Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor. PATIENTS AND METHODS: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21-80) and the median number of prior regimens was four (range, 1-9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months. CONCLUSIONS: CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors.

Emerging targets for cancer treatment: S100A9/RAGE.

Developing better treatments that work for the majority of patients with brain metastasis (BM) is highly necessary. Complementarily, avoiding those therapeutic procedures that will not benefit a specific patient is also very relevant. In general, existing therapies for patients with BM could be improved in terms of molecular stratification and therapeutic efficacy. By questioning the benefit of whole brain radiotherapy as provided nowadays and the lack of biomarkers detecting radioresistance, we identified S100A9 and receptor for advanced glycation end-products (RAGE) as a liquid biopsy biomarker and a potential target for a radiosensitizer, respectively. Both of them are being clinically tested as part of the first comprehensive molecular strategy to personalized radiotherapy in BM.

SEOM clinical guideline for management of adult medulloblastoma (2020).

Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.

Recent advances in neoadjuvant immunotherapy for urothelial bladder cancer: What to expect in the near future.

Urothelial bladder cancer (UC) is the most common malignancy involving the urinary system and represents a significant health problem. Immunotherapy has been used for decades for UC with intravesical bacillus Calmette-Guérin (BCG) set as the standard of care for non-muscle-invasive bladder cancer (NMIBC). The advent of immune checkpoint inhibitors (ICIs) has completely transformed the treatment landscape of bladder cancer enabling to expand the treatment strategies. Novel ICIs have successfully shown improved outcomes on metastatic disease to such an extent that the standard of care paradigm has changed leading to the development of different trials with the aim of determining whether ICIs may have a role in early disease. The localized muscle-invasive bladder cancer (MIBC) scenario remains challenging since the recurrence rate continues to be high despite all therapeutic efforts. This article will review the current experience of ICIs in the neoadjuvant setting of UC, the clinical trials landscape and finally, an insight of what to expect in the immediate and mid-term future.

Recommendations by the Spanish Society of Hospital Pharmacy, the Spanish Society of Oncology Nursing and the Spanish Society of Medical Oncology for the safe management of antineoplastic medication in cancer patients.

AIM: To define recommendations that permit safe management of antineoplastic medication, minimise medication errors and improve the safety of cancer patients undergoing treatment. METHODS: By reviewing the literature and consulting the websites of various health organisations and agencies, an expert committee from the Spanish Society of Hospital Pharmacy and the Spanish Society of Medical Oncology defined a set of safe practices covering all stages of providing cancer therapy to patients. The Spanish Society of Oncology Nursing revised and endorsed the final list. RESULTS: In total, 68 recommendations arranged in five sections were defined. They include issues concerning the training of health professionals, the technological resources needed, treatment planning, informing the patient and his/her family, the processes of prescribing, preparing, dispensing and administering cancer therapy (orally, parenterally or intrathecally), assessing patient adherence and treatment toxicity. CONCLUSIONS: It is essential for healthcare establishments to implement specific measures designed to prevent medication errors, in order to ensure the safety of cancer patients treated with antineoplastic medication.

Morphologic Features on MR Imaging Classify Multifocal Glioblastomas in Different Prognostic Groups.

BACKGROUND AND PURPOSE: Multifocal glioblastomas (ie, glioblastomas with multiple foci, unconnected in postcontrast pretreatment T1-weighted images) represent a challenge in clinical practice due to their poor prognosis. We wished to obtain imaging biomarkers with prognostic value that have not been found previously. MATERIALS AND METHODS: A retrospective review of 1155 patients with glioblastomas from 10 local institutions during 2006-2017 provided 97 patients satisfying the inclusion criteria of the study and classified as having multifocal glioblastomas. Tumors were segmented and morphologic features were computed using different methodologies: 1) measured on the largest focus, 2) aggregating the different foci as a whole, and 3) recording the extreme value obtained for each focus. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell concordance indices (c-indices) were used for the statistical analysis. RESULTS: Age (P < .001, hazard ratio = 2.11, c-index = 0.705), surgery (P < .001, hazard ratio = 2.04, c-index = 0.712), contrast-enhancing rim width (P < .001, hazard ratio = 2.15, c-index = 0.704), and surface regularity (P = .021, hazard ratio = 1.66, c-index = 0.639) measured on the largest focus were significant independent predictors of survival. Maximum contrast-enhancing rim width (P = .002, hazard ratio = 2.05, c-index = 0.668) and minimal surface regularity (P = .036, hazard ratio = 1.64, c-index = 0.600) were also significant. A multivariate model using age, surgery, and contrast-enhancing rim width measured on the largest foci classified multifocal glioblastomas into groups with different outcomes (P < .001, hazard ratio = 3.00, c-index = 0.853, median survival difference = 10.55 months). Moreover, quartiles with the highest and lowest individual prognostic scores based on the focus with the largest volume and surgery were identified as extreme groups in terms of survival (P < .001, hazard ratio = 18.67, c-index = 0.967). CONCLUSIONS: A prognostic model incorporating imaging findings on pretreatment postcontrast T1-weighted MRI classified patients with glioblastoma into different prognostic groups.

Oxcarbazepine monotherapy in carbamazepine-unresponsive trigeminal neuralgia.

The objective of this prospective open-label study was to evaluate the efficacy and tolerability of oxcarbazepine in trigeminal neuralgia (TN) unresponsive to treatment with the standard antiepileptic drug, carbamazepine. Thirty-five patients with idiopathic TN, who underwent treatment with oxcarbazepine monotherapy for at least 12 weeks, were studied. Pain was assessed using mean pain frequency, responder rate, pain-free patients and clinical global impression. The mean maintenance dose was 773.7 mg/day. There was a significant decrease in the mean of the main scores following 12 weeks of treatment (p<0.05) compared with baseline. Oxcarbazepine was effective from the first month of treatment. There was a significant reduction in pain frequency, leading to improvements in patient satisfaction. In general, oxcarbazepine was well tolerated. Oxcarbazepine appears to be an important alternative therapeutic approach for patients affected by TN. This study adds to the existing literature arriving at the same findings.

Leakage decrease detected by dynamic susceptibility-weighted contrast-enhanced perfusion MRI predicts survival in recurrent glioblastoma treated with bevacizumab.

BACKGROUND AND PURPOSE: In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome. MATERIALS AND METHODS: We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan-Meier method and comparing subgroups by log rank probability test. RESULTS: Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5. CONCLUSIONS: Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival.

SEOM clinical guideline for management of adult medulloblastoma (2020)

Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up (AU)

A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma.

PURPOSE: The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. PATIENTS AND METHODS: Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m(2) days 1-7 and 15-21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. RESULTS: Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44%) had gross total resection. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9% (95% CI 9.3-40.0%). The median PFS and overall survival (OS) were 4.2 months (95% CI 3.6-5.4 months) and 7.3 months (95% CI 5.8-8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19%; 95% CI 7.2-36.4) were long-term survivors, with a median PFS and OS (50% events) of 9.5 months (95% CI 7.9-23.6) and 15.4 (95% CI 8.9-NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. CONCLUSIONS: This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy.

A prognostic model based on preoperative MRI predicts overall survival in patients with diffuse gliomas.

BACKGROUND AND PURPOSE: Diffuse gliomas are classified as grades II-IV on the basis of histologic features, with prognosis determined mainly by clinical factors and histologic grade supported by molecular markers. Our aim was to evaluate, in patients with diffuse gliomas, the relationship of relative CBV and ADC values to overall survival. In addition, we also propose a prognostic model based on preoperative MR imaging findings that predicts survival independent of histopathology. MATERIALS AND METHODS: We conducted a retrospective analysis of the preoperative diffusion and perfusion MR imaging in 126 histologically confirmed diffuse gliomas. Median relative CBV and ADC values were selected for quantitative analysis. Survival univariate analysis was made by constructing survival curves by using the Kaplan-Meier method and comparing subgroups by log-rank probability tests. A Cox regression model was made for multivariate analysis. RESULTS: The study included 126 diffuse gliomas (median follow-up of 14.5 months). ADC and relative CBV values had a significant influence on overall survival. Median overall survival for patients with ADC < 0.799 × 10(-3) mm(2)/s was <1 year. Multivariate analysis revealed that patient age, relative CBV, and ADC values were associated with survival independent of pathology. The preoperative model provides greater ability to predict survival than that obtained by histologic grade alone. CONCLUSIONS: ADC values had a better correlation with overall survival than relative CBV values. A preoperative prognostic model based on patient age, relative CBV, and ADC values predicted overall survival of patients with diffuse gliomas independent of pathology. This preoperative model provides a more accurate predictor of survival than histologic grade alone.

Should we continue temozolomide beyond six cycles in the adjuvant treatment of glioblastoma without an evidence of clinical benefit? A cost analysis based on prescribing patterns in Spain.

PURPOSE: The standard adjuvant treatment for glioblastoma is temozolomide concomitant with radiotherapy, followed by a further six cycles of temozolomide. However, due to the lack of empirical evidence and international consensus regarding the optimal duration of temozolomide treatment, it is often extended to 12 or more cycles, even in the absence of residual disease. No clinical trial has shown clear evidence of clinical benefit of this extended treatment. We have explored the economic impact of this practice in Spain. MATERIALS AND METHODS: Spanish neuro-oncologists completed a questionnaire on the clinical management of glioblastomas in their centers. Based on their responses and on available clinical and demographic data, we estimated the number of patients who receive more than six cycles of temozolomide and calculated the cost of this extended treatment. RESULTS: Temozolomide treatment is continued for more than six cycles by 80.5 % of neuro-oncologists: 44.4 % only if there is residual disease; 27.8 % for 12 cycles even in the absence of residual disease; and 8.3 % until progression. Thus, 292 patients annually will continue treatment beyond six cycles in spite of a lack of clear evidence of clinical benefit. Temozolomide is covered by the National Health Insurance System, and the additional economic burden to society of this extended treatment is nearly 1.5 million euros a year. CONCLUSIONS: The optimal duration of adjuvant temozolomide treatment merits investigation in a clinical trial due to the economic consequences of prolonged treatment without evidence of greater patient benefit.

The added value of apparent diffusion coefficient to cerebral blood volume in the preoperative grading of diffuse gliomas.

BACKGROUND AND PURPOSE: In cerebral gliomas, rCBV correlates with tumor grade and histologic findings of vascular proliferation. Moreover, ADC assesses water diffusivity and is inversely correlated with tumor grade. In the present work, we have studied whether combined rCBV and ADC values improve the diagnostic accuracy of MR imaging in the preoperative grading of gliomas. MATERIALS AND METHODS: One hundred sixty-two patients with histopathologically confirmed diffuse gliomas underwent DWI and DSC. Mean rCBV and ADC values were compared among the tumor groups with the Student t test or ANOVA. ROC analysis was used to determine rCBV and ADC threshold values for glioma grading. RESULTS: rCBV had significantly different values between grade II and IV gliomas and between grade III and IV tumors, but there were no significant differences between grade II and III gliomas (P > .05). Grade II and III tumors also did not differ when astrocytomas, oligodendrogliomas, and oligoastrocytomas were considered separately. ADC values were significantly different for all 3 grades. The ADC threshold value of 1.185 × 10(-3) mm(2)/s and the rCBV cutoff value of 1.74 could be used with high sensitivity in the characterization of high-grade gliomas. The area under the ROC curve for the maximum rCBV and minimum ADC was 0.72 and 0.75, respectively. The combination of rCBV and ADC values increased the area under the ROC curve to 0.83. CONCLUSIONS: ADC measurements are better than rCBV values for distinguishing the grades of gliomas. The combination of minimum ADC and maximum rCBV improves the diagnostic accuracy of glioma grading.

HDM2 overexpression and focal loss of p14/ARF expression may deregulate the p53 tumour suppressor pathway in meningeal haemangiopericytomas. Study by double immunofluorescence and laser scanning confocal microscopy.

AIMS: To investigate the p53 pathway in meningeal haemangiopericytomas (MHPCs), p14/ARF, p53 protein expression and two wild-type (wt) p53-induced proteins (HDM2 and p21/WAF1) were studied in 18 MHPCs, 11 primary, four of them recurrent on one, one, two and four occasions. METHODS: Immunohistochemical detection of p14/ARF, p53, p21/WAF1, HDM2 and Ki67 proliferative index (PI) protein expression. RESULTS: Ki67 index was > 5% in eight out 18 cases (44.4%). The PI in recurrent cases increased with neoplastic progression. Simultaneous p53 and wt p53 transactivated gene (p21/WAF, HDM2) expression occurred in all cases. This argues against p53 mutation. HDM2 overexpression was observed in 10 cases (55.5%). Double-immunofluorescence staining and laser scanning confocal microscopy (LSCM) displayed HDM2 and p53 colocalization. This strongly suggests that HDM2 binds and inactivates p53 that could be pathogenic for MHPCs, by a different mechanism than point mutation. p14/ARF expression > 5% was observed in 12 cases (66.6%). A normal (diffuse) pattern of expression was seen in 13 cases (72.2%). Focal loss of expression was observed in five patients (27.7%): three primary cases and two recurrences. Therefore, p14/ARF down-regulation may also contribute to the development of MHPC. CONCLUSION: HDM2 overexpression, sometimes combined with focal loss of p14/ARF expression, may play a pathogenic role in MHPCs.

[Anticoagulant treatment in hemorrhagic brains infarts due to large sinus venous thrombosis]. / Anticoagulación en infartos cerebrales hemorrágicos por extensa trombosis de senos venosos.

Cerebral venous and sinus thrombosis is an infrequent condition which presents with a wide spectrum of signs and a variable mode of onset. Sinus thrombosis may cause isolated intracranial hypertension but also may cause cerebral venous infarcts, which are frequently hemorrhagic. Treatment with antithrombotic agents is controversial because there is only one randomised controlled trial with unfractionated heparin. We report a 46- years-old man complaining of progressive headache, paraparesis and dysphasia. After admission, his neurological status worsened and he developed tetraparesis, depressed level of consciousness and seizures. A cranial computarized tomography (CT) scan showed multiple hyperdensities suggestive of hemorrhagic infarcts. Magnetic resonance imaging (MRI) study confirmed extensive cerebral venous thrombosis. Unfractionated heparin was administered for two weeks followed by acenocumarol. Within a few days his neurological status improved, and five weeks after admission the patient only hadd slight neurological deficit. After 11 years of follow-up, he has had a complete recovery. The G20210A mutation in the prothrombin gene was detected as a likely risk factor for venous thrombosis. Therapeutical and diagnosis aspects are discussed. We review the previous literature on the topic.

Enfermedad por cuerpos de poliglucosano del adulto: diagnóstico por biopsia muscular / No disponible

No disponible