PatientsLikeMe and atopic dermatitis: characterizing the atopic dermatitis patient profile.

INTRODUCTION: Atopic Dermatitis (AD) is a common dermatologic disorder that affects 17.8 million individuals in the United States. Online medical communities have become increasingly popular over the last several years, providing an additional avenue of therapy for patients. PURPOSE: This retrospective analysis looks to characterize the AD patient profile to better assess features of the AD community and appraise PatientsLikeMe data with current AD literature. METHODS: PatientsLikeMe data recorded by April 2018 from persons who reported AD as their primary or secondary diagnosis were included in the analysis. RESULTS: The PatientsLikeMe database had 410 individuals reporting AD as of April 2018. Of these, 61.46% (252/410) report AD as their primary disease. Of those reporting, 180/199 (90.45%) were diagnosed by a medical professional whereas 19/199 (9.55%) were self-diagnosed. The number of persons recording predefined PatientsLikeMe symptoms are as follows: stress (20), fatigue (132), pain (126), anxious mood (118), and depressed mood (103). SIGNIFICANCE: Patient-oriented medical communities are a valuable resource for those affected by various conditions. Although clinical applications are still uncertain, this data allows practitioners access to profiles self-defined by online users.

Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly.

BACKGROUND: Studies comparing primary medical treatment of acromegaly with surgery are often non-randomized, and not stratified by illness severity. We prospectively compared primary medical therapy with pituitary surgery in patients with acromegaly. All patients had macroadenomas, at least one random human growth hormone (GH) level ≥12.5 ng/mL, elevated IGF-I levels and failure to suppress GH to <1 ng/mL during an oral glucose tolerance test (oGTT). METHODS: Forty-one patients from seven centers were randomized to primary treatment with octreotide LAR, 30 mg every 4 weeks × 3 months (ARM A, N = 15), or pituitary surgery (ARM B, N = 26) using a 1:2 randomization design. Patients cured by surgery (defined as nadir GH during oGTT <1 ng/mL and normal IGF-I) received no subsequent treatment. Those not cured surgically were then treated with octreotide LAR (SubArm B1) for 3 months. RESULTS: Only one of the 15 patients in ARM A (6.7%) had normalization of both GH and IGF-I. In contrast, 13/26 patients had normalization of both GH and IGF-I after surgery alone (50%). Of the remaining 13 patients who did not normalize with surgery alone, treatment with octreotide LAR resulted in a normal nadir GH and normal serum IGF-I in 7 (53.9%). In total, 20/26 in ARM B (76.9%) experienced normalization of defined biochemical acromegaly parameters. CONCLUSIONS: Pituitary surgery alone was more effective than primary medical treatment (p = 0.006), and the combination of surgery followed by medical therapy was even more effective (p < 0.0001). Subjects treated with medical therapy after surgical debulking had a significant improvement in response rate compared to matched subjects treated with primary medical therapy.

"Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era.

PURPOSE: Approximately 25 % of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community. METHODS: A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015. RESULTS: Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7 ng/mL, was 31 %. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26 % from 2001 to 2005, 19 % from 2006 to 2010, and 47 % from 2011 to 2015. Mean pituitary tumor size was 1.8 ± 0.1 cm for the group with elevated GH, and 1.2 ± 0.1 cm for the group with "normal" GH (p < 0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12 %, p < 0.001), and tumors >2 cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14 %, p < 0.001). CONCLUSIONS: Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.

Repeat endoscopic transsphenoidal surgery for acromegaly: remission and complications.

Reported biochemical remission rates following surgical intervention for acromegaly range from 38 to 83%. In patients not achieving surgical remission, few options remain, mostly limited to medical management and radiation therapy. There is debate over whether or not to offer reoperation to patients in whom surgical remission is not achieved with initial resection. Retrospective chart review was undertaken to determine all patients having acromegaly with persistently elevated GH and/or IGF-1 levels after initial pituitary adenoma resection, and who underwent reoperation using endoscopic endonasal approach at a single institution. Biochemical remission was defined as a postoperative GH level <1 ng/mL and a normal postoperative IGF-1 level in the absence of any medical therapy. In total, 14 patients underwent repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach. Of the 14 patients, 8 (57%) achieved biochemical remission following repeat surgical intervention. Lower preoperative GH levels were associated with greater chance of biochemical remission (P = 0.048). New endocrinopathies were seen in 2 patients (14%), and both were transient diabetes insipidus. Meningitis occurred in 2 patients (14%); both were aseptic meningitis with no sequelae. No mortality was encountered. Repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach appears safe and effective. With no mortality and minimal morbidity, repeat surgical intervention via endoscopic transsphenoidal approach appears a reasonable option for these hard-to-treat patients and should be considered for patients in whom surgical remission is not achieved with initial surgery.

Can Syndesmosis Screws Displace the Distal Fibula?

Background. There has been historical debate as to whether the distal tibiofibular syndesmosis can be overtightened during operative fixation. We used finite-element analysis to determine if overtightening of syndesmotic screws can cause widening of the lateral gutter clear space in the ankle joint. Methods. A 3D finite-element model was constructed and analyzed using geometries from a computed tomography scan of a cadaveric lower leg. Starting 2 cm from the plafond, screw fixation was simulated at 5-mm increments to a distance of 5 cm from the plafond. The fibula was compressed 2 mm toward the tibia at each interval, and the change in distance between the lateral talus and distal fibula was measured. Results. Medial deflection of the fibula resulted in widening of the lateral clear space, which was proportional to the amount of deflection. The effect increased as screws were placed closer to the plafond, with 1.5 mm of widening at 2 cm (0.76 mm/mm) versus 0.7 mm at 5 cm (0.34 mm/mm). Conclusion. Our finite-element model demonstrated that overtightening of the distal tibiofibular syndesmosis with medial fibular displacement can cause widening of the lateral clear space. Clinical relevance. The results suggest that screws placed farther from the plafond widen the lateral clear space to a lesser degree, which may be advantageous during surgical fixation to prevent clear space widening and increased tibiotalar contact forces.Levels of Evidence: Level I.

Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant.

CONTEXT: Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. OBJECTIVE: The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a GH receptor antagonist, pegvisomant. DESIGN: This was a descriptive case series of up to 3.5 yr duration. SETTING: The study was conducted at a university hospital. PATIENTS: Patients included three children (one female, two males) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery, somatostatin analog, and dopamine agonist. INTERVENTION: The intervention was administration of pegvisomant. MAIN OUTCOME MEASURES: Plasma IGF-I and growth velocity were measured. RESULTS: In all three children, pegvisomant rapidly decreased plasma IGF-I concentrations. Growth velocity declined to subnormal or normal values. Statural growth fell into lower growth percentiles and acromegalic features resolved. Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog. CONCLUSIONS: Pegvisomant may be an effective modality for the therapy of pituitary gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular surveillance of tumor size is mandatory.

Treatment of pituitary tumors: a surgical perspective.

Surgical intervention is a necessary part of a multimodal approach to pituitary lesions. This article summarizes the surgical approach to different neoplastic processes affecting the sellar region.

Intraoperative acquisition of three-dimensional imaging for frameless stereotactic guidance during transsphenoidal pituitary surgery using the Arcadis Orbic System.

OBJECT: Intraoperative fluoroscopy has long been used for anatomical localization in transsphenoidal pituitary surgery. More recently, frameless stereotaxy has been used to supplement 2D sagittal radiographs with 3D multiplanar reconstructions. Use of Arcadis Orbic allows both conventional fluoroscopic views and multiplanar reconstructions to be acquired intraoperatively without need for preoperative planning studies. The authors report their initial experience using Arcadis Orbic during transsphenoidal pituitary surgery. METHODS: To test the system, the authors placed a dehydrated human skull in a radiolucent head holder, and obtained standard 2D fluoroscopic images of the skull base and sella turcica. Arcadis Orbic was then used with frameless stereotaxy to register 3D multiplanar reconstructed images of skull base anatomy. The authors then used Arcadis Orbic in 26 transsphenoidal pituitary tumor resections and compared image quality, accuracy, and ease-of-use to standard techniques. RESULTS: Arcadis Orbic 2D fluoroscopic images matched or exceeded the quality of images acquired by standard C-arm machines. Arcadis Orbic multiplanar reconstructions provided excellent images of the skull base when compared with preoperative Stealth computed tomography (CT) studies. Intraoperative frameless stereotactic navigation using Arcadis Orbic was highly accurate and more reliable than registering preoperative CT images. CONCLUSIONS: Arcadis Orbic provides excellent quality 2- and 3D images during transsphenoidal pituitary surgery, and intraoperative frameless navigation using these images is highly accurate. Arcadis Orbic is easy to use, even in patients with large body habitus, and image acquisition takes no longer than registration during a frameless stereotactic case. Based upon our preliminary experience, Arcadis Orbic precludes the need for preoperative CT studies in patients with pituitary lesions requiring frameless stereotactic navigation.

The role of endogenous growth hormone-releasing hormone in acromegaly.

CONTEXT: Some indirect evidence suggests hypothalamic control of GH secretion in acromegaly. OBJECTIVE: The objective of the study is to examine whether GH secretion in acromegaly is dependent on endogenous GHRH. PATIENTS AND STUDY DESIGN: We studied eight patients with untreated acromegaly due to a GH-producing pituitary tumor. All patients received an iv infusion of normal saline for 24 h and GHRH-antagonist (GHRH-ant) at 50 microg/kg x h for 7 d. GH was measured every 10 min for 24 h during the normal saline infusion and on the last day of the GHRH-ant infusion. A group of nine different patients with untreated acromegaly served as the control group and underwent blood sampling for GH every 10 min for two 24-h periods to assess the day-to-day variability of GH secretion. SETTING: The study was set in a university referral center. MAIN OUTCOME MEASURE: Twenty-four-hour mean GH was the main outcome measured. RESULTS: In six of eight subjects treated with GHRH-ant, 24-h mean GH decreased by 5.8-30.0% during iv GHRH-ant and, in three subjects, the change in the 24-h mean GH was greater than the upper limit of the 95% confidence interval of the spontaneous day-to-day variability of the mean GH in patients with acromegaly. Based on the binomial distribution, the probability of this magnitude of change to occur in three of eight subjects by chance alone is 0.0008. CONCLUSION: In some patients with acromegaly due to a pituitary adenoma, GH secretion is under partial control by endogenous GHRH.

Phase II study of 9-nitro-camptothecin in patients with advanced chordoma or soft tissue sarcoma.

PURPOSE: The purpose of this trial was to assess the objective clinical response, toxicity, and time to progression of treatment with 9-Nitro-Camptothecin (9-NC) in patients with advanced chordoma, soft tissue sarcoma (STS), and gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Patients with locally advanced and/or metastatic chordoma, STS, or GIST received 9-NC 1.25 mg/m2 orally for 5 consecutive days followed by 2 days of rest. Patients continued on therapy until disease progression, uncontrollable toxicity, or withdrawal of consent. RESULTS: From January 2000 to May 2003, 51 patients (15 chordoma, 23 STS, 13 GIST patients) enrolled. One patient (7%) with chordoma and one patient (4%) with STS had an objective response. Median time to progression was 9.9, 8.0, and 8.3 weeks for chordoma, STS, and GIST patients, respectively. Three- and 6-month progression-free survival rates were 47% and 33% for chordoma patients, 26% and 22% for STS patients, and 31% and 23% for GIST patients, respectively. Ten patients (10%) stopped study drug before disease progression secondary to toxicity. Common adverse events included anemia (42 patients, seven with grade 3/4 toxicity), leukopenia (33 patients, nine with grade 3/4 toxicity), fatigue (30 patients, three with grade 3/4 toxicity), nausea (34 patients, six with grade 3/4 toxicity), and diarrhea (28 patients, five with grade 3/4 toxicity). CONCLUSION: 9-NC has modest activity in delaying progression in patients with unresectable or metastatic chordoma. 9-NC is associated with moderate toxicity and shows little benefit in patients with advanced STS and GIST.

Outcome of Transsphenoidal Surgery for Cushing Disease: A Single-Center Experience Over 32 Years.

BACKGROUND: Transsphenoidal surgery is the standard approach for treating Cushing disease. Evidence is needed to document effectiveness. OBJECTIVE: To analyze results of transsphenoidal surgery in 276 consecutive patients, including 19 children. METHODS: Medical records were reviewed for patients treated initially with surgery for Cushing disease from 1980 to 2012. Radiographic features, pathology, remissions, recurrences, and complications were recorded. Patients were categorized for statistical analysis based on tumor size (microadenomas, macroadenomas, and negative imaging) and remission type (type 1 = morning cortisol ≤3 µg/dL; type 2 = morning cortisol normal). RESULTS: Females comprised 78% of patients and were older than men. Imaging showed 50% microadenomas, 13% macroadenomas, and 37% negative for tumor. Remission rates for microadenomas, macroadenomas, and negative imaging were 89%, 66%, and 71%, respectively. Patients with microadenomas were more likely to have type 1 remission. Pathology showed adrenocorticotropic hormone-secreting adenomas in 82% of microadenomas, in 100% of macroadenomas, and in 43% of negative imaging. The incidence of hyperplasia was 8%. The finding of hyperplasia or no tumor on pathology predicted treatment failure. The recurrence rate was 17%, with an average time to recurrence of 4.0 years. Patients with type 1 remission had a lower rate of recurrence (13% type 1 vs 50% type 2) and a longer time to recurrence. Children had similar imaging findings, remission rates, and pathology. There were no operative deaths. CONCLUSION: Transsphenoidal surgery provides a safe and effective treatment for Cushing disease. For both adults and children, the best outcomes occurred in patients with microadenomas and/or those with type 1 remission.

Clinically silent somatotropinomas may be biochemically active.

The diagnosis of acromegaly is suspected based on the typical clinical presentation and is subsequently confirmed biochemically by elevated GH and IGF-I concentrations. We report three female patients with pituitary tumors who presented without any signs or symptoms of acromegaly but with elevated IGF-I levels. Plasma GH was measured every 10 min for 24 h, and an oral glucose tolerance test was performed. All patients had abnormally elevated mean and trough plasma GH levels as well as post-glucose nadir GH concentrations. All patients had magnetic resonance imaging scans revealing pituitary tumors and underwent transsphenoidal surgery. Histologically, they had GH-producing pituitary tumors. Plasma IGF-I levels returned to normal in two patients after surgery. Some pituitary adenomas are true GH-secreting tumors despite not being accompanied by obvious clinical stigmata of acromegaly. Natural history of this disease is unknown because of the small number of reported patients and inconsistent results of biochemical testing. Based on the results of this and previous reports, we propose that all patients with known pituitary tumors, especially younger women with normal or mildly elevated prolactin level, be evaluated for GH excess.

Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results.

PURPOSE: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). MATERIALS AND METHODS: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. RESULTS: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination. CONCLUSION: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.

Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly.

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease.

Glucocorticoids have major effects on adipose tissue metabolism. To study tissue mRNA expression changes induced by chronic elevated endogenous glucocorticoids, we performed RNA sequencing on the subcutaneous adipose tissue from patients with Cushing's disease (n=5) compared to patients with nonfunctioning pituitary adenomas (n=11). We found a higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as a decreased expression of transcripts involved in inflammation and protein synthesis. To further study this in a model system, we subjected mice to dexamethasone treatment for 12 weeks and analyzed their inguinal (subcutaneous) fat pads, which led to similar findings. Additionally, mice treated with dexamethasone showed drastic decreases in lean body mass as well as increased fat mass, further supporting the human transcriptomic data. These data provide insight to transcriptional changes that may be responsible for the comorbidities associated with chronic elevations of glucocorticoids.

Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up.

The biochemical diagnosis of acromegaly is conventionally based on elevated plasma GH levels that fail to suppress after an oral glucose load. We studied 16 newly diagnosed patients with acromegaly with normal mean plasma GH but elevated age and gender-adjusted plasma IGF-I concentrations (476 +/- 29 microg/liter, mean +/- SE). Plasma GH was sampled every 10 min for 24 h, and an oral glucose tolerance test was performed. The control group included 46 healthy subjects. All patients had 24-h mean GH values that overlapped with those of the healthy controls. Mean plasma GH was less than 2.5 microg/liter in 12 patients. Patients had higher 24-h nadir GH values than healthy controls (P < 0.001). During the oral glucose tolerance test, nadir plasma GH was less than 1 micro g/liter in eight patients. Plasma IGF-I normalized in 11 of 14 patients after transsphenoidal surgery. Four patients with normal IGF-I after transsphenoidal surgery were restudied. Mean and nadir GH decreased in all of them. In our experience in many patients with acromegaly, the diagnosis could be missed if only the existing GH-based criteria are used. Revised GH criteria in combination with plasma IGF-I should be used for the diagnosis and follow-up of acromegaly.

The role of radiation therapy after surgical resection of nonfunctional pituitary macroadenomas.

OBJECTIVE: Radiotherapy after aggressive surgical resection of nonfunctional macroadenoma (NFA) of the pituitary remains controversial. Historically, immediate postoperative radiotherapy has been recommended to decrease risk of recurrence. With the availability of high-resolution imaging, most neurosurgeons now withhold radiation until recurrence. There is relatively little evidence to support this practice, however. This study reviews postoperative results in a large number of patients with NFA, the majority of whom did not undergo prophylactic radiation. METHODS: Of the 258 patients who underwent surgery from 1979 to 1999 for NFA, medical records were available for 176. Forty-four patients were treated with immediate postoperative radiotherapy after tumor resection, and the remaining 132 patients were followed up with serial imaging studies and treated with radiotherapy only when a recurrence was documented by follow-up imaging. RESULTS: Patients in the group that received immediate postoperative radiotherapy at time of initial diagnosis and surgery did not differ significantly with respect to age or sex from those in the group that was observed. Five- and 10-year recurrence rates were 2.3 and 2.3%, respectively, for patients who received immediate postoperative radiotherapy, as compared with 15.2 and 50.5%, respectively, for patients who were followed up and did not receive radiotherapy unless there was evidence of recurrence or progression. No patient had symptomatic recurrence in the group that was observed if consistent follow-up was performed. Of the 26 patients who received radiotherapy at time of tumor recurrence or progression, 18 had adequate follow-up, and in all cases, the tumors either remained stable or regressed. CONCLUSION: Withholding radiotherapy after a high-percentage resection of NFA leads to a higher recurrence rate, but it avoids exposing all patients to the risks of radiation. Deferring radiotherapy for patients with complete or near-complete resection seems to be a safe and prudent approach, as our data suggest that recurrences may be detected early with high-resolution imaging and treated effectively with radiation at time of recurrence. Therefore, immediate postoperative radiotherapy may be eliminated for patients with complete or near complete resection of NFA and who agree to undergo close follow-up for a long period.

Management options for persistent functional tumors.

This article describes in detail the current management of patients with functional pituitary tumors that demonstrate persistent function after surgical intervention. After providing a clear definition of "persistent function" for each specific type of tumor, the medical, surgical, and radiation options for each type are provided. Functional tumors include those that produce growth hormone, adrenocorticotrophic hormone, prolactin, and thyroid stimulating hormone.