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Objective: In a cohort of medullary thyroid cancer (MTC) patients with biochemical incomplete responses, 37 to 48% developed structural persistent disease; however, few indictors were available to distinguish those patients who were more likely to develop structural disease. We hypothesized that the relationship between preoperative calcitonin (Ctn) and postoperative Ctn (within 3 days after surgery) could be used to predict early prognosis of these patients., Methods: A total of 92 sporadic MTC patients were enrolled in this study. Our team proposed a novel indicator of structural persistent MTC called the calcitonin ratio (CR; CR = postoperative Ctn/preoperative Ctn). Cox regression models and the Kaplan-Meier method were used to evaluate the prognostic capability of CR. The area under the time-dependent receiver-operating characteristic curves (AUC) and the Harrell concordance index (C-index) were used for analysis., Results: The cutoff CR value used to determine MTC prognosis was 0.15. Multivariate Cox analysis revealed that CR (hazard ratio &lsqb;HR]: 22.974, 95% confidence interval &lsqb;CI]: 3.259 to 161.959, P = .002), tumor-node-metastasis (HR: 3.968, 95% CI: 1.360 to 21.857; P = .031), and multifocality (HR: 8.466, 95% CI: 1.286 to 55.716; P = .026) independently correlated with MTC prognosis. Kaplan-Meier survival curves demonstrated a lower proportion with structural persistent disease in patients with CR <0.15 (P<.001). The 3, 5, and 10-year AUC values were 0.798, 0.752, and 0.743, respectively. The C-index of CR was 0.788 (95% CI: 0.763 to 0.813)., Conclusion: In this study, CR was identified as a sensitive and specific risk stratification marker for patients with biochemical incomplete responses in sporadic MTC., Abbreviations: ATA = American Thyroid Association; AUC = area under curve; CEA = carcinoembryonic antigen; CR = calcitonin ratio; Ctn = calcitonin; HR = hazard ratio; MTC = medullary thyroid cancer; ROC = receiver operating characteristic; TNM = tumor-node-metastasis., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Osteosarcoma (OS) is the most common malignant bone tumor with high metastasis and mortality. Neoadjuvant chemotherapy is an effective therapeutic regimen, but the clinical application is limited by the unsatisfactory efficacies and considerable side effects. In this study, the reduction-responsive polypeptide micelles based on methoxy poly(ethylene glycol)-block-poly(S-tert-butylmercapto-L-cysteine) copolymers (mPEG 113 -b-PBMLC 4 , P4M, and mPEG 113 -b-PBMLC 9 , P9M) were developed to control the delivery of doxorubicin (DOX) in OS therapy. Compared to free DOX, P4M/DOX and P9M/DOX exhibited 2.6 and 3.5 times increase in the area under the curve of pharmacokinetics, 1.6 and 2.0 times increase in tumor accumulation, and 1.6 and 1.7 times decrease of the distribution in the heart. Moreover, the selective accumulation of micelles, especially P9M/DOX, in tumors induced stronger antitumor effects on both primary and lung metastatic OSs with less systematic toxicity. These micelles with smart responsiveness to intracellular microenvironments are highly promising for the targeted delivery of clinical chemotherapeutic drugs in cancer therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Timolol Maleate is a non-selective beta-adrenergic blocker that is commonly used to treat open-angle glaucoma. Despite its topical administration, ophthalmic timolol enters systemic circulation and produces a systemic beta-adrenergic blockade. We report a case of long-term timolol use that uncovered and worsened an underlying cardiac conduction defect demonstrated as a third degree atrioventricular (AV) block., Case Presentation: A 62-year old male with a 13-year history of glaucoma was hospitalized due to shortness of breath, dizziness, and amaurosis. Electrocardiography indicated a heart rate (HR) of 29 bpm with complete atrioventricular (AV) block, and the HR was significantly increased with the treatment of isoprenaline. However, the patient experienced bradycardic episodes (- 20 Δbpm) immediately after self-administration of timolol eye drops. The AV block and bradycardia resolved 48-h after timolol cessation. The man was discharged 1 week later with an asymptomatic first-degree A-V block. However, he presented with a worsened A-V block at his one-year checkup., Conclusion: We conclude that chronic topical timolol administration may aggravate a cardiac conduction defect leading to an AV block that is only temporarily resolved by timolol cessation. Patients taking timolol should be routinely monitored for cardiovascular aberrations and if any detected, immediately discontinue timolol therapy. Individuals experiencing timolol induced cardiovascular side effects should receive long term follow-up even if symptoms resolve, as they may be indicative of an underlying conduction defect.

Introduction: Despite the crucially prognostic value of lymph node metastasis (LNM) in patients with medullary thyroid cancer (MTC), only the LNM compartment alone was reflected in the 8th edition of the American Joint Committee on Cancer (AJCC) system., Objective: This study aimed to incorporate the metastatic lymph node number and metastatic lymph node ratio to generate a more accurate and appropriate N staging system for patients with MTC based on recursive partitioning analysis., Design, Setting, and Patients: Two cohorts were included in the analysis, including 1374 MTC patients from the Surveillance, Epidemiology, and End Results database as the derivation cohort, and 164 patients from Fudan University Shanghai Cancer Center as the validation cohort. The predictive performance of the alternative proposed N staging system was compared with that of the 8th AJCC system by using the Harrell concordance index (C-index) and the area under the receiver operating characteristic curve (AUC)., Results: In the derivation cohort, the C-index and the AUC at 10 years were 0.778 and 0.789, respectively, for the novel N staging system, and 0.749 and 0.741, respectively, for the 8th AJCC N staging system. Similar trends were also observed in the validation cohort. The proposed N staging system had a better prognostic performance., Conclusion: With some improvements, the novel N staging system for MTC suggested from this research may be assessed for potential adoption in the next edition of the AJCC N staging system.

Introduction: To investigate whether the positive lymph node number (PLNN) and positive lymph node ratio (PLNR) could predict the prognosis of patients with major salivary gland cancer (MSGC) and to identify the optimal cutoff points for these variables that stratify patients according to their risk of survival., Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify all patients with MSGC between 1988 and 2014. A logistic regression analysis was carried out to evaluate the risk factors for lymph node metastasis (LNM) in MSGC. The X-tile program was used to identify the cutoff values for the PLNN and PLNR in MSGC patients with LNM. Cox proportional hazards regression models were performed to identify the predictors of cancer-specific survival (CSS)., Results: In the SEER database, 8668 eligible patients were identified and 3046 of them had LNM. The logistic regression analysis indicated that older age, male sex, larger tumor size, higher grade, tumor extension and high-risk pathology were associated with LNM. The X-tile program showed that a PLNN>4 and a PLNR>0.15 were prognostic indicators of CSS. A multivariable analysis indicated that, after the factors that might potentially affect the prognosis were adjusted for, the PLNN and PLNR were still associated with CSS., Conclusions: Our Results demonstrated that the PLNN and PLNR were independent prognostic indicators for MSGC patients with lymph node metastasis., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Osteosarcoma (OS) is ranked as the most common primary bone malignancy in children and adolescents worldwide, and the 5-year overall survival rate of OS is not optimistic. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been implicated in tumor cell growth, proliferation, and anti-apoptosis in OS. Therefore, the discovery of novel molecular compounds that can effectively block STAT3 activation, is essential for the treatment of OS and improving prognosis. Here, we investigate whether Glaucocalyxin A (GLA), derived from Rabdosia japonica, exhibit the potential anticancer effects in OS. First of all, we identify that GLA potently suppressed cell proliferation, induced G2/M phase arrest and promoted substantial apoptosis in OS. Next, we conclude that GLA could induce Reactive oxygen species (ROS)-mediated oxidative stress via an imbalance of GSH and GSSG. Then, we elucidate for the first time that GLA could significantly inhibit both constitutive and IL-6-inducible activation of STAT3 (Tyr705) and JAK2, the upstream regulator of STAT3. Furthermore, we elucidate that the inhibition of STAT3 is mainly induced by ROS-mediated oxidative stress. Overall, our findings demonstrate that GLA could exhibit potent anticancer effects through effectively blocking the STAT3 signaling pathway, which was induced by ROS-mediated oxidative stress in OS in vitro and in vivo., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To evaluate whether elective neck dissection (END) was beneficial for cN0 patients with salivary gland carcinoma., Materials and Methods: The rates of regional failure-free survival and disease-free survival were calculated using Kaplan-Meier methods and Cox models. The risk factors for occult lymph node metastasis (OLNM) in cN0 patients undergoing END was analyzed using logistic regression. A nomogram was formulated to calculate the estimated probability of OLNM., Results: Neck dissection was performed in 84 patients (43.3%). OLNM was detected in eight of the patients who underwent END. During the follow-up period, regional recurrences involving cervical lymph nodes were found in 10 patients. Cox model analysis revealed that neck dissection was not related to regional failure-free survival and disease-free survival. Logistic regression analysis revealed that older age, neural symptoms, and positive adjacent lymph nodes were associated with OLNM. A nomogram comprising age, neural symptoms, and adjacent lymph nodes was developed to predict the risk of OLNM., Conclusion: The incidence of OLNM was low in cN0 patients after detailed preoperative evaluations. There was no strong evidence supporting END as a conventional therapy in cN0 patients with salivary cancers. Our nomogram is a simple and practical instrument for strengthening the prediction of OLNM., (Copyright © 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: There are two surgical strategies for bilateral neck dissection (BND), simultaneous and two-stage operations. The aim of the study was to compare the cost-effectiveness BND with this two operations in papillary thyroid carcinoma (PTC) patients., Materials and Methods: Consecutive PTC patients undergoing BND were studied retrospectively, and were classified into simultaneous group (Group A) and two-stage group (Group B). Demographic, medical costs, complication and surgical variables were recorded., Results: This study included 256 PTC patients, of which 175 (68.4%) underwent simultaneous BND and 81 (31.6%) patients underwent two-stage. Patients in Group B spent almost twice as much on medical costs as patients in Group A ($4145.3 vs. $7352.5). Group A patients also had shorter hospital stays (11.71 ± 5.12 vs. 23.10 ± 7.11, P < .0001) and surgery times (203.61 ± 61.43min vs. 279.58 ± 71.59min, P < .0001). The average radioactive iodine therapy delay was 67 days in Group B. There was no significant difference in complications (34 vs. 18, P = .605) or disease-free-survival (93.71% vs. 90.12%, P = .243) between the two groups. No difference was found in rates of recurrent laryngeal nerve invasion/resection (12 vs. 11, P = .08; 10 vs. 6, P = .353) or tracheotomy (32 vs. 14, P = .846). However, internal jugular vein invasions were more common in patients with two-stage BND (7 vs. 9, P = .029)., Conclusion: Simultaneous BND is the most cost-effective strategy for the management of PTC patients without bilateral internal jugular veins invasion, due to lower treatment cost and the ability to avoid RAI delay., (Copyright © 2017. Published by Elsevier Ltd.)

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (As 2 S 2 ), the main active ingredient of the traditional Chinese medicine realgar, has been proved to have antitumor efficacy in several tumor types including acute promyelocytic leukemia, gastric cancer and colon cancer. Here, we investigated the efficacy and mechanism of As 2 S 2 in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that As 2 S 2 potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As 2 S 2 induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. As 2 S 2 was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As 2 S 2 -induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As 2 S 2 inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As 2 S 2 -induced apoptosis and autophagy. Finally, As 2 S 2 in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As 2 S 2 induced G2/M phase arrest, apoptosis, and autophagy via activing ROS/JNK and blocking Akt/mTOR signaling pathway in human osteosarcoma cells. Arsenic sulfide may be a potential clinical antitumor drugs targeting osteosarcoma., (Copyright © 2017. Published by Elsevier Inc.)

Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive malignancy with high rates of invasion and distant metastasis. This study was to explore the ability of intensity-modulated radiotherapy (IMRT) combined with chemotherapy to manage unresectable PDTC. Between February 2011 and April 2012, 5 patients with unresectable PDTC were treated by IMRT at our institution and were included in this analysis. The median radiotherapy dose to the gross tumor volume (GTV) was 66 Gy/33 fractions/6.4 weeks. All patients received chemotherapy, and one patient with tumor compression symptoms had a tracheotomy before treatment. The mean survival time of the 5 patients was 41.6 months. The direct causes of death were distant metastases (40%) and progression of the locoregional disease (20%). In conclusion, IMRT combined with chemotherapy for unresectable PDTC might be beneficial to improve locoregional control. Further new therapies are needed to control metastases.

In this study, we evaluated the photodynamic efficacy of a new photosensitizer, benzochloroporphyrin derivative 18 (BCPD-18), in Ewing sarcoma. We found that BCPD-18 decreased the viability of TC-71 cells irradiated by 670nm laser in a concentration dependent manner. We also observed cells undergoing apoptosis as well as cell cycle arrest at the G2M phase after BCPD-18-mediated photodynamic therapy (BCPD-PDT). In addition, in vivo study (subcutaneous and orthotopic models) showed that BCPD-PDT reduced tumor size, tumor weight and tumor-bearing leg weight. After PDT, apoptosis was shown in vivo. Bax expression was increased, and Bcl-2 expression was decreased. This study provides evidence that BCPD-18 could probably be a useful photosensitizer in PDT for Ewing sarcoma., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To evaluate the risk factors influencing the recurrence of papillary thyroid carcinoma., Methods: This meta-analysis used MEDLINE (PubMed), EMBASE and CNKI including all cohort studies reporting the risk factors influencing the recurrence after the initial operation on PTC up to February 23, 2014. Software RevMan 5.2 was used for meta-analysis., Results: Thirteen studies with a total of 7048 patients were included in our meta-analysis. Of all variables, gender, extrathyroid extension, LNM, tumor size, distance metastasis, thyroid surgery types and 131-I given or not were significantly correlated with recurrence, While overall recurrence was similar between the group of ≤ 45 years and > 45 years, multifolicality and solitary. However, when stratified the participants by study location (ie, Asian including China, Korea, Japan, Western country including America, France, Italy, Australia), a statistically significant summary odds ratio for age were found in Western country but none in Asian., Conclusion: The risk factors influencing recurrence includes male, extrathyroid extension, LNM, tumor size more than 2 cm, distance metastasis and subtotal thyroidectomy. However, selection of operation mode should be based on not only the recurrence but the comprehensive consideration of the clinical features.