Total Versus Near-total Thyroidectomy in Graves Disease: Results of the Randomized Controlled Multicenter TONIG-trial.

BACKGROUND: Previous data suggest that the incidence of hypoparathyroidism after surgery for Graves disease (GD) is lower after subtotal thyroidectomy compared to total thyroidectomy (TT). The present study evaluated the incidence of postoperative hypoparathyroidism after near-total (NTT) versus TT in GD. METHODS/DESIGN: In a multicenter prospective randomized controlled clinical trial, patients with GD were randomized intraoperatively to NTT or TT. Primary endpoint was the incidence of transient postoperative hypoparathyroidism. Secondary endpoints were permanent hypoparathyroidism, transient recurrent laryngeal nerve palsy (RLNP), reoperations for bleeding, inadvertently removed parathyroid glands, and recurrent hyperthyroidism after 12 months. RESULTS: Eighteen centers randomized 205 patients to either TT (n = 102) or NTT (n = 103) within 16 months. According to intention-to-treat postoperative transient hypoparathyroidism occurred in 19% (20/103) patients after NTT and in 21% (21 of 102) patients after TT (P = 0.84), which persisted >6 months in 2% and 5% of the NTT and TT groups (P = 0.34). The rates of parathyroid autotransplantation (NTT 24% vs TT 28%, P = 0.50) and transient RLNP (NTT 3% vs TT 4%, P = 0.35) was similar in both groups. The rate of reoperations for bleeding tended to be higher in the NTT group (3% vs 0%, P = 0.07) and the rate of inadvertently removed parathyroid glands was significantly higher after NTT (13% vs 3%, P = 0.01). An existing endocrine orbitopathy improved in 35% and 24% after NTT and TT (P = 0.61). Recurrent disease occurred in only 1 patient after TT (P = 0.34). CONCLUSION: NTT for GD is not superior to TT regarding transient postoperative hypoparathyroidism.

Superficial Surgical Site Infection Following the Use of Intracutaneous Sutures Versus Staples.

BACKGROUND: Superficial wound infections after gastrointestinal surgery markedly impair the affected patients' quality of life. As it is still unknown which method of skin closure is best for the reduction of wound infections in elective gastrointestinal sur- gery, we compared the frequency of wound infections after intracutaneous suturing versus skin stapling. METHODS: In a prospective, randomized, single-center study, patients undergoing elective gastrointestinal surgery were intraoperatively randomized to skin closure either with an intracutaneous suture or with staples. The primary endpoint-the occurrence of a grade A1 wound infection within 30 days of surgery-was evaluated according to the intention-to-treat principle. RESULTS: Out of a total of 280 patients, 141 were randomized to intracutaneous suturing and 139 to stapling. The groups did not differ significantly with respect to age, sex, or ASA classification. 19 of the 141 patients in the intracutaneous suturing group (13.5%) had a grade A1 wound infection, compared with 23 of 139 in the stapling group (16.6%) (odds ratio [OR]: 0.79; 95% confidence interval: [0.41; 1.52]; p = 0.47). A multiple regression analysis revealed that the type of surgery (colorectal vs. other), the approach, and the incision length were independent risk factors for a grade A1 wound infection. When wound dehiscences were additionally considered, wound complications were found to have arisen significantly more often in the stapling group than in the intracutaneous suturing group (16.3% [23/141] versus 30.2% [42/139], OR: 0.45 [0.25; 0.80]; p = 0.006). CONCLUSION: In elective gastrointestinal surgery, intracutaneous suturing was not found to be associated with a lower rate of superficial wound infections than skin stapling, but fewer wound dehiscences occurred in the intracutaneous suturing group.

Intracutaneous suture versus transcutaneous skin stapling for closure of midline or horizontal skin incision in elective abdominal surgery and their outcome on superficial surgical site infections--INTRANS: study protocol for a randomized controlled trial.

BACKGROUND: Surgical site infections are the third most frequent type of nosocomial infections. Evidence-based recommendations have been given regarding preoperative hospitalization, hygiene and air-conditioning, patient conditions, and wound dressing. However, no general recommendations concerning wound closure exist. Systematic reviews and meta-analyses suppose a benefit of intracutaneous suture compared to skin staples in orthopedic and obstetric surgery. Literature data for skin closure in elective abdominal surgery are still deficient. METHODS/DESIGN: Patients scheduled for any elective abdominal surgery requiring midline or horizontal laparotomy are potentially eligible for the trial. Trial-specific exclusion criteria are date of admission exceeding four days prior to surgery, antibiotic treatment within the past 14 days, any previous midline or horizontal laparotomy in case the procedure requires the same skin incision as before, neurophysiological deficits or severe psychiatric or neurologic diseases that do not allow an informed consent or compliance, and participation in any other interventional trial with interference of intervention and outcome. The trial is created for process innovation within standardized surgical procedures. It is designed as a prospective randomized controlled single center trial in a parallel design including an active comparator and an intervention group. The intervention addresses the closure of skin after the main surgical procedure: intracutaneous suture in the intervention group and transcutaneous skin stapling in the control group. The rate of superficial surgical site infections is defined as the primary endpoint. Secondary endpoints are time for skin closure, satisfaction with the cosmetic outcome 30 days after surgery, prolongation of hospital stay, and duration of sick-leave due to surgical site infections. The primary efficacy analysis follows the intention-to-treat principle. A χ2 test will be applied. DISCUSSION: The trial is expected to balance the shortcomings of the current evidence. It will help to define the gold standard for wound closure in elective abdominal surgery. Patients' safety and quality of life are assumed to be enhanced. Therapy costs are likely to be reduced and health care optimized. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00004542.

Total versus near-total thyroidectomy in Graves' disease and their outcome on postoperative transient hypoparathyroidism: study protocol for a randomized controlled trial?

BACKGROUND: Graves' disease is an independent risk factor for transient postoperative hypoparathyroidism. Besides the disease itself, preparation techniques are influential. Transient postoperative hypoparathyroidism has severe consequences for patients' physical and psychological state. It can be life threatening during the acute phase and may impair patients' health, psyche and quality of life thereafter. For the surgical therapy of Graves' disease, total thyroidectomy is recommended according to the national S2-guideline. The evidence- based on a metaanalysis- is criticized by the Cochrane diagnostic review commentary for substantial methodological deficits. Two randomized controlled trials lead to the hypothesis that a near-total resection with bilateral remnants of ≤ 1g on each side compared to total thyroidectomy will significantly reduce the occurrence of transient postoperative hypoparathyroidism with equal therapeutic safety. METHODS/DESIGN: Patients with Graves' disease indicated for definite surgery are eligible for the trial. Trial-specific exclusion criteria are: conservative treatment, malignancy, previous thyroid surgery and coincident hypoparathyroidism. The trial is created for therapeutic purpose through process innovation. It is designed as a prospective randomized controlled patient and observer blinded multicentered trial in a parallel design including an active comparator and an intervention group. The intervention addresses the surgical procedure: near-total thyroidectomy leaving bilateral remnants of ≤ 1g on each side in the intervention group and total thyroidectomy in the control group. The occurrence of transient postoperative hypoparathyroidism is defined as primary endpoint. Secondary endpoints are: reoperations due to bleeding, recurrent laryngeal nerve palsy, permanent hypoparathyroidism, recurrent disease, changes of endocrine orbitopathy and quality of life within a one-year follow-up period. The primary efficacy analysis follows the intention-to-treat principle. A binary logistic regression model will be applied. Complications and serious adverse events will be descriptively analyzed. DISCUSSION: The trail is expected to balance out the shortcomings of the current evidence. It will define the surgical gold standard for the surgical therapy of Graves' disease. Patients' safety and quality of life are assumed to be enhanced. Therapy costs are likely to be reduced and health care optimized. The conduction of the trial is feasible through the engagement and commitment of the German association of endocrine surgeons and the National Network for Surgical Trials. TRIAL REGISTRATION: German clinical trials register (DRKS) DRKS00004161.

Call-associated acute fatigue in surgical residents--subjective perception or objective fact? A cross-sectional observational study to examine the influence of fatigue on surgical performance.

BACKGROUND: The effect of acute partial sleep deprivation on surgical proficiency is still controversially discussed. The present study correlated physiological parameters of fatigue with objective technical and cognitive skills, as well as subjective sleepiness of surgical residents. The aim of the study was to assess the effect of acute partial sleep deprivation on surgical performance. METHODS: Thirty-eight surgeons were interviewed on three consecutive mornings: prior to a 24 h call, post-call, and after 24 h of rest. Reported hours of sleep were recorded. Subjective alertness was assessed with the standardized Stanford-Sleepiness-Scale (SSS). Saliva cortisol concentrations and pupillary activity were measured by standardized ELISA and pupillography. The virtual reality (VR)-simulator LapSim was used to assess technical skills through low-fidelity VR-tasks ("cutting," "clip applying") and cognitive skills through high-fidelity VR-tasks ("intracorporeal suturing," "VR-cholecystectomy"). Objective alertness was measured by the standardized d2-Paper-Pencil Test. RESULTS: Recorded hours of sleep (p = 0.001) and subjective alertness (SSS) decreased (p = 0.001) significantly post-call. None of the three factors studied-saliva cortisol concentration (p = 0.313), pupillary activity (p = 0.998), or VR-performance of low-fidelity VR-tasks-differed significantly between assessments. Surprisingly, VR-performance of high-fidelity VR-tasks (error-score p = 0.044, time to complete task p = 0.0001, economy of instrument motion p = 0.0001) and objective alertness (d2-Paper-Pencil Test p = 0.027) significantly improved in the post-call setting. CONCLUSIONS: Acute call-associated fatigue seems to be a predominantly subjective perception. Physiological factors seem to outbalance an anticipated fatigue-associated impairment of technical performances within low-fidelity VR-tasks. In surgical residents, acute partial sleep deprivation seems to have a positive short-term effect on cognitive skills, leading to enhanced technical performance and increased objective alertness within complex tasks.

Vascular clips versus ligatures in thyroid surgery--results of a multicenter randomized controlled trial (CLIVIT Trial).

BACKGROUND: New techniques using vascular clips or ultrasonically activated shears have been suggested to shorten operation time without compromising safety. The objective of the CLIVIT Trial was to compare ligatures with vascular clips for hemostasis in elective benign thyroid surgery. METHODS: This multicenter, randomized, controlled, parallel group superiority trial was conducted in 13 German surgical centers. Patients scheduled for at least subtotal resection bilaterally were intraoperatively randomized. The primary endpoint was resection time. Secondary endpoints were the amount of postoperative bleeding, reoperation due to bleeding, wound infection, temporary (reversal within 12 months) and permanent (over 1 year) recurrent laryngeal nerve (RLN) paralysis, length of hospital stay, and safety. REGISTRATION: ISRCTN 96901396. RESULTS: Two hundred fifty patients were treated with ligatures and 241 with vascular clips. No differences in patients' baseline and surgical characteristics were observed. No difference was detected for mean resection time (clip 63.5 min ± 29.6, ligature 66.1 min ± 29.3, P = 0.258). Postoperative bleeding (mean 86 ml ± 93), reoperation due to bleeding (clips 4, ligature 2), wound infections (clips 4, ligature 4), postoperative hospital stay (mean 3.0 ± 1.9), and safety data also did not vary significantly. The rates of temporary and permanent RLN paralysis were 6.9 % (34/491) and 2.9 % (14/491), respectively. Not using a surgical drain (123 patients) was not associated with a higher rate of complications. CONCLUSION: Vascular clips did not reduce the resection time. However, a 2.9 % rate of permanent RLN paralysis is of concern. Drains in elective surgery may be of no benefit.

Epithelial-mesenchymal transition is a critical step in tumorgenesis of pancreatic neuroendocrine tumors.

The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro, in vivo and human tumor specimen. Expression of EMT markers was analyzed using immunohistochemistry and real-time PCR. For in vitro studies, BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail, and cell aggregation assays were performed. To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor cell proliferation and apoptosis. Snail and Twist was expressed in 61 % and 64% of PNETs. This was associated with loss of E-cadherin. RT-PCR revealed conservation of the EMT markers Slug and Snail in BON-1 cells. Transfection with siRNA against Slug was associated with upregulation of E-cadherin, enhanced cell-cell adhesion and inhibition of cell proliferation. Snail-inhibition in vivo by PEG was associated with increased apoptosis, decreased tumor cell proliferation and dramatic reduced tumor volume in Rip1Tag2 mice. The presented data show that EMT plays a key role in tumorgenesis of PNETs. The activation of Snail in a considerable subset of human PNETs and the successful effect of Snail inhibition by PEG in islet cell tumors of transgenic mice provides first evidence of Snail as a drug target in PNETs.

Sorafenib inhibits tumor growth and improves survival in a transgenic mouse model of pancreatic islet cell tumors.

BACKGROUND: The purpose of the study was to evaluate Sorafenib (BAY 43-9006) derived receptor tyrosine kinase inhibition on tumor progression in murine islet cell tumors. Sorafenib is considered to be a potent inhibitor of tumor angiogenesis and neovascularization in various solid tumors. Rip1Tag2 mice were treated in two different groups according to the model of tumor progression: the early treatment group received vehicle or Sorafenib from 10 to 14 weeks of age and the late treatment group from week 12 until death. Tumor surface, tumor cell proliferation, and apoptosis were measured in both treatment groups to assess the in vivo effects of Sorafenib. Survival was recorded for the late treatment group. In the early treatment group Sorafenib led to a dramatic decrease in tumor volume compared to the control group. Apoptosis was significantly augmented and cell proliferation was inhibited. As a single therapy Sorafenib significantly improved survival in the late treatment group. Conclusion. Sorafenib may provide a new paradigm for the therapy of islet cell tumors.

Impact of CT-based diagnostic imaging on management and outcome of nonfunctioning pancreatic tumors.

BACKGROUND: Sporadic malignant non-functioning pancreatic endocrine tumors (NF-PETs) are an important subset of pancreatic neoplasms. The aim of this study was to assess the impact of improved imaging on these features in a tertiary referral centre within a 20-year follow-up. PATIENTS AND METHODS: From 1988 to 2009, 51 patients were treated for sporadic malignant NF-PETs. Forty-one patients who underwent tumor resection were retrospectively attributed according to the date of the initial diagnosis, group 1: 1988-1999 vs. group 2: 2000-2009. RESULTS: Cross-sectional imaging led to positive prediction of NF-PETs in all patients. Curative resection was achieved in 76%. Synchronous metastases were present in 56% with a positive prediction of 43%. In group 1, the mean reported CT-determined tumor size was 56 vs. 54 mm in group 2 (p = 0.89). Synchronous metastases were present in 61% in group 1 vs. 57% (p = 0.99) in group 2. Metachronous metastases were recorded in 39% in group 1 vs. 43% (p = 0.84) in group 2. The mean interval from initial resection to diagnosis of metastatic disease was significantly shorter (p = 0.01) in patients from group 1 (14 vs. 61 months). Cumulative 5- and 10-year survival rates were 77% and 72% in group 1 vs. a 5-year survival rate of 66% in group 2. CONCLUSION: So far, improved CT-based imaging has no impact on earlier detection of initial synchronous metastases in sporadic malignant NF-PETs, while metachronous metastases are detected earlier.

Sonic hedgehog and pancreatic-duodenal homeobox 1 expression distinguish between duodenal and pancreatic gastrinomas.

Some 80-90% of gastrinomas are located in the gastrinoma triangle, which includes the duodenum, the pancreatic head, and the hepatoduodenal ligament. The natural history of the tumors depends on their origin. Duodenal gastrinomas are much less aggressive than pancreatic primaries and infrequently develop liver metastases. The reason therefore is unclear. The transcription factor pancreatic-duodenal homeobox 1 (Pdx1) is important in differentiation and development of the pancreas and duodenum. In embryonic development, Sonic hedgehog (Shh) expression establishes a sharp molecular boundary, which allows for the proper patterning of the duodenal and pancreatic epithelium. Pancreatic polypeptide (PP) is expressed in pancreatic islets and is known to be expressed in pancreatic endocrine tumors. This study aims to clarify the expression pattern of Pdx1, Shh, and PP in duodenal and pancreatic gastrinomas. Tissue from 15 patients with duodenal and from 11 patients with pancreatic gastrinomas that underwent surgery between 1987 and 2007 at our institution because of a gastrinoma were evaluated by immunohistochemistry (IHC). Furthermore, tissue from lymph node metastases from two patients with a so far undetected primary gastrinoma was analyzed. IHC revealed strong Pdx1 expression in pancreatic gastrinomas, but not in duodenal gastrinomas. By contrast, there was no Shh expression detectable in pancreatic gastrinomas, but found in all duodenal gastrinomas. This pattern was also true for associated metastases. Shh expression combined with absence of Pdx1 expression in lymph node metastases from patients with an unknown location of the primary suggests a so far undetected duodenal gastrinoma. We show for the first time that only pancreatic, but not duodenal gastrinomas express Pdx1. Moreover, only duodenal gastrinomas express Shh, suggesting a different genetic background of these two tumors. Whereas the expression of Pdx1 in pancreatic gastrinomas might suggest their endocrine origin from islets, duodenal gastrinomas develop from a Pdx1 negative cell cluster. The expression pattern of Pdx1, Shh, and PP in resected metastases can help to locate an otherwise undetected primary gastrinoma.

Are diabetic patients at a greater risk to develop a vocal fold palsy during thyroid surgery than nondiabetic patients?

BACKGROUND: Diabetic neuropathy is reported to be an independent risk factor for the development of a vocal fold palsy (VFP), and nerves in diabetic patients are suspected to have an increased vulnerability to mechanical trauma. This retrospective study was performed to find out whether diabetic patients were at a greater risk to acquire VFP than were nondiabetic patients in a large cohort who underwent thyroid surgery. METHODS: Records of patients who underwent initial thyroid surgery at our institution between 1995 and 1999 were reevaluated. Results of preoperative and postoperative laryngoscopy, repeated laryngoscopy 6 months after operation, and concomitance of diabetes were registered. RESULTS: Six hundred thirty patients were retrospectively analyzed. Preoperative laryngoscopy revealed a unilateral VFP in 3 of 44 diabetic patients (6.8%) and in 4 of 586 (0.7%) nondiabetic patients. Five of 44 diabetic patients (11.4%) and 49 of 586 nondiabetic patients (8.4%) acquired VFP perioperatively, which was permanent in 2 diabetic patients (4.5%) and 8 nondiabetic patients (1.4%). The incidence of preoperative VFP in the diabetic patients was significantly greater than in nondiabetic patients (P = .0091). The incidence of postoperative and permanent VFP did not differ significantly. CONCLUSION: Thyroid surgery can be performed safely in diabetic patients, as they are not at a greater risk to acquire VFP than nondiabetic patients.

Laryngoscopy in thyroid surgery--essential standard or unnecessary routine?

BACKGROUND: Preoperative and postoperative laryngoscopy has been recommended for diagnostic and forensic reasons as a standard procedure in all patients who undergo thyroid surgery. The aim of this study was to find a more selective approach by defining patients at risk of developing vocal fold palsy (VFP). METHODS: The history of neck explorations, results of laryngoscopy, and histology were registered in all patients who underwent thyroid surgery at our institution between 1995 and 1999. Patients with pathologic findings at postoperative laryngoscopy underwent reassessment of voice and vocal fold (VF) mobility 6 months later. RESULTS: Unilateral VFP was detected preoperatively in 13 of 695 patients (1.9%). Of the 13 patients, only 1 patient was asymptomatic, had no history of neck surgery, and had no suspected malignancy. Postoperative laryngoscopy revealed a new development of VFP in 68 of 695 patients (9.8%). All patients with a permanent VFP had symptoms immediately after operation. Asymptomatic VFPs always recovered. CONCLUSIONS: Preoperative laryngoscopy is justified in symptomatic patients who undergo reoperation or in patients when malignancy is suspected. The necessity of a preoperative laryngoscopy in all other patients must be questioned. Postoperative laryngoscopy and additional diagnostic testing should be reserved for symptomatic patients.

Novices in surgery are the target group of a virtual reality training laboratory.

BACKGROUND: This study aims to establish which physicians represent the suitable target group of a virtual training laboratory. METHODS: Novices (48 physicians with fewer than 10 laparoscopic operations) and intermediate trainees (19 physicians who performed 30-50 laparoscopic operations) participated in this study. Each participant performed the basic module 'clip application' at the beginning and after a 1-hour short training course on the LapSim. The course consisted of the tasks coordination, lift and grasp, clip application, cutting with diathermy and fine dissection at increasing difficulty levels. The time taken to complete the tasks, number of errors, and economy of motion parameters (path length and angular path) were analyzed. RESULTS: Following training with the simulator, novices completed the task significantly faster (p = 0.001), demonstrated a greater economy of motion [path length (p = 0.04) and angular path (p = 0.01)]. In contrast, the intermediate trainees showed a reduction of their errors, but without reaching statistical significance. They showed no improvement in economy of motion and completed the task significantly slower (p = 0.03). CONCLUSION: Novices, in comparison to intermediate trainees, tend to benefit most during their first exposure to a laparoscopy simulator.

Paneling human thyroid cancer cell lines for candidate proteins for targeted anti-angiogenic therapy.

Tumor angiogenesis is believed to result from an imbalance of pro- and anti-angiogenic factors, some of which are candidates for targeted therapy. Such therapy has raised hopes for patients with undifferentiated thyroid carcinomas, who are facing a grave prognosis with a survival of only months. In this study, in vivo growth of xenografted human thyroid carcinomas unexpectedly responded quite differently to neutralizing anti-vascular endothelial growth factor (VEGF) antibody. In particular, lasting inhibition as well as accelerated growth occurred after treatment. Consequently, a panel of anti-angiogenic factors was addressed in a representative sample of thyroid carcinoma lines. VEGF, fibroblast growth factor (FGF-2), and endostatin were demonstrated by Western blotting and EIA, whereas PDGF-A, PDGF-B, and IL-6 were negative. Quantification of VEGF, FGF-2, and endostatin revealed a wide range of concentrations from 500 to 4,200 pg/ml VEGF, 5 to 60 pg/ml FGF-2, and 50 to 300 pg/ml endostatin, not related to a particular histologic thyroid carcinoma background. Angiostatin (kringles 1-3) was detected in all, but one of the cell lines. Finally, aaATIII was confirmed in FTC133 cells. These data highlight the complex regulation of angiogenesis in thyroid carcinoma cell lines and suggest that the array of angiogenic factors differs markedly between individual cell lines. For the first time, angiostatin, endostatin, and possibly also aaATIII are identified as novel candidate regulators of angiogenesis in thyroid carcinoma cells.