Complete Resection of Ampullary Paragangliomas Confined to the Submucosa on Endoscopic Ultrasound May Be Best Achieved by Radical Surgical Resection

Paragangliomas of the gastrointestinal tract generally are benign tumors usually found in the second portion of the duodenum. We present a case of paraganglioma of the ampulla of Vater confined to the submucosa on endoscopic ultrasound examination. This was initially treated by endoscopic resection, followed by pancreaticoduodenectomy after local resection margins were positive. Histopathology showed a well-differentiated ampullary paraganglioma confined to the submucosa, but with involvement of one regional lymph node. Only 25 prior cases of paraganglioma at the ampulla of Vater have been reported, and nine of these have demonstrated local or distant metastases. Because of their malignant potential, ampullary paragangliomas should be treated with radical resection if the goal is to achieve complete resection, even if preoperative imaging shows local confinement

The DREADD Agonist Clozapine N -oxide (CNO) is Reverse-Metabolized to Clozapine and Produces Clozapine-Like Interoceptive Stimulus Effects in Rats and Mice

Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0 mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25 mg/kg clozapine from vehicle, CNO (1.0-20.0 mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine-like behavioral effects in both mice and rats further emphasizes the need for appropriate control groups in studies employing DREADDs, and highlights the utility of the drug discrimination procedure as a tool with which to screen the off-target effects of novel DREADD agonists

Muskellunge and Northern Pike Ecology and Management: Important Issues and Research Needs

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141909/1/fsh0258.pd

Salvage Fractionated Stereotactic Re-irradiation (FSRT) for Patients with Recurrent High Grade Gliomas Progressed after Bevacizumab Treatment

Purpose/Objectives: Bevacizumab failure is a major clinical problem in the manage- ment of high grade gliomas (HGG), with a median overall survival of less than 4 months (m). This study evaluated the efficacy of fractionated stereotactic re-irradiation (FSRT) for patients with HGG after progression on Bevacizumab. Materials/Methods: Retrospective review was conducted of patients treated with FSRT after progression on bevacizumab. A total of 36 patients were identified. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. Results: Among the 36 patients, 31 patients had recurrent glioblastoma, and 5 patients had recurrent anaplastic astrocytoma. The median time from initial bevacizumab treatment to FSRT was 8.5 m (range 2.3 – 32.0 m). The median plan target volume for FSRT was 27.5 cc (range 1.95 – 165 cc). With a median follow up of 20.4 m, the overall survival of the patients since initial diagnosis was also 24.9 m. The median overall survival after initiation of bevacizumab was 13.4 months. The median overall survival from FSRT was 4.8 m. FSRT treatment was well tolerated with no Grade \u3e3 toxicity. Conclusions: Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment

Determining the Role of Surgery in Diagnosis and Treatment of Primary CNS Lymphoma

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare entity typically treated with a combination of chemotherapy and radiation. The role of surgery is controversial, and biopsy may be non-definitive or injurious. We review our series of stereotactic and excisional biopsy as well as surgical debulking of PCNSL to quantify overall risk and benefits. Methods: Patients with biopsy-confirmed intracranial PCNSL were identified from a large singlecenter academic institution between 2012-2018. Preoperative factors and perioperative outcomes were retrospectively reviewed. Results: A total of 61 cases of PCNSL were identified. Most patients presented with confusion (23.0%), weakness/paralysis (19.7%), and gait disturbance (18.0%). 1.6% were incidentally identified. HIV status was positive in 8.2% of cases. CSF cytology was positive for malignancy in 33.3% of applicable cases. Of all procedures, 44.3% were needle biopsy, 27.9% were open excisional biopsies, and 27.9% were surgical debulking procedures. Prior biopsy had been performed in 9.8%, of which 83.3% (5/6) were positive for PCNSL. Intraoperative frozen pathology failed to illicit a definitive diagnosis in 39.3% of cases despite adequate sampling. Stereotactic biopsies did not demonstrate an increased risk of non-diagnostic frozen pathology compared to open excisional biopsy. Intraoperative complications, 30-day mortality, and long-term survival was not associated with open vs. stereotactic biopsy. Discussion: Biopsy of PCNSL carries a moderate surgical risk that should not be discounted, particularly in the setting of previously diagnosed PCNSL or with evidence of malignancy in CSF cytology. Early initiation of chemotherapy continues to be the mainstay of long-term response and control

Phase I Study of Ipilimumab Combined with Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients with Brain Metastases

Purpose: We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) in patients with brain metastases (BM) from melanoma. Methods: Based on intracranial (IC) disease burden, patients were treated with WBRT (Arm A) or SRS (Arm B). Ipilimumab starting dose was 3 mg/kg (every 3 weeks, starting on day 3 of WBRT or 2 days after SRS). Ipilimumab was escalated to 10 mg/kg using a two-stage, 3+3 design. The primary endpoint was to determine the MTD of ipilimumab combined with radiotherapy. Secondary endpoints were overall survival (OS), IC and extracranial (EC) control, progression free survival (PFS), and toxicity. This trial is regis- tered with ClinicalTrials.gov, number NCT01703507. Results: Characteristics of the 16 patients enrolled between 2011 and 2014 were: mean age, 60; median BM, 2 (1 to \u3e10); number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), ipilimumab 3mg/kg (n=7), 10 mg/kg (n=9). Median follow-up was 8 months (Arm A) and 10.5 months (Arm B). There were 21 grade 1-2 neuro- toxic effects with no dose-limiting toxicities (DLTs). One patient experienced grade 3 neurotoxicity prior to ipilimumab administration. Ten additional grade 3 toxicities were reported with gastrointestinal (n=5, 31%) as the most common. There were no grade 4/5 toxicities. Median PFS and OS, respectively, in Arm A were 2.5 months and 8 months, and in Arm B were 2.1 months and not reached. Conclusion: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early due to slow accrual, but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced DLT. Larger studies with ipilimumab 10 mg/kg and SRS are warranted

Deep Supratentorial Extension is Associated with Poor Clinical Outcomes After Glioblastoma Resection

Introduction: Glioblastoma (GBM) often extends to deep supratentorial locations, which limits the extent of maximal safe resection. Deep supratentorial extension (DSE) may be a clinically convenient prognostic indicator following GBM resection. Methods: 582 GBM resections from 2012-2018 were retrospectively reviewed. DSE was defined as tumoral extension to the basal ganglia, thalamus, corpus callosum, internal capsule, hypothalamus, caudate, or putamen as identified on preoperative imaging. Results: DSE was identified in 32.9% cases (192), while 52.5% (306) involved only superficial supratentorial locations (frontal, parietal, temporal and occipital lobes). Within the DSE cohort, the most commonly affected anatomical locations were the corpus callosum (18.9%), basal ganglia (10.8%), and thalamus (5.5%). DSE was associated with a significantly higher rate of residual tumor (71.9%vs59.3%, p=.015), larger size (48.3 vs 43.6 mm, p=.007), and lower rate of radiological gross total resection (GTR) (55.6% vs 70.6%, p=.005). DSE was also associated with a worse progression free survival (PFS) (5.55vs8.32 months, p = .009) and overall survival (OS) (9.89vs14.23 months, p=.000). Kaplan-Meier curves showed worse OS with DSE (log rank=.003), and worse OS with involvement of 2+ DSE structures as compared to 1 or none (log rank=.000). DSE had no effect on OS among those achieving GTR (log rank=.626), but without GTR, DSE significantly worsened survival (log rank=.030) on Kaplan-Meier. Discussion: DSE portended higher rates of residual tumor, lower rates of GTR, and worse PFS and OS, particularly among those not achieving GTR and with involvement of 2+ structures. DSE in GBM is a convenient and reliable negative prognostic factor

Edge-Coupling of O-Band InP Etched-Facet Lasers to Polymer Waveguides on SOI by Micro-Transfer-Printing

O-band InP etched facets lasers were heterogeneously integrated by micro-transfer-printing into a 1.54~\mu \text{m} deep recess created in the 3~\mu \text{m} thick oxide layer of a 220 nm SOI wafer. A 7\times 1.5\,\,\mu \text{m}^{2} cross-section, 2 mm long multimode polymer waveguide was aligned to the ridge post-integration by e-beam lithography with \u3c 0.7~\mu \text{m} lateral misalignment and incorporated a tapered silicon waveguide. A 170 nm thick metal layer positioned at the bottom of the recess adjusts the vertical alignment of the laser and serves as a thermal via to sink the heat to the Si substrate. This strategy shows a roadmap for active polymer waveguide-based photonic integrated circuits

Middle Fossa Extension of Posterior Fossa Meningiomas is Associated with Poorer Clinical Outcomes

Introduction: Progression of posterior fossa meningiomas (PFMs) can lead to extension into the middle cranial fossa. Pre-operative imaging allows for quantification of middle fossa extension (MFE). We aimed to determine the clinical impact of MFE on surgical and clinical outcomes during resection of PFMs. Methods: Craniotomies for meningiomas performed at a large single center academic institution from January 2012 to December 2018 were identified. Preoperative MRI and CT imaging was reviewed to determine the presence of MFE of posterior fossa meningiomas and correlated to post-operative outcomes. Results: 65 PFMs were identified and mean follow-up was 28.8 ± 20.1 months. 13/65 PFMs showed MFE preoperatively. Average size of PFMs with MFE (36.1 cm ± 12.1 cm) was similar to PFMs without MFE (33.5 cm ± 9.2 cm, p \u3e 0.05). 9/13 PFMs with MFE were petrous or petroclival, and 4/13 involved the cavernous sinus. Retrosigmoid craniotomy was the most utilized approach for both isolated PFMs (51.9%) and PFMs with MFE (76.9%). Anterior approaches were used in 2/13 PFMs with MFE. Presence of MFE was strongly associated with decreased rates of GTR (RR= 0.1; p \u3c 0.05). MFE wasn’t associated with longer LOS or rates of readmission within 30 days of discharge, but was associated with a significantly higher rate of overall mortality at last follow-up (RR=5.3; 95%; p \u3c 0.05). Conclusion: PFMs with MFE are easily identifiable and are associated with decreased rates of GTR and overall prognosis and may suggest the need for anterior or combined approaches