. In the current work, we sought to identify the protein responsible for the 11-cis-RE-synthase activity in Müller cells. We evaluated multifunctional O-acyltransferase (MFAT) as a candidate for this synthase. MFAT, also called acyl-CoA wax-alcohol acyltransferase-2 (AWAT2), catalyzes palm CoA-dependent synthesis of triglycerides, wax monoesters, and retinyl esters (18). It is present in the endoplasmic reticulum and predominantly expressed in skin (18). The retinol-isomer specificity of MFAT, and its expression in ocular tissues, has not been studied.     

Can dehydrated human amnion/chorion membrane accelerate the return to potency after a nerve-sparing robotic-assisted radical prostatectomy? Propensity score-matched analysis

The objective of this study is to determine if the use of dehydrated human amnion/chorion membrane (dHACM) allograft wrapped around the NVB during a robotic-assisted radical prostatectomy (RARP) accelerates the return to potency. 940 patients with preoperative SHIM >20 underwent RARP with some degree of bilateral NS. Of these, 235 patients underwent RARP, with bilateral placement of dHACM graft around the NVBs. They were matched in a 1:3 proportion with a similar group of patients (n = 705) who did not receive the allograft (control group or group 2). Minimum follow-up was 12 months. Postoperative outcomes were analyzed between propensity-matched dHACM graft (group 1) and non-graft groups (group 2). Kaplan–Meier survival curves were compared across techniques using the log-rank test. There were no significant demographic differences between the two groups. Potency was defined as the ability to achieve and maintain satisfactory erections firm enough for sexual intercourse, with or without the use of PDE-5 inhibitors. The mean time to potency was significantly lower in group 1 (2.37 months) versus group 2 (3.94 months) (p < 0.0001). The potency recovery rates were superior for group 1 at all early time points measured except at 12 months. The time to potency was significantly shorter in the dHACM group with full NS, 2.19 ± 1.84 versus 2.78 ± 2.70 mo. in the non-dHACM with full NS (p = 0.029). In the dHACM group with partial NS, the mean time to potency was 3.05 ± 2.32 versus 3.92 ± 3.42 mo. in the non-dHACM with partial NS (p = 0.021). Patients who received the dHACM wrap around the NVB after RARP accelerates the return to potency when compared to a similar control group without the use of the allograft. We also demonstrated that this faster return to potency occurs regardless of the degree of the NS preservation. Younger patients (<55 years of age) had the highest overall advantage if they received the graft. Our results indicate that dHACM placement at the site of the prostatic NVB does not increase the risk of BCR after RARP, neither in the presence of PSM, extra-prostatic disease (≥pT3) nor high Gleason score (Gleason ≥8).     

Treatment of murine candidiasis and cryptococcosis with amphotericin B incorporated into egg lecithin-bile salt mixed micelles.

Amphotericin B (AmB) with deoxycholate (Fungizone) and AmB incorporated into mixed micelles (AmB-mixMs) composed of egg lecithin with glycocholate, deoxycholate, or taurocholate were compared as treatments for murine infections. For mice infected with Candida albicans, treatment consisted of a single intravenous injection; for mice infected with Cryptococcus neoformans, treatment consisted of two intravenous injections. The maximal tolerated doses of AmB as Fungizone were 1.25 mg/kg of body weight in mice with candidiasis and 2.5 mg/kg of body weight in mice with cryptococcosis. The AmB-mixMs were nontoxic to mice at doses of 80 and 100 mg/kg of body weight and were therapeutically more active than the maximal tolerated dose of Fungizone in both models of infection. However, when Fungizone or AmB-mixMs were administered at equivalent doses of AmB, AmB-mixMs were more active in treating murine candidiasis, whereas Fungizone was more active in treating murine cryptococcosis.     

CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A-HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a "lock and key" interaction is typical of innate receptor-ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.     

Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases

Cathelicidin LL-37 is one of the few human bactericidal peptides with potent antistaphylococcal activity. In this study we examined the susceptibility of LL-37 to proteolytic degradation by two major proteinases produced by Staphylococcus aureus, a metalloproteinase (aureolysin) and a glutamylendopeptidase (V8 protease). We found that aureolysin cleaved and inactivated LL-37 in a time- and concentration-dependent manner. Analysis of the generated fragments by mass spectroscopy revealed that the initial cleavage of LL-37 by aureolysin occurred between the Arg19-Ile20, Arg23-Ile24, and Leu31-Val32 peptide bonds, instantly annihilating the antibacterial activity of LL-37. In contrast, the V8 proteinase hydrolyzed efficiently only the Glu16-Phe17 peptide bond, rendering the C-terminal fragment refractory to further degradation. This fragment (termed LL-17-37) displayed antibacterial activity against S. aureus at a molar level similar to that of the full-length LL-37 peptide, indicating that the antibacterial activity of LL-37 resides in the C-terminal region. In keeping with LL-37 degradation by aureolysin, S. aureus strains that produce significant amounts of this metalloprotease were found to be less susceptible to LL-17-37 than strains expressing no aureolysin activity. Taken together, these data suggest that aureolysin production by S. aureus contributes to the resistance of this pathogen to the innate immune system of humans mediated by LL-37.