Frameless image-guided linear accelerator (LINAC) stereotactic radiosurgery for medically refractory trigeminal neuralgia: Clinical outcomes in 116 patients.

Background: Frameless image-guided radiosurgery (IGRS) is an effective and non-invasive method of treating patients who are unresponsive to medical management for trigeminal neuralgia (TN). This study evaluated the use of frameless IGRS to treat patients with medically refractory TN. Methods: We performed a retrospective review of records of 116 patients diagnosed with TN who underwent frameless IGRS using a linear accelerator (LINAC) over 10 years (March 2012-February 2023). All patients had failed medical management for TN. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. Each patient received a BNI score before frameless IGRS and following treatment. Failure was defined as a BNI score IV-V at the last follow-up and/or undergoing a salvage procedure following IGRS. Results: All patients had a BNI score of either IV or V before the frameless IGRS. The mean follow-up duration for all 116 patients following IGRS was 44.1 months. Most patients (81 [69.8%]) had not undergone surgery (microvascular decompression [MVD] or rhizotomy) or stereotactic radiosurgery (SRS) for TN before frameless IGRS. A total of 41 (35.3%) patients underwent a salvage procedure (MVD, rhizotomy, or an additional IGRS) following frameless IGRS. The mean duration between the initial frameless IGRS and salvage procedure was 20.1 months. At the last follow-up, a total of 110 (94.8%) patients had a BNI score of I-III. No complications were reported after the frameless IGRS. The BNI score at the last follow-up was lower compared to the initial BNI for patients regardless of prior intervention (P < 0.001). Patients who failed IGRS had a higher BNI score at the last follow-up compared to those who did not fail IGRS (2.8 vs. 2.5, P = 0.05). Patients with pain relief had a shorter follow-up compared to those with pain refractory to SRS (38.0 vs. 55.1, P = 0.005). Conclusion: In this large cohort of patients with medically refractory TN, frameless IGRS resulted in durable pain control in the majority of patients without any toxicity.

Impact of Reirradiation Utilizing Fractionated Stereotactic Radiotherapy for Recurrent Glioblastoma.

BACKGROUND: Patients with recurrent glioblastoma (GBM) have limited treatment options. This study determined whether patients with recurrent GBM treated with initial radiation/temozolomide (TMZ) and reirradiation using fractionated stereotactic radiotherapy (FSRT) had improved outcomes. MATERIALS AND METHODS: We identified 95 patients with recurrent GBM, 50 of whom underwent FSRT at recurrence and 45 who had systemic treatment only (control). The median total FSRT dose at the time of GBM recurrence was 30 Gy in five fractions of the gadolinium-enhanced tumor only. RESULTS: With a median follow-up of 18 months, the progression-free survival (PFS) and overall survival (OS) following initial GBM diagnosis were longer in the reirradiation group compared to the control group (13.5 vs. 7.5 months [p=0.001] and 24.6 vs. 12.6 months [p<0.001], respectively). For patients who underwent reirradiation, the median time interval between the end of the initial radiation and reirradiation was 15.2 months. The median OS after GBM recurrence was longer in the reirradiation group versus the control group (9.9 vs. 3.5 months [p<0.001]), with a one-year OS survival rate of 22%. The hazard ratio for death of patients in the reirradiation group was 0.31 [0.19-0.50]. The reirradiation group had a higher percentage of patients who received bevacizumab (BEV, 62.0% vs. 28.9%, p=0.002) and a lower percentage of patients whose TMZ was discontinued due to toxicity (8.0% vs. 28.9%, p=0.017) compared to the control group. CONCLUSIONS: Reirradiation utilizing FSRT was associated with improved PFS and OS after GBM recurrence compared to the control group who did not receive additional irradiation.

Impact of Distance From the Hospital and Patient Transfer on Pediatric Testicular Torsion Outcomes.

BACKGROUND: Testicular torsion is the most common pediatric emergency that requires prompt diagnosis and surgical treatment to prevent testicular loss. Distance from the hospital where the patient will be undergoing treatment for testicular torsion and transfer from an outside facility are factors that may impact whether a testis is salvageable. We sought to determine whether these factors play a role in pediatric testicular torsion outcomes.  Materials and Methods: We identified males aged 1-18 years with testicular torsion between January 1, 2015 and December 31, 2020. The patients' distance from our hospital and whether they were transferred from an outlying hospital were a particular focus.  Results: The number of miles from our hospital and transfer from an outlying hospital were not significantly different between boys who underwent an orchiectomy versus an orchiopexy (p=0.258 and p=0.574, respectively). The number of miles from our hospital was negatively correlated to age at surgery (rho=-0.22, p=0.01). Significantly (p<0.001) more transfers were seen in patients who lived far (>22.1 miles) from our hospital (32/69 (46%)) versus near our hospital (10/68 (15%)). For every mile boys lived from our hospital, there was no difference (adjusted odds ratio (OR)=0.98 (0.96, 1.00), p=0.10) in the likelihood of receiving an orchiectomy versus an orchiopexy when adjusting for age, symptom duration, and degrees of torsion. CONCLUSIONS: Our study determined that neither distance from our hospital nor transfer from an outlying hospital affected the orchiectomy rate. An expedited medical evaluation and surgery offer the best prognosis for salvaging the testes.

Sonography Findings Predict Testicular Viability in Pediatric Patients With Testicular Torsion.

BACKGROUND: Testicular torsion poses a pediatric surgical emergency that necessitates rapid diagnosis and surgery to prevent testicular loss. We sought to determine whether any particular findings on Doppler ultrasound (US) were predictive of testicular viability in pediatric patients with testicular torsion. MATERIALS AND METHODS: We identified males between ages one and 18 years who experienced testicular torsion over a six-year period (January 1, 2015-December 31, 2020). All patients were evaluated at our institution's emergency department by a pediatric urologist and underwent a Doppler scrotal US. RESULTS: Of the 140 patients with testicular torsion, 56 (40%) had a non-viable testis and underwent an orchiectomy, while 84 (60%) had a viable testis and orchiopexy. Testicular heterogeneity (47 [84%] vs 48 [57%], p = 0.001), epididymis heterogeneity (23 [41%] vs 21 [25%], p = 0.063), and scrotal wall thickening (25 [45%] vs 5 [6%], p < 0.001) were significantly associated with a non-viable testis. Epididymis heterogeneity (adj. odds ratio [OR] = 0.33 [0.13, 0.79], p = 0.013) and scrotal wall thickening (adj. OR = 0.08 [0.03, 0.24], p < 0.001) exhibited significantly lower odds for viability. Testicular heterogeneity and scrotal wall thickening were more likely to develop with a longer duration of symptoms (both p < 0.001). CONCLUSION: Our study determined that certain Doppler scrotal US findings, specifically, testicular and epididymal heterogeneity as well as a thickened scrotal wall, are associated with testicular demise in patients with testicular torsion. As testicular heterogeneity and scrotal wall thickening are more likely to arise with a longer symptom duration, an urgent diagnosis and prompt surgical intervention are imperative to avert testicular loss.

Surge in testicular torsion in pediatric patients during the COVID-19 pandemic.

BACKGROUND: Testicular torsion is a pediatric surgical emergency, and prompt diagnosis and treatment is imperative. During the COVID-19 pandemic, pediatric patients with symptoms of testicular torsion may be reluctant to seek medical care which increases the likelihood of delayed presentation and the need for an orchiectomy. This observational study sought to determine whether there was a higher number of testicular torsion cases during COVID-19. METHODS: As the first patient with COVID-19 was admitted to our facility on March 6, 2020, we identified male children ages 1-18 years with testicular torsion between March 1-December 31, 2020 (during COVID-19) compared to the same time period between 2015 and 2019 (prior to COVID-19). All patients were evaluated at our Institution's Emergency Department by a pediatric urologist. RESULTS: There were 38 cases of testicular torsion between March 1-December 31, 2020 compared to 15.8 cases on average during the same 10-month period between 2015 and 2019 (a total of 79 cases). There was a statistically significant increase in testicular torsion cases during the COVID-19 pandemic compared to equivalent time periods in 2015-2019 (38 vs. 15.8, p = 0.05). Patients with testicular torsion during the COVID-19 pandemic were younger, had a longer duration of symptoms, and had a higher number of orchiectomies (although not statistically significant). CONCLUSION: During the COVID-19 pandemic, an escalation in testicular torsion cases was observed. Timely assessment, diagnosis, and surgery are crucial to prevent testicular loss and potential infertility in the future. Further evaluation is needed to elucidate the surge in testicular torsion and possible mechanisms.

Thromboembolic events in metastatic testicular cancer treated with cisplatin-based chemotherapy.

BACKGROUND: Testicular germ cell tumor (TGCT) is the most curable solid tumor and most common cancer among men 18-39 years. While cisplatin-based chemotherapy has significantly lengthened the survival of patients with TGCT, it is associated with a high rate of thromboembolic events (TEE). AIM: To summarize our single-center experience highlighting patients who were diagnosed with TGCT and received platinum-based chemotherapy, with special attention to those patients who suffered a TEE. METHODS: A retrospective analysis of the medical records and imaging studies of 68 consecutive individuals who were diagnosed with TGCT and received platinum-based chemotherapy at our Institution in a metropolitan community between January 1, 2014 and December 31, 2019. RESULTS: A total of 19 (28%) patients experienced a TEE following orchiectomy which occurred during chemotherapy in 13 (68%) of these patients. Patients with a higher pathologic stage (stage III) were significantly (P = 0.023) more likely to experience a TEE compared to patients who had a lower stage. Additionally, patients who were treated with 3 cycles of bleomycine, etoposide, and cisplatin and 1 cycle of etoposide and cisplatin or 4 cycles of etoposide and cisplatin were significantly 5 (P = 0.02) times more likely to experience a TEE compared to patients who were treated with only 3 cycles of bleomycine, etoposide, and cisplatin. CONCLUSION: Due to numerous factors that predispose to a TEE such as large retroperitoneal disease, higher clinical stage, greater number of chemotherapy cycle, central venous catheter, cigarette smoking, and possible cannabis use, high-risk ambulatory patients with TGCT treated with cisplatin-based chemotherapy may benefit from prophylactic anticoagulation. Randomized studies to evaluate the safety and efficacy of prophylactic anticoagulants are warranted in this young patient population generally devoid of medical co-morbidities.

Protocol-driven prevention of perioperative hypothermia in the pediatric neurosurgical population.

OBJECTIVE: Perioperative hypothermia (PH) is a preventable, pathological, and iatrogenic state that has been shown to result in increased surgical blood loss, increased surgical site infections, increased hospital length of stay, and patient discomfort. Maintenance of normothermia is recommended by multiple surgical quality organizations; however, no group yet provides an ergonomic, evidence-based protocol to reduce PH for pediatric neurosurgery patients. The authors' aim was to evaluate the efficacy of a PH prevention protocol in the pediatric neurosurgery population. METHODS: A prospective, nonrandomized study of 120 pediatric neurosurgery patients was performed. Thirty-eight patients received targeted warming interventions throughout their perioperative phases of care (warming group-WG). The remaining 82 patients received no extra warming care during their perioperative period (control group-CG). Patients were well matched for age, sex, and preparation time intraoperatively. Hypothermia was defined as < 36°C. The primary outcome of the study was maintenance of normothermia preoperatively, intraoperatively, and postoperatively. RESULTS: WG patients were significantly warmer on arrival to the operating room (OR) and were 60% less likely to develop PH (p < 0.001). Preoperative forced air warmer use both reduced the risk of PH at time 0 intraoperatively and significantly reduced the risk of any PH intraoperatively (p < 0.001). All patients, regardless of group, experienced a drop in core temperature until a nadir occurred at 30 minutes intraoperatively for the WG and 45 minutes for the CG. At every time interval, from preoperatively to 120 minutes intraoperatively, CG patients were between 2 and 3 times more likely to experience PH (p < 0.001). All patients were warm on arrival to the postanesthesia care unit regardless of patient group. CONCLUSIONS: Preoperative forced air warmer use significantly increases the average intraoperative time 0 temperature, helping to prevent a fall into PH at the intraoperative nadir. Intraoperatively, a strictly and consistently applied warming protocol made intraoperative hypothermia significantly less likely as well as less severe when it did occur. Implementation of a warming protocol necessitated only limited resources and an OR culture change, and was well tolerated by OR staff.

Relationships of protein biomarkers of the urokinase plasminogen activator system with expression of their cognate genes in primary breast carcinomas.

BACKGROUND: uPA, its receptor uPAR, and inhibitors PAI-1 and PAI-2 play key roles in membrane remodeling/invasion and in predicting response to chemotherapy. We identified novel relationships of these biomarkers with ER/PR that indicate clinical utility for assessing breast carcinoma outcomes. METHODS: Retrospective studies were performed with de-identified results of (a) uPA, uPAR, and PAI-1; (b) estrogen (ER) and progestin receptor (PR); and (c) clinical outcomes. Relative expression of 22 000 genes from microarray of RNA from LCM-procured breast cancer cells was used with R Studio version 3.4.1. RESULTS: Primary ER/PR status was related to uPA, uPAR, or PAI-1 levels. ER- or PR- cancers expressed elevated uPA, uPAR, and PAI2 mRNA compared to ER+ or PR+ cells. Inverse relationships between ER/PR protein and expression of uPA, uPAR, and PAI-2 were observed, whereas HER2 status was unrelated. qPCR analyses showed RERG and NQO-1 expressions were elevated in uPA- lesions, while CD34 and EDG-1 were elevated in uPAR- cancers. ERBB4 was overexpressed in PAI-1+ carcinomas. Cox regression analyses revealed relationships of ER/PR status and uPA system members with regard to clinical outcomes of breast cancer. CONCLUSIONS: uPA, uPAR, PAI1, or PAI2 expression was increased in either ER- or PR- cancers similar to that of protein content in ER-/PR- carcinomas, suggesting sex hormones regulate the uPA system in breast cancer. Results revealed protein content of uPA system members was related to ER/PR status of primary lesions. Use of LCM-procured carcinoma cells uncovered relationships between expression of known cancer-associated genes and protein content of uPA system members. Collectively, results indicate evaluation of ER and PR protein of primary breast cancers combined with analyses of uPA, uPAR, and PAI-1 protein content improves assessment of clinical outcomes.

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC.

Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR. IMPLICATIONS: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFR-driven NSCLC.

Expression of Genes for Methylxanthine Pathway-Associated Enzymes Accompanied by Sex Steroid Receptor Status Impacts Breast Carcinoma Progression.

Consumption of methylxanthine alkaloids appears to induce activities by antagonizing adenosine receptors, implicated in breast cancer behavior in vitro. Our goal was to evaluate expression of genes for methylxanthine receptors and metabolizing enzymes to assess risk of breast carcinoma recurrence. Clinical outcomes, estrogen/progestin receptor results, and gene expression assays guided selection. RNA was isolated from laser capture microdissection-procured carcinoma cells for microarray using established protocols. Gene expression levels of eight methylxanthine receptors, eight metabolizing enzymes, and various phosphodiesterases were retrieved from microarray results. Univariable Cox regressions and Kaplan-Meier plots were determined for each gene with R software. Individually, lower expressions of PDE4A, CYP2A6, or CYP2E were related to decreased progression-free survival (PFS) and overall survival (OS). PDE1A over-expression predicted decreased PFS and OS. ADORA2B and RYR1 over-expressions predicted diminished OS. ER+ cancers exhibited lower ADORA1, ADORA2B, and RYR1 and elevated PDE4A, CYP2A6, and CYP2E expressions. Of PR+ carcinomas, diminished ADORA2B and RYR1 and elevated expressions of ADORA3, PDE4A, CYP2C8, and CYP2E were noted. Least absolute shrinkage and selection operator (LASSO) revealed that CYP2E, PDE1A, and PDE4A expressions collectively predicted PFS whereas ADORA1, CYP2E, PDE1A, PDE1B, and PDE4A expressions jointly predicted OS. Models were clinically significant when validated externally. LASSO also derived a six-gene model and five-gene model that predicted PFS of ER- or PR- carcinomas, respectively. Similarly, five-gene and four-gene models predicted OS in ER- or PR- carcinomas, respectively. Collectively, expression of genes involved in methylxanthine action and metabolism in single-cell types predicted clinical outcomes of breast carcinoma indicating promise for developing diagnostics and design of new therapeutics.

Clinical outcomes linked to expression of gene subsets for protein hormones and their cognate receptors from LCM-procured breast carcinoma cells.

PURPOSE: Certain peptide hormones and/or their cognate receptors influencing normal cellular pathways also have been detected in breast cancers. The hypothesis is that gene subsets of these regulatory molecules predict risk of breast carcinoma recurrence in patients with primary disease. METHODS: Gene expression levels of 61 hormones and 81 receptors were determined by microarray with LCM-procured carcinoma cells of 247 de-identified biopsies. Univariable and multivariable Cox regressions were determined using expression levels of each hormone/receptor gene, individually or as a pair. RESULTS: Molecular signatures for ER+/PR+, ER-/PR-, and ER- carcinoma cells deciphered by LASSO were externally validated at HRs (CI) of 2.8 (1.84-4.4), 1.53 (1.01-2.3), and 1.72 (1.15-2.56), respectively. Using LCM-procured breast carcinoma cells, a 16-gene molecular signature was derived for ER+/PR+ biopsies, whereas a 10-gene signature was deciphered for ER-/PR- cancers. Four genes, POMC, CALCR, AVPR1A, and GH1, of this 10-gene signature were identified in a 6-gene molecular signature for ER- specimens. CONCLUSIONS: Applying these signatures, Kaplan-Meier plots definitively identified a cohort of patients with either ER-/PR- or ER- carcinomas that exhibited low risk of recurrence. In contrast, the ER+/PR+ signature identified a cohort of patients with high risk of breast cancer recurrence. Each of the three molecular signatures predicted clinical outcomes of breast cancer patients with greater accuracy than observed with either single-gene analysis or by ER/PR protein content alone. Collectively, our results suggest that gene expression profiles of breast carcinomas with suspected poor prognosis (ER-/PR-) have identified a subset of patients with decreased risk of recurrence.