Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) are a group of rare tumors previously known as mixed adenoneuroendocrine carcinomas (MANECs). The neuroendocrine component is high-grade and may consist of small-cell carcinoma or large-cell neuroendocrine carcinoma. The nonneuroendocrine component may consist of adenocarcinoma or squamous cell carcinoma. We report a unique case of a MiNEN with trilineage differentiation: large-cell neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma. The reported patient presented with symptoms of an upper gastrointestinal bleed and was ultimately diagnosed with a MiNEN with trilineage differentiation. This is the first report of this exceedingly rare tumor type to include next-generation sequencing of the 3 separate tumor entities. In addition, we review the current literature and discuss the role of next-generation sequencing in classifying and treating MiNEN tumors.
Adenocarcinoma ; Carcinoma, Neuroendocrine ; Carcinoma, Squamous Cell ; Humans ; Precision Medicine ; Stomach Neoplasms

In this paper, we investigate cross-platform interoperability for natural language processing (NLP) and, in particular, annotation of textual resources, with an eye toward identifying the design elements of annotation models and processes that are particularly problematic for, or amenable to, enabling seamless communication across different platforms. The study is conducted in the context of a specific annotation methodology, namely machine-assisted interactive annotation (also known as human-in-the-loop annotation). This methodology requires the ability to freely combine resources from different document repositories, access a wide array of NLP tools that automatically annotate corpora for various linguistic phenomena, and use a sophisticated annotation editor that enables interactive manual annotation coupled with on-the-fly machine learning. We consider three independently developed platforms, each of which utilizes a different model for representing annotations over text, and each of which performs a different role in the process.
Linguistics ; Machine Learning ; Natural Language Processing

BACKGROUND AND OBJECTIVES: The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-β-cyclodextrin (HPβCD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HPβCD could partially resolve the symptoms in both animals and human patients. Despite its desirable effect, HPβCD can induce hearing loss, which is the only major side effect noted to date. Understanding of the pathophysiology of hearing impairment after administration of HPβCD and further development of preventive methods are essential to reduce the ototoxic side effect. The mechanisms of HPβCD-induced ototoxicity remain unknown, but the resulting pathology bears some resemblance to other ototoxic agents, which involves oxidative stress pathways. To indirectly determine the involvement of oxidative stress in HPβCD-induced ototoxicity, we tested the efficacy of an antioxidant reagent, ebselen, on the extent of inner ear side effects caused by HPβCD. MATERIALS AND METHODS: Ebselen was applied prior to administration of HPβCD in mice. Auditory brainstem response thresholds and otopathology were assessed one week later. Bilateral effects of the drug treatments also were examined. RESULTS: HPβCD-alone resulted in bilateral, severe, and selective loss of outer hair cells from base to apex with an abrupt transition between lesions and intact areas. Ebselen co-treatment did not ameliorate HPβCD-induced hearing loss or alter the resulting histopathology. CONCLUSIONS: The results indirectly suggest that cochlear damage by HPβCD is unrelated to reactive oxygen species formation. However, further research into the mechanism(s) of HPβCD otopathology is necessary.
Animals ; Ear, Inner ; Evoked Potentials, Auditory, Brain Stem ; Hair Cells, Auditory, Outer ; Hearing Loss ; Hearing ; Humans ; Mice ; Oxidative Stress ; Pathology ; Reactive Oxygen Species ; Sphingolipidoses ; Tight Junctions

A tooth is a complex biological organ and consists of multiple tissues including the enamel, dentin, cementum and pulp. Tooth loss is the most common organ failure. Can a tooth be regenerated? Can adult stem cells be orchestrated to regenerate tooth structures such as the enamel, dentin, cementum and dental pulp, or even an entire tooth? If not, what are the therapeutically viable sources of stem cells for tooth regeneration? Do stem cells necessarily need to be taken out of the body, and manipulated ex vivo before they are transplanted for tooth regeneration? How can regenerated teeth be economically competitive with dental implants? Would it be possible to make regenerated teeth affordable by a large segment of the population worldwide? This review article explores existing and visionary approaches that address some of the above-mentioned questions. Tooth regeneration represents a revolution in stomatology as a shift in the paradigm from repair to regeneration: repair is by metal or artificial materials whereas regeneration is by biological restoration. Tooth regeneration is an extension of the concepts in the broad field of regenerative medicine to restore a tissue defect to its original form and function by biological substitutes.
Adult Stem Cells ; Animals ; Humans ; Regeneration ; Regenerative Medicine ; Signal Transduction ; Stem Cell Transplantation ; Tissue Engineering ; Tissue Scaffolds ; Tooth ; physiology

STUDY DESIGN: A retrospective study. OBJECTIVES: The purpose of this study was to compare the results between Smith-Petersen and pedicle subtraction osteotomies for fixed sagittal imbalance, and to determine the specific indications for each. LITERATURE REVIEW SUMMARY: Smith-Petersen (SPO) and pedicle subtraction osteotomies (PSO) are the techniques most commonly used to correct fixed sagittal imbalance of the spine, but there are no reports regarding the superiority of either technique. A Smith-Petersen osteotomy is an anterior opening wedge osteotomy, which hinges on the posterior edge of the intervertebral disc, while a pedicle subtraction osteotomy is a posterior closing wedge osteotomy, without distracting the anterior column, with the hinge on the anterior aspect of the vertebral body. MATERIALS AND METHODS: Thirty patients (mean age 40.1 years, range 20 ~64 years), who underwent a SPO, were compared with forty-one patients (mean age 54.5 years, range 21 ~73 years) who underwent a PSO. The SPO was carried out in more than three segments (3 SPOs) in fourteen of the SPO group. The average follow-up periods were 4.6 years, ranging from 2 to 11.5 years, and 3.8 years, ranging from 2 to 7.1 years, for the SPO and PSO groups, respectively. Patients were evaluated by standing radiographs, chart review and outcome questionnaires. RESULTS: The mean correction of the kyphotic angle at the osteotomy sites for the SPOs was 10.7 per segment, and for those with 3 SPOs and the PSO group the average total corrections were 33.0+/-9.2 and 31.7+/-9.0, respectively. However, the improvement in sagittal balance was less statistically significantly with 3 SPOs (5.5+/-4.5 cm) than with a PSO (11.2+/-7.2 cm; p<0.01). Comparing 3 SPOs to one PSO, the SPO group decompensated the patients more substantially to the concavity (p<0.02). The mean estimated blood loss (adding up all anterior and posterior surgeries) for the procedures were 1398+/-738 (1392+/-664 mL in the 3 SPO group), and 2617+/-1645 mL in the SPO and PSO groups, respectively (p<0.001; p<0.01). The total operative times for the SPO versus the PSO groups were similar, with no statistical difference. There were substantial complications in both groups, with 13 in the 30 SPO and 30 in the 41 PSO patients. In the SPO group, 1 patient had a non-union at an osteotomy site; in the PSO group, 2 patients had a non-union at an osteotomy site. The mean Oswestry score improved from 42.3+/-14.2 to 21.3+/-14.8 postoperatively at the last visit for the SPO group and, it improved from 47.9+/-15.8 preoperatively to 29.7+/-18.3 at the last visit in PSO group (p=0.35). CONCLUSIONS: When comparing 3 Smith-Petersen osteotomies to one pedicle subtraction osteotomy, the corrections of kyphosis were almost identical, but the improvement in the C7 plumb was significantly better in the PSO group. There was a significantly greater likelihood of decompensating the patient to the concavity with the 3 SPOs than with a single PSO (p<0.02). The total operative time for the SPO versus the PSO groups showed no statistical difference. However, the blood loss was substantially greater in the PSO group (p<0.001).
Follow-Up Studies ; Humans ; Intervertebral Disc ; Kyphosis ; Operative Time ; Osteotomy* ; Surveys and Questionnaires ; Retrospective Studies ; Spine

STUDY DESIGN: A retrospective study. OBJECTIVES: The purpose of this study was to compare the results between Smith-Petersen and pedicle subtraction osteotomies for fixed sagittal imbalance, and to determine the specific indications for each. LITERATURE REVIEW SUMMARY: Smith-Petersen (SPO) and pedicle subtraction osteotomies (PSO) are the techniques most commonly used to correct fixed sagittal imbalance of the spine, but there are no reports regarding the superiority of either technique. A Smith-Petersen osteotomy is an anterior opening wedge osteotomy, which hinges on the posterior edge of the intervertebral disc, while a pedicle subtraction osteotomy is a posterior closing wedge osteotomy, without distracting the anterior column, with the hinge on the anterior aspect of the vertebral body. MATERIALS AND METHODS: Thirty patients (mean age 40.1 years, range 20 ~64 years), who underwent a SPO, were compared with forty-one patients (mean age 54.5 years, range 21 ~73 years) who underwent a PSO. The SPO was carried out in more than three segments (3 SPOs) in fourteen of the SPO group. The average follow-up periods were 4.6 years, ranging from 2 to 11.5 years, and 3.8 years, ranging from 2 to 7.1 years, for the SPO and PSO groups, respectively. Patients were evaluated by standing radiographs, chart review and outcome questionnaires. RESULTS: The mean correction of the kyphotic angle at the osteotomy sites for the SPOs was 10.7 per segment, and for those with 3 SPOs and the PSO group the average total corrections were 33.0+/-9.2 and 31.7+/-9.0, respectively. However, the improvement in sagittal balance was less statistically significantly with 3 SPOs (5.5+/-4.5 cm) than with a PSO (11.2+/-7.2 cm; p<0.01). Comparing 3 SPOs to one PSO, the SPO group decompensated the patients more substantially to the concavity (p<0.02). The mean estimated blood loss (adding up all anterior and posterior surgeries) for the procedures were 1398+/-738 (1392+/-664 mL in the 3 SPO group), and 2617+/-1645 mL in the SPO and PSO groups, respectively (p<0.001; p<0.01). The total operative times for the SPO versus the PSO groups were similar, with no statistical difference. There were substantial complications in both groups, with 13 in the 30 SPO and 30 in the 41 PSO patients. In the SPO group, 1 patient had a non-union at an osteotomy site; in the PSO group, 2 patients had a non-union at an osteotomy site. The mean Oswestry score improved from 42.3+/-14.2 to 21.3+/-14.8 postoperatively at the last visit for the SPO group and, it improved from 47.9+/-15.8 preoperatively to 29.7+/-18.3 at the last visit in PSO group (p=0.35). CONCLUSIONS: When comparing 3 Smith-Petersen osteotomies to one pedicle subtraction osteotomy, the corrections of kyphosis were almost identical, but the improvement in the C7 plumb was significantly better in the PSO group. There was a significantly greater likelihood of decompensating the patient to the concavity with the 3 SPOs than with a single PSO (p<0.02). The total operative time for the SPO versus the PSO groups showed no statistical difference. However, the blood loss was substantially greater in the PSO group (p<0.001).
Follow-Up Studies ; Humans ; Intervertebral Disc ; Kyphosis ; Operative Time ; Osteotomy* ; Surveys and Questionnaires ; Retrospective Studies ; Spine

Objective: : The purpose of this study was to identify risk factors for distal adding on (AO) or distal junctional kyphosis (DJK) in adolescent idiopathic scoliosis (AIS) treated by posterior spinal fusion (PSF) to L3 with a minimum 2-year follow-up. Methods: : AIS patients undergoing PSF to L3 by two senior surgeons from 2000–2010 were analyzed. Distal AO and DJK were deemed poor radiographic results and defined as >3 cm of deviation from L3 to the center sacral vertical line (CSVL), or >10° angle at L3–4 on the posterior anterior- or lateral X-ray at ultimate follow-up. New stable vertebra (SV) and neutral vertebra (NV) scores were defined for this study. The total stability (TS) score was the sum of the SV and NV scores. Results: : Ten of 76 patients (13.1%) were included in the poor radiographic outcome group. The other 66 patients were included in the good radiographic outcome group. Lower Risser grade, more SV-3 (CSVL doesn’t touch the lowest instrumented vertebra [LIV]) on standing and side bending films, lesser NV and TS score, rigid L3–4 disc, more rotation and deviation of L3 were identified risk factors for AO or DJK. Age, number of fused vertebrae, curve correction, preoperative coronal/sagittal L3–4 disc angle did not differ significantly between the two groups. Multiple logistic regression results indicated that preoperative Risser grade 0, 1 (odds ratio [OR], 1.8), SV-3 at L3 in standing and side benders (OR, 2.1 and 2.8, respectively), TS score -5, -6 at L3 (OR, 4.4), rigid disc at L3–4 (OR, 3.1), LIV rotation >15° (OR, 2.9), and LIV deviation >2 cm from CSVL (OR, 2.2) were independent predictive factors. Although there was significant improvement of the of Scoliosis Research Society-22 average scores only in the good radiographic outcome group, there was no significant difference in the scores between the groups. Conclusion : The prevalence of AO or DJK at ultimate follow-up for AIS with LIV at L3 was 13.1%. To prevent AO or DJK following fusion to L3, we recommend that the CSVL touch L3 in both standing and side bending, TS score is -4 or less, the L3/4 disc is flexible, L3 is neutral (<15°) and ≤2 cm from the midline and the patient is ≥ Risser 2.

Objective: : The purpose of this study was to identify risk factors for distal adding on (AO) or distal junctional kyphosis (DJK) in adolescent idiopathic scoliosis (AIS) treated by posterior spinal fusion (PSF) to L3 with a minimum 2-year follow-up. Methods: : AIS patients undergoing PSF to L3 by two senior surgeons from 2000–2010 were analyzed. Distal AO and DJK were deemed poor radiographic results and defined as >3 cm of deviation from L3 to the center sacral vertical line (CSVL), or >10° angle at L3–4 on the posterior anterior- or lateral X-ray at ultimate follow-up. New stable vertebra (SV) and neutral vertebra (NV) scores were defined for this study. The total stability (TS) score was the sum of the SV and NV scores. Results: : Ten of 76 patients (13.1%) were included in the poor radiographic outcome group. The other 66 patients were included in the good radiographic outcome group. Lower Risser grade, more SV-3 (CSVL doesn’t touch the lowest instrumented vertebra [LIV]) on standing and side bending films, lesser NV and TS score, rigid L3–4 disc, more rotation and deviation of L3 were identified risk factors for AO or DJK. Age, number of fused vertebrae, curve correction, preoperative coronal/sagittal L3–4 disc angle did not differ significantly between the two groups. Multiple logistic regression results indicated that preoperative Risser grade 0, 1 (odds ratio [OR], 1.8), SV-3 at L3 in standing and side benders (OR, 2.1 and 2.8, respectively), TS score -5, -6 at L3 (OR, 4.4), rigid disc at L3–4 (OR, 3.1), LIV rotation >15° (OR, 2.9), and LIV deviation >2 cm from CSVL (OR, 2.2) were independent predictive factors. Although there was significant improvement of the of Scoliosis Research Society-22 average scores only in the good radiographic outcome group, there was no significant difference in the scores between the groups. Conclusion : The prevalence of AO or DJK at ultimate follow-up for AIS with LIV at L3 was 13.1%. To prevent AO or DJK following fusion to L3, we recommend that the CSVL touch L3 in both standing and side bending, TS score is -4 or less, the L3/4 disc is flexible, L3 is neutral (<15°) and ≤2 cm from the midline and the patient is ≥ Risser 2.

In order to develop a structured and objective diagnostic instrument, authors completed: (1) the translation and back translation of the Korean version of the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL) and (2) the examination of its validity and reliability of the K-SADS-PL-Korean version (K-SADS- PL) when used with Korean children. A total of 91 study subjects were recruited from child and adolescent psychiatry outpatient clinics. Clinical diagnoses were used as a gold standard for the examination of validity of K-SADS-PL-K. Consensual validity of threshold and sub-threshold diagnoses were good to excellent for attention-deficit/hyperactivity disorder (ADHD), fair for tic and oppositional defiant disorders, and poor to fair for anxiety and depressive disorders. Inter-rater and test-retest reliabilities were fair to excellent for ADHD and tic disorder. The significant correlations between the K-SADS-PL-K and Korean Child Behavior Checklist (K-CBCL) were found, which provided additional support for the concurrent validity of the K-SADS-PL-K. Sensitivities varied according to the diagnostic categories, but specificities remained high over all diagnoses, suggesting that the K-SADS-PL-K is a desirable confirmatory diagnostic tool. The results of this study suggest that the K-SADS-PL-K is an effective instrument for diagnosing major child psychiatric disorders, including ADHD, behavioral disorders and tic disorders in Korean children. Future studies will examine the validity and reliability of the K-SADS-PL-K in larger samples, including adolescents and community samples on a variety of child and adolescent psychiatric disorders.
Adolescent ; Child ; Human ; Korea ; Mood Disorders/*diagnosis ; Predictive Value of Tests ; *Psychiatric Status Rating Scales ; Reproducibility of Results ; Schizophrenia/*diagnosis ; Sensitivity and Specificity ; Support, Non-U.S. Gov't ; Translations

PURPOSE: Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials. MATERIALS AND METHODS: This analysis evaluated previously treated and untreated patients in two randomized, open-label phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and “as-treated” populations for efficacy and safety endpoints, respectively. RESULTS: In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. CONCLUSION: These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.
Asia ; Asian Continental Ancestry Group* ; Carboplatin ; Carcinoma, Non-Small-Cell Lung* ; Cisplatin ; Continental Population Groups ; Diarrhea ; Disease-Free Survival ; Drug Therapy* ; Humans ; Incidence ; Lymphoma ; Nausea ; Pemetrexed ; Phosphotransferases ; Vision Disorders