Objective: After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. Design and methods: This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Results: Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Conclusions: Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Significance statement: This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Introduction: Usually benign, pituitary tumors (PT) can be invasive and aggressive with a propensity to progress and/or recur. Trouillas's clinicopathological classification attempts to predict the evolutionary risk of a PT. In this study, we assessed the prognostic value of this classification in an independent patient cohort and analyzed its impact on treatment strategies. Patients and methods: In this study, 607 patients operated on between 2008 and 2018 for a PT were included. Grading was established based on invasion, proliferative activity (Ki-67, mitotic index) and p53 positivity. The therapeutic management following surgery was analyzed. Progression-free survival (PFS) of the graded tumors was estimated (Kaplan–Meier method and log-rank test) and a multivariate analysis was performed (Cox regression model). Results: Grading identified non-invasive PT without (grade 1a: 303 cases) or with proliferative activity (grade 1b: 53 cases) and invasive PT without (grade 2a: 202 cases) or with proliferative activity (grade 2b: 49 cases). The mean follow-up was 47 ± 30 months (median: 38 months). Progression/recurrence occurred in 127 cases. Grades were significant and independent predictors of PFS (P < 0.001) with a 4.8-fold higher risk of progression/recurrence in grade 2b as compared to grade 1a. As second-line therapy, gamma knife or conventional radiotherapy controlled tumor growth in 91.6 and 100% of cases, respectively, irrespective of the grade. Proliferative tumors exposed the patient to a 9.5-fold higher risk of having ≥3 adjuvant therapeutic lines as compared to non-proliferative tumors. Discussion: Grading of a PT according to Trouillas's classification predicts its risk of progression and should advocate for a personalized therapeutic approach in invasive and proliferative tumors. Significance statement: This is the first study to assess, on a cohort of 607 well-characterized patients, the real-life therapeutic impact of the five-tiered clinicopathological classification of pituitary tumors. First, we validate that pituitary tumor grades predict the evolutionary risk of the tumor, with a significant higher risk of progression/recurrence in invasive and/or proliferative tumors (mean follow-up: 47 ± 30 months, median: 38 months). Moreover, our study provides evidence that patients with proliferative tumors have a higher risk to be retreated after primary surgery and point toward the fact that radiotherapy can successfully control tumor growth in case of progression or recurrence. Our findings advocate for a personalized therapeutic approach in clinically aggressive pituitary tumors.

Context Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically-negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. Objective To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. Design Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. Patients We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French TENGEN network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants, i.e. with genetically-confirmed MEN4 diagnosis, in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. Results From 5600 MEN1-suspected patients analyzed, four patients with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, PHPT and adrenal nodule, isolated PHPT, PHPT and pNET. We listed 29 patients with CDKN1B class 4/5 variants from literature. Compared to matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. Conclusion The prevalence of MEN4 is low. PHPT and PA represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Toxoplasma gondii is a zoonotic protozoan with a worldwide occurrence, but the determinants of the current pattern in the geographical distribution of T. gondii lineages and strains remain poorly understood. To test the influence of human trade on T. gondii populations, we conducted a population genetic study of 72 T. gondii animal isolates from Senegal, a West African country in which the ongoing inland progress of invasive murine hosts (introduced in port cities of Senegal since the 16^th century by European sailors) is well described. Isolates were mainly collected on free-range poultry, which are considered as relevant bioindicators of T. gondii strain diversity in the domestic environment. Sampling was conducted in two port cities of Senegal (Dakar and Saint-Louis) and in one inland region (Kedougou). Population genetic analyses using 15 microsatellite markers revealed different patterns between port cities where lineages non-virulent for mice (type II, type III, and Africa 4) were predominant, and Kedougou where the mouse-virulent Africa 1 lineage was the most common. By considering the current spatial pattern in the inland progress of invasive rodents in Senegal, our results suggest that the invasive house mouse Mus musculus domesticus counter-selects the Africa 1 lineage in the invaded areas. The comparison of the microsatellite alleles of type II strains from Senegal to type II strains from other areas in Africa and Western Europe, using discriminant analysis of principal components and Network analysis, point to a mainly Western European origin of the type II lineage in Senegal. Collectively, these findings suggest that human-mediated intercontinental migrations of murine hosts are important vectors of T. gondii strains. Differential susceptibility of endemic and introduced murine hosts to various T. gondii strains probably determines the persistence of these strains in the environment, and therefore their availability for human and animal infection. Toxoplasma gondii is a zoonotic protozoan with a worldwide distribution and which can infects virtually all warm-blooded species, including human. Clinical expression of human toxoplasmosis, as well as T. gondii strains diversity, exhibit contrasting patterns across geographic regions. The determinants of this geographical structure are poorly understood, but a growing body of evidence supports an important role of human-mediated migrations of T. gondii hosts in the intercontinental dissemination of some parasite lineages. The results of our study conducted in Senegal suggest that the invasive house mouse—which was introduced in the port cities of this country through maritime trade since colonial times—has a dramatic influence on the T. gondii populations of invaded areas. This important T. gondii reservoir seems to be a vector for the intercontinental migrations of T. gondii. In addition, it may have a role in the selection (or the counter-selection) of local T. gondii populations found in invaded areas. This study provides insights into the mechanisms shaping T. gondii populations, thereby determining which strains will be available for human and animal infection.

The parasellar region, located around the sella turcica, is an anatomically complex area representing a crossroads for important adjacent structures. Several lesions, including tumoral, inflammatory vascular, and infectious diseases may affect this area. Although invasive pituitary tumors are the most common neoplasms encountered within the parasellar region, other tumoral (and cystic) lesions can also be detected. Craniopharyngiomas, meningiomas, as well as Rathke’s cleft cysts, chordomas, and ectopic pituitary tumors can primarily originate from the parasellar region. Except for hormone-producing ectopic pituitary tumors, signs and symptoms of these lesions are usually nonspecific, due to a mass effect on the surrounding anatomical structures (i.e., headache, visual defects), while a clinically relevant impairment of endocrine function (mainly anterior hypopituitarism and/or diabetes insipidus) can be present if the pituitary gland is displaced or compressed. Differential diagnosis of parasellar lesions mainly relies on magnetic resonance imaging, which should be interpreted by neuroradiologists skilled in base skull imaging. Neurosurgery is the main treatment, alone or in combination with radiotherapy. Of note, recent studies have identified gene mutations or signaling pathway modulators that represent potential candidates for the development of targeted therapies, particularly for craniopharyngiomas and meningiomas. In summary, parasellar lesions still represent a diagnostic and therapeutic challenge. A deeper knowledge of this complex anatomical site, the improvement of imaging tools, as well as novel insights into the pathophysiology of presenting lesions are strongly needed to improve the management of parasellar lesions.

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.