Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

Indication for Liver Transplantation After Direct-Acting Agents in the Treatment of Patients With Hepatitis C.

BACKGROUND: The development of new direct-acting antivirals (DAA) for hepatitis C virus (HCV) treatment has reduced the indications for liver transplantation (LT). We analyzed the indications, characteristics, and evolution of patients with HCV infection who were treated with DAA-based therapies and who underwent LT. MATERIAL AND METHODS: A retrospective single-center study was performed. Data were collected of patients undergoing LT owing to HCV infection between January 2016 and August 2020. Overall characteristics of the patients were analyzed and divided into 2 groups according to the indication for LT: hepatocellular carcinoma (HCC) or decompensated cirrhosis (DC). Differences between biliary and vascular complications after surgery and survival time were compared. RESULTS: Of 156 LTs, 33 (22%) were performed in patients with HCV infection in this period, which shows a decrease of nearly 16% when comparing this period with the interferon/ribavirin era. Indications for LT were 56.7% in patients with HCC and 43.3% in patients with DC. After DAA treatment, all patients developed a sustained viral response. Mean age of the global series, HCC group, and DC group were 56.9, 58.71, and 54.4 years, respectively (P = .041); 53.8% of the HCV-DC group initiated DAA treatment by the time to be included at the waiting list, compared with 17.6% of HCV-HCC group (P = .045). There were no statistically significant differences in terms of survival or biliary and vascular complications after LT. CONCLUSION: Patients with HCV are still part of the waiting list, mainly because of HCC. No statistical differences were shown in terms of postoperative complications or survival. Studies with a higher number of patients are needed.

Efficacy and safety of preoperative preparation with Lugol's iodine solution in euthyroid patients with Graves' disease (LIGRADIS Trial): Study protocol for a multicenter randomized trial.

BACKGROUND: Currently, both the American Thyroid Association and the European Thyroid Association recommend preoperative preparation with Lugol's Solution (LS) for patients undergoing thyroidectomy for Graves' Disease (GD), but their recommendations are based on low-quality evidence. The LIGRADIS trial aims to provide evidence either to support or refute the systematic use of LS in euthyroid patients undergoing thyroidectomy for GD. METHODS: A multicenter randomized controlled trial will be performed. Patients ≥18 years of age, diagnosed with GD, treated with antithyroid drugs, euthyroid and proposed for total thyroidectomy will be eligible for inclusion. Exclusion criteria will be prior thyroid or parathyroid surgery, hyperparathyroidism that requires associated parathyroidectomy, thyroid cancer that requires adding a lymph node dissection, iodine allergy, consumption of lithium or amiodarone, medically unfit patients (ASA-IV), breastfeeding women, preoperative vocal cord palsy and planned endoscopic, video-assisted or remote access surgery.Between January 2020 and January 2022, 270 patients will be randomized for either receiving or not preoperative preparation with LS. Researchers will be blinded to treatment assignment. The primary outcome will be the rate of postoperative complications: hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, surgical site infection or death. Secondary outcomes will be intraoperative events (Thyroidectomy Difficulty Scale score, blood loss, recurrent laryngeal nerve neuromonitoring signal loss), operative time, postoperative length of stay, hospital readmissions, permanent complications and adverse events associated to LS. CONCLUSIONS: There is no conclusive evidence supporting the benefits of preoperative treatment with LS in this setting. This trial aims to provide new insights into future Clinical Practice Guidelines recommendations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03980132.

Usefulness of the Wisconsin and CaPTHUS indices for predicting multiglandular disease in patients with primary hyperparathyroidism in a southern European population.

BACKGROUND: Focused parathyroidectomy is a safe technique for the treatment of primary hyperparathyroidism. The CaPTHUS score and the Wisconsin index are preoperative diagnostic tools designed to distinguish between single- and multigland disease. The aim of the study is to evaluate the usefulness of these models for predicting multiglandular disease in a European population. METHODS: Retrospective review of a database of patients operated upon for primary hyperparathyroidism at a referral center. The sensitivity, specificity, positive and negative predictive values, and reliability of both scores for the prediction of multiglandular disease, were calculated. Receiver operating characteristic (ROC) curves were constructed to assess the sensitivity and specificity of CaPTHUS score and Wisconsin Index for predicting single-gland disease. A level of P<0.05 was accepted as significant. RESULTS: Two hundred and eighty-one patients who underwent successful surgery from January 2001 to December 2018 were included. Single-gland disease was detected in 92.5%, and 73.7% had a CaPTHUS score of ≥3. The sensitivity, specificity, positive and negative predictive values of this model for predicting single-gland disease with a score of ≥3 were 76.9%, 66.7%, 96.6%, and 18.9% respectively. The area under the curve value of the CaPTHUS score for predicting single-gland disease was 0.74. A Wisconsin Index >2,000 and an excised gland weight above one gram presented a positive predictive value for single-gland disease of 92.5%. CONCLUSIONS: Despite the good performance of both scales, the established cut-off points did not definitively rule out parathyroid multiglandular disease in our population. In cases with a minimal suspicion of this condition, additional intraoperative techniques must be used, or bilateral neck explorations should be performed.

Development and validation of a new model for predicting hypocalcaemia after total thyroidectomy: the NuGra model.

BACKGROUND: Hypocalcaemia is the most frequent complication after total thyroidectomy. Finding a method for its early detection has become a priority. A single-center prospective cohort study was conducted to identify risk factors for postoperative hypocalcaemia, develop an early detection model, and test its validity in a different group of patients. METHODS: The sample was composed of patients who underwent a total thyroidectomy between May 2012 and September 2015. Demographic, clinical, laboratory, and surgical data were collected. The incidence of hypocalcaemia and permanent hypoparathyroidism was calculated. Bivariate and multivariate analysis identified several independent predictors of hypocalcaemia, which were used to design a predictive model. The validity of the model was subsequently tested in a different cohort. Area under the ROC curve (AUROC) was calculated to determine its predictive power. RESULTS: The study and validation groups included 352 and 118 patients, respectively. Seventy-three patients developed laboratory-confirmed hypocalcaemia (20.7%), and symptomatic in 43 (12.2%). Multivariate analysis confirmed as independent predictors of hypocalcaemia the higher number of parathyroid glands identified [OR 1.41(0.98, 2.02); p = 0.063] and pre-to-postoperative gradient of parathormone decline [OR 1.06(1.04, 1.08); p < 0.001]. Based on these variables, the NuGra (Number of parathyroid glands identified-Gradient of decline) model was developed for predicting laboratory-confirmed hypocalcaemia. Its predictive power was high (AUROC 0.902, CI 0.857-0.947) for the study and the validation group (AUROC 0.956, CI 0.919-0.993). CONCLUSIONS: A higher number of parathyroid glands identified and a higher gradient of parathormone decline are risk factors for post-thyroidectomy hypocalcaemia. The NuGra model is useful for early prediction of individual risk for hypocalcaemia.

Prophylaxis of venous thromboembolism in general surgery in Spain. Analysis of a national survey. / Profilaxis del tromboembolismo venoso en cirugía general en España. Análisis de una encuesta nacional.

INTRODUCTION: Venous thromboembolism (VTE) represents a serious postoperative complication that can be prevented by adequate thromboprophylaxis. Surveys provide relevant information about clinician's attitudes and preferences regarding VTE prophylaxis. METHODS: Transversal, descriptive study based on a survey sent to general surgeons members of the Spanish Association of Surgeons (AEC), that included 31 questions regarding postoperative VTE and its prevention, as well as three clinical scenarios. RESULTS: 530 surgeons, 21.8% of the 2,429 invited by electronic mail to participate, completed the survey. Most of the answering clinicians work on in big teaching hospitals, and 28.5% are residents. VTE represents a serious problem for 28% of participants. Although 81% consider that their knowledge on the prevention of postoperative VTE is adequate, a similar percentage recognizes the need for further education. The vast majority (98.7%) use low molecular weight heparins, which are considered the most effective and safe modality, followed by mechanical methods. The Caprini risk assessment score is used by 81% of surgeons, who usually start pharmacological prophylaxis preoperatively. However, there are remarkable differences in the dosing of heparins, timing of initiation, and duration, especially in non-oncologic surgical patients. CONCLUSIONS: Most Spanish surgeons are interested in the prevention of postoperative VTE. Overall, the level of knowledge on thromboprophylaxis is adequate. However, our results indicate that there is a need for better education on relevant practical aspects of prophylaxis that could be achieved by incorporating recommendations from recent guidelines to local hospital-based protocols.

Cholangiocarcinoma, 10-Year Survival After Liver Transplantation: A Case Report.

Cholangiocarcinoma is the second most common neoplasm in the liver, with a very poor, short-term prognosis. Today, surgery associated with or without an adjuvant is the only curative treatment. Liver transplantation (LT) is the best treatment for hepatocellular carcinoma tumor. In recent years, treatment of hilar cholangiocarcinoma by LT associated with neoadjuvant therapy has been studied under a criterion. But could it be possible to apply LT like the curative treatment of intrahepatic cholangiocarcinoma (iCC)? Initially the answer is no, but there are different studies about incidental LT in patients with iCC that demonstrate survival over 40% to 50%. In our center, we conducted a review of 468 transplants completed between 2002 and 2018, and we identified 1 case of incidental LT in a patient with iCC with an overall survival of 10 years. Because there is currently an increase in donors owing to the expansion of the criteria, a study to consider extending the criteria of LT to include iCC would be beneficial.

Compliance with recommendations on surgery for primary hyperparathyroidism-from guidelines to real practice: results from an Iberian survey.

PURPOSE: Knowledge about compliance with recommendations derived from the positional statement of the European Society of Endocrine Surgeons on modern techniques in primary hyperparathyroidism surgery and the Third International Workshop on management of asymptomatic primary hyperparathyroidism is scarce. Our purpose was to check it on a bi-national basis and determine whether management differences may have impact on surgical outcomes. METHODS: An online survey including questions about indications, preoperative workup, surgical approach, intraoperative adjuncts, and outcomes was sent to institutions affiliated to the endocrine surgery divisions of the National Surgical Societies from Spain and Portugal. A descriptive evaluation of the responses was performed. Finally, we assessed the correlation between the different types of management with the achievement of optimal results, defined as a cure rate equal or greater than the median of all interviewed institutions. RESULTS: Fifty-seven hospitals (41 Spanish, 16 Portuguese) answered the survey. First-ordered imaging tests were neck ultrasound and sestamibi scan. Facing negative or non-concordant results, 44 % of surgeons ordered additional tests before first-time surgery, and 84 % before reoperations. When indicated, selective parathyroidectomy was an acceptable option for 95 % of institutions as first-time surgery and for 51 % in reoperations. Intraoperative parathormone measurements were used by 92 % of departments. The surgical outcomes were good in most institutions (median cure rate 97 %) and were influenced mostly by the presence of an endocrine surgery unit in the surgical department (p = 0.038). CONCLUSIONS: Practice of Iberian endocrine surgeons is consistent with current recommendations on surgery for primary hyperparathyroidism, with variability in some areas.

Clinical Pathway for Thyroidectomy.

Clinical pathways are care plans applicable to patient care procedures that present variations in practice and a predictable clinical course. They are designed not as a substitute for clinical judgment, but rather as a means to improve the effectiveness and efficiency of the procedures. This clinical pathway is the result of a collaborative work of the Sections of Endocrine Surgery and Quality Management of the Spanish Association of Surgeons. It attempts to provide a framework for standardizing the performance of thyroidectomy, the most frequently performed operation in endocrine surgery. Along with the usual documents of clinical pathways (temporary matrix, variance tracking and information sheets, assessment indicators and a satisfaction questionnaire) it includes a review of the scientific evidence around different aspects of pre, intra and postoperative management. Among others, antibiotic and antithrombotic prophylaxis, preoperative preparation in hyperthyroidism, intraoperative neuromonitoring and systems for obtaining hemostasis are included, along with management of postoperative hypocalcemia.

Prognostic factors and staging systems in parathyroid cancer: a multicenter cohort study.

BACKGROUND: Parathyroid carcinoma (PC) is an uncommon disease that generally is detected postoperatively and traditionally is associated with a poor prognosis. Our purpose was to evaluate treatment outcomes, prognostic factors, and usefulness of some proposed staging systems for this disease. METHODS: A multicenter review of patients with surgically resected PC was performed, led by the Spanish Association of Surgery. All surgical units affiliated with its endocrine surgery section were invited to answer a questionnaire that collected several hospital-related, clinical, biochemical, operative, pathologic, and follow-up data. Their relationships with prognosis were assessed by both univariate and multivariate analysis, as well as the effectiveness of three staging systems for parathyroid carcinoma. RESULT: Of the 6,863 patients undergoing parathyroidectomy, 62 (0.9%) had PC. Of them, 12 (19.3%) died, in 5 cases (8%) because of disease, and 14 (22.6%) suffered recurrence, after a median follow-up of 55 months. The most predictive independent variables on tumor recurrence were intraoperative tumor rupture (hazard ratio [HR] 6.22; 95% confidence interval [CI] 1.19-32.36; P = .030); the presence of mitotic figures within tumor parenchyma cells (HR 4.76; 95% CI 1.24-18.21; P = .022); and allocation in class III according to Schulte differentiated staging classification (HR 5.23; 95% CI 1.41-19.31; P = .013). As to disease-specific survival, poor outcomes were associated with intraoperative tumor rupture (HR 58.71; 95% CI 2.39-1,439.96; P = .013) and distant recurrence (HR 38.74; 95% CI 3.44-435.62; P = .003). CONCLUSION: In addition to factors associated with tumor histopathology and stage, prognosis of PC is greatly influenced by surgeon's performance, which emphasizes the importance of preoperative diagnosis.

Adrenalectomy for solid tumor metastases: results of a multicenter European study.

BACKGROUND: We assessed the results of adrenalectomy for solid tumor metastases in 317 patients recruited from 30 European centers. METHODS: Patients with histologically proven adrenal metastatic disease and undergoing complete removal(s) of the affected gland(s) were eligible. RESULTS: Non-small cell lung cancer (NSCLC) was the most frequent tumor type followed by colorectal and renal cell carcinoma. Adrenal metastases were synchronous (≤6 months) in 73 (23%) patients and isolated in 213 (67%). The median disease-free interval was 18.5 months. Laparoscopic resection was used in 46% of patients. Surgery was limited to the adrenal gland in 73% of patients and R0 resection was achieved in 86% of cases. The median overall survival was 29 months (95% confidence interval, 24.69-33.30). The survival rates at 1, 2, 3, and 5 years were 80%, 61%, 42%, and 35%, respectively. Patients with renal cancer showed a median survival of 84 months, patients with NSCLC 26 months, and patients with colorectal cancer 29 months (P = .017). Differences in survival between metachronous and synchronous lesions were also significant (30 vs. 23 months; P = .038). CONCLUSION: Surgical removal of adrenal metastasis is associated with long-term survival in selected patients.

Reduction of false-negative papillary thyroid carcinomas by the routine analysis of BRAF(T1799A) mutation on fine-needle aspiration biopsy specimens: a prospective study of 814 thyroid FNAB patients.

OBJECTIVES: To evaluate prospectively the usefulness of the routine determination of BRAF(T1799A) mutation on thyroid fine-needle aspiration biopsy (FNAB) to detect cytopathology false negative papillary thyroid carcinomas (PTC) and, therefore, as a tool to improve the sensitivity of the preoperative cytopathological diagnosis of PTC in thyroid nodules. BACKGROUND: FNAB is the most reliable diagnostic test to discriminate between malignant and benign thyroid nodules, but nondiagnostic results remain a clinical management dilemma. BRAF(T1799A) mutation is the most prevalent genetic alteration in thyroid cancers and is specific for PTC, characteristics that make it the most potentially helpful genetic tool to improve the diagnostic accuracy of FNAB. METHODS: An exhaustive recruitment of all patients subjected to thyroid FNAB in our institution during 4 years was performed. BRAF(T1799A) mutation was determined on thyroid FNAB specimens by PCR and restriction fragment length polymorphism, plus direct sequencing in positive samples. RESULTS: BRAF(T1799A) mutation on FNAB detected 47.2% (17/36) of PTC cases. It confirmed preoperatively 45.5% (5/11) of the PTC cases in the indeterminate category and decreased the rate of cytopathology false-negatives in 33.3% (6/18), improving the combined (BRAF(T1799A) mutation + cytopathological analysis) sensitivity of the detection of PTC on FNAB in 16.7%. CONCLUSIONS: BRAF(T1799A) mutation improves the diagnosis of PTC on FNAB, mainly because of the detection of cytopathology false-negatives, and it can be helpful in the routine analysis of thyroid nodules, especially in clinical settings with moderate sensitivity to detect PTC on FNAB.

Outcome of operation in patients with adrenocortical cancer invading the inferior vena cava--a European Society of Endocrine Surgeons (ESES) survey.

BACKGROUND: Most patients with adrenocortical cancer (ACC) continue to present with advanced disease. Invasion into the inferior vena cava (IVC) defines stage III disease and the management of such patients raises additional difficulties. METHOD: A multicentre survey was organized by emailing a standardized proforma to members of the European Society of Endocrine Surgery (ESES). Anonymised retrospective clinical data were collected. RESULTS: Replies were received from 18 centres in nine countries. ACC with IVC invasion was encountered in 38 patients (18F:20M, age 15-84 years, median 54 years). There were 16 nonfunctioning tumours and 22 functioning tumours predominantly right-sided (26R:12L) and measuring 18-255 mm (median 115 mm). Fourteen patients had metastatic disease at presentation. Tumour thrombus extended in the prehepatic IVC (n = 21), subdiaphragmatic IVC (n = 6) or into the SVC/right atrium (n = 3). Open adrenalectomy was associated with resection of surrounding viscera in 24 patients (nephrectomy n = 16, liver resection n = 14, splenectomy n = 3, Whipple procedure n = 2). IVC was controlled locally (n = 27), at suprahepatic levels (n = 6) or necessitated cardiac bypass (n = 5). Complete resection (R0, n = 20) was achieved in the majority of patients, with a minority having microscopic persistent disease (R1, n = 7) or macroscopic residual disease (R2, n = 4). Perioperative 30-day mortality was 13% (n = 5). Postoperative Mitotane was used in 23 patients and chemotherapy in eight patients. Twenty-five patients died 2-61 months after their operation (median 5 months). Currently, 13 patients are alive at 2-58 months (median 16 months) with known metastatic disease (n = 7) or with no signs of distant disease (n = 6). CONCLUSION: This dataset is limited by the lack of a denominator as it remains unknown how many other patients with ACC presenting with IVC invasion did not undergo surgery. The relatively low perioperative mortality and the long disease-free survival achieved by some patients should encourage surgeons with adequate experience to offer surgical treatment to patients presenting with advanced adrenocortical cancers.

[Adrenal surgery in Spain: final results of a national survey]. / Cirugía suprarrenal en España: resultados finales de una encuesta nacional.

INTRODUCTION: The indications for adrenalectomy could be changing by the availability of laparoscopy and the growing detection of incidentalomas. The Endocrine Surgery Section of the Spanish Association of Surgeons conducted a survey to analyse the current indications for adrenalectomy and their results in Spanish surgical departments. MATERIAL AND METHODS: Data was gathered as regards the type of hospital and department, volume of procedures, localisation studies and pre-surgical preparations, indications, surgical approach, and results in terms of morbidity and hospital stay. The results of the centres were compared as regards their volume of activity using the Mann-Whitney Test for the quantitative variables and chi squared for the qualitative ones. RESULTS: Thirty-six centres completed the questionnaire and 301 adrenalectomies were reported to be performed in 2008. Most frequent indications were pheochromocytoma (25.2%), non-functioning adenoma (16.2%), aldosteronoma (15.9%), Cushing adenoma (11.2%), metastasis (10.3%), myelolipoma (5.6%), and carcinoma (4.9%). Laparoscopic adrenalectomy was performed in 83.7% of cases (6.7% required conversion to laparotomy). The mean hospital stay was 3.9 days for laparoscopic adrenalectomy and 7.4 days for laparotomy. High-volume units (more than 10 per year) used more frequently the laparoscopic approach (P=.019), and had a shorter overall hospital stay (P<.0001). Laparoscopic adrenalectomy was also associated with a shorter hospital stay (P<.0001). CONCLUSIONS: Laparoscopy for adrenalectomy has become the standard practice in Spain, with good results in terms of morbidity and hospital stay. High volume centres have better results as regards the use of minimally invasive surgery and hospital stay.

[BRAF(T1799A) mutation in the primary tumor as a marker of risk, recurrence, or persistence of papillary thyroid carcinoma]. / Presencia de la mutación BRAF(T1799A) en el tumor primario como indicador de riesgo, recidiva o persistencia de carcinoma papilar de tiroides.

BACKGROUND AND OBJECTIVE: The BRAF(T1799A) mutation is reported to be associated to aggressive, persistent, and recurrent tumor in papillary thyroid carcinoma (PTC) patients. Association of the BRAF(T1799A) mutation in the primary tumor with the clinicopathological characteristics of PTC patients was analyzed. PATIENTS, MATERIAL AND METHODS: Ninety-seven PTC patients were followed up for a median of 64.1 months. The BRAF(T1799A) mutation was analyzed in DNA from initial thyroidectomy biopsies by PCR amplification and restriction fragment length polymorphism using TspRI enzyme. Positive cases were confirmed by DNA sequencing. Statistical association between BRAF(T1799A) mutation and clinicopathological characteristics was analyzed by the relevant hypothesis tests and logistic regression. RESULTS: 46.4% of patients were positive for the BRAF(T1799A) mutation. Bivariate and multivariate analysis showed the BRAF(T1799A) mutation to be only associated to age over 60years (odds ratio [OR] = 5.5; 95% confidence interval [CI],1.4-21.9; p=0.019) and to tumor size of 1cm or greater (OR=3.6, 95% CI, 1.2-10.3; p=0.016). The BRAF(T1799A) mutation was not associated to histological subtype, metastasis, recurrence, more aggressive treatments (ablative I(131) therapy or surgery), or PTC persistence at the end of follow-up. CONCLUSIONS: The BRAFT1799A mutation is associated to age over 60 and a tumor size of 1cm or greater, but not to other clinicopathological characteristics, tumor recurrence or PTC persistence.