Methylation signature of lymph node metastases in breast cancer patients.

BACKGROUND: Invasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers. METHODS: The quantitative methylation analysis was performed using the SEQUENOM's EpiTYPER? assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: The quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis. CONCLUSIONS: The results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.

Synchronous Digital Hierarchy implementation to a Radio Transmission Node

Kiristyville markkinoille on aina tuotava jotain uutta tarjottavaa ja SDH-kortti on yksi sellainen tuote jonka Nokia Networks julkistaa osaksi uutta Nokia Flexihub Nodea. Tavoitteena on suunnitella VC-12kanavoitu STM-1 kortti yhdistämään ylemmän tason tietoliikenneverkko suuren kapasiteetin radioon. Ennen kuin markkinoilla on valmis tuote, on sen takana valtaisa määrä työtä. Erilaisia dokumentteja on pitänyt tuottaa ja sopimuksia tehdä. Esimerkiksi vaatimusmäärittelyt on oltava selvät, jotta tiedetään mitä tuotteelta halutaan. Tätä ennen on kuitenkin pitänyt ymmärtää miten SDHtoimii ja miten otsikkotavuja käsitellään. Myös erilaiset piirivalinnat aiheuttavat miettimistä, sillä markkinoilla on runsaasti valmiita piirejä SDH signaalinkäsittelyyn. Varma tiedonsiirto on tärkeää puhelinoperaattorille ja siksi joudutaan miettimään varmennuksia ja niiden toteuttamista. Myös synkronointi on tärkeä osa SDH järjestelmää ja sen toteuttaminen hyvin on tärkeää. Hälytykset on otettava huomioon ja mietittävä, miten niiden käsittely saadaan hoidettua järkevästi, ilman että mikään järjestelmän osa ruuhkautuu kohtuuttomasti. Tässä Diplomityössä on tutustuttu SDH-järjestelmään, otsikkotavujen käsittelyyn ja vaatimusmäärittelyihin.

Prognostic value of sentinel node biopsy in 327 prospective melanoma patients from a single institution

Résumé Etude de la valeur pronostique de la biopsie du ganglion sentinelle dans une étude prospective monocentrique de 327 patients atteints de mélanome malin But II s'agit de confirmer la validité de la biopsie du ganglion sentinelle, d'en définir la morbidité, d'investiguer les facteurs prédictifs pour le statut du ganglion sentinelle ainsi que de déterminer les facteurs pronostiques pour la survie sans récidive et la survie spécifique liée à la maladie. Matériel et méthode D'octobre 1997 à décembre 2004, 327 patients consécutifs présentant un mélanome cutané primaire des membres, du tronc et de la tête, sans adénopathie clinique ni métastase à distance ont été inclus. La biopsie du ganglion sentinelle a été réalisée selon la triple technique (lymphoscintigraphie, colorant bleu vital et sonde de détection gamma). Les paramètres et la survie ont été évalués par différentes analyses de régression logistique multiple selon Cox et la survie évaluée selon Kaplan Meier. Résultats Vingt-trois pour cent des patients présentaient au moins un ganglion sentinelle métastatique, ce qui était associé de façon significative à l'épaisseur selon Breslow (p<0.001). Le taux de succès de la biopsie du ganglion sentinelle était de 99.1% et sa morbidité de 7.6%. Avec une durée médiane de suivi de 33 mois, la survie sans récidive à 5 ans était de 43% pour les patients avec un ganglion sentinelle positif et de 83.5% pour ceux avec un ganglion sentinelle négatif. La survie spécifique liée à la maladie à 5 ans était de 49% pour les patients avec un ganglion sentinelle positif et de 87.4% pour ceux avec un ganglion sentinelle négatif. Le taux de faux négatif de la biopsie du ganglion sentinelle était de 8.6%. L'analyse multivariée a démontré que la survie sans récidive était significativement péjorée par :l'épaisseur selon Breslow (RR=5.6, p<0.001), un ganglion sentinelle positif (RR=5.0, p<0.001), et le sexe masculin (RR=2.9, p=0.001). La survie spécifique liée à la maladie était significativement diminuée par : un ganglion sentinelle métastatique (RR=8.4, p<O.OOI), le sexe masculin (RR=6.1, p<0.001), l'épaisseur selon Breslow (RR=3.2, p=0.013), et la présence d'une ulcération (RR=2.6, p=0.015). Conclusion La biopsie du ganglion sentinelle est une procédure fiable avec une haute sensibilité (91.4%) et une faible morbidité (7.6%). L'épaisseur selon Breslow était le seul facteur prédictif significatif pour le statut du ganglion sentinelle. La survie sans récidive était péjorée selon un ordre décroissant par :l'épaisseur selon Breslow, un ganglion sentinelle métastatique, et le sexe masculin. De façon similaire la survie spécifique liée à la maladie était péjorée par : un ganglion sentinelle métastatique, le sexe masculin, l'épaisseur selon Breslow, et une ulcération. Ces données renforcent le statut du ganglion sentinelle en tant que puissant moyen pour évaluer le stade tumoral ainsi que le pronostic.

Adjuvant cisplatin-based combined chemotherapy for lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC): a retrospective international study of >1500 patients.

OBJECTIVE: To compare outcomes of patients with lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) treated with or without cisplatin-based combined adjuvant chemotherapy (AC) after radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analysed 1523 patients with LN-positive UCB, who underwent RC with bilateral pelvic LN dissection. All patients had no evidence of disease after RC. AC was administered within 3 months. Competing-risks models were applied to compare UCB-related mortality. RESULTS: Of the 1523 patients, 874 (57.4%) received AC. The cumulative 1-, 2- and 5-year UCB-related mortality rates for all patients were 16%, 36% and 56%, respectively. Administration of AC was associated with an 18% relative reduction in the risk of UCB-related death (subhazard ratio 0.82, P = 0.005). The absolute reduction in mortality was 3.5% at 5 years. The positive effect of AC was detectable in patients aged ≤70 years, in women, in pT3-4 disease, and in those with a higher LN density and lymphovascular invasion. This study is limited by its retrospective and non-randomised design, selection bias, the absence of central pathological review and lack in standardisation of LN dissection and cisplatin-based protocols. CONCLUSION: AC seems to reduce UCB-related mortality in patients with LN-positive UCB after RC. Younger patients, women and those with high-risk features such as pT3-4 disease, a higher LN density and lymphovascular invasion appear to benefit most. Appropriately powered prospective randomised trials are necessary to confirm these findings.

Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients.

One hundred twenty-two early-stage anal canal cancer patients (median age: 69 years) were treated with curative radiotherapy with (70 patients) or without (52 patients) concomitant chemotherapy. Median follow-up was 65 months (range: 4-238). At multivariate analysis, concomitant chemotherapy significantly improved local control (p = .007). Local control significantly influenced all considered endpoints, except the metastases free survival. The global rates of G3-G4 acute and late toxicity were 13.1% and 8.2%, respectively, and they were not increased by concomitant chemotherapy. Finally, concomitant chemotherapy is efficacious and safe in the treatment of T1-2N0 anal canal cancer patients and should be prospectively studied.

The role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study.

OBJECTIVE: To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. PATIENTS AND METHODS: We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. RESULTS: In all patients (Tall N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. CONCLUSIONS: AC seems to reduce mortality in patients with pT3-4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.

Local behavior and lymph node metastases of Wilms' tumor: accuracy of computed tomography

Objective To evaluate the accuracy of computed tomography for local and lymph node staging of Wilms' tumor. Materials and Methods Each case of Wilms' tumor was evaluated for the presence of abdominal lymph nodes by a radiologist. Signs of capsule and adjacent organ invasion were analyzed. Surgical and histopathological results were taken as the gold standard. Results Sensitivity was 100% for both mesenteric and retroperitoneal lymph nodes detection, and specificity was, respectively, 12% and 33%, with positive predictive value of 8% and 11% and negative predictive value of 100%. Signs of capsular invasion presented sensitivity of 87%, specificity of 77%, positive predictive value of 63% and negative predictive value of 93%. Signs of adjacent organ invasion presented sensitivity of 100%, specificity of 78%, positive predictive value of 37% and negative predictive value of 100%. Conclusion Computed tomography tumor showed low specificity and low positive predictive value in the detection of lymph node dissemination. The absence of detectable lymph nodes makes their presence unlikely, and likewise regarding the evaluation of local behavior of tumors.

Clinically occult metastases in patients with cutaneous melanoma. Detection with sentinel lymph node biopsy and whole body positron emission tomography

Objective: The aim of this study was to investigate the use of sentinel lymph node biopsy (SLNB) and whole body positron emission tomography (PET), with emphasis on surgical treatment and prognosis, in the detection of clinically occult metastases in patients with clinically localized cutaneous melanoma. Patients and methods: The study population consisted of 1255 patients with clinical stage I–II cutaneous melanoma, operated at Turku University Hospital between 1983 and 2007. 334 patients underwent SLNB and they were compared to 921 retrospective patients. A subgroup of 30 symptom-free patients with high risk melanoma underwent prospectively whole body PET 6–24 months postoperatively. Results: Overall, the disease-specific survival rate was 84.4 % at five years. Sex, Breslow thickness, age and nodal status were independent prognostic factors for survival. SLNB revealed occult nodal metastases in 17 % of the patients. There was no significant difference in disease-specific overall survival between SLNB patients and controls, but the nodal disease-free time was significantly longer suggesting better local control after SLNB and subsequent completion lymph node dissection. The followup time was different between the study cohorts and initial surgery was performed during different time periods. SLNB detected micrometastases in seven of 155 patients (4.5 %) with thin T1 primary melanoma and in four of 25 patients (16 %) with head and neck melanoma. In six of 30 asymptomatic patients with high risk melanoma (20 %), whole body PET detected occult distant metastases. Conclusion: Both SLNB and whole body PET were reliable methods to detect clinically occult metastases in patients with cutaneous melanoma. This upstaging altered the treatment in each case.

Lymph node metastasis in early gastric cancer

OBJECTIVE: to evaluate the incidence of lymph node metastasis in early gastric cancer, identifying risk factors for its development. METHODS: we conducted a prospective study of patients with gastric cancer admitted to the Section of the Esophago-Gastric Surgery of the Surgery of Service HUCFF-UFRJ, from January 2006 to May 2012. RESULTS: the rate of early gastric cancer was 16.3%. The incidence of nodal metastases was 30.8% and occurred more frequently in patients with tumors with involvement of the submucosa (42.9%), in those poorly differentiated (36.4%), in tumors larger than 2 cm (33.3%) and in type III ulcerated lesions (43.8%). CONCLUSION: the incidence of lymph node metastases in patients was very high and suggests that one should keep the radicality of resection in early gastric cancer, particularly in relation to D2 lymphadenectomy, recommended for advanced gastric cancer. Conservative resections, with lymphadenectomies smaller than D2, should be performed only in selected cases, well-studied as for the risk factors of lymph node metastasis. Despite the small number of cases did not permit to relate the rate of lymph node metastasis to the risk factors considered, we noted a strong tendency for the occurrence of these metastases in the poorly differentiated, type III, larger than 2 cm tumors, and in the Lauren diffuse types.

Localization of metastasis within the sentinel lymph node biopsies: a predictor of additional axillary spread of breast cancer?

PURPOSE: To explore the relationship between morphological characteristics and histologic localization of metastasis within sentinel lymph nodes (SLN) and axillary spread in women with breast cancer. METHODS: We selected 119 patients with positive SLN submitted to complete axillary lymph node dissection from July 2002 to March 2007. We retrieved the age of patients and the primary tumor size. In the primary tumor, we evaluated histologic and nuclear grade, and peritumoral vascular invasion (PVI). In SLNs we evaluated the size of metastasis, their localization in the lymph node, number of foci, number of involved lymph nodes, and extranodal extension. RESULTS: Fifty-one (42.8%) patients had confirmed additional metastasis in non-sentinel lymph nodes (NLSN). High histologic grade, PVI, intraparenchymatous metastasis, extranodal neoplastic extension and size of metastasis were associated with positive NLSN. SLN metastasis affecting the capsule were associated to low risk incidence of additional metastasis. After multivariate analysis, PVI and metastasis size in the SLN remained as the most important risk factors for additional metastasis. CONCLUSIONS:The risk of additional involvement of NSLN is higher in patients with PVI and it increases progressively according the histologic localization in the lymph node, from capsule, where the afferent lymphatic channel arrives, to the opposite side of capsule promoting the extranodal extension. Size of metastasis greater than 6.0 mm presents higher risk of additional lymph node metastasis.

Uterine lymphangiography: comparison of two methods for locating the medial iliac lymph node

Different methods for lymphatic mapping in dogs, such as infusing tissues with vital dyes or radioactive substances, have been studied, aiming at the early detection of lymph node metastasis. Thus, one could anticipate therapeutic measures and, consequently, prolong the survival and improve the quality of life of the patients. The objectives of this experiment were to locate the nodes responsible for draining the uterine body and horns and to try to establish the relationship between the uterus and the medial iliac lymph nodes to contribute to the early diagnosis and prognosis of uterine disorders. We studied 15 female dogs divided into two groups (5 dead and 10 intraoperative ovariohysterectomy bitches). The dye used was patent blue V (Patent Bleu V®). It was observed that the iliac lymph node chain receives much of the uterine (horns) drainage. This method should be considered for safer studies of uterine sanity. This information suggests that evaluating these lymph nodes will allow correlating changes in their physiological status with uterine pathologies.

Geometric nonlinear dynamic analysis of plates and shells using eight-node hexahedral finite elements with reduced integration

This work presents a geometric nonlinear dynamic analysis of plates and shells using eight-node hexahedral isoparametric elements. The main features of the present formulation are: (a) the element matrices are obtained using reduced integrations with hourglass control; (b) an explicit Taylor-Galerkin scheme is used to carry out the dynamic analysis, solving the corresponding equations of motion in terms of velocity components; (c) the Truesdell stress rate tensor is used; (d) the vector processor facilities existing in modern supercomputers were used. The results obtained are comparable with previous solutions in terms of accuracy and computational performance.

Lymph node transfer in the treatment of postmastectomy lymphedema

Background: Lymphedema is a debilitating disorder with few treatment options. Clinical studies have shown that microvascular lymph node transfer may improve the lymphatic function of the affected limb. This study provides information about the clinical efficacy and safety of this procedure. Further, the biological background of this technique is clarified with an analysis of postoperative production of lymphatic growth factors and cytokines related to lymphangiogenesis. Patients and Methods: The effect of lymph node transfer to recipient and donor sites was analyzed with lymphoscintigraphy, limb circumference measurements, and appearance of clinical symptoms. Axillary seroma samples were analyzed from four patient groups: Axillary lymph node removal (ALND), Microvascular breast reconstruction (BR), lymph node transfer (LN) and combined lymph node transfer and breast reconstruction (LN-BR). Results: The postoperative lymphatic transport index was improved in 7/19 patients. Ten patients were able to reduce or discontinue compression therapy 6 - 24 months postoperatively. The donor lower limb lymphatic flow was slightly impaired (Ti >10) in 2 patients. No donor site lymphedema symptoms appeared during the 8 – 56-month follow-up. A high concentration of the VEGF-C protein was detected in the seroma fluid of all flap transfer groups. The concentration of the anti-inflammatory and anti-fibrotic cytokine IL-10 was increased in the LN-BR group samples when compared to the ALND or BR group. Conclusions: According to this preliminary study, the lymph node transfer seems to be beneficial for the lymphedema patients. However, a randomized study comparing the effect of BR and LN-BR is needed to evaluate the clinical efficacy of lymph node transfer. In addition, the effect of this surgery on the donor site needs to be studied further. The clinical effects of the lymph node transfer might be partly mediated by increased production of the lymphangiogenic growth factor (VEGF-C) as well as the anti-fibrotic cytokine (IL-10).

DataONE Member Node Implementation Workshop

Workshop at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014