BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

Diagnosis and management of children and adult craniopharyngiomas: a French Endocrine Society/French Society for Paediatric Endocrinology & Diabetes Consensus Statement.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

A quick access to information on influenza burden and prevention in Lyon university hospital: A prospective QR code-based information campaign in 2022-2023.

BACKGROUND: Influenza vaccines are effective in decreasing hospitalizations and mortality related to influenza and its complications. However, the Vaccine Coverage Rate of influenza remains low and multifaceted efforts are required to improve it. The aim of this study was to assess the impact on influenza vaccine perception using a digital tool among outpatients and health care workers (HCWs). METHODS: A study was performed among outpatients and the HCWs of 23 hospital departments from 4 hospitals affiliated to Lyon university Hospitals (France), between October 2022 and February 2023. By scanning QR (Quick Response) codes, displayed on posters for patients, their companions, as well as in the letters sent to HCWs, users accessed anonymously to a web-application (ELEFIGHT®), which provided information on influenza and invited them to initiate a discussion on influenza prevention with their physicians during the consultation. Patients were also invited to complete a questionnaire regarding their perception of influenza vaccination before and after reading the information on ELEFIGHT®. The retention rate (RR = proportion of people who remain on the page for >2 s), the conversion rate (CR = proportion of people who click on the "Call-To-Action" button) and the absolute variation (difference in the perception before/after) and relative variation (absolute change as a percentage of the initial perception) in perception regarding influenza vaccination before and after consulting the application were calculated. RESULTS: 3791 scans were performed by 3298 patients and/or their companions with a RR of 52% and a CR of 55.1% and 253 scans by 221 HCWs with a RR of 71.2% and a CR of 115.3%. Participants spent an average of 47 s on the application. The questionnaire on influenza vaccination perception was completed by 1533 participants (46.5%); 1390 (90.7%) maintained the same position (neutral, favorable or unfavorable) on this vaccination before and after consulting the application. The relative variations in favor of vaccination were + 7.2% (unfavorable then favorable) and + 19.8% (neutral then favorable). CONCLUSION: This study suggests that a facilitated direct access to medical information through QR codes disseminated in health settings can help nudge people to foster their awareness of influenza and its prevention. Future deployments in a similar context or to other populations could be envisaged. Other vaccine-preventable and/or chronic diseases could also be the target of similar projects as part of public health programs.

Acromegaly Disease Control Maintained After Switching From Injected Somatostatin Receptor Ligands to Oral Paltusotine.

CONTEXT: Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs). METHODS: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL. RESULTS: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs. CONCLUSION: Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.

Gonadotropic status in adult women with pituitary stalk interruption syndrome.

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.

Impact of exenatide on weight loss and eating behavior in adults with craniopharyngioma-related obesity: the CRANIOEXE randomized placebo-controlled trial.

IMPORTANCE: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. OBJECTIVE: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO. DESIGN: A double-blind multicenter superiority randomized clinical in trial in two parallel arms. SETTING: Eleven French University Hospital Centers. PARTICIPANTS: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year. INTERVENTIONS: Exenatide or placebo injected subcutaneously twice a day during 26 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile. RESULTS: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events). CONCLUSIONS AND RELEVANCE: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.

A proposed clinical classification for pituitary neoplasms to guide therapy and prognosis.

No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas.

Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide.

Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.

Carney complex predisposes to breast cancer: prospective study of 50 women.

OBJECTIVE: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. DESIGN: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. METHODS: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. RESULTS: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. CONCLUSIONS: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT00668291.

Pituitary apoplexy score, toward standardized decision-making: a descriptive study.

Pituitary apoplexy (PA), a rare and life-threatening complication of pituitary adenomas, prompts urgent glucocorticoid administration. The optimal surgical approach is debated, and the Pituitary Apoplexy Score (PAS) aids decision-making. Our retrospective study (2003-2022) assesses variables in PA patient groups (surgical vs. non-surgical), applying PAS to establish a significant threshold for surgical decisions. Additionally, we aim to compare the rates of ophthalmological and endocrine deficit between both groups and identify any associated variables. PAS discrepancies were observed, with averages of 1.7 ± 1.7 (p < 0.0001) for conservative and 3.9 ± 1.7 (p < 0.0001) for surgical groups, confirmed by multivariate analysis (p = 0.009). A PAS threshold of 5, showing over 80% positive predictive value, was established. Patients with low prolactin levels (< 5 ng/ml) had higher corticotropic deficiency prevalence at 3-month and 1-year follow-ups (p = 0.017 and 0.027). Our study supports PAS as a valuable PA management tool, suggesting potential variable adjustments. Multicenter studies are crucial due to PA's low incidence.

Pasireotide: potential treatment option for McCune-Albright-associated acromegaly.

Only 30% of patients with McCune-Albright syndrome (MAS)-associated acromegaly achieve biochemical control under first-generation somatostatin receptor ligands (fg-SRLs), while pegvisomant fails to normalize insulin-like growth factor 1 (IGF-I) in >20% of cases. Here, we report all the patients with MAS-associated acromegaly treated with pasireotide long-acting release (LAR) in our center. Pasireotide LAR 20 mg/month resulted in rapid and long-term IGF-I normalization in patients #1 and #3. Patient #3 was resistant to fg-SRLs, while patient #1 was also controlled on fg-SRLs. In patient #2, resistant to fg-SRLs and uncontrolled on pegvisomant 40 mg/day combined with cabergoline 0.5 mg/day, pegvisomant was replaced with pasireotide LAR 40 mg/month, resulting in the near normalization of IGF-I levels. All 3 patients developed intermittent impaired fasting glucose, without the need for glucose-lowering drugs. Thus, pasireotide LAR is clearly useful as third-line therapy, and potentially even as second-line therapy, in MAS-associated acromegaly.

scAN1.0: A reproducible and standardized pipeline for processing 10X single cell RNAseq data.

Single cell transcriptomics has recently seen a surge in popularity, leading to the need for data analysis pipelines that are reproducible, modular, and interoperable across different systems and institutions.To meet this demand, we introduce scAN1.0, a processing pipeline for analyzing 10X single cell RNA sequencing data. scAN1.0 is built using the Nextflow DSL2 and can be run on most computational systems. The modular design of Nextflow pipelines enables easy integration and evaluation of different blocks for specific analysis steps.We demonstrate the usefulness of scAN1.0 by showing its ability to examine the impact of the mapping step during the analysis of two datasets: (i) a 10X scRNAseq of a human pituitary gonadotroph tumor dataset and (ii) a murine 10X scRNAseq acquired on CD8 T cells during an immune response.

First evidence of anti-VEGF efficacy in an adult case of adamantinomatous craniopharyngioma: Case report and illustrative review.

BACKGROUND: Craniopharyngioma (CP) is a neurosurgical challenge, due to location and to the substantial risk of morbidity associated with surgical resection. Recent advances in molecular research have identified a mutation signature in papillary craniopharyngiomas: BRAF V600E. This has led to targeted therapy, yielding positive results. Despite numerous studies of the pathophysiology of adamantinomatous craniopharyngioma, treatment options for molecular-based therapy are still lacking. The objective of our study was to provide an illustrative review of the literature on possible molecular targets in adamantinomatous craniopharyngioma and to report the case of a patient harboring an adamantinomatous craniopharyngioma deemed unsuitable for surgical resection, in which an anti-VEGF antibody was used to achieve tumor control. CASE REPORT: An 84-year-old-man was referred to our department with a history of visual loss caused by recurrent infundibular adamantinomatous craniopharyngioma. A first surgical attempt to reduce the cystic portion of the tumor compressing the optic pathway failed. Due to rapid worsening of visual function, adjuvant therapy with bevacizumab was initiated before radiotherapy. RESULTS: Neuroradiological and ophthalmological follow-up showed a decrease in tumor volume and improvement in visual function as early as 6 weeks after commencing therapy. These results were confirmed 3 months after commencement of chemotherapy. Radiotherapy was scheduled for long-term tumor control. CONCLUSIONS: To the best of our knowledge, our case is the first in the literature in which targeted therapy using anti-VEGF was successfully used as a single agent to treat adamantinomatous craniopharyngioma, with favorable outcome in terms of tumor shrinkage and clinical improvement. These preliminary results may open new perspectives for the management of adamantinomatous craniopharyngioma. Validation of this approach requires additional clinical evidence.