No abstract

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha-stimulatory subunit of GPCRs (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally-inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through GPCRs requiring Gsα (eg., PTH, TSH, GHRH, calcitonin) and severe obesity. Paternally-inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue-specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal-increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized an AHO mouse model generated in our laboratory to address whether Gsα heterozygous inactivation by the targeted disruption of exon 1 of Gnas differentially affects bone remodeling based on the parental inheritance of the mutation. Mice with paternally-inherited (Gnas E1+/-p) and maternally-inherited (Gnas E1+/-m) mutations displayed reductions in osteoblasts along the bone surface compared to wildtype. Gnas E1+/-p mice displayed reduced cortical and trabecular bone parameters due to impaired bone formation and excessive bone resorption. Gnas E1+/-m mice however displayed enhanced bone parameters due to increased osteoblast activity and normal bone resorption. These distinctions in bone remodeling between Gnas E1+/-p and Gnas E1+/-m mice appear to be secondary to changes in the bone microenvironment driven by calcitonin-resistance within Gnas E1+/-m osteoclasts and therefore warrant further studies into understanding how Gsα influences osteoblast-osteoclast coupling interactions.

TPS1121 Background: Cutaneous metastases occur in approximately 20% of patients (pts) with metastatic breast cancer (mBC) and can be highly symptomatic and distressing. Radiation is frequently offered, but progression often occurs quickly. Photodynamic therapy is a promising approach with encouraging results in small studies. Here we will evaluate a novel Continuous Low-Irradiance Photodynamic Therapy (CLIPT) system that emits 690nm LED via a handheld powerpack attached to a single-use sterile light patch to deliver a total energy level of 10J/cm2. Verteporfin (Visudyne) is a photosensitizer approved for ophthalmological use that when combined with CLIPT generates activated oxygen species which can destroy tumor cells with limited normal tissue reaction. Methods: This open label, phase 2 study will evaluate the efficacy and safety of CLIPT with verteporfin in 15 pts with cutaneous lesions from mBC. Pts will receive a single IV injection of verteporfin on day 1. The 9x9cm patch with an adhesive border is placed over the treatment site and attached to the CLIPT portable power pack. The pt turns the device on at home 6 hours after the verteprofin injection and it automatically turns off after 24 hours. The pt will remove the patch and return to clinic on day 3. The primary endpoint is objective response rate (RR) at 3 weeks following CLIPT using a modified RECIST which accounts for nodular or diffuse plaque-like lesions. Secondary endpoints include RR at 2, 8 and 12 weeks, toxicity, and quality of life (using FACT-B, a Participant Symptom Scale, and Brief Pain Inventory). Pts who derive clinical benefit may be retreated up to 3 times to the same or different region. Eligible pts will have: cutaneous metastases from mBC with measurable disease by protocol defined modified RECIST 1.1, ≥ 1 line of prior systemic or local therapy for mBC, ≥ 14 days from prior systemic therapy or 60 days from radiation to target lesion, and no expectation for systemic therapy for ≥ 14 days after CLIPT. RR will be reported with 95% CI. If ≥ 3 responses (RR ≥ 20%) are observed, the null hypothesis of RR ≤ 5% will be rejected. At the time of abstract submission, 1 patient has been accrued. Clinical trial information: NCT02939274.

Clear cell meningiomas are rare meningioma variants and are recognized as World Health Organization grade II tumours. They may be difficult to manage given their propensity to recur early especially if present in surgically challenging locations. We describe a rare case of a fourth ventricular clear cell meningioma without dural attachment in a 14-year-old boy with an unusual presentation of failure to thrive. The case is presented in detail and a review of the recent literature is discussed.

Background The optimal treatment for acute stroke attributable to isolated cervical internal carotid artery occlusion without intracranial target is unclear. The purpose of our study was to examine whether endovascular therapy for acute stroke attributable to isolated cervical internal carotid artery occlusion was associated with improved clinical outcome. Methods We identified patients from 2 comprehensive stroke centers during the period January 2009 to December 2019, with acute ischemic stroke attributable to cervical internal carotid artery occlusion without an intracranial occlusion. We categorized patients into 2 groups: endovascular therapy and medical therapy. Clinical outcome (modified Rankin scale score at 90 days poststroke) was compared between the 2 groups. Results Seventy‐three patients were included (26 women [36%]; median age, 69 [interquartile range (IQR), 60–80] years; median National Institutes of Health Stroke Scale score, 11 [IQR, 5–16]). Of these, 40 patients received endovascular therapy, and 33 patients were managed with medical therapy alone. The endovascular therapy group had a significantly higher median National Institutes of Health Stroke Scale score on presentation (13 versus 3; P <0.0001). Rates of thrombolysis were also significantly higher in the endovascular group (50% versus 15%; P =0.002). There were no other significant differences in baseline characteristics between the 2 groups. Good clinical outcome (modified Rankin scale score 0–2 at 90 days or no decline in modified Rankin scale score from baseline at 90 days) was seen in 73% of the endovascular therapy group compared with the 61% of the medical management group (odds ratio [OR] for good outcome, 1.7 [95% CI, 0.64–4.6]), despite the large discrepancy in baseline stroke severity. When restricted to patients with presenting National Institutes of Health Stroke Scale score ≥6, endovascular therapy was associated with higher rates of good clinical outcome (66% versus 18%; OR for good outcome, 9.0 [95% CI, 1.65–49.0]). Conclusions Endovascular therapy in isolated cervical internal carotid artery occlusion may be associated with improved outcome when compared with medical therapy. However, the significant differences in baseline characteristics between the groups limit interpretation. Randomized controlled trials are necessary.