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Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (Ikbkb GoF/GoF ) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. Ikbkb GoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation., (© 2024. The Author(s).)

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57 + CD4 + T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57 + CD4 + T cells from blood and tonsil samples. Circulating CD57 + CD4 + T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8 + effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57 + CD4 + T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4 + T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection., (© 2023. The Author(s).)

Background: Fractionated stereotactic radiotherapy (FSRT) is a noninvasive treatment for acoustic neuromas (ANs). Initial reports from our institution demonstrated that the reduction of treatment dose to 46.8 Gy resulted in improved preservation of functional hearing status., Objective: We now report the tumor control (TC), symptomatic outcome, and hearing preservation (HP) rate in patients treated with reduced-dose FSRT., Methods: We analyzed all patients with AN treated from 2002 to 2011. All patients received 46.8 Gy in 1.8-Gy fractions. Follow-up audiogram and magnetic resonance imaging were performed in ≤ 1-year intervals. TC and HP were calculated by the Kaplan-Meier method. Analysis of HP, defined as Gardner-Robertson value ≤ 2, was determined by audiometric data. Non-hearing-related symptoms were defined by Common Terminology Criteria for Adverse Events version 4., Results: In total, 154 patients were analyzed. At a median follow-up of 35 months (range, 4-108), TC was achieved in 96% of patients (n = 148/154) and at 3 and 5 years was 99% and 93%. Eighty-seven patients had serviceable hearing at the time of FSRT and evaluable audiometric follow-up. Overall HP was 67% and at 3 and 5 years was 66% and 54%. Pure tone average decreased by a median of 13 dB in all patients. Nineteen percent (n = 31) of patients experienced symptom improvement, and 8% (n = 13) had worsening of symptoms. Cranial nerve dysfunction occurred in 3.8% of patients (n = 6)., Conclusion: Reduced-dose FSRT to 46.8 Gy for AN achieves excellent functional HP rates and limited toxicity without compromising long-term TC. Based on these promising outcomes, further attempts at dose deescalation may be warranted.

Objective: Despite the success of stereotactic radiosurgery, large inoperable arteriovenous malformations (AVMs) of 14 cm3 or more have remained largely refractory to stereotactic radiosurgery, with much lower obliteration rates. We review treatment of large AVMs either previously untreated or partially obliterated by embolization with fractionated stereotactic radiotherapy (FSR) regimens using a dedicated linear accelerator (LINAC)., Methods: Before treatment, all patients were discussed at a multidisciplinary radiosurgery board and found to be suitable for FSR. All patients were evaluated for pre-embolization. Those who had feeding pedicles amenable to glue embolization were treated. LINAC technique involved acquisition of a stereotactic angiogram in a relocatable frame that was also used for head localization during treatment. The FSR technique involved the use of six 7-Gy fractions delivered on alternate days over a 2-week period, and this was subsequently dropped to 5-Gy fractions after late complications in one of seven patients treated with 7-Gy fractions. Treatments were based exclusively on digitized biplanar stereotactic angiographic data. We used a Varian 600SR LINAC (Varian Medical Systems, Inc., Palo Alto, CA) and XKnife treatment planning software (Radionics, Inc., Burlington, MA). In most cases, one isocenter was used, and conformality was established by non-coplanar arc beam shaping and differential beam weighting., Results: Thirty patients with large AVMs were treated between January 1995 and August 1998. Seven patients were treated with 42-Gy/7-Gy fractions, with one patient lost to follow-up and the remaining six with previous partial embolization. Twenty-three patients were treated with 30-Gy/5-Gy fractions, with two patients lost to follow-up and three who died as a result of unrelated causes. Of 18 evaluable patients, 8 had previous partial embolization. MeanAVM volumes at FSR treatment were 23.8 and 14.5 cm3, respectively, for the 42-Gy/7-Gy fraction and 30-Gy/5-Gy fraction groups. After embolization, 18 patients still had AVM niduses of 14 cm3 or more: 6 in the 7-Gy cohort and 12 in the 5-Gy cohort. For patients with at least 5-year follow-up, angiographically documented AVM obliteration rates were 83%for the 42-Gy/7-Gy fraction group, with a mean latency of 108 weeks (5 of 6 evaluable patients), and 22% for the 30-Gy/5-Gy fraction group, with an average latency of 191 weeks (4 of 18 evaluable patients) (P = 0.018). For AVMs that remained at 14 cm3 or more after embolization (5 of 6 patients), the obliteration rate remained 80% (4 of 5 patients) for the 7-Gy cohort and dropped to 9% for the 5-Gy cohort. A cumulative hazard plot revealed a 7.2-fold greater likelihood of obliteration with the 42-Gy/7-Gy fraction protocol (P = 0.0001), which increased to a 17-fold greater likelihood for postembolization AVMs of 14 cm3 or more (P = 0.003)., Conclusion: FSR achieves obliteration for AVMs at a threshold dose, including large residual niduses after embolization. With significant treatment-related morbidities, further investigation warrants a need for better three-dimensional target definition with higher dose conformality.

Background: Medically refractory trigeminal neuralgia (TN) has been treated with a variety of minimally invasive techniques, all of which have been compared with microvascular decompression. For patients not considered good surgical candidates, percutaneous retrogasserian glycerol rhizotomy (GR) and gamma knife (GK) radiosurgery are two minimally invasive techniques in common practice worldwide and used routinely at Jefferson Hospital for Neuroscience. Using a common pain scale outcomes questionnaire, we sought to analyze efficacies and morbidities of both treatments., Methods and Materials: Between June 1994 and December 2002, 79 patients were treated with GR and 109 patients underwent GK for the treatment of TN. GR was performed with fluoroscopic guidance as an overnight inpatient procedure. GK was performed using a single 4-mm shot positioned at the root exit zone of the trigeminal nerve. Radiation doses of 70-90 Gy prescribed to the 100% isodose line were used. Treatment outcomes including pain response, pain recurrence, treatment failure, treatment-related side effects, and overall patient satisfaction with GK and GR were compared using a common outcomes scale. Using the Barrow Neurologic Institute pain scale, patients were asked to define their level of pain both before and after treatment: I, no pain and no pain medication required; I, occasional pain not requiring medication; IIIa, no pain and pain medication used; IIIb, some pain adequately controlled with medication; IV, some pain not adequately controlled with medication; and V, severe pain with no relief with medication. We used posttreatment scores of I, II, IIIa, and IIIb to identify treatment success, whereas scores of IV and V were considered treatment failure. Results were compiled from respondents and analyzed using SAS software. Statistical comparisons used log-rank test, univariate and multivariate logistic regression, Fisher's exact test, and Wilcoxon test with significance established at p < 0.05., Results: There were 63 evaluable GK patients and 36 evaluable GR patients. The median follow-up time was 34 and 29 months for the GR and GK groups, respectively. The median age was 69 and 70 years and the median number of years with TN pain was 6 and 7 years in the GR and GK groups, respectively. Thirty-one GR (86%) and 58 GK (92%) patients achieved a successful treatment outcome (p = 0.49). The median time to pain relief was < or = 24 h in the GR group and 3 weeks in the GK group (p < 0.001, ordinal logistic regression). Nineteen GR and 26 GK patients experienced pain recurrence or pain never relieved (p = 0.30). The median time to pain recurrence was 5 and 8 months in the GR and GK groups, respectively (p = 0.22). At last follow-up, however, a statistically significant greater number of GR vs. GK patients had failed treatment. Twelve or 33% of GR patients, whereas 8 or 13% of GK patients, had BNI scores of 4 or 5 (p = 0.019, Fisher's exact test). When both initial and late treatment failures were combined, the overall rate of treatment failures was 39% in the GR group and 24% in the GK group (p = 0.023, log-rank). More GR patients developed facial numbness and facial numbness morbidity than GK patients: 19 GR (54%) and 17 GK patients (30%) developed new facial numbness and 12 GR and 7 GK patients reported either somewhat or very bothersome facial numbness (p = 0.018). On multivariate analysis, only treatment with GK and severity of pain before treatment significantly predicted treatment response. GK patients were more likely to have a lower pain score at last follow-up than were GR patients (p = 0.005, OR = 4.3), and patients with pretreatment pain scores of 5 were more likely to have lower posttreatment pain scores than patients with pretreatment pain scores of 4 and lower (p = 0.003, OR = 4.0)., Conclusion: Despite greater facial numbness morbidity and a higher failure rate, GR provided more immediate pain relief than GK. GR therefore should be considered in patients with disabling trigeminal pain requiring urgent pain relief. For all other patients, GK provides better long-term pain relief with less treatment-related morbidity, and should therefore be considered the preferred treatment for patients with medically refractory trigeminal neuralgia who are not suitable candidates for microvascular nerve decompression.

Objective: To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) after surgery in the management of residual or recurrent nonfunctioning pituitary adenomas with respect to tumor control and the development of complications., Methods and Materials: The clinical records of patients with nonfunctioning pituitary adenomas who underwent FSRT were retrospectively analyzed. For newly diagnosed tumors, transsphenoidal surgery was performed, and, if residual tumor was identified at 3 months, FSRT was performed. If significant tumor volume persisted, transcranial surgery was performed before FSRT. We originally initiated FSRT with 2-Gy fractions to 46 Gy. We escalated the dose to 50.4 Gy thereafter. As a final modification, we dropped the daily dose to 1.8-Gy fractions delivered within 6 weeks. High-dose conformality and homogeneity was achieved with arc beam shaping and differential beam weighting. The radiographic, endocrinologic, and visual outcomes after FSRT were evaluated., Results: The 68 patients included 36 males and 32 females with an age range of 15-81 years. The median follow-up was 30 months (range, 2-82 months), and the median tumor volume was 6.2 cm(3). Of the 68 patients, 20 were treated to 46 Gy and 48 to 50-52.2 Gy. Most were treated to 50.4 Gy. Eleven patients had recurrent tumors, 54 had residual tumors, and no surgery was performed in 3 patients before FSRT. We noted no radiation-induced acute or late toxicities, except for radiation-induced optic neuropathy in 2 patients. At latest follow-up, the tumor had decreased in size in 26 patients and remained stable in 41 of the 42 remaining patients. Of the 68 patients, 4 (6%) developed hypopituitarism at 6, 11, 12, and 17 months after FSRT. Reviewing available serial Humphrey visual fields, visual fields were objectively improved in 28 patients, and remained stable in 24 patients, and worsened in 2 patients., Conclusion: The findings of this analysis support the use of surgery followed by FSRT as a safe, effective, and integrated treatment for nonfunctioning pituitary adenomas. Additional follow-up is needed to document the long-term tumor control rates, preservation rates for vision and pituitary function, and neurocognitive outcomes.

Objective: Despite the success of stereotactic radiosurgery, large inoperable arteriovenous malformations (AVMs) of 14 cm(3) or more have remained largely refractory to stereotactic radiosurgery, with much lower obliteration rates. We review treatment of large AVMs either previously untreated or partially obliterated by embolization with fractionated stereotactic radiotherapy (FSR) regimens using a dedicated linear accelerator (LINAC)., Methods: Before treatment, all patients were discussed at a multidisciplinary radiosurgery board and found to be suitable for FSR. All patients were evaluated for pre-embolization. Those who had feeding pedicles amenable to glue embolization were treated. LINAC technique involved acquisition of a stereotactic angiogram in a relocatable frame that was also used for head localization during treatment. The FSR technique involved the use of six 7-Gy fractions delivered on alternate days over a 2-week period, and this was subsequently dropped to 5-Gy fractions after late complications in one of seven patients treated with 7-Gy fractions. Treatments were based exclusively on digitized biplanar stereotactic angiographic data. We used a Varian 600SR LINAC (Varian Medical Systems, Inc., Palo Alto, CA) and XKnife treatment planning software (Radionics, Inc., Burlington, MA). In most cases, one isocenter was used, and conformality was established by non-coplanar arc beam shaping and differential beam weighting., Results: Thirty patients with large AVMs were treated between January 1995 and August 1998. Seven patients were treated with 42-Gy/7-Gy fractions, with one patient lost to follow-up and the remaining six with previous partial embolization. Twenty-three patients were treated with 30-Gy/5-Gy fractions, with two patients lost to follow-up and three who died as a result of unrelated causes. Of 18 evaluable patients, 8 had previous partial embolization. Mean AVM volumes at FSR treatment were 23.8 and 14.5 cm(3), respectively, for the 42-Gy/7-Gy fraction and 30-Gy/5-Gy fraction groups. After embolization, 18 patients still had AVM niduses of 14 cm(3) or more: 6 in the 7-Gy cohort and 12 in the 5-Gy cohort. For patients with at least 5-year follow-up, angiographically documented AVM obliteration rates were 83% for the 42-Gy/7-Gy fraction group, with a mean latency of 108 weeks (5 of 6 evaluable patients), and 22% for the 30-Gy/5-Gy fraction group, with an average latency of 191 weeks (4 of 18 evaluable patients) (P = 0.018). For AVMs that remained at 14 cm(3) or more after embolization (5 of 6 patients), the obliteration rate remained 80% (4 of 5 patients) for the 7-Gy cohort and dropped to 9% for the 5-Gy cohort. A cumulative hazard plot revealed a 7.2-fold greater likelihood of obliteration with the 42-Gy/7-Gy fraction protocol (P = 0.0001), which increased to a 17-fold greater likelihood for postembolization AVMs of 14 cm(3) or more (P = 0.003)., Conclusion: FSR achieves obliteration for AVMs at a threshold dose, including large residual niduses after embolization. With significant treatment-related morbidities, further investigation warrants a need for better three-dimensional target definition with higher dose conformality.

Objective: We investigated the safety and efficacy of stereotactic radiotherapy as an alternative therapy to surgical resection for optic nerve sheath meningiomas (ONSMs)., Methods: Thirty patients and 33 optic nerves with ONSMs were treated with conventional fractionated stereotactic radiotherapy treatment (CF-SRT) between July 1996 and May 2001 with the use of a 6-MeV LINAC designed for and dedicated to radiosurgery. The LINAC technique involved daily CF-SRT involving a relocatable frame, an average of three isocenters, and high-radiation dose conformality established by noncoplanar arc beam shaping and differential beam weighting. The patients who were treated with CF-SRT were followed clinically with serial visual fields and radiographically with both magnetic resonance imaging and functional (111)In-octreotide single-photon emission computed tomography. The results of treatment were compared with a historical control group of ONSM patients who were either observed or treated surgically and then observed., Results: Our study population comprised 18 women and 12 men with a median age of 44 years (age range, 20-76 yr). The median isosurface radiation dose was 51 Gy (dose range, 50-54.0 Gy), and the median clinical follow-up time was 89 weeks (range, 9-284 wk). Of 22 optic nerves with vision before CF-SRT, 20 nerves (92%) demonstrated preserved vision, and 42% manifested improvement in visual acuity and/or visual field at follow-up. Comparison of our patients with a historical control group revealed preserved vision in only 16% of patients in a comparable period of observation, along with a 150% greater probability of visual improvement. Four patients (13%) had posttreatment morbidities, including visual loss (two patients), optic neuritis (one patient), and transient orbital pain (one patient). On magnetic resonance imaging studies, there was no evidence of tumor progression or recurrence in all patients, including tumor volume reductions noted in four patients. All six patients monitored with (111)In-octreotide scintigraphy demonstrated significant decreases in tumor activity after CF-SRT., Conclusion: To date, this article describes the largest reported series of ONSMs. Although longer follow-up is necessary, we think that CF-SRT represents a safe alternative to surgery and offers a higher likelihood of preserved or improved vision in patients with ONSM. Our analysis suggests that CF-SRT is also preferable to observation. Functional (111)In-octreotide single-photon emission computed tomographic scintigraphy provides a useful technique for the assessment of tumor control that complements serial posttreatment magnetic resonance imaging in patients with ONSMs.

Background: Stereotactic radiosurgery (SRS) and, more recently, fractionated stereotactic radiotherapy (SRT) have been recognized as noninvasive alternatives to surgery for the treatment of acoustic schwannomas. We review our experience of acoustic tumor treatments at one institution using a gamma knife for SRS and the first commercial world installation of a dedicated linac for SRT., Methods: Patients were treated with SRS on the gamma knife or SRT on the linac from October 1994 through August 2000. Gamma knife technique involved a fixed-frame multiple shot/high conformality single treatment, whereas linac technique involved daily conventional fraction treatments involving a relocatable frame, fewer isocenters, and high conformality established by noncoplanar arc beam shaping and differential beam weighting., Results: Sixty-nine patients were treated on the gamma knife, and 56 patients were treated on the linac, with 1 NF-2 patient common to both units. Three patients were lost to follow-up, and in the remaining 122 patients, mean follow-up was 119 +/- 67 weeks for SRS patients and 115 +/- 96 weeks for SRT patients. Tumor control rates were high (> or =97%) for sporadic tumors in both groups but lower for NF-2 tumors in the SRT group. Cranial nerve morbidities were comparably low in both groups, with the exception of functional hearing preservation, which was 2.5-fold higher in patients who received conventional fraction SRT., Conclusion: SRS and SRT represent comparable noninvasive treatments for acoustic schwannomas in both sporadic and NF-2 patient groups. At 1-year follow-up, a significantly higher rate of serviceable hearing preservation was achieved in SRT sporadic tumor patients and may therefore be preferable to alternatives including surgery, SRS, or possibly observation in patients with serviceable hearing.

Purpose: This study was undertaken to determine the impact of geometric distortions on the spatial accuracy of magnetic resonance imaging (MRI)-guided stereotactic localization for gamma knife functional radiosurgery., Method: The spatial accuracy of MRI was evaluated by comparing stereotactic coordinates of intracranial targets, external fiducials, and anatomic structures defined by computed tomographic and MRI studies of the Radionics skull phantom (Radionics, Inc., Burlington, MA), the Rando head phantom, and 11 patients who underwent gamma knife functional radiosurgery. The distortion in MRI was assessed from computed tomographic and MRI fusion studies for these patients, as well as from MRI studies acquired by swapping the direction of the magnetic field gradients for five patients who underwent gamma knife radiosurgery and three patients who underwent MRI-guided frameless surgery. A follow-up program to compare the location of the created lesion with the intended target complemented the analysis., Results: The average difference between computed tomographic and MRI stereotactic coordinates of external fiducials, intracranial targets, and anatomic landmarks was of the order of 1 pixel size (0.9 x 0.9 x 1 mm3) along the x, y, and z axes. The average linear scaling along these axes as determined by fusion studies was approximately 0.8% and consistent with a single pixel. The follow-up studies, available for seven patients, revealed good agreement between the location of the created lesion and the intended target., Conclusion: The spatial accuracy of an MRI-based localization system can be comparable to computed tomography-based localization with the added benefit of MRI resolution. Both machine- and object-related MRI distortions can be reduced to an acceptable level with contemporary scanners, optimized scanning sequences, and distortion-resistant stereotactic instruments.

A stereotactic radiosurgery and radiotherapy (SRS/SRT) system on a dedicated Varian Clinac-600SR linear accelerator with Brown-Roberts-Wells and Gill-Thomas-Cosman relocatable frames along with the Radionics (RSA) planning system is evaluated. The Clinac-600SR has a single 6-MV beam with the same beam characteristics as that of the mother unit, the Clinac-600C. The primary collimator is a fixed cone projecting to a 10-cm diameter at isocenter. The secondary collimator is a heavily shielded cylindrical collimator attached to the face plate of the primary collimator. The tertiary collimation consists of the actual treatment cones. The cone sizes vary from 12.5 to 40.0 mm diameter. The mechanical stability of the entire system was verified. The variations in isocenter position with table, gantry, and collimator rotation were found to be < 0.5 mm with a compounded accuracy of < or = 1.0 mm. The radiation leakage under the cones was < 1% measured at a depth of 5 cm in a phantom. The beam profiles of all cones in the x and y directions were within +/- 0.5 mm and match with the physical size of the cone. The dosimetric data such as tissue maximum ratio, off-axis ratio, and cone factor were taken using film, diamond detector, and ion chambers. The mechanical and dosimetric characteristics including dose linearity of this unit are presented and found to be suitable for SRS/SRT. The difficulty in absolute dose measurement for small cone is discussed.