Sex-dependent evolution of whole-body postural alignment with age.

PURPOSE: The goal of this study was to explore sex-related variations of global alignment parameters and their distinct evolution patterns across age groups. METHODS: This multicentric retrospective study included healthy volunteers with full-body biplanar radiographs in free-standing position. All radiographic data were collected from 3D reconstructions: global and lower limb parameters, pelvic incidence (PI) and sacral slope (SS). Lumbar lordosis (LL), thoracic kyphosis (TK) and cervical lordosis (CL) were also assessed as well as the lumbar and thoracic apex, and thoracolumbar inflexion point. The population was divided into five 5 age groups: Children, Adolescents, Young, Middle-Aged and Seniors. RESULTS: This study included 861 subjects (53% females) with a mean age of 34 ± 17 years. Mean PI was 49.6 ± 11.1 and mean LL was - 57.1 ± 11.6°. Females demonstrated a PI increase between Young and Middle-Aged groups (49 ± 11° vs. 55 ± 12°, p < 0.001) while it remained stable in males. SS and LL increased with age in females while remaining constant in males between Children and Middle-aged and then significantly decreased for both sexes between Middle-Aged and Seniors. On average, lumbar apex, inflexion point, and thoracic apex were located one vertebra higher in females (p < 0.001). After skeletal maturity, males had greater TK than females (64 ± 11° vs. 60 ± 12°, p = 0.04), with significantly larger CL (-13 ± 10° vs. -8 ± 10°, p = 0.03). All global spinal parameters indicated more anterior alignment in males. CONCLUSION: Males present more anteriorly tilted spine with age mainly explained by a PI increase in females between Young and Middle-Aged, which may be attributed to childbirth. Consequently, SS and LL increased before decreasing at senior age.

Revision Strategy for Proximal Junctional Failure: Combined Effect of Proximal Extension and Focal Correction.

STUDY DESIGN: Retrospective review of a prospectively-collected multicenter database. OBJECTIVES: The objective of this study was to determine optimal strategies in terms of focal angular correction and length of proximal extension during revision for PJF. METHODS: 134 patients requiring proximal extension for PJF were analyzed in this study. The correlation between amount of proximal junctional angle (PJA) reduction and recurrence of proximal junctional kyphosis (PJK) and/or PJF was investigated. Following stratification by the degree of PJK correction and the numbers of levels extended proximally, rates of radiographic PJK (PJA >28° & ΔPJA >22°), and recurrent surgery for PJF were reported. RESULTS: Before revision, mean PJA was 27.6° ± 14.6°. Mean number of levels extended was 6.0 ± 3.3. Average PJA reduction was 18.8° ± 18.9°. A correlation between the degree of PJA reduction and rate of recurrent PJK was observed (r = -.222). Recurrent radiographic PJK (0%) and clinical PJF (4.5%) were rare in patients undergoing extension ≥8 levels, regardless of angular correction. Patients with small reductions (<5°) and small extensions (<4 levels) experienced moderate rates of recurrent PJK (19.1%) and PJF (9.5%). Patients with large reductions (>30°) and extensions <8 levels had the highest rate of recurrent PJK (31.8%) and PJF (16.0%). CONCLUSION: While the degree of focal PJK correction must be determined by the treating surgeon based upon clinical goals, recurrent PJK may be minimized by limiting reduction to <30°. If larger PJA correction is required, more extensive proximal fusion constructs may mitigate recurrent PJK/PJF rates.

Distal junctional kyphosis in adult cervical deformity patients: where does it occur?

PURPOSE: To evaluate the impact of the lowest instrumented vertebra (LIV) on Distal Junctional kyphosis (DJK) incidence in adult cervical deformity (ACD) surgery. METHODS: Prospectively collected data from ACD patients undergoing posterior or anterior-posterior reconstruction at 13 US sites was reviewed up to 2-years postoperatively (n = 140). Data was stratified into five groups by level of LIV: C6-C7, T1-T2, T3-Apex, Apex-T10, and T11-L2. DJK was defined as a kyphotic increase > 10° in Cobb angle from LIV to LIV-1. Analysis included DJK-free survival, covariate-controlled cox regression, and DJK incidence at 1-year follow-up. RESULTS: 25/27 cases of DJK developed within 1-year post-op. In patients with a minimum follow-up of 1-year (n = 102), the incidence of DJK by level of LIV was: C6-7 (3/12, 25.00%), T1-T2 (3/29, 10.34%), T3-Apex (7/41, 17.07%), Apex-T10 (8/11, 72.73%), and T11-L2 (4/8, 50.00%) (p < 0.001). DJK incidence was significantly lower in the T1-T2 LIV group (adjusted residual = -2.13), and significantly higher in the Apex-T10 LIV group (adjusted residual = 3.91). In covariate-controlled regression using the T11-L2 LIV group as reference, LIV selected at the T1-T2 level (HR = 0.054, p = 0.008) or T3-Apex level (HR = 0.081, p = 0.010) was associated with significantly lower risk of DJK. However, there was no difference in DJK risk when LIV was selected at the C6-C7 level (HR = 0.239, p = 0.214). CONCLUSION: DJK risk is lower when the LIV is at the upper thoracic segment than the lower cervical segment. DJK incidence is highest with LIV level in the lower thoracic or thoracolumbar junction.

Spinopelvic sagittal compensation in adult cervical deformity.

OBJECTIVE: The objective of this study was to evaluate spinopelvic sagittal alignment and spinal compensatory changes in adult cervical kyphotic deformity. METHODS: A database composed of 13 US spine centers was retrospectively reviewed for adult patients who underwent cervical reconstruction with radiographic evidence of cervical kyphotic deformity: C2-7 sagittal vertical axis > 4 cm, chin-brow vertical angle > 25°, or cervical kyphosis (T1 slope [T1S] cervical lordosis [CL] > 15°) (n = 129). Sagittal parameters were evaluated preoperatively and in the early postoperative window (6 weeks to 6 months postoperatively) and compared with asymptomatic control patients. Adult cervical deformity patients were further stratified by degree of cervical kyphosis (severe kyphosis, C2-T3 Cobb angle ≤ -30°; moderate kyphosis, ≤ 0°; and minimal kyphosis, > 0°) and severity of sagittal malalignment (severe malalignment, sagittal vertical axis T3-S1 ≤ -60 mm; moderate malalignment, ≤ 20 mm; and minimal malalignment > 20 mm). RESULTS: Compared with asymptomatic control patients, cervical deformity was associated with increased C0-2 lordosis (32.9° vs 23.6°), T1S (33.5° vs 28.0°), thoracolumbar junction kyphosis (T10-L2 Cobb angle -7.0° vs -1.7°), and pelvic tilt (PT) (19.7° vs 15.9°) (p < 0.01). Cervicothoracic kyphosis was correlated with C0-2 lordosis (R = -0.57, p < 0.01) and lumbar lordosis (LL) (R = -0.20, p = 0.03). Cervical reconstruction resulted in decreased C0-2 lordosis, increased T1S, and increased thoracic and thoracolumbar junction kyphosis (p < 0.01). Patients with severe cervical kyphosis (n = 34) had greater C0-2 lordosis (p < 0.01) and postoperative reduction of C0-2 lordosis (p = 0.02) but no difference in PT. Severe cervical kyphosis was also associated with a greater increase in thoracic and thoracolumbar junction kyphosis postoperatively (p = 0.01). Patients with severe sagittal malalignment (n = 52) had decreased PT (p = 0.01) and increased LL (p < 0.01), as well as a greater postoperative reduction in LL (p < 0.01). CONCLUSIONS: Adult cervical deformity is associated with upper cervical hyperlordotic compensation and thoracic hypokyphosis. In the setting of increased kyphotic deformity and sagittal malalignment, thoracolumbar junction kyphosis and lumbar hyperlordosis develop to restore normal center of gravity. There was no consistent compensatory pelvic retroversion or anteversion among the adult cervical deformity patients in this cohort.

Enhanced Recovery after Lumbar Spine Fusion: A Randomized Controlled Trial to Assess the Quality of Patient Recovery.

BACKGROUND: Prospective trials of enhanced recovery after spine surgery are lacking. We tested the hypothesis that an enhanced recovery pathway improves quality of recovery after one- to two-level lumbar fusion. METHODS: A patient- and assessor-blinded trial of 56 patients randomized to enhanced recovery (17 evidence-based pre-, intra-, and postoperative care elements) or usual care was performed. The primary outcome was Quality of Recovery-40 score (40 to 200 points) at postoperative day 3. Twelve points defined the clinically important difference. Secondary outcomes included Quality of Recovery-40 at days 0 to 2, 14, and 56; time to oral intake and discharge from physical therapy; length of stay; numeric pain scores (0 to 10); opioid consumption (morphine equivalents); duration of intravenous patient-controlled analgesia use; complications; and markers of surgical stress (interleukin 6, cortisol, and C-reactive protein). RESULTS: The analysis included 25 enhanced recovery patients and 26 usual care patients. Significantly higher Quality of Recovery-40 scores were found in the enhanced recovery group at postoperative day 3 (179 ± 14 vs. 170 ± 16; P = 0.041) without reaching the clinically important difference. There were no significant differences in recovery scores at days 0 (175 ± 16 vs. 162 ± 22; P = 0.059), 1 (174 ± 18 vs. 164 ± 15; P = 0.050), 2 (174 ± 18 vs. 167 ± 17; P = 0.289), 14 (184 ± 13 vs. 180 ± 12; P = 0.500), and 56 (187 ± 14 vs. 190 ± 8; P = 0.801). In the enhanced recovery group, subscores on the Quality of Recovery-40 comfort dimension were higher (longitudinal mean score difference, 4; 95% CI, 1, 7; P = 0.008); time to oral intake (-3 h; 95% CI, -6, -0.5; P = 0.010); and duration of intravenous patient-controlled analgesia (-11 h; 95% CI, -19, -6; P < 0.001) were shorter; opioid consumption was lower at day 1 (-57 mg; 95% CI, -130, -5; P = 0.030) without adversely affecting pain scores (-2; 95% CI, -3, 0; P = 0.005); and C-reactive protein was lower at day 3 (6.1; 95% CI, 3.8, 15.7 vs. 15.9; 95% CI, 6.6, 19.7; P = 0.037). CONCLUSIONS: Statistically significant gains in early recovery were achieved by an enhanced recovery pathway. However, significant clinical impact was not demonstrated.

Establishing the minimum clinically important difference in Neck Disability Index and modified Japanese Orthopaedic Association scores for adult cervical deformity.

OBJECTIVE: It is being increasingly recognized that adult cervical deformity (ACD) is correlated with significant pain, myelopathy, and disability, and that patients who undergo deformity correction gain significant benefit. However, there are no defined thresholds of minimum clinically important difference (MCID) in Neck Disability Index (NDI) and modified Japanese Orthopaedic Association (mJOA) scores. METHODS: Patients of interest were consecutive patients with ACD who underwent cervical deformity correction. ACD was defined as C2-7 sagittal Cobb angle ≥ 10° (kyphosis), C2-7 coronal Cobb angle ≥ 10° (cervical scoliosis), C2-7 sagittal vertical axis ≥ 4 cm, and/or chin-brow vertical angle ≥ 25°. Data were obtained from a consecutive cohort of patients from a multiinstitutional prospective database maintained across 13 sites. Distribution-based MCID, anchor-based MCID, and minimally detectable measurement difference (MDMD) were calculated. RESULTS: A total of 73 patients met inclusion criteria and had sufficient 1-year follow-up. In the cohort, 42 patients (57.5%) were female. The mean age at the time of surgery was 62.23 years, and average body mass index was 29.28. The mean preoperative NDI was 46.49 and mJOA was 13.17. There was significant improvement in NDI at 1 year (46.49 vs 37.04; p = 0.0001). There was no significant difference in preoperative and 1-year mJOA (13.17 vs 13.7; p = 0.12). Using multiple techniques to yield MCID thresholds specific to the ACD population, the authors obtained values of 5.42 to 7.48 for the NDI, and 1.00 to 1.39 for the mJOA. The MDMD was 6.4 for the NDI, and 1.8 for the mJOA. Therefore, based on their results, the authors recommend using an MCID threshold of 1.8 for the mJOA, and 7.0 for the NDI in patients with ACD. CONCLUSIONS: The ACD-specific MCID thresholds for NDI and mJOA are similar to the reported MCID following surgery for degenerative cervical disease. Additional studies are needed to verify these findings. Nonetheless, the findings here will be useful for future studies evaluating the success of surgery for patients with ACD undergoing deformity correction.

Endoscopic Transaxillary Versus Inframammary Approaches for Breast Augmentation Using Shaped Implants: A Matched Case-Control Study.

PURPOSE: The incision for breast augmentation can be chosen from the transaxillary, inframammary fold, periareolar, or transumbilical approaches. While the inframammary fold approach is commonly used worldwide, the transaxillary approach is more popular in Asia due to the more conservative location of the scar. In this study, we performed augmentation mammoplasty using anatomically shaped implants via the endoscopic transaxillary and inframammary fold incisions and compared the outcomes. METHODS: Three hundred sixty-four patients who underwent breast augmentation with shaped implants were enrolled. All were primary and bilateral cases. In total, 728 shaped implants were used. Patients' demographics, incision type, and complications were documented. Complications such as capsular contracture, hematoma, infection, implant malposition, wound problem, and chronic seroma were observed during the average 27 months of follow-up period and analyzed. RESULTS: One hundred ninety-five patients underwent augmentation mammoplasty via the inframammary approach, whereas 169 patients underwent the endoscopic transaxillary approach. Implant type and size were matched between the two groups. Complication rates were 1.8% and 2.7% in the inframammary and transaxillary approach, respectively. There was no significant difference between the two approaches in terms of surgical complications (p = 0.593). CONCLUSION: This study demonstrates that the endoscopic transaxillary approach is not inferior to the inframammary approach when shaped implants are used for augmentation mammoplasty. Therefore, the transaxillary approach may be an alternative method when using shaped implants for augmentation mammoplasty, especially for women who wish to avoid a visible scar on the inframammary fold. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Despite worse baseline status depressed patients achieved outcomes similar to those in nondepressed patients after surgery for cervical deformity.

OBJECTIVE Depression and anxiety have been demonstrated to have negative impacts on outcomes after spine surgery. In patients with cervical deformity (CD), the psychological and physiological burdens of the disease may overlap without clear boundaries. While surgery has a proven record of bringing about significant pain relief and decreased disability, the impact of depression and anxiety on recovery from cervical deformity corrective surgery has not been previously reported on in the literature. The purpose of the present study was to determine the effect of depression and anxiety on patients' recovery from and improvement after CD surgery. METHODS The authors conducted a retrospective review of a prospective, multicenter CD database. Patients with a history of clinical depression, in addition to those with current self-reported anxiety or depression, were defined as depressed (D group). The D group was compared with nondepressed patients (ND group) with a similar baseline deformity determined by propensity score matching of the cervical sagittal vertical axis (cSVA). Baseline demographic, comorbidity, clinical, and radiographic data were compared among patients using t-tests. Improvement of symptoms was recorded at 3 months, 6 months, and 1 year postoperatively. All health-related quality of life (HRQOL) scores collected at these follow-up time points were compared using t-tests. RESULTS Sixty-six patients were matched for baseline radiographic parameters: 33 with a history of depression and/or current depression, and 33 without. Depressed patients had similar age, sex, race, and radiographic alignment: cSVA, T-1 slope minus C2-7 lordosis, SVA, and T-1 pelvic angle (p > 0.05). Compared with nondepressed individuals, depressed patients had a higher incidence of osteoporosis (21.2% vs 3.2%, p = 0.028), rheumatoid arthritis (18.2% vs 3.2%, p = 0.012), and connective tissue disorders (18.2% vs 3.2%, p = 0.012). At baseline, the D group had greater neck pain (7.9 of 10 vs 6.6 on a Numeric Rating Scale [NRS], p = 0.015), lower mean EQ-5D scores (68.9 vs 74.7, p < 0.001), but similar Neck Disability Index (NDI) scores (57.5 vs 49.9, p = 0.063) and myelopathy scores (13.4 vs 13.9, p = 0.546). Surgeries performed in either group were similar in terms of number of levels fused, osteotomies performed, and correction achieved (baseline to 3-month measurements) (p < 0.05). At 3 months, EQ-5D scores remained lower in the D group (74.0 vs 78.2, p = 0.044), and NDI scores were similar (48.5 vs 39.0, p = 0.053). However, neck pain improved in the D group (NRS score of 5.0 vs 4.3, p = 0.331), and modified Japanese Orthopaedic Association (mJOA) scores remained similar (14.2 vs 15.0, p = 0.211). At 6 months and 1 year, all HRQOL scores were similar between the 2 cohorts. One-year measurements were as follows: NDI 39.7 vs 40.7 (p = 0.878), NRS neck pain score of 4.1 vs 5.0 (p = 0.326), EQ-5D score of 77.1 vs 78.2 (p = 0.646), and mJOA score of 14.0 vs 14.2 (p = 0.835). Anxiety/depression levels reported on the EQ-5D scale were significantly higher in the depressed cohort at baseline, 3 months, and 6 months (all p < 0.05), but were similar between groups at 1 year postoperatively (1.72 vs 1.53, p = 0.416). CONCLUSIONS Clinical depression was observed in many of the study patients with CD. After matching for baseline deformity, depression symptomology resulted in worse baseline EQ-5D and pain scores. Despite these baseline differences, both cohorts achieved similar results in all HRQOL assessments 6 months and 1 year postoperatively, demonstrating no clinical impact of depression on recovery up until 1 year after CD surgery. Thus, a history of depression does not appear to have an impact on recovery from CD surgery.

Age-Adjusted Alignment Goals Have the Potential to Reduce PJK.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To explore proximal junctional kyphosis (PJK) as a function of age-adjusted surgical correction goals. SUMMARY OF BACKGROUND DATA: Recent adult spinal deformity (ASD) studies show that alignment targets are age-specific. Despite recognizing age and malalignment as PJK risk factors, no study has assessed the age-specific effects of alignment on PJK. METHODS: ASD patients with fusions to the pelvis were included and stratified into three groups: young adults (YA <40 years old), middle aged (MA: 40-65 years old), and the elderly (ED >65 years old). Analysis of variance compared the groups with respect to 1-year postoperative alignments and 1-year offsets from age-specific alignment targets. RESULTS: A total of 679 patients were enrolled (mean age = 61 years old, 77% female, body mass index = 28.1). At 1 year postoperatively, there was a significant decrease in pelvic tilt (PT; 29-23°), spinopelvic mismatch (pelvic incidence [PI]-lumbar lordosis [LL]) (28-5°), and sagittal vertical axis (SVA; 110-37 mm); overall incidence of PJK was 45.1%. Stratification by age (YA, n = 28; MA, n = 389; ED, n = 262) revealed an increase in PJK incidence with age: YA = 17.9%, MA = 43.8%, and ED = 50.2% (P < 0.001). PJK patients had smaller postoperative PI-LL mismatches (ED 0.8° vs. 9.8°, MA 3.1° vs. 7.3°) than non-PJK patients, without any significant differences in PT or SVA. Analysis of the postoperative offsets from age-specific norms revealed that PJK patients in the two older subgroups and in the study cohort as a whole were overcorrected as compared to non-PJK patients (PI-LL offset-all: -5.2° vs. 2.8°, MA: -1° vs. +4°, ED: -11° vs. -2°; SVA offset-all: -10 mm vs. 7 mm, MA: -3 mm vs. 10 mm, ED: -18 mm vs. -6 mm). The correlation coefficients between PJK angles and the offsets from age-adjusted objective were small (0.320 for PI-LL, 0.114 for PT, and 0.136 for SVA). CONCLUSION: Overall, this study suggests that PJK patients were overcorrected when compared to age-adjusted alignment goals. Certainly, elderly patients are subject to independent risk factors for PJK, making the prevention of PJK complex. However, individualized optimization of surgical alignment can improve outcomes. This emphasizes the need for surgeons to incorporate age-specific alignment targets into the standard preoperative planning process. LEVEL OF EVIDENCE: 3.

Expressions and Clinical Significances of Angiopoietin-1, Angiopoietin-2, and Tie-2 Receptor in Patients With Colorectal Cancer.

PURPOSE: Angiopoietin-1 (Ang-1) plays a crucial role in vascular and hematopoietic development, mainly through its cognate receptor, Tie-2. Increased levels of Ang-2 have been shown to be correlated with abnormal tumor angiogenesis in several malignancies. Hence, we estimated the increased expression of Ang-2 relative to Ang-1 in patients with colorectal cancer and correlated our finding with prognosis in order to investigate the relationships between the expressions of Ang-1/Ang-2/Tie-2 receptor and the clinical parameters or overall survival of such patients. METHODS: We retrospectively analyzed 114 tissue samples from patients with colorectal cancer by using immunohistochemistry (IHC) to examine Ang-1, Ang-2, and Tie-2 expressions and to investigate the relationship between those expressions and clinical parameters or overall survival of such patients. A Western blot analysis was used for Ang-2 expression. RESULTS: IHC staining showed a link between Ang-1 and Tie-2 (P = 0.018), as well as meaningful correlations between Ang-2 and Tie-2 receptor (P = 0.022) and between lymph-node metastasis and Ang-2 (P = 0.025). The stronger the IHC staining for Ang-2 expression was, the shorter the cumulative survival was (P = 0.016). CONCLUSION: A relationship was found to exist between Ang-2 and Tie-2 expressions. The Ang-2 was correlated with lymph-node metastasis, and high expression of Ang-2 was indicative of poor overall survival. These findings suggest that Ang-2 is a useful prognostic marker in the management of patients with colorectal cancer. In addition, we suggest that Ang/Tie-2 signaling plays an important role in the progression of colorectal cancer.

Patient Satisfaction After Adult Spinal Deformity Surgery Does Not Strongly Correlate With Health-Related Quality of Life Scores, Radiographic Parameters, or Occurrence of Complications.

STUDY DESIGN: This is a multicenter retrospective review of prospectively collected cases. OBJECTIVE: Our objective was to evaluate the relationship between patient satisfaction, health-related quality of life (HRQoL) scores, complications, and radiographic measures at 2 years postoperative follow-up. SUMMARY OF BACKGROUND DATA: For patients receiving operative management for adult spine deformity (ASD), the relationship between HRQoL measures, radiographic parameters, postoperative complications, and self-reported satisfaction remains unclear. METHODS: Data from 248 patients across 11 centers within the United States who underwent thoracolumbar fusion for ASD and had a minimum of 2 years follow-up was collected. Pre- and postoperative scores were obtained from the Scoliosis Research Society 22-item (SRS-22r), the Oswestry Disability Index (ODI), the 36-Item Short Form Health Survey (SF-36), and the Visual Analogue Scale. Sagittal vertical axis, coronal C7 plumbline, lumbar lordosis, pelvic tilt, T1 pelvic angle, and the difference between pelvic incidence and lumbar lordosis were assessed using postoperative radiographic films. Satisfaction (SAT) was assessed using the SRS-22r; patients were categorized as highly satisfied (HS) or less satisfied (LS). The correlation between SAT and HRQoL scores, radiographic parameters, and complications was determined. RESULTS: When compared with LS (n = 60) patients, HS (n = 188) patients demonstrated greater improvement in final ODI, SF-36 component scores, SRS-Total, and Visual Analogue Scale back scores (P < 0.05). The correlations between SAT and the final follow-up and 2 year change from baseline values were moderate for Mental Component Summary, Physical Component Summary, and ODI or weak for HRQoL scores (P < 0.0001). The HS and LS groups were equal in pre- or final postoperative radiographic parameters. Occurrence of complications had no effect on satisfaction. CONCLUSION: Among operatively treated ASD patients, satisfaction was moderately correlated with some HRQoL measures, and not with radiographic changes or postoperative complications. Other factors, such as patient expectations and relationship with the surgeon, may be stronger drivers of patient satisfaction. LEVEL OF EVIDENCE: 3.

Intrathecal Trastuzumab Treatment in Patients with Breast Cancer and Leptomeningeal Carcinomatosis.

Leptomeningeal carcinomatosis is a fatal manifestation of metastatic breast cancer. Investigation of intrathecal (IT) trastuzumab for leptomeningeal carcinomatosis is currently underway; however, there has been no consensus. We report on two cases of human epidermal growth factor receptor 2 positive (HER2+) breast cancer following IT trastuzumab for leptomeningeal carcinomatosis. The first patient was treated with weekly IT 15 mg methotrexate plus IT 50 mg trastuzumab for 7 months, followed by IT trastuzumab (50 mg > 25 mg) for 18 months. The other patient received IT trastuzumab with systemic chemotherapy (trastuzumab and/or paclitaxel) for 13 months. Good control of leptomeningeal disease was achieved with IT trastuzumab in both patients, with survival durations of 20 and 29 months, respectively. We suggest that IT trastuzumab is a promising treatment for patients with HER2+ breast cancer and leptomeningeal carcinomatosis.

Mechanistic elements and critical factors of cellular reprogramming revealed by stepwise global gene expression analyses.

A better understanding of the cellular and molecular mechanisms involved in the reprogramming of somatic cells is essential for further improvement of induced pluripotent stem (iPS) cell technology. In this study, we enriched for cells actively undergoing reprogramming at different time points by sorting the cells stained with a stem cell-selective fluorescent chemical probe CDy1 for their global gene expression analysis. Day-to-day comparison of differentially expressed genes showed highly dynamic and transient gene expressions during reprogramming, which were largely distinct from those of fully-reprogrammed cells. An unbiased analysis of functional regulation indicated robust modulation of concurrent programs at critical junctures. Globally, transcriptional programs involved in cell proliferation, morphology and signal transduction were instantly triggered as early as 3 days-post-infection to prepare the cell for reprogramming but became somewhat muted in the final iPS cells. On the other hand, the highly coordinated metabolic reprogramming process was more gradually activated. Subsequent network analysis of differentially expressed genes indicated PDGF-BB as a core player in reprogramming which was verified by our gain- and loss-of-function experiments. As such, our study has revealed previously-unknown insights into the mechanisms of cellular reprogramming.

A multicenter retrospective analysis of the clinical features of pernicious anemia in a Korean population.

To determine the approximate incidence and clinical features of pernicious anemia in a Korean population, we retrospectively analyzed clinical data for patients with pernicious anemia who were diagnosed between 1995 and 2010 at five hospitals in Chungnam province. Ninety-seven patients were enrolled, who accounted for 24% of patients with vitamin B(12) deficiency anemia. The approximate annual incidence of pernicious anemia was 0.3 per 100,000. The median age was 66 (range, 32-98) yr, and the male/female ratio was 1.25. Anemia-associated discomfort was the most common symptom (79.4%), followed by gastrointestinal and neurological symptoms (78.4% and 38.1%, respectively). Pancytopenia was found in 36 patients (37.1%), and autoimmune disorders were found in 15 patients (15.5%). Antibody to intrinsic factor was detected in 62 (77.5%) of 80 patients examined, and antibody to parietal cells was detected in 35 (43.2%) of 81 patients examined. Of the 34 patients who underwent tests for Helicobacter pylori, 7 (12.5%) were positive. The anemia-associated and gastrointestinal symptoms resolved completely in all patients after intramuscular injection of cobalamin, whereas neurological symptoms remained in some. In conclusion, pernicious anemia is less frequent in Koreans than in Western populations; however, the clinical features of this disorder in Koreans do not differ from those of Western cases.

Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities.

With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC(50) values of 0.58 and 2.72 µM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t(1/2)) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.

A colorimetric pH indicators and boronic acids ensemble array for quantitative sugar analysis.

The colorimetric response patterns of pH indicators and boronic acids ensemble array were used to analyze serial concentrations of mono-, disaccharides quantitatively. Furthermore, this ensemble array was successfully applied to quantify the sugar content in clinically used saline solutions.

Quantitative Structure-Fluorescence Property Relationship Analysis of a Large BODIPY Library.

A quantitative structure-fluorescence property relationship (QSPR) analysis of a large 288-membered library based on a single fluorescent BODIPY scaffold is presented for the first time. BODIPY is a versatile fluorescent scaffold with outstanding photophysical properties. Absorption (λabs ) and fluorescence emission (λem ) wavelength maxima were modeled with help of stepwise multiple linear regression (MLR) and support vector regression (SVR). The models were rigorously validated by 10-times 10-fold cross-validation (CV), y-scrambling CV and with an external validation set. Non-linear SVR models (R(2) =0.92 and Q(2) =0.71 for λabs ; R(2) =0.89 and Q(2) =0.69 for λem ) performed significantly better than linear models. A small root mean squared error (RMSE) of 5.62 nm and 11.07 nm was achieved for λabs and λem , respectively, and confirmed by external validation. A novel intramolecular charge transfer descriptor was developed based on the QSPR analysis and its inclusion in the modeling significantly improved models of λem . We conclude that QSPR is a useful tool for modeling λabs and λem of BODIPY fluorophores and suggest QSPR as an ideal partner for the design of compounds with tailored fluorescence properties in a diversity-oriented fluorescence library approach (DOFLA).

Classification models for CYP450 3A4 inhibitors and non-inhibitors.

Cytochrome P450 3A4 (CYP3A4) is the predominant enzyme involved in the oxidative metabolic pathways of many drugs. The inhibition of this enzyme in many cases leads to an undesired accumulation of the administered therapeutic agent. The purpose of this study is to develop in silico model that can effectively distinguish human CYP3A4 inhibitors from non-inhibitors. Structural diversity of the drug-like compounds CYP3A4 inhibitors and non-inhibitors was obtained from Fujitsu Database and Korea Research Institute of Chemical Technology (KRICT) as training and test sets, respectively. Recursive Partitioning (RP) method was introduced for the classification of inhibitor and non-inhibitor of CYP3A4 because it is an easy and quick classification method to implement. The 2D molecular descriptors were used to classify the compounds into respective inhibitors and non-inhibitors by calculation of the physicochemical properties of CYP3A4 inhibitors such as molecular weights and fractions of 2D VSA chargeable groups. The RP tree model reached 72.33% of accuracy and exceeded this percentage for the sensitivity (75.82%) parameter. This model is further validated by the test set where both accuracy and sensitivity were 72.58% and 82.64%, respectively. The accuracy of the random forest model was increased to 73.8%. The 2D descriptors sufficiently represented the molecular features of CYP3A4 inhibitors. Our model can be used for the prediction of either CYP3A4 inhibitors or non-inhibitors in the early stages of the drug discovery process.

Design, synthesis, and discovery of stilbene derivatives based on lithospermic acid B as potent protein tyrosine phosphatase 1B inhibitors.

Dihydroxy stilbene derivatives were designed based on lithospermic acid B and were prepared from 4-(chloromethyl)benzoic acid. The inhibitory activities of the novel compounds against protein tyrosine phosphatase 1B (PTP1B) were evaluated. 3,4-Dihydroxy stilbene carbonyl compounds (7, 11b, 27b) inhibited PTP1B with IC50 values comparable to molybdate, while the conjugation-extended compound (15b) showed inhibition 3-fold better than preclinical RK682. The introduction of electron withdrawing groups or amides into the second phenyl ring, or extension of the conjugation into the stilbene molecule may increase stability of the generated radicals.