Publications by authors named "John Flickinger"

344 Publications

Clinical and Imaging Response to Trigeminal Schwannoma Radiosurgery: A Retrospective Analysis of a 28-Year Experience.

J Neurol Surg B Skull Base 2021 Oct 14;82(5):491-499. Epub 2020 Aug 14.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States.

 The purpose of this study was to evaluate long-term clinical outcomes and tumor control after stereotactic radiosurgery (SRS) for trigeminal schwannoma (TS).  During a 28-year period (1989-2017), 50 patients underwent SRS for TS. The median patient age was 51 years (range: 15-87 years). A total of 17 patients had a previous tumor resection: 10 had a single procedure, 5 had two procedures, and 2 had three procedures. The median and mean times between tumor resection and SRS were 12 and 24 months (range: 1-90 months), respectively. Four patients had neurofibromatosis II (NF2). Based on location, tumors were classified as root type (7), ganglion type (22), or dumbbell type (21). The median radiosurgery target volume was 3.4 cm (range: 0.10-18 cm ), median target dose was 14 Gy (range: 12-20 Gy), and the median number of isocenters was 6 (range: 1-15). The median and mean times to last follow-up was 36.9 and 55.2 months (range: 4-205 months), respectively. Eighteen patients (36%) had longer than 5-year follow-up, and seven patients (14%) had longer than 10-year follow-up.  The tumor control rate was 92% and the clinical improvement or stabilization rate was 94%. After SRS, the rates of progression free survival (PFS) at 1, 5, and 10 years were 98, 84, and 84%, respectively. Factors associated with improved PFS were female sex (  = 0.014) and smaller tumor volume (  = 0.022). In this series, we did not find that tumor type (root, ganglion, and dumbbell) had a statistically significant correlation to PFS. Forty-seven patients had neurological signs or symptoms at presentation. At last follow-up, neurological signs or symptoms improved in 22/47 (47%), remained unchanged in 24/50 (48%), and worsened due to tumor progression in 3/50 (6%). One patient (2%) developed temporary symptomatic adverse radiation effect (ARE) and three additional patients (6%) had transient imaging evidence of peritumoral reactive edema but no new symptoms.  As a single outpatient procedure, SRS was associated with long-term freedom from additional management in 84% of patients. Nearly half the treated patients experienced improvement in neurological symptoms or signs.
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http://dx.doi.org/10.1055/s-0040-1714110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421123PMC
October 2021

Does Variceal Drainage Affect Arteriovenous Malformation Obliteration and Hemorrhage Rates After Stereotactic Radiosurgery? A Case-Matched Analysis.

Neurosurgery 2021 Sep;89(4):680-685

Department of Neurological Surgery and Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Stereotactic radiosurgery (SRS) is widely accepted as a minimally invasive alternative to surgery in the management of arteriovenous malformations (AVMs). Dilated AVM outflow veins or varices may be caused by high-flow or partial outflow obstruction, which may increase the risk of a hemorrhage before or after SRS.

Objective: To compare the obliteration and hemorrhage risks in patients with and without AVM varices (AVMv).

Methods: From our prospective database of 1012 AVM patients who underwent Gamma Knife® (Elekta) SRS, we identified 103 patients with AVMv, and 847 patients without varices. The median follow-up was 52 mo. Balancing variable score matching was performed to compare obliteration and hemorrhage rates between the 2 groups.

Results: Obliteration rates in the AVMv group were 38% at 3 yr, 65% at 4 yr, and 70% at 5 yr. Patients with an AVMv had no difference in the final obliteration rate compared to patients who did not have variceal drainage (P = .35). Actuarial hemorrhage after SRS in the matched patients with AVMv was 4.9%, 13%, and 13.7%, at 1, 3, and 5 yr, respectively. The rate of hemorrhage in the group with no varix was 2.9%, 5.4%, and 9.1% at 1, 3, and 5 yr, respectively (P = .14).

Conclusion: The presence of AVM variceal venous drainage did not affect the obliteration rate and did not confer a higher risk of a subsequent hemorrhage both before and after SRS.
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http://dx.doi.org/10.1093/neuros/nyab256DOI Listing
September 2021

Optimizing stereotactic radiosurgery in patients with recurrent or residual craniopharyngiomas.

J Neurooncol 2021 Aug 20;154(1):113-120. Epub 2021 Jul 20.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Purpose: Stereotactic radiosurgery (SRS) is an important management strategy for residual and recurrent craniopharyngiomas. The current study evaluated the factors which affected tumor control and complications in craniopharyngioma SRS.

Methods: This study includes 53 consecutive patients who underwent single-session SRS for recurrent or residual craniopharyngiomas. The median age was 41 years with 28 male and 25 females. The median tumor volume was 0.63 cm and median margin dose was 12 Gy (range 9-25 Gy).

Results: The overall 3-, 5-, and 10-year survival rates were 97.8%, 92.7% and 88.5%. The overall 3-, 5-, and 10-year tumor control rates were 81.0%, 72.1%, and 53.4%. In univariate analysis, ≥ 3 mm distance from optic structures (p = 0.002), only solid or cystic tumor type (p = 0.037), and ≥ 12 Gy to ≥ 85% of the tumor (p < 0.001) were significantly associated with improved tumor control. In multivariate analysis, only solid or cystic tumor type, (p = 0.034), and ≥ 85% of the tumor receiving ≥ 12 Gy (p = 0.004) were significantly associated with better tumor control. When ≥ 85% of the tumor received ≥ 12 Gy the tumor control rates at 3-, 5-, and 10-year were 100%, 93.3%, and 93.3%. Higher conformity index was not associated with better tumor control.

Conclusions: The tumor control rates after recurrent or residual craniopharyngiomas SRS were improved by ensuring that at least 85% of the tumor received ≥ 12 Gy even when the distance between the tumor and the optic system is < 3 mm. This concept refutes the conformity theory that a high conformity index is a critical feature of effective SRS.
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http://dx.doi.org/10.1007/s11060-021-03806-7DOI Listing
August 2021

GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer.

Expert Rev Precis Med Drug Dev 2021 2;6(2):117-129. Epub 2021 Feb 2.

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States.

Introduction: Colorectal cancer (CRC) is one of the most-deadly malignancies worldwide. Current therapeutic regimens for CRC patients are relatively generic, based primarily on disease type and stage, with little variation. As the field of molecular oncology advances, so too must therapeutic management of CRC. Understanding molecular heterogeneity has led to a new-found promotion for precision therapy in CRC; underlining the diversity of molecularly targeted therapies based on individual tumor characteristics.

Areas Covered: We review current approaches for the treatment of CRC and discuss the potential of precision therapy in advanced CRC. We highlight the utility of the intestinal protein guanylyl cyclase C (GUCY2C), as a multi-purpose biomarker and unique therapeutic target in CRC. Here, we summarize current GUCY2C-targeted approaches for treatment of CRC.

Expert Opinion: The GUCY2C biomarker has multi-faceted utility in medicine. Developmental investment of GUCY2C as a diagnostic and therapeutic biomarker offers a variety of options taking the molecular characteristics of cancer into account. From GUCY2C-targeted therapies, namely cancer vaccines, CAR-T cells, and monoclonal antibodies, to GUCY2C agonists for chemoprevention in those who are at high risk for developing colorectal cancer, the utility of this protein provides many avenues for exploration with significance in the field of precision medicine.
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http://dx.doi.org/10.1080/23808993.2021.1876518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133521PMC
February 2021

Useful hearing preservation is improved in vestibular schwannoma patients who undergo stereotactic radiosurgery before further hearing deterioration ensues.

J Neurooncol 2021 May 17;152(3):559-566. Epub 2021 Mar 17.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Suite B-400, UPMC, Presbyterian, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.

Introduction: The present study evaluates whether hearing deterioration during observation reduces serviceable hearing preservation rates after stereotactic radiosurgery (SRS) in vestibular schwannoma (VS) patients with useful hearing.

Methods: We retrospectively analyzed 1447 VS patients who underwent SRS between 1992 and 2017. We identified 100 VS patients who had Grade I Gardner- Robertson (GR) hearing at initial diagnosis but were observed without surgery or SRS. We compared hearing after SRS in 67 patients who retained GR Grade I hearing from initial diagnosis to SRS (the hearing maintenance or HM group) to 33 patients whose hearing worsened from GR grade I to grade II (the hearing deterioration or HD group). We also investigated whether a decline in pure tone average (PTA) or speech discrimination score (SDS) before SRS affected hearing preservation after SRS.

Results: The serviceable hearing (GR I and II) preservation in HM patients was 80%s, 63%, and 51% at 3, 5, and 10 years, respectively. The serviceable hearing preservation in HD patients was 40%, 33%, and 20% at 3, 5, and 10 years, respectively. In multivariate analysis, younger age (< 55 years, p = 0.045) and HM during observation (p = 0.001) improved serviceable hearing preservation rates. Patients whose PTA increased ≥ 15 dB (p = 0.024) or whose SDS declined ≥ 10% (p = 0.019) had reduced serviceable hearing preservation rates.

Conclusions: Hearing deterioration during observation before SRS reduced long term hearing preservation rate in VS patients with GR grade I hearing at initial diagnosis. SRS before hearing deterioration was recommended for hearing preservation.
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http://dx.doi.org/10.1007/s11060-021-03726-6DOI Listing
May 2021

Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers.

Immunotherapy 2021 May 16;13(7):561-564. Epub 2021 Mar 16.

Departments of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Tweetable abstract US FDA-approved immune checkpoint inhibitors have limited efficacy for gastrointestinal cancers such as #colorectalcancer and #pancreaticcancer. Could combinations with experimental cancer 'vaccines' be the key?
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http://dx.doi.org/10.2217/imt-2021-0012DOI Listing
May 2021

Stereotactic radiosurgery as the primary management for patients with Koos grade IV vestibular schwannomas.

J Neurosurg 2021 Feb 12:1-9. Epub 2021 Feb 12.

Departments of1Neurological Surgery and.

Objective: While extensive long-term outcome studies support the role of stereotactic radiosurgery (SRS) for smaller-volume vestibular schwannomas (VSs), its role in the management for larger-volume tumors remains controversial.

Methods: Between 1987 and 2017, the authors performed single-session SRS on 170 patients with previously untreated Koos grade IV VSs (volumes ranged from 5 to 20 cm3). The median tumor volume was 7.4 cm3. The median maximum extracanalicular tumor diameter was 27.5 mm. All tumors compressed the middle cerebellar peduncle and distorted the fourth ventricle. Ninety-three patients were male, 77 were female, and the median age was 61 years. Sixty-two patients had serviceable hearing (Gardner-Robertson [GR] grades I and II). The median margin dose was 12.5 Gy.

Results: At a median follow-up of 5.1 years, the progression-free survival rates of VSs treated with a margin dose ≥ 12.0 Gy were 98.4% at 3 years, 95.3% at 5 years, and 90.7% at 10 years. In contrast, the tumor control rate after delivery of a margin dose < 12.0 Gy was 76.9% at 3, 5, and 10 years. The hearing preservation rates in patients with serviceable hearing at the time of SRS were 58.1% at 3 years, 50.3% at 5 years, and 35.9% at 7 years. Younger age (< 60 years, p = 0.036) and initial GR grade I (p = 0.006) were associated with improved serviceable hearing preservation rate. Seven patients (4%) developed facial neuropathy during the follow-up interval. A smaller tumor volume (< 10 cm3, p = 0.002) and a lower margin dose (≤ 13.0 Gy, p < 0.001) were associated with preservation of facial nerve function. The probability of delayed facial neuropathy when the margin dose was ≤ 13.0 Gy was 1.1% at 10 years. Nine patients (5%) required a ventriculoperitoneal shunt because of delayed symptomatic hydrocephalus. Fifteen patients (9%) developed detectable trigeminal neuropathy. Delayed resection was performed in 4% of patients.

Conclusions: Even for larger-volume VSs, single-session SRS prevented the need for delayed resection in almost 90% at 10 years. For patients with minimal symptoms of tumor mass effect, SRS should be considered an effective alternative to surgery in most patients, especially those with advanced age or medical comorbidities.
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http://dx.doi.org/10.3171/2020.8.JNS201832DOI Listing
February 2021

Guanylyl cyclase C as a biomarker for immunotherapies for the treatment of gastrointestinal malignancies.

Biomark Med 2021 02 20;15(3):201-217. Epub 2021 Jan 20.

Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Gastrointestinal cancers encompass a diverse class of tumors arising in the GI tract, including esophagus, stomach, pancreas and colorectum. Collectively, gastrointestinal cancers compose a high fraction of all cancer deaths, highlighting an unmet need for novel and effective therapies. In this context, the transmembrane receptor guanylyl cyclase C (GUCY2C) has emerged as an attractive target for the prevention, detection and treatment of many gastrointestinal tumors. GUCY2C is an intestinally-restricted protein implicated in tumorigenesis that is universally expressed by primary and metastatic colorectal tumors as well as ectopically expressed by esophageal, gastric and pancreatic cancers. This review summarizes the current state of GUCY2C-targeted modalities in the management of gastrointestinal malignancies, with special focus on colorectal cancer, the most incident gastrointestinal malignancy.
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http://dx.doi.org/10.2217/bmm-2020-0359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293028PMC
February 2021

Stereotactic Radiosurgery for Choroid Plexus Tumors: A Report of the International Radiosurgery Research Foundation.

Neurosurgery 2021 03;88(4):791-796

Department of Neurological Surgery and Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background: Choroid plexus tumors (CPT) are rare epithelial tumors of the choroid plexus. Gross total resection (GTR) may be curative, but it is not always possible.

Objective: To evaluate the role of Gamma Knife stereotactic radiosurgery (GKSRS) as either a primary or adjuvant management option for WHO grade I-III CPT through a multicenter project.

Methods: A total of 32 patients (20 females) with a total of 43 treated tumors were included in the analysis. A total of 25 patients (78%) had undergone initial surgical resection. The median total tumor volume was 2.2 cc, and the median margin and maximum doses were 13 and 25.5 Gy, respectively.

Results: Local tumor control was achieved in 69% of cases. Local tumor progression-free survival (PFS) rate for low-grade tumors at 1, 3, and 5 yr was 90%, 77%, 58%, respectively. The actuarial local tumor PFS rate for high-grade tumors at 1, 3, and 5 yr was 77%, 62%, and 62%, respectively. There was no significant difference in local tumor control rates between low- and high-grade CPT (P = .3). Gender, age, and degree of resection were not associated with treated tumor PFS. Distant intracranial spread developed in 6 patients at a median of 22 mo after initial SRS. Actuarial distant brain tumor PFS rate at 1, 2, 5, and 10 yr was 93%, 88%, 78%, and 65%, respectively. Three patients (9%) developed persistent symptomatic adverse radiation effects at a median of 11 mo after the procedure.

Conclusion: GKSRS represents a minimally invasive alternative management strategy for imaging defined or surgically recurrent low- and high-grade CPT.
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http://dx.doi.org/10.1093/neuros/nyaa538DOI Listing
March 2021

Long term outcomes with linear accelerator stereotactic radiosurgery for treatment of jugulotympanic paragangliomas.

Head Neck 2021 02 13;43(2):449-455. Epub 2020 Oct 13.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Background: Data supporting linear accelerator (linac) stereotactic radiosurgery (SRS) for jugulotympanic paragangliomas (JTPs) come from small series with minimal follow-up. Herein, we report a large series of JTPs with extended follow-up after frameless linac-based SRS.

Methods: JTPs treated with linac-based SRS from 2002 to 2019 with 1+ follow-up image were reviewed for treatment failure (radiographic or clinical progression, or persistent symptoms after SRS requiring intervention) and late toxicities (CTCAE v5.0).

Results: Forty JTPs were identified; 30 were treated with a multifraction regimen. Median clinical and radiographic follow-up was 79.7 (interquartile range [IQR] 31.7-156.9) and 54.4 months (IQR 17.9-105.1), respectively, with a median 4.5 follow-up scans (IQR 2-9). Seven-year progression-free survival (PFS) was 97.0% (95% confidence interval 91.1%-100.0%). PFS was similar between single- and multifraction regimens (log rank P = .99). Toxicity was seen in 7.7% (no grade III).

Conclusions: With extended clinical and radiographic follow-up, frameless linac-based SRS provides excellent local control with mild toxicity <8%.
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http://dx.doi.org/10.1002/hed.26497DOI Listing
February 2021

Salvage Gamma Knife Stereotactic Radiosurgery for Recurrent Intracranial Langerhans Cell Histiocytosis: A 36-Year Saga.

World Neurosurg 2020 12 22;144:205-208. Epub 2020 Sep 22.

Department of Neurological Surgery and Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Management of intracranial Langerhans cell histiocytosis generally includes surgical resection.

Case Description: A female patient with a diagnosis of Langerhans cell histiocytosis developed multiple brain lesions. As part of her multimodality treatment, she underwent Gamma Knife stereotactic radiosurgery on 4 occasions over a 20-year period. All tumors showed significant shrinkage on serial imaging after initially demonstrating a transient expansion. No permanent postradiosurgery complications occurred.

Conclusions: As part of multimodality management of this recurrent and refractory disease, Gamma Knife stereotactic radiosurgery should be considered an important salvage option that can control local disease and obviate the need for invasive surgery.
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http://dx.doi.org/10.1016/j.wneu.2020.09.090DOI Listing
December 2020

Clinico-Radiologic Outcomes After Stereotactic Radiosurgery for Patients with Complex High-Risk Multiple Arteriovenous Malformations.

World Neurosurg 2020 12 18;144:e244-e252. Epub 2020 Aug 18.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Center for Image-Guided Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address:

Objective: The present study aims to define the outcome and risks of patients with multiple arteriovenous malformations (AVMs) treated by stereotactic radiosurgery (SRS).

Methods: We retrospectively analyzed the records of 1232 patients with AVMs who underwent SRS at our center between 1987 and 2017. We identified 10 patients who had SRS for multiple AVMs (total of 25). Eight patients presented with intracranial hemorrhage before SRS. Four patients had hereditary hemorrhagic telangiectasia. A Spetzler-Martin grade I AVM was diagnosed in 11 AVMs, grade II in 7, grade III in 6, and grade IV in 1 AVM. The median maximum diameter was 12 mm, the median target volume was 1.1 cm, and the median margin dose was 20 Gy. Twenty-four AVMs were treated with single-session SRS, and 1 AVM was treated with volume-staged SRS.

Results: The angiographic complete obliteration rate of each AVM was 18.2%, 58.0%, and 66.4% at 3, 5, and 7 years, respectively. The angiographic complete obliteration rate of all treated AVMs in each patient was 11.1%, 51.4%, and 51.4% at 3, 5, and 7 years, respectively. In multivariate analysis, higher marginal dose (≥18 Gy, P = 0.031) was significantly associated with complete obliteration of AVMs. After obliteration of all their AVMs was confirmed no patient bled.

Conclusions: Patients with complex multiple AVMs often presented with a brain hemorrhage. Reduction in bleeding risk after SRS requires complete obliteration that is more likely if the initial AVM margin dose is ≥18 Gy for each AVM.
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http://dx.doi.org/10.1016/j.wneu.2020.08.099DOI Listing
December 2020

Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity.

J Immunother Cancer 2020 08;8(2)

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Background: Adenovirus serotype 5 (Ad5) is a commonly used viral vector for transient delivery of transgenes, primarily for vaccination against pathogen and tumor antigens. However, endemic infections with Ad5 produce virus-specific neutralizing antibodies (NAbs) that limit transgene delivery and constrain target-directed immunity following exposure to Ad5-based vaccines. Indeed, clinical trials have revealed the limitations that virus-specific NAbs impose on the efficacy of Ad5-based vaccines. In that context, the emerging focus on immunological approaches targeting cancer self-antigens or neoepitopes underscores the unmet therapeutic need for more efficacious vaccine vectors.

Methods: Here, we evaluated the ability of a chimeric adenoviral vector (Ad5.F35) derived from the capsid of Ad5 and fiber of the rare adenovirus serotype 35 (Ad35) to induce immune responses to the tumor-associated antigen guanylyl cyclase C (GUCY2C).

Results: In the absence of pre-existing immunity to Ad5, GUCY2C-specific T-cell responses and antitumor efficacy induced by Ad5.F35 were comparable to Ad5 in a mouse model of metastatic colorectal cancer. Furthermore, like Ad5, Ad5.F35 vector expressing GUCY2C was safe and produced no toxicity in tissues with, or without, GUCY2C expression. Importantly, this chimeric vector resisted neutralization in Ad5-immunized mice and by sera collected from patients with colorectal cancer naturally exposed to Ad5.

Conclusions: These data suggest that Ad5.F35-based vaccines targeting GUCY2C, or other tumor or pathogen antigens, may produce clinically relevant immune responses in more (≥90%) patients compared with Ad5-based vaccines (~50%).
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http://dx.doi.org/10.1136/jitc-2020-001046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443303PMC
August 2020

The Incidence of Node-Positive Non-small-Cell Lung Cancer Undergoing Sublobar Resection and the Role of Radiation in Its Management.

Front Oncol 2020 26;10:417. Epub 2020 May 26.

University of Massachusetts Medical School, Worcester, MA, United States.

To identify the incidence, preoperative risk factors, and prognosis associated with pathologically positive lymph node (pN+) in patients undergoing a sub-lobar resection (SLR). This is a retrospective study using the National Cancer Database (NCDB) from 2004 to 2014 analyzing SLR excluding those with any preoperative chemotherapy and/or radiation, follow-up <3 months, stage IV disease, or >1 tumor nodule. Multivariable modeling (MVA) was used to determine factors associated with overall survival (OS). Propensity score matching (PSM) was used to determine preoperative risk factors for pN+ in patients having at least one node examined to assess radiation's effect on OS in those patients with pN+ and to determine whether SLR was associated with inferior OS as compared to lobectomy for each nodal stage. A total of 40,202 patients underwent SLR, but only 58.3% had one lymph node examined. Then, 2,615 individuals had pN which decreased progressively from 15.1% in 2004 to 8.9% in 2014 (N1, from 6.3 to 3.0%, and N2, from 8.4 to 5.9%). A lower risk of pN+ was noted for squamous cell carcinomas, bronchioloalveolar adenocarcinoma (BAC), adenocarcinomas, and right upper lobe locations. In the pN+ group, OS was worse without chemotherapy or radiation. Radiation was associated with a strong trend for OS in the entire pN+ group ( = 0.0647) which was largely due to the effects on those having N2 disease ( = 0.009) or R1 resections ( = 0.03), but not N1 involvement ( = 0.87). PSM noted that SLR was associated with an inferior OS as compared to lobectomy by nodal stage in the overall patient population and even for those with tumors <2 cm. pN+ incidence in SLRs has decreased over time. SLR was associated with inferior OS as compared to lobectomy by nodal stage. Radiation appears to improve the OS in patients undergoing SLR with pN+, especially in those with N2 nodal involvement and/or positive margins.
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http://dx.doi.org/10.3389/fonc.2020.00417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264374PMC
May 2020

Clinical dose profile of Gamma Knife stereotactic radiosurgery for extensive brain metastases.

J Neurosurg 2020 May 8;134(5):1430-1434. Epub 2020 May 8.

3Neurological Surgery and the Center for Image-Guided Neurosurgery, University of Pittsburgh, Pennsylvania; and.

Objective: The use of Gamma Knife stereotactic radiosurgery (GKSRS) for the treatment of extensive intracranial metastases has been expanding due to its superior dosimetry and efficacy. However, there remains a dearth of data regarding the dose parameters in actual clinical scenarios. The authors endeavored to calculate the radiation dose to the brain when treating ≥ 15 brain metastases with GKSRS.

Methods: This retrospective analysis reviewed dosage characteristics for patients requiring single-session GKSRS for the treatment of ≥ 15 brain metastases. Forty-two patients met the inclusion criteria between 2008 and 2017. The median number of tumors at the initial GKSRS procedure was 20 (range 15-39 tumors), accounting for 865 tumors in this study. The median aggregate tumor volume was 3.1 cm3 (range 0.13-13.26 cm3), and the median marginal dose was 16 Gy (range 14-19 Gy).

Results: The median of the mean brain dose was 2.58 Gy (range 0.95-3.67 Gy), and 79% of patients had a dose < 3 Gy. The 12-Gy dose volume was a median of 12.45 cm3, which was equivalent to 0.9% of the brain volume. The median percentages of brain receiving 5 Gy and 3 Gy were 6.7% and 20.4%, respectively. There was no correlation between the number of metastases and the mean dose to the brain (p = 0.8). A greater tumor volume was significantly associated with an increased mean brain dose (p < 0.001). The median of the mean dose to the bilateral hippocampi was 2.3 Gy. Sixteen patients had supplementary GKSRS, resulting in an additional mean dose of 1.4 Gy (range 0.2-3.8 Gy) to the brain.

Conclusions: GKSRS is a viable means of managing extensive brain metastases. This procedure provides a relatively low dose of radiation to the brain, especially when compared with traditional whole-brain radiation protocols.
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http://dx.doi.org/10.3171/2020.3.JNS193369DOI Listing
May 2020

Talkin' Toxins: From Coley's to Modern Cancer Immunotherapy.

Toxins (Basel) 2020 04 9;12(4). Epub 2020 Apr 9.

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.

The ability of the immune system to precisely target and eliminate aberrant or infected cells has long been studied in the field of infectious diseases. Attempts to define and exploit these potent immunological processes in the fight against cancer has been a longstanding effort dating back over 100 years to when Dr. William Coley purposefully infected cancer patients with a cocktail of heat-killed bacteria to stimulate anti-cancer immune processes. Although the field of cancer immunotherapy has been dotted with skepticism at times, the success of immune checkpoint inhibitors and recent FDA approvals of autologous cell therapies have pivoted immunotherapy to center stage as one of the most promising strategies to treat cancer. This review aims to summarize historic milestones throughout the field of cancer immunotherapy as well as highlight current and promising immunotherapies in development.
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http://dx.doi.org/10.3390/toxins12040241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232517PMC
April 2020

Radiotherapy of Parasellar Tumours.

Neuroendocrinology 2020 4;110(9-10):848-858. Epub 2020 Mar 4.

Radiation Oncology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy,

Parasellar tumours represent a wide group of intracranial lesions, both benign and malignant. They may arise from several structures located within the parasellar area or they may infiltrate or metastasize this region. The treatment of the tumours located in these areas is challenging because of their complex anatomical location and their heterogenous histology. It often requires a multimodal approach, including surgery, radiation therapy (RT), and medical therapy. Due to the proximity of critical structures and the risks of side effects related to the procedure, a successful surgical resection is often not achievable. Thus, RT plays a crucial role in the treatment of several parasellar tumours. Conventional fractionated RT and modern radiation techniques, like stereotactic radiosurgery and proton beam RT, have become a standard management option, in particular for cases with residual or recurrent tumours after surgery and for those cases where surgery is contraindicated. This review examines the role of RT in parasellar tumours analysing several techniques, outcomes and side effects.
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http://dx.doi.org/10.1159/000506902DOI Listing
July 2021

Radiosurgery to the spinal dorsal root ganglion induces fibrosis and inhibits satellite glial cell activation while preserving axonal neurotransmission.

J Neurosurg Spine 2020 Jan 31:1-9. Epub 2020 Jan 31.

Departments of1Neurosurgery and.

Objective: Stereotactic radiosurgery (SRS) has been used to treat trigeminal neuralgia by targeting the cisternal segment of the trigeminal nerve, which in turn triggers changes in the gasserian ganglion. In the lumbar spine, the dorsal root ganglion (DRG) is responsible for transmitting pain sensitivity and is involved in the pathogenesis of peripheral neuropathic pain. Therefore, radiosurgery to the DRG might improve chronic peripheral pain. This study evaluated the clinical and histological effects of high-dose radiosurgery to the DRG in a rodent model.

Methods: Eight Sprague-Dawley rats received either 40- or 80-Gy SRS to the fifth and sixth lumbar DRGs using the Leksell Gamma Knife Icon. Animals were euthanized 3 months after treatment, and the lumbar spine was dissected and taken for analysis. Simple histology was used to assess collagen deposition and inflammatory response. GFAP, Neu-N, substance P, and internexin were used as a measure of peripheral glial activation, neurogenesis, pain-specific neurotransmission, and neurotransmission in general, respectively. The integrity of the spinothalamic tract was assessed by means of the von Frey test.

Results: The animals did not exhibit any signs of motor or sensory deficits during the experimentation period. Edema, fibrosis, and vascular sclerotic changes were present on the treated, but not the control, side. SRS reduced the expression of GFAP without affecting the expression of Neu-N, substance P, or internexin. The von Frey sensory perception elicited equivalent results for the control side and both radiosurgical doses.

Conclusions: SRS did not alter sensory or motor function but reduced the activation of satellite glial cells, a pathway for DRG-mediated pain perpetuation. Radiosurgery provoked changes equivalent to the effects of focal radiation on the trigeminal ganglion after SRS for trigeminal neuralgia, suggesting that radiosurgery could be successful in relieving radiculopathic pain.
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http://dx.doi.org/10.3171/2019.11.SPINE191176DOI Listing
January 2020

Long term results of primary radiosurgery for vestibular schwannomas.

J Neurooncol 2019 Nov 18;145(2):247-255. Epub 2019 Sep 18.

Departments of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.

Background: Stereotactic radiosurgery (SRS) has become a primary option for management for both newly diagnosed vestibular schwannomas (VS), as well as VS that enlarge after initial observation.

Methods: A retrospective review of our prospectively maintained data base found 871 patients who underwent Gamma knife® SRS as their initial (primary) management between 1987 and 2008. Follow-up ranged from 1-25 years (median = 5.2 years) Median tumor volume was 0.9 cc (0.02-36) and median margin dose was 13 Gy (12-25).

Results: Progression free survival (PFS) after SRS was 97% at 3 years, 95% at 5 years, and 94% at 10 years. Freedom from delayed surgical resection was found in 98.7% of patients. Smaller tumor volume was significantly associated with improved PFS. There were 326 patients with serviceable hearing (Gardner-Robertson 1 or 2) at the time of SRS with audiological follow-up of ≥ 1 year. Serviceable hearing preservation rates after SRS were 89.8% at 1 year, 76.9% at 3 years, 68.4% at 5 years, 62.5% at 7 years, and 51.4% at 10 years. Factors associated with improved serviceable hearing preservation included younger age, Gardner-Robertson grade 1 at SRS, and absence of subjective complaints of dysequilibrium or vertigo (vestibulopathy). Fifty-one patients (5.8%) developed trigeminal neuropathy. Fourteen (1.6%) developed a transient House-Brackmann grade 2 or 3 facial neuropathy.

Conclusions: In this report with extended follow-up, primary SRS achieved tumor growth control in 94% of patients. Optimization of long- term cranial nerve outcomes remains an important achievement of this management strategy for VS.
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http://dx.doi.org/10.1007/s11060-019-03290-0DOI Listing
November 2019

Predicting hearing outcomes before primary radiosurgery for vestibular schwannomas.

J Neurosurg 2019 Sep 6:1-7. Epub 2019 Sep 6.

Departments of1Neurological Surgery and.

Objective: Optimizing outcomes in the management of patients with vestibular schwannomas (VSs) requires consideration of the patient's goals. Earlier recognition of VS by imaging has led to an evolution in management. Stereotactic radiosurgery (SRS) has emerged as a frequently used strategy designed to reduce management risks, obtain long-term tumor control, and preserve current neurological function. The authors analyzed features that impact hearing preservation rates in patients with serviceable hearing prior to SRS.

Methods: The study included 307 patients who had serviceable hearing (Gardner-Robertson hearing scale [GR] grade 1 or 2, speech discrimination score ≥ 50%, pure tone average ≤ 50 dB) at the time of SRS. The authors evaluated parameters that included age, tumor volume, hearing status, disequilibrium, tinnitus, Koos class, sex, and tumor margin dose. The Pittsburgh Hearing Prediction Score (PHPS) was evaluated as a method to predict long-term hearing outcomes in these cases.

Results: At a median of 7.6 years after SRS (range 1-23 years), tumor control was achieved in 95% of patients. The overall serviceable hearing preservation rate was 77.8% at 3 years, 68.8% at 5 years, and 51.8% at 10 years. The PHPS assigns a total of 5 points based on patient age (1 point if < 45 years, 2 points if 45-59 years, and 3 points if ≥ 60 years), tumor volume (0 points if < 1.2 cm3, 1 point if ≥ 1.2 cm3), and GR grade (0 points if grade 1 hearing, 1 point if grade 2 hearing) The serviceable hearing preservation rate was 92.3% at 10 years in patients whose score total was 1. In contrast, none of the patients whose PHPS was 5 maintained serviceable hearing at 10 years (p < 0.001).

Conclusions: SRS resulted in a high rate of long-term tumor control and cranial nerve preservation. The PHPS helped to predict long-term hearing preservation rates in patients who underwent SRS when they still had serviceable hearing. The best long-term hearing preservation rates were found in younger patients with smaller tumor volumes.
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http://dx.doi.org/10.3171/2019.5.JNS182765DOI Listing
September 2019

Primary or salvage stereotactic radiosurgery for brain metastatic small cell lung cancer.

J Neurooncol 2019 Aug 22;144(1):217-225. Epub 2019 Jun 22.

Department of Neurosurgery and Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, USA.

Purpose: We evaluated the outcomes after stereotactic radiosurgery (SRS) for patients who developed new or progressive brain disease regardless of whether they had no prior radiation, PCI, or WBRT.

Methods: We retrospectively identified 90 SCLC patients who had SRS between 1991 and 2018. Thirty-one patients had no evidence of brain disease at the time of initial diagnosis but received prophylactic cranial irradiation. Twenty-six without initial brain disease underwent delayed SRS after brain disease was identified. Seventeen patients with synchronous systemic and brain disease underwent WBRT at the time of diagnosis. Fifteen patients had brain disease detected at the time of initial diagnosis and had initial SRS.

Results: We found no difference in overall survival between patients who received initial PCI or WBRT compared to patients treated with SRS alone at the time when brain metastases were identified. PCI was not associated with a longer duration between initial diagnosis and the development of brain metastasis. Local tumor control was achieved in 49 out of 58 patients who had follow up MRI available for review (84.5%). Actuarial local tumor control at 3, 6, and 12 months was calculated as 92%, 85%, and 80%, respectively. Radiation therapy (PCI or WBRT) before SRS was not associated with better or worse local tumor control.

Conclusion: In this experience neither prior PCI nor WBRT improved survival or local tumor control in SCLC patients who underwent SRS for new or recurrent brain disease.
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http://dx.doi.org/10.1007/s11060-019-03224-wDOI Listing
August 2019

Leksell Stereotactic Radiosurgery for Cavernous Malformations.

Prog Neurol Surg 2019 16;34:260-266. Epub 2019 May 16.

Departments of Neurosurgery and Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Cavernous malformations (CM) represent a distinct subgroup of brain vascular malformations that are characterized by small sinusoidal vascular channels with hyaline degeneration and old blood pigments. Because of the increasing availability of magnetic resonance imaging (MRI) they are detected much more frequently in the present era. CM may be solitary or found in the context of a familial variant that results in an increasing number of CM developing as the patient ages. Because of the variable risk of subacute bleeding, their management options have been controversial. The annual risk of an incidentally detected CM bleeding is <0.5% each year. Leksell radiosurgery is used for a subgroup of patients who have repeatedly bled. In general, CM best considered for stereotactic radiosurgery are deep seated and do not pre-sent to a pial or ependymal surface where microsurgical corridors for removal are feasible. When radiosurgery is used for patients at high risk for both re-bleeding as well as microsurgical resection, the risk of bleeding can be reduced from as high as 33% each year to <0.5% each year after a 2-year latency interval. The target lies within the hemosiderin rim detected during the MRI that is part of planning. Marginal doses are significantly less than those used for angiographically visible arteriovenous malformations.
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http://dx.doi.org/10.1159/000493072DOI Listing
December 2019

Guidelines for Multiple Brain Metastases Radiosurgery.

Prog Neurol Surg 2019 16;34:100-109. Epub 2019 May 16.

Departments of Neurological Surgery and Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Stereotactic radiosurgery (SRS) is an effective treatment for patients with multiple brain metastases. Three decades of increasingly powerful scientific studies have shown that SRS improves outcomes and reduces toxicity when it replaces whole-brain radiation therapy (WBRT). Expert opinion surveys of clinicians have reported that the total intracranial tumor volume rather than the number of brain metastases is related to outcomes. As a result, an increasing number of treating and referring physicians have replaced the reflex use of WBRT with SRS, unless the patient has miliary disease or carcinomatous meningitis. In the current era of immunotherapy and targeted therapies with potentially increased systemic disease survival, 10 or more tumors are routinely treated with SRS alone at most academic medical centers. In a single SRS session we routinely treat patients with cumulative tumor volumes of 25 cm3 even if they have ≥10 metastases.
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http://dx.doi.org/10.1159/000493055DOI Listing
December 2019

The First North American Clinical Gamma Knife Center.

Prog Neurol Surg 2019 16;34:9-18. Epub 2019 May 16.

Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

A decision to develop a stereotactic radiosurgery center and install the first 201 cobalt-60 Gamma Knife in Pittsburgh was made in 1981 after gathering regional and leadership support. This was part of a 7-year quest that required overcoming barriers to a new technology unfamiliar to US regulatory authorities and insurance companies. The first patient was treated in August 1987. Since that time our center has installed each succeeding Gamma Knife device developed. During an initial 30-year experience we performed more than 14,750 patient procedures. In addition to patient care our Center's goal was to develop a major teaching and clinical research program that eventually led to the training of more than 2,500 physicians and medical physicists, the publication of more than 600 peer-reviewed clinical outcome research studies, and 4 books. This report summarizes the rationale for acquisition, the challenges and the early years, and then the evolution of our center which installed the first US 201 source Gamma Knife.
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http://dx.doi.org/10.1159/000493045DOI Listing
December 2019

Leksell Radiosurgery for Orbital, Uveal, and Choroidal Tumors.

Prog Neurol Surg 2019 16;34:298-305. Epub 2019 May 16.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Stereotactic radiosurgery using the Leksell Gamma Knife has proven to be a valuable alternative to orbital enucleation or fractionated radiation therapy for primary tumors of the orbit, metastatic tumors to the choroid, and primary uveal melanomas. With this approach in a single outpatient setting, the eye is immobilized by a local block after which high-definition MRI or CT is performed to define the target. After rapid dose planning, radiation delivery is completed before the local block dissipates. The tumor response is often dramatic. The risk of acute narrow-angle glaucoma, radiation-related retinopathy, or cataract formation has been relatively low. Other worldwide centers have confirmed that this approach is superior to either enucleation or fractionated radiation therapy for these relatively rare problems.
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http://dx.doi.org/10.1159/000493077DOI Listing
December 2019

The risk/benefit ratio of radiotherapy in pituitary tumors.

Best Pract Res Clin Endocrinol Metab 2019 04 16;33(2):101269. Epub 2019 Apr 16.

Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Radiation therapy (RT) is an effective treatment for patients with either nonfunctioning or secreting pituitary adenomas unsuccessfully treated by surgery and/or medical therapy, resulting in local control of 90-95% at 5-10 years and variable normalization of hormonal hypersecretion for patients with GH-, ACTH-, and prolactin-secreting adenomas in the range of 40-80% at 5 years; however, its use has been limited because of concerns regarding potential late toxicity of radiation and delayed efficacy in normalization of hormone hypersecretion. In the last decades, there have been advances in all aspects of radiation treatment, including more accurate immobilization, imaging, treatment planning and dose delivery. RT has evolved with the development of highly conformal stereotactic techniques and new planning and dose delivery techniques, including intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). All these new techniques allow precise and sharply focused radiation delivery reducing the dose to surrounding critical neurovascular and brain structures, and potentially limiting the long-term consequences of radiation treatments. In this review, we present a critical analysis of the more recent available literature on the use of RT in patients with both nonfunctioning and secreting pituitary adenomas, focussing particularly on the risk/benefit ratio of modern radiation techniques.
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http://dx.doi.org/10.1016/j.beem.2019.04.003DOI Listing
April 2019

Therapeutic targeting of gastrointestinal cancer stem cells.

Regen Med 2019 05 26;14(4):331-343. Epub 2019 Apr 26.

Pharmacology & Experimental Therapeutics, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA.

Gastrointestinal cancers remain a tremendous burden on society. Despite advances in therapy options, including chemotherapy and radiation, cancer mortality from recurrences and metastases occur frequently. Cancer stem cells (CSCs) drive disease recurrence and metastasis, as these cells are uniquely equipped to self-renew and evade therapy. Therefore, cancer eradication requires treatment strategies that target CSCs in addition to differentiated cancer cells. This review highlights current literature on therapies targeting CSCs in gastrointestinal cancer.
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http://dx.doi.org/10.2217/rme-2018-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886570PMC
May 2019

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

J Immunother Cancer 2019 04 23;7(1):104. Epub 2019 Apr 23.

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, JAH 368, Philadelphia, PA, 19107, USA.

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8, but not CD4, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy.

Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 10 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes.

Results: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8 cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4 T cells are eliminated by self-tolerance, while CD8 T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies.

Conclusions: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8, but not autoimmune CD4, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector.

Trial Registration: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737.
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http://dx.doi.org/10.1186/s40425-019-0576-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477737PMC
April 2019

Tumor Control and Cranial Nerve Outcomes After Adjuvant Radiosurgery for Low-Grade Skull Base Meningiomas.

World Neurosurg 2019 Jul 14;127:e221-e229. Epub 2019 Mar 14.

Department of Neurological Surgery and Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Objective: We evaluated the tumor control and cranial nerve (CN) outcomes after adjuvant stereotactic radiosurgery (SRS) for petroclival, cavernous sinus, and cerebellopontine angle meningiomas.

Methods: From our prospectively maintained database of 2022 patients with meningioma who had undergone Leksell SRS during a 30-year interval, we found 43 patients with petroclival, 94 with cavernous sinus, and 13 patients with cerebellopontine angle meningiomas who had undergone adjuvant SRS after surgical resection of the meningioma. The patients included in the present report had had ≥1 CN deficit at the initial presentation and a minimum follow-up period of 12 months. The median age at SRS was 54 years (range, 22-81). SRS was performed for residual tumor in 104 patients (69%) and recurrent tumor in 46 patients (31%). The median tumor volume treated with SRS was 8.1 cm (range, 0.3-42), and the median margin dose was 13 Gy (range, 10-20).

Results: Tumor control was achieved in 135 patients (90%) at a median follow-up point of 75 months. The progression-free survival rate after SRS was 99.5% at 1 year, 98% at 3 years, 95% at 5 years, and 90% at 10 years. Overall, 29 of the 150 patients (19%) reported improvement in CN function. Deterioration in CN function after SRS developed in 15 patients (10%). The rate of deterioration was 3.5% at 1 year, 5.5% at 3 years, and 7% at 5 years.

Conclusions: Adjuvant SRS provides effective tumor control and a low rate of new or worsening CN deficits.
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http://dx.doi.org/10.1016/j.wneu.2019.03.052DOI Listing
July 2019
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