Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes.

PURPOSE: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. EXPERIMENTAL DESIGN: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. RESULTS: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. CONCLUSIONS: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.

Fantastic Four: Age, Spinal Cord Stimulator Waveform, Pain Localization and History of Spine Surgery Influence the Odds of Successful Spinal Cord Stimulator Trial.

BACKGROUND: There is a dearth in our understanding of the factors that are predictive of successful spinal cord stimulator (SCS) trials and eventual conversion to permanent implants. Knowledge of these factors is important for appropriate patient selection and treatment optimization. OBJECTIVES: Although previous studies have explored factors predictive of trial success, few have examined the role of waveform in trial outcomes. This study sought to establish the relationship of neuraxial waveform and related measures to trial outcomes. STUDY DESIGN: This study used a retrospective chart review design. METHODS: Data were retrospectively collected on 174 patients undergoing SCS trials upon institutional review board approval of the study protocol. Indications for SCS were: complex regional pain syndrome, failed back surgery syndrome with radicular symptoms, peripheral neuropathy, and axial low back pain. Descriptive statistics and logistic regression analyses were used to assess the association of demographic and clinical variables with SCS trial outcomes. RESULTS: The study population comprised 56% women, had a median age of 55 (interquartile range [IQR], 44-64), and 32 of 174 (18%) patients failed SCS trials. Individuals with successful trials (>= 50% pain relief) were significantly younger and had a median age of 54 years (IQR, 42-60) compared to those who failed SCS trials (median age 66 years; IQR, 50-76; P = .005). Adjusting for age, gender, number of leads, pain category, and diagnoses: surgical history (odds ratio [OR] = 4.4; 95% confidence interval [CI], 1.3-15.8) and paresthesia-based tonic-stimulation (OR = 10.3; 95% CI, 1.7-62.0), but not burst or high frequency, were significantly associated with successful trials. Of note, the number of leads (whether dual or single), pain duration, characteristics, and category (nociceptive vs neuropathic) were not significant factors. An interaction between surgical spine history and lower extremity pain was significantly associated with a positive trial (P = .005). LIMITATIONS: This study was limited by its retrospective nature and focus on a patient population at a single major academic medical center. CONCLUSIONS: Paresthesia-based tonic stimulation, age, and surgical history have significant effects on SCS trials. Prospective and randomized controlled studies may provide deeper insights regarding impact on costs and overall outcomes.IRB Approval #: 2018P002216. KEY WORDS: Pain duration, pain location, spinal cord stimulator trial, stimulator waveform, surgical history.

Neuropathic Pain Medication Use Does Not Alter Outcomes of Spinal Cord Stimulation for Lower Extremity Pain.

INTRODUCTION: Spinal cord stimulation (SCS) for the treatment of lower extremity pain is believed to the result of increased activity in the descending inhibitory and decreased activity in the ascending excitatory tracts. Evidence suggests that the analgesia afforded by SCS may be altered using certain neuropathic pain medications that also modulate neurotransmitters in these sensory tracts. We hypothesize that neuropathic pain medications may alter the response to SCS therapy. METHODS: One hundred and fifteen subjects undergoing SCS therapy for lower extremity pain were retrospectively examined. The pharmacologic profile, including stable use of neuropathic and opioid medications, were recorded. Three separate logistic regression models examined the odds ratio of primary outcomes; a successful SCS trial, a 50% decrease in pain or a 50% reduction in opioid use one year after implant. RESULTS: Neither the use of opioids or neuropathic pain medications were associated with changes in the odds of a successful SCS trial or a 50% pain reduction. A higher dose of chronic opioids use prior to a trial was associated with greater odds of having a 50% reduction in opioid use following implant. OR 1.02, 95% CI 1.01-1.02, p-value < 0.01). CONCLUSIONS: The use of neuropathic pain medications did not change the odds of either a successful SCS trial, or of experiencing a 50% reduction in pain at one year. The association between higher opioid doses and greater odds of a 50% reduction in opioid use may be the reflective of SCS's ability to reduce opioid reliance in chronic pain patients.

Ultrasmall Superparamagnetic Iron Oxide Imaging Identifies Tissue and Nerve Inflammation in Pain Conditions.

Objective: Correlation between radiologic structural abnormalities and clinical symptoms in low back pain patients is poor. There is an unmet clinical need to image inflammation in pain conditions to aid diagnosis and guide treatment. Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, is clinically used to treat iron deficiency anemia and showed promise in imaging tissue inflammation in human. We explored whether ferumoxytol can be used to identify tissue and nerve inflammation in pain conditions in animals and humans. Methods: Complete Freud's adjuvant (CFA) or saline was injected into mice hind paws to establish an inflammatory pain model. Ferumoxytol (20 mg/kg) was injected intravenously. Magnetic resonance imaging (MRI) was performed prior to injection and 72 hours postinjection. The changes in the transverse relaxation time (T2) before and after ferumoxytol injection were compared between mice that received CFA vs saline injection. In the human study, we administered ferumoxytol (4 mg/kg) to a human subject with clinical symptoms of lumbar radiculopathy and compared the patient with a healthy subject. Results: Mice that received CFA exhibited tissue inflammation and pain behaviors. The changes in T2 before and after ferumoxytol injection were significantly higher in mice that received CFA vs saline (20.8 ± 3.6 vs 2.2 ± 2.5, P = 0.005). In the human study, ferumoxytol-enhanced MRI identified the nerve root corresponding to the patient's symptoms, but the nerve root was not impinged by structural abnormalities, suggesting the potential superiority of this approach over conventional structural imaging techniques. Conclusions: Ferumoxytol-enhanced MRI can identify tissue and nerve inflammation and may provide a promising diagnostic tool in assessing pain conditions in humans.

Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity.

Nanoparticles found in air pollutants can alter neurotransmitter profiles, increase neuroinflammation, and alter brain function. Therefore, the assay described here will aid in elucidating the role of microglia in neuroinflammation and neurodegenerative diseases. The use of microglia, resident immune cells of the brain, as a surrogate biosensor provides novel insight into how inflammatory responses mediate neuronal insults. Here, we utilize an immortalized murine microglial cell line, designated BV2, and describe a method for nanoparticle exposure using silver nanoparticles (AgNPs) as a standard. We describe how to expose microglia to nanoparticles, how to remove nanoparticles from supernatant, and how to use supernatant from activated microglia to determine toxicity, using hypothalamic cell survival as a measure. Following AgNP exposure, BV2 microglial activation was validated using a tumor necrosis factor alpha (TNF-α) enzyme linked immunosorbent assay (ELISA). The supernatant was filtered to remove the AgNP and to allow cytokines and other secreted factors to remain in the conditioned media. Hypothalamic cells were then exposed to supernatant from AgNP activated microglia and survival of neurons was determined using a resazurin-based fluorescent assay. This technique is useful for utilizing microglia as a surrogate biomarker of neuroinflammation and determining the effect of neuroinflammation on other cell types.

Epidural blood patch for postdural puncture positional vertigo.

STUDY DESIGN: Case report. OBJECTIVE: To report an unusual case of refractory positional vertigo without headache that developed after the placement of an epidural catheter for postoperative pain and that was treated with an epidural blood patch. SUMMARY OF THE BACKGROUND DATA: Although it is common practice to use epidural blood patch (EBP) to treat positional headache from postdural puncture (PDP), the literature is limited to one letter to the editor describing PDP positional vertigo treated with EBP. METHODS: Description of a clinical case. RESULTS: Here we present a case where the patient presented with the complaint of vertigo without headache and had a characteristic onset with upright position and marked relief when lying down. The patient received an EBP with complete resolution of her symptoms. CONCLUSIONS: This case illustrates patient can present with an isolated symptom such as dizziness without headache after PDP. The patient received an EBP with complete resolution of her symptom of postdural dizziness.

Perioperative immunosuppression in cancer patients.

Cancer patients commonly undergo surgical procedures. The perioperative period is characterized by immunosuppression and may predispose already immunosupressed cancer patients to tumor spread. Cancer patients typically show depression of both cellular and humoral immune functions. Possible mediating factors for immunosuppression during the perioperative period include anesthetic agents, opioids, surgery, blood transfusions, temperature changes, pain, and psychological stress. A surgically mediated decrease in natural killer (NK) cell activity has been implicated as the major contributing factor associated with an increase in metastasis. The decreased NK cell activity during the perioperative period is associated with increased risk of mortality and cancer. Commonly used anesthetic agents and opioids are known to inhibit NK cell activity. Despite the in vivo evidence of anesthetic- and analgesic-agent-mediated immunosupression, surgery by itself results in a three- to four-fold increase in retention of metastasis when compared to the groups in which anesthesia and analgesia were combined. The negative consequences associated with perioperative immunosuppression may be decreased by several strategies, including aggressive pain control, selection of specific anesthetic and analgesic agents, avoidance of unnecessary transfusions, and delay of elective surgeries until the patient's nutritional and immune status is optimized. Recognizing and neutralizing its mediating factors, perioperative immunosuppression in cancer patients may be reduced.

Complex regional pain syndrome type I after myocardial infarction treated with spinal cord stimulation.

OBJECTIVE: A rare case of Complex Regional Pain Syndrome (CRPS) type I after myocardial infarction (MI) and significant comorbid illness with few treatment options for pain control was successfully managed with the placement of a spinal cord stimulator (SCS). CASE REPORT: A 44-year-old man presented with left upper extremity burning pain after MI. His past medical history included insulin-dependent diabetes mellitus, oxygen-dependent idiopathic pulmonary fibrosis, and recent coronary revascularization surgery. His pain was presumed to be related to his MI and a clinical diagnosis of CRPS type I (or reflex sympathetic dystrophy) was made. Facing limited medical and less invasive options for his pain relief, he underwent a spinal cord stimulation trial with excellent response. He had more than 70% pain relief from the spinal cord stimulation at the last follow-up, 2 years later. CONCLUSION: CRPS type I after MI can be difficult to treat because of other comorbid illnesses. SCS can be a safe and effective mode of therapy for patients facing limited treatment options.