Cleavage of an Aromatic C-C Bond in Ferrocene by Insertion of an Iridium Nitrido Nitrogen Atom.

The intermolecular cleavage of C-C bonds is a rare event. Herein, we report on a late transition-metal terminal nitrido complex, which upon oxidation undergoes insertion of the nitrido nitrogen atom into the aromatic C-C bond of ferrocene. This reaction path was confirmed through 15N and deuterium isotope labeling experiments of the nitrido complex and ferrocenium, respectively. Cyclic voltammetry and UV/vis spectroscopy monitoring of the reaction revealed that oxidation is the initial step, yielding the tentative radical cationic nitrido complex, which is experimentally supported by extended X and Q-band electron paramagnetic resonance (EPR) and ENDOR, UV/vis, vT 1H NMR, and vibrational spectroscopic data. Density functional theory (DFT) and multireference calculations of this highly reactive intermediate revealed an S = 1/2 ground state. The high reactivity can be traced to the increased electrophilicity in the oxidized complex. Based on high-level PNO-UCCSD(T) calculations and UV/vis kinetic measurements, it is proposed that the reaction proceeds by initial electrophilic exo attack of the nitrido nitrogen atom at the cyclopentadienyl ring and consecutive ring expansion to a pyridine ring.

AZD8055 enhances in vivo efficacy of afatinib in chordomas.

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Intracranial cellular schwannomas: a clinicopathological study of 20 cases.

AIMS: Cellular schwannoma is a specific subtype of schwannoma, prone to misinterpretation as a malignant neoplasm. Involvement of the intracranial compartment by these tumours is extremely rare. We aim to characterise this clinicopathological subgroup. METHODS AND RESULTS: We identified a total of 20 cellular schwannomas with predominant intracranial involvement. The mean age of the patients at the time of surgery was 37 years (range = 16-81), with a slight female predominance (1.5:1 ratio). The most common sites were the eighth (n = 8) and fifth (n = 6) cranial nerves. Three tumours involved the anterior cranial fossa/olfactory groove, and a single case involved the glossopharyngeal nerve. All tumours met established criteria for cellular schwannoma, and were composed of interlacing fascicles of spindle cells lacking Verocay bodies with minimal Antoni B pattern and variable chronic inflammation and foamy histiocytes. Rare findings included haemosiderin deposition (n = 6), necrosis (n = 4), brisk mitotic activity (>10 mitoses per 10 high-power fields) (n = 2), focal epithelioid morphology (n = 2), myxoid areas (n = 2), neuroblastoma-like pattern (n = 1) and granular cells (n = 1). Immunohistochemical stains demonstrated expression of Schwann cell markers (S100 protein, SOX10, collagen IV) and preserved H3 K27 trimethylation in all cases tested. Fourteen patients had postoperative follow-up, ranging from 2 months to 21 years (mean = 66 months). In patients with follow-up, local recurrence/persistence developed in six cases; five tumours were initially incompletely resected. No metastatic disease or deaths were reported. CONCLUSIONS: Intracranial cellular schwannomas share morphological and immunophenotypical features with cellular schwannomas at others sites may demonstrate locally aggressive growth but appear to lack metastatic potential.

Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types.

DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.

The consistency of neuropathological diagnoses in patients undergoing surgery for suspected recurrence of glioblastoma.

PURPOSE: Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor progression from pseudo-progression. As a result, surgery is commonly recommended to establish a final diagnosis. However, studies evaluating the pathologists' agreement on pathologic diagnoses in this setting have not been previously evaluated. METHODS: A hypothetical clinical history coupled with images of histological sections from 13 patients with glioblastoma who underwent diagnostic surgery for suspected early recurrence were sent to 101 pathologists from 50 NCI-designated Cancer Centers. Pathologists were asked to provide a final diagnosis (active tumor, treatment effect, or unable to classify) and to report on percent active tumor, treatment effect, and degree of cellularity and degree of mitotic activity. RESULTS: Forty-eight pathologists (48%) from 30 centers responded. In three cases > 75% of pathologists diagnosed active tumor. In two cases > 75% diagnosed treatment effect. However, in the remaining eight cases the disparity in diagnoses was striking (maximum agreement on final diagnosis ranged from 36 to 68%). Overall, only marginal agreement was observed in the overall assessment of disease status [kappa score 0.228 (95% CI 0.22-0.24)]. CONCLUSIONS: Confidence in any clinical diagnostic assay requires that very similar results are obtained from identical specimens evaluated by sophisticated clinicians and institutions. The findings of this study illustrate that the diagnostic agreement between different cases of repeat resection for suspected recurrent glioblastoma can be variable. This raises concerns as pathological diagnoses are critical in directing standard and experimental care in this setting.

Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma.

Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group.

BACKGROUND: Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. PROCEDURE: Patients enrolled in the study had high-risk disease defined as ≥1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. RESULTS: Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). CONCLUSIONS: Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data.

Intramedullary amputation neuroma: a case report and review of the literature.

BACKGROUND AND IMPORTANCE: Amputation neuromas consist of non-neoplastic collections of myelinated axons and Schwann cells and typically arise in injured peripheral nerves. Rarely, however, neuromas occur within the spinal cord. Intramedullary amputation neuromas have been described both with and without a history of trauma within the peripheral nervous system. We report a rare case of an isolated intramedullary spinal cord amputation neuroma. CLINICAL PRESENTATION: This 43-year-old man presented with progressive and severe gait deterioration for ~ 7 years. Neurological exam revealed multiple positive findings consistent with cervical myelopathy, including positive Babinski and Hoffman signs, sustained clonus with patellar and Achilles reflexes, bilateral lower extremity weakness with increased muscular tone and spasticity, and inability to tandem walk. Magnetic resonance imaging demonstrated a 0.6-cm, homogeneously enhancing, intramedullary tumor with surrounding signal change at the C6 level. The lesion was excised and histologic examination revealed microscopic features compatible with an amputation neuroma. CONCLUSION: Intramedullary amputation neuromas are rare and associated with either trauma or other CNS lesions. Our case represents an amputation neuroma in an unusual location in a patient without subjective preceding history of trauma or presence of a second lesion.
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Microglioma in a child - a further case in support of the microglioma entity and distinction from histiocytic sarcoma.

Microglia are not generally known to cause brain tumors but one bona fide case of adult microglioma has been published [9]. This tumor was highly malignant. We now report on a second, juvenile case, which showed a less aggressive course. Microglioma is a primary central nervous system (CNS) neoplasm distinct from glioma and other known brain tumor entities, based on its strong immunoreactivity for the macrophage marker CD163, the microglia marker Iba1, and the complete absence of neural as well as lymphocyte antigens. Furthermore, we have analyzed the literature and identified a number of cases that qualify as primary parenchymal histiocytic sarcomas of the CNS, which lack microglial morphology. Considering the non-hematopoietic developmental origin of the vast majority of microglia and the distinct morphological as well as immunophenotypic similarity of their neoplastic counterparts, we suggest using the term microglioma. More cases will be required along with appropriately-collected tissue to establish the molecular genetic profile of this extremely rare entity.

Management of pediatric intracranial low-grade gliomas: long-term follow-up after radiation therapy.

INTRODUCTION: The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. METHODS: Thirty-four patients <21 years old with intracranial LGG who were treated with RT at the Johns Hopkins Hospital were included in this retrospective analysis. Patients were evaluated for overall survival (OS), progression-free survival (PFS), recurrence patterns, and treatment toxicities using descriptive statistics, Kaplan-Meier curves, and Cox proportional hazard regressions. RESULTS: The mean age at diagnosis was 7.9 years (range 1.2-18.3 years) and mean age at RT was 9.8 years (range 3.0-28.9 years). The median follow-up time was 9.8 years after radiation (range 0.8-33.3 years). The estimated 10-year OS and PFS after RT were 92 and 74 %, respectively. Twelve patients had disease progression after RT, and all recurrences were local. Two patients died due to disease progression 2.3 and 9.1 years after RT. One patient had malignant transformation of LGG to high-grade glioma. No significant predictors of PFS were identified on uni- or multivariate analysis. Late effects of LGG and treatment seen were endocrine deficiencies in 16 patients, visual problems in 10 patients, hearing loss in 4 patients, special education requirements for 5 patients, and a vascular injury/demyelination secondary to RT in 1 patient. CONCLUSION: Our study suggests that the use of radiation in patients with intracranial LGG results in excellent OS and PFS with acceptable toxicity at long-term follow-up.

A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation.

Among brain tumors, the BRAF (V600E) mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF (V600) mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (

Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945.

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment.

Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children's Oncology Group.

BACKGROUND: Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial. PROCEDURE: Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine. RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five-year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M-stage was prognostic. Five-year OS and PFS for 37 patients with non-pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/- 11.4% for those undergoing complete resection versus 10.4 +/- 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) "classic" sPNET, 8 (22%) "undifferentiated" and 13 (35%) "malignant gliomas." There was no significant difference between the subgroups, although survival distributions approached significance when the combined "classic" and "undifferentiated" group was compared to the "malignant gliomas." CONCLUSIONS: Carboplatin during RT followed by 6 months of non-intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult.

Does perthionitrite (SSNO(-)) account for sustained bioactivity of NO? A (bio)chemical characterization.

Hydrogen sulfide (H2S) and nitric oxide (NO) are important signaling molecules that regulate several physiological functions. Understanding the chemistry behind their interplay is important for explaining these functions. The reaction of H2S with S-nitrosothiols to form the smallest S-nitrosothiol, thionitrous acid (HSNO), is one example of physiologically relevant cross-talk between H2S and nitrogen species. Perthionitrite (SSNO(-)) has recently been considered as an important biological source of NO that is far more stable and longer living than HSNO. In order to experimentally address this issue here, we prepared SSNO(-) by two different approaches, which lead to two distinct species: SSNO(-) and dithionitric acid [HON(S)S/HSN(O)S]. (H)S2NO species and their reactivity were studied by (15)N NMR, IR, electron paramagnetic resonance and high-resolution electrospray ionization time-of-flight mass spectrometry, as well as by X-ray structure analysis and cyclic voltammetry. The obtained results pointed toward the inherent instability of SSNO(-) in water solutions. SSNO(-) decomposed readily in the presence of light, water, or acid, with concomitant formation of elemental sulfur and HNO. Furthermore, SSNO(-) reacted with H2S to generate HSNO. Computational studies on (H)SSNO provided additional explanations for its instability. Thus, on the basis of our data, it seems to be less probable that SSNO(-) can serve as a signaling molecule and biological source of NO. SSNO(-) salts could, however, be used as fast generators of HNO in water solutions.

Expression of the pituitary stem/progenitor marker GFRα2 in human pituitary adenomas and normal pituitary.

PURPOSE: Recent studies suggest that adult pituitary stem cells may play a role in pituitary tumorigenesis. We sought to explore whether the Glial cell-line derived neurotrophic factor receptor alpha 2 (GFRα2), a recently described pituitary stem/progenitor marker, might be differentially expressed in pituitary adenomas versus normal pituitary. METHODS: The expression of GFRα2 and other members of the GFR receptor family (GFRα1, α3, α4) were analyzed using RT-PCR, western blot, and immunohistochemistry in 39 pituitary adenomas, 14 normal pituitary glands obtained at autopsy, and cDNA from 3 normal pituitaries obtained commercially. RESULTS: GFRα2 mRNA was ~2.6 fold under-expressed in functioning adenomas (p < 0.01) and ~3.5 fold over-expressed in non-functioning adenomas (NFAs) (p < 0.05) compared to normal pituitary. Among NFAs, GFRα2 was significantly over-expressed (~5-fold) in the gonadotropinoma subtype only (p < 0.05). GFRα2 protein expression appeared to be higher in most NFAs, although there was heterogeneity in protein expression in this group. GFRα2 protein expression appeared consistently lower in functioning adenomas by IHC and western blot. In normal pituitary, GFRα2 was localized in Rathke's remnant, the putative pituitary stem cell niche, and in corticotropes. CONCLUSION: Our results suggest that the pituitary stem cell marker GFRα2 is under-expressed in functioning adenomas and over-expressed in NFAs, specifically gonadotropinomas. Further studies are required to elucidate whether over-expression of GFRα2 in gonadotropinomas might play a role in pituitary tumorigenesis.

Long-term survival of children less than six years of age enrolled on the CCG-945 phase III trial for newly-diagnosed high-grade glioma: a report from the Children's Oncology Group.

BACKGROUND: We analyzed the long-term survival of children under 6 years of age (<6 years) enrolled upon the Children's Cancer Group (CCG)-945 high-grade glioma (HGG) study to determine the impact of intrinsic biological characteristics as well as treatment upon both survival and quality of life (QOL) in this younger age population. PROCEDURE: Analyses were undertaken on patients <6 years with institutionally diagnosed HGG enrolled on the CCG-945 trial. Comparisons of survival were performed for patients <3 years of age (<3 years) (treated with intent to avoid irradiation) versus those between 3 and 6 years of age (3-6 years) (treated with irradiation and chemotherapy) at diagnosis. Discordance between the institutional diagnoses of HGG and consensus-reviewed diagnoses led us to perform further survival analyses for both groups. We compared the two groups of patients for biological markers, and evaluated the neuropsychological and QOL outcomes of long-term survivors. RESULTS: Patients <3 years (n = 49, 19.5% of all enrolled patients) at diagnosis had a 10-year EFS and OS of 29 ± 6.5% and 37.5 ± 7%, respectively, while for patients 3-6 years (n = 34, 13.5% of all enrolled patients) 10-year EFS and OS were 35 ± 8% and 36 ± 8%, respectively. Molecular marker analysis showed that a smaller proportion of patients <3 years harbored TP53 mutations (P = 0.05). Analysis of QOL outcomes with a median length of follow-up of 15.1 years (9.5-19.2) showed comparable results. CONCLUSIONS: QOL and survival data were similar for the two groups. A larger prospective study is justified to study the efficacy of chemotherapy only regimens in younger children.

Invasive adenoma and pituitary carcinoma: a SEER database analysis.

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until identification of metastases. Optimal management and survival outcomes for both are not clearly defined. The purpose of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to report patterns of care and compare survival outcomes in a large series of patients with invasive adenomas or pituitary carcinomas. One hundred seventeen patients diagnosed between 1973 and 2008 with pituitary adenomas/adenocarcinomas were included. Eighty-three invasive adenomas and seven pituitary carcinomas were analyzed for survival outcomes. Analyzed prognostic factors included age, sex, race, histology, tumor extent, and treatment. A significant decrease in survival was observed among carcinomas compared to invasive adenomas at 1, 2, and 5 years (p = 0.047, 0.001, and 0.009). Only non-white race, male gender, and age ≥65 were significant negative prognostic factors for invasive adenomas (p = 0.013, 0.033, and <0.001, respectively). There was no survival advantage to radiation therapy in treating adenomas at 5, 10, 20, or 30 years (p = 0.778, 0.960, 0.236, and 0.971). In conclusion, pituitary carcinoma patients exhibit worse overall survival than invasive adenoma patients. This highlights the need for improved diagnostic methods for the sellar phase to allow for potentially more aggressive treatment approaches.

Si-H activation in an iridium nitrido complex--a mechanistic and theoretical study.

Si-H activation in triethyl- and triarylsilanes by a square-planar pyridine-diimine iridium complex with a terminal nitrido unit leads to the corresponding silyl amido complexes, which were unambiguously characterized by X-ray crystallography. Based on detailed combined kinetic and theoretical studies (DFT), direct addition of the Si-H bond to the iridium nitrido unit is proposed. The electronic propensities of the transition states for the Si-H activation were probed with a Hammett series of para-substituted triarylsilanes HSi(C6H5)2(4-C6H4-X). Based on the combination of experimental and theoretical studies, two independent pathways for this process are proposed, which point toward an ambiphilic propensity of the nitrido unit. Alternative pathways and the charge transfer in the transition states were also investigated. Furthermore, the barriers for the related H-H and C-H activation processes in dihydrogen and methane were analyzed.

Diffusion tensor imaging in a child with hypertrophic olivary degeneration.

Hypertrophic olivary degeneration (HOD) is caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). We present conventional magnetic resonance and diffusion tensor imaging (DTI) findings in a 6-year-old girl with HOD after surgery for a midbrain pilocytic astrocytoma. To our knowledge, this is the first dedicated DTI analysis of GMT in a child with HOD in the literature. In our patient, we found higher fractional anisotropy (FA) and axial diffusivity values of the inferior olivary nucleus (ION) and lower FA, but higher radial diffusivity (RD) values of all other GMT components compared to age-matched controls. Increased FA values of the ION may be explained by increased packing of white matter fibers. However, associated hyperintense T2 signal is contradictory and the association between increased FA values and hyperintense T2 signal remains unclear. Low FA and high RD values of the other GMT components likely reflect demyelination with axonal degeneration and correlate well with histopathological findings.