Anti-Angiogenic Tyrosine Kinase Inhibitor-Related Toxicities Among Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Targeting of angiogenesis has become a major therapeutic approach for the treatment of various advanced cancers. There are many unresolved questions on the toxicity of anti-angiogenic tyrosine kinase inhibitors (TKIs). OBJECTIVE: We performed a meta-analysis to assess the toxicity prevalence of the different anti-angiogenic TKIs among cancer patients and in subpopulations of interest including patients with renal cell carcinoma. PATIENTS AND METHODS: We searched the MEDLINE and Cochrane Library databases to November 2023. Clinical trials were eligible if they set out to report the grade ≥3 toxicities related to one of the seven currently approved anti-angiogenic TKIs as monotherapies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was applied with PROSPERO (CRD42023411946). RESULTS: The 421 eligible studies included a total of 56,895 cancer patients treated with anti-angiogenic TKI monotherapy. Twenty-four different cancer types were identified, mainly renal cell carcinoma (41.9% of the patients). The anti-angiogenic TKI was sorafenib (34.5% of the patients), sunitinib (30.5%), regorafenib (10.7%), pazopanib (9.4%), cabozantinib (7.7%), axitinib (4.3%), and lenvatinib (2.9%). The pooled prevalence of grade 3 and 4 toxicities was 56.1% (95% confidence interval 53.5-58.6), with marked between-study heterogeneity (I2 = 96.8%). Toxicity profiles varied considerably depending on the type of TKI, the cancer type, and the specific patient characteristics. In particular, Asian patients and elderly people had higher prevalences of severe toxicities, with pazopanib being the best-tolerated drug. For patients treated with sunitinib, particularly those with metastatic RCC, there was no significant difference in terms of toxicity according to the regimen schedule. CONCLUSIONS: This meta-analysis highlights the toxicity profiles of anti-angiogenic TKI monotherapies, and thus enables high-level recommendations for the choice of anti-angiogenic TKIs on the basis of the patient's age, ethnicity, comorbidities, and comedications, for personalized treatment.

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries.

BACKGROUND: Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend human papilloma virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically distinguish individuals with neoplasia. We investigated whether a quantitative molecular test that measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. RESULTS: Marker discovery was performed in TCGA-CESC Infinium Methylation 450 K Array database and verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation-Specific PCR in tissue sections (N = 252) and cervical smears (N = 244) from the USA, South Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from all three countries showed highly significant differential methylation in squamous cell carcinoma (SCC) with a sensitivity of 100% [95% CI 74.12-100.00], and specificity of 91% [95% CI 62.26-99.53] to 96% [95% CI 79.01-99.78], and receiver operating characteristic area under the curve (ROC AUC) = 1.000 [95% CI 1.00-1.00] compared to benign cervical tissue, and cervical intraepithelial neoplasia 2/3 with sensitivity of 55% [95% CI 37.77-70.84] to 89% [95% CI 67.20-98.03], specificity of 93% [95% CI 84.07-97.38] to 96% [95% CI 79.01-99.78], and a ROC AUC ranging from 0.793 [95% CI 0.68-0.89] to 0.99 [95% CI 0.97-1.00] compared to CIN1. In cervical smears, the marker panel detected SCC with a sensitivity of 87% [95% CI 77.45-92.69], specificity 95% [95% CI 88.64-98.18], and ROC AUC = 0.925 [95% CI 0.878-0.974] compared to normal, and high-grade squamous intraepithelial lesion (HSIL) at a sensitivity of 70% (95% CI 58.11-80.44), specificity of 94% (95% CI 88.30-97.40), and ROC AUC = 0.884 (95% CI 0.822-0.945) compared to low-grade intraepithelial lesion (LSIL)/normal in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. CONCLUSIONS: This 5-marker panel detected SCC and HSIL in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk HSIL will lead to timely treatment for those in need and prevent unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

Modified Radical Neck Dissection for Papillary Thyroid Carcinoma via a Combined Endoscopy Approach: The Transoral Approach and the Chest Approach.

BACKGROUND: Recently, modified radical neck dissection (MRND) for papillary thyroid carcinoma (PTC) has been performed by the transoral endoscopic approach.1 However, dissection of level II lymph nodes using only the transoral approach is highly difficult because of the inadequate axis of surgical view. Hence, we decided to combine the transoral and chest approaches to perform MRND. To the best of our knowledge, this is the first video case of MRND using the combined approach. PATIENT AND METHODS: A 35-year-old woman was diagnosed with cT1aN1bM0 right PTC (metastatic to right level III lymph nodes). The patient underwent total thyroidectomy, bilateral central neck dissection (CND), and right MRND via a combined endoscopic approach: the transoral and chest approaches. Total thyroidectomy and bilateral central neck dissection were performed via the transoral approach, similar to prior studies.2-6 The chest approach can help the surgeon to perform level II and the transoral approach was used to dissect the lymph node of levels III and IV. RESULTS: The total time for total thyroidectomy, bilateral CND, and right MRND was 190 min. The time for MRND was 90 min. The number of harvested lymph nodes were 14 in the right lateral compartments, and the number of metastatic lymph nodes were 2 in the lateral compartments. There were no major postoperative complications. The patient was completely satisfied with the cosmetic result. CONCLUSIONS: The combined approach of the transoral and chest approaches was sufficient to perform total thyroidectomy and MRND for levels II, III, and IV.

Transoral endoscopic thyroidectomy vestibular approach as a novel technique for pediatric populations: Results from a single surgeon.

Background: The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is increasingly being adopted worldwide because of its many advantages. However, there are few reports on the effectiveness and safety of TOETVA in children. In this study, we report the results of the application of TOETVA on 27 pediatric patients in Vietnam. To the best of our knowledge, this is also the largest sample size of the TOETVA technique performed by a single surgeon on pediatric patients worldwide. Patients and methods: From June 2020 to February 2022, we performed TOETVA on 27 pediatric patients (≤ 18 years old). The outcomes of the procedure were retrospectively reviewed. Results: Our study was conducted on 27 pediatric patients, of whom 24 were female (88.9%). The mean age was 16.3 ± 2 (range 10-18). Fifteen patients had benign thyroid nodules with a mean nodule size of 31.6 ± 7.1 (range 20-50mm), and 12 patients had papillary thyroid carcinoma with a mean nodule size of 10.2 ± 5.6 (range 4-19mm). All 27 patients underwent successful TOETVA without any conversion to open surgery. The 15 patients with benign thyroid nodules had lobectomies with a mean operative time of 83.3 ± 10.5 (range 60-105 minutes). Among the 12 patients diagnosed with thyroid cancer, ten had a lobectomy, isthmusectomy, and central neck dissection, with a mean operative time of 89.8 ± 5.7 (range 80-100 minutes). The other two underwent total thyroidectomy with central lymph node dissection with a mean operative time of 132.5 minutes. The mean hospital stay was 4.7 ± 0.9 (range 3-7 days). No patient had permanent complications, such as hypocalcemia, recurrent laryngeal nerve injury, or mental nerve injury. The rates of temporary recurrent laryngeal nerve injury and mental nerve injury were 3.7% and 11.1% respectively. Conclusions: TOETVA may be a feasible and safe surgical method for children with thyroid disease. However, we recommend that only high-volume thyroid surgeons with experience in TOETVA should perform TOETVA on the pediatric population.

Three-Port Transoral Robotic Thyroidectomy in Papillary Thyroid Carcinoma.

BACKGROUND: Although transoral thyroidectomy has become popular in thyroid surgery, transoral robotic thyroidectomy (TORT) has only been successfully applied in a very small number of medical centers worldwide.[1,2,3,4,5] In this video, we show a three-port TORT without an axillary incision for papillary thyroid carcinoma. PATIENT AND METHODS: A 35-year-old female with cT1aN0M0 papillary thyroid carcinoma had a strong motivation to proceed with surgery but avoid external neck incisions. Thus, we decided to perform a hemithyroidectomy with isthmusectomy using a transoral robotic approach, employing the da Vinci Xi surgical system. RESULTS: The operation was completed successfully without conversion to open surgery. The working space creation time, docking time, and console time were 30 min, 40 min, and 130 min, respectively. The pathological results were papillary thyroid carcinoma with 6- and 5-mm tumors. The patient was discharged 4 days after surgery without any complications such as bleeding, infection, mental nerve damage, permanent hoarseness, or hypoparathyroidism. The patient was completely satisfied with the cosmetic result. CONCLUSION: Three-port TORT without an axillary incision is a promising approach with optimal cosmetic outcomes. For Vietnam, a developing country, success in the application of TORT using the new da Vinci Xi robotic platform for thyroid cancer is an important milestone in the development of thyroid surgery.

Three-port transoral robotic thyroidectomy without axillary incision: A preliminary report on a case series from Vietnam.

BACKGROUND: Transoral robotic thyroidectomy (TORT) is one of the newest approaches and draws attention because of its cosmetic excellence. Here, we present our preliminary data from the initial 5 consecutive patients to explore the feasibility of three-port TORT without axillary incision. METHODS: From August 2022 to December 2022, we performed TORT using three ports via the da Vinci Xi system with three robotic arms. RESULTS: All 5 patients had cT1aN0M0 papillary thyroid carcinomas with a mean tumour size of 6 mm. All patients underwent lobectomy with ipsilateral central neck dissection. The mean surgical time was 170 ± 15,8 min; the average length of hospital stay is 4.2 days. The number of retrieved central lymph nodes was 4.2 ± 0.8. All patients were discharged uneventfully without complications and completely satisfied with the cosmetic results. CONCLUSIONS: TORT is feasible and safe when performed on carefully selected patients by experienced surgeons.

Quality of Life and Surgical Outcome of Transoral Endoscopic Thyroidectomy Vestibular Approach (TOETVA) versus Open Thyroid Surgery: Experience from a Single Center in Vietnam.

Background: It has been widely assumed that TOETVA has demonstrated a new technique and a promising approach as it is both minimally invasive and optimally cosmetic. The objective of this study was to assess the surgical outcome, aesthetic satisfaction, and postoperative quality of life of TOETVA in comparison with open thyroid surgery. Patients and Methods. The study was designed as a prospective study, in which 121 patients from a single center in Vietnam underwent thyroid surgery, and the study was divided into two groups: 60 patients in the TOETVA group and 61 patients in the open surgery group. The patients have been followed up including surgical outcomes, cosmetic satisfaction, and quality of life. These criteria were assessed at 4 weeks, 8 weeks, and 12 weeks after the surgery using SF-36 and thyroid surgery-specific questionnaire. Results: Patients in the TOETVA group are significantly younger than patients in the open surgery group (35.8 + 10.3 vs 46.9 + 11.5, p < 0.001). The mean operating time was longer in the TOETVA group (102.9 ± 26.1 mins) than that in the open surgery group (66.8 ± 23.8 mins) with p = 0.0001. Cosmetic outcomes and overall satisfaction were significantly greater in the TOETVA group p = 0.0001. The SF-36 QOL scores of the patients in the TOETVA group were generally higher than the open surgery group. Conclusions: TOETVA has been widely used with a low complication rate, cosmetic appeal, and surgical efficacy. Postoperative quality of life, cosmetic outcomes, and overall satisfaction were significantly superior to the open surgery group.

Comparison of Transoral Endoscopic Thyroidectomy Vestibular Approach and Conventional Open Thyroidectomy in Benign Thyroid Tumors.

Conventional open thyroidectomy remains the standard treatment of surgery for benign thyroid tumors but leaves a permanent scar in the neck. We conducted this study to compare the surgical outcomes of transoral endoscopic thyroidectomy vestibular approach (TOETVA) versus conventional open thyroidectomy (COT), and thence analyze the safety and viability of this approach. Seventy-eight patients who had undergone either COT or TOETVA from 2020 to 2021 in our institution to treat benign thyroid tumors were prospectively studied. Outcomes between the two groups were analyzed, including time of operation, blood loss, hospital stay, postoperative complications, and level of satisfaction. A total of 78 patients, in which TOETVA was applied to 47 patients and COT thyroid surgery was applied to 31 patients, participated in this study. COT has a shorter operative time (59.8 ± 10.8 min versus 102.3 ± 34.9 min, p < .001). TOETVA is less painful postoperatively (visual analog scale score on day 4 of 1.1 ± 1.2 versus 1.8 ± 0.7, p < .001). There were no significant differences between TOETVA and COT groups regarding incidences of transient recurrent laryngeal nerve (RLN) injury (10.6% and 6.5%, respectively, p = .697) and both transient and permanent hypoparathyroidism (8.5% versus 3.5%, p = .644 with transient and 0% versus 6.7%, p = .166 with permanent). Other complications were comparable between two arms such as bleeding, seroma, and infection. At 3 months after surgery, the TOETVA group had the significantly higher proportion of the very satisfied level than the COT group (80.9% versus 35.4%, p < .001). TOETVA in patients with favorable features is a safe, viable alternative to open thyroidectomy regarding postoperative outcomes and provide higher satisfaction after surgery in the long term.

Risk factors for lateral lymph node metastasis of papillary thyroid carcinoma in children.

INTRODUCTION: Lateral cervical lymph node metastases (LNM) for pediatric patients with papillary thyroid cancer (PTC) is a poor prognostic factor. We aimed to identify risk factors for lateral LNM. METHODS: This retrospective study had included 48 pediatric patients with papillary thyroid cancer underwent total thyroidectomy and central cervical lymphadenectomy at K hospital from 2016 to 2020. RESULTS: The number of patients in each T stage was as follows: 24 (50.0%) in stage 1, 9 (18.7%) in Stage 2, 8 (16.7%) in Stage 3, and 7 (14.6%) in Stage 4. Most of the patients had LNM with N1a and N1b rates of 83.3% and 62.5%, respectively. Lung metastases were observed at presentation in three patients (6.3%). Univariate analysis revealed that age (p = 0.021), male (p = 0.011), tumor size > 10 mm (p = 0.002), multifocality (p < 0.001), extrathyroidal extension (p = 0.001) and central LNM (p < 0.001) were factors that increase the risk of metastasis to lateral LNM. CONCLUSION: Approximately 62.5% of pediatric patients with PTC exhibited lateral LNM at the time of diagnosis. Our study confirmed that multifocality, maximum tumor diameter, extrathyroidal extension and central LNM were independent risk factors for lateral LNM in pediatric PTC. LEVEL OF EVIDENCE: Level IV.

Transoral Endoscopic Thyroidectomy via Vestibular Approach With 4 Trocars: A New Technique.

OBJECTIVES: The objective of this study was to report the feasibility and safety of a novel 4-trocar approach for transoral endoscopic thyroidectomy via the vestibular. METHODS: In this study, we first used 4 trocars via vestibular area to perform transoral endoscopic thyroidectomy. We reported the safety and surgical feasibility of transoral endoscopic thyroidectomy using a 4-trocar technique in our institute from February 1, 2020, to May 10, 2020. RESULTS: Transoral endoscopic thyroidectomy via the vestibular approach using 4 trocars was carried out in 5 patients. No complications such as bleeding, mental nerve injury, recurrent laryngeal nerve injury, or hypoparathyroidism were reported. All patients were completely satisfied with the cosmetic results. CONCLUSIONS: Transoral endoscopic thyroidectomy with 4 trocars via vestibular approach is an effective and feasible method. Markedly, this technique can assist surgeons to expose and preserve both parathyroid glands and recurrent laryngeal nerve easily when performing transoral endoscopic thyroidectomy.

Transoral endoscopic thyroidectomy by vestibular approach in Viet Nam: surgical outcomes and long-term follow-up.

BACKGROUND: The transoral endoscopic thyroidectomy by vestibular approach (TOETVA) has been developed for early-stage thyroid cancer treatment as well as benign thyroid nodules worldwide including Viet Nam, with low rate of complications and excellent results. However, there has not been any comprehensive studies with a large number of patients and long-term follow-up in our country. Therefore, we conducted this study to evaluate the results of treatment by TOETVA for benign and malignant lesions of thyroid gland in Viet Nam. METHODS: A prospective study was performed on 326 eligible patients who underwent TOETVA due to thyroid cancer and benign thyroid nodules in Department of Oncology and Palliative Care, Hanoi Medical University Hospital from July 2018 to April 2021. The clinical, surgical, and pathological characteristics, postoperative complications, and visual analog scale (VAS, 0-10 cm) score in day 1, 4, and 7 after surgery, long-term oncological and surgical outcomes were recorded. RESULTS: The mean age was 36.9 ± 9.8 years. 231 patients (70.9%) were diagnosed with differentiated cancer and 95 patients (29.1%) were diagnosed benign tumors of thyroid gland. In the cancer group, 12 patients (5.2%) undergone TOETVA had T3b-intraoperative-stage diagnosis, 219 patients (92.2%) were diagnosed T1 according to AJCC 8th. After 1 month of surgery, among thyroid cancer patients, there was no abnormality reported by thyroid scintigraphy and neck ultrasound as well as in unstimulated-Tg and anti-Tg values. The mean number lymph-node dissected in the cancer group was 6.1 ± 4.1 (range 0-21 nodes). However, only 2.6 ± 1.8 metastasis nodes were discovered (range 1-8 nodes), and the maximum size of these nodes was less than 2 mm. 81 patients presented occult lymph-node metastasis among thyroid cancer patients with cN0 stage (account for 35%). The occult lymph-node metastasis was 34.2% and 50% in patients diagnosed with T1 and T3b groups, respectively. The median postoperative hospital stay was 5.4 ± 0.7 days. Postoperatively, transient hypoparathyroidism was recorded in 12 patients (4.8%), transient hoarse was noted in 9 patients (3.6%), and numb chin was identified in 7 patients (2.8%). No permanent complication was noted. VAS score on first postoperative day was 4.5 ± 0.8. Median follow-up time was 12 (3-25) months. No recurrence was recorded. CONCLUSIONS: TOETVA is an innovative and revolutionary technique in the treatment of benign thyroid nodules, as well as early-stage differentiated thyroid cancer. The results of oncology, postoperative complications, and satisfied outcomes supported the wide application of TOETVA in Viet Nam.

Transoral Endoscopic Modified Radical Neck Dissection for Papillary Thyroid Carcinoma.

BACKGROUND: Recently, transoral endoscopic thyroidectomy via the vestibular approach (TOETVA) has become popular worldwide.1-3 After controlling for the technique, the authors used the transoral endoscopic approach to modified radical neck dissection (MRND) for papillary thyroid carcinoma with clinically positive lymph nodes in the lateral compartments. To the best of their knowledge, the authors report the first case of TOETVA for MRND. PATIENT: A 27-year-old woman had a diagnosis of cT1aN1bM0 right papillary thyroid carcinoma (metastatic to a small right level 4 lymph node). Therefore, total thyroidectomy, bilateral central neck dissection, and MRND of right levels 2, 3, and 4 were performed via the transoral endoscopic approach. METHODS: Total thyroidectomy and bilateral central lymph node dissections were performed based on the three-trocar Anuwong technique.4 Then, the fourth incision was made near the sixth teeth in the right oral vestibular area for insertion of the fourth 5-mm trocar, which was used to expose the lateral lymph compartment and to perform right MRND easily. RESULTS: The operation was completed successfully without conversion to open surgery. The total operative time was 170 min, and the operating time for MRND was 55 min. The numbers of harvested lymph nodes were 7 and 8 in the central and right lateral compartments, respectively. The numbers of metastatic lymph nodes were 2 and 1 in the central and lateral compartments, respectively. No major postoperative complications occurred. CONCLUSION: Transoral endoscopic MRND of levels 2, 3, and 4 can be feasible and safe for highly selected patients.

Pediatric thyroid cancer: Risk factors for central lymph node metastasis in patients with cN0 papillary carcinoma.

INTRODUCTION: Prophylactic central neck node dissection (CND) for pediatric patients with papillary thyroid cancer (PTC) is still controversial. We aimed to identify the incidence and the predictive parameters of the central lymph node metastasis (CLN) in pediatric patients with cN0 PTC. METHODS: This retrospective study had included 32 pediatric patients with cN0 PTC who underwent total thyroidectomy and prophylactic CND from 2015 to 2019. RESULTS: The proportion of CLN metastasis was 75.0%. Univariate logistic regression demonstrated that CLN metastasis was associated with age (≤15 years; p = 0.028), tumour size > 1 cm (p = 0.008), multifocality (p = 0.028) and external extension (p = 0.041) Multivariate logistic regression revealed that age (≤15 years), multifocality, tumour size (>1 cm) and external extension were independent risk factors of CLN metastasis in pediatric patients. CONCLUSIONS: In summary, central lymph node metastasis occurred in 75% of cN0 pediatric patient and were more common in larger tumour size (>1 cm), multifocal tumours, extrathyroidal extension, and younger age.

Effects of high fat diet and perinatal dioxin exposure on development of body size and expression of platelet-derived growth factor receptor ß in the rat brain.

Environmental exposure to dioxins, consumption of a high fat diet, and platelet-derived growth factor receptor ß signaling in the brain affect feeding behavior, which is an important determinant of body growth. In the present study, we investigated the effects of prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and high fact diet after weaning on body growth and expression of platelet-derived growth factor receptor ß in the brain in rat pups. Subjects from the control and dioxin exposure groups were assigned to 1 of 3 different diet groups: standard diet, high fat diet in the juvenile period, or high fat diet in adulthood. Body weight gain rate in the juvenile high fat diet group and the length gain rate in the adult high fat diet group were greater than the corresponding values in the standard diet group only in male offspring, although the effects of dioxin exposure on growth were not significant. Consumption of a high fat diet decreased platelet-derived growth factor receptor ß levels in the amygdala and hippocampus in both sexes compared to control groups, while 2,3,7,8-tetrachlorodibenzo-p-dioxin decreased platelet-derived growth factor receptor platelet-derived growth factor receptor ß levels in the amygdala and striatum only in females receiving an high fat diet. Furthermore, platelet-derived growth factor receptor ß levels in the hippocampus and platelet-derived growth factor receptor ß striatum were inversely correlated with increases in body length, while changes in platelet-derived growth factor receptor ß in the amygdala and nucleus accumbens were significantly correlated to body weight gain or body mass index. In conclusion, these findings suggest that these 2,3,7,8-tetrachlorodibenzo-p-dioxin and high fat diet-induced changes in body growth and feeding behaviors might be partially mediated by changes in brain platelet-derived growth factor receptor ß levels.