Outcomes of a multidisciplinary Diabetic Foot Day Unit.

OBJECTIVE: To analyse the main characteristics of patients and the health outcomes obtained and to evaluate the impact of peripheral artery disease (PAD) in patients treated in our multidisciplinary Diabetic Foot Unit. RESEARCH DESIGN AND METHODS: Observational prospective study. 273 patients from two different populations (with and without PAD - classified according to the presence of distal pulses) treated over a 14-month period in the multidisciplinary Diabetic Foot Unit were included. The data on patient characteristics and outcomes were analysed for the purpose of comparison. For the inference study, a comparison of medians with the non-parametric test for independent samples for the quantitative variables and a χ2 test for the comparison of proportions in qualitative variables were performed. RESULTS: Patients with PAD ulcers were older (60 (54-67) vs. 64 (75-81), p=0.000) and had a higher macrovascular burden (8.1% vs. 29% for ischaemic heart disease history, p=0.000; 6.7% vs. 18.1% for cerebrovascular disease history, p=0.004). Their Texas Score was higher (p=0.000) and their major amputation rate was higher (1.4% vs. 12.3%, p=0.001). They had less background of previous ulcers (52.6% vs. 26.8%, p=0.000), their episode duration was shorter (4 (0-10) vs. 0 (0-3) weeks, p=0.000), and their proportional need for antibiotic therapy was lower (64.4% vs. 51.4%, p=0.03). CONCLUSIONS: The differences found between ulcers with and without vascular involvement support the need for a different approach and for the inclusion of vascular surgeons on the team. The multidisciplinary care model for diabetic foot patients could be effective and improve health outcomes.

Telemedicine screening program for diabetic retinopathy in patients with type 1 diabetes mellitus.

PURPOSE: To analyze the results of the telemedicine screening program for diabetic retinopathy (DR) in patients with type 1 diabetes conducted by the Endocrinology and Nutrition Management Unit of Virgen del Rocío University Hospital. METHODS: This cross-sectional study comprised patients with type 1 diabetes mellitus (DM) in our DR screening program from January 2018 to November 2020. Fundus photographs are performed by trained nurses and reviewed by a trained endocrinologist. Those suggestive of pathology are sent to ophthalmology through a telematic program for review. RESULTS: Of the 995 fundus photographs evaluated, 646 (65.3%) showed no evidence of DR, 327 (33.1%) presented possible DR, and 16 (1.6%) were not gradable. The diagnosis was confirmed in 254 patients after reviewing by ophthalmology, and the screening program achieved a positive predictive value for DR of 77.7%. Seventy-three were excluded by ophthalmology due to the absence of DR (false positive rate - 22.3%). In 92.5% of the cases classified by the ophthalmologist, the degree of DR was mild or very mild. CONCLUSION: Our telemedicine screening program for DR in patients with type 1 DM is consistent with the literature. Effective screening for DR is performed, with patients diagnosed in the early stages. Telemedicine programs facilitate efficient communication among healthcare personnel.

Maternal-fetal outcomes of pregnancies in women treated at an inborn errors of metabolism unit.

INTRODUCTION: Intermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-fetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. METHODS: Retrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50 (P25-P75). RESULTS: 24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother's disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31 + 5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. CONCLUSIONS: Pregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and fetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.

Effectiveness and Safety of an Advanced Hybrid Closed-Loop System in Adolescents and Adults with Type 1 Diabetes Previously Treated with Continuous Subcutaneous Insulin Infusion and Flash Glucose Monitoring.

This study aimed to evaluate the effectiveness and safety of the MiniMed™ 780G advanced hybrid closed-loop (AHCL) system in people with type 1 diabetes (T1D) previously treated with continuous subcutaneous insulin infusion combined with flash glucose monitoring in a real-life setting. A total of 47 subjects (mean age 41 ± 13.6 years, 60% females, diabetes duration 28 ± 11 years) were included and switched to an AHCL system. Baseline and 6-month data were analyzed. Time in range 70-180 mg/dL increased from 65.3% at baseline to 73.8% at 6 months. Time in hyperglycemia >180 mg/dL decreased from 26.6% to 19.3%. Time in hypoglycemia <70 mg/dL decreased from 4.6% to 2.3%. The coefficient of variation also decreased from 36% to 31.6%. No episodes of severe hypoglycemia, diabetes ketoacidosis, or diabetes-related hospital admissions occurred. In conclusion, the MiniMed 780G AHCL system enables the safe achievement of recommended glycemic targets in people with T1D after 6 months of use.

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice.

Objectives: The aim of this study is to investigate in depth diabetes mellitus associated with immune checkpoint inhibitors (DM-ICIs) by analysing a case series. We also evaluated the clinical impact of flash glucose monitoring (FGM) systems in the management of this entity. Methods: We conducted an observational cohort study of DM-ICIs diagnosed in two hospitals in Seville (Spain). Patients with a new diagnosis of diabetes mellitus (DM) or with sudden worsening of preexisting DM after starting treatment with ICIs, with a random 5 hour-postprandial C-peptide value of <0.6 nmol/L and without possibility of subsequent withdrawal of insulin treatment, were included. Results: A total of 7 cases were identified, mostly males (n = 6; 85.7%), with a mean age of 64.9 years. The mean glycated hemoglobin (HbA1c) upon diagnosis was 8.1%, with diabetic ketoacidosis (DKA) observed in 6 cases (85.7%). Subcutaneous flash glucose monitoring (FGM) systems were used in six cases, with a mean follow-up period of 42.7 weeks. During the first 90 days of use, mean average glucose was 167.5 mg/dL, with a coefficient of variation (CV) of 34.6%. The mean time in the range 70-180 mg/dL (TIR) was 59.7%, with a mean time above range (TAR) 181-250 mg/dL of 27.8% and a mean TAR > 250 mg/dL of 10.2%. The mean time below range (TBR) 54-69 mg/dL was 2%, while the mean TBR < 54 mg/dL was 0.3%. The mean glucose management indicator (GMI) was 7.3%. No significant differences were observed in FGM values for the following 90 days of follow-up. A progressive improvement in all parameters of glycaemic control was observed between the first month of FGM use and the sixth month of FGM use. Of note, there was a decrease in mean CV (40.6% to 34.1%, p = 0.25), mean TAR 181-250 (30.3% to 26%, p = 0.49), mean TAR > 250 mg/dL (16.3% to 7.7%, p = 0.09), mean TBR 54-69 mg/dL (5.2% to 2%, p = 0.16), and mean TBR < 54 mg/dL (1.8% to 0.2%, p = 0.31), along with an increase in mean values of TIR 70-180 mg/dL (46.5% to 60.5%, p = 0.09). The lack of statistical significance in the differences observed in the mean FGM values over the follow-up period may be related to the small sample size. Conclusion: DM-ICI is recognised by a state of sudden-onset insulinopenia, often associated with DKA. The use of FGM systems may be a valid option for the effective management of DM-ICIs and for the prevention of severe hyperglycaemic and hypoglycaemic episodes in this condition.

Postoperative water and electrolyte disturbances after extended endoscopic endonasal transsphenoidal surgery.

Introduction: Water and electrolyte disturbances are common after pituitary surgery and can generally be classified into transient hypotonic polyuria and transient or permanent diabetes insipidus (DI). The prevalence varies in the literature between 31-51% for transient hypotonic polyuria, 5.1-25.2% for transient DI, and 1-8.8% for permanent DI. Objective: The aim of this study was to identify the prevalence of water and electrolyte disturbances with polyuria and the preoperative and postoperative predictive factors in patients undergoing surgery with an extended endoscopic endonasal approach. Material and methods: This retrospective observational descriptive study included 203 patients with a diagnosis of pituitary adenoma who underwent their first transsphenoidal surgery via the extended endoscopic endonasal approach between April 2013 and February 2020. The diagnosis of water and electrolyte disturbances was based on the criterion for polyuria (>4 ml/kg/h). Postoperative polyuria was defined as those cases diagnosed during the immediate postsurgical period that resolved prior to discharge. Transient DI included all cases with a duration of less than 6 months but still present at hospital discharge, and permanent DI included cases lasting more than 6 months. Results: The overall prevalence of water and electrolyte disorders was 30.5% (62), and the prevalence of postoperative polyuria was 23.6% (48). The median number of desmopressin doses administered to patients with postoperative polyuria was one dose (interquartile range [IQR] 1-2), and thus the median duration of treatment was 0 days. The median initiation of desmopressin was the second day after surgery (IQR 1-2). The overall prevalence of DI was 6.89%. Among the patients with transient DI, the duration was less than 3 months in three patients (1.47%), and between 3 and 6 months in two (0.98%). Nine patients had permanent DI (4.43%). (4.43%). Conclusions: The prevalence of electrolyte disturbances in our study was high, although similar to that found in the literature. Most of the cases were transient hypotonic polyuria that resolved within one day. The prevalence of transient DI in our cohort was lower than that described in the literature, while permanent DI was similar.

Prevalence of non-alcoholic fatty liver disease (NAFLD) in a cohort of patients with type 2 diabetes: the PHIGNA-DM2 study.

Introduction: Background: type 2 diabetes (T2D) is a risk factor for nonalcoholic fatty liver disease (NAFLD). Objective: to evaluate the prevalence of NAFLD in a cohort of patients with T2D. Methods: an observational, descriptive study performed between May 2018 and December 2019 at the Endocrinology and Nutrition Unit. The χ² test was performed for qualitative variables and a non-parametric test for the comparison of medians of quantitative variables. Steatosis degree was defined by the coefficient attenuated parameter (CAP): (S0: < 248 dB/m; S1: 248-268 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) or stiffness: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, using transient elastography (TE) (FibroScan®). A univariate analysis was performed and subsequently a multivariate analysis with statistically significant variables used to study the predictive factors of intense steatosis and advanced fibrosis. Results: n = 104 patients with T2D; 84 (80.7 %) were obese. TE demonstrated advanced fibrosis in 20 % and intense steatosis (S3) in more than 50 %. Lower total bilirubin (OR: 0.028; 95 % CI: (0.002-0.337); p = 0.005) was found to be an independent factor for S3 steatosis in the multivariate analysis. BMI ((OR: 1.497; 95 % CI: (1.102-2.034); p = 0.01)) was a predictive factor for advanced fibrosis in a multivariate analysis. Conclusions: NAFLD-associated intense steatosis and NAFLD-associated fibrosis were commonly found in patients with T2DM and obesity. Diabetic patients should be screened for liver disease as one more target organ.

Introducción: Antecedentes: la diabetes de tipo 2 (DM2) es un factor de riesgo para la enfermedad del hígado graso no alcohólico (EHGNA). Objetivo: evaluar la prevalencia de la EHGNA en una cohorte de pacientes con DM2. Métodos: estudio descriptivo observacional realizado entre mayo de 2018 y diciembre de 2019 en la Unidad de Endocrinología y Nutrición. Se realizó una prueba de χ² para las variables cualitativas y una prueba no paramétrica para la comparación de medianas de variables cuantitativas. El grado de esteatosis se definió mediante el parámetro coeficiente atenuado (CAP): (S0: < 248 dB/m; S1: 248-288 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) o rigidez: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, usando la elastografía transitoria (TE) (FibroScan®). Se realizó un análisis univariante y posteriormente un análisis multivariante con las variables estadísticamente significativas para estudiar los factores predictivos de esteatosis intensa y fibrosis avanzada. Resultados: n = 104 pacientes con DM2; 84 (80,7 %) eran obesos. La TE demostró fibrosis avanzada en el 20 % y esteatosis intensa (S3) en más del 50 %. Los niveles disminuidos de bilirrubina total (OR: 0.028; 95 % CI: (0.002-0.337); p = 0.005) se encontraron como factores independientes para la esteatosis S3 en el analisis multivariable. El IMC (OR: 1.497; 95 % CI: (1.102-2.034); p = 0.01) fue un factor predictivo de fibrosis avanzada. Conclusiones: la esteatosis intensa asociada a EHGNA y la fibrosis asociada a EHGNA se encontraron comúnmente en pacientes con DM2 y obesidad. Los pacientes diabéticos deben someterse a pruebas de detección de enfermedad hepática como un órgano diana más.

Prevalence of non-alcoholic fatty liver disease (NAFLD) in a cohort of patients with type 2 diabetes: the PHIGNA-DM2 study / Prevalencia de la hepatopatía grasa no alcohólica (HGNA) en una cohorte de pacientes con diabetes de tipo 2: el estudio PHIGNA-DM2

Background: type 2 diabetes (T2D) is a risk factor for nonalcoholic fatty liver disease (NAFLD). Objective: to evaluate the prevalence of NAFLD in a cohort of patients with T2D. Methods: an observational, descriptive study performed between May 2018 and December 2019 at the Endocrinology and Nutrition Unit. The χ² test was performed for qualitative variables and a non-parametric test for the comparison of medians of quantitative variables. Steatosis degree was defined by the coefficient attenuated parameter (CAP): (S0: < 248 dB/m; S1: 248-268 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) or stiffness: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, using transient elastography (TE) (FibroScan®). A univariate analysis was performed and subsequently a multivariate analysis with statistically significant variables used to study the predictive factors of intense steatosis and advanced fibrosis. Results: n = 104 patients with T2D; 84 (80.7 %) were obese. TE demonstrated advanced fibrosis in 20 % and intense steatosis (S3) in more than 50 %. Lower total bilirubin (OR: 0.028; 95 % CI: [0.002-0.337]; p = 0.005) was found to be an independent factor for S3 steatosis in the multivariate analysis. BMI (OR: 1.497; 95 % CI: [1.102-2.034]; p = 0.01) was a predictive factor for advanced fibrosis in a multivariate analysis. Conclusions: NAFLD-associated intense steatosis and NAFLD-associated fibrosis were commonly found in patients with T2DM and obesity. Diabetic patients should be screened for liver disease as one more target organ. (AU)

Antecedentes: la diabetes de tipo 2 (DM2) es un factor de riesgo para la enfermedad del hígado graso no alcohólico (EHGNA). Objetivo: evaluar la prevalencia de la EHGNA en una cohorte de pacientes con DM2. Métodos: estudio descriptivo observacional realizado entre mayo de 2018 y diciembre de 2019 en la Unidad de Endocrinología y Nutrición. Se realizó una prueba de χ² para las variables cualitativas y una prueba no paramétrica para la comparación de medianas de variables cuantitativas. El grado de esteatosis se definió mediante el parámetro coeficiente atenuado (CAP): (S0: < 248 dB/m; S1: 248-288 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) o rigidez: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, usando la elastografía transitoria (TE) (FibroScan®). Se realizó un análisis univariante y posteriormente un análisis multivariante con las variables estadísticamente significativas para estudiar los factores predictivos de esteatosis intensa y fibrosis avanzada. Resultados: n = 104 pacientes con DM2; 84 (80,7 %) eran obesos. La TE demostró fibrosis avanzada en el 20 % y esteatosis intensa (S3) en más del 50 %. Los niveles disminuidos de bilirrubina total (OR: 0.028; 95 % CI: (0.002-0.337); p = 0.005) se encontraron como factores independientes para la esteatosis S3 en el analisis multivariable. El IMC (OR: 1.497; 95 % CI: (1.102-2.034); p = 0.01) fue un factor predictivo de fibrosis avanzada. Conclusiones: la esteatosis intensa asociada a EHGNA y la fibrosis asociada a EHGNA se encontraron comúnmente en pacientes con DM2 y obesidad. Los pacientes diabéticos deben someterse a pruebas de detección de enfermedad hepática como un órgano diana más. (AU)

The Quadrangular Space, Endonasal Access to the Meckel Cave: Technical Considerations and Clinical Series.

OBJECTIVE: An anteromedial corridor via an expanded endoscopic endonasal approach to the Meckel cave (MC) was described more than a decade ago. However, few clinical series or endoscopic endonasal technical contributions exist concerning this type of approach to this complex region. METHODS: We present a detailed description of the surgical technique for this approach reviewing the original technique and adding clarifying conceptual notions. We conducted a multicenter retrospective study selecting patients who underwent endonasal endoscopic surgery for lesions exclusively limited to the MC in the past 6 years. Intraoperative and postoperative complications were analyzed. The study of 10 cadaveric specimens provides additional information. RESULTS: We performed a fully endoscopic anteromedial corridor to the MC in 18 patients. The most prevalent pathologic finding was schwannoma of the V nerve in 4 patients. Sixth cranial nerve palsy (13 patients) and trigeminal dysfunction (10 patients) were the predominant preoperative clinical signs. There were no remarkable intraoperative complications. Corneal keratopathy caused by dry eye syndrome affected 3 patients and V2 residual neuralgia appeared postoperatively in 2 patients. Six patients recovered from sixth cranial nerve palsy, and 2 showed improvement in preoperatively referred facial pain. CONCLUSIONS: The front door to the MC via the endonasal anteromedial corridor could be a good option. Understanding of the anatomy and the concept of the quadrangular space is crucial to performing this technique safely, which has few complications in experienced hands. Recovery from sixth nerve palsy is possible with this approach. Corneal keratopathy in these patients is a potential complication.

Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease.

CONTEXT: Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. OBJECTIVES: This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. METHODS: A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. RESULTS: Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). CONCLUSION: This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.

Cardiometabolic and Nutritional Morbidities of a Large, Adult, PKU Cohort from Andalusia.

The establishment of national neonatal screening systems has resulted in improved quality of life and life expectancy in patients with phenylketonuria (PKU). This has led to the development of multidisciplinary treatment units for adult patients with PKU. We present a retrospective descriptive study of a cohort of 90 adult patients (>16 years) with PKU under active follow-up in two reference centers in Andalusia. We analyzed disease severity, treatment type, demographic variables, cardiovascular risk factors, vitamin and hormone profiles, and bone metabolism. The median (interquartile range)age was 29 (23−38) years, 47 (52.2%) were women and 43 (47.8%) were men. Eighty (88.9%) had classical PKU, five (5.6%) moderate PKU, and five (5.6%) mild PKU. Diagnosis was by neonatal screening in 62 (68.9%) of the patients. The rest had late diagnosis. Treatment with sapropterin was given to 18 (20%) patients and diet and nutrition therapy to 72 (80%). There was adequate metabolic control according to Phe levels in 43 (47.78%) patients. Body mass index was 26.61 (22.7−31.1) kg/m2. Twenty-six (29.2%) patients had obesity, 7 (7.9%) hypertension, 2 (2.2%) type 2 diabetes, 26 (28.89%) dyslipidemia, 14 (15.6%) elevated total cholesterol, 9 (15.8%) decreased high-density lipoprotein cholesterol and 16 (17.8%) hypertriglyceridemia. Seven (10.3%) patients had osteoporosis and 28 (41.17%) osteopenia. Twenty-six (30.6%) had vitamin D (25OH) deficiency and four (4.5%) vitamin B12 deficiency. Although we observed no differences with most vascular risk factors, we found a high prevalence of obesity in relation to the age of the cohort. A continued evaluation of comorbidities in these patients is therefore needed, despite adequate metabolic control.

Description of a Cohort of Type 1 Diabetes Patients: Analysis of Comorbidities, Prevalence of Complications and Risk of Hypoglycemia.

BACKGROUND: Despite major medical advances, Type 1 Diabetes (T1D) patients still have greater morbimortality than the general population. Our aim was to describe our cohort of T1D patients and identify potential risk factors susceptible to prevention strategies. METHODS: Cross-sectional, observational study, including T1D patients treated at our center, from 1 March 2017 to 31 March 2020. INCLUSION CRITERIA: T1D, age > 14 years and signed informed consent. EXCLUSION CRITERIA: diabetes other than T1D, age < 14 years and/or refusal to participate. RESULTS: Study population n = 2181 (49.8% females, median age at enrollment 41 years, median HbA1c 7.7%; 38.24% had at least one comorbidity). Roughly 7.45% had severe hypoglycemia (SH) within the prior year. Macro/microvascular complications were present in 42.09% (5.83% and 41.14%, respectively). The most frequent microvascular complication was diabetic retinopathy (38.02%), and coronary disease (3.21%) was the most frequent macrovascular complication. The risk of complications was higher in males than in females, mainly macrovascular. Patients with SH had a higher risk of complications (OR 1.42; 1.43 in males versus 1.42 in females). CONCLUSIONS: Our T1D population is similar to other T1D populations. We should minimize the risk of SH, and male patients should perhaps be treated more aggressively regarding cardiovascular risk factors.

Sex Hormone Receptor Expression in Craniopharyngiomas and Association with Tumor Aggressiveness Characteristics.

Craniopharyngiomas (CPs) are rare tumors of the sellar and suprasellar regions of embryonic origin. The primary treatment for CPs is surgery but it is often unsuccessful. Although CPs are considered benign tumors, they display a relatively high recurrence rate that might compromise quality of life. Previous studies have reported that CPs express sex hormone receptors, including estrogen and progesterone receptors. Here, we systematically analyzed estrogen receptor α (ERα) and progesterone receptor (PR) expression by immunohistochemistry in a well-characterized series of patients with CP (n = 41) and analyzed their potential association with tumor aggressiveness features. A substantial proportion of CPs displayed a marked expression of PR. However, most CPs expressed low levels of ERα. No major association between PR and ERα expression and clinical aggressiveness features was observed in CPs. Additionally, in our series, ß-catenin accumulation was not related to tumor recurrence.