[Current approach in cases of persistence and recurrence of primary hyperparathyroidism]. / Aktuelles Vorgehen bei Persistenz und Rezidiv eines primären Hyperparathyreoidismus.

Primary hyperparathyroidism (pHPT) is now diagnosed much earlier and is often asymptomatic. Biochemically mild pHPT is characterized by small parathyroid adenomas (NSDA) and the results of localization diagnostics as well as surgical treatment are poorer. The frequency of redo surgery is 3-14% in large registries. The planning of a reoperation is no different from the basic principles for the first intervention. Diagnosis and differential diagnoses must be checked. This is followed by a review of the first operation and the associated histology as well as imaging and the course of parathyroid hormone (PTH) values. The next step is to check whether the reoperation is necessary. Most patients still have comprehensible indications that correspond to the guidelines and also ex-post. In contrast to the first intervention, there is always a need to attempt to localize the NSDA. The first procedure is a surgically performed ultrasound. Other localization options are MIBI-SPECT scintigraphy, 4D-CT and FEC-PET-CT, with the latter having the highest sensitivity. There is a clear relationship between higher case numbers and better surgical outcomes. Personal experience is decisive and in terms of predicting success this is even more important than the results of localization procedures. The goal of maximizing the outcome and minimizing morbidity justifies what is from the perspective of those affected probably the most important requirement for the future: no redo surgery for HPT outside of a high-volume center.

How Long Does It Take to Regain Normocalcaemia in the Event of Postsurgical Hypoparathyroidism? A Detailed Time Course Analysis.

Background: Postsurgical hypoparathyroidism (PH) is the most common side effect of bilateral thyroid resections. Data regarding the time course of recovery from PH are currently unavailable. Therefore, a detailed analysis of the time course of PH recovery and conditions associated with rapid recovery was conducted. Methods: This is a retrospective analysis of prospectively documented data. Patients with biochemical signs of PH or need for calcium supplementation were followed-up for 12 months. Logistic regression analyses were used to identify covariates of early as opposed to late recovery from PH. Results: There were 1097 thyroid resections performed from 06/2015 to 07/2016 with n = 143 PH. Median recovery time was 8 weeks and six patients (1.1% of total thyroid resections) required calcium supplementation > 12 months. Recovery of PH within 4 and 12 weeks was characterized by high PTH levels on the first postoperative day (4 weeks: OR 1.13, 95% CI 1.06−1.20; 12 weeks: OR 1.08, 95%CI 1.01−1.16). Visualization of all PTGs emerged as an independent predictor of recovery within 12 months (OR 2.32, 95% CI 1.01−4.93) and 24 weeks (OR 2.69, 95% CI 1.08−6.69). Conclusion: In the setting of specialized high-volume endocrine surgery, permanent PH is rare. However, every second patient will require more than 2 months of continued medical surveillance. Early recovery was associated with only moderately decreased postsurgical PTH-levels. Successful late recovery appeared to be associated with the number of parathyroid glands visualized during surgery.

Short-Term Hypocalcemia Prophylaxis With Calcitriol Before Thyroidectomy.

BACKGROUND: Total thyroidectomy is the most common surgical treatment of thyroid diseases, and postoperative hypocalcemia is its most common complication. Hypocalcemia prolongs the patient's hospital stay and impairs his or her quality of life. Although a low vitamin D level is a recognized risk factor, the utility of preoperative vitamin D administration to prevent postoperative hypocalcemia is unclear. In this trial, therefore, we studied the effect of giving vitamin D before total thyroidectomy. METHODS: In a multicenter, randomized, minimally interventional trial (registration number: DRKS 00005615), patients about to undergo total thyroidectomy were randomized either to an intervention group that received 0.5 µg of calcitriol per os twice daily for three days up to the day immediately before surgery, or to a control group that did not (no placebo was given). The primary endpoint was the absence of hypocalcemia (serum calcium <2.1 mmol/L) in the postoperative course. RESULTS: Of the 287 patients recruited in six hospitals over the period 23 July 2014 to 20 March 2017, 246 were included in the final analysis. The intervention and control groups did not differ significantly with respect to the rate of postoperative hypocalcemia (29.2% and 33.6%, respectively; p = 0.546, power 8.8%). The duration of postoperative hypocalcemia was, however, shorter in the intervention group (3.5 vs. 7 days; p = 0.016, power 68%). The rates of hypocalcemia in the individual trial locations varied widely, ranging from 13.9% to 71.4%. CONCLUSION: Short-term administration of calcitriol did not affect the rate of occurrence of hypocalcemia after thyroidectomy, but did shorten its duration. The rate of postoperative hypocalcemia varied widely across hospitals, probably because of differences in surgical technique.

FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale.

Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

[Cystic cervical lymph node swelling - Thyroglobin-FNA allows to diagnose metastasizing papillary thyroid carcinoma]. / Zystische zervikale Lymphknotenschwellung ­ TG-Bestimmung im Punktat sichert das lymphatisch metastasierte papilläre Schilddrüsenkarzinom.

HISTORY: A patient presented with a cystic mass in the lateral triangle of the neck. FINDINGS AND DIAGNOSIS: After ultrasound and MRI, a fine needle aspiration cytology (FNAC) was performed. It did not reveal malignant disease. By virtue of repeated FNAC and detection of thyroglobin in the cyst fluid, the diagnosis of thyroid carcinoma was firmly established. THERAPY AND COURSE: The necessary surgery could be performed in a single step intervention. Three weeks after surgery, radioiodine therapy with 3.7 GBq I131 was performed. CONCLUSION: Swelling of the cervical lymph nodes may have many causes, and rarely may be the metastasis of a thyroid carcinoma. We present a simple way to detect lymphatic metastatic thyroid carcinoma with the help of a case report.

[18F]fluoro-ethylcholine-PET Plus 4D-CT (FEC-PET-CT): A Break-Through Tool to Localize the "Negative" Parathyroid Adenoma. One Year Follow Up Results Involving 170 Patients.

BACKGROUND: The diagnostic performance of [18F]fluoro-ethylcholine-PET-CT&4D-CT (FEC-PET&4D-CT) to identify parathyroid adenomas (PA) was analyzed when ultrasound (US) or MIBI-Scan (MS) failed to localize. Postsurgical one year follow-up data are presented. METHODS: Patients in whom US and MS delivered either incongruent or entirely negative findings were subjected to FEC-PET&4D-CT and cases from July 2017 to June 2020 were analyzed, retrospectively. Cervical exploration with intraoperative PTH-monitoring (IO-PTH) was performed. Imaging results were correlated to intraoperative findings, and short term and one year postoperative follow-up data. RESULTS: From July 2017 to June 2020 in 171 FEC-PET&4D-CTs 159 (92.9%) PAs were suggested. 147 patients already had surgery, FEC-PET&4D-CT accurately localized in 141; false neg. 4, false pos. 2, global sensitivity 0.97; accuracy 0.96, PPV 0.99. All of the 117 patients that already have completed their 12-month postoperative follow up had normal biochemical parameter, i.e., no signs of persisting disease. However, two cases may have a potential for recurrent disease, for a cure rate of at least 98.3%. CONCLUSION: FEC-PET&4D-CT shows unprecedented results regarding the accuracy localizing PAs. The one-year-follow-up data demonstrate a high cure rate. We, therefore, suggest FEC-PET-CT as the relevant diagnostic tool for the localization of PAs when US fails to localize PA, especially after previous surgery to the neck.

Neuromonitoring of the Recurrent Laryngeal Nerve Reduces the Rate of Bilateral Vocal Cord Dysfunction in Planned Bilateral Thyroid Procedures.

PURPOSE: Bilateral vocal cord dysfunction (bVCD) is a rare but feared complication of thyroid surgery. This long term retrospective study determined the effect of intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) during thyroid surgeries with regard to the rate of bVCD and evaluated the frequency as well as the outcome of staged operations. METHODS: Retrospective analysis of prospectively documented data (2000-2019) of a tertiary referral centers' database. IONM started in 2000 and, since 2010, discontinuation of surgery was encouraged in planned bilateral surgeries to prevent bVCD, if non-transient loss of signal (ntLOS) occurred on the first side. Datasets of the most recent 40-month-period were assessed in detail to determine the clinical outcome of unilateral ntLOS in planned bilateral thyroid procedures. RESULTS: Of 22,573 patients, 65 had bVCD (0.288%). The rate of bVCD decreased from 0.44 prior to 2010 to 0.09% after 2010 (p < 0.001, Chi2). Case reviews of the most recent 40 months period identified ntLOS in 113/3115 patients (3.6%, 2.2% NAR), of which 40 ntLOS were recorded during a planned bilateral procedure (n = 952, 2.1% NAR). Of 21 ntLOS occurring on the first side of the bilateral procedure, 15 procedures were stopped, subtotal contralateral resections were performed, and thyroidectomy was continued in 3 patients respectively, with the use of continuous vagal IONM. Eighteen cases of VCD were documented postop, and all but one patient had a full recovery. Seven patients had staged resections after 1 to 18 months (median 4) after the first procedure. CONCLUSION: IONM facilitates reduced postoperative bVCD rates. IONM is, therefore, recommendable in planned bilateral procedures. The rate of non-complete bilateral surgery after intraoperative non-transient LOS was 2%.

Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

Are routine ultrasound examinations helpful in the detection of bleeding complications following laparoscopic inguinal hernia repair?

PURPOSE: Intraabdominal bleeding is a dreaded complication after laparoscopic transabdominal preperitoneal inguinal hernia repairs. Routine postoperative sonographic (US) examination and hemoglobin measurement have been suggested to identify bleeding after surgery. We retrospectively assessed the value of these tests. METHODS: A total of 995 consecutive patients admitted for laparoscopic inguinal hernia repair to a single teaching hospital were analyzed. US examinations were performed postoperatively on the operative day to identify intraabdominal bleeding. In addition, hemoglobin measurements were obtained on the first postoperative day. RESULTS: Postoperative US examinations were performed on 971 patients (97.6%). Of these, 945 were examined within 24 hours of surgery. Reoperation was necessary in 1.1% (11/995) of the patients because of a persistent seroma in five cases, intraabdominal or inguinal bleeding or hematomas in five cases, and a trocar hernia in one case. In none of the 11 patients requiring reoperation did US examination or hemoglobin measurement indicate acute bleeding or hematoma. CONCLUSIONS: Routine postoperative US examination and hemoglobin measurement within the first 24 hours of surgery are not suitable for identifying patients with intraabdominal bleeding who require a reoperation. Instead, US examination and hemoglobin measurement should be part of the patient workup when there is a clinical suspicion of a postoperative complication. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:145-149, 2017.

Teaching and training in laparoscopic inguinal hernia repair (TAPP): impact of the learning curve on patient outcome.

BACKGROUND: On the basis of lower incidence of postoperative pain and faster recovery compared with open techniques, the laparoscopic transabdominal preperitoneal patch plastic (TAPP) technique was established as a leading mode of inguinal hernia repair. In contrast to open hernia repairs, which are well integrated in the training of young surgeons, TAPP is still considered a more difficult surgical procedure, raising the questions of how to include this technique in trainee programs and how to provide appropriate training. METHODS: Out of 15,101 TAPP procedures performed in our department between 1993 and 2007, we analyzed 254 operations that occurred from April 2004 to February 2007 by young trainees (between the second and fourth years of surgical training). The analysis compared the trainees' TAPP operations with 3,200 TAPP procedures performed by experienced surgeons in the same time period, and with the first 254 TAPP operations in our department performed by pioneers who introduced this technique in 1993. RESULTS: In the 254 operations performed by young trainees, the mean operation time was 59 min, the morbidity rate was 3.2 %, and the recurrence rate was 0.4 %. Compared to experienced surgeons, we found no significant difference in recurrence rate and morbidity. For operation time, however, the young trainees demonstrated a learning curve with continuous improvement until the end of the study period approaching expert level. Pioneers also demonstrated a clear learning curve in operation time and additionally also regarding morbidity and recurrence rate. CONCLUSIONS: Our study demonstrates that the TAPP learning curve of young trainees is only related to operation time. Therefore, TAPP is a safe and reproducible technique when performed by young trainees under the supervision of experienced laparoscopic surgeons. With an adequate program, the technique can be learned quickly, skillfully, and safely when a standardized technique is used. It should be included as a fundamental part of state-of-the-art trainee programs.