Publications by authors named "Christopher Farrell"

101 Publications

Assessment of the Validity of the Sinonasal Outcomes Test-22 in Pituitary Surgery: A Multicenter Prospective Trial.

Laryngoscope 2021 Jul 1. Epub 2021 Jul 1.

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Objectives/hypothesis: Sinonasal Outcomes Test-22 (SNOT-22) is used widely as a patient-reported sinonasal quality-of-life (QOL) instrument for endoscopic endonasal pituitary surgery. However, it has never been validated in this population. This study explores the psychometric validity of SNOT-22 to determine if it is a valid scale in patients undergoing endoscopic pituitary surgery.

Study Design: Multicenter prospective trial.

Methods: Adult patients (n = 113) with pituitary tumors undergoing endoscopic surgery were enrolled in a multicenter study. Patient-reported QOL was assessed using SNOT-22 and the Anterior Skull Base Nasal Inventory-12. Face validity, internal consistency, responsiveness to clinical change, test-retest reliability, and concurrent validity were determined using standard statistical methods.

Results: Internal consistency using Cronbach's alpha at baseline and 2 weeks postoperatively were 0.911 and 0.922, indicating SNOT-22 performed well as a single construct. Mean QOL scores were significantly worse at 2 weeks than baseline (16.4 ± 15.1 vs. 23.1 ± 16.4, P < .001), indicating the scale is responsive to clinical change. However, only 11/22 items demonstrated significant changes in mean scores at 2 weeks. Correlation between scores at 2 and 3 weeks was high, suggesting good test-retest reliability, r(107) = 0.75, P < .001. Factor analysis suggests the five-factor solution proposed for the SNOT-22 in rhinosinusitis patients is not valid in pituitary surgery patients.

Conclusions: The SNOT-22 is a valid QOL instrument in patients undergoing endoscopic pituitary surgery. However, because it includes 22 items, can be applied only as a single construct, 50% of the items do not demonstrate changes after surgery, and is not as sensitive to change as other scales, shorter instruments developed specifically for this patient population may be preferable.

Level Of Evidence: II Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29711DOI Listing
July 2021

The impact of pharmacogenetic testing in patients exposed to polypharmacy: a scoping review.

Pharmacogenomics J 2021 Aug 17;21(4):409-422. Epub 2021 Jun 17.

School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC, USA.

Polypharmacy poses a significant risk for adverse reactions. While there are clinical decision support tools to assist clinicians in medication management, pharmacogenetic testing to identify potential drug-gene or drug-drug-gene interactions is not widely implemented in the clinical setting. A PRISMA-compliant scoping review was performed to determine if pharmacogenetic testing for absorption, distribution, metabolism, and excretion (ADME)-related genetic variants is associated with improved clinical outcomes in patients with polypharmacy. Six studies were reviewed. Five reported improved clinical outcomes, reduced side effects, reduction in the number of drugs used, or reduced healthcare utilization. The reviewed studies varied in methodological quality, risk of bias, and outcome measures. Age, diet, disease state, and treatment adherence also influence drug response, and may confound the relationship between genetic polymorphisms and treatment outcomes. Further studies using a randomized control design are needed. We conclude that pharmacogenetic testing represents an opportunity to improve health outcomes in patients exposed to polypharmacy, particularly in patients with psychiatric disorders and the elderly.
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http://dx.doi.org/10.1038/s41397-021-00224-wDOI Listing
August 2021

Resected WHO grade I meningioma and predictors of local control.

J Neurooncol 2021 Mar 9;152(1):145-151. Epub 2021 Jan 9.

Department of Radiation Oncology, Sidney Kimmel Medical College, Philadelphia, PA, USA.

Introduction: Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas.

Methods: The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion.

Results: Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002).

Conclusions: WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.
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http://dx.doi.org/10.1007/s11060-020-03688-1DOI Listing
March 2021

Preoperative Screening for Obstructive Sleep Apnea Prior to Endoscopic Skull Base Surgery: A Survey of the North American Skull Base Society.

Allergy Rhinol (Providence) 2020 Jan-Dec;11:2152656720968801. Epub 2020 Nov 12.

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

Background: Obstructive sleep apnea (OSA) is a commonly seen comorbidity in patients undergoing endoscopic skull base surgery and its presence may influence perioperative decision-making. Current practice patterns for preoperative screening of OSA are poorly understood.

Objective: The objective of this study was to assess how endoscopic skull base surgeons screen for OSA, and how knowledge of OSA affects perioperative decision-making.

Methods: Seven question survey distributed to members of the North American Skull Base Society.

Results: Eighty-eight responses (10% response rate) were received. 60% of respondents were from academic centers who personally performed >50 cases per year. Most respondents noted that preoperative knowledge of OSA and its severity affected postoperative care and increased their concern for complications. Half of respondents noted that preoperative knowledge of OSA and its severity affects intraoperative skull base reconstruction decision-making. 70% of respondents did not have a preoperative OSA screening protocol. Body mass index and patient history were most frequently used by those who screened. Validated screening questionnaires were rarely used. 76% of respondents agreed or somewhat agreed that a preoperative polysomnogram should ideally be performed for patients with suspected OSA; however, 50% of respondents reported that <20% of their patients with suspected OSA are advised to obtain a preoperative polysomnogram.

Conclusion: This study reveals that most endoscopic skull base surgeons agree that OSA affects postoperative patient care, but only a minority have a preoperative screening protocol in place. Additional study is needed to assess the most appropriate screening methods and protocols for OSA patients undergoing endoscopic skull base surgery.
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http://dx.doi.org/10.1177/2152656720968801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672726PMC
November 2020

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of emerging developments in the management of newly diagnosed glioblastoma.

J Neurooncol 2020 Nov 19;150(2):269-359. Epub 2020 Nov 19.

Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.

Target Population: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma.

Imaging: Question What imaging modalities are in development that may be able to provide improvements in diagnosis, and therapeutic guidance for individuals with newly diagnosed glioblastoma?

Recommendation: Level III: It is suggested that techniques utilizing magnetic resonance imaging for diffusion weighted imaging, and to measure cerebral blood and magnetic spectroscopic resonance imaging of N-acetyl aspartate, choline and the choline to N-acetyl aspartate index to assist in diagnosis and treatment planning in patients with newly diagnosed or suspected glioblastoma.

Surgery: Question What new surgical techniques can be used to provide improved tumor definition and resectability to yield better tumor control and prognosis for individuals with newly diagnosed glioblastoma?

Recommendations: Level II: The use of 5-aminolevulinic acid is recommended to improve extent of tumor resection in patients with newly diagnosed glioblastoma. Level II: The use of 5-aminolevulinic acid is recommended to improve median survival and 2 year survival in newly diagnosed glioblastoma patients with clinical characteristics suggesting poor prognosis. Level III: It is suggested that, when available, patients be enrolled in properly designed clinical trials assessing the value of diffusion tensor imaging in improving the safety of patients with newly diagnosed glioblastoma undergoing surgery.

Neuropathology: Question What new pathology techniques and measurement of biomarkers in tumor tissue can be used to provide improved diagnostic ability, and determination of therapeutic responsiveness and prognosis for patients with newly diagnosed glioblastomas?

Recommendations: Level II: Assessment of tumor MGMT promoter methylation status is recommended as a significant predictor of a longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level II: Measurement of tumor expression of neuron-glia-2, neurofilament protein, glutamine synthetase and phosphorylated STAT3 is recommended as a predictor of overall survival in patients with newly diagnosed with glioblastoma. Level III: Assessment of tumor IDH1 mutation status is suggested as a predictor of longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level III: Evaluation of tumor expression of Phosphorylated Mitogen-Activated Protein Kinase protein, EGFR protein, and Insulin-like Growth Factor-Binding Protein-3 is suggested as a predictor of overall survival in patients with newly diagnosed with glioblastoma.

Radiation: Question What radiation therapy techniques are in development that may be used to provide improved tumor control and prognosis for individuals with newly diagnosed glioblastomas?

Recommendations: Level III: It is suggested that patients with newly diagnosed glioblastoma undergo pretreatment radio-labeled amino acid tracer positron emission tomography to assess areas at risk for tumor recurrence to assist in radiation treatment planning. Level III: It is suggested that, when available, patients be with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of radiation dose escalation, altered fractionation, or new radiation delivery techniques.

Chemotherapy: Question What emerging chemotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas?

Recommendation: Level III: As no emerging chemotherapeutic agents or techniques were identified in this review that improved tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of chemotherapy.

Molecular And Targeted Therapy: Question What new targeted therapy agents are available to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas?

Recommendation: Level III: As no new molecular and targeted therapies have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of molecular and targeted therapies IMMUNOTHERAPY: Question What emerging immunotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas?

Recommendation: Level III: As no immunotherapeutic agents have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of immunologically-based therapies.

Novel Therapies: Question What novel therapies or techniques are in development to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas?

Recommendations: Level II: The use of tumor-treating fields is recommended for patients with newly diagnosed glioblastoma who have undergone surgical debulking and completed concurrent chemoradiation without progression of disease at the time of tumor-treating field therapy initiation. Level II: It is suggested that, when available, enrollment in properly designed studies of vector containing herpes simplex thymidine kinase gene and prodrug therapies be considered in patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1007/s11060-020-03607-4DOI Listing
November 2020

Breast carcinoma metastasis in a resected meningioma with early diagnosis of oligometastatic disease: a case report.

Chin Clin Oncol 2020 Oct;9(5):71

Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.

Tumor-to-tumor metastasis describes the ability of primary tumors to metastasize to other primary tumors. These events generally occur in aggressive and widely-metastatic disease, with the appropriate management and significance of these events unknown. A 56-year-old woman with a history of bilateral, localized, invasive lobular breast carcinoma treated with surgery, systemic therapy, and adjuvant radiation presented five and two years post-treatment with progressive neurological symptoms. Imaging revealed an intracranial meningioma, and the patient underwent resection. Pathology revealed metastatic invasive lobular carcinoma cells within the resected meningioma, and the patient was treated with postoperative radiation without sequelae. Subsequent staging scans revealed a single osseous lesion suggestive of oligometastatic disease, and the patient was promptly started on systemic therapy.
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http://dx.doi.org/10.21037/cco-20-122DOI Listing
October 2020

Cerebral deep venous thrombosis and COVID-19: case report.

J Neurosurg 2020 Sep 4:1-4. Epub 2020 Sep 4.

Herein, the authors present the case of a 54-year-old male diagnosed with coronavirus disease 2019 (COVID-19) during a screening test. The patient was asked to self-isolate at home and report with any exacerbations of symptoms. He presented later with pneumonia complicated by encephalopathy at days 14 and 15 from initial diagnosis, respectively. MRI of the brain showed bithalamic and gangliocapsular FLAIR signal abnormality with mild right-sided thalamic and periventricular diffusion restriction. A CT venogram was obtained given the distribution of edema and demonstrated deep venous thrombosis involving the bilateral internal cerebral veins and the vein of Galen. CSF workup was negative for encephalitis, as the COVID-19 polymerase chain reaction (PCR) test and bacterial cultures were negative. A complete hypercoagulable workup was negative, and the venous thrombosis was attributed to a hypercoagulable state induced by COVID-19. The mental decline was attributed to bithalamic and gangliocapsular venous infarction secondary to deep venous thrombosis. Unfortunately, the patient's condition continued to decline, and care was withdrawn.
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http://dx.doi.org/10.3171/2020.5.JNS201542DOI Listing
September 2020

A narrative review of targeted therapy in meningioma, pituitary adenoma, and craniopharyngioma of the skull base.

Chin Clin Oncol 2020 Dec 17;9(6):75. Epub 2020 Aug 17.

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Management of solid tumors involving the skull base are primarily managed with surgery and radiation, though proximity to important vascular and neuroanatomic structures often limit the extent of resection and permissible radiation dose. Meningiomas are the most common primary brain tumor in adults, and although the majority of skull base meningiomas are low-grade, their location in proximity to critical anatomical structures precludes aggressive surgical resection, and larger tumors are often resistant to radiation treatment. In patients with clinically aggressive, unresectable meningiomas, several molecular biomarkers of angiogenesis, as well as genetic mutations (SMO, AKT1, PIK3CA, KLF4, POLR2, SMARCE1, and TRAF7), have been shown to play a crucial role in the pathophysiology of these tumors. Pituitary adenomas are commonly slow growing tumors that are amenable to surgical resection, but tumors with higher Ki67 proliferative indices are associated with an increased risk of relapse and resistance to standard therapies. Chemotherapeutic agents and checkpoint inhibitors have been trialed, albeit with limited success, to treat these aggressive pituitary adenomas. Craniopharyngiomas are categorized as adamantinomatous and papillary subtypes, each with unique molecular mechanisms that drive pathogenesis of these tumors, and have introduced the possibility that targeted therapies may be developed for improved neurologic and endocrinological outcomes. Skull base tumors that exhibit recurrence despite surgical resection and radiation treatment pose a unique challenge, and systemic agents offer a non-invasive option of treating tumors that are refractory to conventional approaches. Recent insights into the molecular aberrations that elucidate the pathophysiology of these difficult-to-treat tumors have provided potential therapeutic targets for drug delivery. In this review, the authors discuss promising therapies and current knowledge gaps needed for the development of effective targeted agents for meningioma, pituitary adenoma, and craniopharyngioma.
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http://dx.doi.org/10.21037/cco-20-168DOI Listing
December 2020

Quantitative determination of the optimal temporoparietal fascia flap necessary to repair skull-base defects.

Int Forum Allergy Rhinol 2020 11 7;10(11):1249-1254. Epub 2020 Jul 7.

Department of Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, PA.

Background: The ability to reconstruct large cranial base defects has greatly improved with the development of pedicled vascularized flaps. The temporoparietal fascia flap (TPFF) is a viable alternative to the Hadad-Bassagasteguy nasoseptal flap for large ventral skull-base defects. This study aims to characterize the size of the TPFF necessary for optimal ventral skull-base reconstruction.

Methods: Eleven formaldehyde-fixed cadaveric heads were used to harvest TPFF of varying heights on each side (total = 22). TPFF was passed through the pterygomaxillary fissure (PMF) to the ventral skull base to assess its coverage. For a subgroup of 12 sides, the TPFF was trimmed to determine the minimum height necessary for coverage.

Results: The TPFF height was (mean ± standard deviation [SD]) 14.72 ± 1.02 cm (range, 12.5 to 16.5 cm) and width was 8.43 ± 1.05 cm (range, 6 to 10.5 cm). The distance from the TPFF pedicle through the PMF was 5.8 ± 0.5 cm (range, 5 to 6.5 cm). All TPFF flaps provided complete ipsilateral coverage of clival defects, and all but 1 covered the entire clivus. All TPFF flaps, when rotated anteriorly, provided coverage up to the cribriform plate. The minimum TPFF height necessary for complete coverage of cribriform defects and ventral defects up to the planum sphenoidale was 12 cm. TPFF height for specimens with and without complete ventral skull-base coverage was significantly different (p < 0.0001).

Conclusion: The TPFF is a versatile alternative to the nasoseptal flap and a height of at least 12 cm can provide enough coverage for all ventral skull base defects.
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http://dx.doi.org/10.1002/alr.22609DOI Listing
November 2020

Predicting prolonged length of stay after endoscopic transsphenoidal surgery for pituitary adenoma.

Int Forum Allergy Rhinol 2020 06 3;10(6):785-790. Epub 2020 May 3.

Department of Otolaryngology-Head & Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, PA.

Background: Endoscopic transsphenoidal surgery (ETS) for the resection of pituitary adenoma has become more common throughout the past decade. Although most patients have a short postoperative hospitalization, others require a more prolonged stay. We aimed to identify predictors for prolonged hospitalization in the setting of ETS for pituitary adenomas.

Methods: A retrospective chart review as performed on 658 patients undergoing ETS for pituitary adenoma at a single tertiary care academic center from 2005 to 2019. Length of stay (LoS) was defined as date of surgery to date of discharge. Patients with LoS in the top 10th percentile (prolonged LoS [PLS] >4 days, N = 72) were compared with the remainder (standard LoS [SLS], N = 586).

Results: The average age was 54 years and 52.5% were male. The mean LoS was 2.1 days vs 7.5 days (SLS vs PLS). On univariate analysis, atrial fibrillation (p = 0.002), hypertension (p = 0.033), partial tumor resection (p < 0.001), apoplexy (p = 0.020), intraoperative cerebrospinal fluid (ioCSF) leak (p = 0.001), nasoseptal flap (p = 0.049), postoperative diabetes insipidus (DI) (p = 0.010), and readmission within 30 days (p = 0.025) were significantly associated with PLS. Preoperative continuous positive airway pressure (CPAP) (odds ratio, 15.144; 95% confidence interval, 2.596-88.346; p = 0.003) and presence of an ioCSF leak (OR, 10.362; 95% CI, 2.143-50.104; p = 0.004) remained significant on multivariable analysis.

Conclusion: For patients undergoing ETS for pituitary adenomas, an ioCSF leak or preoperative use of CPAP predicted PLS. Additional common reasons for PLS included postoperative CSF leak (10 of 72), management of DI or hypopituitarism (15 of 72), or reoperation due to surgical or medical complications (14 of 72).
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http://dx.doi.org/10.1002/alr.22540DOI Listing
June 2020

Successful stereotactic radiotherapy of meningiomas in a patient with Cowden syndrome: a case report.

Chin Clin Oncol 2020 06 24;9(3):38. Epub 2020 Apr 24.

Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.

Cowden's Syndrome (CS) is a rare disease with increased risk for several carcinomas. Experimental studies and limited case reports have described the negative effects of radiotherapy. A 35-yearold woman presented with newly diagnosed CS and multiple meningiomas. She underwent subtotal resection of a right petroclival meningioma to relieve brainstem compression and received adjuvant fractionated stereotactic radiotherapy 50 Gy in 25 fractions with minimal side effects. Twenty months post-operatively the patient presented with neurological deficits from progression of additional meningiomas. Craniotomy was performed and gross total resection was achieved for all sites of disease. Imaging five months after surgery demonstrated progressive left tentorial meningioma. She underwent definitive stereotactic radiosurgery to 15 Gy and tolerated treatment well. At 32 and 7 months post-RT, the patient has reported no side effects or toxicity as a result of RT, demonstrating for the first time in the literature, to the best of our knowledge, the use of intracranial RT without significant toxicity in CS.
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http://dx.doi.org/10.21037/cco.2020.03.04DOI Listing
June 2020

Atypical presentation of spinal intramedullary astrocytoma in a patient presenting with isolated signs of intracranial hypertension.

Spinal Cord Ser Cases 2020 04 9;6(1):20. Epub 2020 Apr 9.

Department of Neurological Surgery, Thomas Jefferson University Hospital, 900 Walnut Street, Philadelphia, PA, 19107, USA.

Introduction: Intramedullary spinal tumors are rare entities that typically present with signs of spinal cord dysfunction including myelopathy, weakness, hypoesthesia, or bladder dysfunction. However, they can present in more insidious ways without signs of spinal cord dysfunction, as we will discuss in this case. Our patient presented with isolated signs of intracranial hypertension including headache and progressive vision loss. Although idiopathic intracranial hypertension (IIH) is significantly more common than spinal cord tumors, a full evaluation to rule out other diagnoses should always occur, as this is an exclusionary diagnosis.

Case Presentation: We describe an interesting case of an obese, middle-aged female who presented with signs and symptoms of elevated intracranial pressure (ICP) including progressive headache, visual changes, and papilledema. This led to a presumptive diagnosis of idiopathic intracranial hypertension (IIH). However, a careful review of her cerebrospinal fluid (CSF) analysis revealed a significantly elevated protein level. This prompted a more thorough workup, including a spinal MRI, that revealed an intramedullary astrocytoma. On her presenting physical exam, she had no upper or lower motor signs, no weakness, and no pathological reflexes.

Discussion: In the evaluation of a patient with isolated signs of increased ICP concerning for IIH, it is important to conduct a thorough workup as this remains a diagnosis of exclusion. Many intracranial and intraspinal pathologies can manifest with similar vague neurological symptoms and masquerade as a more benign disease as shown in our patient who, unfortunately, died from a spinal astrocytoma.
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http://dx.doi.org/10.1038/s41394-020-0268-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145812PMC
April 2020

Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma.

J Neurooncol 2020 May 23;147(3):653-661. Epub 2020 Mar 23.

Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.

Introduction: Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields.

Methods: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma.

Results: We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70-90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months).

Conclusions: Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

Trial Registration: Clinicaltrials.gov Identifier NCT03477110.
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http://dx.doi.org/10.1007/s11060-020-03466-zDOI Listing
May 2020

Management and Surveillance of Frontal Sinus Violation following Craniotomy.

J Neurol Surg B Skull Base 2020 Feb 21;81(1):1-7. Epub 2019 Jan 21.

Department of Otolaryngology and Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

 In the setting of craniotomy, complications after traversing the frontal sinus can lead to mucocele formation and frontal sinusitis. We review the etiology of frontal sinus violation, timeline to mucocele development, intraoperative management of the violated sinus, and treatment of frontal mucoceles.  Case series in conjunction with a literature review.  A total of 35 patients were included in this meta-analysis. Nine of these patients were treated at a tertiary academic medical center between 2005 and 2014. The remaining patients were identified through a literature review for which 2,763 articles were identified, of which 4 articles met inclusion criteria.  Etiology of frontal violation, timeline to mucocele development, and method of management.  The overall interval from initial frontal sinus violation until mucocele identification was 14.5 years, with a range of 3 months to 36 years. The most common cause of mucocele formation was obstruction of the frontal recess with incomplete removal of the frontal sinus mucosa. The majority of patients were successfully managed with an endoscopic endonasal approach.  Violation of the frontal sinus during craniotomy can result in mucocele formation as an early or late sequela. Image guidance may help avoid unnecessary frontal sinus violation. Mucoceles may develop decades after the initial frontal sinus violation, and long-term follow-up with imaging is recommended. While the endoscopic endonasal approach is usually the preferred method to treat these lesions, it may be necessary to perform obliteration or cranialization in unique situations.
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http://dx.doi.org/10.1055/s-0038-1676826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997004PMC
February 2020

Management of Nonfunctioning Recurrent Pituitary Adenomas.

Neurosurg Clin N Am 2019 Oct 7;30(4):473-482. Epub 2019 Aug 7.

Department of Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA.

Pituitary adenomas are typically slow-growing benign tumors. However, 50% to 60% of tumors progress following subtotal resection and up to 30% recur after apparent complete resection. Options for treatment of recurrent pituitary adenomas include repeat surgical resection, radiation therapy, and systemic therapies. There is no consensus approach for the management of recurrent pituitary adenomas. This article reviews the natural history of recurrent adenomas and emerging biomarkers predictive of clinical behavior as well as the outcomes associated with the various treatment modalities for these challenging tumors, with an emphasis on the surgical treatment.
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http://dx.doi.org/10.1016/j.nec.2019.05.006DOI Listing
October 2019

Adenosine-induced transient hypotension for carotid artery injury during endoscopic skull-base surgery: case report and review of the literature.

Int Forum Allergy Rhinol 2019 09 10;9(9):1023-1029. Epub 2019 Jul 10.

Department of Neurosurgery and Neurological Sciences, Thomas Jefferson University Hospitals, Philadelphia, PA.

Background: As the management of ventral skull-base pathology has transitioned from open to endonasal treatment, there has been an increased focus on the prevention and endoscopic endonasal management of internal carotid artery (ICA) and major vascular injury. The use of adenosine to induce transient hypotension or flow arrest has been previously described during intracranial aneurysm surgery; however, there have been no reports of the technique being used during endonasal skull-base surgery to achieve hemostasis following major vascular injury.

Methods: Case report (n = 1) and literature review.

Results: A 25-year-old female underwent attempted endoscopic endonasal resection of an advanced right-sided chondrosarcoma. During resection of the tumor, brisk arterial bleeding was encountered consistent with focal injury to the right cavernous ICA. Stable vascular hemostasis could not be achieved with tamponade. An intravenous bolus dose of adenosine was administered to induce a transient decrease in systemic blood pressure and facilitate placement of the muscle patch over the direct site of vascular injury. The patient subsequently underwent endovascular deconstruction of the right ICA.

Conclusion: This is the first reported use of adenosine to induce transient hypotension for a major vascular injury sustained during endonasal skull-base surgery. Based on well-established safety data from neurosurgical application, adenosine has the potential to be used as a safe and effective adjunctive technique in similar endonasal circumstances and may represent an additional tool in the armamentarium of the skull-base surgeon. Surgeons should consider having adenosine available when a risk of ICA injury is anticipated.
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http://dx.doi.org/10.1002/alr.22381DOI Listing
September 2019

Spontaneous Otogenic Pneumocephalus: Reporting a Unique Site of Dehiscence.

OTO Open 2019 Jan-Mar;3(1):2473974X18821931. Epub 2019 Jan 30.

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1177/2473974X18821931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572922PMC
January 2019

Rapid Early Tumor Progression is Prognostic in Glioblastoma Patients.

Am J Clin Oncol 2019 05;42(5):481-486

Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.

Objectives: Determine the prognostic significance of rapid early tumor progression before radiation and chemotherapy for glioblastoma patients.

Methods: A retrospective review of glioblastoma patients was performed. Rapid early progression (REP) was defined as new enhancing tumor or >25% increase in enhancement before radiotherapy. The pre/postoperative magnetic resonance imaging was compared with the preradiation magnetic resonance imaging to determine REP. A blinded review of imaging was performed. Kaplan-Meier curves were generated to compare progression-free and overall survival (OS). Univariate analysis was performed using the log-rank test for categorical variables and Cox proportional hazards for continuous variables. Multivariable logistic regression was performed to assess factors related to early progression and Cox proportional hazards model was used for multivariate analysis of OS.

Results: Eighty-seven patients met entry criteria. A total of 52% of patients developed REP. The OS in the REP group was 11.5 months (95% confidence interval [CI]: 7.4-17.6) and 20.1 months (95% CI: 17.8-26.1) without REP (P=0.013). On multivariate analysis including significant prognostic factors, presence of REP was found to increase the risk of death (hazard ratio: 2.104, 95% CI: 1.235-3.583, P=0.006). A total of 74% of patients recurred in the site of REP.

Conclusions: REP was common and independently predicted for a worse OS. Integrating REP with MGMT promotor methylation improved prognostic assessment. The site of REP was a common site of tumor progression. Our findings are hypothesis generating and may indicate a particular subset of glioblastoma patients who are resistant to current standard of care therapy. Further study to determine other molecular features of this group are underway.
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http://dx.doi.org/10.1097/COC.0000000000000537DOI Listing
May 2019

Cesium-131 Interstitial Brachytherapy for Recurrent Malignancies of Skull Base.

J Neurol Surg Rep 2019 Apr 9;80(2):e23-e26. Epub 2019 Apr 9.

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

 Recurrent malignancy of the skull base poses a treatment challenge due to a lack of treatment options and potential for damage to surrounding structures.  Case report of two patients with recurrent nasopharyngeal carcinoma (NPC) of skull base previously treated with adjuvant chemoradiotherapy using intensity-modulated radiation therapy (IMRT).  In both cases, the recurrent tumor was treated with endoscopic surgical resection and intraoperative cesium-131 (Cs-131) interstitial brachytherapy (IBT). Total dose delivered to tumor bed was 57 and 60 Gy, respectively. With a half- life of 9 days, the majority of the radiation dose had been delivered within the first 40 days following implant and there have been no treatment-related complications reported.  Intraoperative Cs-131 IBT is a feasible adjuvant treatment option for patients with recurrent malignancies of the skull base. These are the first known cases of Cs-131 IBT used for recurrent NPC.
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http://dx.doi.org/10.1055/s-0039-1687848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456353PMC
April 2019

Expanding Pharmacist and Student Pharmacist Access to Genetics/Genomics/Pharmacogenomics Competency Education.

J Med Educ Curric Dev 2019 Jan-Dec;6:2382120519834325. Epub 2019 Mar 12.

Pharmaceutical and Administrative Sciences, Presbyterian College, Clinton, SC, USA.

Background: As pharmacogenomics (PGx), a component of genetics/genomics and precision medicine, gains traction in the clinical setting, education of health care providers and health professions students must be made broadly available to improve accessibility of such services to patients. As medication experts with education in pharmacology, pharmacokinetics, and pharmacodynamics, pharmacists must further their education to include pharmacogenomics. Currently, few opportunities exist to gain this type of education, and therefore, these services are not yet broadly available to the public.

Objective: The specific goal of this study was to evaluate pharmacists' and student pharmacists' self-assessed perception of competence related to genetics, genomics, and pharmacogenomics as presented via an online "pharmacogenomics certification program" (PGx program).

Design: The PGx program was delivered online with the content consisting of 3 background lessons and 8 specific drug-gene lessons presented in the context of pharmacist competency statements. In addition, 11 "video modules" with competency-related PGx content were included to provide a comprehensive program. A pre- and post-course survey instrument was used to evaluate the participants' self-assessed perception of competence related to each of 16 statements.

Results: One hundred thirty-seven (137) individuals enrolled in and completed the pharmacogenomics certification program. Overall, participants reported self-perceived improved competency as evidenced by the pre-course survey as compared with the post-course survey for each of the 16 competency statements related to genetics/genomics, including pharmacogenomics. Similar results were observed for the subgroups of student pharmacists (n = 63) and pharmacists (n = 74).

Future Direction: This study showed that dissemination of genetics/genomics/pharmacogenomics competency statements education can be accomplished via online delivery. This delivery approach can expand genetics/genomics/pharmacogenomics content dissemination. The intent is to reach a broader population of pharmacy students, pharmacists, and other health care providers and health professions students to potentially advance the availability of such services, which can improve the safety and efficacy of medication use for patients.
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http://dx.doi.org/10.1177/2382120519834325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415470PMC
March 2019

Phase I trial of alisertib with concurrent fractionated stereotactic re-irradiation for recurrent high grade gliomas.

Radiother Oncol 2019 03 4;132:135-141. Epub 2019 Jan 4.

Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, United States. Electronic address:

Background And Purpose: We conducted a phase I trial of alisertib, an oral aurora kinase inhibitor, with fractionated stereotactic re-irradiation therapy (FSRT) for patients with recurrent high grade glioma (HGG).

Materials And Methods: Adult patients with recurrent HGG were enrolled from Feb 2015 to Feb 2017. Patients were treated with concurrent FSRT and alisertib followed by maintenance alisertib. Concurrent alisertib dose was escalated from 20 mg to 50 mg twice daily (BID).

Results: 17 patients were enrolled. Median follow-up was 11 months. Median FSRT dose was 35 Gy. There were 6, 6, 3, and 2 patients enrolled in 20 mg, 30 mg, 40 mg, and 50 mg cohort, respectively. Only one DLT was observed. One patient in the 20 mg cohort had severe headache (Grade 3) resolved with steroids. There was no non-hematological grade 3 or higher toxicity. There were two Grade 4 late toxicities (one with grade 4 neutropenia and leukopenia, one with pulmonary embolism). One patient developed radiation necrosis (Grade 3). Sixteen patients finished concurrent treatment and received maintenance therapy (median cycles was 3, range 1-9). OS for all cohorts at 6 months was 88.2% with median survival time of 11.1 months. PFS at 6 months was 35.3% with median time to progression of 4.9 months. The trial stopped early due to closure of alisertib program with only 2 of 3 planned patients enrolled in the 50 mg cohort.

Conclusion: Re-irradiation with FSRT combined with alisertib is safe and well tolerated for HGG with doses up to 40 mg BID. Although no DLT observed in the 50 mg cohort, this cohort was not fully enrolled and MTD was not reached. Clinical outcomes appear comparable to historical results. (NCT02186509).
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http://dx.doi.org/10.1016/j.radonc.2018.12.019DOI Listing
March 2019

Chronic Skull Base Erosion from Temporomandibular Joint Disease Causes Generalized Seizure and Profound Lactic Acidosis.

Case Rep Crit Care 2018 27;2018:8795036. Epub 2018 Sep 27.

Professor and Executive Vice Chair of Anesthesiology, Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.

This report displays a rare presentation of lactic acidosis in the setting of status epilepticus (SE). The differential diagnosis of lactic acidosis is broad and typically originates from states of shock; however, this report highlights an alternative and rare etiology, SE, due to chronic skull base erosion from temporomandibular joint (TMJ) disease. Lactic acidosis is defined by a pH below 7.35 in the setting of lactate values greater than 5 mmol/L. Two broad classifications of lactic acidosis exist: a type A lactic acidosis which stems from global or localized tissue hypoxia or a type B lactic acidosis which occurs once mitochondrial oxidative capacity is unable to match glucose metabolism. SE is an example of a type A lactic acidosis in which oxygen delivery is unable to meet increased cellular energy requirements. This report is consistent with a prior case series that consists of five patients experiencing generalized tonic-clonic (GTC) seizures and lactic acidosis. These patients presented with a pH range of 6.8-7.41 and lactate range of 3.8-22.4 mmol/L. Although severe lactic acidosis following GTC has been described, this is the first report in the literature of chronic skull base erosion from TMJ disease causing SE.
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http://dx.doi.org/10.1155/2018/8795036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180988PMC
September 2018

Beyond the didactic lecture: pharmacogenomics in pharmacy education.

Per Med 2018 01;15(1):9-12

Associate Professor of Pharmaceutical & Administrative Sciences, Presbyterian College, School of Pharmacy, Clinton, SC, USA.

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http://dx.doi.org/10.2217/pme-2017-0056DOI Listing
January 2018

Clinical Outcomes After Endoscopic Endonasal Resection of Giant Pituitary Adenomas.

World Neurosurg 2018 Jun 12;114:e447-e456. Epub 2018 Mar 12.

Department of Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA; Department of Otolaryngology, Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA. Electronic address:

Background: Giant pituitary adenomas represent a surgical challenge. We present the results of the endoscopic endonasal approach (EEA) for giant pituitary adenomas.

Methods: We retrospectively reviewed the medical records of 55 patients with giant pituitary adenomas (>4 cm in maximum diameter) who underwent surgery with an EEA between 2008 and 2016. Factors affecting the extent of resection were evaluated.

Results: The mean patient age was 55.5 years. Tumors were nonfunctional in all but 4 patients, including 2 with growth hormone-secreting tumors, 1 with an adrenocorticotropic hormone-secreting tumor, and 1 with prolactinoma. Gross total resection was achieved in 24 patients (44%), and near-total resection (>90%) was achieved in 26 patients (47%). A multilobular configuration (P = 0.002) and cavernous sinus invasion (P = 0.044) negatively affected the extent of resection, whereas tumor size, intraventricular, and anterior or posterior fossa extension did not. Ten patients underwent adjuvant radiotherapy. All patients with hormone-secreting adenomas required adjuvant medical and/or radiotherapy to achieve biochemical remission. Postoperative vision was improved or normalized in 32 patients (66%), stable in 15 patients (31%), and worsened in 1 patient. A new hormonal deficit occurred in 8 patients (17%), whereas recovery of an existing hormonal deficit occurred in 6 patients (20%). The mean duration of follow-up was 41 months. Tumor recurrence/progression occurred in 6 patients (11%). Complications included apoplexy of residual tumor resulting in ischemic stroke in 1 patient, postoperative cerebrospinal fluid leak in 1 patient, and permanent diabetes insipidus in 4 patients (7%).

Conclusions: Surgery with the EEA is an excellent option for managing giant pituitary adenomas. It results in superior clinical outcomes to those obtained using traditional microscopic transsphenoidal and transcranial approaches as reported in the literature.
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http://dx.doi.org/10.1016/j.wneu.2018.03.006DOI Listing
June 2018

'Et tu, inhibitor?': the potential for HIV inhibitors to prime P-gp-mediated chemoresistance in cancer.

Future Sci OA 2018 Feb 23;4(2):FSO269. Epub 2017 Nov 23.

Department of Pharmaceutical & Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC 29325, USA.

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http://dx.doi.org/10.4155/fsoa-2017-0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778385PMC
February 2018

Correction to: Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

J Neurooncol 2018 Mar;137(1):179

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

The fourth author's name was incorrect in the initial online publication. The original article has been corrected.
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http://dx.doi.org/10.1007/s11060-018-2744-5DOI Listing
March 2018

Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment.

J Neurooncol 2018 Mar 12;137(1):171-177. Epub 2017 Dec 12.

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of < 4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re-irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. 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. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. 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.
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http://dx.doi.org/10.1007/s11060-017-2709-0DOI Listing
March 2018

Clinical Outcome after Endoscopic Endonasal Resection of Tuberculum Sella Meningiomas.

Oper Neurosurg (Hagerstown) 2018 05;14(5):494-502

Department of Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

Background: In select cases, the endoscopic endonasal approach (EEA) has distinct advantages for resection of tuberculum sella meningiomas (TSM).

Objective: To report the extent of resection (EOR), complication rates, and outcomes in a large series of TSM treated by the EEA.

Methods: Twenty-five consecutive TSM cases treated by EEA from 2008 to 2016 were retrospectively reviewed. Patient history, imaging, volumetric EOR, complications, and outcomes are presented.

Results: Mean patient age was 53.9 yr, with female predominance (84%). Preoperatively, 84% of patients had vision impairment and 68% had optic canal tumor invasion. The tumor was abutting or partially encasing the anterior cerebral artery in 14 (56%) and 3 (12%) patients, respectively. The supraclinoid internal carotid artery (ICA) was partially or completely encased in 4 (16%) and 4 (16%) patients, respectively. Gross total resection (GTR) was achieved in 19/25 (76%) cases. Complete ICA encasement was the most common reason for subtotal resection. Among patients without complete ICA encasement, GTR was achieved in 19/20 (95%) patients. Optic canal invasion, tumor volume, intratumoral calcifications, and partial vascular encasement were not limiting factors for GTR. Eighty-eight percent of patients with preoperative visual impairment had improvement or normalization of vision. No patient experienced permanent visual deterioration or new permanent pituitary dysfunction. Cerebrospinal fluid leakage occurred in 2 (8%) cases.

Conclusion: The EEA for resection of TSM provides high rates of GTR and visual improvement with a low rate of complications. Direct contact or partial encasement of the ICA and anterior cerebral artery does not limit the EOR.
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http://dx.doi.org/10.1093/ons/opx165DOI Listing
May 2018