Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations.

BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. RESULTS: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). CONCLUSIONS: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Risk factors associated with in-hospital complications for pediatric sickle-cell disease-associated moyamoya syndrome: a nationwide cross-sectional study.

PURPOSE: Sickle-cell disease-associated moyamoya syndrome (SCD-MMS) carries a high risk for recurrent strokes and cerebrovascular morbidity in children. However, few data are available about complications that occur in children hospitalized with SCD-MMS. The purpose of this analysis was to determine the risk factors for in-hospital complications in pediatric SCD-MMS admissions, and thus aid physicians in optimizing future treatment plans. METHODS: A national database of pediatric hospital admissions was examined across the years 2003-2019. ICD-9 and ICD-10 diagnosis codes were analyzed to identify discharges with a primary diagnosis of SCD-MMS and identify in-hospital complications, defined as complication-associated diagnostic codes logged during the same admission. Patient demographics, comorbidities, and hospital characteristics were examined using univariate and multivariate logistic regression analyses to determine associations with in-hospital complications. RESULTS: In total, 274 admissions with a primary diagnosis of SCD-MMS were identified. During 64 (23.4%) admissions, transfusion therapy was given, and in 86 admissions (31.4%), surgical revascularization was performed. In 10 admissions (3.6%), a total of 11 in-hospital complications were identified. After multivariate regression, both comorbid chronic lung disease (adjusted OR 5.3 [1.1, 26.9], P = 0.04) and surgical revascularization (adjusted OR 10.2 [2.0, 52.4], P = 0.006) were associated with development of complications. CONCLUSIONS: In this nationwide database of pediatric SCD-MMS hospitalizations, comorbid chronic lung disease and surgical revascularization were associated with development of in-hospital complications. Patients with comorbid chronic lung disease or who are admitted for revascularization may warrant closer monitoring and greater medical optimization during the hospitalization.

Socioeconomic differences between medically and surgically treated prolactinomas: a retrospective review of 598 patients.

OBJECTIVE: Socioeconomic status (SES) is known to affect presentations and outcomes in pituitary neuroendocrine tumor resections, but there is a paucity of literature examining its impact specifically on patients with prolactinomas, who may be treated medically or surgically. The authors sought to determine whether SES was associated with differences in treatment choice or outcomes for prolactinoma patients. METHODS: The authors retrospectively reviewed patient records at a high-volume academic pituitary center for prolactinoma diagnoses. Patients were split into medically and surgically treated cohorts. Race, ethnicity, insurance status, primary care physician (PCP) status, and zip code-based income data were collected and examined as socioeconomic covariates. Outcomes of interest included pretreatment likelihood of surgical cure, medical versus surgical treatment allocation, and posttreatment remission rates. RESULTS: The authors analyzed 568 prolactinoma patients (351 medically treated and 217 surgically treated). Patients receiving surgery were more likely to have Medicaid or private insurance (p < 0.001) and have lower incomes (p < 0.001) than medically treated patients. Lower-income surgical patients were more likely to require surgical intervention for an indication such as tumor decompression than higher-income patients (p = 0.023). Surgical patients with a PCP had a higher estimated likelihood of surgical cure (p = 0.008), while no SES-based differences in surgical remission likelihood existed in the medical cohort. After surgery, surgical patients who achieved remission had significantly higher income than those who did not (p < 0.001). Other SES factors were not associated with surgical remission, and among medically treated patients, remission rates were not affected by any SES factor. Income was inversely related to prolactinoma size in both cohorts (surgical, p < 0.001; medical, p = 0.005) but was associated more prominently in surgical patients (surgical, -0.65 mm per $10,000; medical, -0.37 mm per $10,000). CONCLUSIONS: While surgical prolactinoma patients were prone to income and PCP-related disparities, no SES disparities were found among medically treated patients. Income had a more pronounced association with tumor size in the surgical cohort and likely contributed to the increased need for surgical intervention seen in low-income surgical patients. Addressing socioeconomic healthcare disparities is needed among surgical prolactinoma patients to increase rates of early presentation and improve the outcomes of low-SES populations.

Superior Hypophyseal Artery Intraoperative Indocyanine Green Angiogram as a Predictor of Postoperative Visual Function After Endoscopic Endonasal Surgery.

BACKGROUND AND OBJECTIVES: To date, there are no tools to intraoperatively predict postoperative visual function after endoscopic endonasal surgery (EES) for suprasellar lesions. The objective of this study was to retrospectively evaluate the utility of indocyanine green (ICG) angiography as an intraoperative tool to measure optic chiasm perfusion and determine its relationship with postoperative visual function. METHODS: Videos of patients undergoing EES for resection of suprasellar lesions were reviewed, where 5 mg of ICG was diluted in 10 mL of saline and administered. Time between luminescence of the anterior cerebral artery and the superior hypophyseal artery branches supplying the optic chiasm was noted, and the percentage of optic chiasm vessels that luminesced was recorded. Postoperative examinations and imaging studies were used to assess visual function. Patients with and without new deficits were compared with examination of trends in ICG findings. RESULTS: A total of 7 trials were reviewed on 6 patients, with no complications occurring from ICG administration. Mean time to chiasm peak luminescence was 3.8 seconds, and 81.8% of chiasm vessels luminesced. Patients with stable or improved vision after resection demonstrated over 90% chiasm luminescence in every case, and mean chiasm time in these postresection ICG administrations was 4.0 seconds. One patient experienced new postoperative visual deficits; on review of their ICG administration, 11.5% of chiasm vessels luminesced, and the chiasm itself failed to display robust luminescence after 30 seconds of direct observation. CONCLUSION: This pilot study showed the capability of intraoperative ICG angiography to demonstrate perfusion of the optic chiasm during EES for resection of suprasellar lesions. While larger studies are required, preliminary results suggest chiasm times under 5 seconds and over 90% chiasm vessel illumination may reflect adequate chiasm perfusion, while those with delayed or absent chiasm luminescence may have compromised chiasm perfusion.

Metabolic Barriers to Glioblastoma Immunotherapy.

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.

Risk Factors for Significant Postoperative Hemorrhage After Pituitary Neuroendocrine Tumor Resection: A Case-Control Study of 1066 Surgeries.

BACKGROUND: Postoperative hemorrhage is a rare but potentially serious complication after pituitary surgery. The risk factors for this complication are mostly unknown, and further knowledge would help guide postoperative management. OBJECTIVE: To investigate the perioperative risks and clinical presentation of significant postoperative hemorrhage (SPH) after endonasal surgery for pituitary neuroendocrine tumors. METHODS: A population of 1066 patients undergoing endonasal (microscopic and endoscopic) surgery for pituitary neuroendocrine tumor resection at a high-volume academic center was reviewed. SPH cases were defined as postoperative hematoma evident on imaging requiring return to the operating room for evacuation. Patient and tumor characteristics were analyzed with uni- and multivariable logistic regression, and postoperative courses were descriptively examined. RESULTS: Ten patients were found to have SPH. On univariable analysis, these cases were significantly more likely to present with apoplexy ( P = .004), have larger tumors ( P < .001), and lower gross total resection rates ( P = .019). A multivariate regression analysis showed that tumor size (odds ratio 1.94, P = .008) and apoplexy at presentation (odds ratio 6.00, P = .018) were significantly associated with higher odds of SPH. The most common symptoms for patients with SPH were vision deficits and headache, and the median time for symptom onset was 1 day after surgery. CONCLUSION: Larger tumor size and presentation with apoplexy were associated with clinically significant postoperative hemorrhage. Patients presenting with pituitary apoplexy are more likely to experience a significant postoperative hemorrhage and should be carefully monitored for headache and vision changes in the days after surgery.

Pituitary adenomas and cerebrovascular disease: A review on pathophysiology, prevalence, and treatment.

Pituitary adenomas (PAs) have been shown to cause excess cardiovascular disease comorbidity and mortality. Cerebrovascular disease (CeVD) is a small subset of cardiovascular disease with high morbidity, and its risk in patients with pituitary adenomas has been sparingly explored. In this review, we examine what is known about the prevalence of cerebrovascular disease in patients with PAs, from its initial discovery in 1970 to present. An abundance of literature describes increased cerebrovascular mortality in patients with acromegaly, while research on other PA subtypes is less frequent but shows a similarly elevated CeVD mortality relative to healthy populations. We also review how cerebrovascular risk changes after PAs are treated, with PA treatment appearing to prevent further accumulation of cerebrovascular risk without reversing prior elevations. While acromegaly-associated CeVD appears to be caused by elevated growth hormone (GH) levels and Cushing disease's elevated glucocorticoids similarly cause durable alterations in cerebrovascular structure and function, less is known about the mechanisms behind CeVD in other PA subpopulations. Proposed pathophysiologies include growth hormone deficiency inducing vessel wall damage or other hormone deficits causing increased atherosclerotic disease. Early diagnosis and treatment of PAs may be the key to minimizing lifetime CeVD risk elevations. More research is needed to better understand the mechanisms behind the increased CeVD seen in patients with PAs. Physicians caring for PA patients must remain vigilant for signs and symptoms of cerebrovascular disease in this patient population.

Correlation between tumor volume and serum prolactin and its effect on surgical outcomes in a cohort of 219 prolactinoma patients.

OBJECTIVE: Prolactinoma is the most common pituitary adenoma and can be managed medically or surgically. The authors assessed the correlation between tumor volume and prolactin level and its effect on surgical outcomes. METHODS: The authors reviewed 219 patients who underwent transsphenoidal prolactinoma resection at a single institution from 2012 to 2019. Outcomes were compared between patients with and without biochemical remission. Tumor volumes were quantified with BrainLab Smartbrush. Correlation analysis and linear regression were used to examine the association between tumor volume and serum prolactin level. Volume-adjusted prolactin level was defined as serum prolactin level divided by tumor volume. The authors utilized receiver operating characteristic (ROC) curve analysis to determine the thresholds for predicting biochemical remission status. RESULTS: The mean tumor volume was 5.66 cm3, and the mean preoperative prolactin level was 752.3 µg/L. Men had larger prolactinomas than women (mean volume 11.32 vs 2.54 cm3; p < 0.001), and women had a greater volume-adjusted prolactin level (mean 412.5 vs 175.9 µg/L/cm3, p < 0.001). In total, 66.7% of surgical patients achieved biochemical remission 6 weeks after surgery, whereas a similar cohort of medically treated patients during the same time frame demonstrated a 69.4% remission rate. Pearson correlation and linear regression analysis revealed a strong association between preoperative tumor volume and prolactin levels, with an increase in serum prolactin level of 101.31 µg/L per 1-cm3 increase in tumor volume (p < 0.001). This held true for men (R = 0.601, p < 0.001) and women (R = 0.935, p < 0.001), with women demonstrating a greater increase in prolactin level per 1-cm3 increase in volume (185.70 vs 79.77 µg/L, p < 0.001). Patients who achieved remission exhibited a 66.08-µg/L increase in preoperative prolactin level per 1 cm3 of preoperative tumor volume (p < 0.001), which was less than the 111.46-µg/L increase per 1 cm3 in patients without remission (p < 0.001). Patients who failed to achieve remission had residual tumors with a 77.77-µg/L increase in prolactin per 1 cm3 of remaining tumor volume after resection (p < 0.001). ROC curve analysis revealed significant thresholds that optimally predicted lack of postoperative remission on the basis of preoperative prolactin and tumor volume. These thresholds were rendered nonsignificant in patients with documented Knosp grade ≥ 3. CONCLUSIONS: Although the authors found a correlation between prolactinoma volume and serum prolactin level, patients without remission had a greater increase in serum prolactin level per increase in preoperative tumor volume than those who achieved remission, suggesting unique tumor composition. The authors also identified prolactin and tumor volume thresholds that optimally predicted biochemical remission status. The authors hope that their results can be used to identify prolactinomas for which surgery could achieve remission as an alternative to medical management.

Development of a customised programme to standardise comorbidity diagnosis codes in a large-scale database.

OBJECTIVES: The transition from ICD-9 to ICD-10 coding creates a data standardisation challenge for large-scale longitudinal research. We sought to develop a programme that automated this standardisation process. METHODS: A programme was developed to standardise ICD-9 and ICD-10 terminology into one system. Code was improved to reduce runtime, and two iterations were tested on a joint ICD-9/ICD-10 database of 15.8 million patients. RESULTS: Both programmes successfully standardised diagnostic terminology in the database. While the original programme updated 100 000 cells in 12.5 hours, the improved programme translated 3.1 million cells in 38 min. DISCUSSION: While both programmes successfully translated ICD-related data into a standardised format, the original programme suffered from excessive runtimes. Code improvement with hash tables and parallelisation exponentially reduced these runtimes. CONCLUSION: Databases with ICD-9 and ICD-10 codes require terminology standardisation for analysis. By sharing our programme's implementation, we hope to assist other researchers in standardising their own databases.

Identifying risk factors for postoperative diabetes insipidus in more than 2500 patients undergoing transsphenoidal surgery: a single-institution experience.

OBJECTIVE: Diabetes insipidus (DI) following transsphenoidal surgery can adversely impact quality of life and be difficult to manage. This study sought to characterize pre- and perioperative risk factors that may predispose patients to DI after pituitary surgery. METHODS: A retrospective review of patients treated at a single institution from 2007 to 2019 was conducted. DI was defined as postoperative sodium > 145 mEq/L and urine output > 300 ml/hr and/or postoperative desmopressin (ddAVP) use. DI was further characterized as transient or permanent. Uni- and multivariate analyses were performed to determine variables associated with postoperative DI. RESULTS: The authors identified 2529 patients who underwent transsphenoidal surgery at their institution. Overall, DI was observed in 270 (10.7%) of the 2529 patients, with 114 (4.5%) having permanent DI and 156 (6.2%) with transient symptoms. By pathology type, DI occurred in 31 (46.3%) of 67 craniopharyngiomas, 10 (14.3%) of 70 apoplexies, 46 (14.3%) of 322 Rathke's cleft cysts, 77 (7.7%) of 1004 nonfunctioning pituitary adenomas (NFPAs), and 62 (7.6%) of 811 functioning pituitary adenomas (FPAs). Final lesion pathology significantly affected DI rates (p < 0.001). Multivariate analysis across pathologies showed that younger age (odds ratio [OR] 0.97, p < 0.001), intraoperative CSF encounter (OR 2.74, p < 0.001), craniopharyngioma diagnosis (OR 8.22, p = 0.007), and postoperative hyponatremia (OR 1.50, p = 0.049) increased the risk of DI. Because surgery for each pathology created specific risk factors for DI, the analysis was then limited to the 1815 pituitary adenomas (PAs) in the series, comprising 1004 NFPAs and 811 FPAs. For PAs, younger age (PA: OR 0.97, p < 0.001; NFPA: OR 0.97, p < 0.001; FPA: OR 0.97, p = 0.028) and intraoperative CSF encounter (PA: OR 2.99, p < 0.001; NFPA: OR 2.93, p < 0.001; FPA: OR 3.06, p < 0.001) increased DI rates in multivariate analysis. Among all PAs, patients with DI experienced peak sodium levels later than those without DI (postoperative day 11 vs 2). Increasing tumor diameter increased the risk of DI in FPAs (OR 1.52, p = 0.008), but not in NFPAs (p = 0.564). CONCLUSIONS: In more than 2500 patients treated at a single institution, intraoperative CSF encounter, craniopharyngioma diagnosis, and young age all increased the risk of postoperative DI. Patients with postoperative hyponatremia exhibited higher rates of DI, suggesting possible bi- or triphasic patterns to DI. Greater vigilance should be maintained in patients meeting these criteria following transsphenoidal surgery to ensure early recognition and treatment of DI.

Transcriptomic Profiles of Normal Pituitary Cells and Pituitary Neuroendocrine Tumor Cells.

The pituitary gland is one of the most cellularly diverse regions of the brain. Recent advancements in transcriptomic biology, such as single-cell RNA sequencing, bring an unprecedented glimpse into the molecular composition of the pituitary, both in its normal physiological state and in disease. Deciphering the normal pituitary transcriptomic signatures provides a better insight into the ontological origin and development of five types of endocrine cells, a process involving complex cascades of transcription factors that are still being established. In parallel with these observations about normal pituitary development, recent transcriptomic findings on pituitary neuroendocrine tumors (PitNETs) demonstrate both preservations and changes in transcription factor expression patterns compared to those seen during gland development. Furthermore, recent studies also identify differentially expressed genes that drive various tumor behaviors, including hormone hypersecretion and tumor aggression. Understanding the comprehensive multiomic profiles of PitNETs is essential in developing molecular profile-based therapies for PitNETs not curable with current treatment modalities and could eventually help align PitNETs with the breakthroughs being made in applying precision medicine to other tumors.

Socioeconomic predictors of case presentations and outcomes in 225 nonfunctional pituitary adenoma resections.

OBJECTIVE: Clinical presentations and outcomes of nonfunctional pituitary adenoma (NFPA) resections can vary widely, and very little prior research has analyzed this variance through a socioeconomic lens. This study sought to determine whether socioeconomic status (SES) influences NFPA presentations and postoperative outcomes, as these associations could aid physicians in understanding case prognoses and complications. METHODS: The authors retrospectively analyzed 225 NFPA resections from 2012 to 2019 at their institution. Race, ethnicity, insurance status, estimated income, and having a primary care provider (PCP) were collected as 5 markers of SES. These markers were correlated with presenting tumor burden, presenting symptoms, surgical outcomes, and long-term clinical outcomes. RESULTS: All 5 examined SES markers influenced variance in patient presentation or outcome. Insurance status's effects on patient presentations disappeared when examining only patients with PCPs. Having a PCP was associated with significantly smaller tumor size at diagnosis (effect size = 0.404, p < 0.0001). After surgery, patients with PCPs had shorter postoperative hospital lengths of stay (p = 0.043) and lower rates of readmission within 30 days of discharge (OR 0.256, p = 0.047). Despite continuing follow-up for longer durations (p = 0.0004), patients with PCPs also had lower rates of tumor recurrence (p < 0.0001). Higher estimated income was similarly associated with longer follow-up (p = 0.002) and lower rates of tumor recurrence (p = 0.013). Among patients with PCPs, income was not associated with recurrence. CONCLUSIONS: This study found that while all 5 variables (race, ethnicity, insurance, PCP status, and estimated income) affected NFPA presentations and outcomes, having a PCP was the single most important of these socioeconomic factors, impacting hospital lengths of stay, readmission rates, follow-up adherence, and tumor recurrence. Having a PCP even protected low-income patients from experiencing increased rates of tumor recurrence. These protective findings suggest that addressing socioeconomic disparities may lead to better NFPA presentations and outcomes.

Plurihormonal PIT-1-Positive Pituitary Adenomas: A Systematic Review and Single-Center Series.

OBJECTIVE: The 2017 World Health Organization classification of pituitary adenomas identified the plurihormonal PIT-1-positive (PP1) adenoma as a distinct subtype. The reported data suggest that PP1 adenomas encompass the former class of silent subtype 3 (SS3) adenomas and might have an aggressive phenotype. In the present study, we summarized the current clinical data on PP1 and SS3 adenomas and compared the reported data with the data from a single institutional cohort. METHODS: Medline and Google Scholar were searched from 1990 to 2020 for clinical series of PP1 and SS3 adenomas in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included if they had reported pituitary pathology as PP1 or SS3 adenomas and had reported the clinical outcomes after surgical intervention. To better define the PP1 phenotype compared with non-PP1 adenomas, we also reviewed the adenomas treated surgically at our institution from 2012 to 2019. RESULTS: Of all the tumors reported in the studies as PP1 or SS3, 99% were macroadenomas and 18% were giant adenomas (>4 cm). Of the reported patients, 31.8% had received radiotherapy, and 22.9% had undergone multiple surgeries for their pituitary tumor. In our single-center experience, 20 patients had an adenoma that met the criteria for a PP1 adenoma. Compared with the 1146 non-PP1 tumors, the PP1 tumors did not show statistically significant differences in the extent of resection, size, number of previous surgeries, future reoperations, rate of radiotherapy, p53 staining, or MIB-1 labeling index. CONCLUSIONS: The findings from the present large, single-center study comparing PP1 and non-PP1 adenomas do not suggest that PP1 tumors are more aggressive. Further work is warranted to identify the pathologic subtypes of pituitary adenomas that are consistently more clinically aggressive.

Clinical characteristics and outcomes in elderly patients undergoing transsphenoidal surgery for nonfunctioning pituitary adenoma.

OBJECTIVE: Life expectancy has increased over the past century, causing a shift in the demographic distribution toward older age groups. Elderly patients comprise up to 14% of all patients with pituitary tumors, with most lesions being nonfunctioning pituitary adenomas (NFPAs). Here, the authors evaluated demographics, outcomes, and postoperative complications between nonelderly adult and elderly NFPA patients. METHODS: A retrospective review of 908 patients undergoing transsphenoidal surgery (TSS) for NFPA at a single institution from 2007 to 2019 was conducted. Clinical and surgical outcomes and postoperative complications were compared between nonelderly adult (age ≥ 18 and ≤ 65 years) and elderly patients (age > 65 years). RESULTS: There were 614 and 294 patients in the nonelderly and elderly groups, respectively. Both groups were similar in sex (57.3% vs 60.5% males; p = 0.4), tumor size (2.56 vs 2.46 cm; p = 0.2), and cavernous sinus invasion (35.8% vs 33.7%; p = 0.6). Regarding postoperative outcomes, length of stay (1 vs 2 days; p = 0.5), extent of resection (59.8% vs 64.8% gross-total resection; p = 0.2), CSF leak requiring surgical revision (4.3% vs 1.4%; p = 0.06), 30-day readmission (8.1% vs 7.3%; p = 0.7), infection (3.1% vs 2.0%; p = 0.5), and new hypopituitarism (13.9% vs 12.0%; p = 0.3) were similar between both groups. Elderly patients were less likely to receive adjuvant radiation (8.7% vs 16.3%; p = 0.009), undergo future reoperation (3.8% vs 9.5%; p = 0.003), and experience postoperative diabetes insipidus (DI) (3.7% vs 9.4%; p = 0.002), and more likely to have postoperative hyponatremia (26.7% vs 16.4%; p < 0.001) and new cranial nerve deficit (1.9% vs 0.0%; p = 0.01). Subanalysis of elderly patients showed that patients with higher Charlson Comorbidity Index scores had comparable outcomes other than higher DI rates (8.1% vs 0.0%; p = 0.006). Elderly patients' postoperative sodium peaked and troughed on postoperative day 3 (POD3) (mean 138.7 mEq/L) and POD9 (mean 130.8 mEq/L), respectively, compared with nonelderly patients (peak POD2: mean 139.9 mEq/L; trough POD8: mean 131.3 mEq/L). CONCLUSIONS: The authors' analysis revealed that TSS for NFPA in elderly patients is safe with low complication rates. In this cohort, more elderly patients experienced postoperative hyponatremia, while more nonelderly patients experienced postoperative DI. These findings, combined with the observation of higher DI in patients with more comorbidities and elderly patients experiencing later peaks and troughs in serum sodium, suggest age-related differences in sodium regulation after NFPA resection. The authors hope that their results will help guide discussions with elderly patients regarding risks and outcomes of TSS.

Clinical characteristics and outcomes of null-cell versus silent gonadotroph adenomas in a series of 1166 pituitary adenomas from a single institution.

OBJECTIVE: Nonfunctioning pituitary adenomas present without biochemical or clinical signs of hormone excess and are the second most common type of pituitary adenomas. The 2017 WHO classification scheme of pituitary adenomas differentiates null-cell adenomas (NCAs) and silent gonadotroph adenomas (SGAs). The present study sought to highlight the differences in patient characteristics and clinical outcomes between NCAs and SGAs. METHODS: The records of 1166 patients who underwent transsphenoidal surgery for pituitary adenoma between 2012 and 2019 at a single institution were retrospectively reviewed. Patient demographics and clinical outcomes were collected. RESULTS: Of the overall pituitary adenoma cohort, 12.8% (n = 149) were SGAs and 9.2% (n = 107) NCAs. NCAs were significantly more common in female patients than SGAs (61.7% vs 26.8%, p < 0.001). There were no differences in patient demographics, initial tumor size, or perioperative and short-term clinical outcomes. There was no significant difference in the amount of follow-up between patients with NCAs and those with SGAs (33.8 months vs 29.1 months, p = 0.237). Patients with NCAs had significantly higher recurrence (p = 0.021), adjuvant radiation therapy usage (p = 0.002), and postoperative diabetes insipidus (p = 0.028). NCA pathology was independently associated with tumor recurrence (HR 3.64, 95% CI 1.07-12.30; p = 0.038), as were cavernous sinus invasion (HR 3.97, 95% CI 1.04-15.14; p = 0.043) and anteroposterior dimension of the tumor (HR 2.23, 95% CI 1.09-4.59; p = 0.030). CONCLUSIONS: This study supports the definition of NCAs and SGAs as separate subgroups of nonfunctioning pituitary adenomas, and it highlights significant differences in long-term clinical outcomes, including tumor recurrence and the associated need for adjuvant radiation therapy, as well as postoperative diabetes insipidus. The authors also provide insight into independent risk factors for these outcomes in the adenoma population studied, providing clinicians with additional predictors of patient outcomes. Follow-up studies will hopefully uncover mechanisms of biological aggressiveness in NCAs and associated molecular targets.

Features of Patients With Severe Hepatitis Due to Mushroom Poisoning and Factors Associated With Outcome.

BACKGROUND & AIMS: Acute liver failure after ingestion of toxic mushrooms is a significant medical problem. Most exposures to toxic mushrooms produce no symptoms or only mild gastroenteritis, but some lead to severe hepatic necrosis and fulminant hepatic failure requiring liver transplantation. We aimed to assess mortality from mushroom poisoning and identify variables associated with survival and liver transplantation. METHODS: We collected information from 27 patients (13 male; median age, 47 years) admitted to the emergency department within 24 hours of ingesting wild mushrooms. They developed severe liver injury (serum levels of transaminases greater than 400 IU/L) and were treated with activated charcoal and N-acetylcysteine at a tertiary medical center in San Francisco, California from January 1997 through December 2014. Viral hepatitis, autoimmune liver disease, acetaminophen, salicylate toxicity, and chronic liver diseases were ruled out for all patients. We analyzed patient demographics, time since ingestion, presenting symptoms, laboratory values, and therapies administered. A good outcome was defined as survival without need for liver transplant. A poor outcome was defined as death or liver transplant. Positive predictive values were calculated, and the χ2 test was used to analyze dichotomous variables. RESULTS: Liver injury was attributed to ingestion of Amanita phalloides in 24 patients and Amanita ocreata in 3 patients. Twenty-four of the patients ingested mushrooms with meals and 3 patients for hallucinogenic purpose. At 24-48 hours after ingestion, all patients had serum levels of alanine aminotransferase ranging from 554 to 4546 IU/L (median, 2185 IU/L). Acute renal impairment developed in 5 patients. Twenty-three patients survived without liver transplantation, and 4 patients had poor outcomes (1 woman underwent liver transplantation on day 20 after mushroom ingestion, and 3 women died of hepatic failure). Of the 23 patients with peak levels of total bilirubin of 2 mg/dL or more during hospitalization, only 4 had a poor outcome. Peak serum level of aspartate aminotransferase less than 4000 IU/L, peak international normalized ratio less than 2, and a value of serum factor V greater than 30% identified patients with good outcomes with 100% positive predictive value; if these peak values were used as a cutoff, 10 of 27 patients (37%), 7 of 27 patients (26%), and 6 of 12 patients (50%), respectively, could have avoided transfer to a transplant center. CONCLUSIONS: In an analysis of 27 patients with hepatocellular damage due to mushroom (Amanita) poisoning and peak levels of total bilirubin greater than 2 mg/dL, the probability of liver transplantation or death is 17%, fulfilling Hy's law. Patients with peak levels of aspartate aminotransferase less than 4000 IU/L can be monitored in a local hospital, whereas patients with higher levels should be transferred to liver transplant centers. Women and older patients were more likely to have a poor outcome than men and younger patients.

Conventional TACE and drug-eluting bead TACE as locoregional therapy before orthotopic liver transplantation: comparison of explant pathologic response.

BACKGROUND: Hepatocellular carcinoma (HCC) is responsible for significant morbidity and mortality worldwide. Despite its increasing incidence, significant progress has been made in the clinical management of HCC. Transarterial chemoembolization (cTACE) has been shown to improve survival in patients with unresectable HCC; it has also been successfully used as bridging therapy before orthotopic liver transplantation (OLT) in efforts to delay tumor growth or to downstage HCC. TACE with drug-eluting beads (DEB-TACE), a novel drug delivery system that produces a slow and sustained release of chemotherapeutic agent, has recently been shown to have similar efficacy to conventional TACE (cTACE); it also exhibits fewer adverse effects resulting from reduced systemic drug concentrations. To date, the pathologic response rate to cTACE compared with DEB-TACE in patients undergoing OLT has not been well described. METHODS: A total of 111 consecutive patients with HCC who underwent cTACE (n=76) or DEB-TACE (n=35) before OLT at a single center between January 2005 and December 2010 were evaluated. RESULTS: Complete necrosis was achieved in 50.9% and 57.1% of cTACE and DEB-TACE patients, respectively; at least 50% necrosis was evident in approximately three fourths of patients in both groups. Rates of necrosis and tumor recurrence did not differ between groups. Dropout from the transplant list was equal in both groups. CONCLUSIONS: Either modality is an acceptable treatment to achieve tumor control for patients awaiting OLT and can be expected to result in excellent necrosis rates in the majority of patients.