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The influence of age at diagnosis in non-small cell lung cancer (NSCLC) prognosis is unclear.To compare in a Brazilian cohort of NSCLC patients of different age groups: 1) The overall survival; 2) Clinical features and treatment options.This is a retrospective cohort study using a hospital-based registry, for NSCLC patients registered in years 2000-2009. Patients were grouped into three age groups: Young adults (YA:40 years), middle-aged (MA: 40-64 years) and elderly (E: ≥ 65 years). Kaplan-Meier was used to estimate overall survival and Cox regression for hazard ratios (HRs) and 95% confidence intervals.17,422 NSCLC patients were included: 370 YA (2.1%), 8,697 MA (49.9%) and 8,355 E (48.0%). Compared with older age groups, the YA group had a higher proportion of females, patients diagnosed with adenocarcinoma and metastatic disease (63.2%). Overall survival was longer in YA in the entire cohort and in all clinical stages (CSs) (p0.001). For YA, higher education level was a good prognosis factor (compared with illiterate and incomplete elementary); advanced or metastatic disease (compared with early-stage disease) and treatment based in radiotherapy or chemotherapy (CT) (without surgery), compared with treatment combinations with surgery, were poor prognostic factors. Young men (but not women) had lower HR of death compared with older groups; YA had lower HR of death in all CSs compared with patients from older groups. A higher percentage of YA were treated with surgery or CT in early-stage disease compared with older groups. Besides that, YA and MA patients treated with surgery or CT had a better prognosis than elderlies. Conclusions: In this Brazilian cohort of NSCLC patients, most young individuals were diagnosed with metastatic disease. YA presented longer survival than older age groups in all CSs, but mainly in CS I/II and III, where some patients may achieve long remissions or cure.

We have investigated Amblyomin-X-treated horse melanomas to better understand its mode of action through transcriptome analysis and the in vivo model. Amblyomin-X is a Kunitz-type homologous protein that selectively leads to the death of tumor cells via ER stress and apoptosis, currently under investigation as a new drug candidate for cancer treatment. Melanomas are immunogenic tumors, and a better understanding of the immune responses is warranted. Equine melanomas are spontaneous and not so aggressive as human melanomas are, as this study shows that the in vivo treatment of encapsulated horse melanoma tumors led to a significant reduction in the tumor size or even the complete disappearance of the tumor mass through intratumoral injections of Amblyomin-X. Transcriptome analysis identified ER- and mitochondria-stress, modulation of the innate immune system, apoptosis, and possibly immunogenic cell death activation. Interactome analysis showed that Amblyomin-X potentially interacts with key elements found in transcriptomics. Taken together, Amblyomin-X modulated the tumor immune microenvironment in different ways, at least contributing to induce tumor cell death.

OBJECTIVE: To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS: Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: ‘‘Group EPO’’, treated with erythropoietin only; ‘‘Group EPO + IL-6’’, treated with both substances; ‘‘Group IL-6’’, receiving IL-6 administration only; ‘‘Group Placebo’’, receiving a placebo solution; and ‘‘Group Sham’’, submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS: The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS: Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.

Retinoblastoma is the most common intraocular malignant neoplasia during childhood and results from the partial or total inactivity of the retinoblastoma protein (pRb). In the absence of pRb, the E2F transcription factors increase the levels of cell cycle proteins as well as some pro-apoptotic proteins. We intended to study the immunohistochemistry profile of apoptotic-related proteins in retinoblastoma. We also evaluated the association between the expression of apoptotic protein and stage of tumor or survivor after a 5year follow up. Apoptosis-related proteins (Apaf-1, Bak, Bax, Bcl-2, Bcl-xL, Bim-long, MDM2, p53, pro-caspase-3, PUMA, Smac/DIABLO and cleaved caspase-3) were evaluated using immunohistochemistry on tissue microarrays which contained samples of retinoblastoma tumors taken from ninety-three patients without any treatment previous to surgery. The immunohistochemistry reactions were evaluated using an optical microscope as well as the ACIS III® platform. The pro-apoptotic proteins (APAF-1, Bax, p53, PUMA, Smac/DIABLO) were more frequently expressed than the anti-apoptotic proteins (Bcl-2, Bcl-xL and MDM2). The protein Bcl-xL had a negative correlation with cleaved caspase-3, a marker of cell apoptosis. Bcl-xL may be implicated in an apoptosis block.

Background: The anterolateral ligament (ALL) of the knee has recently been described in detail. Most studies of the ALL have been conducted in adults; therefore, little is known about the anatomy and histology of the ALL in younger patients, and nothing is known about the fetal presence of the ALL. Purpose: To evaluate the ALL in human fetuses to determine its presence or absence and to describe its microscopic anatomy and histological features compared with the findings of studies conducted in adults. Study Design: Descriptive laboratory study. Methods: Twenty human fetal cadaveric specimens were used. The mean age of the fetuses was 28.64 ± 3.20 weeks. The ALL was dissected in the anterolateral region of the knee, and its anatomic parameters, including its origin, insertion, and path in relation to known adjacent anatomic landmarks, in addition to its length, width, and thickness over the path toward the tibia, were measured. After dissection, the ALL was removed en bloc with a portion of the lateral meniscus for histological analysis of 4-μm sections, hematoxylin and eosin staining, and immunohistochemical staining for type I collagen. Results: The ALL was located in all dissected knees. Its origin was located at a mean distance of 1.87 mm from the origin of the lateral collateral ligament, with variations from the center of the lateral epicondyle to posterior and proximal to it, and it exhibited an anterior-inferior path toward the tibia, an insertion in the lateral meniscus approximately 2.08 mm anterior to the popliteal tendon, and another insertion in the tibia between the Gerdy tubercle and the fibular head at 2.46 mm below the articular cartilage. The histological sections of the ALL showed well-organized, dense collagenous tissue fibers with elongated fibroblasts (mean, 1631 fibroblasts/mm2) and a predominance of type I collagen. Conclusion: The ALL is present during fetal development, with anatomic and histological features similar to those of the adult ALL. Clinical Relevance: The findings of this study help to better understand the ALL’s anatomy and histology from the fetal period to adulthood. The study presents the existence of the ALL since fetal development, emphasizes the characterization of the ALL, and brings important information to future pediatric ALL lesion studies.

Objectives Several cases of bilateral diffuse pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor have been described in the literature. Nevertheless, some presentations are rare and differential diagnoses are necessary. Methods The purpose of this study was to perform a systematic review of the literature related to PVNS and to report a rare supra-patellar bilateral and focal presentation. We performed a systematic data review in the Pubmed Clinical Queries database using MeSH and keywords related to PVNS and tenosynovial giant cell tumor. Results Two cases of bilateral and local PVNS had been previously described, but neither was localized in the supra-patellar compartment. To our knowledge, this case report is the first to describe supra-patellar bilateral and localized PVNS of the knee. This case involves a 28 -year-old woman with bilateral localized PVNS of the supra-patellar recess of the knee. MRI showed a low-signal intensity nodule in T1- and T2-weighted images. These were associated with hemosiderin pigmentation. Conclusion The most important finding of the case reported is related to rarity and location. Histopathology analysis confirmed a rare case of hemosiderin pigmentation in the capsular nodule with internal non-pigmented villous content. Lipoma arborescens in the supra-patellar form must be ruled out as a differential diagnosis since it occurs in the same site. Level of Evidence IV; Case series. RESUMO Objetivos Diversos casos de sinovite vilonodular pigmentada difusa bilateral (SVNP) ou tumor de células gigantes tenossinoviais foram descritos na literatura. Entretanto, algumas apresentações são raras e o diagnóstico diferencial é necessário. Métodos O objetivo do estudo foi realizar uma revisão da literatura relacionada à SVNP e relatar uma apresentação de forma bilateral e localizada rara na região supra-patelar. Foi realizada uma revisão dos bancos de dados do Pubmed Clinical Queries, MeSH e unitermos relacionados com SVNP e tumor de células gigantes tenossinoviais. Resultados Dois casos de SVNP bilateral e local foram descritos anteriormente. No entanto, nenhum deles foi localizado no compartimento supra-patelar. Até onde sabemos, este relato é o primeiro caso descrito de SVNP bilateral localizada supra-patelar. Apresentamos uma mulher de 28 anos com SVNP bilateral no recesso supra-patelar do joelho. A RM mostrou baixo sinal dos nódulos nas imagens ponderadas em T1 e T2, associados ao pigmento hemossiderina. Conclusão O achado mais importante está relacionado à raridade e localização. A histopatologia confirmou um caso raro de pigmento de hemossiderina no nódulo da cápsula com conteúdo viloso não pigmentado internamente. O diagnóstico diferencial com lipoma arborescens na forma supra-patelar é necessário devido à localização comum. Nível de Evidência IV; Série de casos.

The aim of this study is to characterize in detail the meniscal insertion of the anterolateral ligament (ALL) of the knee, establishing parameters regarding the circumference of the lateral meniscus and the popliteal muscle tendon (PMT) groove in addition to its histological analysis. A total of 33 knees of cadavers were dissected. The ALL and the lateral meniscus were removed en bloc. After removal of the anatomical specimen, the meniscus circumference, the ALL insertion points on the external surface of the lateral meniscus, and the PMT groove were measured. Eight menisci were subjected to histological analysis. The ALL was found in all dissections performed. The ALL insertion occurred macroscopically in the transition between the anterior horn and the lateral meniscus body, specifically beginning at 36.0 % and ending at 41.9 % of the meniscal circumference, occupying a mean area of 5.6 mm. The distance between the end of the ALL meniscal insertion and the beginning of the PMT groove averaged 12.9 mm. In the histological evaluation, in longitudinal sections, we observed dense collagen fibers of the ligament inserting on the external surface of the meniscus. It is possible to observe a spreading of collagen fibers at the moment of meniscal insertion. The ALL meniscal insertion was found in all dissected specimens, beginning with approximately 36 % of the meniscal outer diameter, 12.9 mm anterior to the beginning of the PMT groove. The histological analysis confirmed the presence of true ligamentous tissue in the dissected specimens.

Purpose To describe the anatomy (quantitative macroscopic and histologic), radiographic parameters of the insertions, and biomechanical characteristics of the medial ligamentous restrictors of the patella (medial patellofemoral ligament [MPFL], medial patellotibial ligament [MPTL], and medial patellomeniscal ligament [MPML]) in cadaveric knees. Because the MPTL and the MPML are not as well known as the MPFL, they were the focus of this study. Methods MPFLs, MPTLs, and MPMLs from 9 knees were dissected. Histologic evaluations were conducted. Length, width, and insertion relations with anatomic references were determined. Metallic spheres were introduced into the insertion points of each ligament, and anteroposterior and lateral radiographs were taken. The distances of the insertions from the baselines were measured on radiographs. Tensile tests of the ligaments were performed. Results All the samples showed dense connective tissue characteristic of ligaments. The MPTL was inserted into the proximal tibia (13.7 mm distal to the joint line) and in the distal end of the patella (3.6 mm proximal to the distal border). The MPTL had a length of 36.4 mm and a width of 7.1 mm. The MPML was inserted into the medial meniscus and distally in the patella (5.7 mm proximal to the distal border). Per radiography, on the anteroposterior view, the tibial insertion of the MPTL was 9.4 mm distal to the joint line and in line with the medial border of the medial spine. On the lateral view, the patellar insertions of the MPTL and MPML were 4.8 and 6.6 mm proximal to its distal border, respectively. The MPTL was stiffer than the MPFL (17.0 N/mm vs 8.0 N/mm, P = .024) and showed less deformation in the maximum tensile strength (8.6 mm vs 19.3 mm, P = .005). Conclusions The MPTL inserts into the proximal tibia and into the distal pole of the patella. The MPML inserts into the medial meniscus and into the distal pole of the patella. They present with identifiable anatomic and radiographic parameters. Grafts commonly used for ligament reconstructions should be adequate for reconstruction of the MPTL. Clinical Relevance The study contributes to the anatomic, radiographic, and biomechanical knowledge of the MPTL to improve the outcomes of its reconstruction.

Background: Although the role of cartilage grafts in reconstruction of the posterior eyelid lamella is well established, spontaneous conjunctival epithelialization on such grafts has yet to be fully proven. The aim of this study was to perform a comparative analysis of the influence of perichondrium on conjunctival epithelialization over conchal cartilage grafts used in eyelid reconstruction in rabbits. Methods: The posterior lamellae of 100 lower eyelids from 50 rabbits were reconstructed with autogenous grafts of conchal ear cartilage. In the right eyelids, cartilage was grafted with the perichondrium in direct contact with the eyeball, and the left eyelids were reconstructed in a similar manner but using cartilage grafts without perichondrium. The animals were killed after 1, 2, 3, 4, and 5 weeks, and their lower eyelids were analyzed macroscopically and histologically. Results: The percentage difference in conjunctival epithelialization on the cartilage with perichondrium and that without perichondrium was 11.41 percent in the first week of the experiment, 13.64 percent in the second week, 18.69 percent in the third week, 10.38 percent in the fourth week, and 6.17 percent in the fifth week. The average percentage conjunctival epithelialization in the eyelids reconstructed with a cartilage graft with perichondrium was significantly higher throughout the 5 weeks of the experiment than in the eyelids reconstructed with cartilage without perichondrium (p Conclusion: It was found that the perichondrium had an important role in conjunctival epithelialization in eyelids reconstructed with a cartilage graft in the present study.

Our goal was to develop a novel technique for inducing Achilles tendinopathy in animal models which more accurately represents the progressive histological and biomechanical characteristic of chronic Achilles tendinopathy in humans. In this animal research study, forty-five rabbits were randomly assigned to three groups and given bilateral Achilles injections. Low dose (LD group) (n = 18) underwent a novel technique with three low-dose (0.1mg) injections of collagenase that were separated by two weeks, the high dose group (HD) (n = 18) underwent traditional single high-dose (0.3mg) injections, and the third group were controls (n = 9). Six rabbits were sacrificed from each experimental group (LD and HD) at 10, 12 and 16 weeks. Control animals were sacrificed after 16 weeks. Histological and biomechanical properties were then compared in all three groups. At 10 weeks, Bonar score and tendon cross sectional area was highest in HD group, with impaired biomechanical properties compared to LD group. At 12 weeks, Bonar score was higher in LD group, with similar biomechanical findings when compared to HD group. After 16 weeks, Bonar score was significantly increased for both LD group (11,8±2,28) and HD group (5,6±2,51), when compared to controls (2±0,76). LD group showed more pronounced histological and biomechanical findings, including cross sectional area of the tendon, Young's modulus, yield stress and ultimate tensile strength. In conclusion, Achilles tendinopathy in animal models that were induced by serial injections of low-dose collagenase showed more pronounced histological and biomechanical findings after 16 weeks than traditional techniques, mimicking better the progressive and chronic characteristic of the tendinopathy in humans.

OBJECTIVE: To standardize a spinal cord lesion mouse model. METHODS: Thirty BALB/c mice were divided into five groups: four experimental groups and one control group (sham). The experimental groups were subjected to spinal cord lesion by a weight drop from different heights after laminectomy whereas the sham group only underwent laminectomy. Mice were observed for six weeks, and functional behavior scales were applied. The mice were then euthanized, and histological investigations were performed to confirm and score spinal cord lesion. The findings were evaluated to prove whether the method of administering spinal cord lesion was effective and different among the groups. Additionally, we correlated the results of the functional scales with the results from the histology evaluations to identify which scale is more reliable. RESULTS: One mouse presented autophagia, and six mice died during the experiment. Because four of the mice that died were in Group 5, Group 5 was excluded from the study. All the functional scales assessed proved to be significantly different from each other, and mice presented functional evolution during the experiment. Spinal cord lesion was confirmed by histology, and the results showed a high correlation between the Basso, Beattie, Bresnahan Locomotor Rating Scale and the Basso Mouse Scale. The mouse function scale showed a moderate to high correlation with the histological findings, and the horizontal ladder test had a high correlation with neurologic degeneration but no correlation with the other histological parameters evaluated. CONCLUSION: This spinal cord lesion mouse model proved to be effective and reliable with exception of lesions caused by a 10-g drop from 50 mm, which resulted in unacceptable mortality. The Basso, Beattie, Bresnahan Locomotor Rating Scale and Basso Mouse Scale are the most reliable functional assessments, and but the horizontal ladder test is not recommended.

Keratoacanthoma generally occurs on the skin; it is rarely found in the conjunctiva. A case of a 34-year-old woman with a rapidly growing conjunctival mass is reported. The tumor was excised with a safety margin to exclude squamous cell carcinoma. Histopathologically it was crateriform and consistent with atypical keratoacanthoma. There has been no recurrence in 2 years of follow-up. Conjunctival keratoacanthoma is rare; differential diagnosis of conventional squamous cell carcinoma and keratoacanthoma can be difficult. We recommend complete surgical excision and careful follow-up of crateriform squamous proliferations.

Keratoacanthoma generally occurs on the skin; it is rarely found in the conjunctiva. A case of a 34-year-old woman with a rapidly growing conjunctival mass is reported. The tumor was excised with a safety margin to exclude squamous cell carcinoma. Histopathologically it was crateriform and consistent with atypical keratoacanthoma. There has been no recurrence in 2 years of follow-up. Conjunctival keratoacanthoma is rare; differential diagnosis of conventional squamous cell carcinoma and keratoacanthoma can be difficult. We recommend complete surgical excision and careful follow-up of crateriform squamous proliferations.Ceratoacantoma geralmente ocorre na pele e raramente é encontrado na conjuntiva. Relatamos um caso de uma mulher de 34 anos que apresentou uma massa conjuntival de rápido crescimento. O tumor foi retirado com margem de segurança para excluir carcinoma de células escamosas. Ao exame histopatológico, o tumor apresentou configuração crateriforme, sendo consistente com ceratoacantoma atípico. Não houve recorrência após dois anos de seguimento. Ceratoacantoma conjuntival é uma doença rara. Um diagnóstico diferencial entre carcinoma de células escamosas e ceratoacantoma pode ser difícil. Recomendamos total remoção e seguimento cuidadoso de pacientes com lesões escamosas crateriformes.

Background: No consensus exists regarding the anatomic characteristics of the knee anterolateral ligament (ALL). A critical analysis of the dissections described in previous studies allows the division of the ALL into 2 groups with similar characteristics. The presence of considerable variability suggests that the authors may not be referring to the same structure. Purpose/Hypothesis: To perform a lateral anatomic dissection, by layers, seeking to characterize the 2 variants described for the ALL on the same knee. We hypothesized that we would identify the 2 variants described for the ALL and that these variants would have distinct characteristics. Study Design: Descriptive laboratory study. Methods: Thirteen unpaired cadaveric knees were used in this study. The dissection protocol followed the parameters described in previous studies. Immediately below the iliotibial tract, we isolated a structure designated as the superficial ALL, whereas between this structure and the articular capsule, we isolated a structure designated as the deep ALL. The 2 structures were measured for length at full extension and at 90° of flexion and for distance from the tibial insertion relative to the Gerdy tubercle. Potential contact with the lateral meniscus was also evaluated. After measurements were obtained, the 2 dissected structures underwent histologic analysis. Results: The superficial ALL presented a posterior and proximal origin to the center of the lateral epicondyle, its length increased on knee extension, and it exhibited no contact with the lateral meniscus. The deep ALL was located in the center of the lateral epicondyle, its length increased on knee flexion, and it presented a meniscal insertion. Both structures had a similar tibial insertion site; however, the insertion site of the deep ALL was located more posteriorly. The analysis of the histological sections for both structures indicated the presence of dense and well-organized collagen fibers. Conclusion: This anatomic study clearly identified 2 structures, described as the superficial and deep ALL, which were consistent with previous but conflicting descriptions of the ALL. Clinical Relevance: This study clarifies numerous controversies encountered in anatomic studies of the ALL. Knowledge regarding the existence of 2 distinct structures in the anterolateral knee will allow more accurate evaluation of their functions and characteristics.

Retinoblastoma is the second most common childhood intraocular malignancy and development of the tumor is initiated by bi-allelic loss of the RB1 gene. Bi-allelic RB1 loss may not always directly lead to malignant retinoblastoma, rather other genetic changes are likely involved. Subsequent mutational events, specifically gain and loss of chromosomal regions harboring key oncogenes and tumor suppressor genes, appear to underlie the progression of precursor lesions such as retinoma to retinoblastoma. Research thus far has implicated several cytogenetic aberrations in this sequence of molecular events, the two most recurrent and notable being the augmented copy number status of KIF14 and MDM4 on 1q and of DEK and E2F3 on 6p. A small subset of retinoblastoma also exhibits high-level amplification of the MYCN gene on chromosome 2p. KIF14, MDM4, DEK, E2F3 and MYCN have been widely characterized as oncogenes in a variety of cancers. The functional roles of the proteins encoded by these genes would also confer tumor cells manifesting these genomic changes with a selective survival and proliferative advantage. Our project is testing the hypothesis that 1q and 6p gain and 2p amplification - defined by extra copies of KIF14 and MDM4, DEK and E2F3 and MYCN respectively - are associated with clinical parameters of progression. The study comprises formalin-fixed paraffin-embedded fluorescence in situ hybridization (FFPE-FISH) analysis of pre-constructed tissue microarrays comprising 121 patient tumours, in order to determine the genomic copy number status of the five aforementioned genes. Results show 1q gain (3-10 copies) in 102/121 (84%), 6p gain in 115/121 (95%), MYCN gain in 14/121 (12%) and MYCN amplification (>10 copies) in 16/121 (14%) patient tumors. Assessment of potential correlations between the copy number status of these genes and clinical variables of disease progression include patient age, pathology at the time of diagnosis, optic nerve invasion, choroid involvement, laterality of the disease, number of tumor foci present at the time of diagnosis and histopathological parameters. To our knowledge, there has been no recent study associating genomic change of these five genes with clinical parameters of progression in a sample size of statistical significance. The large cohort and consequent statistical power of our results will facilitate a better understanding of the biological role of these genes in the progression from retinoma to retinoblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4361.