Complete Response of a Patient With a Mismatch Repair Deficient Aggressive Pituitary Adenoma to Immune Checkpoint Inhibitor Therapy: A Case Report.

BACKGROUND AND IMPORTANCE: Aggressive pituitary adenomas (APAs) are pituitary tumors that are refractory to standard treatments and carry a poor prognosis. Current treatment guidelines are not standardized but combine surgical resection, radiation therapy, and chemotherapy. Temozolomide is the only chemotherapeutic agent with documented effectiveness and is recommended for APA in European Society of Endocrinology clinical guidelines. CLINICAL PRESENTATION: A 57-year-old man presented with visual deterioration and bitemporal hemianopsia. MRI of the brain demonstrated a sellar mass suspected to be pituitary macroadenoma with displacement of the stalk and optic nerve impingement. The patient underwent stereotactic endoscopic transsphenoidal resection of the mass. Postoperative MRI demonstrated gross total resection. Pathology revealed a sparsely granulated corticotroph adenoma with malignant transformation. Immunohistochemistry showed loss of expression of MLH1 and PMS2 in the tumor cells. Proton therapy was recommended given an elevated Ki67 index and p53 positivity. Before radiotherapy, there was no radiographic evidence of residual tumor. Temozolomide therapy was initiated after surveillance MRI showed recurrence at 16 months postoperatively. However, MRI demonstrated marked progression after 3 cycles. Next-generation sequencing using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C . Immunotherapy with ipilimumab/nivolumab was initiated, and MRI demonstrated no residual tumor burden 34 months postoperatively. CONCLUSION: APA is a tumor with frequent recurrence and a short median expected length of survival. Here, we demonstrate the utility of immunotherapy in a single case report of APA, with complete resolution of recurrent APA and improved survival compared with life expectancy.

Comprehensive Diagnosis and Surgical Management of Cushing Disease: Two-Dimensional Angiographic and Operative Video.

Cushing disease (CD), or hypercortisolemia secondary to an adrenocorticotropic hormone-secreting (ACTH-secreting) pituitary adenoma, is the most common etiology of noniatrogenic Cushing syndrome.1 The diagnostic algorithm employed in the patient with suspected CD is complex and includes consideration for inferior petrosal sinus sampling (IPSS).2,3 When workup is consistent with CD, extracapsular resection of the ACTH-secreting pituitary adenoma through the endonasal corridor is the preferred operative strategy.4 In this publication, we discuss the case of a 26-year-old woman who presented with 9 months of weight gain (Video 1). Initial labs, including low- and high-dose dexamethasone suppression tests, were consistent with CD. Findings on dynamic magnetic resonance imaging were suggestive of a left 2-mm microadenoma. IPSS confirmed central origin of hypercortisolemia and was indicative of a left-sided focus. The patient was taken to the operating room for endoscopic endonasal approach for extracapsular resection of left-sided, ACTH-secreting microadenoma. Following surgery, the patient required glucocorticoid supplementation after her cortisol levels decreased to 2 ug/dL the evening of surgery. Subsequent laboratory analysis has been consistent with hormonal cure.5,6 The accompanying video manuscript describes 1) preoperative diagnostic evaluation of the patient with suspected CD, 2) indications for and techniques of IPSS, 3) nuances of endoscopic transsphenoidal surgical management, and 4) relevant considerations in postoperative care. Of note, full patient consent for photography and/or recording of other forms of video/imaging was obtained in the preoperative period.7-10.

Case Report of Transgender Patient with Gonadotropic Dysfunction Secondary to Craniopharyngioma: Toward Improving Understanding of Biopsychosocial Dynamics of Gender Identity in Neurosurgical Care.

BACKGROUND: There is a paucity of information in the literature linking possible neuroendocrinologic repercussions of anterior pituitary insufficiency from tumor-associated mass effect with gender identity in transindividuals. The authors present the case of a 26-year-old transgender woman who was found to have a sellar/suprasellar neoplasm after reporting loss of vision in a bitemporal distribution. CASE DESCRIPTION: Magnetic resonance imaging demonstrated a 2.6-cm complex cystic and solid sellar/suprasellar mass, suggestive of craniopharyngioma, intimately associated with the pituitary stalk. Importantly, this radiographic diagnosis was made 2 years following the initiation of gender-affirming hormone therapy (HT). Laboratory testing following radiographic diagnosis demonstrated evidence of diffuse anterior pituitary insufficiency with decreased morning cortisol, free thyroxine, insulin-like growth factor-1, and testosterone. Following optimization with the endocrinology team, the patient was taken to the operating room for expanded endonasal resection of tumor with lumbar drain insertion and nasoseptal flap coverage. Gross total resection was achieved with marked improvement in vision noted following surgery. The patient continued her HT following surgery. CONCLUSIONS: In hindsight, the neuroendocrinologic manifestations of the craniopharyngioma may have influenced distressing pubertal experiences that distanced her from her assigned male sex, as well as the desired effects of feminization HT in this patient, ultimately delaying her presentation to the neurosurgery service and diagnosis of craniopharyngioma. As the first report of the neurosurgical evaluation and treatment of a transgender patient with anterior pituitary insufficiency secondary to craniopharyngioma, this case examines the biopsychosocial interplay between the development of gender identity and the neuroendocrinologic manifestations of craniopharyngioma.

An algorithm to improve lateralization accuracy of inferior petrosal sinus sampling: procedural nuances for complex patterns of venous drainage. Patient series.

BACKGROUND: Inferior petrosal sinus sampling (IPSS) is a useful technique in the diagnosis of Cushing's disease (CD) when the imaging finding is negative or equivocal. Different authors have reported considerable variability in the ability to determine tumor laterality with IPSS. Here the authors present a retrospective case series of 7 patients who underwent IPSS using a systematic algorithm to improve lateralization accuracy by identifying optimal sampling sites on the basis of individual cavernous sinus drainage patterns in each patient. OBSERVATIONS: Of the 7 patients identified, 6 were determined to have CD and subsequently underwent surgery. IPSS was accurate in all patients from whom laterality was predicted. Arterial and venous angiography were used to define cavernous sinus drainage patterns and determine optimal sampling sites. All patients who underwent surgery achieved hormonal cure. LESSONS: All IPSS predictions of lateralization were correct when available, and all patients who underwent surgery achieved hormonal cure. Advances in angiographic techniques for identification of the site of primary drainage from the cavernous sinus and subsequent optimization of microcatheter placement may improve the ability to predict tumor laterality.

Impaired ribosome biogenesis disrupts the integration between morphogenesis and nuclear duplication during the germination of Aspergillus fumigatus.

Aspergillus fumigatus is an important opportunistic fungal pathogen that is responsible for high mortality rates in the immunosuppressed population. CgrA, the A. fumigatus ortholog of a Saccharomyces cerevisiae nucleolar protein involved in ribosome biogenesis, contributes to the virulence of this fungus by supporting rapid growth at 37 degrees C. To determine how CgrA affects ribosome biogenesis in A. fumigatus, polysome profile and ribosomal subunit analyses were performed on both wild-type A. fumigatus and a DeltacgrA mutant. The loss of CgrA was associated with a reduction in the level of 80S monosomes as well as an imbalance in the 60S:40S subunit ratio and the appearance of half-mer ribosomes. The gene expression profile in the DeltacgrA mutant revealed increased abundance of a subset of translational machinery mRNAs relative to the wild type, suggesting a potential compensatory response to CgrA deficiency. Although DeltacgrA conidia germinated normally at 22 degrees C, they swelled excessively when incubated at 37 degrees C and accumulated abnormally high numbers of nuclei. This hypernucleated phenotype could be replicated pharmacologically by germinating wild-type conidia under conditions of reductive stress. These findings indicate that the germination process is particularly vulnerable to global disruption of protein synthesis and suggest that CgrA is involved in both ribosome biogenesis and polarized cell growth in A. fumigatus.

Aggressive granular cell tumor of the neurohypophysis with optic tract edema and invasion into third ventricle.

BACKGROUND: Granular cell tumors (GCTs) of the neurohypophysis are parasellar tumors arising from pituicytes in the neurohypophysis and are generally considered benign slow-growing tumors. We present a case of sellar GCT with aggressive features. CASE DESCRIPTION: A 70-year-old female presented with progressive vision impairment found to have bitemporal visual field defects. Subsequent magnetic resonance imaging (MRI) revealed a 2.9 cm × 2.5 cm × 2.5 cm parasellar mass with extension into the third ventricle and causing optic tract edema (OTE). Right frontotemporal orbital craniotomy was performed and the tumor was partially removed to decompress optic nerves. Pathology identified the tumor as granular tumor of the sellar region. The patient's vision improved minimally after the surgery. Follow-up MRI after 3 months and 11 months showed stable left OTE. CONCLUSION: GCTs were thought to be benign tumors with slow growth, but they could potentially possess aggressive features and invade into surrounding structures as described in this case. OTE can be a rare MRI finding of GCTs. Only one case of GCT-related OTE has been reported in literature to our best knowledge.

Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status.

Context: During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role. Objective: To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls. Design: Randomized, placebo-controlled, double-blinded crossover study. Setting: Academic clinical research unit. Participants: Eleven normal, postmenarcheal girls, ages 12 to 15 years. Intervention: Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover). Main Outcome Measures: LH pulse frequency during waking and sleeping hours. Results: Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007). Conclusions: In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.

Doxycycline-regulated gene expression in the opportunistic fungal pathogen Aspergillus fumigatus.

BACKGROUND: Although Aspergillus fumigatus is an important human fungal pathogen there are few expression systems available to study the contribution of specific genes to the growth and virulence of this opportunistic mould. Regulatable promoter systems based upon prokaryotic regulatory elements in the E. coli tetracycline-resistance operon have been successfully used to manipulate gene expression in several organisms, including mice, flies, plants, and yeast. However, the system has not yet been adapted for Aspergillus spp. RESULTS: Here we describe the construction of plasmid vectors that can be used to regulate gene expression in A. fumigatus using a simple co-transfection approach. Vectors were generated in which the tetracycline transactivator (tTA) or the reverse tetracycline transactivator (rtTA2s-M2) are controlled by the A. nidulans gpdA promoter. Dominant selectable cassettes were introduced into each plasmid, allowing for selection following gene transfer into A. fumigatus by incorporating phleomycin or hygromycin into the medium. To model an essential gene under tetracycline regulation, the E. coli hygromycin resistance gene, hph, was placed under the control of seven copies of the TetR binding site (tetO7) in a plasmid vector and co-transfected into A. fumigatus protoplasts together with one of the two transactivator plasmids. Since the hph gene is essential to A. fumigatus in the presence of hygromycin, resistance to hygromycin was used as a marker of hph reporter gene expression. Transformants were identified in which the expression of tTA conferred hygromycin resistance by activating expression of the tetO7-hph reporter gene, and the addition of doxycycline to the medium suppressed hygromycin resistance in a dose-dependent manner. Similarly, transformants were identified in which expression of rtTA2s-M2 conferred hygromycin resistance only in the presence of doxycycline. The levels of doxycycline required to regulate expression of the tetO7-hph reporter gene were within non-toxic ranges for this organism, and low-iron medium was shown to reduce the amount of doxycycline required to accomplish regulation. CONCLUSIONS: The vectors described in this report provide a new set of options to experimentally manipulate the level of specific gene products in A. fumigatus.

Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report.

INTRODUCTION: Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor. CASE PRESENTATION: Our patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight. CONCLUSIONS: The rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.

The Aspergillus fumigatus metacaspases CasA and CasB facilitate growth under conditions of endoplasmic reticulum stress.

We have examined the contribution of metacaspases to the growth and stress response of the opportunistic human mould pathogen, Aspergillus fumigatus, based on increasing evidence implicating the yeast metacaspase Yca1p in apoptotic-like programmed cell death. Single metacaspase-deficient mutants were constructed by targeted disruption of each of the two metacaspase genes in A. fumigatus, casA and casB, and a metacaspase-deficient mutant, DeltacasA/DeltacasB, was constructed by disrupting both genes. Stationary phase cultures of wild-type A. fumigatus were associated with the appearance of typical markers of apoptosis, including elevated proteolytic activity against caspase substrates, phosphatidylserine exposure on the outer leaflet of the membrane, and loss of viability. By contrast, phosphatidylserine exposure was not observed in stationary phase cultures of the DeltacasA/DeltacasB mutant, although caspase activity and viability was indistinguishable from wild type. The mutant retained wild-type virulence and showed no difference in sensitivity to a range of pro-apoptotic stimuli that have been reported to initiate yeast apoptosis. However, the DeltacasA/DeltacasB mutant showed a growth detriment in the presence of agents that disrupt endoplasmic reticulum homeostasis. These findings demonstrate that metacaspase activity in A. fumigatus contributes to the apoptotic-like loss of membrane phospholipid asymmetry at stationary phase, and suggest that CasA and CasB have functions that support growth under conditions of endoplasmic reticulum stress.

Nucleolar localization of Aspergillus fumigatus CgrA is temperature-dependent.

Pathogenic fungi must adapt to multiple adverse environmental conditions during the transition from the environment to a mammalian host, one of which is temperature. The ability of Aspergillus fumigatus to grow optimally under conditions of thermal stress requires the nucleolar protein CgrA. In this study, we have determined how temperature affects the intracellular localization of CgrA in A. fumigatus using a green fluorescent protein (GFP)-tagging approach. At 22 degrees C, CgrA was almost exclusively in the nucleolus, with a ratio of nucleolar to cytoplasmic fluorescence of 10:1. At 37 degrees C, the ratio of nucleolar to cytoplasmic fluorescence was reduced fivefold, and increased correspondingly in the cytoplasm. This effect was not seen with the nucleolar protein NopA in wild-type A. fumigatus. However, in a DeltacgrA mutant NopA was delocalized from the nucleolus at 37 degrees C but not at 22 degrees C. These results provide evidence for a temperature-dependent mechanism of intracellular localization for CgrA, and suggest that CgrA facilitates nucleolar compartmentalization of NopA at higher temperature.

A fungus-specific ras homolog contributes to the hyphal growth and virulence of Aspergillus fumigatus.

The Ras family of GTPase proteins has been shown to control morphogenesis in many organisms, including several species of pathogenic fungi. In a previous study, we identified a gene encoding a fungus-specific Ras subfamily homolog, rasB, in Aspergillus fumigatus. Here we report that deletion of A. fumigatus rasB caused decreased germination and growth rates on solid media but had no effect on total biomass accumulation after 24 h of growth in liquid culture. The DeltarasB mutant had an irregular hyphal morphology characterized by increased branching. Expression of rasBDelta113-135, a mutant transgene lacking the conserved rasB internal amino acid insertion, did not complement the deletion phenotype of delayed growth and germination rates and abnormal hyphal morphology. Virulence of the rasB deletion strain was diminished; mice infected with this strain exhibited approximately 65% survival compared to approximately 10% with wild-type and reconstituted strains. These data support the hypothesis that rasB homologs, which are highly conserved among fungi that undergo hyphal growth, control signaling modules important to the directional growth of fungal hyphae.

Disruption of the Aspergillus fumigatus gene encoding nucleolar protein CgrA impairs thermotolerant growth and reduces virulence.

Aspergillus fumigatus CgrA is the ortholog of a yeast nucleolar protein that functions in ribosome synthesis. To determine how CgrA contributes to the virulence of A. fumigatus, a Delta cgrA mutant was constructed by targeted gene disruption, and the mutant was reconstituted to wild type by homologous introduction of a functional cgrA gene. The Delta cgrA mutant had the same growth rate as the wild type at room temperature. However, when the cultures were incubated at 37 degrees C, a condition that increased the growth rate of the wild-type and reconstituted strains approximately threefold, the Delta cgrA mutant was unable to increase its growth rate. The absence of cgrA function caused a delay in both the onset and rate of germination at 37 degrees C but had little effect on germination at room temperature. The Delta cgrA mutant was significantly less virulent than the wild-type or reconstituted strain in immunosuppressed mice and was associated with smaller fungal colonies in lung tissue. However, this difference was less pronounced in a Drosophila infection model at 25 degrees C, which correlated with the comparable growth rates of the two strains at this temperature. To determine the intracellular localization of CgrA, the protein was tagged at the C terminus with green fluorescent protein, and costaining with propidium iodide revealed a predominantly nucleolar localization of the fusion protein in living hyphae. Together, these findings establish the intracellular localization of CgrA in A. fumigatus and demonstrate that cgrA is required for thermotolerant growth and wild-type virulence of the organism.