Publications by authors named "Emmanuel Jouanneau"

105 Publications

Assessment of Pressure-Volume Index During Lumbar Infusion Study: What Is the Optimal Method?

Acta Neurochir Suppl 2021 ;131:335-338

Department of Neurosurgery B, Neurological Hospital Pierre Wertheimer, University Hospital, Lyon, France.

Introduction: Assessment of the pressure-volume index (PVI) during lumbar infusion study (LIS) has been proposed to evaluate the overall compliance of the cranio-spinal system. It is calculated from the measurement of CSF pressure changes, ΔP from Pb to Pp, in response to repeated bolus injections of a volume (ΔV) within the lumbar subarachnoid space.

Material And Methods: We retrospectively analyzed 18 patients who underwent LIS for suspicion of normal pressure hydrocephalus, including a series of three fast bolus injections of 3 mL of saline at different levels of CSF pressure. We compared two methods for PVI calculation: (a) PVI using the slope α of a linear fit ΔP = α(Pb - P ), PVI = ΔV/log(α + 1); (b) PVI using the PVI calculated independently for each bolus injection assuming P  = 0, PVI = mean(ΔV/log(Pp/Pb)).

Results: We found a significant discrepancy between the two methods: the average difference (PVI - PVI) was -3.93 mL (95% confidence interval [8.77; -16.64]). In the PVI, method, the mean P was 2.12 mmHg (±3.41 mmHg).

Discussion: The clinical reliability of PVI (assuming P  = 0) depends on the value of P . PVI provides results, independent of P . Future studies should focus on determining pathological PVI range rather than fixed cut-off values.
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http://dx.doi.org/10.1007/978-3-030-59436-7_64DOI Listing
January 2021

Should the Impact of Postural Change of Intracranial Pressure After Surgical Repair of Skull Base Cerebrospinal Fluid Leaks Be Considered? A Preliminary Survey.

Acta Neurochir Suppl 2021 ;131:329-333

Skull Base Unit, Department of Neurosurgery B, Neurological Hospital Pierre Wertheimer, University Hospital of Lyon, Lyon, France.

Introduction: Managing skull base cerebrospinal fluid (CSF) leaks is often challenging. Postoperative care, especially regarding postural restrictions and bedrest recommendations, is variable and continues to be based on empirical habits.

Methods: An electronic survey was submitted to French experts in skull base surgery to evaluate current practice of postoperative postural recommendations in patients treated for skull base CSF leaks.

Results: Thirty-nine experts completed the survey. Postoperative recommendations were heterogenous. They depended on the size of defects: half of the surgeons did not recommend any constraints of posture for small defects; 84% recommended bed rest for large defects. The most preferred bed-rest modality was Fowler's position (20°-30° tilt). Standing/walking during short periods was allowed in up to 73%. From a physiological viewpoint, head elevation decreases ICP and thus limits the risk of recurrence of CSF leak. However, ICP can fall below 0 in the standing position, favouring pneumocephalus.

Discussion: These results confirmed that postural recommendations for patients surgically treated for skull base CSF leaks remain variable. Recommendations should take into consideration the postural change in ICP. Fowler's position may represent the best compromise between risk of recurrence of CSF leak and the risk of pneumocephalus in large CSF leaks.
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http://dx.doi.org/10.1007/978-3-030-59436-7_63DOI Listing
January 2021

Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening.

J Neurooncol 2021 Apr 10. Epub 2021 Apr 10.

Centre Léon Bérard, 28 Prom. Lea et Napoleon Bullukian, 69008, Lyon, France.

Purpose: Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group).

Methods: It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death.

Results: 99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p = 0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]).

Conclusions: Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.
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http://dx.doi.org/10.1007/s11060-021-03751-5DOI Listing
April 2021

Multimodal management of surgery- and radiation-refractory meningiomas: an analysis of the French national tumor board meeting on meningiomas cohort.

J Neurooncol 2021 Mar 28. Epub 2021 Mar 28.

Department of Neurosurgery, Sorbonne Universités, Groupe Hospitalier Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Paris, France.

Purpose: Meningiomas represent the most frequent tumor of the central nervous system in adults. While most meningiomas are efficiently treated by surgery and radiotherapy/radiosurgery, there is a small portion of radiation- and surgery-refractory tumors for which there is no clear recommendation for optimal management. The French National Tumor Board Meeting on Meningiomas (NTBM) offers a glimpse on the current management of such patients.

Methods: We retrospectively reviewed the charts of patients presented to the multidisciplinary Meeting between 2016 and 2019. We selected patients with a progressive disease after at least two treatments, including surgery and radiotherapy.

Results: In this multicentric cohort of 86 cases, patients harbored 17 (19.8%) WHO Grade I, 48 (55.8%) WHO Grade II and 21 (24.4%) WHO Grade III tumors. The median number of treatments received before inclusion was 3 (range: 2 - 11). Following the Board Meeting, 32 patients (37.2%) received chemotherapy, 11 (12.8%) surgery, 17 (19.8%) radiotherapy, 14 (16.3%) watchful observation and 12 (13.9%) palliative care. After a mean follow-up of 13 months post-inclusion, 32 patients (37.2%) had died from their disease. The mean progression free survival was 27 months after radiotherapy, 10 months after surgery, 8.5 months after chemotherapy (Bevacizumab: 9 months - Octreotide/Everolimus: 8 months).

Conclusions: Surgery- and radiation-refractory meningiomas represent a heterogeneous group of tumors with a majority of WHO Grade II cases. If re-irradiation and redo-surgery are not possible, bevacizumab and octreotide-everolimus appear as a valuable option in heavily pre-treated patients considering the current EANO guidelines.
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http://dx.doi.org/10.1007/s11060-021-03741-7DOI Listing
March 2021

Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis.

Acta Neuropathol Commun 2020 11 10;8(1):190. Epub 2020 Nov 10.

Fédération d'endocrinologie, Centre de Référence des Maladies Rares Hypophysaires, Groupement Hospitalier Est, Hospices Civils de Lyon, 8 av Doyen Lepine, 69677, Bron Cedex, France.

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min-max) = 38% (0-97) of probes) compared to corticotroph (11% (0-77)), somatotroph (5% (0-99)), gonadotroph (0% (0-10)) and immunonegative tumors (0% (0-17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn't show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same 'quiet' profile, leaving the mechanism underlying tumorigenesis open to question.
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http://dx.doi.org/10.1186/s40478-020-01067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653703PMC
November 2020

A key role for conservative treatment in the management of pituitary apoplexy.

Endocrine 2021 Jan 21;71(1):168-177. Epub 2020 Sep 21.

Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677, Bron, France.

Purpose: The management of pituitary apoplexy, a rare emergency neuroendocrine condition, is controversial. The aim of the present study is to compare the outcomes of patients with pituitary apoplexy managed either by a conservative or surgical approach.

Methods: A retrospective cohort study including patients diagnosed between 2007 and 2018 in a tertiary French university hospital. Pituitary Apoplexy Score (PAS) was retrospectively applied in the perspective of therapeutic decision support.

Results: Forty-six patients were treated for pituitary apoplexy either with conservative management (n = 27) or surgery (n = 19). At initial evaluation, visual field defects (VFD) and visual acuity impairment were more frequent in patients from the surgery group. At 1 year there were no statistical differences in the rates of complete/near-complete resolution of VFD (100 vs. 91.7%), visual acuity impairment (100 vs. 87.5%), and cranial nerve palsies (83.3 vs. 100%), between conservative and surgical treatment groups. There were more endocrine deficits at 1 year in the surgical group (p = 0.029). PAS (n = 41) was 3.4 on average in the early surgery group and 1.3 in the conservative treatment/delayed surgery group. Among patients with a score < 4, 31.3% were operated at first line and did not present better outcomes than patients managed conservatively. In all, 88.9% of patients with a score ≥ 4 underwent surgery.

Conclusions: PAS may be a reliable parameter for defining therapeutic strategy. Patients with non-severe and nonprogressive neuro-ophthalmological deficits can be managed conservatively without negative impact on outcomes, thus surgery should be reserved only for those patients with a PAS ≥ 4.
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http://dx.doi.org/10.1007/s12020-020-02499-8DOI Listing
January 2021

Immune Landscape of Pituitary Tumors Reveals Association Between Macrophages and Gonadotroph Tumor Invasion.

J Clin Endocrinol Metab 2020 11;105(11)

Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France.

Purpose: Pituitary neuroendocrine tumors (PitNETs) are frequent intracranial neoplasms that present heterogenic characteristics. Little is known about the immune cell network that exists in PitNETs and its contribution to their aggressive behavior.

Methods: Here we combined flow cytometry, t-SNE analysis, and histological approaches to define the immune landscape of surgically resected PitNETs. Xenografts of rodent pituitary tumor cells and resected PitNETs were performed in Rag2KO mice, in combination with in vitro analysis aimed at dissecting the role of pituitary tumor-cells in monocyte recruitment.

Results: We report that gonadotroph PitNETs present an increased CD68+ macrophage signature compared to somatotroph, lactotroph, and corticotroph PitNETs. Transcriptomic and histological characterizations confirmed gonadotroph infiltrating macrophages expressed CD163, MRC-1, ARG1, and CSF1R M2 macrophage markers. Use of growth hormone (GH)3/GH4 somatotroph and LβT2/αT3.1 gonadotroph cells drove THP1 macrophage migration through respective expression of CCL5 or CSF1. Although both LβT2 and GH3 cells recruited F4/80 macrophages following their engraftment in mice, only LβT2 gonadotroph cells showed a capacity for M2-like polarization. Similar observations were performed on patient-derived xenografts from somatotroph and gonadotroph tumors. Analysis of clinical data further demonstrated a significant correlation between the percentage of CD68+ and CD163+ infiltrating macrophages and the invasive character of gonadotroph tumors.

Conclusions: Gonadotroph tumor drive the recruitment of macrophages and their subsequent polarization to an M2-like phenotype. More importantly, the association between infiltrating CD68+/CD163+ macrophages and the invasiveness of gonadotroph tumors points to macrophage-targeted immunotherapies being a potent strategy to limit the progression of gonadotroph PitNETs.
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http://dx.doi.org/10.1210/clinem/dgaa520DOI Listing
November 2020

Aggressive Pituitary Adenomas and Carcinomas.

Endocrinol Metab Clin North Am 2020 09 8;49(3):505-515. Epub 2020 Jul 8.

Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, "Claude Bernard" Lyon 1 University, Hôpital Louis Pradel, 59 Pinel Boulevard, Lyon, Bron 69677, France. Electronic address:

A subset of pituitary tumors present an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. The current European Society for Endocrinology (ESE) guidelines for the management of aggressive pituitary tumors and carcinomas provide valuable guidance, but several issues remain unaddressed because of the scarcity of data in the literature. This article presents key clinical aspects regarding aggressive pituitary tumors and carcinomas, and also discusses some of the unanswered questions of the ESE guidelines, focusing on both diagnosis and treatment.
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http://dx.doi.org/10.1016/j.ecl.2020.05.008DOI Listing
September 2020

Surgical management for large vestibular schwannomas: a systematic review, meta-analysis, and consensus statement on behalf of the EANS skull base section.

Acta Neurochir (Wien) 2020 11 29;162(11):2595-2617. Epub 2020 Jul 29.

Department of Neurosurgery Service and Gamma Knife Center, University hospital of Lausanne and Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland.

Background And Objective: The optimal management of large vestibular schwannomas continues to be debated. We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of this problem from a European perspective.

Material And Methods: A systematic review of MEDLINE database, in compliance with the PRISMA guidelines, was performed. A subgroup analysis screening all surgical series published within the last 20 years (January 2000 to March 2020) was performed. Weighted summary rates for tumor resection, oncological control, and facial nerve preservation were determined using meta-analysis models. This data along with contemporary practice patterns were discussed within the task force to generate consensual recommendations regarding preoperative evaluations, optimal surgical strategy, and follow-up management.

Results: Tumor classification grades should be systematically used in the perioperative management of patients, with large vestibular schwannomas (VS) defined as > 30 mm in the largest extrameatal diameter. Grading scales for pre- and postoperative hearing (AAO-HNS or GR) and facial nerve function (HB) are to be used for reporting functional outcome. There is a lack of consensus to support the superiority of any surgical strategy with respect to extent of resection and use of adjuvant radiosurgery. Intraoperative neuromonitoring needs to be routinely used to preserve neural function. Recommendations for postoperative clinico-radiological evaluations have been elucidated based on the surgical strategy employed.

Conclusion: The main goal of management of large vestibular schwannomas should focus on maintaining/improving quality of life (QoL), making every attempt at facial/cochlear nerve functional preservation while ensuring optimal oncological control, thereby allowing to meet patient expectations. Despite the fact that this analysis yielded only a few Class B evidences and mostly expert opinions, it will guide practitioners to manage these patients and form the basis for future clinical trials.
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http://dx.doi.org/10.1007/s00701-020-04491-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550309PMC
November 2020

Conventional MRI radiomics in patients with suspected early- or pseudo-progression.

Neurooncol Adv 2019 May-Dec;1(1):vdz019. Epub 2019 Sep 1.

Université Claude Bernard Lyon 1, Villeurbanne, France.

Background: After radiochemotherapy, 30% of patients with early worsening MRI experience pseudoprogression (Psp) which is not distinguishable from early progression (EP). We aimed to assess the diagnostic value of radiomics in patients with suspected EP or Psp.

Methods: Radiomics features (RF) of 76 patients (53 EP and 23 Psp) retrospectively identified were extracted from conventional MRI based on four volumes-of-interest. Subjects were randomly assigned into training and validation groups. Classification model (EP versus Psp) consisted of a random forest algorithm after univariate filtering. Overall (OS) and progression-free survivals (PFS) were predicted using a semi-supervised principal component analysis, and forecasts were evaluated using C-index and integrated Brier scores (IBS).

Results: Using 11 RFs, radiomics classified patients with 75.0% and 76.0% accuracy, 81.6% and 94.1% sensitivity, 50.0% and 37.5% specificity, respectively, in training and validation phases. Addition of promoter status improved accuracy to 83% and 79.2%, and specificity to 63.6% and 75%. OS model included 14 RFs and stratified low- and high-risk patients both in the training (hazard ratio [HR], 3.63; = .002) and the validation (HR, 3.76; = .001) phases. Similarly, PFS model stratified patients during training (HR, 2.58; = .005) and validation (HR, 3.58; = .004) phases using 5 RF. OS and PFS forecasts had C-index of 0.65 and 0.69, and IBS of 0.122 and 0.147, respectively.

Conclusions: Conventional MRI radiomics has promising diagnostic value, especially when combined with promoter status, but with moderate specificity. In addition, our results suggest a potential for predicting OS and PFS.
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http://dx.doi.org/10.1093/noajnl/vdz019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212855PMC
September 2019

Gonadotroph Tumors Show Subtype Differences That Might Have Implications for Therapy.

Cancers (Basel) 2020 Apr 20;12(4). Epub 2020 Apr 20.

Endocrinology Department, "Groupement Hospitalier Est" Hospices Civils de Lyon, 69677 Bron, France.

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men ( = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype ( = 0.01 and = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted -value = 0.0001) and in male (rho = 0.51, adjusted -value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted -value = 0.0005) and in female (rho = 0.58, adjusted -value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options.
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http://dx.doi.org/10.3390/cancers12041012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226008PMC
April 2020

Surgical management of craniopharyngiomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section.

Acta Neurochir (Wien) 2020 05 28;162(5):1159-1177. Epub 2020 Feb 28.

Department of Neurosurgery, University Hospital of Lausanne, Lausanne, Switzerland.

Background And Objective: Craniopharyngiomas are locally aggressive neuroepithelial tumors infiltrating nearby critical neurovascular structures. The majority of published surgical series deal with childhood-onset craniopharyngiomas, while the optimal surgical management for adult-onset tumors remains unclear. The aim of this paper is to summarize the main principles defining the surgical strategy for the management of craniopharyngiomas in adult patients through an extensive systematic literature review in order to formulate a series of recommendations.

Material And Methods: The MEDLINE database was systematically reviewed (January 1970-February 2019) to identify pertinent articles dealing with the surgical management of adult-onset craniopharyngiomas. A summary of literature evidence was proposed after discussion within the EANS skull base section.

Results: The EANS task force formulated 13 recommendations and 4 suggestions. Treatment of these patients should be performed in tertiary referral centers. The endonasal approach is presently recommended for midline craniopharyngiomas because of the improved GTR and superior endocrinological and visual outcomes. The rate of CSF leak has strongly diminished with the use of the multilayer reconstruction technique. Transcranial approaches are recommended for tumors presenting lateral extensions or purely intraventricular. Independent of the technique, a maximal but hypothalamic-sparing resection should be performed to limit the occurrence of postoperative hypothalamic syndromes and metabolic complications. Similar principles should also be applied for tumor recurrences. Radiotherapy or intracystic agents are alternative treatments when no further surgery is possible. A multidisciplinary long-term follow-up is necessary.
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http://dx.doi.org/10.1007/s00701-020-04265-1DOI Listing
May 2020

Avoiding New Biopsies by Identification of IDH1 and TERT Promoter Mutation in Nondiagnostic Biopsies From Glioma Patients.

Neurosurgery 2020 09;87(4):E513-E519

Centre de recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Cancer Cell Plasticity department, Transcriptome Diversity in Stem Cells laboratory, Lyon, France.

Background: Biopsies in patients with a suspected glioma are occasionally nondiagnostic.

Objective: To explore the utility of molecular testing in this setting by determining whether IDH1 and TERT promoter (pTERT) mutations could be detected in nondiagnostic biopsies from glioma patients.

Methods: Using SNaPshot polymerase chain reaction, we retrospectively assessed IDH1 and pTERT mutation status in nondiagnostic biopsies from 28 glioma patients.

Results: The nondiagnostic biopsy (needle biopsy n = 25, open or endoscopic biopsy n = 3) consisted of slight glial cell hypercellularity, hemorrhage, and/or necrosis. After another biopsy (n = 23) or a subsequent surgical resection (n = 5) the diagnosis was an IDH1-wildtype (WT) pTERT-mutant glioma (glioblastoma n = 16, astrocytoma n = 4), an IDH1-mutant pTERT-mutant oligodendroglioma (n = 1), an IDH1-mutant pTERT-WT astrocytoma (n = 1), and an IDH1-WT pTERT-WT glioblastoma (n = 6). An IDH1 mutation was identified in the nondiagnostic biopsies of the 2 IDH-mutant gliomas, and a pTERT mutation in the nondiagnostic biopsies of 16 out of the 21 of pTERT mutant-gliomas (76%). Overall, an IDH1 and/or a pTERT mutation were detected in 17 out of 28 (61%) of nondiagnostic biopsies. Retrospective analysis of the nondiagnostic biopsies based on these results and on imaging characteristics suggested that a new biopsy could have been avoided in 6 patients in whom a diagnosis of "molecular glioblastoma" could have been done with a high level of confidence.

Conclusion: In the present series, IDH1 and pTERT mutations could be detected in a high proportion of nondiagnostic biopsies from glioma patients. Molecular testing may facilitate the interpretation of nondiagnostic biopsies in patients with a suspected glioma.
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http://dx.doi.org/10.1093/neuros/nyaa025DOI Listing
September 2020

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors.

Endocr Connect 2020 Feb 1. Epub 2020 Feb 1.

H Lasolle, Service d'Endocrinologie, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Objective: Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in 5 patients.

Design: Retrospective cohort study.

Methods: Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS>1 being considered positive) and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations.

Results: SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P=0.04) and had a lower grade (P=0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P=0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P=0.007). Among treated patients, normal urinary free cortisol levels were obtained in 3 patients (IRS 0, 2, 6) while a 4-fold decrease was observed in one patient (IRS 4).

Conclusion: SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.
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http://dx.doi.org/10.1530/EC-20-0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077525PMC
February 2020

MRI monitoring of small and medium-sized vestibular schwannomas: predictors of growth.

Acta Otolaryngol 2020 May 12;140(5):361-365. Epub 2020 Feb 12.

Department of Otolaryngology and Otoneurosurgery, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Claude Bernard University Lyon 1, Lyon, France.

Vestibular schwannomas are among the most common intracranial tumours. Their growth is difficult to predict. To study the evolution of small and medium-sized vestibular schwannomas (VSs) and identify factors predictive of growth. This was a retrospective longitudinal study at a tertiary referral centre from January 2011 to January 2018. The inclusion criteria were radiological diagnosis of sporadic unilateral VS of stage I or II. Radiological and clinical data were analysed descriptively and by multivariate logistic regression to identify factors predictive of growth. A total of 1105 cases were discussed in multidisciplinary meetings and 336 patients were included with a mean age of 57.8 years and a mean follow-up time of 24 months. Around two thirds of these patients (62.8%) had non-progressive tumours. Factors identified as predictive of VS growth were the size at diagnosis (OR = 2.622, 95% CI, 1.50-4.66;  = .001) and internal auditory canal filling (OR = 7.672; 95% CI, 4.52-13.43;  < .001). Monitoring is the primary treatment modality for small or medium-sized VSs. As reported here for the first time, internal auditory canal filling is significantly associated with VS growth.
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http://dx.doi.org/10.1080/00016489.2020.1717608DOI Listing
May 2020

Evolution of macroprolactinomas during pregnancy: A cohort study of 85 pregnancies.

Clin Endocrinol (Oxf) 2020 05 4;92(5):421-427. Epub 2020 Feb 4.

Service d'Endocrinologie - Diabète - Nutrition, Centre Hospitalier Universitaire de Reims, Reims, France.

Objective: Pregnancy in patients with macroprolactinomas has been associated with a higher risk of pituitary tumour growth. However, the incidence and risk factors remain unclear. We aimed to evaluate the evolution of macroprolactinomas during pregnancy and to identify potential risk factors.

Design, Patients And Measurements: This is a two-centre, retrospective, observational study. All patients with macroprolactinomas, treated with a dopamine receptor agonist (DA), and who had at least one pregnancy were included.

Results: There were a total of 85 viable pregnancies in 46 patients with macroprolactinomas. At diagnosis, mean size of pituitary adenomas was 17.9 ± 8.2 mm (10-43 mm) and mean plasma prolactin level was 1012.2 ± 1606.1 µg/L (60-7804 µg/L). Tumour growth-related symptoms were identified 12 times in 9 patients (19.6%) including 3 cases of apoplexy. Restarting, changing and/or increasing DA treatment was effective in 10 cases. Emergency surgery had to be performed twice (due to pituitary apoplexy). Patients with tumour progression tended to present with larger tumours after initial treatment and before pregnancy (9.9 vs 5.9 mm; P = .0504 and 11.5 vs 7.3 mm; P = .0671, respectively), whereas adenoma size at diagnosis did not seem to be a significant factor. The obstetrical outcomes were comparable to the general population.

Conclusions: Symptomatic growth of macroprolactinoma during pregnancy occurred in 19.6% of medically treated patients. This risk seems higher for patients with poor initial tumour response to the DA treatment. Tumour progression is generally well controlled with medical treatment during pregnancy.
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http://dx.doi.org/10.1111/cen.14162DOI Listing
May 2020

Current status and treatment modalities in metastases to the pituitary: a systematic review.

J Neurooncol 2020 Jan 13;146(2):219-227. Epub 2020 Jan 13.

Department of Skull Base and Pituitary Surgery, Neurological Hospital Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France.

Background: Metastases to the pituitary (MP) are uncommon, accounting for 0.4% of intracranial metastases. Through advances in neuroimaging and oncological therapies, patients with metastatic cancers are living longer and MP may be more frequent. This review aimed to investigate clinical and oncological features, treatment modalities and their effect on survival.

Methods: A systematic review was performed according to PRISMA recommendations. All cases of MP were included, excepted primary pituitary neoplasms and autopsy reports. Descriptive and survival analyses were then conducted.

Results: The search identified 2143 records, of which 157 were included. A total of 657 cases of MP were reported, including 334 females (50.8%). The mean ± standard deviation age was 59.1 ± 11.9 years. Lung cancer was the most frequent primary site (31.0%), followed by breast (26.2%) and kidney cancers (8.1%). Median survival from MP diagnosis was 14 months. Overall survival was significantly different between lung, breast and kidney cancers (P < .0001). Survival was impacted by radiotherapy (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.35-0.67; P < .0001) and chemotherapy (HR 0.58; 95% CI 0.36-0.92; P = .013) but not by surgery. Stereotactic radiotherapy tended to improve survival over conventional radiotherapy (HR 0.66; 95% CI 0.39-1.12; P = .065). Patients from recent studies (≥ 2010) had longer survival than others (HR 1.36; 95% CI 1.05-1.76; P = .0019).

Conclusion: This systematic review based on 657 cases helped to better identify clinical features, oncological characteristics and the effect of current therapies in patients with MP. Survival patterns were conditioned upon primary cancer histologies, the use of local radiotherapy and systemic chemotherapy, but not by surgery.
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http://dx.doi.org/10.1007/s11060-020-03396-wDOI Listing
January 2020

Surgical management of Tuberculum sellae Meningiomas: Myths, facts, and controversies.

Acta Neurochir (Wien) 2020 03 13;162(3):631-640. Epub 2019 Dec 13.

Service of Neurosurgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.

Background: The optimal management of tuberculum sellae (TS) meningiomas, especially the surgical strategy, continues to be debated along with several controversies that persist.

Methods: A task force was created by the EANS skull base section committee along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumors on a European perspective. To achieve this, the task force also reviewed in detail the literature in this field and had formal discussions within the group.

Results: The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological and endocrinological assessments, optimal surgical strategies, and follow-up management.

Conclusion: This article represents the consensually derived opinion of the task force with respect to the surgical treatment of tuberculum sellae meningiomas. Areas of uncertainty where further clinical research is required were identified.
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http://dx.doi.org/10.1007/s00701-019-04114-wDOI Listing
March 2020

Diagnosis, pathology, and management of TSH-secreting pituitary tumors. A single-center retrospective study of 20 patients from 1981 to 2014.

Ann Endocrinol (Paris) 2019 Sep 26;80(4):216-224. Epub 2019 Jul 26.

Université de Lyon, Lyon1, 69372 Lyon, France; Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Fédération d'endocrinologie, centre de référence maladies rares hypophysaire HYPO, groupement hospitalier Est, hospices Civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France. Electronic address:

TSH (thyroid-stimulating hormone)-secreting tumors are the rarest type of pituitary tumor. The objective of this study was to describe initial presentation and follow-up in patients presenting TSH-secreting tumors and to characterize the pathological features, based on a cohort of 20 patients treated in our referral center, between 1981 and 2014. Most of the patients (75%) were female, aged around 50 years (mean: 50±13 years). Initial symptoms were hyperthyroidism (8/20) and/or tumor mass-related symptoms. Median time to diagnosis was 18 months. Biochemical hyperthyroidism was found in 15 patients. Most of the tumors were macroadenomas (75%) and 30% were invasive. Seventeen patients underwent transsphenoidal surgery. All tumors expressed TSH, with>50% positive cells. Eleven were monohormonal and 6 plurihormonal, expressing βTSH plus growth hormone (GH) and/or prolactin (PRL). Both subtypes showed high expression of Pit-1 and SSTR somatostatin receptors. SSTR was slightly expressed in the plurihormonal subtype. Ki-67 index was elevated (≥3%) in only one tumor. Signs of hyperthyroidism were more frequent in the plurihormonal than in the monohormonal subtype. At final follow-up (median: 34.79±66.7 months), 75% of the patients were in complete remission after surgery; persistent hyperthyroidism was controlled by somatostatin analogs, alone (n=3) or associated to radiotherapy (n=1). The multidisciplinary approach promoted early diagnosis and control of hyperthyroidism by neurosurgical treatment, associated to somatostatin analogs or not. Clinical/pathological correlations highlighted the variations in immune profiles and in clinical and biological symptoms.
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http://dx.doi.org/10.1016/j.ando.2019.06.006DOI Listing
September 2019

Ommaya Reservoir System for the Treatment of Cystic Craniopharyngiomas: Surgical Results in a Series of 11 Adult Patients and Review of the Literature.

World Neurosurg 2019 Dec 7;132:e869-e877. Epub 2019 Aug 7.

Service de NeuroChirurgie de la base du Crâne et de l'hypophyse, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.

Objective: Treatment of cystic craniopharyngiomas can be challenging and recurrences are frequent, even after total resection. In selected cases, less-aggressive surgery with the sole drainage of the cyst reliefs symptoms caused by mass effect and represents a valid alternative option, notably in pediatric population. We herein analyze a series of adult cystic craniopharyngiomas, managed with Ommaya Reservoir implant, focusing on local tumor control and eventual complications.

Methods: In total, 11 nonconsecutive adult cystic craniopharyngiomas (7 recurrent lesions) were treated with Ommaya Reservoir System (ORS), in 2 neurosurgical centers. ORS was placed in 9 cases using minimally invasive procedures: 6 burr-hole endoscopic insertion and 3 navigated electromagnetic placement; in the remaining 2 patients, the Ommaya reservoir was used as a shunt to prevent cyst recollection during a transcranial approach.

Results: The main presenting symptoms were visual impairment (75%), cognitive and behavioral disorders (66.7%), hypopituitarism (38%), headache (30.8%), and hypothalamic obesity (8%). The median follow-up period was 41.4 months. In all patients, the visual function and intracranial hypertension improved after decompression. Local tumor control was accomplished in 8 patients (72.7%), without the need of adjuvant treatments. The endoscopic vision carried similar rates of tumor control than stereotaxy (75% vs. 66.7%).

Conclusions: In selected patients, tailored procedures are required to achieve long-term tumor control and as well limit surgery-related morbidity. ORS could represent a safe and effective treatment option for cystic craniopharyngiomas, providing also reduced surgical-related morbidity, especially in recurrent lesions and in patients not suitable for radical surgery.
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http://dx.doi.org/10.1016/j.wneu.2019.07.217DOI Listing
December 2019

Minimal-Access Endoscopic Endonasal Management of Dysthyroid Optic Neuropathy: The Dysthone Study.

Neurosurgery 2019 12;85(6):E1059-E1067

Department of Neurosurgery, Pierre Wertheimer Neurological and Neurosurgical Hospital, Hospices Civils de Lyon, Lyon, France.

Background: Dysthyroid optic neuropathy (DON) is a devastating complication of thyroid eye disease. Corticosteroids are the primary medical treatment for DON, but some refractory patients may require surgical management.

Objective: To evaluate the efficacy of endoscopic endonasal decompression of the orbital apex in refractory DON.

Methods: This study included patients with refractory DON who underwent endoscopic endonasal decompression of the orbital apex from February 2015 to October 2016. A total of 23 orbital apices were decompressed across 17 patients. Visual acuity, ophthalmometry, tonometry, and visual field were evaluated at the preoperative, early and delayed postoperative stages. Statistical analyses were performed using RStudio software. A Wilcoxon test for matched data was performed to determine if there was a statistically significant difference between pre- and postsurgical treatment for the following items: visual acuity, proptosis, visual field, and intraocular pressure.

Results: Visual acuity improved in 69.5% of the cases with a mean gain of 2.5 points ± 1.6 (P < .05). Additionally, there was an 18.3% reduction in mean proptosis across all cases (P < .05) and a 13.7% decrease in intraocular pressure (P < .05) for all patients. Finally, visual field improved in 82.6% (P < .05) of the cases. The mean time for follow-up was of 6.28 ± 3.7 mo. There were 3 cases of transient postoperative rhinitis and 2 cases of transient diplopia. Two patients experienced recurrence at 4 and 8 mo, respectively.

Conclusion: Endoscopic endonasal decompression of the orbital apex significantly improves visual parameters. As a result, multidisciplinary screening for patients is crucial to ensure prompt surgical decompression.
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http://dx.doi.org/10.1093/neuros/nyz268DOI Listing
December 2019

Predicting early post-operative remission in pituitary adenomas: evaluation of the modified knosp classification.

Pituitary 2019 Oct;22(5):467-475

Fédération d'Endocrinologie, Centre de Référence Maladies Rares hypophysaires, Groupement Hospitalier Est, Hospices Civils de Lyon, 69677, Bron, France.

Purpose: Cavernous sinus invasion by pituitary adenomas is an important prognostic factor for evaluating the possibilities of complete remission and to guide patient management. A widely used Magnetic Resonance Imaging grading system, suggested by Knosp in 1993, has recently been revised by the same group. The aims of our study were to apply this revised grading system to our surgical series, to determine its association with surgical outcomes, gross-total resection (GTR) and endocrinological remission (ER), paying particular attention to grades 3A and 3B, which represent the novelty of this revised classification.

Methods: We included consecutive patients who underwent endoscopic endonasal surgery for a macroadenoma from September 2012 to December 2016. MRI images were reviewed and classified according to the revised Knosp classification. Surgical reports indicated the intra-operative CS invasion. GTR and ER were evaluated on 3-months post-operative MRI and endocrine evaluation.

Results: 254 patients were included in this study. We found a total rate of cavernous sinus invasion of 18.4%. Different outcomes were observed for each grade, with an increased rate of cavernous sinus invasion with each grade. Per-operative rates of invasion were 61.5 and 78.6% in grades 3A and 3B respectively. GTR was negatively correlated with the grade, while rates were 55.8% and 30.0% for grades 3A and 3B respectively.

Conclusion: The revised Knosp radiological classification contributes to the prediction of surgical outcomes and early ER in pituitary adenomas. To manage, as precisely as possible, the risk of early recurrence in pituitary adenomas, clinicians should also consider other recognized prognostic factors, such as the proliferative status of the tumor.
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http://dx.doi.org/10.1007/s11102-019-00976-6DOI Listing
October 2019

Extra-intradural extracavernous subtemporal approach for chondrosarcomas: technical note and case report.

Acta Neurochir (Wien) 2019 11 4;161(11):2349-2352. Epub 2019 Jul 4.

Skull Base Surgery Unit, Department of Neurosurgery B, Hospices Civils de Lyon, University Hospital of Lyon, Lyon, France.

Background: Skull base chondrosarcomas are rare tumors often invading the petrous apex and cavernous sinus, and many surgical approaches have been described. For most of them, these tumors grow slowly and their partial removal can be a first option before complementary radiotherapy. We described herein a minimally invasive approach that could be useful for soft non-calcified chondrosarcomas.

Method And Results: We report a case of right parasellar chondrosarcoma, for which an extra-intradural extracavernous subtemporal approach allowed a safe effective partial removal.

Conclusion: This surgical approach is indicated in selected cases to obtain good decompression or partial removal of lesions involving the parasellar space and the petrous apex.
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http://dx.doi.org/10.1007/s00701-019-03989-zDOI Listing
November 2019

Is Gross Total Resection Reasonable in Adults with Craniopharyngiomas with Hypothalamic Involvement?

World Neurosurg 2019 Sep 14;129:e803-e811. Epub 2019 Jun 14.

Skull Base and Pituitary Surgical Department, Neurological Hospital Pierre Wertheimer, Hospices Civils de Lyon, Lyon; Inserm U1052, CNRS UMR5286, Lyon I University, Signaling, Metabolism and Tumor Progression, Cancer Center of Lyon, Lyon, France; University of Lyon, Université Claude Bernard, Lyon, France.

Objective: The treatment of hypothalamus-invading craniopharyngiomas, based on pediatric experience, is subtotal resection (STR) with radiotherapy. This strategy sometimes leads to uncontrollable tumor progression. In adults, with the use of endoscopic endonasal surgery (EES), does removing the hypothalamic part of the tumor-whenever possible-compromise the outcome of the patients?

Methods: We included adults with craniopharyngioma treated by a first EES in 2008-2016 by senior neurosurgeon (E.J.). Endocrine, ophthalmologic, and hypothalamic data were retrospectively collected, including body mass index (BMI), cognitive and social status, with a systematic follow-up interview. Magnetic resonance imaging scans were graded according to Puget classification: 0, no hypothalamic involvement; 1, hypothalamic displacement; and 2, hypothalamic involvement. Grade 2 tumors were separated into gross total resection (GTR) or STR.

Results: We included 22 patients aged 18-79 years. Presenting symptoms were visual (14, 64%), endocrine dysfunction (10, 45%), BMI >30 (8, 36%), and cognitive/psychiatric impairment (9, 41%). Fourteen (64%) were grade 2 craniopharyngiomas. GTR was performed in 14 (64%) patients. Postoperatively, 12/14 (86%) cases improved visually, and 20 (91%) needed hormone replacement therapy. There was no difference in BMI evolution in the GTR versus STR group, cognitive status was stable or improved in all patients except 1; 4/8 patients with STR experienced progression needing adjuvant treatment versus no patient with GTR.

Conclusions: EES GTR of grade 2 craniopharyngiomas does not cause major hypothalamic worsening, in contrast with children operated by cranial approaches. The surgeon's experience is key in deciding when to stop the dissection. Offering GTR whenever possible aims at avoiding tumor progression and radiotherapy.
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http://dx.doi.org/10.1016/j.wneu.2019.06.037DOI Listing
September 2019

Confirmation of a new therapeutic option for aggressive or dopamine agonist-resistant prolactin pituitary neuroendocrine tumors.

Eur J Endocrinol 2019 Aug;181(2):C1-C3

Fédération d'Endocrinologie, Centre de Référence Maladies Rares Hypophysaires (HYPO), Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine-resistant or aggressive prolactinomas. We discussed the two published cases and describe another case of poorly differentiated plurihormonal PIT-1-positive adenoma with moderate SSTR2 expression and intense STTR5 expression successfully treated with PAS-LAR 40 mg/month.
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http://dx.doi.org/10.1530/EJE-19-0359DOI Listing
August 2019

Full tractography for detecting the position of cranial nerves in preoperative planning for skull base surgery: technical note.

J Neurosurg 2019 Apr 19;132(5):1642-1652. Epub 2019 Apr 19.

4Department of Neurosurgery, Stanford University Medical Center, Stanford, California.

Objective: Diffusion imaging tractography has allowed the in vivo description of brain white matter. One of its applications is preoperative planning for brain tumor resection. Due to a limited spatial and angular resolution, it is difficult for fiber tracking to delineate fiber crossing areas and small-scale structures, in particular brainstem tracts and cranial nerves. New methods are being developed but these involve extensive multistep tractography pipelines including the patient-specific design of multiple regions of interest (ROIs). The authors propose a new practical full tractography method that could be implemented in routine presurgical planning for skull base surgery.

Methods: A Philips MRI machine provided diffusion-weighted and anatomical sequences for 2 healthy volunteers and 2 skull base tumor patients. Tractography of the full brainstem, the cerebellum, and cranial nerves was performed using the software DSI Studio, generalized-q-sampling reconstruction, orientation distribution function (ODF) of fibers, and a quantitative anisotropy-based generalized deterministic algorithm. No ROI or extensive manual filtering of spurious fibers was used. Tractography rendering was displayed in a tridimensional space with directional color code. This approach was also tested on diffusion data from the Human Connectome Project (HCP) database.

Results: The brainstem, the cerebellum, and the cisternal segments of most cranial nerves were depicted in all participants. In cases of skull base tumors, the tridimensional rendering permitted the visualization of the whole anatomical environment and cranial nerve displacement, thus helping the surgical strategy.

Conclusions: As opposed to classical ROI-based methods, this novel full tractography approach could enable routine enhanced surgical planning or brain imaging for skull base tumors.
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http://dx.doi.org/10.3171/2019.1.JNS182638DOI Listing
April 2019

Clinical, Pathological, and Molecular Factors of Aggressiveness in Lactotroph Tumours.

Neuroendocrinology 2019 3;109(1):70-76. Epub 2019 Apr 3.

Université de Lyon 1, Université de Lyon, Lyon, France.

The behaviour of lactotroph tumours varies between benign tumours, those cured by treatment, and that of aggressive tumours, and carcinomas with metastasis. Identification of clinical, pathological and molecular factors is essential for the early identification of patients that may have such aggressive tumours. Plasma prolactin levels and tumour size and invasion, per se, are not prognostic factors. However, tumours appearing at a young age (<20 years), especially in boys, and the presence of genetic predisposition have a poorer prognosis. In addition, lactotroph tumours in men differ from those in women, being larger, more often invasive, and resistant to dopamine agonists. They are also more often high-grade with a high risk of recurrence and malignancy. The expression of estrogen receptor α is lower than in women and is closely correlated to aggressiveness. Proliferation markers (Ki-67 expression: ≥3%, mitotic count n > 2) are correlated to invasion and proliferation, but, taken alone, their prognostic value is debatable. Based on a 5-tiered clinicopathological classification, and taking into account invasion and proliferation, a grade 2b (aggressive) lactotroph tumour has a 20× risk of progression compared to a grade 1a (benign) tumour. Moreover, lactotroph tumours are the second-most frequent aggressive and malignant tumour. Other factors, such as the expression of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]), the genes regulating invasion, differentiation and proliferation, adhesion molecules (E-cadherin), matrix metalloproteinase 9, and chromosome abnormalities (chromosomes 11, 19, and 1), have also been correlated with aggressiveness. Currently, clinical signs, a prognostic classification, and molecular and genetic markers may all help the clinician in the early identification of aggressive lactotroph tumours and enable stratification of their management.
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http://dx.doi.org/10.1159/000499382DOI Listing
May 2020

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability.

Front Endocrinol (Lausanne) 2018 30;9:706. Epub 2018 Nov 30.

Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France.

Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as , and , were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes () located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men.
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http://dx.doi.org/10.3389/fendo.2018.00706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283894PMC
November 2018

Pathological markers of somatotroph pituitary neuroendocrine tumors predicting the response to medical treatment.

Minerva Endocrinol 2019 Jun 7;44(2):129-136. Epub 2018 Dec 7.

University of Lyon 1, Lyon, France -

Acromegaly is mainly due to the somatotroph pituitary neuroendocrine tumors (PitNET)s. These have been subtyped into densely granulated (DG) and sparsely granulated (SG) tumors, which differ in clinical, histological and biological characteristics and in response to somatostatin analogs (SA)s. The variable remission rate after surgical resection, as first line treatment, has increased interest in identifying pathological markers to better predict the response to medical treatment. Several techniques have shown somatotroph tumors to express somatostatin receptors (SSTR)s, and mainly SSTR2 and SSTR5. The molecular methods appear to give contradictory results, are expansive and cannot be routinely performed. Immunohistochemistry, while being the most powerful technique, requires optimal fixation and the use of monoclonal antibodies against at least SSTR2 and SSTR5. Almost all somatotroph tumors express SSTR2 or SSTR5, and, in great majority, at a high level. More importantly, the type of SSTR, the level of expression, and the response to SA treatment appear well correlated. Indeed, a significantly higher expression of SSTR2 in DG compared to in SG tumors likely explains the better response of DG tumors to the normalization of growth hormone and insulin-like growth factor-1 under SA. However, a reproducible scoring and a cut-off from which the SA efficacy can be reliably predicted, remain to be found. In conclusion, the SSTR expression profile and morphological subtypes of the somatotroph tumor may help predict the response to medical treatment. Such pathological profiling could become a useful decision-making tool for clinicians in the context of a multidisciplinary approach, after surgery failure.
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http://dx.doi.org/10.23736/S0391-1977.18.02933-4DOI Listing
June 2019

Probabilistic Tractography to Predict the Position of Cranial Nerves Displaced by Skull Base Tumors: Value for Surgical Strategy Through a Case Series of 62 Patients.

Neurosurgery 2019 07;85(1):E125-E136

CREATIS Laboratory CNRS UMR5220, Inserm U1206, INSA-Lyon, University of Lyon 1, Lyon, France.

Background: Predicting the displacement of cranial nerves by tumors could make surgery safer and the outcome better. Recent advances in imaging and processing have overcome some of the limits associated with cranial nerve tractography, such as spatial resolution and fiber crossing. Among others, probabilistic algorithms yield to a more accurate depiction of cranial nerve trajectories.

Objective: To report how cranial nerve probabilistic tractography can help the surgical strategy in a series of various skull base tumors.

Methods: After distortion correction and region of interest seeding, a probabilistic tractography algorithm used the constrained spherical deconvolution model and attempted the reconstruction of cranial nerve trajectories in both healthy and displaced conditions.

Results: Sixty-two patients were included and presented: vestibular schwannomas (n = 33); cerebellopontine angle meningiomas (n = 15); arachnoid or epidermoid cysts (n = 6); cavernous sinus and lower nerves schwannomas (n = 4); and other tumors (n = 4). For each patient, at least one 'displaced' cranial nerve was not clearly identified on classical anatomical MRI images. All 372 cranial nerves were successfully tracked on each healthy side; among the 175 cranial nerves considered 'displaced' by tumors, 152 (87%) were successfully tracked. Among the 127 displaced nerves of operated patients (n = 51), their position was confirmed intraoperatively for 118 (93%) of them. Conditions that led to tractography failure were detailed. On the basis of tractography, the surgical strategy was adjusted for 44 patients (71%).

Conclusion: This study reports a cranial nerve probabilistic tractography pipeline that can: predict the position of most cranial nerves displaced by skull base tumors, help the surgical strategy, and thus be a pertinent tool for future routine clinical application.
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http://dx.doi.org/10.1093/neuros/nyy538DOI Listing
July 2019