End to side circular stapled anastomosis during robotic-assisted Ivor Lewis minimally invasive esophagectomy (RAMIE).

Robotic-assisted minimally invasive esophagectomy (RAMIE) represents an established approach for the treatment of esophageal cancer. Aim of this study is to evaluate the feasibility and safety of our technique for performing the intrathoracic anastomosis during RAMIE.All the procedures were performed by the same surgeon using the same technique for performing the intrathoracic anastomosis. Intraoperative and postoperative outcomes were recorded. Postoperative complications were classified according to the Esophagectomy Complications Consensus Group (ECCG); the primary outcome was the evaluation of the feasibility and safety of our technique. From 2016 to 2021, 204 patients underwent Ivor Lewis RAMIE at our Center. Two patients (0.9%) were converted during the thoracic phase. The anastomosis was completed in all the other patients forming complete anastomotic rings. The median duration for the robotic-assisted thoracoscopic phase was 224 minutes. Twenty-two of the RAMIE-Ivor Lewis patients had an anastomotic leakage (10.3%). The overall 90-day postoperative mortality was 1.9%. The procedure resulted to be feasible and safe in our cohort of patients.

Thyroid surgery in children and young adults: potential overtreatment and complications.

PURPOSE: Thyroid nodules in the pediatric population are more frequently associated with malignant thyroid disease than in adult cohorts. Yet, there is a potential risk of surgical overtreatment. With this single center study, an analysis of potential overtreatment for suspected malignant thyroid disease in children and young adults was aimed for. METHODS: In a period from 2005 to 2018, 155 thyroid operations in children and young adults performed at the University Medical Center Mainz, Germany, were analyzed (patient age 3-20 years, 117 female). Cases were categorized for preoperative diagnosis: non-malignant (group I, n = 45) and malignant thyroid disease (group II, n = 110). Postoperative parameters (histology, complication rates) were assessed and compared between groups. RESULTS: 91.1% of group I were histologically benign. 44.5% of group II harbored malignancy. Permanent hypoparathyroidism was documented in group I (2.7%) and in group II (1.4%, p = 1.000). Wound infections were absent in group I but observed in group II (0.9%, p = 1.000). Transient vocal cord palsy was recorded only in group I (2.3%, 2/85 vs. 0/177 nerves at risk, p = 0.104). Permanent vocal cord palsies were absent. CONCLUSION: Preoperative diagnoses were correct in over 90% of group I and in nearly 45% of group II. The high proportion of carcinomas in group II ruled out the issue of potential overtreatment. The risk of severe postoperative complications was equally low in both patient groups.

Surgical treatment strategies for giant inguinoscrotal hernia - a case report with review of the literature.

BACKGROUND: An inguinoscrotal hernia is defined as "giant" if descending below the midpoint of the inner thigh of a patient in upright position. In developed countries this is a rare entity. In the literature different surgical techniques have been reported so far to achieve a successful treatment. CASE PRESENTATION: We present the case of a 63 year-old man suffering from a giant inguinoscrotal hernia, whom we treated using a combined open transabdominal and inguinal approach following an unsuccessful laparoscopic attempt. Meshes were placed in a premuscular position (Lichtenstein's procedure) and in a preperitoneal position. In addition, a reconstruction of the abdominal wall by modified components separation technique was performed. During the early postoperative period no complications were registered. Intensive care treatment was not necessary. The patient was discharged on postoperative day 8 in an excellent condition. Six months after surgery a scrotal hematocele was diagnosed and operatively removed. After a follow-up of 1.5 years neither hernia recurrence, nor chronic groin pain were recorded. The patient reported to be sexually active. His quality of life improved notably. Additionally, a Medline and PubMed database research was performed to create an overall picture of the existing surgical treatment strategies. Included were patients with diagnosis of primary giant inguinoscrotal hernia according to the given definition. Emergency interventions and cases without details of the surgical approach were excluded. CONCLUSIONS: Firstly, this report describes a novel, successful surgical treatment of a giant inguinoscrotal hernia without administering preoperative progressive pneumoperitoneum therapy or visceral resection. Secondly, we summarize cases previously reported as a practical guide for possible surgical therapy approaches.

[Current indications and operative strategy for renal hyperparathyroidism]. / Aktuelle Indikation und operative Strategie beim renalen Hyperparathyreoidismus.

BACKGROUND: Renal hyperparathyroidism results from pathophysiologic changes induced and maintained by terminal renal failure. Surgical treatment is possible using various resection strategies. AIM OF THE WORK (RESEARCH QUESTION): The aim of this work is to illustrate the indications, techniques and resection strategies for surgical treatment of renal hyperparathyroidism. MATERIAL AND METHODS: National and international guidelines regarding the surgical treatment of renal hyperparathyroidism were analyzed. Furthermore, our own practical experience was integrated into the article. RESULTS: While the indications for surgery according to the Surgical Working Group Endocrinology (CAEK) guidelines are given in cases of clinical impairment and renal hyperparathyroidism that cannot be controlled by medication, international guidelines additionally refer to the absolute parathyroid hormone level for deciding for surgery. DISCUSSION: Individual patient consultation is necessary in the case of renal hyperparathyroidism in order to determine the right time for surgical treatment as well as the most suitable surgical technique, taking into account the individual risk profile and other therapeutic perspectives, including renal transplantation.

Evaluation of intraoperative neuromonitoring (IONM) data with the Mainz IONM Quality Assurance and Analysis tool.

BACKGROUND: Intraoperative neuromonitoring is widely used in thyroid and parathyroid surgery to prevent unilateral and especially bilateral recurrent nerve paresis. Reference values for amplitude and latency for the recurrent laryngeal nerve and vagus nerve have been published. However, data quality measures that exclude errors of the underlying intraoperative neuromonitoring (IONM) data (immanent software errors, false data labelling) before statistical analysis have not yet been implemented. METHODS: The authors developed an easy-to-use application (the Mainz IONM Quality Assurance and Analysis tool) using the programming language R. This tool allows visualization, automated and manual correction, and statistical analysis of complete raw data sets (electromyogram signals of all stimulations) from intermittent and continuous neuromonitoring in thyroid and parathyroid surgery. The Mainz IONM Quality Assurance and Analysis tool was used to evaluate IONM data generated and exported from 'C2' and 'C2 Xplore' neuromonitoring devices (inomed Medizintechnik GmbH) after surgery. For the first time, reference values for latency and amplitude were calculated based on 'cleaned' IONM data. RESULTS: Intraoperative neuromonitoring data files of 1935 patients consecutively operated on from June 2014 to May 2020 were included. Of 1921 readable files, 34 were excluded for missing data labelling. Automated plausibility checks revealed: less than 3 per cent device errors for electromyogram signal detection; 1138 files (approximately 60 per cent) contained potential labelling errors or inconsistencies necessitating manual review; and 915 files (48.5 per cent) were indeed erroneous. Mean(s.d.) reference onset latencies for the left vagus nerve, right vagus nerve, recurrent laryngeal nerve, and external branch of the superior laryngeal nerve were 6.8(1.1), 4.2(0.8), 2.5(1.1), and 2.1(0.5) ms, respectively. CONCLUSION: Due to high error frequencies, IONM data should undergo in-depth review and multi-step cleaning processes before analysis to standardize scientific reporting. Device software calculates latencies differently; therefore reference values are device-specific (latency) and/or set-up-specific (amplitude). Novel C2-specific reference values for latency and amplitude deviate considerably from published values.

Approach to risk stratification for papillary thyroid carcinoma based on molecular profiling: institutional analysis.

BACKGROUND: Currently, treatment recommendations for papillary thyroid carcinoma are not based on the genetic background causing tumourigenesis. The aim of the present study was to correlate the mutational profile of papillary thyroid carcinoma with clinical parameters of tumour aggressiveness, to establish recommendations for risk-stratified surgical treatment. METHOD: Papillary thyroid carcinoma tumour tissue of patients undergoing thyroid surgery at the University Medical Centre Mainz underwent analysis of BRAF, TERT promoter and RAS mutational status as well as potential RET and NTRK rearrangements. Mutation status was correlated with clinical course of disease. RESULTS: One hundred and seventy-one patients operated for papillary thyroid carcinoma were included. The median age was 48 years (range 8-85) and 69 per cent (118/171) of patients were females. One hundred and nine papillary thyroid carcinomas were BRAF-V600E mutant, 16 TERT promotor mutant and 12 RAS mutant; 12 papillary thyroid carcinomas harboured RET rearrangements and two papillary thyroid carcinomas showed NTRK rearrangements. TERT promoter mutant papillary thyroid carcinomas had a higher risk of distant metastasis (OR 51.3, 7.0 to 1048.2, P < 0.001) and radioiodine-refractory disease (OR 37.8, 9.9 to 169.5, P < 0.001). Concomitant BRAF and TERT promoter mutations increased the risk of radioiodine-refractory disease in papillary thyroid carcinoma (OR 21.7, 5.6 to 88.9, P < 0.001). RET rearrangements were associated with a higher count of tumour-affected lymph nodes (OR 7950.9, 233.7 to 270495.7, P < 0.001) but did not influence distant metastasis or radioiodine-refractory disease. CONCLUSIONS: Papillary thyroid carcinoma with concomitant BRAF-V600E and TERT promoter mutations demonstrated an aggressive course of disease, suggesting the need for a more extensive surgical strategy. RET rearrangement-positive papillary thyroid carcinoma did not affect the clinical outcome, potentially obviating the need for prophylactic lymphadenectomy.

Real-world EUROCRINE® registry data challenge the reliability of Bethesda cytopathology for thyroid surgery indication.

Objectives: Fine-needle aspiration cytology (FNAC) is recommended by international guidelines for the preoperative evaluation of suspicious thyroid nodules >1 cm. Despite robust evidence from endocrine centers demonstrating the key role of FNAC results for the indication of surgery, the method is not routinely used in European clinics. The database EUROCRINE®, which was introduced in 2015 with the scope of registering operations of the endocrine system, allows for a large-scale analysis of the current service reality in Europe concerning FNAC use and associated accuracy. Methods: Operations performed to "exclude malignancy", registered from January 2015 to December 2018 in EUROCRINE®, were analyzed. Parameters of accuracy were calculated for FNAC. FNAC results were considered "test positive" in the case of Bethesda category IV, V, and VI, since these categories usually prompt surgical interventions in European centers for thyroid surgery. Bethesda category II and III were considered "test negative". Results: Of 8,791 operations, 5,780 had preoperative FNAC (65.7%). The overall malignancy rate was 28.3% (2,488/8,791). Malignancy rates were 68.8% for Bethesda VI, 69.9% for Bethesda V, 32.6% for Bethesda IV, 28.2% for III, 20.2% for Bethesda II, and 24.5% for Bethesda I. After exclusion of papillary microcarcinomas (PTMCs), the sensitivity of FNAC was 71.7% and specificity 43.5%, the positive predictive value was 29.1% and the negative predictive value 82.7%. Conclusions: Although the indication to "exclude malignancy" was the predominant reason that prompted thyroid resection in the present cohort, FNAC was only used in about 65.7% of cases. When performed, FNAC was associated with unexpectedly low accuracy. Interestingly, in Bethesda II, 20.2% of malignant entities were present (13.3% after the exclusion of PTMCs).

Multicenter Experience in Robot-Assisted Minimally Invasive Esophagectomy - a Comparison of Hybrid and Totally Robot-Assisted Techniques.

BACKGROUND: Oncological esophageal surgery has evolved significantly in the last decades. From open esophagectomy over (hybrid) minimally invasive surgery, nowadays, robot-assisted minimally invasive esophagectomy (RAMIE) approaches are applied. Current techniques require an analysis of possible advantages and disadvantages indicating the direction towards a novel gold standard. METHODS: Robot-assisted Ivor Lewis esophagectomies, performed in the period from April 2017 to June 2019 in five German centers (Berlin, Cologne, Hamburg, Kiel, Mainz), were included in this study. Pre-, intra-, and postoperative parameters were assessed. Cases were grouped for hybrid (H-RAMIE) versus totally robot-assisted (T-RAMIE) approaches. Postoperative parameters and complications were compared using risk ratios. RESULTS: A total of 175 operations were performed as T-RAMIE and 67 as H-RAMIE. Patient age (median age 62 years) and sex (83.1% male) were similarly distributed in both groups. Median duration of esophagectomy was significantly lower in the T-RAMIE group (385 versus 427 min, p < 0.001). The risks of "overall morbidity" (32.0 versus 47.8%; risk ratio [RR], 95% confidence interval (CI): 1.5, 1.1-2.1; p = 0.026), "anastomotic leak" (10.3 versus 22.4%; RR, CI: 2.2, 1.2-4.1; p = 0.020), and "respiratory failure" (1.1 versus 7.5%; RR, CI: 6.5, 1.3-32.9; p = 0.019) were significantly higher in case of H-RAMIE. CONCLUSIONS: In the five participating German centers, T-RAMIE was the preferred procedure (72.3% of operations). In comparison to H-RAMIE, T-RAMIE was associated with a significantly reduced risk of postoperative morbidity, anastomotic leak, and respiratory failure as well as a significantly reduced time necessary for esophagectomy.

The surgical dilemma of primary surgery for follicular thyroid neoplasms.

Follicular thyroid carcinoma is the second most prevalent form of differentiated thyroid carcinoma, following papillary thyroid carcinoma. Preoperative diagnosis is hampered by the fact that fine-needle aspiration cytology as well as supplemental molecular analysis cannot unambiguously distinguish between follicular thyroid carcinoma and benign follicular thyroid adenoma. The 2017 WHO classification defines three histological subtypes of follicular thyroid carcinoma: minimally invasive (excellent prognosis), encapsulated angioinvasive, and widely invasive type (higher risk of recurrence and metastatic spread). The fact that definite characterization of follicular neoplasms is predominantly a postoperative histological diagnosis (core criteria: capsular, vascular and adjacent tissue invasion) translates into the challenge for the thyroid surgeon to plan preoperatively for presence of malignancy and, if required, to adapt the surgical strategy according to intraoperative (frozen section) or postoperative histological findings. Until improved tools for pre-/intraoperative diagnosis are available, the malignant potential of a follicular thyroid lesion can be assessed by stratifying the patient according to clinical risk factors (presence of metastases, advanced patient age, tumor size). A stepwise, escalating surgical approach with restricted primary resection (hemithyroidectomy) and completion surgery based on the definite histopathology is another option to solve this dilemma. The currently recommended surgical treatment strategies for FTCs as published by ATA, BTA, CAEK and ESES are discussed. There is consensus that prophylactic lymphadenectomy is not required for FTCs and that hemithyroidectomy is sufficient in low-risk FTCs (capsular invasion only) whereas thyroidectomy with postoperative radioiodine therapy is indicated in high-risk FTCs (angioinvasion; widely invasive FTC).

ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma.

BACKGROUND: Rearrangements of RET are drivers of oncogenesis, traceable in different cancer types as papillary thyroid carcinoma (PTC), non-small cell lung cancer, colorectal or breast cancer. Anchored multiplex PCR based next-generation sequencing (NGS) can detect RET rearrangements involving previously unknown partner genes. METHODS: A sample of PTC underwent NGS, following detection of RET rearrangement by fluorescence in situ hybridization. Expression analysis of ANKRD26 and RET was performed for the tumor harboring ANKRD26-RET, for corresponding normal thyroid tissue and PTC tumors with representative genetic alterations (BRAFV600E, CCDC6-RET), complemented by a comparative search in the "UniProt" database. RESULTS: NGS analysis resulted in the discovery of the fusion ANKRD26-RET. ANKRD26 mRNA was expressed in all PTC tumors (ANKRD26-RET, BRAFV600E, CCDC6-RET) and in normal thyroid tissue, whereas RET mRNA was detected only in the tumors with RET rearrangement. On protein level, ANKRD26-RET combines the RET tyrosine kinase to ankyrin repeat and coiled-coil domains. CONCLUSIONS: ANKRD26-RET is a novel rearrangement of the RET gene, associated with RET expression in thyroid tissue. The result is a fusion of the RET tyrosine kinase to prominent protein-protein interaction motifs. Further studies are required to investigate the influence of different RET rearrangements on metastasis and disease-free survival in PTC.

Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques - A molecular and clinical analysis.

INTRODUCTION: Oncogenic BRAF and RAS mutations as well as multiple known (and yet unknown) RET fusion oncogenes comprise the majority of causative molecular alterations in papillary thyroid carcinoma (PTC). Apparently "mutation-negative" PTCs encompass a heterogenous group impeding analysis of prognostic significance of underlying genetics. MATERIAL AND METHODS: BRAF wild type PTC tissue of 56 patients was analyzed using two established methods: hybrid-specific RT-PCR for the predominant rearrangement RET/PTC1 and fluorescent in situ hybridization (FISH). Clinical features of the cases with and without RET rearrangement were compared (patient age, gender, tumor size, focality, lymph node affection, and iodine avidity). RESULTS: RT-PCR revealed RET/PTC1 rearrangements in five of 56 tumors (9%). FISH confirmed these, and identified four additional RET rearrangements (9/56; 16%). Loss of the iodine avidity only occurred in cases of RET/PTC hybrids (7/9 tumors), but not in RET/PTC-negative PTCs (0/41 tumors with available uptake information; p = 0.029). The risk to develop lymph node metastases was eight times higher in presence of RET rearrangements (p = 0.010). CONCLUSIONS: FISH analysis, in contrast to hybrid-specific RT-PCR, revealed infrequent and unknown RET fusion genes. The presence of RET rearrangements was associated with a significantly elevated risk to develop iodine refractory disease and lymph node metastases. Of note, significant clinical discrimination was only achievable when taking the FISH results into account; differences would have been missed when using the RT-PCR method only. Increasing evidence of the clinical impact of RET/PTC-positivity may influence the decision on the extent of surgical resection, especially on lymph node dissection, in PTCs.

Novel rearrangements involving the RET gene in papillary thyroid carcinoma.

BACKGROUND: In the field of gene fusions driving tumorigenesis in papillary thyroid carcinoma (PTC), rearrangement of the proto-oncogene RET is the most frequent alteration. Apart from the most common rearrangement of RET to CCDC6, more than 15 partner genes are yet reported. The landscape of RET rearrangements in PTC ("RET-PTC") can notably be enlarged by modern targeted next-generation sequencing, indicating similarities between oncogenic pathways in other cancer types with identical genetic alterations. METHODS: Targeted next-generation sequencing was performed for two cases of BRAF-wild type PTC with confirmation of the results by Sanger sequencing. A "UniProt" database research was performed to assess protein alterations resulting from RET rearrangements. RESULTS: RUFY2-RET and KIAA1468-RET were detected. The fusion genes were not present in normal tissue of the index patients. The rearrangement RUFY2-RET lead to a fusion of the RET tyrosine kinase domain to a RUN domain and a coiled-coil domain. For KIAA1468-RET, a fusion to a LisH domain and two coiled-coil domains resulted. CONCLUSIONS: RUFY2-RET and KIAA1468-RET are novel RET/PTC rearrangements. The fusions were previously described in non-small cell lung cancer. The rearrangement results in a fusion of the RET tyrosine kinase to regulatory domains of RUFY2 and KIAA1468.

The Gatekeepers in the Mouse Ophthalmic Artery: Endothelium-Dependent Mechanisms of Cholinergic Vasodilation.

Cholinergic regulation of arterial luminal diameter involves intricate network of intercellular communication between the endothelial and smooth muscle cells that is highly dependent on the molecular mediators released by the endothelium. Albeit the well-recognized contribution of nitric oxide (NO) towards vasodilation, the identity of compensatory mechanisms that maintain vasomotor tone when NO synthesis is deranged remain largely unknown in the ophthalmic artery. This is the first study to identify the vasodilatory signalling mechanisms of the ophthalmic artery employing wild type mice. Acetylcholine (ACh)-induced vasodilation was only partially attenuated when NO synthesis was inhibited. Intriguingly, the combined blocking of cytochrome P450 oxygenase (CYP450) and lipoxygenase (LOX), as well as CYP450 and gap junctions, abolished vasodilation; demonstrating that the key compensatory mechanisms comprise arachidonic acid metabolites which, work in concert with gap junctions for downstream signal transmission. Furthermore, the voltage-gated potassium ion channel, Kv1.6, was functionally relevant in mediating vasodilation. Its localization was found exclusively in the smooth muscle. In conclusion, ACh-induced vasodilation of mouse ophthalmic artery is mediated in part by NO and predominantly via arachidonic acid metabolites, with active involvement of gap junctions. Particularly, the Kv1.6 channel represents an attractive therapeutic target in ophthalmopathologies when NO synthesis is compromised.