KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

IMPORTANCE: A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. OBJECTIVE: We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. RESULTS: One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Prognostic impact of hypothalamic perforation in adult patients with craniopharyngioma: a cohort study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension and hypothalamic involvement are essential for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in three groups, depending on the type of hypothalamus involvement assessed by preoperative MRI: infra-hypothalamic (type A, n=33); perforating the hypothalamus (type B, n=40); supra-hypothalamic (type C, n=6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%) and 5/6 (83%) patients in type A, B and C respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable or worsened in 6/40 (15%), 32/40 (80%) and 2/40 (5%) patients respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%) and 3/6 (50%) patients in types A, B and C respectively. In four patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF-mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

Endoscopic endonasal access to the lateral recess of the sphenoid sinus.

BACKGROUND: The standard endoscopic endonasal approach gives access to the median sphenoid sinus, but not to its lateral part. We propose an endoscopic technique for lesions in the lateral sphenoid sinus. METHOD: Based on our experience with 28 patients, we have developed a less invasive approach to the lateral recess of the sphenoid sinus, limiting the opening of the maxillary sinus while avoiding resection of the inferior turbinate and ethmoidal cells. The technique is described. CONCLUSION: The proposed endoscopic approach is reliable and safe to treat CSF leak or tumours located within the lateral recess of the sphenoid sinus.

Pituitary surgery outcome in patients 75 years and older: a retrospective study.

BACKGROUND: As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. METHODS: A retrospective cohort study of patients with pituitary adenomas and Rathke's cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. RESULTS: Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3-96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing's disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. CONCLUSIONS: Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

Anatomical variations of the cavernous Internal Carotid Artery: Validation of an MRI-based classification.

OBJECTIVE: Variations of the cavernous Internal Carotid Artery (ICA) angulation (C4-bend) have been classified into 4 anatomical subtypes with particular surgical relevance, as a very angulated ICA comes in closest contact with the pituitary gland leading to higher risk of iatrogenic vascular injury. This study aimed to validate this classification using current routine imaging techniques. METHODS: The different cavernous ICA bending angles were measured on 109 MRI TOF sequences, within a retrospective database of patients with no sellar lesions. Each ICA was classified into one of 4 anatomical subtypes as already defined in a previous study [1]. Interrater agreement was assessed by a Kappa Correlation Coefficient. RESULTS: Kappa Correlation Coefficient was of 0.90 [0.82-0.95], validating the strong level of agreement between all observers when using the present classification. CONCLUSION: Classification of the cavernous ICA in 4 subtypes appears statistically valid on routinely used pre-operative MRI, providing an efficient tool to estimate the vascular iatrogenic risk prior to endoscopic endonasal transsphenoidal surgery.

Corticotroph tumor progression speed after adrenalectomy.

Objectives: After bilateral adrenalectomy in Cushing's disease, corticotroph tumor progression occurs in one-third to half of patients. However, progression speed is variable, ranging from slow to rapid. The aim was to explore corticotroph progression speed, its consequences and its risk factors. Design: A retrospective single-center observational study. Methods: In total,103 patients with Cushing's disease who underwent bilateral adrenalectomy between 1990 and 2020 were included. Clinical, biological, histological and MRI features were collected. Median duration of follow-up after bilateral adrenalectomy was 9.31 years. Results: In total,44 patients progressed (43%). Corticotroph tumor progression speed ranged from 1 to 40.7 mm per year. Progression speed was not different before and after bilateral adrenalectomy (P = 0.29). In univariate analyses, predictive factors for rapid corticotroph tumor progression included the severity of Cushing's disease before adrenalectomy as the cause of adrenalectomy, high ACTH in the year following adrenalectomy and high Ki67 immunopositivity in the tumor. During follow-up, early morning ACTH absolute variation was associated with corticotroph tumor progression speed (P-value = 0.001). ACTH measurement after dynamic testing did not improve this association. Conclusion: After adrenalectomy, corticotroph progression speed is highly variable and manageable with MRI and ACTH surveillance. Progression speed does not seem related to bilateral adrenalectomy but rather to intrinsic properties of highly proliferative and secreting tumors.

Expanded endoscopic endonasal approach for the resection of midline craniopharyngiomas with hypothalamic involvement.

BACKGROUND: With relevant surrounding neurological structures and potential involvement of the hypothalamus, the surgical management of craniopharyngiomas is complex. Compared to the transcranial approach, the expanded endoscopic endonasal approach provides direct access to the supradiaphragmatic and retrochiasmatic areas without crossing nerves and arteries. METHOD: Based on our substantial experience of 68 patients operated on between 2008 and 2022 by endoscopic surgery, our strategy has evolved such that all of our midline infundibular craniopharyngiomas with hypothalamic involvement are currently treated with an expanded endonasal route, except for tumours isolated to the third ventricle. Vascularized mucosal nasoseptal flaps are required for closure. Fine details of the related anatomy and surgical technique are described. CONCLUSION: Expanded endoscopic endonasal approach is a safe and effective route for resection of midline suprasellar craniopharyngiomas with hypothalamic involvement in centres of expertise.

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study.

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.

Outcome of giant pituitary tumors requiring surgery.

Objective: The management of giant pituitary tumors is complex, with few publications and recommendations. Consequently, patient's care mainly relies on clinical experience. We report here a first large series of patients with giant pituitary tumors managed by a multidisciplinary expert team, focusing on treatments and outcome. Methods: A retrospective cohort study was conducted. Giant pituitary tumors were defined by a main diameter > 40mm. Macroprolactinomas sensitive to dopamine agonists were excluded. All patients were operated by a single neurosurgical team. After surgery, multimodal management was proposed, including hormone replacement, radiotherapy and anti-tumor medical therapies. Outcome was modeled using Kaplan-Meyer representation. A logistic regression model was built to identify the risk factors associated with surgical complications. Results: 63 consecutive patients presented a giant adenoma, most often with visual defects. Patients were operated once, twice or three times in 59%, 40% and 1% of cases respectively, mainly through endoscopic endonasal approach. Giant adenomas included gonadotroph, corticotroph, somatotroph, lactotroph and mixed GH-PRL subtypes in 67%, 14%, 11%, 6% and 2% of patients respectively. Vision improved in 89% of patients with prior visual defects. Severe surgical complications occurred in 11% of patients, mainly for tumors > 50 mm requiring microscopic transcranial approach. Additional radiotherapy was needed for 29% of patients, 3 to 56 months after first surgery. For 6% of patients, Temozolomide treatment was required, 19 to 66 months after first surgery. Conclusions: Giant pituitary tumors require multimodal management, with a central role of surgery. Most often, tumor control can be achieved by expert multidisciplinary teams.

Double pedicled nasoseptal flap for skull base repair after endoscopic expanded endonasal approach.

BACKGROUND: Expanded endonasal approach offers a spectacular corridor for skull base tumour resection but requires reliable multilayer reconstruction techniques with a vascularized nasoseptal flap. METHOD: On the basis on our substantial experience of 136 patients operated on between January 2008 and January 2020, the double pedicled nasoseptal flap technique was developed for skull base repair. The technique is finely detailed. The nasal floor mucosa was preserved. CSF leakage occurred in 4% of patients. CONCLUSION: Double pedicled nasoseptal flap is a reproducible and efficient technique for skull base reconstruction after expanded endonasal approach and is associated with limited rhinological complications.

Closure strategy for endoscopic pituitary surgery: Experience from 3015 patients.

Introduction: Effective strategies are required to ensure optimal management of the crucial closure step in endoscopic pituitary surgery. Many surgical techniques have been reported but no significant consensus has been defined. Methods: Between January 2006 and March 2022, 3015 adult patients with pituitary adenomas were operated on by a single expert neurosurgical team, using a mononostril endoscopic endonasal approach. Based of preoperative risk factors of and operative findings, a detailed closure strategy was used. Body mass index >40, sellar floor lysis, number of surgeries>2, large skull base destruction, prior radiotherapy were considered as preoperative risk factors for closure failure. All patients treated with an expanded endonasal approach were excluded. Results: Patients were mostly women (F/M ratio: 1.4) with a median age of 50 (range: 18 -89). Intraoperative CSF leak requiring specific surgical management was observed in 319/3015 (10.6%) of patients. If intraoperative leak occurred, patients with predictive risk factors were managed using a Foley balloon catheter in case of sellar floor lysis or BMI>40 and a multilayer repair strategy with a vascularized nasoseptal flap in other cases. Postoperative CSF leak occurred in 29/3015 (1%) of patients, while meningitis occurred in 24/3015 (0.8%) of patients. In patients with intraoperative leak, closure management failed in 11/319 (3.4%) of cases. Conclusion: Based on our significant 16-year experience, our surgical management is reliable and easy to follow. With a planned and stepwise strategy, the closure step can be optimized and tailored to each patient with a very low failure rate.

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.

OBJECTIVE: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. DESIGN: Follow-up of a cohort of consecutive patients treated by surgery. METHODS: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. RESULTS: Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. CONCLUSIONS: In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.

Pituitary surgery for Cushing's disease.

BACKGROUND: Surgery is currently the first-line treatment of Cushing's disease. Surgery for Cushing's patients requires technical specificity, especially if no adenoma is identified on dedicated preoperative pituitary MRI. METHOD: From 2006 to 2020, 683 patients with Cushing's disease were operated on with a mononostril endoscopic endonasal approach by the same two senior neurosurgeons. Here, we report the particularities of this challenging surgery. CONCLUSION: A rigorous and planned surgical strategy avoids the pitfalls of Cushing's disease surgery and leads to a high rate of endocrine remission.

Cognitive versus virtual reality simulation for evaluation of technical skills in neurosurgery.

OBJECTIVE: Simulation is gaining momentum as a new modality of medical training, particularly in acute care settings such as surgery. In the present study, the authors aimed to compare individual cognitive skills with manual abilities as assessed by virtual reality (VR) simulation among neurosurgical residents. METHODS: Participants were asked to complete a multiple-choice questionnaire assessing their surgical abilities regarding three basic neurosurgical procedures (endoscopic third ventriculostomy, cranial meningioma, and lumbar laminectomy). They subsequently performed these same three procedures on a VR simulator (NeuroTouch). RESULTS: The authors found that cognitive scores correlated with self-evaluation of surgical experience and autonomy. On the contrary, VR simulation, as assessed by NeuroTouch automated scoring, did not reflect participants' cognitive or self-evaluation of their surgical proficiency. CONCLUSIONS: The results of this study suggest that neurosurgical education should focus as much on cognitive simulation (e.g., careful planning and critical appraisal of actual procedures) as on VR training of visuomotor skills.

Sustained Tumor Control With MAPK Inhibition in BRAF V600-Mutant Adult Glial and Glioneuronal Tumors.

OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.

Clinical characteristics and long-term surgical outcome of spinal myxopapillary ependymoma: a French cohort of 101 patients.

PURPOSE: Myxopapillary ependymoma (MPE) is the most frequent tumor affecting the medullary conus. The surgical therapeutic management is still debated and only few studies have focused on the postoperative clinical outcome of patients. This study aimed to demonstrate long-term postoperative outcome and to assess the predictive factors of recurrence as well as the clinical evolution of these patients. METHODS: From 1984 to 2019, in four French centers, 101 adult patients diagnosed with MPE were retrospectively included. RESULTS: Median age at surgery was 39 years. Median tumor size was 50 mm and lesions were multifocal in 13% of patients. All patients benefited from surgery and one patient received postoperative radiotherapy. Gross total resection was obtained in 75% of cases. Sixteen percent of patients presented recurrence after a median follow-up of 70 months. Progression free survival at 5 and 10 years were respectively estimated at 83% and 79%. After multivariable analysis, sacral localization, and subtotal resection were shown to be independently associated with tumor recurrence. 85% of the patients had a favorable evolution concerning pain. 12% of the patients presented a postoperative deterioration of sphincter function and 4% of motor function. CONCLUSION: Surgery alone is an acceptable option for MPE patients. Patients with sacral location or incomplete resection are at high risk of recurrence and should be carefully monitored.

Mononostril endoscopic endonasal approach for pituitary surgery.

BACKGROUND: Most surgical teams currently consider that endoscopy has become the "gold standard" technique for the transsphenoidal approach to pituitary surgery. Pituitary adenomas are commonly benign tumours and should benefit from the least invasive approach. METHOD: In Foch Hospital, from 2006 to 2020, 2835 patients with pituitary adenomas were treated with a mononostril endoscopic endonasal approach. Here we describe the fine details of the nasal, sphenoidal and sellar steps of this technique. CONCLUSION: Complete preservation of the nasal corridor, luxation of the nasal septum and tailored sellar bone resection are essential for safe resection of pituitary adenomas.

Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis.

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.

Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature.

Once temozolomide has failed, no other treatment is recommended for pituitary carcinomas and aggressive pituitary tumors. Recently, the use of immune checkpoint inhibitors (ICIs) has raised hope, but so far, only one corticotroph carcinoma and one aggressive corticotroph tumor treated with immunotherapies have been reported in the literature. Here, we present two cases, one corticotroph carcinoma and one aggressive prolactinoma (the first one reported in the literature) treated with ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) every three weeks, followed by maintenance treatment with nivolumab (3 mg/kg every 2 weeks) in the case of the corticotroph carcinoma, and we compare them with the two previously reported cases. Patient #1 presented a biochemical partial response (plasma ACTH decreased from 13,813 to 841 pg/mL) and dissociated radiological response to the combined ipilimumab and nivolumab-the pituitary mass decreased from 37 × 32 × 41 to 29 × 23 × 42 mm, and the pre-existing liver metastases decreased in size (the largest one from 45 to 14 mm) or disappeared, while a new 11-mm liver metastasis appeared. The maintenance nivolumab (21 cycles) resulted in a stable disease for the initial liver metastases, and in progressive disease for the newly appeared metastasis (effectively treated with radiofrequency ablation) and the pituitary mass. Patient #2 presented radiological and biochemical progressive disease after two cycles of ICIs-the pituitary mass increased from 38 × 42 × 26 to 53 × 57 × 44 mm, and the prolactin levels increased from 4410 to 9840 ng/mL. In conclusion, ICIs represent a promising therapeutic option for aggressive pituitary tumors and carcinomas. The identification of subgroups of responders will be key.