TN-RS: a novel scoring system predicts Gamma Knife Radiosurgery outcome for trigeminal neuralgia patients.

BACKGROUND: Gamma Knife Radiosurgery (GKRS) is an effective treatment option for medically refractory trigeminal neuralgia (TN). This study examines GKRS outcome in a large cohort of TN patients and highlights pretreatment factors associated with pain relief. METHODS: This is a single-center retrospective analysis of patients treated with GKRS for TN between 2011 and 2019. Pain relief was assessed at 1 year, and 2-3 years following GKRS. Multivariable analysis identified several factors that predicted pain relief. These predicting factors were applied to establish a pain relief scoring system. RESULTS: A total of 162 patients met inclusion criteria. At 1 year post-GKRS, the breakdown of Barrow Neurological Institute (BNI) score for pain relief was as follows: 77 (48%) score of I, 13 (8%) score of II, 37 (23%) score of III, 22 (14%) score of IV, and 13 (8%) score of V. Factors that were significantly associated with pain-free outcome at 1 year were: Typical form of TN (OR = 2.2 [1.1, 4.9], p = 0.049), No previous microvascular decompression (OR = 4.4 [1.6, 12.5], p = 0.005), Response to medical therapy (OR = 2.7 [1.1, 6.1], p = 0.018), and Seniority > 60 years (OR = 2.8 [1.4, 5.5], p = 0.003). The term "Trigeminal Neuralgia-RadioSurgery" was used to create the TN-RS acronym representing the significant factors. A stepwise increase in the median predicted probability of pain-free outcome at 1 year from 3% for patients with a score of 0 to 69% for patients with a maximum score of 4. CONCLUSION: The TN-RS scoring system can assist clinicians in identifying patients that may benefit from GNRS for TN by predicting 1-year pain-free outcomes.

The impact of cobalt-60 source age on biologically effective dose in high-dose functional Gamma Knife radiosurgery.

OBJECTIVE Functional Gamma Knife radiosurgery (GKRS) procedures have been increasingly used for treating patients with tremor, trigeminal neuralgia (TN), and refractory obsessive-compulsive disorder. Although its rates of toxicity are low, GKRS has been associated with some, if low, risks for serious sequelae, including hemiparesis and even death. Anecdotal reports have suggested that even with a standardized prescription dose, rates of functional GKRS toxicity increase after replacement of an old cobalt-60 source with a new source. Dose rate changes over the course of the useful lifespan of cobalt-60 are not routinely considered in the study of patients treated with functional GKRS, but these changes may be associated with significant variation in the biologically effective dose (BED) delivered to neural tissue. METHODS The authors constructed a linear-quadratic model of BED in functional GKRS with a dose-protraction factor to correct for intrafraction DNA-damage repair and used standard single-fraction doses for trigeminal nerve ablation for TN (85 Gy), thalamotomy for tremor (130 Gy), and capsulotomy for obsessive-compulsive disorder (180 Gy). Dose rate and treatment time for functional GKRS involving 4-mm collimators were derived from calibrations in the authors' department and from the cobalt-60 decay rate. Biologically plausible values for the ratio for radiosensitivity to fraction size (α/ß) and double-strand break (DSB) DNA repair halftimes (τ) were estimated from published experimental data. The biphasic characteristics of DSB repair in normal tissue were accounted for in deriving an effective τ1 halftime (fast repair) and τ2 halftime (slow repair). A sensitivity analysis was performed with a range of plausible parameter values. RESULTS After replacement of the cobalt-60 source, the functional GKRS dose rate rose from 1.48 to 2.99 Gy/min, treatment time fell, and estimated BED increased. Assuming the most biologically plausible parameters, source replacement resulted in an immediate relative BED increase of 11.7% for GKRS-based TN management with 85 Gy, 15.6% for thalamotomy with 130 Gy, and 18.6% for capsulotomy with 180 Gy. Over the course of the 63-month lifespan of the cobalt-60 source, BED decreased annually by 2.2% for TN management, 3.0% for thalamotomy, and 3.5% for capsulotomy. CONCLUSIONS Use of a new cobalt-60 source after replacement of an old source substantially increases the predicted BED for functional GKRS treatments for the same physical dose prescription. Source age, dose rate, and treatment time should be considered in the study of outcomes after high-dose functional GKRS treatments. Animal and clinical studies are needed to determine how this potential change in BED contributes to GKRS toxicity and whether technical adjustments should be made to reduce dose rates or prescription doses with newer cobalt-60 sources.

Preoperative MRI improves prediction of extensive occult axillary lymph node metastases in breast cancer patients with a positive sentinel lymph node biopsy.

RATIONALE AND OBJECTIVES: To test the ability of quantitative measures from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict, independently and/or with the Katz pathologic nomogram, which breast cancer patients with a positive sentinel lymph node biopsy will have four or more positive axillary lymph nodes on completion axillary dissection. MATERIALS AND METHODS: A retrospective review was conducted to identify clinically node-negative invasive breast cancer patients who underwent preoperative DCE-MRI, followed by sentinel node biopsy with positive findings and complete axillary dissection (June 2005-January 2010). Clinical/pathologic factors, primary lesion size, and quantitative DCE-MRI kinetics were collected from clinical records and prospective databases. DCE-MRI parameters with univariate significance (P < .05) to predict four or more positive axillary nodes were modeled with stepwise regression and compared to the Katz nomogram alone and to a combined MRI-Katz nomogram model. RESULTS: Ninety-eight patients with 99 positive sentinel biopsies met study criteria. Stepwise regression identified DCE-MRI total persistent enhancement and volume adjusted peak enhancement as significant predictors of four or more metastatic nodes. Receiver operating characteristic curves demonstrated an area under the curve of 0.78 for the Katz nomogram, 0.79 for the DCE-MRI multivariate model, and 0.87 for the combined MRI-Katz model. The combined model was significantly more predictive than the Katz nomogram alone (P = .003). CONCLUSIONS: Integration of DCE-MRI primary lesion kinetics significantly improved the Katz pathologic nomogram accuracy to predict the presence of metastases in four or more nodes. DCE-MRI may help identify sentinel node-positive patients requiring further local-regional therapy.

Dynamic contrast-enhanced magnetic resonance imaging and invasive breast cancer: primary lesion kinetics correlated with axillary lymph node extracapsular extension.

PURPOSE: To determine if dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) peak enhancement (PE) of primary breast cancer can predict the presence of lymph node extracapsular extension (LNECE) in patients with axillary metastatic disease. MATERIALS AND METHODS: In all, 167 patients treated with radiotherapy for invasive breast cancer from January 1, 2006 to November 1, 2007 were retrospectively identified. Patients with DCE-MRI and surgical axillary staging were included in this study. PE of primary tumors was compared according to axillary nodal status: negative, positive without LNECE, or positive with LNECE. A receiver operator characteristic curve (ROC) was plotted to determine accuracy of PE to predict LNECE. RESULTS: Forty-six patients met the study criteria. Thirty-two (70%) were node-negative, 9 (19%) were node-positive without LNECE, and 5 (11%) were node-positive with LNECE. PE was greater for patients with LNECE (mean 365%) compared to node-positive patients without LNECE (mean 183%) P = 0.05 and node-negative patients (mean 144%) P = 0.0012. Area under the ROC curve was 0.93. CONCLUSION: DCE-MRI PE may be a surrogate marker for LNECE. If validated, DCE-MRI may provide noninvasive kinetic information informing axillary nodal status for patients who receive chemotherapy prior to surgical axillary staging or forego axillary dissection after a positive sentinel node biopsy.

The emerging use of IMRT for treatment of cervical cancer.

Radiation therapy plays an important role in both the definitive and adjuvant treatment of patients with cervical cancer. However, although radiation therapy is effective in controlling tumor growth, associated acute and chronic adverse effects are well known. Intensity-modulated radiation therapy (IMRT) is increasingly being used to treat cervical cancer and has the potential to improve the therapeutic ratio because of its ability to escalate dose to cancer targets while sparing adjacent healthy tissue. Multiple dosimetric studies were initially performed, establishing the conceptual feasibility of IMRT in patients with cervical cancer. Subsequent early reported series of patients treated with IMRT showed dosimetric and clinical benefits, with reduction in acute gastrointestinal and hematologic toxicity compared with historic controls, particularly in the posthysterectomy setting. Consensus is evolving regarding the use of IMRT in treating cervical cancer, particularly in the posthysterectomy setting, and for dose escalation to para-aortic nodes and bulky sidewall disease. Target delineation in the context of internal organ motion and tumor shrinkage during a course of fractionated external-beam radiotherapy remains an area of active investigation. IMRT in treating cervical cancer in the setting of an intact uterus remains in its nascent stage and should be used judiciously only within clinical trials. Although not a routine substitute for brachytherapy, it may be considered as a boost for highly selected patients who are not brachytherapy candidates.

Dynamic contrast-enhanced MRI kinetics of invasive breast cancer: a potential prognostic marker for radiation therapy.

PURPOSE: Our goal was to determine the correlations between dynamic contrast-enhanced MRI (DCE-MRI) kinetics of breast cancers and axillary nodal status (ANS) which may have prognostic value in designing radiation therapy recommendations. METHODS AND MATERIALS: A retrospective review identified 167 consecutive patients treated with external beam radiotherapy for invasive breast cancer from Jan 1, 2006 to Nov 1, 2007. Patients with DCE-MRI kinetic data from our institution who underwent axillary surgical staging prior to chemotherapy were included. ANS was assessed as positive or negative by pathology record review. For each primary cancer, maximum tumor diameter and kinetic values for initial peak enhancement (PE), percent initial rapid enhancement (RE), and percent delayed washout enhancement (WE) were measured with a computer-aided evaluation program. Univariate, multivariate, and receiver operating characteristic curve analyses were performed according to the ANS. RESULTS: Forty-six patients met study criteria, with 32 (70%) node-negative and 14 (30%) node-positive patients. Median PE was significantly greater in node-positive patients (209%) than in node-negative patients (138%, p = 0.0027). Similarly, median RE was significantly greater in node-positive patients (57%) than in node-negative patients (27%, p = 0.0436). WE was not different between groups (p = 0.9524). Median maximum tumor diameter was greater in node-positive patients (26 mm) than in node-negative patients (15 mm, p = 0.015). Multivariate analysis showed that only PE trended toward significance (p = 0.18). CONCLUSIONS: DCE-MRI kinetics of primary breast cancers correlate with ANS. Multivariate analysis demonstrates the correlation is not due simply to underlying lesion size. If validated prospectively, DCE-MRI kinetics may aid as a tool in selecting patients or designing fields for radiation therapy.

Radiation, chemotherapy, and symptom management in cancer-related cognitive dysfunction.

Patients with cancer are concerned about their ability to interact with friends and family and to perform activities associated with daily living. The combined effects of the disease process, its treatment with surgery, radiation, and chemotherapy, and the medications used to manage symptoms may all impact cognitive function. Minimizing the effect of each treatment modality on cognitive processing requires an understanding of how these treatment modalities may impact cognition.

Analysis of the Pro-Qura Database: rectal dose, implant quality, and brachytherapist's experience.

PURPOSE: This study analyzed rectal dosimetry outcomes of Pro-Qura proctored implants to assess the achievability of proposed rectal dose constraints in the setting of standardized pre- and postimplant dosimetry in community-based brachytherapy programs. METHODS AND MATERIALS: From August 2005 to July 2007, 713 postimplant CT scans were evaluated from 26 brachytherapists actively participating in Pro-Qura. Postimplant dosimetry was performed in a standardized fashion. The entirety of the rectal wall was contoured and evaluated for dose. Rectal dose was defined in terms of the volume of the rectum receiving 100% of the prescription dose (R(100)). Criteria for implant adequacy for both (103)Pd and (125)I included a prostate the percentage of the prostate volume covered by the prescription dose (V(100))>80%, a prostate the maximum dose covering 90% of the prostate volume (D(90)) of 90-140%, and an R(100)<1.0cm(3) for early (Day 0-7) dosimetry and <1.3cm(3) for late (Day 20-45) dosimetry. RESULTS: Mean prostatic volume was 35.1cm(3). The mean time from implant to CT scan was 29.9 days (range, 0-45 days). The respective mean overall prostate V(100) and D(90) were 89% and 101%, respectively, and remained consistent for sequence groups 1 through 6. Overall, the mean R(100) was 0.97+/-1.04cm(3). The R(100) was 1.15cm(3) for sequence Group 1 and with each subsequent sequence group decreased with a nadir of 0.83cm(3) in sequence Group 6 (p=0.22). Rectal dosimetry was deemed inadequate in 39% of Group 1 implants but only 22% in Group 6 (p=0.016). The reduced rectal doses did not impact prostate gland coverage. CONCLUSIONS: Using standardized dosimetry, R(100) improved with increasing brachytherapist's experience, reaching a plateau after approximately 20 patients.

Microinfusion of antineuronal antibodies into rodent striatum: failure to differentiate between elevated and low titers.

An autoimmune-mediated mechanism has been proposed for several pediatric movement disorders. In a three-center (Brown, Yale, and Johns Hopkins) collaborative effort, serum antineuronal antibodies (ANAb) were measured by use of ELISA or immunohistochemical techniques on 35 children (mean age 11.4 years) with Tourette syndrome, attention deficit hyperactivity disorder, and/or obsessive compulsive disorder. Eight sera, 4 containing the highest and 4 the lowest levels of ANAb, were identified at each institution. Selected sera (total of 9 with elevated and 7 with low ANAb) were re-encoded and sent to each center for infusion into the ventrolateral striatum of 16 male Sprague-Dawley rats. Animals were observed for behavioral abnormalities for 3 days before the start of infusion, during infusion on days 2-4, and for 2 days after infusion. Combined stereotypy scores increased after antibody infusion, but there was no significant effect based on serum titer (p=0.85). Scores differed among centers, but analyses based on individual institutional data again failed to show an effect based on elevated or low ANAb values (Brown, p=0.95; Yale and Johns Hopkins, p=0.81). Post hoc studies with sham surgery and infusion of phosphate-buffered saline support suggestions of nonspecific behavioral effects unrelated to antibody titer. This report emphasizes that any conclusions about antibody-mediated movement disorders that are based upon results from the rodent infusion model must be considered with caution.

Microarray analysis in Tourette syndrome postmortem putamen.

Gene expression patterns in the postmortem putamen of patients with Tourette syndrome (TS) were investigated using cDNA microarrays. A cDNA neuroarray comprising 1537 genes known to be related to neurological or neuropsychiatric disorders was used to compare patient samples (n=3) with those from control subjects (n=4). Z test and Z ratio were used to analyze results; seven genes were found to be upregulated according to our definition (P<0.1, two-tailed, for Z test; P<0.05 for Z ratio) and three were found to be downregulated. Validation experiments were performed using reverse transcription polymerase chain reaction (RT-PCR) and semiquantitative Western blot analyses. RT-PCR showed concordance with microarray in seven of nine selected genes. In contrast, Western blot analyses performed with five proteins showed that only two of five had similar trends between protein content and level of gene expression. The authors note the inherent difficulty in applying microarray technology to complex neurological disorders such as the TS and conclude that further investigations are required to understand how altered expression of these genes is related to the pathophysiology of the disorder.

Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes.

Rodent striatal microinfusions have been suggested as a model for assessing the behavioral effects induced by antineuronal antibodies. We used this approach to evaluate the proposed autoimmune etiology for Tourette syndrome (TS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Sera were assessed from patients with TS (n = 9) preselected based on the presence of elevated enzyme-linked immunosorbent assay optical densities against putamen homogenate and sera from patients with PANDAS (n = 8), selected from a larger group assayed for antibodies against a putamen synaptosomal preparation. The effect of antibodies against the streptococcal M5 protein were also studied. A total of 44 Fischer rats received bilateral infusion of sera: 23 ventral striatum (5 PANDAS, 5 TS, 5 anti-M5 protein, and 8 control); 21 ventrolateral striatum (5 PANDAS, 5 TS, 5 anti-M5 protein, and 6 controls). Cannulas were placed bilaterally and symmetrically by stereotactic techniques. After animals were allowed to recover for 1 week, sera were microinfused for 3 days. Animal behavior was then simultaneously quantified by daily observation and monitoring using automated activity boxes for 10 days after infusion. No significant alterations in stereotypic behavior or movement were observed between the PANDAS, TS, or anti-M5 protein and control groups. Our findings are in contrast to previous reports, and suggest the need for further investigations to determine the validity of the model and of autoimmune-mediated hypotheses for pediatric movement disorders.

Anti-basal ganglia antibodies in PANDAS.

An autoimmune-mediated mechanism involving molecular mimicry has been proposed for a variety of pediatric movement disorders that occur after a streptococcal infection. In this study, anti-basal ganglia antibodies (ABGA) were measured in 15 children with the diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and compared with those in 15 controls. ELISA and Western immunoblotting (WB) methods were used to detect ABGA against supernatant (S1), pellet (P2), and synaptosomal preparations from adult postmortem caudate, putamen, and globus pallidus. ELISA optical density values did not differ between PANDAS patients and controls across all preparations. Immunoblotting identified multiple bands in all subjects with no differences in the number of bands or their total density. Discriminant analysis, used to assess mean binding patterns, showed that PANDAS patients differed from controls only for the caudate S1 fraction (Wilks' lambda = 0.0236, P < 0.0002), with PANDAS-primarily tic subjects providing the greatest discrimination. Among the epitopes contributing to differences between PANDAS and control in the caudate S1 fraction, mean binding to the epitope at 183 kDa was the most different between groups. In conclusion, ELISA measurements do not differentiate between PANDAS and controls, suggesting a lack of major antibody changes in this disorder. Further immunoblot analyses using a caudate supernatant fraction are required to completely exclude the possibility of minor antibody repertoire differences in PANDAS subjects, especially in those who primarily have tics.

PANDAS: a commentary.

PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection. As defined, the criteria include prepubertal children with either a tic or obsessive-compulsive disorder in whom a Group A beta-hemolytic streptococcal infection (GABHS) triggers the abrupt onset or exacerbation of tics/obsessive-compulsive behaviors. Pathophysiologically, it is proposed that antibodies produced against GABHS cross-react with neuronal cells, in a process involving molecular mimicry. Although PANDAS has received widespread notoriety, the existence of this condition has been questioned. This commentary reviews clinical and laboratory issues pertinent to the diagnosis of this entity. We conclude that PANDAS is an intriguing hypothesis that requires further confirmation.

Antistreptococcal, neuronal, and nuclear antibodies in Tourette syndrome.

Previous studies have suggested associations between Tourette syndrome and attention-deficit-hyperactivity disorder and antistreptococcal antibodies and between Tourette syndrome and antinuclear antibodies. In this study, antistreptolysin O, antideoxyribonuclease B, antinuclear, and antineuronal antibodies were measured in 41 children with Tourette syndrome and 38 controls, selected without regard to history of streptococcal infection. Results revealed that mean antistreptococcal titers did not differ between diagnostic groups. In addition, multiple regression analysis was unable to predict antistreptococcal antibody titers according to age and diagnosis. The frequency of elevated antistreptolysin O titers, based on a cutoff of 1:240, was significantly higher (P = 0.04) in patients with attention-deficit-hyperactivity disorder (64%) than in the group without attention-deficit-hyperactivity disorder (34%) but not when dichotomized according to age-matched normal values. No analysis of antideoxyribonuclease B titers identified any differences between groups. Antinuclear antibody titers were at least 1:160 in three of 33 Tourette syndrome patients; only one subject manifested a homogeneous staining pattern. Multiple regression analyses were unable to predict antinuclear, antineuronal, or anti-HTB-10 antibody titers according to the combination of age, diagnosis, and antistreptococcal titer. We suggest that longitudinal rather than single-point-in-time laboratory measurements be evaluated before definitive conclusions are drawn on associations between the diagnosis of Tourette syndrome, attention-deficit-hyperactivity disorder, or obsessive-compulsive disorders and antistreptococcal or antinuclear antibody titers.

Anti-basal ganglia antibody abnormalities in Sydenham chorea.

Anti-basal ganglia antibodies (ABGA) were measured in nine children with Sydenham chorea (SC) and compared to nine controls. Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) methods were used to detect ABGA against supernatant (S1), pellet, and synaptosomal preparations from adult and pediatric postmortem caudate, putamen, and globus pallidus. ELISA optical density (OD) values were higher in SC patients than controls across all preparations, but did not reach a level of significance. Although WB identified multiple bands in all subjects, discriminant analysis showed that the mean binding patterns of SC patients were significantly different from control, most notably in the caudate S1 fraction (Wilks' lambda=0.011, p<0.0001). Numerous antigens contributed to differences between groups; the two most defining molecular masses were at 126 and 113 kDa. In contrast to WB with discriminant analysis, ELISA measurements did not significantly differentiate between the SC group and controls.