High-Grade Progression, Sarcomatous Transformation, and/or Metastasis of Pituitary Neuroendocrine Neoplasms (PitNENs): The UCSF Experience.

Pituitary neuroendocrine tumors (PitNET) that metastasize comprise ~ 0.2% of adenohypophyseal tumors are aggressive and are challenging to treat. However, many non-metastatic tumors are also aggressive. Herein, we review 21 specimens from 13 patients at UCSF with metastatic PitNETs (CSF or systemic, N = 7 patients), high-grade pituitary neuroendocrine neoplasms (HG-PitNEN, N = 4 patients), and/or PitNETs with sarcomatous transformation (PitNET-ST, N = 5 patients). We subtyped cases using the World Health Organization (WHO) and International Agency for Research on Cancer (IARC) criteria for neuroendocrine neoplasms (NENs). Lineage subtypes included acidophil stem cell, null cell, thyrotroph, corticotroph, lactotroph, and gonadotroph tumors. The median Ki-67 labeling index was 25% (range 5-70%). Lack of p16 was seen in 3 cases, with overexpression in 2. Strong diffuse p53 immunopositivity was present in 3 specimens from 2 patients. Loss of Rb expression was seen in 2 cases, with ATRX loss in one. Molecular analysis in 4 tumors variably revealed TERT alterations, homozygous CDKN2A deletion, aneuploidy, and mutations in PTEN, TP53, PDGFRB, and/or PIK3CA. Eight patients (62%) died of disease, 4 were alive at the last follow-up, and 1 was lost to the follow-up. All primary tumors had worrisome features, including aggressive lineage subtype, high mitotic count, and/or high Ki-67 indices. Additional evidence of high-grade progression included immunohistochemical loss of neuroendocrine, transcription factor, and/or hormone markers. We conclude that metastatic PitNET is not the only high-grade form of pituitary NEN. If further confirmed, these histopathologic and/or molecular features could provide advanced warning of biological aggressiveness and be applied towards a future grading scheme.

Impaired 11ß-HSD1 Activity in a Male Patient With Cushing Disease Resulting in Lack of the Full Cushingoid Phenotype.

We present a patient who had surgically confirmed CD but without the full cushingoid phenotype despite markedly elevated cortisol. Nonpathologic causes of elevated ACTH and cortisol were eliminated as were pathogenic variants in the glucocorticoid receptor gene. Further studies of urine metabolites, cortisol half-life, and the ratios of cortisone to cortisol conversion revealed impaired 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. There have only been 2 prior reports of impaired 11ß-HSD1 resulting in lack of classic cushingoid features in the past 2 decades. Our patient's presentation and previous reports demonstrate the key role of 11ß-HSD1 in modulating intracellular cortisol concentration, therefore shielding the peripheral tissues from the effects of excess cortisol. When patients present with markedly elevated cortisol but without classic cushingoid features, impaired 11ß-HSD1 should be considered in the differential diagnosis.

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.

Bilateral Superficial Trigeminal Nerve Blocks are not More Effective than a Placebo in Abolishing Post-operative Headache Pain in Pituitary Transsphenoidal Neurosurgery: A Prospective, Randomized, Doubleblinded Clinical Trial.

BACKGROUND: Pituitary neurosurgery executed via the transsphenoidal endonasal approach is commonly performed for pituitary adenomas. Reasons for prolonged hospital stay include postoperative headache and protracted nausea with or without vomiting. Bilateral superficial trigeminal nerve blocks of the supra-orbital V1 and infra-orbital V2 (SION) nerves performed intra-operatively as a regional anesthetic adjunct to general anesthesia were hypothesized to decrease 6 hours postoperative morphine PCA (patient-controlled analgesia) use by patients. METHODS: Forty-nine patients, following induction of general anesthesia for their transsphenoidal surgery, were prospectively randomized in a double-blinded fashion to receive additional regional anesthesia as either a block (0.5% ropivacaine with epi 1:200,000) or placebo/sham (0.9% normal saline). The primary endpoint of the study was systemic morphine PCA opioid consumption by the two groups in the first 6-hours postoperatively. The secondary endpoints included (1) pain exposure experienced postoperatively, (2) incidence of postoperative nausea and vomiting, and (3) time to eligibility for PACU discharge. RESULTS: Of the 49 patients that were enrolled, 3 patients were excluded due to protocol violations. Ultimately, there was no statistically significant difference between morphine PCA use in the 6 hours postoperatively between the block and placebo/sham groups. There was, however, a slight visual tendency in the block group for higher pain scores, morphine use p=0.046, and delayed PACU discharge. False discovery rate corrected comparisons at each time point and then revealed no statistically significant difference between the two groups. There were no differences between the two groups for secondary endpoints. CONCLUSION: It was found that a 6-hour postoperative headache after endoscopic trans-sphenoidal pituitary surgery likely has a more complicated mechanism involving more than the superficial trigeminovascular system and perhaps is neuro-modulated by other brain nuclei.

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.

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.

Calcifying pseudoneoplasm of the neuraxis within the sellar region: illustrative case.

BACKGROUND: There are numerous atypical lesions of the sellar and suprasellar region that are often mistaken for pituitary adenomas. It is important to consider rare mimics of more common pathologies in this region. OBSERVATIONS: The authors detail the case of a 37-year-old woman with hypopituitarism who was found to have an atypical sellar mass with slow growth on interval imaging. The lesion was debulked via a microscopic endonasal transsphenoidal approach and found to be a calcifying pseudoneoplasm of the neuraxis (CAPNON). LESSONS: CAPNON is a rare disease entity that may affect the sellar region. CAPNON should be on the differential diagnosis for sellar masses that are associated with T1 and T2 hypointensity on magnetic resonance imaging with minimal enhancement. Although CAPNON is not at risk for malignant progression, these benign lesions can continue to grow after a subtotal resection and require follow-up.

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.

Femoral nerve neuromonitoring for lateral lumbar interbody fusion surgery.

BACKGROUND CONTEXT: The transpsoas lateral lumbar interbody fusion (LLIF) technique is an effective alternative to traditional anterior and posterior approaches to the lumbar spine; however, nerve injuries are the most reported postoperative complication. Commonly used strategies to avoid nerve injury (eg, limiting retraction duration) have not been effective in detecting or preventing femoral nerve injuries. PURPOSE: To evaluate the efficacy of emerging intraoperative femoral nerve monitoring techniques and the importance of employing prompt surgical countermeasures when degraded femoral nerve function is detected. STUDY DESIGN/SETTING: We present the results from a retrospective analysis of a multi-center study conducted over the course of 3 years. PATIENT SAMPLE: One hundred and seventy-two lateral lumbar interbody fusion procedures were reviewed. OUTCOME MEASURES: Intraoperative femoral nerve monitoring data was correlated to immediate postoperative neurologic examinations. METHODS: Femoral nerve evoked potentials (FNEP) including saphenous nerve somatosensory evoked potentials (snSSEP) and motor evoked potentials with quadriceps recordings were used to detect evidence of degraded femoral nerve function during the time of surgical retraction. RESULTS: In 89% (n=153) of the surgeries, there were no surgeon alerts as the FNEP response amplitudes remained relatively unchanged throughout the surgery (negative group). The positive group included 11% of the cases (n=19) where the surgeon was alerted to a deterioration of the FNEP amplitudes during surgical retraction. Prompt surgical countermeasures to an FNEP alert included loosening, adjusting, or removing surgical retraction, and/or requesting an increase in blood pressure from the anesthesiologist. All the cases where prompt surgical countermeasures were employed resulted in recovery of the degraded FNEP amplitudes and no postoperative femoral nerve injuries. In two cases, the surgeons were given verbal alerts of degraded FNEPs but did not employ prompt surgical countermeasures. In both cases, the degraded FNEP amplitudes did not recover by the time of surgical closure, and both patients exhibited postoperative signs of sensorimotor femoral nerve injury including anterior thigh numbness and weakened knee extension. CONCLUSIONS: Multimodal femoral nerve monitoring can provide surgeons with a timely alert to hyperacute femoral nerve conduction failure, enabling prompt surgical countermeasures to be employed that can mitigate or avoid femoral nerve injury. Our data also suggests that the common strategy of limiting retraction duration may not be effective in preventing iatrogenic femoral nerve injuries.

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.

Are preoperative chlorhexidine gluconate showers associated with a reduction in surgical site infection following craniotomy? A retrospective cohort analysis of 3126 surgical procedures.

OBJECTIVE: Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery. METHODS: In November 2013, a preoperative CHG shower protocol was implemented at the authors' institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates. RESULTS: The overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67-13.1; p = 0.15). CONCLUSIONS: This is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.

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.

The genetic landscape of gliomas arising after therapeutic radiation.

Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.

Necrotizing Autoimmune myopathy: A case report on statin induced rhabdomyolysis requiring immunosuppressive therapy.

Statins can cause a wide spectrum of muscular adverse effects ranging from asymptomatic elevation of Creatine Kinase (CK), myalgia and exercise intolerance to rhabdomyolysis. Most of these effects generally resolve on stopping the medication. However, statins can be associated with a unique autoimmune myopathy wherein symptoms persist or even progress after statin discontinuation and require immunosuppressive therapy. The case presented is a 60-year-old woman who was on statin treatment for a period of 2 years. She developed muscle weakness with a limb girdle distribution. She had persistent elevation of CK even after discontinuation of statin therapy. EMG done revealed irritable myopathy and muscle biopsy showed necrosis without inflammation. She subsequently tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMG CoA) antibody which is found to be present in patients with statin-associated necrotizing autoimmune myopathy. Patient was started on steroid without much improvement in her symptoms. After a month of follow up, her upper extremity strength was back but lower extremity continued to be weak which prompted us to start her on Methotrexate and Azathioprine. Like our patient, there are rare subgroup of patients with an immune-mediated necrotizing myopathy that does not improve after discontinuation of the drug and requires aggressive treatment with immunosuppressive agents. Awareness and early recognition of this disease is very important in patients who continue to have CK elevation and weakness after discontinuation of statin therapy.

Growth hormone and prolactin-staining tumors causing acromegaly: a retrospective review of clinical presentations and surgical outcomes.

OBJECTIVE: Acromegaly results in disfiguring growth and numerous medical complications. This disease is typically caused by growth hormone (GH)-secreting pituitary adenomas, which are treated first by resection, followed by radiation and/or medical therapy if needed. A subset of acromegalics have dual-staining pituitary adenomas (DSPAs), which stain for GH and prolactin. Presentations and treatment outcomes for acromegalics with DSPAs are not well understood. METHODS: The authors retrospectively reviewed the records of more than 5 years of pituitary adenomas resected at their institution. Data were collected on variables related to clinical presentation, tumor pathology, radiological size, and disease recurrence. The Fisher's exact test, ANOVA, Student t-test, chi-square test, and Cox proportional hazards and multiple logistic regression were used to measure statistical significance. RESULTS: Of 593 patients with pituitary adenoma, 91 presented with acromegaly. Of these 91 patients, 69 (76%) had tumors that stained for GH only (single-staining somatotrophic adenomas [SSAs]), while 22 (24%) had tumors that stained for GH and prolactin (DSPAs). Patients with DSPAs were more likely to present with decreased libido (p = 0.012), signs of acromegalic growth (p = 0.0001), hyperhidrosis (p = 0.0001), and headaches (p = 0.043) than patients with SSAs. DSPAs presented with significantly higher serum prolactin (60.7 vs 10.0 µg/L, p = 0.0002) and insulin-like growth factor-1 (IGF-1) (803.6 vs 480.0 ng/ml, p = 0.0001), and were more likely to have IGF-1 levels > 650 ng/ml (n = 13 [81.3%] vs n = 6 [21.4%], p = 0.0001) than patients with SSAs despite similar sizes (1.8 vs 1.7 cm, p = 0.5). Patients with DSPAs under 35 years of age were more likely to have a recurrence (n = 4 [50.0%] vs n = 3 [11.1%], p = 0.01) than patients with SSAs under the age of 35. DSPA patients were less likely to achieve remission with surgery than SSA patients (n = 2 [20%] vs n = 19 [68%], p = 0.01). Univariate analysis identified single-staining tumors (p = 0.02), gross-total resection (p = 0.02), and tumor diameter (p = 0.05) as predictors of surgical remission. Multiple logistic regression demonstrated that SSAs (p = 0.04) were independently associated with surgical remission of acromegaly. Kaplan-Meier analysis revealed that DSPAs had more time until disease remission (p = 0.033). CONCLUSIONS: Acromegalics with tumors that stain for prolactin and GH, which represented almost a quarter of acromegalics in this cohort, had more aggressive clinical presentations and postoperative outcomes than SSAs. Prolactin staining provides useful information for acromegalics undergoing pituitary surgery.

Surgical intervention for pituitary apoplexy: an analysis of functional outcomes.

OBJECTIVE Pituitary apoplexy is a clinical syndrome consisting of neurological and endocrine abnormalities secondary to hemorrhage or ischemia of an underlying pituitary adenoma. The authors investigated whether there was a significant difference in neurological, endocrine, and nonneuroendocrine outcomes for patients with pituitary apoplexy, based on the time between symptom onset and surgical intervention. METHODS The authors retrospectively analyzed the medical records of 32 patients who had presented to their institution with acute pituitary apoplexy and subsequently undergone endonasal transsphenoidal resection in the period from 2003 to 2014. All patients had undergone preoperative MRI demonstrating evidence of apoplexy in the form of intratumoral hemorrhage, ischemia, and necrosis. Neurological deficits, partial or complete endocrinopathy, and nonneuroendocrine abnormalities were analyzed both pre- and postoperatively. RESULTS Preoperatively, neurological deficits including visual loss and cranial nerve palsies were found in 31 (97%) of the 32 patients, endocrinopathy in the form of partial or panhypopituitarism was seen in 28 patients (88%), and nonneuroendocrine signs and symptoms were seen in 32 patients (100%). Thirteen patients (41%) underwent surgery within 72 hours of symptom onset ("early"), whereas 19 patients (59%) underwent surgery more than 72 hours from symptom onset ("delayed"). Early versus delayed resection did not appear to significantly improve visual deficits, total visual loss, resolution of oculomotor palsy, recovery from hypopituitarism, or nonneuroendocrine signs and symptoms such as headache and encephalopathy. Overall, visual improvement was seen in 77% of patients, complete restoration of normal vision in 38% of patients, and resolution of preoperative oculomotor palsies in 81% of patients. Only 6 (21%) of 28 patients showed evidence of partial hormone recovery following preoperative hypopituitarism. An absence of benefit for early surgery held true even when considering time to surgery from symptom onset as a continuous variable. CONCLUSIONS Neurological deficits such as visual loss and cranial neuropathies show moderate improvement following surgical decompression, as does preoperative hypopituitarism. The timing of surgical intervention relative to the onset of symptoms does not appear to significantly affect the resolution of neurological or endocrinological deficits.

Atypical pituitary adenoma: a clinicopathologic case series.

OBJECTIVE In 2004, the WHO classified atypical pituitary adenoma as a distinct adenoma subtype. However, the clinical significance of this distinction remains undetermined. The authors sought to define patient characteristics, tumor features, and treatment outcomes associated with atypical pituitary adenoma. METHODS The authors reviewed records of patients who underwent resection of pituitary adenoma at the University of California, San Francisco, between 2007 and 2014. Per institutional protocol, adenomas exhibiting mitotic activity underwent evaluation for all 3 markers of atypicality (mitotic index, extensive p53 staining, and MIB-1 index ≥ 3%). Statistical analyses were performed using χ2, Fisher's exact test, t-test, log-rank, and logistic regression. RESULTS Between 2007 and 2014, 701 patients underwent resection for pituitary adenoma. Among these patients, 122 adenomas exhibited mitotic activity and therefore were evaluated for all 3 markers of atypicality, with 36 tumors (5%) proving to be atypical. There were 21 female patients (58%) and 15 male patients (42%) in the atypical cohort, and 313 female patients (47%) and 352 male patients (53%) in the nonatypical cohort (p = 0.231). The mean age of patients in the atypical cohort was 37 years (range 10-65 years), which was significantly lower than the mean age of 49 years (range 10-93 years) for patients in the nonatypical cohort (p < 0.001). The most common presenting symptoms for patients with atypical adenomas were headaches (42%) and visual changes (33%). Atypical adenomas were more likely to be functional (78%) than nonatypical adenomas (42%; p < 0.001). Functional atypical adenomas were significantly larger than functional nonatypical adenomas (mean diameter 2.2 vs 1.4 cm; p = 0.009), as were nonfunctional atypical adenomas compared with nonfunctional nonatypical adenomas (mean diameter 3.3 vs 2.3 cm; p = 0.01). Among the entire adenoma cohort, larger presenting tumor size was associated with cavernous sinus invasion (p < 0.001), and subtotal resection was associated with cavernous sinus invasion (p < 0.001) and larger size (p < 0.001) on binomial multivariate regression. The median time until recurrence was 56 months for atypical adenomas, 129 months for functional nonatypical adenomas, and 204 months for nonfunctional nonatypical adenomas (p < 0.001). Functional atypical adenomas recurred more frequently and significantly earlier than functional nonatypical adenomas (p < 0.001). When accounting for extent of resection, cavernous sinus invasion, size, age, sex, and functional subtype, atypicality remained a significant predictor of earlier recurrence among functional adenomas (p = 0.002). CONCLUSIONS When compared with nonatypical pituitary adenomas, atypical adenomas are more likely to present in younger patients at a larger size, are more often hormonally hypersecretory, and are associated with earlier recurrence. These features lend credence to atypical pituitary adenomas being a distinct clinical entity in addition to a discrete pathological diagnosis.