MicroRNA31 and MMP-1 contribute to the differentiated pathway of invasion -with enhanced epithelial-to-mesenchymal transition- in squamous cell carcinoma of the skin.

Epithelial to mesenchymal transition (EMT) is an important mechanism of invasion in cutaneous squamous cell carcinomas (cSCCs) and has been found to be enhanced in tumors originated from actinic keratosis with transformation limited to the basal epithelial layer -differentiated pathway-, compared to cases with invasion subsequent to complete epidermal transformation -classical pathway-. Several microRNAs and proteins can contribute to EMT modulation in cSCCs. MicroRNA21 and microRNA31 are involved in posttranscriptional regulation of protein expression and could play a relevant role in EMT and cSCC progression. Throughout the EMT process upregulation of matrix metalloproteinases (MMPs) enhances invasiveness and MMP-1 and MMP-3 contribute to local invasion, angiogenesis and metastasis in cSCCs. Additionally, cSCC development is associated with PTEN loss and NF-κB, NOTCH-1 and p63 activation. The aim of this work is to identify differences in the expression of those molecules between both pathways of cSCCs development. Eight tissue microarrays from 80 consecutive cSCCs were analyzed using LNA-based miRNA in situ hybridization for miRNA21 and miRNA31 evaluation, and immunohistochemistry for MMP-1, MMP-3, PTEN, NOTCH-1, NF-κB, p63 and CD31. Significantly higher expression of miRNA31 (p < 0.0001) and MMP-1 (p = 0.0072) and angiogenesis (p = 0.0199) were found in the differentiated pathway, whereas PTEN loss (p = 0.0430) was more marked in the classical pathway. No significant differences were found for the other markers. Our findings support a contribution of miRNA31 and MMP-1 in the differentiated pathway, associated to EMT and increased microvascularization. The greater PTEN loss in the classical pathway indicate that its relevance in cSCC is not EMT-related.

Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns

Background There is growing evidence that the subventricular zone (SVZ) may be involved in both the initiation and progression of glioblastoma (GB). We aimed to assess tumor proximity to the SVZ as a potential prognostic factor in GB. Method Retrospective study of 133 patients diagnosed with primary GB who underwent surgery followed by temozolomide-based chemoradiation between 2010 and 2016. All lesions were classified according to their anatomic relation with the SVZ. We determined the effect of tumor contact with the SVZ on progression-free survival (PFS), overall survival (OS), type, and patterns of recurrence. Results At a median follow-up of 18.6 months (95% CI 15.9–21.2), PFS and OS were 7.5 (95% CI 6.7–8.3) and 13.9 (95% CI 10.9–16.9) months, respectively. On the univariate analyses, initial contact with the SVZ was a factor for poor prognosis for both PFS (6.1 vs. 8.7 months; p = 0.006) and OS (10.6 vs. 17.9 months; p = 0.037). On the multivariate analysis, tumor contact with the SVZ remained statistically significant for PFS, but not OS. Patients with SVZ-contacting tumors presented a higher rate of aggressive clinical progression (30.9% vs. 11.3%; p = 0.007) and contralateral relapse patterns (23.4% vs. 9.1%; p = 0.048). Conclusions Our results suggest that glioblastoma contact with the SVZ appears to be an independent prognostic factor for poor PFS. The presence of an SVZ-contacting tumor was associated with more aggressive recurrences and a higher rate of contralateral relapses. These findings suggest that this variable may be a new prognostic factor in glioblastoma (AU)

Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns.

BACKGROUND: There is growing evidence that the subventricular zone (SVZ) may be involved in both the initiation and progression of glioblastoma (GB). We aimed to assess tumor proximity to the SVZ as a potential prognostic factor in GB. METHOD: Retrospective study of 133 patients diagnosed with primary GB who underwent surgery followed by temozolomide-based chemoradiation between 2010 and 2016. All lesions were classified according to their anatomic relation with the SVZ. We determined the effect of tumor contact with the SVZ on progression-free survival (PFS), overall survival (OS), type, and patterns of recurrence. RESULTS: At a median follow-up of 18.6 months (95% CI 15.9-21.2), PFS and OS were 7.5 (95% CI 6.7-8.3) and 13.9 (95% CI 10.9-16.9) months, respectively. On the univariate analyses, initial contact with the SVZ was a factor for poor prognosis for both PFS (6.1 vs. 8.7 months; p = 0.006) and OS (10.6 vs. 17.9 months; p = 0.037). On the multivariate analysis, tumor contact with the SVZ remained statistically significant for PFS, but not OS. Patients with SVZ-contacting tumors presented a higher rate of aggressive clinical progression (30.9% vs. 11.3%; p = 0.007) and contralateral relapse patterns (23.4% vs. 9.1%; p = 0.048). CONCLUSIONS: Our results suggest that glioblastoma contact with the SVZ appears to be an independent prognostic factor for poor PFS. The presence of an SVZ-contacting tumor was associated with more aggressive recurrences and a higher rate of contralateral relapses. These findings suggest that this variable may be a new prognostic factor in glioblastoma.

The depth of follicular extension in actinic keratosis correlates with the depth of invasion in squamous cell carcinoma: implication for clinical treatment.

BACKGROUND: Actinic keratosis (AK) may show extension down follicles, not only in cases with full-thickness epidermal atypia ('bowenoid' AK), but also in cases with atypia limited to the epidermal basalis. Previous studies have demonstrated that, in bowenoid AK, follicular extension is usually superficial, being limited to the upper follicular segment. Little is known about the depth of follicular involvement in cases of invasive squamous cell carcinoma of the skin (iSCC) arising from AK and the role of the follicle in iSCC pathogenesis. OBJECTIVE: This study investigated the relationship between follicular extension of atypical keratinocytes in an AK and the development of iSCC from the follicular wall. The depth of follicular extension was correlated with the depth invasion of iSCC. Differences between the differentiated and classical pathways of iSCC were also examined. METHODS: We performed a retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK. We assessed the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumour (Breslow) thickness and the follicular unit level (infundibular, isthmic and subisthmic), as well as iSCC being present directly adjacent to the follicular basalis. RESULTS: Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; subisthmic 5/5). CONCLUSION: The depth of follicular extension of atypical keratinocytes in an AK correlates with the development of depth of invasion of an associated iSCC, irrespective of the pathway of origin. It is therefore important to note the presence and the depth of follicular extension when diagnosing an AK, as follicular extension likely accounts for a significant proportion of recurrent AK and the development of iSCC following superficial treatment modalities.

SEOM clinical guidelines for diagnosis and treatment of glioblastoma (2017)

Glioblastoma (GB) is the most common brain malignancy and accounts for over 50% of all high-grade gliomas. Radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy is the current standard of care for patients with newly diagnosed GB up to age 70. Recently, a new standard of care has been adopted for elderly patients (≥ 65 years) based on short course of RT and TMZ. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent GB is not well defined, and decision-making is usually based on prior strategies as well as several clinical and radiological factors. The presence of neurologic deficits and seizures can significantly impact quality of life (AU9

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Epithelial-to-mesenchymal transition contributes to invasion in squamous cell carcinomas originated from actinic keratosis through the differentiated pathway, whereas proliferation plays a more significant role in the classical pathway.

BACKGROUND: Every actinic keratosis (AK) starts with atypia at the basal layers of the epidermis (AK I). Progression into invasive squamous cell carcinoma (iSCC) may occur following two main pathways, classical and differentiated. In the former, iSCC only occurs after involvement of the upper epidermal layers by atypical cells (AK III), while in the latter iSCC develops directly from AK I. In the anogenital mucosa, these two pathways are associated with differential expression of p53 and p16. OBJECTIVE: To explore differences between both pathways in the pathogenesis of AK, focusing on Ki67, p53, p16 and molecules that reveal epithelial-mesenchymal transition (EMT). METHODS: Tissue microarrays representative of superficial and deep portions of 80 consecutive iSCCs (53 DP/27CP) were studied immunohistochemically using antibodies against Ki67, p53, p16, vimentin, E-cadherin, ß-catenin and D2-40. The evaluation was performed by three researchers and the results compared to consensus. RESULTS: Invasive squamous cell carcinomas originated through the differentiated pathway exhibited significantly lower proliferative activity (Ki67) (30% vs 46%, P = 0.003) and significantly lower expression of vimentin (P < 0.001), E-cadherin (P < 0.001) and membranous ß-catenin (P < 0.001) than iSCCs developed through the classical pathway. The expression of E-cadherin and membranous ß-catenin was significantly correlated (Pearson's r = 0.386, Spearman's Rho < 0.001). There were no significant differences regarding the expressions of p53, p16 and D2-40. CONCLUSION: Epithelial-mesenchymal transition participates in transformation from AK I into iSCC (differentiated pathway), whereas a higher proliferative capacity facilitates intraepidermal extension in the classical pathway. Podoplanin, which is also involved in tumour invasion, does not seem to play a differential role in either pathway. Finally, the absence of differences in p53 and p16 expressions is at variance with other epithelia where the classical pathway is associated with human papillomavirus infection and can be explained by the fact that both AK pathways share identical mechanisms of actinic oncogenesis.

SEOM clinical guidelines for diagnosis and treatment of glioblastoma (2017).

Glioblastoma (GB) is the most common brain malignancy and accounts for over 50% of all high-grade gliomas. Radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy is the current standard of care for patients with newly diagnosed GB up to age 70. Recently, a new standard of care has been adopted for elderly patients (≥ 65 years) based on short course of RT and TMZ. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent GB is not well defined, and decision-making is usually based on prior strategies as well as several clinical and radiological factors. The presence of neurologic deficits and seizures can significantly impact quality of life.

Linfoma no-Hodgkin primario del sistema nervioso central asociado a sida en un paciente con panuveítis por virus Epstein-Barr. Reporte clínico-patológico / Aids-related primary CNS non-Hodgkin's lymphoma in a patient with previous Epstein-Barr virus panuveitis. A clinico-pathological report

CASO CLÍNICO: Paciente con sida y uveítis por virus Epstein-Barr (VEB). La PCR de VEB fue positiva para humor acuoso y vítreo. Las cuantificaciones del virus fueron 56,602 × 106 copias/ml en humor vítreo, 173.400 copias/ml en sangre periférica y negativo en líquido cefalorraquídeo (LCR). El paciente desarrolló un linfoma no-Hodgkin (LNH) diagnosticado en la necropsia. CONCLUSIÓN: La uveítis por VEB es poco frecuente y para el diagnóstico es necesario realizar una PCR cuantitativa. Una elevada cantidad de DNA de VEB se ha asociado con mayor incidencia de LNH

CLINICAL CASE: Patient with AIDS and Epstein-Barr virus (EBV) uveitis. The PCR of the aqueous and vitreous humor was positive for EBV, and DNA quantification was 56.602 × 106 copies/ml in the vitreous humor, 173,400 copies/ml in the peripheral blood, and negative in the cerebrospinal fluid (CSF). The patient developed a non-Hodgkin's lymphoma (NHL), diagnosed in the autopsy. CONCLUSION: The EBV is a rare cause of uveitis and it may be necessary to perform a quantitative PCR to reach the diagnosis. High amounts of EBV DNA are associated with a greater incidence of NHL

Actinic keratosis with atypical basal cells (AK I) is the most common lesion associated with invasive squamous cell carcinoma of the skin.

BACKGROUND: Progression from actinic keratosis (AK) to invasive squamous cell carcinoma (iSCC) of the skin is thought to occur after the development of full thickness epidermal neoplasia, as in the classic pathway of cervical cancer. Nevertheless, cutaneous iSCC may also directly arise from a proliferation of atypical basaloid cells limited mostly to the epidermal basal layer (AK I), akin to what happens in the 'differentiated pathway' of iSCC of the vulva, oral cavity and other locations. OBJECTIVE: To evaluate the prevalence of classic and differentiated pathways in the development of cutaneous iSCC. METHODS: The epidermis adjacent to and overlying iSCC, assumed to be representative of pre-existing lesions, was histologically studied in 196 skin biopsy specimens showing iSCC. RESULTS: AK I, AK II and AK III lesions overlying iSCC were present in 63.8%, 17.9% and 18.4% of cases respectively. The corresponding percentages in the epidermis adjacent to iSCC were 77.9%, 6.6% and 8.3% respectively (stage could not be assessed in 8.1% of cases). Focal epidermal ulceration overlying iSCC was seen in 32% of AK I, 28.6% of AK II and 33.3% of AK III instances. Adnexal involvement by atypical keratinocytes (proliferative AK) was present more frequently in cases with overlying AK I (39/125, 31.2%) than with AK II (8/35, 22.9%) and AKII I (5/36, 13.9%). CONCLUSION: Direct invasion from proliferating basaloid atypical keratinocytes limited to the epidermal basal layer (AK I), known as the differentiated pathway, was the most common form of progression to cutaneous iSCC in our series. On the other hand, stepwise progression from AK I to AK II and AK III (classic pathway) was seen to be operative in a substantial proportion of iSCC cases. All AK lesions, irrespective of intraepidermal neoplasia thickness, are therefore potentially invasive and tumour advance along adnexal structures might facilitate iSCC development from AK I lesions.

[AIDS-related primary CNS non-Hodgkin's lymphoma in a patient with previous Epstein-Barr virus panuveitis. A clinico-pathological report]. / Linfoma no-Hodgkin primario del sistema nervioso central asociado a sida en un paciente con panuveítis por virus Epstein-Barr. Reporte clínico-patológico.

CLINICAL CASE: Patient with AIDS and Epstein-Barr virus (EBV) uveitis. The PCR of the aqueous and vitreous humor was positive for EBV, and DNA quantification was 56.602×10(6) copies/ml in the vitreous humor, 173,400 copies/ml in the peripheral blood, and negative in the cerebrospinal fluid (CSF). The patient developed a non-Hodgkin's lymphoma (NHL), diagnosed in the autopsy. CONCLUSION: The EBV is a rare cause of uveitis and it may be necessary to perform a quantitative PCR to reach the diagnosis. High amounts of EBV DNA are associated with a greater incidence of NHL.

Tumour and serum MGMT promoter methylation and protein expression in glioblastoma patients

INTRODUCTION: Methylation of the promoter of the MGMT gene and MGMT protein expression are recognized as predictive markers for response to alkylating chemotherapy in glioblastoma (GB). MATERIAL AND METHODS: We have assessed MGMT methylation with the methylation-specific polymerase chain reaction (MSP) in tumor samples from 70 GB patients and in serum samples from 37 of these patients. We have also assessed MGMT protein expression by immunohistochemical (IHC) analysis in tissue samples from 63 of these patients. RESULTS: We found concordance between MGMT methylation status in tissue and serum (Cohen's Kappa = 0.586; p<0.0001). MSP for detection of non-methylated MGMT promoter in serum showed a sensitivity of 95.4% and a specificity of 60%, while the IHC methylation test showed a low specificity (8.9%). Patients whose MGMT promoter was methylated in tissue attained longer progression-free and overall survival. In the multivariate analysis, serum MGMT promoter methylation emerged as an independent factor for longer progression-free and overall survival. CONCLUSION: Serum-based MGMT methylation analysis offers a promising alternative to tumor-based MGMT analysis in cases where tissue samples are unavailable (AU)

BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer.

BACKGROUND: neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients. PATIENTS AND METHODS: we assessed BRCA1 messenger RNA expression levels in paraffin-embedded pre-treatment tumor samples obtained by transurethral resection from 57 patients with locally advanced bladder cancer subsequently treated with neoadjuvant cisplatin-based chemotherapy. BRCA1 levels were divided into terciles and correlated with pathological response and survival. RESULTS: a significant pathological response (pT0-1) was attained in 66% (24 of 39) of patients with low/intermediate BRCA1 levels compared with 22% (4 of 18) of patients with high BRCA1 levels (P = 0.01). Median survival was 168 months in patients with low/intermediate levels and 34 months in patients with high BRCA1 levels (P = 0.002). In the multivariate analysis for survival, only BRCA1 expression levels and lymphovascular invasion emerged as independent prognostic factors. CONCLUSIONS: our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.

Oligodendrogliomas: características morfológicas y alteraciones moleculares / Oligoendrogliomas: their morphological characteristics and molecular alterations

Introducción. Los oligodendrogliomas constituyen un grupo de gliomas infiltrantes con una buena respuesta al tratamiento radio y quimioterapéutico, por lo que es importante distinguirlos del resto de gliomas, sobre todo de los astrocitomas. Aunque los oligodendrogliomas, en su mayor parte, presentan una histología típica y son fácilmente diagnosticables, en ocasiones poseen una morfología mixta o híbrida que hacen que su clasificación sea difícil y ambigua. En estos casos la inmunohistoquímica es poco útil, pues hasta la fecha no se dispone de marcadores que permitan distinguir de forma fiable entre el oligodendroglioma y el astrocitoma. Desarrollo. En esta revisión se repasan los criterios histológicos de los tumores oligodendrogliales y cómo distinguirlos de otros tumores cerebrales a los que se asemejan morfológicamente. Además, se expone cómo las alteraciones del brazo corto del cromosoma 1 y del brazo largo del cromosoma 19 (codeleción de 1p/19q), objetivables mediante FISH o PCR, permiten, por un lado, clasificar los tumores de hábito mixto oligoastrocitario y, por otro, definir subgrupos de oligodendrogliomas con diferencias en cuanto al pronóstico y la respuesta al tratamiento. Conclusiones. En la práctica diaria, el análisis del estado de 1p y 19q debería realizarse en todos los tumores con fenotipo histológico oligodendroglial, puesto que permite definir subgrupos con diferente pronóstico y respuesta al tratamiento

Introduction. Oligodendrogliomas constitute a group of infiltrating gliomas with a good response to radio and chemotherapy, which makes it important to distinguish them from the other gliomas and more especially from astrocytomas. Although oligodendrogliomas generally present typical histological features and are easy to diagnose, they sometimes have a mixed or hybrid morphology that makes their classification difficult and ambiguous. In these cases immunohistochemistry is of little use, since to date no markers have been found that enable a reliable distinction to be made between oligodendrogliomas and astrocytomas. Development. Here we review the histological criteria of oligodendroglial tumours and how to distinguish them from other morphologically similar brain tumours. We also discuss how alterations to the short arm of chromosome 1 and to the long arm of chromosome 19 (co-deletion of 1p/19q), which can be detected using FISH or PCR, enable us to classify mixed oligoastrocytic tumours and to define subgroups of oligodendrogliomas with different prognoses and responses to treatment. Conclusions. In daily practice, the status of 1p and 19q should be analysed in all tumours with an oligodendroglial histological phenotype, because this makes it possible to define subgroups each having different prognoses and responses to therapy

Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is characterized by the widespread presence of Lewy bodies (LBs) in the brain. alpha-Synuclein, the main component of LBs, is expressed as two main isoforms (112 and 140), but little is known about their differential expression in the brain. We compared alpha-synuclein 112 and alpha-synuclein 140 expression levels in the prefrontal cortices of six DLB patients, eight Alzheimer disease (AD) patients, and six control subjects. Relative alpha-synuclein 112 and alpha-synuclein 140 expression levels were determined by real-time polymerase chain reaction with competimer technology using a LightCycler System. Whereas total alpha-synuclein levels were just marginally elevated in DLB in comparison with the other groups, alpha-synuclein 112 was seen to be markedly increased in DLB compared with AD cases and controls. In contrast, alpha-synuclein 140 levels were significantly diminished in both neurodegenerative disorders in comparison with controls. These results show differential overexpression of alpha-synuclein 112 in DLB, a finding that could be of importance in DLB pathogenesis.

Differential apomucin expression in normal and neoplastic human gastrointestinal tissues.

BACKGROUND/AIMS: The cloning of genes encoding human mucins is the basis for the study of their normal tissue distribution and the alterations associated with cancer. The aim of this study was to determine the normal and tumor tissue expression of MUC1, MUC2, MUC5B, and MUC5C. METHODS: The reactivity of apomucin-specific antibodies with fresh normal and tumor tissues was analyzed using immunohistochemical techniques. RESULTS: Anti-MUC1 antibodies reacted with most glandular epithelia. Anti-MUC2 antibody was mainly reactive with intestinal goblet cells and cervical mucous cells. Anti-MUC5B was reactive with a wide range of epithelial tissues whereas anti-MUC5C was reactive with stomach, trachea, and endocervix. Double-labeling experiments showed coexpression of MUC1/MUC2 and MUC2/MUC5C in colonic tissue. Multiple apomucins were detected in colon cancers, but no relationship to histochemical mucus stains was observed. CONCLUSIONS: It is concluded that (1) each apomucin shows a distinct tissue expression pattern; (2) multiple apomucins are present in a single tissue and at the single cell level; and (3) altered apomucin expression takes place in pathological colonic tissue.

Altered expression of MUC2, MUC4, and MUC5 mucin genes in pancreas tissues and cancer cell lines.

BACKGROUND/AIMS: Neoplastic transformation of epithelial cells is commonly associated with altered synthesis and structure of mucin glycoproteins. The aim of the study was to determine if altered mucin gene expression takes place in pancreas cancer. METHODS: To examine mucin gene expression in normal pancreas and pancreas cancer, antibodies detecting the MUC1, MUC2, MUC5B, and MUC5C apomucins were used in immunohistochemical techniques and complementary DNA probes specific for the MUC1-MUC5 genes were used in Northern blots. RESULTS: MUC1 is the major apomucin expressed in normal pancreas, whereas MUC2-MUC5 are weakly expressed or undetectable. In pancreas cancer tissues and cell lines, increased expression of MUC2, MUC4, and MUC5C is shown. The cytoplasmic expression of MUC2 and MUC5C in tumor cells suggests that these apomucins are underglycosylated and abnormally compartmentalized. CONCLUSIONS: Enhanced expression of MUC2, MUC4, and MUC5C genes is a frequent event in pancreas cancer and may contribute to the alterations in the biochemical structure of pancreas cancer mucins.