Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells.

We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.

A tale of five stories: Defence spending and economic growth in NATO´s countries.

This article examines the relationship between defence expenditure and its impact on the growth of NATO's countries between 2005 and 2018. The aim is to determine if this relation exists and to test if it is possible to discover different models across the countries. The results obtained using the Arellano-Bond estimator, suggest that there is more than one model, and confirm, through the poolability test, the existence of five different groups of countries within the Alliance, with different impacts of the defence expenditure on their gross domestic product. These findings are in line with the review of existing literature that reveals heterogeneity in the results due to different parameters used.

Can invasive breast carcinoma with close or positive margins be managed without a new surgery?

We present the long-term outcome (FU 127 months) of a prospective study with 248 breast cancer patients with close or positive surgical margin, treated with 50 Gy whole breast irradiation plus high-dose-rate boost, 3 × 4.4 Gy. Actuarial breast failure at 10/15 years was 6.5%/11.6%; with positive margin (120) 6.8%/14.8%, with margin ≤2 mm (76) 9.8%/9.8%, with margin >2 mm <5 mm (52) 2%/2%. In 90 patients aged ≤50 was 11.9%/17.8%, between 51 and 70, 3.8%/8.2%, >70, 0%. Fibrosis appeared in 26.7%. Cosmetic outcome was excellent/good in 85.8%. This approach avoids a second surgery in women >50 with positive surgical margin, or with close margins in all ages.

High-dose-rate interstitial brachytherapy boost in inoperable locally advanced tongue carcinoma.

PURPOSE: Locally advanced tongue carcinomas (LATCs) in inoperable lesions are managed with external beam radiation therapy (EBRT) and chemotherapy. In our institution, the boost to the gross tumor volume is delivered with high-dose-rate brachytherapy (HDR-BT) after EBRT. We review the outcome of these patients when HDR-BT is added as a boost. METHODS AND MATERIALS: From May 2000 to December 2014, a total of 24 patients with LATC, nonsurgical oral tongue, and base of tongue carcinomas were treated with EBRT and with interstitial plastic tubes for brachytherapy; median dose was 18-24 Gy in 6-8 fractions after 50-60 Gy of EBRT. Mean age was 60 years, 20 men and 4 women. The distribution by stages was 11 patients in Stage III and 13 patients in Stage IV. All cases but one received chemotherapy. RESULTS: With a median followup of 44 months, local control (LC) rate at 4 years was 80% for the entire group, 78% in Stage III, and 90% in Stage IV. The cause-specific survival was 68% at 4 years; the regional control was 76%. Four patients developed distant metastasis with disease free from distant metastasis of 77% at 4 years. The overall survival was 68% at 4 years. CONCLUSIONS: HDR-BT yields similar results to low dose rate in treatment of patients with LATC, with better results than those reported with exclusive EBRT. HDR-BT allows to increase the local dose, with good LC rates. In patients with large tumors requiring very mutilating surgery and patients who refuse surgery, EBRT with HDR-BT boost is a good option to increase the LC and cause-specific survival while keeping a better functional outcome.

Braquiterapia de alta tasa en el carcinoma escamoso de labio en estadios iniciales / High dose rate brachytherapy in early stage squamous-cell carcinoma of the lip

Introducción y objetivos: Analizar los resultados obtenidos en el tratamiento del carcinoma escamoso de labio en estadios iniciales (T1-T2) con braquiterapia de alta tasa y evaluar la eficacia para el control local y regional de dicho tratamiento. Material y métodos: Análisis retrospectivo de los tratamientos realizados entre marzo de 1999 y marzo de 2013 con braquiterapia de alta tasa de dosis con agujas rígidas, a 68 pacientes, 63 varones y 5 mujeres. Treinta y siete pacientes (54,4%) presentaban un tumor igual o menor de 2cm (T1), y 31 (45,6%) de 2-4cm (T2). En todos se indicó braquiterapia radical con una dosis total mediana de 45Gy, con una dosis por fracción de 5Gy x 9 fracciones, dos veces al día, en un ingreso de cinco días. Resultados: Con 56,4 meses de seguimiento medio el control local fue 96,9%. En pacientes con tumores T1 el control local fue del 100%, mientras en T2 fue 93,2% (2 recidivas locales). El control regional a 5 años, en T1 fue 93,8% y en T2 80,8%. En once casos con profilaxis cervical no hubo recaídas. En cuanto a toxicidad, ningún paciente presentó necrosis de tejidos blandos ni ósea y en todos ellos se consiguieron resultados cosméticos y funcionales buenos o excelentes. Conclusiones: La braquiterapia de alta tasa permite realizar métodos seguros y efectivos para tratamiento del carcinoma escamoso de labio, con buenos resultados estéticos y funcionales y mínimas complicaciones y puede considerarse una alternativa válida al tratamiento quirúrgico en estadios iniciales (AU)

Introduction and goals: To analyze the results obtained after treatment of early stage (T1-T2) squamous cell carcinoma of the lip with high dose rate brachytherapy and evaluate the efficacy of this treatment in both local and regional control. Materials and methods: Retrospective analysis of the treatments performed at our department from March 1999 to March 2013 with high dose rate brachytherapy with rigid needles. We included 68 patients, 63 men and 5 women; 37 patients (54.4%) presented a T1 tumour, less than or equal to 2cm, while the other 31 (45.6%) were classified as T2. Median total dose was 45Gy, with a median dose per fraction of 5Gy x 9 fractions twice a day for 5 days. Results: With a mean follow-up of 56.4 months, local control was 96.9%. Stratifying by tumour size, local control of T1 cases was 100%, while T2 achieved 93.2% (2 local recurrences). Regional control at 5 years was 93.8% for T1, and 80.8% for T2. In 11 cases with elective cervical treatment, no regional failure happened. As for toxicity, no patient presented soft tissue, or bone, necrosis. All patients achieved good or excellent cosmetic and functional results. Conclusions: High dose rate brachytherapy allows effective, safe treatments for squamous cell carcinoma of the lip, with good aesthetic and functional results. It can be considered a valid alternative for surgery in early stage tumours (AU)

High dose rate brachytherapy in early stage squamous-cell carcinoma of the lip. / Braquiterapia de alta tasa en el carcinoma escamoso de labio en estadios iniciales.

INTRODUCTION AND GOALS: To analyze the results obtained after treatment of early stage (T1-T2) squamous cell carcinoma of the lip with high dose rate brachytherapy and evaluate the efficacy of this treatment in both local and regional control. MATERIALS AND METHODS: Retrospective analysis of the treatments performed at our department from March 1999 to March 2013 with high dose rate brachytherapy with rigid needles. We included 68 patients, 63 men and 5 women; 37 patients (54.4%) presented a T1 tumour, less than or equal to 2cm, while the other 31 (45.6%) were classified as T2. Median total dose was 45Gy, with a median dose per fraction of 5Gy x 9 fractions twice a day for 5 days. RESULTS: With a mean follow-up of 56.4 months, local control was 96.9%. Stratifying by tumour size, local control of T1 cases was 100%, while T2 achieved 93.2% (2 local recurrences). Regional control at 5 years was 93.8% for T1, and 80.8% for T2. In 11 cases with elective cervical treatment, no regional failure happened. As for toxicity, no patient presented soft tissue, or bone, necrosis. All patients achieved good or excellent cosmetic and functional results. CONCLUSIONS: High dose rate brachytherapy allows effective, safe treatments for squamous cell carcinoma of the lip, with good aesthetic and functional results. It can be considered a valid alternative for surgery in early stage tumours.

Comparison of permanent (125)I seeds implants with two different techniques in 500 cases of prostate cancer.

PURPOSE: To perform a comparative study of 500 consecutive (125)I seeds implants for intracapsular prostate carcinoma with two techniques differing in terms of both strand implantation and planning. MATERIAL AND METHODS: From 2002 to 2007 we performed 250 implants with fixed stranded seeds (RapidStrand™) and a preplanning system and from 2007 to 2010, 250 with real-time and ProLink™ system. Mean age was 68 and 66, respectively, median PSA (prostate-specific antigen) 7.3 and 7.2, stage T1-T2a in 98% and 94%, and Gleason ≤ 6 in 96% and 86%. Low risk cases were 81% and 71%. The prescribed dose was 145 Gy to the prostate volume, or 108 Gy plus EBRT 46 Gy in some intermediate risk cases. Hormonal treatment was given to 42% and 28%. RESULTS: Median follow-up was 48 and 47 months, respectively, 14 patients in the first group and 7 patients in the second developed biochemical failure (BF). Actuarial biochemical relapse-free survival (bRFS) at 5 years increased from 90.2% to 97.2% (low risk from 91.3% to 97.2%, intermediate risk from 84.2% to 97.1%). Biochemical failure was independent of hormone treatment. Rectal complications were G1-2 in 1.2% and 5.2%, respectively. A urinary catheter was necessary in 6.9% and 9.6%, and urethral resection in 1.9% and 4.4%. Genitourinary toxicity was G1-2 in 4.6% and 12%, G3-4 in 1.9% and 4.8%. An assessment of mean D90 in a sample of patients showed that the dosimetry in postoperative planning based on CT improved from a mean D90 of 143 Gy to 157 Gy. CONCLUSIONS: The outcome of patients with low risk prostate carcinoma treated with (125)I seed is very good with low complications rate. The real-time approach in our hands achieved a more precise seed implantation, better dosimetry, and a statistically non-significant better biochemical control. We have made this our standard technique.