Multistaged Stereotactic Radiosurgery for Complex Large Lobar Arteriovenous Malformations: A Case Series.

BACKGROUND AND OBJECTIVES: Although stereotactic radiosurgery (SRS) has well defined outcomes in the management of smaller-volume arteriovenous malformations (AVM), this report evaluates the outcomes when SRS is used for large-volume (≥10 cc) lobar AVMs. METHODS: Between 1990 and 2022, a cohort of 1325 patients underwent Leksell Gamma Knife SRS for brain AVMs. Among these, 40 patients (25 women; median age: 37 years) with large lobar AVMs underwent volume-staged SRS followed by additional SRS procedures if needed (2-5 procedures). The patients presented with diverse AVM locations and Spetzler-Martin Grades. Before SRS, 16 patients underwent a total of 43 embolization procedures. RESULTS: Over a median follow-up of 73 months, 20 patients achieved AVM obliteration. The 3, 5, and 10-year obliteration rates were 9.3%, 15.3%, and 53.3%, respectively. During the latency interval between the first SRS procedure and the last follow-up, 11 patients had intracerebral hemorrhages (ICH) and 6 developed new neurological deficits unrelated to ICH. The postoperative hemorrhage risk after the first SRS was 13.8% at 3 years, 16.6% at 5 years, and 36.2% at 10 years. No hemorrhagic event was documented after confirmed obliteration. Compared with the modified Rankin Scale (mRS) scores before SRS, the mRS improved or remained stable in 28 patients. Nine patients died during the observation interval. Five were related to ICH. CONCLUSION: These outcomes underscore both the potential effectiveness and the limitations of multistage SRS procedures for complex high-risk large volume AVMs in critical brain lobar locations. Most patients retained either stable or improved long-term mRS scores. During the latency interval from the first SRS until obliteration, achieved after two or more procedures, the risk of hemorrhage and treatment-related complications persists.

Stereotactic Radiosurgery for Patients with Brain Metastases from Hepatopancreaticobiliary Cancers.

BACKGROUND: The role of stereotactic radiosurgery (SRS) for patients with brain metastases from hepatopancreaticobiliary (HPB) cancers has yet to be established. The authors present a single-institution experience of patients with HPB cancers who underwent SRS when their cancer spread to the brain. METHODS: We surveyed our Gamma Knife SRS data base of 18,000 patients for the years 1987-2022. In total, 19 metastatic HPB cancer patients (13 male) with 76 brain metastases were identified. The median age at SRS was 61 years (range: 48-83). The primary cancer sites were hepatocellular carcinoma (HCC, 11 patients), cholangiocarcinoma (CCC, 2 patients), and pancreatic carcinoma (PCC, 6 patients). The median Karnofsky Performance Score (KPS) was 80 (range: 50-90). Two patients underwent pre-SRS whole-brain fractionated radiation therapy (WBRT) and eight patients underwent pre-SRS surgical resection. All SRS was delivered in single session. The median margin dose was 18 Gy (range: 15-20). The median cumulative tumor volume was 8.1 cc (range: 1.0-44.2). RESULTS: The median patient overall survival (OS) after SRS was 7 months (range 1-79 months). Four patients had documented local tumor progression after SRS at a median time of 8.5 months (range: 2-15) between SRS and progression. Out of 76 treated tumors, 72 tumors exhibited local control. The local tumor control rate per patient was 78.9%. The local tumor control per tumor was 94.7%. Four patients developed new brain metastases at a median of 6.5 months (range: 2-17) after SRS. No patient experienced adverse radiation effects (AREs). At the last follow-up, 18 patients had died, all from systemic disease progression. CONCLUSIONS: Metastatic spread to the brain from HPB cancers occurs late in the course of the primary disease. In this study, all deceased patients ultimately died from primary disease progression. SRS is a non-invasive strategy that maximally preserves quality of life, and our results reported favorable outcomes compared to the existing literature. SRS should be considered as one of the primary management strategies for patients with brain metastatic spread from HPB cancer.

The role of spine stereotactic radiosurgery for patients with breast cancer metastases.

PURPOSE: Breast cancer that metastasizes to the spine is associated with low quality of life and poor survival. Radiosurgery has an increasing role in this patient population. This single-institution (2003-2023) study analyzes clinical outcomes and prognostic factors for patients who underwent spinal stereotactic radiosurgery (SSRS) for metastatic breast cancer. METHODS: Ninety patients (155 unique breast cancer spinal metastases) were treated with SSRS. The median age was 57 years (range: 35-88), and the median KPS was 80 (range: 40-100). Forty-two (27%) lesions were managed surgically prior to radiosurgery. At SSRS, 75 (48%) lesions impinged or compressed the spinal cord per the epidural spinal cord scale (ESCC). Seventy-nine (51%) lesions were categorized as potentially unstable or unstable by the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 15 months (range: 1-183). The median single-session tumor volume was 25.4 cc (range: 2-197), and the median single-fraction prescription dose was 17 Gy (range: 12-25). Seven (5%) lesions locally progressed. The 1-, 2-, and 5-year local control rates were 98%, 97%, and 92%, respectively. The median overall survival (OS) for the cohort was 32 months (range: 2-183). The 1-, 2-, and 5-year OS rates were 72%, 53%, and 30%, respectively. On univariate analysis, KPS ≥ 80 (p = 0.009, HR: 0.51, 95% CI: 0.31-0.84) was associated with improved OS. Patient-reported pain improved (68%), remained stable (29%), or worsened (3%) following radiosurgery. Fifteen (10%) radiation-induced toxicities were reported. CONCLUSIONS: Spinal radiosurgery is a safe and highly effective long-term treatment modality for metastases to the spine that originate from breast cancer.

Stereotactic Radiosurgery for Patients with Spinal Metastases from Thyroid Cancer: A 20-Year Experience.

OBJECTIVE: Primary thyroid cancer metastasizing to the spine portends poor survival and low quality of life. Current management strategies continue to evolve. This single-institution retrospective study analyzes outcomes after spinal stereotactic radiosurgery for patients with spinal metastases from thyroid cancer. METHODS: Nineteen patients (median age: 64.5 years) were treated with stereotactic radiosurgery (SRS) for spinal primary thyroid metastases (40 metastases, 47 vertebral levels) between 2003 and 2023. Nineteen (47.5%) lesions had epidural involvement and 20 (50%) lesions were classified as potentially unstable or unstable via the Spinal Instability Neoplastic Score. The median tumor volume per lesion was 33 cc (range: 1.5-153). The median single fraction prescription dose was 20 Gy (range: 12-23.5). RESULTS: The median follow-up period was 15 months (range: 2-40). Five (12.8%) lesions locally progressed at a median of 9 months (range: 4-26) after SRS. The 1-, 2-, and 3-year local tumor control rates per lesion were 90.4%, 83.5%, and 75.9%, respectively. On univariate analysis, age at SRS >70 years (P = 0.05, hazard ratio: 6.86, 95% confidence interval: 1.01-46.7) was significantly correlated with lower rates of local tumor control. The median overall survival was 35 months (range: 2-141). The 1-, 2-, and 3-year overall survival rates were 73.7%, 50.4%, and 43.2%, respectively. For 33 lesions initially associated with pain, patients reported pain improvement (22 lesions, 66.7%), stability (10 lesions, 30.3%), and worsening (1 lesion, 3.0%) after SRS. One patient developed dysphagia 4 months after SRS treatment. CONCLUSIONS: SRS can be utilized as an effective and safe primary and adjuvant treatment option for primary thyroid metastases to the spine.

Single Versus Fractionated Gamma Knife Radiosurgery for Nonfunctioning Pituitary Adenomas Close to the Optic Pathway: A Multicenter Propensity Score Matched Study.

BACKGROUND AND OBJECTIVES: Gamma Knife radiosurgery (GKRS), typically administered in a single session (S-GKRS), is an effective treatment for nonfunctioning pituitary adenoma (NFPA). For lesions close to the optic pathway, the use of hypofractionated radiosurgery is growing. This study seeks to compare the results of S-GKRS vs fractionated-GKRS (F-GKRS) for NFPAs adjacent to the optic pathway. METHODS: Two cohorts of patients with residual or recurrent NFPAs in contact to the optic pathway were retrospectively included in this study: (1) a group of patients who underwent a 3-day course of F-GKRS in Europe and (2) a group of patients treated with S-GKRS in the United States. A propensity score matching (ratio 1:1) was carried out to obtain and compare 2 homogeneous groups of patients with NFPA. RESULTS: A total of 84 patients were included for analysis (42 in the S-GKRS cohort and 42 in the F-GKRS group). The 2 cohorts did not differ for age, sex, number of previous surgical procedure, tumor volume, and follow-up. The mean follow-up was 60.2 ± 37.0 months and 62.4 ± 37.4 months for F-GKRS and S-GKRS cohort, respectively ( P = .38). The overall tumor control at last follow-up was achieved in 95.2% and 92.9% of patients in F-GKRS and S-GKRS, respectively ( P = .64). The 1-year, 3-year, 5-year, and 7-year progression-free survival rate after F-GKRS was 100%, 97.1%, 97.1%, and 91%, respectively. In the S-GKRS sample, progression-free survival rates were 100%, 100%, 92.5%, and 92.5% at 1, 3, 5, and 7 years after treatment, respectively. Two patients (4.7%) from the F-GKRS cohort and 2 (4.7%) from the S-GKRS cohort sustained visual worsening after radiosurgery ( P = 1.0). CONCLUSION: In the management of NFPAs adjacent to the optic pathway both F-GKRS and S-GKRS had comparable outcomes and risks at 7 years. Future prospective studies including larger cohorts with longer follow-up are needed to confirm our results.

Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825.

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Chimeric adenoviral (Ad5.F35) and listeria vector prime-boost immunization is safe and effective for cancer immunotherapy.

Strategies to augment immunity to self/neoantigens expressed by cancers are urgently needed to expand the proportion of patients benefiting from immunotherapy, particularly for GI cancers where only a fraction of patients respond to immunotherapies. However, current vaccine strategies are limited by poor immunogenicity, pre-existing vector-specific immunity, and vaccine-induced vector-specific immunity. Here, we examined a prime-boost strategy using a chimeric adenoviral vector (Ad5.F35) that resists pre-existing immunity followed by recombinant Listeria monocytogenes (Lm) to amplify immunity to the GI cancer antigen GUCY2C. This previously unexplored combination enhanced the quantity, avidity, polyfunctionality, and antitumor efficacy of GUCY2C-specific effector CD8+ T cells, without toxicity in any tissue, including GUCY2C-expressing intestines and brain. Importantly, this combination was partially resistant to pre-existing immunity to Ad5 which is endemic in human populations and vector-specific immunity did not limit the ability of multiple Lm administrations to repeatedly enhance GUCY2C-specific responses. Broadly, these findings suggest that cancer patient immunizations targeting self/neoantigens, as well as immunizations for difficult infectious diseases (HIV, malaria, etc), may be most successful using a combination of Ad5.F35-based priming, followed by Lm-based boosting. More specifically, Lm-GUCY2C may be utilized to amplify GUCY2C-specific immunity in patients receiving adenovirus-based GUCY2C vaccines currently in clinical trials to prevent or treat recurrent GI cancer.

T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C.

The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C vaccine previously shown to induce robust GUCY2C254-262 immunity completely suppressed GUCY2C254-262 responses. Comparison of immunogenic Lm-derived peptides to GUCY2C254-262 revealed that Lm-derived peptides form highly stable peptide-MHC complexes with H-2Kd compared to GUCY2C254-262 peptide. Moreover, amino acid substitution at a critical anchoring residue for H-2Kd binding, producing GUCY2CF255Y, significantly improved stability with H-2Kd and rescued GUCY2C254-262 immunogenicity in the context of Lm vaccination. Collectively, these studies suggest that Lm antigens may compete with and suppress the immunogenicity of target vaccine antigens and that use of altered peptide ligands with enhanced peptide-MHC stability may be necessary to elicit robust immune responses. These studies suggest that optimizing target antigen competitiveness with Lm antigens or alternative immunization regimen strategies, such as prime-boost, may be required to maximize the clinical utility of Lm-based vaccines.

Is Halcyon feasible for single thoracic or lumbar vertebral segment SBRT?

PURPOSE: Halcyon linear accelerators employ intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) techniques. The Halcyon offers translational, but not rotational, couch correction, which only allows a 3 degrees of freedom (3-DOF) correction. In contrast, the TrueBeam (TB) linear accelerator offers full 6-DOF corrections. This study aims to evaluate the difference in treatment plan quality for single thoracic or lumbar vertebral segment SBRT between the Halcyon and TB linear accelerators. In addition, this study will also investigate the effect of patient rotational setup errors on the final plan quality. METHODS: We analyzed 20 patients with a single-level spine metastasis located between the T7 and L5 vertebrae near the spinal canal. The median planning target volume was 52.0 cm3 (17.9-138.7 cm3 ). The median tumor diameter in the axial plane was 4.6 cm (range 1.7-6.8 cm), in the sagittal plane was 3.3 cm (range 2-5 cm). The prescription doses were either 12-16 Gy in 1 fraction or 18-24 Gy in 3 fractions. All patients were treated on the TB linear accelerator with a 2.5 mm Multi-Leaf Collimator (MLC) leaf width. Treatment plans were retrospectively created for the Halcyon, which has a 5 mm effective MLC leaf width. The 20 patients had a total of 50 treatments. Analysis of the 50 cone beam computed tomography (CBCT) scans showed average rotational setup errors of 0.6°, 1.2°, and 0.8° in pitch, yaw, and roll, respectively. Rotational error in roll was not considered in this study, as the original TB plans used a coplanar volumetric modulated arc therapy (VMAT) technique, and each 1° of roll will contribute an error of 1/360. If a plan has 3 arcs, the contribution from errors in roll will be < 0.1%. To simulate different patient setup errors, for each patient, 12 CT image datasets were generated in Velocity AI with different rotational combinations at a pitch and yaw of 1°, 2°, and 3°, respectively. We recalculated both the TB and Halcyon plans on these rotated images.  The dosimetric plan quality was evaluated based on the percent tumor coverage, the Conformity Index (CI), Gradient Index (GI), Homogeneity index (HI), the maximum dose to the cord/cauda, and the volume of the cord/cauda receiving 8, 10, and 12 Gy (V8Gy, V10Gy and V12Gy). Paired t-tests were performed between the original and rotated plans with a significance level of 0.05. RESULTS: The Eclipse based VMAT plans on Halcyon achieved a similar target coverage (92.3 ± 3.0% vs. 92.4 ± 3.3%, p = 0.82) and CI (1.0 ± 0.1 vs. 1.1 ± 0.2, p = 0.12) compared to the TB plans. The Gradient index of Halcyon is higher (3.96 ±0.8) than TB (3.85 ±0.7), but not statistically significant. The maximum dose to the spinal cord/cauda was comparable (11.1 ± 2.8 Gy vs. 11.4 ± 3.6 Gy, p = 0.39), as were the V8Gy, V10Gy and V12Gy to the cord/cauda. The dosimetric influence of patient rotational setup error was statistically insignificant for rotations of up to 1° pitch/yaw (with similar target coverage, CI, max cord/cauda dose and V8Gy, V10Gy, V12Gy for cord/cauda). The total number of monitor units (MUs) for Halcyon (4998 ± 1688) was comparable to that of TB (5463 ± 2155) (p = 0.09). CONCLUSIONS: The Halcyon VMAT plans for a single thoracic or lumbar spine metastasis were dosimetrically comparable to the TB plans. Patient rotation within 1° in the pitch and yaw directions, if corrected by translation, resulted in insignificant dosimetric effects. The Halcyon linear accelerator is an acceptable alternative to TB for the treatment of single thoracic or lumbar spinal level metastasis, but users need to be cautious about the patient rotational setup error.  It is advisable to select patients appropriately, including only those with the thoracic or lumbar spine involvement and keeping at least 2 mm separation between the target and the cord/cauda. More margin is needed if the distance between the isocenter and cord/cauda is larger. It is advisable to place the planning isocenter close to the spinal canal to further mitigate the rotational error. SUMMARY: We simulated various scenarios of patient setup errors with different rotational combinations of pitch and yaw with 1°, 2°, and 3°, respectively. Rotation was corrected with translation only to mimic the Halcyon treatment scenario. Using the Halcyon for treating a tumor in a single thoracic or lumbar vertebral segment is feasible, but caution should be noted in patients requiring rotational corrections of > 1° in the absence of 6-DOF correction capabilities.

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.

BACKGROUND/PURPOSE: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. METHODS: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. RESULTS: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. CONCLUSIONS: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .

Gamma Knife Radiosurgery for Pituitary Tumors: A Systematic Review and Meta-Analysis.

To describe and evaluate outcomes of Gamma Knife radiosurgery (GK) for the treatment of pituitary tumors over the past twenty years, a systematic review and meta-analysis according to PRISMA statement was performed. Articles counting more than 30 patients were included. A weighted random effects models was used to calculate pooled outcome estimates. From 459 abstract reviews, 52 retrospective studies were included. Among them, 18 reported on non-functioning pituitary adenomas (NFPA), 13 on growth hormone (GH)-secreting adenomas, six on adrenocorticotropic hormone (ACTH)-secreting adenomas, four on prolactin hormone (PRL)-secreting adenomas, and 11 on craniopharyngiomas. Overall tumor control and five-year progression free survival (PFS) estimate after one GK procedure for NFPA was 93% (95% CI 89-97%) and 95% (95% CI 91-99%), respectively. In case of secreting pituitary adenomas, overall remission (cure without need for medication) estimates were 45% (95% CI 35-54%) for GH-secreting adenomas, 64% (95% CI 0.52-0.75%) for ACTH-secreting adenomas and 34% (95% CI: 19-48%) for PRL-secreting adenomas. The pooled analysis for overall tumor control and five-year PFS estimate after GK for craniopharyngioma was 74% (95% CI 67-81%) and 70% (95% CI: 64-76%), respectively. This meta-analysis confirms and quantifies safety and effectiveness of GK for pituitary tumors.

Stereotactic radiosurgery as the first-line treatment for intracanalicular vestibular schwannomas.

OBJECTIVE: This report evaluates the outcomes of stereotactic radiosurgery (SRS) as the first-line treatment of intracanalicular vestibular schwannomas (VSs). METHODS: Between 1987 and 2017, the authors identified 209 patients who underwent SRS as the primary intervention for a unilateral intracanalicular VS. The median patient age was 54 years (range 22-85 years); 94 patients were male and 115 were female. Three patients had facial neuropathy at the time of SRS. One hundred fifty-five patients (74%) had serviceable hearing (Gardner-Robertson [GR] grades I and II) at the time of SRS. The median tumor volume was 0.17 cm3 (range 0.015-0.63 cm3). The median margin dose was 12.5 Gy (range 11.0-25.0 Gy). The median maximum dose was 24.0 Gy (range 15.7-50.0 Gy). RESULTS: The progression-free survival rates of all patients with intracanalicular VS were 97.5% at 3 years, 95.6% at 5 years, and 92.1% at 10 years. The rates of freedom from the need for any additional intervention were 99.4% at 3 years, 98.3% at 5 years, and 98.3% at 10 years. The serviceable hearing preservation rates in GR grade I and II patients at the time of SRS were 76.6% at 3 years, 63.5% at 5 years, and 27.3% at 10 years. In univariate analysis, younger age (< 55 years, p = 0.011), better initial hearing (GR grade I, p < 0.001), and smaller tumor volumes (< 0.14 cm3, p = 0.016) were significantly associated with improved hearing preservation. In multivariate analysis, better hearing (GR grade I, p = 0.001, HR 2.869, 95% CI 1.569-5.248) and smaller tumor volumes (< 0.14 cm3, p = 0.033, HR 2.071, 95% CI 1.059-4.047) at the time of SRS were significantly associated with improved hearing preservation. The hearing preservation rates of patients with GR grade I VS were 88.1% at 3 years, 77.9% at 5 years, and 38.1% at 10 years. The hearing preservation rates of patients with VSs smaller than 0.14 cm3 were 85.5% at 3 years, 77.7% at 5 years, and 42.6% at 10 years. Facial neuropathy developed in 1.4% from 6 to 156 months after SRS. CONCLUSIONS: SRS provided sustained tumor control in more than 90% of patients with intracanalicular VS at 10 years and freedom from the need for additional intervention in more than 98% at 10 years. Patients with initially better hearing and smaller VSs had enhanced serviceable hearing preservation during an observation interval up to 10 years after SRS.

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

Objective The purpose of this study was to evaluate long-term clinical outcomes and tumor control after stereotactic radiosurgery (SRS) for trigeminal schwannoma (TS). Methods 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 3 (range: 0.10-18 cm 3 ), 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. Results 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 ( p = 0.014) and smaller tumor volume ( p = 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. Conclusion 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.

Optimizing stereotactic radiosurgery in patients with recurrent or residual craniopharyngiomas.

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 cm3 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.

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

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.

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

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?

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

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.

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

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.

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

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.