PMCA inhibition reverses drug resistance in clinically refractory cancer patient-derived models.

BACKGROUND: Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive. METHODS: We investigated the PGC1α-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1α in selected and parental tumor cells. RESULTS: Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage. CONCLUSIONS: Our results suggest that PGC1α is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers.

Association between preoperative frontal electroencephalogram alpha asymmetry and postoperative quality of recovery: an observational study.

BACKGROUND: Left-sided frontal alpha asymmetry on electroencephalograms, which indicates decreased relative left-hemispheric activity, has been associated with depression, anxiety, and stress responsivity. We aimed to evaluate the association between perioperative measures of frontal alpha asymmetry and quality of recovery (QoR) after surgery. METHODS: We enrolled 110 female patients undergoing thyroidectomy and recorded perioperative electroencephalograms. The power of the prefrontal alpha band (8-13 Hz) was measured in the Fp1 and Fp2 leads. Left-sided frontal alpha asymmetry was defined as a higher alpha band power in Fp1 than in Fp2 and vice versa. QoR was assessed using the QoR-15 score on the day before surgery and postoperative days 1 and 2. The primary study endpoint was a difference in postoperative global QoR-15 score between preoperative left-sided and right-sided alpha asymmetry groups. The predictability of frontal alpha asymmetry for poor QoR-15 score was also evaluated. RESULTS: The global QoR-15 score showed a significant group-by-time interaction, and post-hoc analysis revealed significantly lower scores on postoperative days 1 (P=0.006) and 2 (P<0.001) in the left-sided frontal alpha asymmetry group. In the multivariate logistic regression analysis, preoperative left-sided frontal alpha asymmetry was associated with a 3.3-fold increased risk of the lowest tertile for the postoperative day 1 QoR-15 score (95% CI: 1.31-8.24; P=0.011). CONCLUSIONS: Preoperative left-sided frontal alpha asymmetry was independently associated with a lower postoperative QoR-15 score in female patients undergoing thyroidectomy, highlighting the potential role of preoperative frontal electroencephalography in predicting patient-centred outcomes after surgery. CLINICAL TRIAL REGISTRATION: KCT0006586 (http://cris.nih.go.kr/).

Bioinformatics and Connectivity Map Analysis Suggest Viral Infection as a Critical Causative Factor of Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) is a common autoimmune disease, and its prevalence is rapidly increasing. Both genetic and environmental risk factors contribute to the development of HT. Recently, viral infection has been suggested to act as a trigger of HT by eliciting the host immune response and subsequent autoreactivity. We analyzed the features of HT through bioinformatics analysis so as to identify the markers of HT development. We accessed public microarray data of HT patients from the Gene Expression Omnibus (GEO) and obtained differentially expressed genes (DEGs) under HT. Gene Ontology (GO) and KEGG-pathway-enrichment analyses were performed for functional clustering of our protein-protein interaction (PPI) network. Utilizing ranked gene lists, we performed a Gene Set Enrichment Analysis (GSEA) by using the clusterprofiler R package. By comparing the expression signatures of the huge perturbation database with the queried rank-ordered gene list, a connectivity map (CMap) analysis was performed to screen potential therapeutic targets and agents. The gene expression profile of the HT group was in line with the general characteristics of HT. Biological processes related to the immune response and viral infection pathways were obtained for the upregulated DEGs. The GSEA results revealed activation of autoimmune-disease-related pathways and several viral-infection pathways. Autoimmune-disease and viral-infection pathways were highly interconnected by common genes, while the HLA genes, which are shared by both, were significantly upregulated. The CMap analysis suggested that perturbagens, including SRRM1, NLK, and CCDC92, have the potential to reverse the HT expression profile. Several lines of evidence suggested that viral infection and the host immune response are activated during HT. Viral infection is suspected to act as a key trigger of HT by causing autoimmunity. SRRM1, an alternative splicing factor which responds to viral activity, might serve as potential marker of HT.

Discovery of New Anti-Cancer Agents against Patient-Derived Sorafenib-Resistant Papillary Thyroid Cancer.

Thyroid cancer is the most well-known type of endocrine cancer that is easily treatable and can be completely cured in most cases. Nonetheless, anti-cancer drug-resistant metastasis or recurrence may occur and lead to the failure of cancer therapy, which eventually leads to the death of a patient with cancer. This study aimed to detect novel thyroid cancer target candidates based on validating and identifying one of many anti-cancer drug-resistant targets in patient-derived sorafenib-resistant papillary thyroid cancer (PTC). We focused on targeting the sarco/endoplasmic reticulum calcium ATPase (SERCA) in patient-derived sorafenib-resistant PTC cells compared with patient-derived sorafenib-sensitive PTC cells. We discovered novel SERCA inhibitors (candidates 33 and 36) by virtual screening. These candidates are novel SERCA inhibitors that lead to remarkable tumor shrinkage in a xenograft tumor model of sorafenib-resistant patient-derived PTC cells. These results are clinically valuable for the progression of novel combinatorial strategies that facultatively and efficiently target extremely malignant cancer cells, such as anti-cancer drug-resistant PTC cells.

Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma.

Drug resistance causes therapeutic failure in refractory cancer. Cancer drug resistance stems from various factors, such as patient heterogeneity and genetic alterations in somatic cancer cells, including those from identical tissues. Generally, resistance is intrinsic for cancers; however, cancer resistance becomes common owing to an increased drug treatment. Unfortunately, overcoming this issue is not yet possible. The present study aimed to evaluate a clinical approach using candidate compounds 19 and 23, which are sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitors, discovered using the evolutionary chemical binding similarity method. mRNA sequencing indicated SERCA as the dominant marker of patient-derived anti-cancer drug-resistant hepatocellular carcinoma (HCC), but not of patient-derived anti-cancer drug-sensitive HCC. Candidate compounds 19 and 23 led to significant tumor shrinkage in a tumor xenograft model of anti-cancer drug-resistant patient-derived HCC cells. Our results might be clinically significant for the development of novel combinatorial strategies that selectively and efficiently target highly malignant cells such as drug-resistant and cancer stem-like cells.

Potential Therapeutic Agents against Paclitaxel-And Sorafenib-Resistant Papillary Thyroid Carcinoma.

Thyroid carcinoma, a disease in which malignant cells form in the thyroid tissue, is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for nearly 80% of total thyroid carcinoma cases. However, the management of metastatic or recurrent therapy-refractory PTC is challenging and requires complex carcinoma therapy. In this study, we proposed a new clinical approach for the treatment of therapy-refractory PTC. We identified sarco/endoplasmic reticulum calcium ATPase (SERCA) as an essential factor for the survival of PTC cells refractory to the treatment with paclitaxel or sorafenib. We validated its use as a potential target for developing drugs against resistant PTC, by using patient-derived paclitaxel- or sorafenib-resistant PTC cells. We further discovered novel SERCA inhibitors, candidates 7 and 13, using the evolutionary chemical binding similarity method. These novel SERCA inhibitors determined a substantial reduction of tumors in a patient-derived xenograft tumor model developed using paclitaxel- or sorafenib-resistant PTC cells. These results could provide a basis for clinically meaningful progress in the treatment of refractory PTC by identifying a novel therapeutic strategy: using a combination therapy between sorafenib or paclitaxel and specific SERCA inhibitors for effectively and selectively targeting extremely malignant cells such as antineoplastic-resistant and carcinoma stem-like cells.

Transoral endoscopic thyroidectomy using the vestibular approach with an endoscopic retractor in thyroid cancer: experience with the first 132 patients.

BACKGROUND: Transoral endoscopic thyroidectomy using the vestibular approach (TOETVA) is a novel technique for thyroid cancer surgery. We aimed to review our initial experiences with TOETVA for the management of thyroid carcinoma, using retrospective analyses of a larger single-center case series. METHODS: From September 2016 to April 2018, 132 patients with thyroid cancer underwent TOETVA. A three-port technique through the oral vestibule was used to perform endoscopic thyroidectomy with ipsilateral central compartment dissection using conventional laparoscopic instruments, and an endoscopic retractor that we developed. RESULTS: All patients had papillary thyroid carcinoma. Less-than total or total thyroidectomy with ipsilateral central compartment node dissection was performed (124 vs. 8). The mean operation time was 87.6 min (range 56-213 min). The average number of lymph nodes resected was 2.6 (range 1-12). Six patients experienced transient hoarseness, which was resolved within 3 months. Most of the patients were discharged within 3 days after surgery. CONCLUSIONS: In this large series from a single center, we found that TOETVA with the endoscopic retractor can be performed safely and radically in selected patients with thyroid cancer.

Patient-Derived, Drug-Resistant Colon Cancer Cells Evade Chemotherapeutic Drug Effects via the Induction of Epithelial-Mesenchymal Transition-Mediated Angiogenesis.

Cancer cells can exhibit resistance to different anticancer drugs by acquiring enhanced anti-apoptotic potential, improved DNA injury resistance, diminished enzymatic inactivation, and enhanced permeability, allowing for cell survival. However, the genetic mechanisms for these effects are unknown. Therefore, in this study, we obtained drug-sensitive HT-29 cells (commercially) and drug-resistant cancer cells (derived from biochemically and histologically confirmed colon cancer patients) and performed microarray analysis to identify genetic differences. Cellular proliferation and other properties were determined after treatment with oxaliplatin, lenvatinib, or their combination. In vivo, tumor volume and other properties were examined using a mouse xenograft model. The oxaliplatin and lenvatinib cotreatment group showed more significant cell cycle arrest than the control group and groups treated with either agent alone. Oxaliplatin and lenvatinib cotreatment induced the most significant tumor shrinkage in the xenograft model. Drug-resistant and metastatic colon cancer cells evaded the anticancer drug effects via angiogenesis. These findings present a breakthrough strategy for treating drug-resistant cancer.

Tumor doubling time predicts response to sorafenib in radioactive iodine-refractory differentiated thyroid cancer.

Sorafenib has emerged as an effective therapeutic option for radioactive iodine (RAI)-refractory, locally advanced or metastatic differentiated thyroid cancer (DTC). We investigated the efficacy and safety of sorafenib treatment in a real-world setting and unveil predictive markers of responsiveness to sorafenib. The treatment response, progression-free survival (PFS), overall survival, and adverse events (AEs) of sorafenib-treated RAI-refractory, locally advanced or metastatic DTC patients at three institutes were retrospectively reviewed, and their tumor doubling time was calculated by three investigators. Total eighty-five patients were treated with sorafenib, and seven patients discontinued sorafenib due to AEs before the first tumor assessment. The median PFS was 14.4 months, and the objective response rate was 10.3% in 78 patients who were able to evaluate the tumor response. Age, sex, histologic type, tumor location, RAI avidity, or the presence of FDG-PET uptake did not affect PFS. However, smaller tumor size (≤1.5 cm) of the target lesions in lung showed better PFS (hazard ratio [HR] 0.39, p = 0.01), and tumors with the shortest doubling time (≤6 months) had worse outcome (HR 2.70, p < 0.01). Because of AEs, dose reductions or drug interruptions were required in 64% of patients, and eventually, 23% of patients discontinued sorafenib permanently. The most common AE was hand-foot skin reaction (HFSR). Patients with severe HFSR showed better PFS, but there were no statistical significance (HR 0.65, p = 0.05). In conclusion, small tumor size and long doubling time of each target lesion can be a prognostic marker to predict the responsiveness to sorafenib in RAI-refractory DTC patients.

SoLAT (Sorafenib Lenvatinib alternating treatment): a new treatment protocol with alternating Sorafenib and Lenvatinib for refractory thyroid Cancer.

BACKGROUND: In the last decade, several tyrosine kinase inhibitors (TKIs), which disrupt pathways involved in the proliferation and tumorigenesis of thyroid cancer, have been extensively studied. Two different TKIs, lenvatinib and sorafenib, were recently approved by both the US FDA and European Medicine Agency. Until date, the duration of the TKI response is not sufficient and resistance eventually occurs. The goal of this study was to investigate a new treatment protocol, SoLAT, using sorafenib and lenvatinib alternatively on refractory thyroid cancer. METHODS: Patient-derived aggressive papillary thyroid cancer (PTC) cell lines from patients with biochemical and histologically proven aggressive RAI-refractory papillary thyroid cancer were exposed to sorafenib and lenvatinib alternatively. Human thyroid cancer cell xenografts were obtained by injecting patient-derived aggressive PTC cell lines into the flank of female BALB/c nude mice. Tumor-bearing mice were treated with sorafenib and lenvatinib alternatively. Cell viability assay, immunofluorescence analysis, confocal imaging, immunoblot analysis, flow cytometry analysis of cell cycle and a tube formation assay were performed. RESULTS: SoLAT was more effective for advanced PTC cell lines than individual treatment. Immunoblot analysis showed that SoLAT markedly increased levels of cell cycle inhibitors (p53 and p21), and pro-apoptotic factors (Apaf-1 and cleaved caspase 3) and decreased levels of positive cell cycle regulators (cyclin D1, CDK4, CDK6) and anti-apoptotic factors (p-NFκB, Bcl-2). Increased sub-G0/G1 population was observed in the SoLAT group, leading to apoptosis, cell cycle arrest, and strong inhibition of advanced PTC cell viability. SoLAT reduced the level of EMT markers such as vimentin, E-cadherin, Snail and Zeb1 by FGFR inhibition. In the xenograft model, individual treatment with sorafenib or lenvatinib did not markedly suppress patient-derived aggressive PTC cell xenograft tumors, whereas SoLAT significantly suppressed the proliferation of these tumors. CONCLUSIONS: SoLAT was more effective than individual treatment with sorafenib or lenvatinib in inhibiting PTC progression by inducing cell cycle arrest. Studies using both in vitro cell culture and an in vivo xenograft model provided evidence of tumor shrinkage with SoLAT. We suggest that these effects may be due to reduced EMT-mediated drug resistance in the aggressive PTC model.

Long-term outcomes of ethanol injection therapy for locally recurrent papillary thyroid cancer.

The standard treatment regimen for locally recurrent lesions is total thyroidectomy, or complete removal of the recurrent thyroid lesion within the thyroid bed. However, reoperation increases the risk of complications and patients have to undergo general anesthesia. Percutaneous ethanol injection therapy represents a far less invasive procedure without general anesthesia and with lower risk of complications. Thirty-four patients who received PEIT at Yonsei University Medical Center between October 2002 and August 2009 for recurrent cervical nodal metastases of differentiated papillary thyroid cancer were included in this retrospective study. During a minimum follow-up of 60 months, treatment outcomes were determined by measuring the lesion size prior to the first injection and 3 months after the last injection. A total of 46 recurrent lesions were detected in 34 patients. Five patients underwent surgery and PEIT was administered to the remaining 19 and 22 lesions in the central compartment and lateral neck lymph nodes, respectively. Size increases were observed in seven (17.1%) lesions, whereas no changes in size and decreases were detected in 10 (24.4%) and 24 (58.5%) lesions. Patients with increased lymph nodes were significantly older (65.3 ± 14.4 vs. 48.2 ± 16.3 years; p = 0.02) and had smaller sizes (9.3 ± 1.0 vs. 12.3 ± 6.4 mm; p = 0.012). Although reoperation remains the first-line treatment for recurrent thyroid cancer, PEIT may be considered as a treatment option in selected patients with lesions larger than 1 cm who are ineligible for surgery or have refused reoperation.

Postoperative biochemical remission of serum calcitonin is the best predictive factor for recurrence-free survival of medullary thyroid cancer: a large-scale retrospective analysis over 30 years.

CONTEXT: The increase in thyroid screening in the general population may lead to earlier detection of medullary thyroid carcinoma (MTC). OBJECTIVE: We aimed to evaluate secular trends in clinicopathological characteristics and long-term prognosis of MTC and its prognostic factors. DESIGN: This was a retrospective analysis from 1982 to 2012. PATIENTS: Three hundred and thirty-one patients with MTC were included and grouped based on the year of diagnosis (1982-2000, 2001-2005, 2006-2010 and 2011-2012). MEASUREMENTS: These included recurrence and mortality as well as biochemical remission (BCR) of serum calcitonin. RESULTS: Mean tumour size (from 2·5 cm to 1·7 cm, P < 0·001) and percentage of extrathyroidal extension (from 52·0% to 26·0%, P = 0·026) decreased. The percentage of patients achieving BCR within six postoperative months (po-BCR) increased with time (from 39·6% to 76·1%, P < 0·001). The 5-year overall recurrence rate significantly decreased in 2006-2012 compared to 1982-2005 (10% vs 18%, respectively, P = 0·031), although the 5-year survival rate did not improve (92% vs 92%, P = 0·929). Failure to achieve po-BCR was the strongest predictive factor associated with recurrence (hazard ratio [HR] = 58·04, 95% CI 7·14-472·11; P < 0·001). Male gender (HR = 3·18, 95% CI 1·18-8·56; P = 0·022), tumour size >2 cm (HR = 18·33, 95% CI 2·35-143·06; P = 0·006) and distant metastasis (HR = 4·00, 95% CI 1·31-12·21; P = 0·015) were significant prognostic factors for mortality. CONCLUSIONS: Clinicopathological characteristics and recurrence of MTC improved with time. Po-BCR was the best predictive factor for recurrence-free survival.

Clinical Experience With n-Butyl-2-Cyanoacrylate in Performing Lateral Neck Dissection for Metastatic Thyroid Cancer.

Background Chyle leakage following lateral neck dissection (LND) is rare, but can induce metabolic disturbances, delay wound healing, and prolong hospitalization. n-Butyl-2-cyanoacrylate (NBCA) has been used to achieve hemostasis and seal tissues in several surgical settings. We here assessed whether application of NBCA to the thoracic duct area is effective in sealing chyle leakage. Methods The medical records of 163 patients who underwent total thyroidectomy with unilateral LND between March 2011 and September 2012 were reviewed. NBCA was applied to 84 patients and not applied to 79. Drainage volume, duration of hospital stay, and incidence of complications were compared between the 2 groups. Results The 2 groups were not different with regard to age, body weight, gender, primary tumor histology, and number of lateral neck nodes harvested. Mean hospital stay was significantly shorter (4.3 ± 1.8 vs 5.7 ± 3.0 days, P < .001), median total drainage volume was significantly smaller (270 mL; range: 97-931 mL vs 328 mL; range: 113-2636 mL; P < .001), and rate of chyle leakage was significantly lower (0% vs 6.3%, P = .025) in the NBCA than in the non-NBCA group. Conclusion NBCA application to the dissected area of the thoracic duct posterior to its angle of junction with the internal jugular and subclavian veins could be safe and effective in reducing surgical complications related to chyle leakage after LND.

Prognostic significance of tumor multifocality in papillary thyroid carcinoma and its relationship with primary tumor size: a retrospective study of 2,309 consecutive patients.

BACKGROUND: Tumor multifocality is frequently observed in papillary thyroid carcinoma (PTC), but its prognostic value is controversial. We investigated the prognostic significance of multifocality in PTCs larger than 1 cm and papillary thyroid microcarcinomas (PTMC). METHODS: Medical records and pathologic results of 2,309 patients who received thyroidectomy and lymph node dissection for PTC were retrospectively reviewed. We identified 648 patients who had PTC with a primary tumor exceeding 1 cm, and 1,661 patients with PTMC. In each group, we compared patients with unifocal and multifocal disease. Cox regression analyses of disease persistence and recurrence were performed to identify the prognostic significance of multifocality. RESULTS: The mean follow-up period was 5.6 years. In the analyses of PTCs larger than 1 cm, the multifocal group included more extensive thyroid surgeries (p = 0.039), radioactive iodine therapies with higher doses (p < 0.001), and significantly higher rates of disease persistence and recurrence (p = 0.001) compared with the unifocal group. In analogous analyses of patients with PTMC, disease persistence and recurrence did not differ significantly between the unifocal and multifocal groups. Cox regression analyses indicated that multifocality was an independent risk factor for disease persistence and recurrence in patients who had PTC with a tumor exceeding 1 cm, but not in patients with PTMC. CONCLUSION: Tumor multifocality appears to be an important prognostic factor for PTCs larger than 1 cm, but may have little or no prognostic significance for PTMC.

Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer.

BACKGROUND: Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. Previous studies showed that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways. METHODS: Experiments were achieved to conclude the effects of HNHA in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) cell lines and xenografts, as compared with two other established HDAC inhibitors (SAHA; suberoylanilide hydroxamic acid and TSA; trichostatin A). RESULTS: Apoptosis, which was induced by all HDAC inhibitors, was particularly significant in HNHA-treated cells, where noticeable B-cell lymphoma-2 (Bcl-2) suppression and caspase activation were observed both in vitro and in vivo. HNHA increased Ca(2+) release from the ER to the cytoplasm. ER stress-dependent apoptosis was induced by HNHA, suggesting that it induced caspase-dependent apoptotic cell death in PTC and ATC. PTC and ATC xenograft studies demonstrated that the antitumor and pro-apoptotic effects of HNHA were greater than those of the established HDAC inhibitors. These HNHA activities reflected its induction of caspase-dependent and ER stress-dependent apoptosis on thyroid cancer cells. CONCLUSIONS: The present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.

Reducing neck incision length during thyroid surgery does not improve satisfaction in patients.

Postoperative neck cosmesis is a major concern of patients undergoing thyroid surgery. Patients will likely be more satisfied with the long-term cosmetic appearance of smaller than larger thyroidectomy scars. We, therefore, investigated the relationship between scar length following conventional thyroid surgery and patient satisfaction. An anonymous scar-assessment questionnaire was administered to patients who underwent conventional thyroid surgery. The 2,041 patients were asked to rate their satisfaction with their scars on a ten-point Likert scale, with one being very unsatisfied and ten being very satisfied. The mean satisfaction score was significantly lower in the benign condition than in malignancy (6.9 ± 2.5 vs. 7.4 ± 2.5; p = 0.021), whereas there were no differences in satisfaction score among subgroups of patients with benign condition (p = 0.837). In patients with thyroid cancer, the mean satisfaction scores were similar among subgroups according to operation type and scar length (p = 0.820). Incision length was not associated with patient satisfaction in thyroid surgery patients and therefore may not be critical in decision making for thyroid cancer surgery.

Lymph node status did not significantly improve the predictability of survival in patients with clinically early-stage endometrial cancer.

OBJECTIVE: The aim of this study was to determine whether knowledge of lymph node status improves survival prediction in clinically early-stage endometrial cancer. METHODS: The records of 661 patients with apparently uterine-confined disease were reviewed. The performance in predicting overall survival and cause-specific survival was compared between a multivariate prognostic model with nodal status and a model without nodal status by calculating Harrell concordance index. RESULTS: Among 661 patients with clinically early-stage endometrial cancer, the lymph node metastasis rate was 8.3% (55/661). Lymph node metastasis independently associated with cause-specific survival only when no stratification according to adjuvant treatment was applied (P = 0.035). After stratification according to adjuvant radiotherapy, lymph node status marginally associated with cause-specific survival (P = 0.073), whereas myometrial invasion retained its strong association with cause-specific survival (P < 0.001). However, there was no significant difference in the performance of the survival model using only uterine factors and the model using lymph node status and uterine factors (concordance index, 0.77 vs 0.77, respectively; P = 0.798). CONCLUSIONS: Knowledge of lymph node status did not significantly improve the performance of survival prediction in apparently uterine-confined endometrial cancer, although it was independently associated with survival. In the patients with clinically early-stage endometrial cancer, the accuracy of the prediction of survival was comparable between risk grouping without lymph node status and that including lymph node status.

A Web-based nomogram predicting para-aortic nodal metastasis in incompletely staged patients with endometrial cancer: a Korean Multicenter Study.

OBJECTIVE: The purpose of this study is to develop a Web-based nomogram for predicting the individualized risk of para-aortic nodal metastasis in incompletely staged patients with endometrial cancer. METHODS: From 8 institutions, the medical records of 397 patients who underwent pelvic and para-aortic lymphadenectomy as a surgical staging procedure were retrospectively reviewed. A multivariate logistic regression model was created and internally validated by rigorous bootstrap resampling methods. Finally, the model was transformed into a user-friendly Web-based nomogram (http://http://www.kgog.org/nomogram/empa001.html). RESULTS: The rate of para-aortic nodal metastasis was 14.4% (57/397 patients). Using a stepwise variable selection, 4 variables including deep myometrial invasion, non-endometrioid subtype, lymphovascular space invasion, and log-transformed CA-125 levels were finally adopted. After 1000 repetitions of bootstrapping, all of these 4 variables retained a significant association with para-aortic nodal metastasis in the multivariate analysis-deep myometrial invasion (P = 0.001), non-endometrioid histologic subtype (P = 0.034), lymphovascular space invasion (P = 0.003), and log-transformed serum CA-125 levels (P = 0.004). The model showed good discrimination (C statistics = 0.87; 95% confidence interval, 0.82-0.92) and accurate calibration (Hosmer-Lemeshow P = 0.74). CONCLUSIONS: This nomogram showed good performance in predicting para-aortic metastasis in patients with endometrial cancer. The tool may be useful in determining the extent of lymphadenectomy after incomplete surgery.

Solitary lateral neck node metastasis in papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is associated with a high incidence of regional node metastasis, but the patterns of lateral neck node metastasis (LNM) vary. Occasionally, a solitary LNM (SLNM) is seen in PTC patients. We therefore assessed whether selective single level node dissection is appropriate in PTC patients with SLNM. METHODS: We retrospectively reviewed the medical records of 241 PTC patients who underwent total thyroidectomy with central neck dissection plus ipsilateral internal jugular node dissection (level II to IV) between January 2010 and December 2011. Of these patients, 51 had SLNM and 190 had multiple LNM (MLNM). The clinicopathologic characteristics of the two groups were compared. RESULTS: Age, gender ratio, and numbers of lateral neck nodes harvested (29.4±11.0 versus 30.3±9.5; P=0.574) were similar in the SLNM and MLNM groups. Mean primary tumor size was significantly smaller in the SLNM than in the MNLM group (1.03 cm versus 1.35 cm; P=0.037). The proportion of patients with primary tumor≤1 cm was significantly greater in the SLNM group (60.8% versus 38.4%; P=0.006), whereas the proportion with maximal node size≤0.7 cm (28.9% versus 73.3%; P<0.001) and the proportion with capsular invasion (62.7% versus 83.7%, P=0.002) were significantly lower in the SLNM than in the MLNM group. CONCLUSIONS: Selective single level neck dissection can be considered as an alternative to systemic lateral neck dissection in PTC patients with SLNM, maximal metastatic node size≤0.7 cm, and no extrathyroidal invasion.

Diagnostic Performance of Preoperative Calcitonin and Procalcitonin Tests for Differential Diagnosis of Medullary Thyroid Cancer.

Medullary thyroid cancer (MTC) shows a relatively poor prognosis among thyroid cancers. Though calcitonin has been used as a diagnostic marker for MTC, it has disadvantages including poor sample stability and discrepancies among results by assay. This study aimed to compare the usefulness of preoperative calcitonin and procalcitonin (PCT) in the diagnosis of MTC. Serum calcitonin and PCT levels were measured before thyroidectomy from MTC (n = 23) and other types of thyroid cancers in patients (n = 1308). Diagnostic performances of calcitonin and PCT for discerning MTC were estimated. In a multivariate analysis, preoperative calcitonin level was independently associated with the diagnosis of MTC, whereas PCT was not. Calcitonin and PCT, respectively, exhibited area under the curve values of 0.997 and 0.979 for the diagnosis of MTC, without significant differences. For calcitonin, the sensitivity, specificity, and positive and negative predictive values were 0.957, 0.992, 0.688, and 0.999, respectively, at a cut-off of 7.2 pg/mL. The corresponding values for PCT were 0.913, 0.995, 0.778, and 0.998 at a cut-off of 0.19 ng/mL. Preoperative calcitonin and PCT showed similar diagnostic utility for MTC. Depending on the patient's clinical status and laboratory environment, these tests can be used as complementary methods for detecting MTC.