Robotic assisted surgery for the treatment of spinal metastases: A case series.

OBJECTIVE: Spinal metastases can significantly affect quality of life in patients with cancer and present complex neurosurgical challenges for surgeons. Surgery with instrumentation is often indicated to alleviate pain, preserve neurological function, and ensure mechanical stability. However, distortions in the bony anatomy due to oncological disease can decrease the accuracy of pedicle screw placement. Robotic-assisted surgery may offer an opportunity to increase screw accuracy and improve navigation of spinal lesions compared to conventional techniques. Therefore, we presented our institutional experience evaluating robotic-assisted surgical fixation for spinal metastases. METHODS: Patients undergoing robotic-assisted surgery at a large tertiary care center between January 2019 - January 2023 for the treatment of spinal metastases were identified. Patient characteristics, including demographics, tumor pathology, surgical complications, and post-operative outcomes were extracted. The Gertzbein Robbins classification system (GRS) was used to assess pedicle screw placement accuracy in patients with post-operative computed tomography. RESULTS: Twenty patients were identified, including 7 females (35 %), with an overall median age of 66 years (range: 39-80 years) and median BMI of 25 kg/m2 (range: 17-34 kg/m2). An average of four spinal levels were instrumented, with metastases located primarily in the thoracic (n=17, 85 %) spine. Common primary tumor types included prostate (n=4), lung (n=2), and plasma cell (n=2) cancers. Most pedicle screws (92 %) were classified as GRS A in patients with postoperative imaging. Post-operative complications were unrelated to the use of the robot, and included pulmonary embolism (n=1), deep vein thrombosis (n=2), and gastric symptoms (n=3). Three patients were readmitted at 30 days, with one reoperation due to tumor recurrence. Four patients were deceased within 6 months of surgery. CONCLUSIONS: Despite the inherent high-risk nature of these surgeries, this study underscores the safety and efficacy of robotic-assisted surgery in the management of spinal metastases. Robots can be helpful in ensuring accuracy of pedicle screw placement in patients with metastatic disease.

Advances in Implant Technologies for Spine Surgery.

Spine implants are becoming increasingly diversified. Taking inspiration from other industries, three-dimensional modeling of the spinal column has helped meet the custom needs of individual patients as both en bloc replacements and pedicle screw designs. Intraoperative tailoring of devices, a common need in the operating room, has led to expandable versions of cages and interbody spacers.

Early versus late surgical decompression for patients with acute traumatic central cord syndrome: a systematic review and meta-analysis.

BACKGROUND CONTEXT: The optimal decompression time for patients presenting with acute traumatic central cord syndrome (ATCCS) has been debated, and a high level of evidence is lacking. PURPOSE: To compare early (<24 hours) versus late (≥24 hours) surgical decompression for ATCCS. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Medline, PubMed, Embase, and CENTRAL were searched from inception to March 15th, 2023. The primary outcome was American Spinal Injury Association (ASIA) motor score. Secondary outcomes were venous thromboembolism (VTE), total complications, overall mortality, hospital length of stay (LOS), and ICU LOS. The GRADE approach determined certainty in evidence. RESULTS: The nine studies included reported on 5,619 patients, of whom 2,099 (37.35%) underwent early decompression and 3520 (62.65%) underwent late decompression. The mean age (53.3 vs 56.2 years, p=.505) and admission ASIA motor score (mean difference [MD]=-0.31 [-3.61, 2.98], p=.85) were similar between the early and late decompression groups. At 6-month follow-up, the two groups were similar in ASIA motor score (MD= -3.30 [-8.24, 1.65], p=.19). However, at 1-year follow-up, the early decompression group had a higher ASIA motor score than the late decompression group in total (MD=4.89 [2.89, 6.88], p<.001, evidence: moderate), upper extremities (MD=2.59 [0.82, 4.36], p=.004) and lower extremities (MD=1.08 [0.34, 1.83], p=.004). Early decompression was also associated with lower VTE (odds ratio [OR]=0.41 [0.26, 0.65], p=.001, evidence: moderate), total complications (OR=0.53 [0.42, 0.67], p<.001, evidence: moderate), and hospital LOS (MD=-2.94 days [-3.83, -2.04], p<.001, evidence: moderate). Finally, ICU LOS (MD=-0.69 days [-1.65, 0.28], p=.16, evidence: very low) and overall mortality (OR=1.35 [0.93, 1.94], p=.11, evidence: moderate) were similar between the two groups. CONCLUSIONS: The meta-analysis of these studies demonstrated that early decompression was beneficial in terms of ASIA motor score, VTE, complications, and hospital LOS. Furthermore, early decompression did not increase mortality odds. Although treatment decision-making has been individualized, early decompression should be considered for patients presenting with ATCCS, provided that the surgeon deems it appropriate.

Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial.

PURPOSE: To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 µm and <125 µm] or ≥1 large drusen [≥125 µm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. INTERVENTION: Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. MAIN OUTCOME MEASURES: Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). RESULTS: Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio = 0.91 [95% confidence interval (CI), 0.32-2.59]; P = 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was -2.1 letters (standard deviation, 5.4 letters) with ranibizumab and -1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference = -0.8 letters [95% CI, -3.7 to 2.2 letters]; P = 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. CONCLUSIONS: Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

Novel MIS 3D NAV Single Step Pedicle Screw System (SSPSS): Workflow, Accuracy and Initial Clinical Experience.

STUDY DESIGN: Prospective case series. OBJECTIVE: SSPSS (single step pedicle screw system) was developed for minimally invasive spine surgery. We performed this study to report on safety, workflow, and our initial clinical experience with this novel technique. METHODS: The prospective study was conducted on patients who underwent pedicle screw fixation between October 2017 and April 2018 using a novel single step 3D navigated pedicle screw system for MIS. Outcome measurements were obtained from intraoperative computerized tomography. The images were evaluated to determine pedicle wall penetration. We used a grading system to assess the severity of the pedicle wall penetration. Breaches were classified as grade 1 (<2 mm), grade 2 (2-4 mm), or grade 3 (<4 mm),1 and as cranial, caudal, medial, and lateral. RESULTS: Our study includes 135 screws in 24 patients. SSPSS eliminated K-wires and multiple steps traditionally necessary for MIS pedicle screw insertion. The median time per screw was 2.45 minutes. 3 screws were corrected intraoperatively. Pedicle wall penetration occurred in 14 screws (10%). Grade 1 breaches occurred in 4 screws (3%) and grade 2 breaches occurred in 10 screws (7%). Lateral breaches were observed more often than medial breaches. The accuracy rate in our study was 90% (Grade 0 breach). No revision surgeries were needed and no complications occurred. CONCLUSIONS: Our study suggests that SSPSS could be a safe, accurate, and efficient tool. Our accuracy rate is comparable to that found in the literature.

Timing of Peak Vision Gains in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab.

PURPOSE: To investigate whether time to peak best-corrected visual acuity (BCVA) was predictive of magnitude of BCVA changes at study end in patients with neovascular age-related macular degeneration (nAMD) who received ranibizumab and assess whether patient baseline characteristics and on-study events were predictive of time to peak BCVA. DESIGN: Exploratory analysis of data from HARBOR (ClinicalTrials.gov identifier, NCT00891735). PARTICIPANTS: Treatment-naïve patients 50 years of age or older with subfoveal nAMD. METHODS: Data by ranibizumab dose were pooled; data by dosing schedule (pro re nata [PRN] and monthly) were evaluated separately. Time to peak BCVA was the monthly evaluation at which the patient's greatest gain in Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline was achieved. Early peakers achieved peak BCVA between day 7 and month 6; late peakers achieved peak BCVA between months 7 and 12, months 13 and 18, and months 19 and 24. Variables evaluated for effect of time to peak BCVA included baseline demographic and clinical characteristics, presence of persistent subretinal fluid (SRF) or intraretinal fluid (IRF), and on-study events (atrophy status, fibrosis, retinal pigment epithelium tears). MAIN OUTCOME MEASURES: Time to peak BCVA and its predictive value for magnitude of BCVA changes and BCVA at month 24 (study end). RESULTS: Most patients reached peak BCVA after more than 6 months of treatment: 64% in the PRN group (301/474) and 70% in the monthly groups (327/469). Thirty-six percent and 30% of patients, respectively, peaked early, and 64% and 70%, respectively, peaked late. At month 24, early peakers on average lost vision (PRN, -1.6 ETDRS letters; monthly, -1.9 ETDRS letters). By contrast, late peakers achieved significantly better vision gains from baseline (PRN, 8.5-17.7 ETDRS letters; monthly, 10.1-18.7 ETDRS letters). No differences were found in patient characteristics, persistent SRF or IRF, or on-study events to account for the observed different outcomes between early and late peakers. CONCLUSIONS: In most treatment-naïve patients with nAMD, vision gains were achieved at a slower rate (>6 months), and a slower response was associated with better vision outcomes after 24 months of ranibizumab. These findings suggest that continued treatment may result in greater vision improvements when consistent anti-vascular endothelial growth factor therapy is maintained over a longer period.

The Value of Prior Response to Anti-Vascular Endothelial Growth Factor for Age-Related Macular Degeneration: A HARBOR Subanalysis.

PURPOSE: To evaluate disease activity-free intervals of patients with neovascular age-related macular degeneration (nAMD) in the pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) to determine whether duration of response to previous treatment with ranibizumab informs future disease activity and need for subsequent injections. DESIGN: Retrospective subgroup analysis of the phase 3 HARBOR study (clinicaltrials.gov identifier, NCT00891735). PARTICIPANTS: Patients from the ranibizumab 0.5 mg pro re nata arm of the phase 3 HARBOR clinical trial who received all 3 loading injections and missed no more than 1 study visit (N = 217). METHODS: A disease activity-free interval was defined as a consecutive period in months when treatment was not required because the patient did not meet protocol retreatment criteria. Percentage of disease activity-free eyes at the next 1 and 2 months after a first disease activity-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was evaluated. Additionally, duration that eyes remained untreated after disease activity-free intervals was evaluated by Kaplan-Meier estimates. MAIN OUTCOME MEASURES: Key outcome measures included duration of the first treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months achieved by each patient; mean number of additional months patients remained treatment free after a treatment-free interval; and percentage of eyes requiring treatment within 2 months after each treatment-free interval. RESULTS: Percentage of eyes requiring retreatment the month after a treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was 60% (90/151), 33% (33/100), 26% (20/77), 36% (24/66), and 19% (9/48), respectively. Percentage of eyes requiring retreatment within 2 months after a treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was 73% (109/149), 53% (53/100), 53% (40/75), 47% (30/64), and 43% (20/46), respectively. After treatment-free intervals of ≥2, ≥3, ≥4, ≥5, and ≥6 months, mean (standard error of the mean) additional time treatment free was 1.3 months (0.17 month), 2.4 months (0.33 month), 2.9 months (0.44 month), 3.2 months (0.50 month), and 4.0 months (0.60 month), respectively. CONCLUSIONS: Longer treatment-free intervals may indicate longer future disease-free intervals; however, this association varies. Thus, although longer intervals suggest greater likelihood of not needing retreatment within 1 to 2 months, regular assessment is warranted owing to the unpredictability of nAMD disease activity.

Treat and extend regimen with aflibercept for chronic central retinal vein occlusions: 2 year results of the NEWTON study.

BACKGROUND: To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY) could continue to extend the macular edema free interval in patients on a treat and extend (TAE) with non-ischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) in the second year. METHODS: Twenty patients with macular edema secondary to non-ischemic CRVOs previously treated with ranibizumab or bevacizumab were prospectively treated with intravitreal aflibercept injection (IAI) using a TAE dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. In the second year of the study, patients who have recurrences of macular edema could be re-challenged with a longer treatment interval under the following criterion: absence of any macular edema on three consecutive visits with the same treatment interval. RESULTS: Twenty patients had an average duration of a CRVO for 22 months (range 7-90) and averaged an anti-VEGF treatment every 42 days (range 28-60 days). The macular edema free interval increased from 38 to 75 days when switched to aflibercept (p = 0.000003) at month 24. There was an average increase of 37 days (median 34 days; range 0-91 days) in the macular edema free interval with aflibercept. At the month 24 visit, 50% (8/16) went > 12 weeks with a macular edema free interval between IAI. There was an improvement in vision (+ 8 ETDRS letters, p = 0.006) and decreased retinal thickness (158 µm, p = 0.00003) with aflibercept treatment at month 24. CONCLUSIONS: The 2-year results of the NEWTON study demonstrated the sustained benefits of a TAE dosing regimen with aflibercept in patients with chronic CRVOs. The visual acuity gains and anatomic improvements observed at year one were maintained through month 24 with less visits and treatments. This may help minimize the treatment burden in patients with recurrent macular edema secondary to non-ischemic CRVO.Trial Registration ClinicalTrials.gov, NCT01870427, Registered June 6, 2013, https://clinicaltrials.gov/ct2/show/NCT01870427?cond=NEWTON&rank=1.Presented at the RETICON 2017: The Retina Congress with Live Surgery, Chennai, India-April 2017.

Aflibercept for Previously Treated Macular Edema Associated with Central Retinal Vein Occlusions: 1-Year Results of the NEWTON Study.

PURPOSE: To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY) can extend the macular edema-free interval in patients with nonischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech, South San Francisco, CA). DESIGN: Prospective, single-arm, interventional study. PARTICIPANTS: Twenty patients with chronic nonischemic CRVOs. METHODS: Patients with nonischemic CRVOs previously treated with ranibizumab or bevacizumab were switched to aflibercept. The inclusion criteria included treatment for ≥6 months with ≥3 initial loading doses and evidence of recurrence of edema when treatment with either ranibizumab or bevacizumab extended beyond 4 weeks. Intravitreal aflibercept was administered with a treat-and-extend dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. MAIN OUTCOME MEASURES: Macular edema-free interval at week 52. RESULTS: Twenty patients had an average duration of a CRVO for 22 months (range, 7-90 months) and averaged an anti-vascular endothelial growth factor (anti-VEGF) treatment every 42 days (range, 28-60 days). These patients received a mean of 15 treatments (range, 5-47 treatments) of ranibizumab or bevacizumab for macular edema secondary to nonischemic CRVO. Among the 17 patients who completed 1 year of follow-up, 94% had a greater macular edema-free interval with aflibercept treatment. The macular edema-free interval increased from 5.4 weeks to 9.1 weeks when treatment was switched to aflibercept (P = 0.000003). There was an average increase of 26 days (range, 0-63 days) in the macular edema free interval with aflibercept. There was an improvement in vision (+6 Early Treatment Diabetic Retinopathy Study letters, P = 0.02) and decreased retinal thickness (152 µm, P = 0.0002) with aflibercept treatment. CONCLUSIONS: In patients previously treated with ranibizumab or bevacizumab for macular edema due to nonischemic CRVO, aflibercept increased the macular edema free interval. This may help minimize the treatment burden in patients with recurrent macular edema secondary to nonischemic CRVO.

Incidence of Presumed Silicone Oil Droplets in the Vitreous Cavity After Intravitreal Bevacizumab Injection With Insulin Syringes.

Importance: Intravitreal bevacizumab is a frequently used antivascular endothelial growth factor medication in the United States, but its off-label use is associated with risks associated with the compounding preparation. Objective: To determine the incidence of presumed silicone oil droplets after intravitreal bevacizumab was prepared in insulin syringes by a compounding pharmacy. Design, Setting, and Participants: A retrospective review was conducted of 60 patients who experienced intravitreal silicone oil droplets in the eye after intravitreal bevacizumab injections from a single specialist practice from October 1, 2015, to November 30, 2016. Bevacizumab, 1.25 mg/0.05 mL, was delivered in insulin syringes with a 31-gauge needle. Main Outcomes and Measures: Small, round clear spheres in vitreous on dilated biomicroscopic retinal examination. Results: Over a 14-month period involving 6632 intravitreal bevacizumab injections, 60 cases (35 [58%] women) of intravitreal silicone droplets were identified. Mean [SD] age of the patients was 80 [12] years; the population comprised 48 white, 9 Asian, and 3 Hispanic patients. The incidence of silicone oil droplet injections was 0.03% (1 of 3230) from October 2015 to April 2016 and 1.7% (59 of 3402) from May to November 2016 (Fisher exact test, P < .001; odds ratio [OR], 57; 95% CI, 9.8-2260). From May to November 2016, nonpriming the syringe before the intravitreal injection had a higher risk of intravitreal silicone oil droplets compared with priming the syringe (6.4% [47 of 739] vs 0.5% [12 of 2627]; Fisher exact test, P < .001; OR, 15.1; 95% CI, 7.9-33.4). Among the 60 cases, 41 patients (68%) were symptomatic, and the main symptom was floaters with spots of light. Among the patients with floaters, 36 (88%) improved over time (range, 2-8 months) despite the silicone droplets still being present on ophthalmoscopic examination. Conclusions and Relevance: An increase in intravitreal silicone oil associated with bevacizumab prepared with insulin syringes was documented. Priming the syringe before injection was associated with a lower frequency of this complication. These findings suggest that physicians should counsel their patients on the risk of floaters with intravitreal bevacizumab preloaded in insulin syringes.

PROSPECTIVE EVALUATION OF A SUSTAINED-RELEASE DEXAMETHASONE INTRAVITREAL IMPLANT FOR CYSTOID MACULAR EDEMA IN QUIESCENT UVEITIS.

PURPOSE: To investigate dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc) in the treatment of uveitic cystoid macular edema that had persisted in the absence of intraocular inflammation. METHODS: In this prospective interventional case series, 10 patients with uveitic cystoid macular edema and quiescent uveitis were treated with dexamethasone intravitreal implant at baseline and evaluated monthly for one year. Patients were retreated whenever cystoid macular edema recurred. The primary outcome measure was best-corrected visual acuity (BCVA) at day 90. RESULTS: At day 90, mean improvement from baseline BCVA was 14.4 letters (P = 0.0003), 70% of patients had a ≥10 letter BCVA improvement, 50% of patients had a ≥15 letter BCVA improvement, and the mean decrease from baseline central subfield retinal thickness was 140 µm (P = 0.008). Improvements were maintained through day 360 with retreatment as needed. At day 360, mean improvement in BCVA was 16.5 letters (P = 0.006) and the mean decrease in central subfield retinal thickness was 158 µm (P = 0.002). One patient experienced intraocular pressure >25 mmHg (managed with topical medication). Two phakic patients (2/8; 25%) had worsening of lens opacity requiring cataract extraction. CONCLUSION: Dexamethasone intravitreal implant may be an effective treatment for patients with persistent cystoid macular edema in quiescent uveitis.

TCDD promotes lung tumors via attenuation of apoptosis through activation of the Akt and ERK1/2 signaling pathways.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multiple-site, multiple-species carcinogen that induces cancer in multiple organs. The molecular mechanisms underlying TCDD-induced lung tumorigenesis remain unclear. In the present study, a two-stage lung tumorigenesis model was established by administrating a single low dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) combined with TCDD to female A/J mice. The results indicated that TCDD combined with low-dose NNK has a significant tumor-promoting effect compared with TCDD or low-dose NNK alone. Resistance to apoptosis is a hallmark of cancer and is thought to be one of the tumor-promoting mechanisms regulated by TCDD. We performed an additional series of experiments in the normal human bronchial epithelial cell line Beas2B cells, in which TCDD was combined with the apoptosis inducer staurosporine. Our in vitro results confirmed that TCDD could rescue cells from apoptosis induced by staurosporine. The inhibition of apoptosis is likely mediated by the activation of the Akt and ERK1/2 pathways, as determined by the effectiveness of pathway-specific inhibitors in abrogating the anti-apoptotic activity of TCDD. In conclusion, we demonstrated that TCDD promoted NNK-induced lung tumorigenesis and revealed that TCDD inhibits staurosporine-induced apoptosis, at least in part, through the Akt and ERK1/2 signaling pathways.

The regulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor promotion by estradiol in female A/J mice.

Epidemiological studies indicate that women are at a higher risk developing lung cancer than men are. It is suggested that estrogen is one of the most important factors in lung cancer development in females. Additionally, cigarette smoke, and environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play salient roles in female lung carcinogenesis. However, the mechanisms responsible for the interaction of these factors in the promotion of lung cancer are still poorly understood. The present study was designed to explore two ideas: first, the synergistic lung tumorigenic effects of 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNK) combined with TCDD, 17ß-estradiol (E2) or both through a long-term treatment experiment, and second, to identify early changes in the inflammatory and signaling pathways through short-term treatment experiments. The results indicate that A/J mice given E2 had strong effects in potentiating NNK-induced activation of MAPK signaling, NFκB, and COX-2 expression. In the long-term exposure model, E2 had a strong tumor promoting effect, whereas TCDD antagonized this effect in A/J mice. We conclude that treatment with NNK combined with either E2 or TCDD induces lung carcinogenesis and the promotion effects could be correlated with lung inflammation. E2 was shown to potentiate NNK-induced inflammation, cell proliferation, thereby leading to lung tumorigenesis.

Predictors of outcome in civilian gunshot wounds to the head.

OBJECT: Civilian gunshot wounds to the head (GSWH) are often deadly, but some patients with open cranial wounds need medical and surgical management and are potentially good candidates for acceptable functional recovery. The authors analyzed predictors of favorable clinical outcome (Glasgow Outcome Scale scores of 4 and 5) after GSWH over a 24-month period. METHODS: The authors posited 2 questions: First, what percentage of civilians with GSWH died in the state of Maryland in a given period of time? Second, what were the predictors of favorable outcome after GSWH? The authors examined demographic, clinical, imaging, and acute care data for 786 civilians who sustained GSWH. Univariate and logistic regression analyses were used to analyze the data. RESULTS: Of the 786 patients in this series, 712 (91%) died and 74 (9%) completed acute care in 9 trauma centers. Of the 69 patients admitted to one Maryland center, 46 (67%) eventually died. In 48 patients who were resuscitated, the Injury Severity Score was 26.2, Glasgow Coma Scale (GCS) score was 7.8, and an abnormal pupillary response (APR) to light was present in 41% of patients. Computed tomography indicated midline shift in 17%, obliteration of basal cisterns in 41.3%, intracranial hematomas in 34.8%, and intraventricular hemorrhage in 49% of cases. When analyzed for trajectory, 57.5% of bullet slugs crossed midcoronal, midsagittal, or both planes. Two subsets of admissions were studied: 27 patients (65%) who had poor outcome (25 patients who died and 2 who had severe disability) and 15 patients (35%) who had a favorable outcome when followed for a mean period of 40.6 months. Six patients were lost to follow-up. Univariate analysis indicated that admission GCS score (p < 0.001), missile trajectory (p < 0.001), surgery (p < 0.001), APR to light (p = 0.002), patency of basal cisterns (p = 0.01), age (p = 0.01), and intraventricular bleed (p = 0.03) had a significant relationship to outcome. Multivariable logistic regression analysis indicated that GCS score and patency of the basal cistern were significant determinants of outcome. Exclusion of GCS score from the regression models indicated missile trajectory and APR to light were significant in determining outcome. CONCLUSIONS: Admission GCS score, trajectory of the missile track, APR to light, and patency of basal cisterns were significant determinants of outcome in civilian GSWH.

Electronic microscopy evidence for mitochondria as targets for Cd/Se/Te-based quantum dot 705 toxicity in vivo.

The safety of quantum dots (QDs) 705 was evaluated in this study. Mice were treated with QD705 (intravenous) at a single dose of (40 pmol) for 4, 12, 16, and 24 weeks. Effects of QD705 on kidneys were examined. While there was a lack of histopathology, reduction in renal functions was detected at 16 weeks. Electron microscopic examination revealed alterations in proximal convoluted tubule (PCT) cell mitochondria at even much earlier time, including disorientation and reduction of mitochondrial number (early change), mitochondrial swelling, and later compensatory mitochondrial hypertrophy (enlargement mitochondria: giant mitochondria with hyperplastic inner cristae) as well as mitochondrial hyperplasia (increase in mitochondrial biogenesis and numbers) were observed. Such changes probably represent compensatory attempts of the mitochondria for functional loss or reduction of mitochondria in QD705 treated animals. Moreover, degeneration of mitochondria (myelin-figure and cytoplasmic membranous body formation) and degradation of cytoplasmic materials (isolated cytoplasmic pockets of degenerated materials and focal cytoplasmic degradation) also occurred in later time points (16-24 weeks). Such mitochondrial changes were not identical with those induced by pure cadmium. Taken together, we suggest that mitochondria appeared to be the target of QD705 toxicity and specific mitochondrial markers may be useful parameters for toxicity assessments of QDs or other metal-based nanomaterials.

Epigenetic effects and molecular mechanisms of tumorigenesis induced by cigarette smoke: an overview.

Cigarette smoking is one of the major causes of carcinogenesis. Direct genotoxicity induced by cigarette smoke leads to initiation of carcinogenesis. Nongenotoxic (epigenetic) effects of cigarette smoke also act as modulators altering cellular functions. These two effects underlie the mechanisms of tumor promotion and progression. While there is no lack of general reviews on the genotoxic and carcinogenic potentials of cigarette smoke in lung carcinogenesis, updated review on the epigenetic effects and molecular mechanisms of cigarette smoke and carcinogenesis, not limited to lung, is lacking. We are presenting a comprehensive review of recent investigations on cigarette smoke, with special attentions to nicotine, NNK, and PAHs. The current understanding on their molecular mechanisms include (1) receptors, (2) cell cycle regulators, (3) signaling pathways, (4) apoptosis mediators, (5) angiogenic factors, and (6) invasive and metastasis mediators. This review highlighted the complexity biological responses to cigarette smoke components and their involvements in tumorigenesis.

Longer-term outcomes of a prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion.

PURPOSE: To evaluate long-term effectiveness and safety of intravitreal injection of ranibizumab as a potential treatment for decreased visual acuity secondary to central retinal vein occlusion. METHODS: In this prospective interventional case series, patients with central retinal vein occlusion were administered intravitreal ranibizumab 0.5 mg at baseline and monthly for 2 additional doses. Thereafter, the patients were given additional ranibizumab if they had macular edema by optical coherence tomography, leakage during fluorescein angiography, or any intraretinal hemorrhage. RESULTS: There were 35 eyes of 35 patients who at baseline had a mean visual acuity of 44.2 Early Treatment Diabetic Retinopathy Study letters and a mean central macular thickness of 638 µm. At 12 months, mean visual acuity of 32 eyes improved by 16.5 letters and macular thickness decreased to 164 µm (P < 0.001 vs. baseline for each). At 24 months, mean visual acuity of 24 eyes improved by 17.8 letters and macular thickness was 263 µm (P < 0.001 vs. baseline for each). Patients received an average of 10.2 injections during the first year and 6.6 injections during the second year. No cases of endophthalmitis, retinal detachment, or neovascularization were observed. CONCLUSION: Intravitreal ranibizumab caused a significant improvement in visual acuity and central retinal thickness, which persisted for up to 2 years with minimal side effects.

Cd/Se/Te-based quantum dot 705 modulated redox homeostasis with hepatotoxicity in mice.

The objective of this study was to investigate whether quantum dot 705 (QD705) disrupts the cellular antioxidant systems leading to hepatotoxicity in mice. Mice were intravenously injected with QD705 and then sacrificed at week 12 or 16. Homeostasis of antioxidant-related metals, antioxidant activities, induction of oxidative stress, and toxicity in the liver were investigated. Although no histopathological change was observed, a time- and dose-dependent increase in metallothionein expression and reduction in liver function was noticed. Increased copper, zinc, and selenium levels and enhancements of the trace metal-corresponding transporters were noted at week 12. At week 16, a decline of selenium from its elevated level at week 12 was observed, which was accompanied by changes in glutathione peroxidase activity as well as in redox status. A significant reduction in superoxide dismutase activity was observed at 16 weeks. Furthermore, a corresponding elevation of heme oxygenase-1 expression, 8-oxo-7,8-dihydro-2'-deoxyguanosine, interleukin-6 and tumor necrosis factor-alpha suggested the presence of oxidative stress, oxidative DNA damage and inflammation.

Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice.

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen, TCDD only induced oxidative DNA damages. In our present study, we combined TCDD with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to investigate their tumorigenic effects on lung tumor formation in A/J mice. Application of NNK at a tumorigenic dose (2 mg/mouse) induced lung adenoma in both male and female A/J mice. Neither application of NNK at a non-tumorigenic dose (1 mg/mouse) nor repeated application of TCDD alone increased tumor incidence. Following the single injection of NNK at a non-tumorigenic dose (1 mg/mouse), repeated application of TCDD significantly increased the lung tumor incidence in female, but not in male, A/J mice 24 weeks later. Utilizing the real-time RT-PCR array, we found that P16 mRNA was significantly reduced in female lung, but not male lung, of NNK/TCDD co-treated A/J mice. With immunohistochemical staining, we confirmed that nuclear P16 protein was reduced in the lungs of NNK/TCDD co-treated female mice. These data suggest that P16 reduction at least partially contributed to synergistic effects of TCDD in lung tumorigenesis.