Metastases affecting cranial nervous structures in male breast cancer: Two cases report.

INTRODUCTION: Breast cancer in males is a very rare entity, and survival is mainly influenced by the stage at diagnosis. The lack of early detection tools in men results in a diagnostic delay of about 5-10 years and a higher percentage of metastatic disease at diagnosis. However, the characteristics of head metastases are not well defined. CASE REPORTS: We present two cases of male breast cancer with metastases affecting cranial nervous structures and we provide imaging and histologic data. Both were middle-aged patients with ductal-type, HER-2 negative and androgen receptor positive primary tumors. DISCUSSION: Although central nervous system involvement is uncommon, this entity should be considered in middle-aged males with focal neurologic symptoms. More cases would be necessary to better understand the biology of this condition in order to establish an adequate diagnosis and treatment.

Differences in the clinical and hormonal presentation of patients with familial and sporadic primary aldosteronism.

Purpose: To compare the clinical and hormonal characteristics of patients with familial hyperaldosteronism (FH) and sporadic primary aldosteronism (PA). Methods: A systematic review of the literature was performed for the identification of FH patients. The SPAIN-ALDO registry cohort of patients with no suspicion of FH was chosen as the comparator group (sporadic group). Results: A total of 360 FH (246 FH type I, 73 type II, 29 type III, and 12 type IV) cases and 830 sporadic PA patients were included. Patients with FH-I were younger than sporadic cases, and women were more commonly affected (P = 0.003). In addition, the plasma aldosterone concentration (PAC) was lower, plasma renin activity (PRA) higher, and hypokalemia (P < 0.001) less frequent than in sporadic cases. Except for a younger age (P < 0.001) and higher diastolic blood pressure (P = 0.006), the clinical and hormonal profiles of FH-II and sporadic cases were similar. FH-III had a distinct phenotype, with higher PAC and higher frequency of hypokalemia (P < 0.001), and presented 45 years before sporadic cases. Nevertheless, the clinical and hormonal phenotypes of FH-IV and sporadic cases were similar, with the former being younger and having lower serum potassium levels. Conclusion: In addition to being younger and having a family history of PA, FH-I and III share other typical characteristics. In this regard, FH-I is characterized by a low prevalence of hypokalemia and FH-III by a severe aldosterone excess causing hypokalemia in more than 85% of patients. The clinical and hormonal phenotype of type II and IV is similar to the sporadic cases.

Renin as a Biomarker to Guide Medical Treatment in Primary Aldosteronism Patients. Findings from the SPAIN-ALDO Registry.

INTRODUCTION: Primary aldosteronism (PA) is associated with several cardiometabolic comorbidities. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy has been reported to reduce the cardiometabolic risk. However, the cardiovascular benefit could depend on plasma renin levels in patients on MRA. AIM: To compare the development of cardiovascular, renal and metabolic complications between medically treated patients with PA and those who underwent adrenalectomy, taking the renin status during MRA treatment into account. METHODS: A multicenter retrospective study (SPAIN-ALDO Register) of patients with PA treated at 35 Spanish tertiary hospitals. Patients on MRA were divided into two groups based on renin suppression (n = 90) or non-suppression (n = 70). Both groups were also compared to unilateral PA patients (n = 275) who achieved biochemical cure with adrenalectomy. RESULTS: Adrenalectomized patients were younger, had higher plasma aldosterone concentration, and lower potassium levels than MRA group. Patients on MRA had similar baseline characteristics when stratified into treatment groups with suppressed and unsuppressed renin. 97 (55.1%) of 176 patients without comorbidities at diagnosis, developed at least one comorbidity during follow-up (median 12 months vs. 12.5 months' follow-up after starting MRA and surgery, respectively). Surgery group had a lower risk of developing new cardiovascular events (HR 0.40 [95% CI 0.18-0.90]) than MRA group. Surgical treatment improved glycemic and blood pressure control, increased serum potassium levels, and required fewer antihypertensive drugs than medical treatment. However, there were no differences in the cardiometabolic profile or the incidence of new comorbidities between the groups with suppressed and unsuppressed renin levels (HR 0.95 [95% CI 0.52-1.73]). CONCLUSION: Cardiovascular, renal, and metabolic events were comparable in MRA patients with unsuppressed and suppressed renin. Effective surgical treatment of PA was associated with a decreased incidence of new cardiovascular events when compared to MRA therapy.

Risk factors for intraoperative hypertensive crisis in patients with pheochromocytomas and sympathetic paragangliomas.

PURPOSE: To identify presurgical and surgical risk factors for intraoperative hypertensive crisis in patients with pheochromocytomas and sympathetic paragangliomas (PGLs) (PPGLs). METHODS: Retrospective multicenter cohort study of patients with PPGLs from 18 tertiary hospitals. Intraoperative hypertensive crisis was defined as systolic blood pressure (SBP) greater than 200 mmHg lasting more than 1 min and postoperative hypertensive crisis as SBP greater than 180 mmHg or diastolic blood pressure (DBP) greater than 110 mmHg. RESULTS: A total of 296 surgeries were included. Alpha presurgical blockade was employed in 93.2% of the cases and beta-adrenergic in 53.4%. Hypertensive crisis occurred in 20.3% ( n  = 60) of the surgeries: intraoperative crisis in 56 and postoperative crisis in 6 cases (2 cases had both types of crises). We identified as risk factors of intraoperative hypertensive crisis, absence of presurgical glucocorticoid therapy (odds ratio [OR] 3.48; 95% confidence interval [CI] 1.19-10.12) higher presurgical SBP (OR 1.22 per each 10 mmHg, 95% CI 1.03-1.45), a larger tumor size (OR 1.09 per each 10 mm, 95% CI 1.00-1.19) and absence of oral sodium repletion (OR 2.59, 95% CI 1.25-5.35). Patients with hypertensive crisis had a higher rate of intraoperative bleeding ( P  < 0.001), of intraoperative hemodynamic instability ( P  < 0.001) and of intraoperative hypotensive episodes ( P  < 0.001) than those without hypertensive crisis. CONCLUSION: Intraoperative hypertensive crisis occurs in up to 20% of the PPGL resections. Patients not pretreated with glucocorticoid therapy before surgery, with larger tumors and higher presurgical SBP and who do not receive oral sodium repletion have a higher risk for developing hypertensive crisis during and after PPGL surgery.

Local recurrence and metastatic disease in pheochromocytomas and sympathetic paragangliomas.

Purpose: To evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence (local recurrence and/or metastatic disease). Methods: This retrospective multicenter study included information of 303 patients with PPGLs in follow-up in 19 Spanish tertiary hospitals. Recurrent disease was defined by the development of local recurrence and/or metastatic disease after initial complete surgical resection. Results: A total of 303 patients with PPGLs that underwent 311 resections were included (288 pheochromocytomas and 15 sympathetic PGLs). After a median follow-up of 4.8 years (range 1-19), 24 patients (7.9%) had recurrent disease (3 local recurrence, 17 metastatic disease and 4 local recurrence followed by metastatic disease). The median time from the diagnosis of the PPGL to the recurrence was of 11.2 months (range 0.5-174) and recurrent disease cases distributed uniformly during the follow-up period. The presence of a pathogenic variant in SDHB gene (hazard ratio [HR] 13.3, 95% CI 4.20-41.92), higher urinary normetanephrine levels (HR 1.02 per each increase in standard deviation, 95% CI 1.01-1.03) and a larger tumor size (HR 1.01 per each increase in mm, 95% CI 1.00-1.02) were independently associated with disease recurrence. Conclusion: The recurrence of PPGLs occurred more frequently in patients with SDHB mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease.

Is adrenal venous sampling always necessary to differentiate between unilateral and bilateral primary aldosteronism? Lesson from the SPAIN-ALDO register.

PURPOSE: To evaluate whether the clinical, biochemical and radiological features of patients with primary aldosteronism (PA) can predict both main subtypes of PA. METHODS: A retrospective multicenter study of PA patients followed in 27 Spanish tertiary hospitals (SPAIN-ALDO Register). Only patients with confirmed unilateral or bilateral PA based on adrenal venous sampling (AVS) and/or postsurgical biochemical cure after adrenalectomy were included. Supervised regression techniques were used for model development. RESULTS: 328 patients [270 unilateral PA (UPA), 58 bilateral PA (BPA)] were included. The area under the curve (AUC) for aldosterone/potassium ratio and aldosterone responses following saline infusion test were 0.602 [95%CI 0.520 to 0.684] and 0.574 [95% CI 0.446-0.701], respectively, to differentiate UPA from BPA. The AUC was 0.825 [95% 0.764-0.886] when the prediction model with seven parameters - comorbidities (dyslipidemia, cerebrovascular disease, sleep apnea syndrome [SAS]), systolic blood pressure (SBP), plasma aldosterone levels (PAC), hypokalemia and unilateral adrenal nodule >1 cm and normal contralateral adrenal gland on CT/MRI - was used. In patients without comorbidities, hypokalemia, SBP > 160 mmHg, PAC > 40 ng/dL, and unilateral adrenal lesions were associated with a likelihood of having a UPA of 98.5%. The chance of BPA was higher in individuals with comorbidities, SBP < 140 mmHg, normokalemia, low PAC levels, and no adrenal tumors on the CT/MRI (91.5%). CONCLUSION: A combination of high PAC, SBP > 160 mmHg, low serum potassium, a unilateral adrenal nodule>1 cm and no comorbidities could predict a UPA with a 98.5% accuracy.

Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes.

Purpose: The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes. Methods: This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 µg/dL (confirmed ACS if >5 µg/dL and possible ACS if 1.8-5 µg/dL) in the absence of specific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels. Results: The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS-PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS-PA and PA-only patients was similar, except for older age and larger tumor size of the adrenal lesion in the ACS-PA group. When comparing the ACS-PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64-22.32)) and cardiovascular events (OR 5.0 (2.29-11.07)) was higher in ACS-PA patients than in ACS patients. The coexistence of ACS in patients with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS-PA and PA-only groups. Conclusion: Co-secretion of cortisol and aldosterone affects almost one-third of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS-PA and PA-only are similar.

An Integrated CT and MRI Imaging Model to Differentiate between Adrenal Adenomas and Pheochromocytomas.

PURPOSE: to perform an external validation of our predictive model to rule out pheochromocytoma (PHEO) based on unenhanced CT in a cohort of patients with PHEOs and adenomas who underwent adrenalectomy. METHODS: The predictive model was previously developed in a retrospective cohort of 1131 patients presenting with adrenal lesions. In the present study, we performed an external validation of the model in another cohort of 214 patients with available histopathological results. RESULTS: For the external validation, 115 patients with PHEOs and 99 with adenomas were included. Our previously described predictive model combining the variables of high lipid content and tumor size in unenhanced CT (AUC-ROC: 0.961) had a lower diagnostic accuracy in our current study population for the prediction of PHEO (AUC: 0.750). However, when we excluded atypical adenomas (with Hounsfield units (HU) > 10, n = 39), the diagnostic accuracy increased to 87.4%. In addition, in the whole cohort (including atypical adenomas), when MRI information was included in the model, the diagnostic accuracy increased to up to 85% when the variables tumor size, high lipid content in an unenhanced CT scan, and hyperintensity in the T2 sequence in MRI were included. The probability of PHEO was <0.3% for adrenal lesions <20 mm with >10 HU and without hyperintensity in T2. CONCLUSION: Our study confirms that our predictive model combining tumor size and lipid content has high reliability for the prediction of PHEO when atypical adrenal lesions are excluded. However, for atypical adrenal lesions with >10 HU in an unenhanced CT scan, MRI information is necessary for a proper exclusion of the PHEO diagnosis.

Diagnostic Accuracy of Adrenal Iodine-131 6-Beta-Iodomethyl-19-Norcholesterol Scintigraphy for the Subtyping of Primary Aldosteronism.

PURPOSE: To evaluate the diagnostic accuracy of the 131I-6ß-iodomethyl-19-norcholesterol (NP-59) adrenal scintigraphy for the subtyping diagnosis of primary aldosteronism (PA), considering as gold standard for the diagnosis of unilateral PA (UPA), either the results of the adrenal venous sampling (AVS) or the outcome after adrenalectomy. METHODS: A retrospective multicenter study was performed on PA patients from 14 Spanish tertiary hospitals who underwent NP-59 scintigraphy with an available subtyping diagnosis. Patients were classified as UPA if biochemical cure was achieved after adrenalectomy or/and if an AVS lateralization index > 4 with ACTH stimulation or >2 without ACTH stimulation was observed. Patients were classified as having bilateral PA (BPA) if the AVS lateralization index was ≤4 with ACTH or ≤2 without ACTH stimulation or if there was evidence of bilateral adrenal nodules >1 cm in each adrenal gland detected by CT/MRI. RESULTS: A total of 86 patients with PA were included (70.9% (n = 61) with UPA and 29.1% (n = 25) with BPA). Based on the NP-59 scintigraphy results, 16 patients showed normal suppressed adrenal gland uptake, and in the other 70 cases, PA was considered unilateral in 49 patients (70%) and bilateral in 21 (30%). Based on 59-scintigraphy results, 10.4% of the patients with unilateral uptake had BPA, and 27.3% of the cases with bilateral uptake had UPA. The AUC of the ROC curve of the NP-59 scintigraphy for PA subtyping was 0.812 [0.707-0.916]. Based on the results of the CT/MRI and NP-59 scintigraphy, only 6.7% of the patients with unilateral uptake had BPA, and 24% of the cases with bilateral uptake had UPA. The AUC of the ROC curve of the model combining CT/MRI and 59-scintigraphy results for subtyping PA was 0.869 [0.782-0.957]. CONCLUSION: The results of NP-59 scintigraphy in association with the information provided by the CT/MRI may be useful for PA subtyping. However, their diagnostic accuracy is only moderate. Therefore, it should be considered a second-line diagnostic tool when AVS is not an option.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

Genetic Study in Pheochromocytoma: Is It Possible to Stratify the Risk of Hereditary Pheochromocytoma?

INTRODUCTION: It is estimated that 30-40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary PHEO based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. METHODS: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index). RESULTS: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels, and tumor size. The area under the ROC curve of this model was 0.800 (0.705-0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: χ2 (1) = 30.05; p < 0.001). CONCLUSION: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion.

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype.

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

"This looks like a movie": a case report of post-surgical amnesia.

A 52-year-old male patient with a background of adaptive personality disorder was admitted for mitral valve repair and cardiac ablation for atrial fibrillation. He suffered intraoperative complications with severe mitral insufficiency that suffered ischemia.. Post-operatively, he demonstrated acute loss of retrograde autobiographical memory, prosopagnosia and a loss of public semantic memory. His CT scan was normal and MRI was not possible due to intra-cardiac leads. An initial diagnosis of hypoxic-ischemic encephalopathy was considered. A neuropsychological examination undertaken 20 days after his surgery showed a severe alteration of retrograde autobiographical memory, marked alteration of semantic knowledge and prosopagnosia. He demonstrated an average performance in tasks measuring constructional praxis, visuospatial ability, and executive functions. 34 days after surgery, and after a short nap, the patient "returns" to the day before admission and consequently recovers his memory. Repeat neuropsychological assessment demonstrated performance within the normal range across all previously tested domains. This sudden recovery of memory, together with a normal MRI, led to a rethinking of the diagnosis of dissociative amnesia. This case illustrates the long-standing discussion about the organic or functional origin of some memory disorders, in which, despite advances in neuroimaging techniques, it is still difficult to know their etiology .

Glycemic disorders in patients with pheochromocytomas and sympathetic paragangliomas.

The objective of our study was to determine the prevalence of glycemic disorders (diabetes mellitus and prediabetes) in patients with pheochromocytomas and sympathetic paragangliomas (PPGLs) and identify risk factors for their development and the likelihood of their resolution after surgery. A multicentric retrospective study of patients with PPGLs submitted to surgery between 2000 and 2021 in 17 Spanish hospitals was performed. Diabetes-specific data were collected at diagnosis, in the immediate- and long-term postsurgical follow-up. A total of 229 patients with PPGLs were included (218 with pheochromocytomas and 11 with sympathetic paragangliomas). Before surgery, glycemic disorders were diagnosed in 35.4% of the patients (n = 81): 54 with diabetes and 27 with prediabetes. The variables independently associated with a higher risk of glycemic disorders were sporadic PPGL (odds ratio (OR) = 3.26 (1.14-9.36)) and hypertension (OR = 3.14 (1.09-9.01)). A significant decrease in fasting plasma glucose and HbA1c levels was observed after surgery, in the short-term and long-term follow-up (P < 0.001). After a median follow-up of 48.5 months (range 3.3-168.9), after surgery, 52% of diabetic and 68% of prediabetic patients experienced a complete resolution. Lower body mass index (BMI) (P = 0.001), lower glucose levels (P = 0.047) and shorter duration of diabetes prior to surgery (P = 0.021) were associated with a higher probability of diabetes resolution. In conclusion, glycemic disorders in patients with PPGLs are present in more than a third of them at diagnosis. Sporadic PPGLs and hypertension are risk factors for their development. More than 50% of cases experience a complete resolution of the glycemic disorder after resection of the PPGLs.

Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.

BACKGROUND AND OBJECTIVES: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. METHODS: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. RESULTS: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. DISCUSSION: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS. TRIAL REGISTRATION INFORMATION: NCT01582763.

Autoantibody screening in Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. METHODS: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. RESULTS: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. CONCLUSION: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients.

OBJECTIVE: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS). METHODS: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year. RESULTS: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (ß -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL). CONCLUSION: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.

Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.

CONTEXT: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. OBJECTIVE: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. DESIGN: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. RESULTS: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. CONCLUSIONS: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Fístula carótido-cavernosa tratada con compresiones carotídeas / Carotid-cavernous fistula successfully treated with carotid compression

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