Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Utilization and Factors Precluding Receipt of Checkpoint Inhibitor Consolidation for Stage III NSCLC in a Large US Academic Health System.

OBJECTIVES: We sought to determine the proportion of patients with stage III non-small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications. MATERIALS AND METHODS: We retrospectively identified consecutive patients with unresectable stage III NSCLC treated with definitive cCRT between October 2017 and December 2021 within a large US academic health system. Patients either received consolidation ICIs (ICI group) or did not (no-ICI group). Baseline characteristics and overall survival (OS) of the groups were assessed. Factors predictive of ICI nonreceipt were evaluated using logistic regression. RESULTS: Of 333 patients who completed cCRT, 229 (69%) initiated consolidation ICIs; 104 (31%) did not. Reasons for ICI nonreceipt included progressive disease post-cCRT (N = 31, 9%), comorbidity or intercurrent illness (N = 25, 8%), cCRT toxicity (N = 23, 7%; 19/23 pneumonitis), and EGFR/ALK alteration (N = 14, 4%). The no-ICI group had worse performance status and a higher rate of baseline pulmonary comorbidity. Larger planning target volume was associated with post-cCRT progressive disease, and higher lung radiation dose with cCRT toxicity. Median OS was 16 months in the no-ICI group and 34.4 months in the ICI group. In the no-ICI group, OS was superior among those with EGFR/ALK alterations (median 44.5 months) and worst among those with progressive disease (median 5.9 months, P < 0.001). CONCLUSION: 31% of patients who completed cCRT for stage III NSCLC did not receive consolidation ICIs. Survival amongst these patients is poor, especially for those with progressive disease post-cCRT.

Toxicities and Deaths From Intercurrent Disease Following Contemporary Postoperative Radiotherapy in Resected Non-Small-Cell Lung Cancer.

INTRODUCTION: The role of postoperative radiotherapy (PORT) in patients with resected locally advanced non-small-cell lung cancer (NSCLC) remains controversial due to the radiation techniques used in randomized trials. We conducted a retrospective cohort study evaluating contemporary PORT techniques to evaluate the safety of PORT and risk of death from intercurrent disease . MATERIALS AND METHODS: We analyzed consecutive patients with NSCLC treated in a single center that underwent PORT for pN2 disease and/or positive margin, with 3-dimensional conformal radiotherapy (3DRT), intensity modulated radiotherapy , or proton RT (PRT), between 2008 and 2019. Clinical details were collected including intercurrent deaths, defined as death without cancer recurrence. Kaplan-Meier and Cox-Proportional Hazards Models were used. RESULTS: Of 119 patients, 21 (17.6%) received 3DRT, 47 (39.5%) intensity modulated radiotherapy, and 51 (42.9%) PRT. Median follow-up was 40 months (range 8-136) and median RT dose was 5040cGy. Most patients (65.5%) received sequential adjuvant chemoRT; 18.5% received concurrent chemoRT. The rate of grade 3 toxicities was 9.2%. There were 13 (10.9%) deaths from intercurrent diseases, including 6 from second primary cancers and 2 from cardiopulmonary diseases. There were 2 additional deaths from cardiopulmonary disease in patients with cancer progression at time of death. Mean, V5Gy, V30Gy heart doses and mean lung doses were significantly lower with PRT. Three-year OS and disease-free-survival were 70.1% and 49.9%. CONCLUSION: PORT using contemporary techniques was well tolerated with acceptable toxicity and low rates of intercurrent deaths. Proton therapy significantly reduced heart and lung doses, but radiotherapy modality was not associated with differences in intercurrent disease.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Use of Glucocorticoids in Patients With Cancer: Potential Benefits, Harms, and Practical Considerations for Clinical Practice.

PURPOSE: Glucocorticoids are commonly used in patients with cancer for symptom relief or as part of their anticancer treatment. Despite their frequent use, indications and dosing regimens are not exclusively evidence-based and can come with a multitude of adverse effects, some of which can be life-threatening. The objective of this review is to update our current state of knowledge on the use of glucocorticoids in adult patients with cancer. METHODS AND MATERIALS: A comprehensive literature review (1949-2022) was conducted using search terms "glucocorticoids," "corticosteroids," and "cancer." Information was organized by main concepts including indications, potential benefits, and prevention and management of common side effects of glucocorticoid therapy, in addition to appropriate dosing and taper regimens. RESULTS: Glucocorticoids can be highly effective in improving outcomes and quality of life in patients with cancer. Their uses include management of disease manifestations, symptoms, and complications of cancer treatment. The lowest effective dose should be used and treatment duration should be minimized as clinically feasible. Side effects can be minimized by careful monitoring, continued assessment of benefits versus harms, and preventative measures for expected side effects. CONCLUSIONS: This review provides general principles and practical recommendations on the use of glucocorticoids in patients with cancer. Further prospective studies on the outcomes of patients on glucocorticoids may help guide practice.

Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy.

INTRODUCTION: Cyclin-dependent-kinase 4/6(CDK4/6) inhibitors are widely used as a first-line systemic treatment for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer. Although many patients with metastatic breast cancer require palliative radiotherapy (RT), there are limited data on the safety of combining a CDK4/6 inhibitor with palliative RT. CASE REPORT: Presented is a case of acute high-grade radiation dermatitis with low-dose palliative RT following administration of palbociclib. A 49-year-old woman with newly diagnosed hormone receptor-positive invasive ductal carcinoma of the left breast presented with lytic bone lesions in the left femur and lumbar spine. The patient initiated treatment with goserelin, tamoxifen, and palbociclib. She underwent prophylactic surgical fixation of the left femur and received post-operative RT encompassing the entire surgical nail (30 Gy/10 fractions) and palliative RT to the lumbar spine for pain relief (20 Gy/5 fractions). During cycle 4, palbociclib was stopped 3 days prior to the start of RT to reduce the risk of toxicity risk. However, 16 days after starting RT, she developed painful erythematous papules and bullae with moist desquamation on the left groin and lumbar spine. MANAGEMENT & OUTCOME: Her symptoms were managed with topical Aquaphor-lidocaine, silver sulfadiazine, and aluminum acetate soaks. Dermatitis subsided to dry desquamation within 2 weeks. The patient denied late toxicity at 11 months follow-up. DISCUSSION: Larger retrospective or prospective studies are needed to further elucidate the safety of combined CDK4/6 inhibitors and RT. In the meantime, special precautions are warranted in patients receiving combined therapy.

Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma.

INTRODUCTION: Memantine is used for neurocognitive protection in patients undergoing cranial radiotherapy for central nervous system tumors and is reported to be well-tolerated. CASE REPORT: Presented is a case of memantine-induced altered mental status requiring an intensive care unit admission. An 18-year-old male with relapsed, progressive medulloblastoma presented with severe altered mental status shortly after the first fraction of palliative whole brain radiotherapy. At the time, the patient was on day five of memantine therapy, which had been prescribed to reduce neurocognitive toxicity risk. MANAGEMENT & OUTCOME: Memantine was withheld while dexamethasone, valproate, and morphine were continued for headache. Approximately 50 h after admission, the patient's confusion significantly improved. Evaluation of acute altered mental status was unrevealing, including but not limited to negative urinary toxicology screen and lack of disease progression on imaging. Whole brain radiotherapy was resumed after a two-day cessation and he was discharged home after four days with complete resolution of symptoms. DISCUSSION: Clinicians should be aware of and consider the risk of altered mental status with memantine, given the increased utilization and upcoming clinical trials in pediatric patients.

Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity-modulated radiation therapy for nonmetastatic head and neck cancers.

BACKGROUND: We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers. METHODS: We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used. RESULTS: Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53-0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41-0.88, p = 0.06). CONCLUSIONS: Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer.

INTRODUCTION: Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition. METHODS: We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging. RESULTS: Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8-40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months. CONCLUSIONS: The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer.

Hypofractionated radiotherapy and surgery compared to standard radiotherapy in early glottic cancer.

PURPOSE: Early-stage glottic laryngeal cancer is treated with surgery or radiotherapy (RT), but limited randomized data exists to support one modality over the other. This study evaluates survival differences in early glottic cancer patients treated with either surgery or RT. MATERIALS AND METHODS: 14,498 patients with early glottic cancer diagnosed from 2004 to 2015 and treated with surgery or RT were identified in the National Cancer Database. Kaplan-Meier method was used to analyze differences in overall survival (OS) by treatment (surgery vs. RT) and radiation dose fractionation. Cox regression modeling and propensity score-matched (PSM) analysis were performed. Adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI) were computed. RESULTS: Median follow-up and median OS for all patients were 49.5 and 118 months, respectively. The estimated 5-year OS for surgery and RT was 77.5% and 72.6%, respectively (P < 0.0001). On multivariate analysis, aHR (95% CI) for surgery compared to RT was 0.87 (0.81-0.94, P = 0.0004). Compared to RT regimen 63-67.5 Gray (Gy) in 28-30 fractions, worse survival was noted for RT regimen 66-70 Gy in 33-35 fractions (aHR 1.15, 95% CI 1.07-1.23, P = 0.0003). When compared with hypofractionated RT (63-67.5 Gy in 28-30 fractions), patients undergoing surgery no longer showed improved OS (aHR 0.94, 95% CI 0.86-1.02, P = 0.154). The finding was confirmed on PSM analysis (surgery aHR 0.95, 95% CI 0.87-1.05, P = 0.322). CONCLUSION: In early glottic tumors, patients treated with surgery demonstrated improved survival compared to RT, but when hypofractionation was considered, there were no significant differences in OS between patients undergoing surgery or RT.

The Impact of Locoregional Treatment on Survival in Patients With Metastatic Breast Cancer: A National Cancer Database Analysis.

BACKGROUND: Although systemic therapy is the standard treatment for metastatic breast cancer, the value of locoregional treatment (LRT) of the primary tumor and its impact on survival is controversial. This study evaluates survival outcomes in patients with metastatic breast cancer after receiving LRT (surgery and/or radiation therapy) of the primary tumor. MATERIALS AND METHODS: The National Cancer Database was used to identify 16,128 qualifying cases of metastatic breast cancer who received systemic therapy with or without LRT from 2004 to 2013. Treatment modality was divided into surgery (Sx), radiation therapy (RT), surgery followed by RT (Sx + RT), and no LRT. The median survival and 3-year actuarial survival rates (OS) were analyzed for each treatment group. On multivariate analyses, adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using Cox regression modeling to adjust for patient and clinicopathologic characteristics. RESULTS: Overall, the median follow-up was 28.3 months, and the median survival for all patients was 37.2 months. With 9761 deaths reported, the estimated 3-year OS was 51.3%. The Sx + RT group (n = 2166) had the highest 3-year OS of 69.4%, followed by the Sx group (n = 4293) with 57.6%, the no LRT group (n = 8955) with 44.3%, and the RT group (n = 714) with 41.5% (P < .0001). On multivariate analysis, compared with the no LRT group, a decreased HR was noted in patients receiving Sx (adjusted HR, 0.68; 95% CI, 0.65-0.71; P < .0001) and Sx + RT (adjusted HR, 0.46; 95% CI, 0.43-0.49; P < .0001). CONCLUSION: LRT, especially surgery followed by RT, in addition to systemic therapy, was associated with improved survival in patients with metastatic breast cancer.

Scholarly Impact of Student Participation in Radiation Oncology Research.

PURPOSE: To evaluate the rate of non-doctoral student authors publishing in an academic journal over time and to analyze the effects student authors have on the scholarly impact of corresponding authors (CAs) by comparing their respective H-index (Hi). METHODS AND MATERIALS: A database was created of authors who published articles in the International Journal of Radiation Oncology, Biology, Physics in 2006, 2010, and 2014 that included CA, degree, and student author designations. Corresponding authors' His were obtained from Scopus (scopus.com). Student authorship rates were compared between the sampled years. The data were divided into 2 groups: CAs publishing with student authors (SA) and those without (nSA). The CAs' median and mean His with standard deviation and a 95% confidence interval were compared between SA and nSA. RESULTS: A total of 1728 published articles were identified with 1477 unique CAs. The percentage of published articles with student authors increased from 44.4% in 2006, to 52.9% in 2010, to 55.9% in 2014 (P = .0003). In overall analysis, mean Hi was higher for SA as compared with nSA (24.3 vs 22.9), although this did not achieve statistical significance (P = .094). Mean Hi (standard deviation) in 2006, 2010, and 2014 was 27.9 (16.6), 23.6 (16.7), and 18.5 (14.6), respectively. Mean Hi was significantly higher for SA compared with nSA in the years 2006 (29.5 vs 26.6, P = .048) and 2010 (24.9 vs 21.9, P = .038) but not in 2014 (18.5 vs 18.4, P = .963). CONCLUSION: Student authorship rates in the International Journal of Radiation Oncology, Biology, Physics are increasing. The data suggest that student participation in research may benefit both corresponding and student authors. Creating and expanding research programs to integrate research into medical education may enhance students' experience and encourage interest in radiation oncology.

Impact of patient demographics, tumor characteristics, and treatment type on treatment delay throughout breast cancer care at a diverse academic medical center.

PURPOSE AND OBJECTIVE: The aim of this study was to examine the impact of patient demographics, tumor characteristics, and treatment type on time to treatment (TTT) in patients with breast cancer treated at a safety net medical center with a diverse patient population. PATIENTS AND METHODS: A total of 1,130 patients were diagnosed and treated for breast cancer between 2004 and 2014 at our institution. We retrospectively collected data on patient age at diagnosis, race/ethnicity, primary language spoken, marital status, insurance coverage, American Joint Committee on Cancer (AJCC) stage, hormone receptor status, and treatment dates. TTT was determined from the date of breast cancer biopsy to treatment start date. Nonparametric Mann-Whitney U-test (or Kruskal-Wallis test when appropriate) and multivariable quantile regression models were employed to assess for significant differences in TTT associated with each factor. RESULTS: Longer median TTT was noted for Black (P=0.002) and single (P=0.002) patients. AJCC stage IV patients had shorter TTT (27.5 days) compared to earlier AJCC patients (36, 35, 37, 37 days for stage 0, I, II, III, respectively), P=0.028. Age, primary language spoken, insurance coverage, and hormone receptor status had no significant impact on TTT. On multivariate analysis, race/ethnicity remained the only significant factor with Black reporting longer TTT, P=0.025. However, race was not a significant factor for time from first to second treatment. More Black patients were noted to be single (P<0.0001) and received chemotherapy as first treatment (P=0.008) compared to White, Hispanic, or other race/ethnicity patients. CONCLUSION: In this retrospective analysis, Black patients had longer TTT, were more likely to receive chemotherapy as first treatment, and have a single marital status. These patient factors will help identify vulnerable patients and guide further research to understand the barriers to care and the impact of treatment delays on outcomes.

Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury(1,2,3).

Traumatic brain injury (TBI) increases hippocampal neurogenesis, which may contribute to cognitive recovery after injury. However, it is unknown whether TBI-induced adult-born neurons mature normally and functionally integrate into the hippocampal network. We assessed the generation, morphology, and synaptic integration of new hippocampal neurons after a controlled cortical impact (CCI) injury model of TBI. To label TBI-induced newborn neurons, we used 2-month-old POMC-EGFP mice, which transiently and specifically express EGFP in immature hippocampal neurons, and doublecortin-CreER(T2) transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, to permanently pulse-label a cohort of adult-born hippocampal neurons. TBI increased the generation, outward migration, and dendritic complexity of neurons born during post-traumatic neurogenesis. Cells born after TBI had profound alterations in their dendritic structure, with increased dendritic branching proximal to the soma and widely splayed dendritic branches. These changes were apparent during early dendritic outgrowth and persisted as these cells matured. Whole-cell recordings from neurons generated during post-traumatic neurogenesis demonstrate that they are excitable and functionally integrate into the hippocampal circuit. However, despite their dramatic morphologic abnormalities, we found no differences in the rate of their electrophysiological maturation, or their overall degree of synaptic integration when compared to age-matched adult-born cells from sham mice. Our results suggest that cells born after TBI participate in information processing, and receive an apparently normal balance of excitatory and inhibitory inputs. However, TBI-induced changes in their anatomic localization and dendritic projection patterns could result in maladaptive network properties.

Prolonged nerve blockade delays the onset of neuropathic pain.

Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting ~1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.