Ka-Wo Lee

The mechanism of recurrent laryngeal nerve injury during thyroid surgery—The application of intraoperative neuromonitoring

BACKGROUND Identification of recurrent laryngeal nerve (RLN) has decreased the rates of permanent RLN palsy during thyroid operations; however, unexpected RLN palsy still occurs, even though the visual integrity was assured and most nerve injuries were not recognized intraoperatively. The aim of this study is to determine the causes of RLN palsy and to identify potentially reversible causes of RLN injury during the operation with the application of intraoperative neuromonitoring (IONM). METHODS One hundred and thirteen patients with 173 nerves at risk were enrolled in this study. All operations were performed by the same surgeon. The 4-step procedure of IONM was designed to obtain electromagnetic (EMG) signals from the vagus nerve and RLN before and after resection of thyroid lobe. RESULTS Sixteen nerves had loss of EMG signals after thyroid dissection, and the causes of nerve injuries were well elucidated with the application of IONM. One nerve injury was caused by inadvertent transection, which led to permanent RLN palsy. Among the remaining 15 nerves, 1 injury was caused by a constricting band of connective tissue, which was detected precisely and released intraoperatively, 2 by inadvertent clamping of the nerve, and 12 by apparent overstretching at the region of Berrys ligament. (Five nerves regained signals before closing the wound, but 1 showed impaired cord movement. Another 7 nerves did not regain signals before closing the wound, and all developed temporary RLN palsy.) CONCLUSIONS Our 4-step procedure of IONM is useful and helpful in elucidating the potential operative pitfalls during dissection near the RLN. Although the rates of RLN palsy were not decreased in this study, the use of neuromonitoring provided instructive information for future operations by ascertaining where and how the RLN has been injured.

Standardization of Intraoperative Neuromonitoring of Recurrent Laryngeal Nerve in Thyroid Operation

BackgroundThe lack of standardized procedures of intraoperative neuromonitoring (IONM) during thyroid operations may lead to highly variable results, and many of these results can cause misleading information and, conversely, increase the risk of recurrent laryngeal nerve (RLN) injury. Therefore, standardization of IONM procedures is necessary.MethodsA total of 289 patients (435 nerves at risk) who underwent thyroidectomy by the same surgeon were enrolled in this study. Each patient was intubated with EMG endotracheal tube by the same anesthesiologist. Standardized IONM procedures were applied in each patient. The procedures include preoperative and postoperative video-recording of vocal cord movement, ensuring the correct position of electrodes after the neck was placed at full extension, vagal stimulation and registration of EMG signals before and after RLN dissection, and photographic documentation of the exposed RLN.ResultsFive patients encountered dysfunction of IONM, which was caused by malposition of electrodes and the problem was detected at once. One patient with non-RLN was detected at the earlier stage of operation. Eighteen nerves experienced loss of EMG signals during thyroid dissection, and the causes of nerve injuries were well elucidated with the application of our standardized IONM procedures.ConclusionsThe standardized IONM procedures are useful and helpful not only to eliminate false IONM results, but also to elucidate the mechanism of RLN injury. After ascertaining the surgical pitfalls and improving the surgical techniques, the palsy rate was significantly reduced in this study.

Different impact from betel quid, alcohol and cigarette: risk factors for pharyngeal and laryngeal cancer.

The risks of betel quid chewing with or without tobacco, alcohol drinking and cigarette smoking have been well explored in the oral cavity but not in the pharynx and larynx. We conducted a case‐control study to investigate the association of these three risk factors to cancers of the pharynx and larynx in Taiwan. A total cases of 148 pharyngeal cancer, 128 laryngeal cancer and 255 hospital controls, all men, were recruited. Betel quid chewing was a significant independent risk factor (adjusted odds ratio [aOR] = 7.7; 95% confidence interval [CI] = 4.1–15.0) similar to that of alcohol drinking (aOR = 6.6; 95% CI = 3.5–13.0) for pharyngeal cancer, but not for laryngeal cancer (aOR = 1.3; 95% CI = 0.7–2.5) on which cigarette smoking (aOR = 7.1) exerts a stronger significant independent risk than alcohol drinking (aOR = 3.8). For pharyngeal cancers, chewers who consumed >20 quid/day, chewed with inflorescence in the quid or swallowed the betel quid juice were at higher risks; significant dose‐response effects were found in daily quantity of drinking and chewing, and cumulative quantity of drinking. Synergistic effects from the 3 risk factors existed both on the pharynx (aOR = 96.9) and the larynx (aOR = 40.3), and attributed for 93.1% and 92.9% respectively. Our study is the first evidence to show that betel quid chewing without tobacco has different impact on the pharynx (digestive tract) and the larynx (airway), and supports the concept that exposure quantity and direct mucosal contact with the betel quid juice may contribute to carcinogenesis. Our results show an important insight into the impact of betel quid chewing on other sites of the digestive tract other than the oral cavity.

Association between polymorphisms in DNA base excision repair genes XRCC1, APE1, and ADPRT and differentiated thyroid carcinoma.

Purpose: DNA BER pathway is related with carcinogenesis. We hypothesized that functional polymorphisms of three BER genes, XRCC1, apurinic/apyrimidinic endonuclease (APE1), and ADPRT, confer risks for DTC and its progression. Experimental Design: Five common nonsynonymous single nucleotide polymorphisms (Arg194Trp, Arg280His, and Arg399Gln for XRCC1; Asp148Glu for APE1; and Val762Ala for ADPRT) were genotyped in Chinese DTC cases and controls. Results: The XRCC1-194Trp/Trp genotype showed a significantly increased risk for DTC (odds ratio, 1.85; 95% confidence interval, 1.11-3.07; P = 0.018). Subset analysis based on regional LN metastasis showed that the genetic effect came primarily from the subjects with LN metastasis (odds ratio, 4.54; 95% confidence interval, 2.11-9.79; P = 0.0001), but no significant association for subjects without LN metastasis. The other four single nucleotide polymorphisms did not show significant results. Haplotype analysis of XRCC1 polymorphisms yielded a significant result (P = 0.004), especially in the subjects with LN metastasis (P = 0.0002). Moreover, we found that XRCC1-194Trp and ADPRT-762Ala variants collectively contributed to an increased risk of the disease and LN metastasis, with the combined variant homozygotes exhibiting the highest 3.18-fold risk for DTC (P = 0.046) and 9.25-fold risk for DTC with LN metastasis (P = 0.004). Conclusions: The XRCC1 polymorphisms, especially the 194Trp allele, may have an effect on DTC development and progression. This variant can interact with ADPRT-762Ala variant to further substantially increase susceptibility to the disease and regional LN metastasis. Identifying these risk genetic markers could provide more insight into the DTC pathogenesis and may also provide information to develop better prevention and therapeutic strategies.

Changes of lipid peroxide levels in blood and liver tissue of patients with obstructive jaundice

Plasma lipid peroxide levels, hereafter referred to as PLP levels, were measured in a group of 40 apparently healthy controls and 64 cholelithiasis patients, 40 with and 24 without jaundice. Hepatic lipid peroxide (HLP) levels were also measured in 26 patients, 15 with and 11 without jaundice. There was a significantly higher mean concentration of PLP in the jaundiced patients than in the control or jaundice-free cases. However, the difference in PLP levels between the jaundice-free and the control cases was insignificant. Meanwhile, patients with jaundice had significantly higher HLP levels than those without jaundice. In the jaundiced cases, the increased PLP and HLP levels were clearly related to the serum levels of bilirubin respectively. In addition, the HLP levels were positively correlated with the PLP levels; however, in the non-jaundiced cases, there was little evidence of these two relationships. Patients with or without jaundice had lower plasma vitamin E levels in comparison to the control cases. The correlation of plasma vitamin E and PLP levels was weak in all of the jaundiced. However, when we subdivided the jaundiced into two groups, the correlation was strong in those with plasma vitamin E levels < 8.5 micrograms/ml, while the correlation was weak in those with plasma vitamin E levels > 8.5 micrograms/ml. Consequently, these results suggest that there is an involvement of lipid peroxidation in liver cells damaged by obstructive jaundice in cholelithiasis patients and there exists a negative correlation between low vitamin E and lipid peroxide levels in plasma.

Arecoline;a major alkaloid of areca nut;inhibits p53;represses DNA repair;and triggers DNA damage response in human epithelial cells.

The International Agency for Research on Cancer declared that areca nut was carcinogenic to human. Areca nut is the main component of betel quid (BQ), which is commonly consumed in Asia. Epidemiological studies have shown that BQ chewing is a predominant risk factor for oral and pharyngeal cancers. It has been known that areca nut is genotoxic to human epithelial cells. However, the molecular and cellular mechanisms underlying areca nut-associated genotoxicity are not fully understood. Here we showed that arecoline, a major alkaloid of areca nut, might contribute to oral carcinogenesis through inhibiting p53 and DNA repair. We found, on the biological aspect, that arecoline could induce gamma-H2AX phosphorylation, a sensitive DNA damage marker, in KB, HEp-2, and 293 cells, suggesting that DNA damages were elicited by arecoline. This phenomenon was supported by the observations of arecoline-induced hyperphosphorylation of ATM, Nbs1, Chk1/2, p53, and Cdc25C, as well as G2/M cell cycle arrest, indicating that a cellular DNA damage response was activated. To explore the possible mechanism accounting for arecoline-elicited DNA damages, we found that arecoline could inhibit p53 by its expression and transactivation function. As a result, the expression of p53-regulated p21(WAF1) and the p53-activated DNA repair were repressed by arecoline. Finally, we showed that p53 mRNA transcripts were frequently down-regulated in BQ-associated oral cancer, suggesting that arecoline-mediated p53 inhibition might play a role in BQ-associated tumorigenesis.

Up-regulation of Inflammatory Signalings by Areca Nut Extract and Role of Cyclooxygenase-2 −1195G>A Polymorphism Reveal Risk of Oral Cancer

Because the mRNA expression of cyclooxygenase-2 (COX-2) is up-regulated by arecoline in human gingival fibroblasts, as shown in our previous study, we further investigated the mRNA expression level of COX-2 and its upstream effectors in three oral epithelial carcinoma cell lines (KB, SAS, and Ca9-22) by using areca nut extract (ANE) and saliva-reacted ANE (sANE). A case-control study of 377 oral squamous cell carcinoma (OSCC) patients and 442 controls was conducted to evaluate the gene-environment interaction between COX-2 promoter polymorphisms and substance use of alcohol, betel quid, and cigarettes (ABC) in risk of OSCC. The heterogeneous characteristics of the oral site and the COX-2 -1195G>A polymorphism in these cell lines showed diverse inflammatory response (KB>>Ca9-22>SAS) after 24-hour ANE/sANE treatments, and the COX-2 up-regulation might be mostly elicited from alternative nuclear factor-kappaB activation. In the case-control study, betel chewing [adjusted odds ratios (aOR), 42.2] posed a much higher risk of OSCC than alcohol drinking and cigarette smoking (aORs, 2.4 and 1.8, respectively), whereas the COX-2 -1195A/A homozygote presented a potential genetic risk (OR, 1.55). The strongest joint effect for OSCC was seen in betel chewers with -1195A/A homozygote (aOR, 79.44). In the non-betel chewing group, the -1195A/G and A/A genotypes together with the combined use of alcohol and cigarettes increased risk to 15.1-fold and 32.1-fold, respectively, compared with the G/G genotype without substance use. Taken together, these findings illustrate a valuable insight into the potential role of the COX-2 promoter region in contributing to the development of betel-related OSCC, including ANE/sANE-induced transcriptional effects and enhanced joint effects of COX-2 -1195A allele with substance use of ABC.

Anatomical Variations of Recurrent Laryngeal Nerve During Thyroid Surgery: How to Identify and Handle the Variations With Intraoperative Neuromonitoring

Recurrent laryngeal nerve (RLN) palsy is the most common and serious complication after thyroid surgery. Visual identification of the RLN during thyroid surgery has been shown to be associated with lower rates of palsy, and although it has been recommended as the gold standard for RLN treatment, it does not guarantee success against postoperative vocal cord paralysis. Anatomical variations of the RLN, such as extra‐laryngeal branches, distorted RLN, intertwining between branches of the RLN and inferior thyroid artery, and non‐recurrent laryngeal nerve, can be a potential cause of nerve injury due to visual misidentification. Therefore, intraoperative verification of functional and anatomical RLN integrity is a prerequisite for a safe thyroid operation. In this article, we review the literature and demonstrate how to identify and handle the anatomical variations of the RLN with the application of intraoperative neuromonitoring in the form of high resolution photography, which can be informative for thyroid surgeons. Anatomical variations of the RLN cannot be predicted preoperatively and might be associated with higher rates of RLN injury. The RLN injury caused by visual misidentification can be rare if the nerve is definitely identified early with intraoperative neuromonitoring.

The Efficacy of Intraoperative Corticosteroids in Recurrent Laryngeal Nerve Palsy after Thyroid Surgery

BackgroundRecurrent laryngeal nerve palsy (RLNP) is one of the most common complications after thyroidectomy. We aim to evaluate the role of intraoperative corticosteroids in preventing or treating postoperative RLNP.Materials and MethodsWe conducted a prospective study of 295 patients who underwent either total lobectomy or total thyroidectomy with or without using intraoperative corticosteroids. All cases were operated on by the same surgeon. Measurement of the RLNP rate was based on the number of nerves at risk. Data were analyzed for differences in postoperative temporary or permanent RLNP rate and recovery days.ResultThe rate of temporary/permanent RLNP was 5.7% (11 out of 194)/0.52% (1 out of 194) and 6.9% (12 out of 173)/0.58% (1 out of 173) according to groups with and without corticosteroids. This difference did not reach statistical significance. Among those 23 patients who recovered from RLNP, the mean time to recovery was significantly shorter for patients receiving intraoperative steroids (28.6 vs. 40.5 days, P = 0.045).ConclusionA single dose of intraoperative corticosteroids did not produce any benefit in terms of reducing the postoperative temporary/permanent RLNP rate, but it did shorten the recovery time for patients suffering from temporary RLNP.

Investigation of optimal intensity and safety of electrical nerve stimulation during intraoperative neuromonitoring of the recurrent laryngeal nerve: a prospective porcine model.

Intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) has recently been more frequently applied in thyroid surgery. However, concerns have been raised regarding the safety and optimal intensity of electrical nerve stimulation.