Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway.

OBJECTIVES: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many human tumors, leading to the activation of p110α enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved. MATERIAL AND METHODS: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n = 243). The results were validated in an independent cohort form the University Hospital of A Coruña (UHAC, n = 62). Expression of the PIK3CA gene protein product (PI3K p110α) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n = 91). RESULTS: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110α levels correlated with YAP nuclear localization in HNSCC tumors. CONCLUSIONS: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients.

Carcinoma análogo secretor de mama: revisión de diagnóstico y tratamiento a propósito de 2 casos / Mammary analogue secretory carcinoma: presentation of 2 cases and a review of its diagnosis and treatment

Introducción. El carcinoma análogo secretor de mama (MASC: mammary analogue secretory carcinoma) es una entidad neoplásica de las glándulas salivares caracterizada por presentar importantes similitudes histológicas e inmunohistoquímicas con el carcinoma secretor de mama. Hasta su descripción en 2010, el MASC era frecuentemente clasificado como carcinoma de células acinares por su solapamiento morfológico. Ante la falta de evidencia científica en la literatura respecto al tratamiento óptimo de estos tumores, el objetivo de este artículo es presentar 2casos tratados recientemente en nuestro servicio y revisar la literatura descrita acerca de su diagnóstico y tratamiento. Material y métodos. Se trata de un paciente varón de 41 años con diagnóstico de MASC de glándula salivar menor en paladar duro y de una paciente de 56 años con el mismo diagnóstico en la glándula submaxilar. Resultados. En ambos casos se realizó resección quirúrgica con márgenes de la lesión. En uno de ellos, al presentar bordes libres, se decidió control clínico, mientras que en el otro se decidió tratamiento adyuvante con radioterapia al presentar un borde cercano a la lesión. Ambos pacientes tras 2años están libres de enfermedad y mantienen seguimiento clínico. Discusión. En la literatura se había descrito la existencia de un tumor de glándulas salivares con unas características morfológicas comunes entre el carcinoma de células acinares y el carcinoma secretor de mama, caracterizado inmunohistoquímicamente por ser positivo a vimentina y a la proteína S-100, pero no fue conocido como MASC hasta su descripción en 2010. La alteración genética asociada al MASC es la presencia de la translocación t(12;15)(p13;q25) en el oncogén ETV6-NTRK3, lo que lo convierte en un marcador prácticamente patognomónico de este tumor. Respecto al tratamiento, existe consenso en el tratamiento quirúrgico de la lesión primario, y no existe consenso respecto a la disección cervical. El valor de la RT postoperatoria es difícilmente valorable por los escasos casos en la literatura. Conclusiones. El MASC es una enfermedad neoplásica de glándula salivar que precisa un diagnóstico correcto previo a la elección de su tratamiento. Debido a su comportamiento como una neoplasia maligna de bajo grado, consideramos que su tratamiento debe ser el quirúrgico, con unos márgenes de seguridad a la lesión, pero en algunos casos su comportamiento puede ser agresivo (AU)

Introduction. Mammary analogue secretory carcinoma (MASC) is a neoplastic tumour of the salivary glands, characterised by having important histological and immuno-histochemical similarities with secretory breast carcinoma. Until its description in 2010, MASC was often diagnosed as carcinoma of acinar cells due to their morphological overlapping. As there is a lack of evidence in the scientific literature concerning the optimal treatment of these tumours, the aim of this article is to present 2recently treated cases, and review the described literature about their diagnosis and treatment. Material and methods. The first case concerns a 41 year-old male with MASC of the minor salivary gland of the hard palate, and the other a 56 year-old patient with the same diagnosis at the level of the submandibular gland. Results. Surgical resection with lesion-free margins was performed in both cases. Clinical surveillance was decided for one case with free margins, while in the other one, it was decided to give adjuvant therapy with radiotherapy due to the narrow lesion free margin. Both patients are disease free and continue on clinical follow-up. Discussion. The literature describes the existence of a salivary glands tumour with common morphological characteristics between acinar cell carcinoma and breast carcinoma, and immunohistochemically characterised by being positive to vimentin and S-100 protein, but it was not known as MASC until its description in 2010. The genetic alteration associated with MASC is the presence of a translocation t(12;15) (q25; Q13) in ETV6-NTRK3, making it a pathognomonic tumour marker. There is consensus in the surgical treatment of primary lesions, but there is no agreement as regards neck dissection. The value of post-surgical radiotherapy is difficult to assess by the few cases in the literature. Conclusions. MASC is a recently described salivary gland tumour characterised by ETV6 translocation. Due to its behaviour as a low grade malignant neoplasm, it is recommended that its treatment should be excision with surgical margins, but in some cases its behaviour can be aggressive (AU)

DEK oncogene is overexpressed during melanoma progression.

DEK is an oncoprotein involved in a variety of cellular functions, such as DNA repair, replication, and transcriptional control. DEK is preferentially expressed in actively proliferating and malignant cells, including melanoma cell lines in which DEK was previously demonstrated to play a critical role in proliferation and chemoresistance. Still, the impact of this protein in melanoma progression remains unclear. Thus, we performed a comprehensive analysis of DEK expression in different melanocytic tumors. The immunostaining results of 303 tumors demonstrated negligible DEK expression in benign lesions. Conversely, malignant lesions, particularly in metastatic cases, were largely positive for DEK expression, which was partially associated with genomic amplification. Importantly, DEK overexpression was correlated with histological features of aggressiveness in primary tumors and poor prognosis in melanoma patients. In conclusion, our study provides new insight into the involvement of DEK in melanoma progression, as well as proof of concept for its potential application as a marker and therapeutic target of melanoma.

Incidence of human papillomavirus-related oropharyngeal cancer and outcomes after chemoradiation in a population of heavy smokers.

BACKGROUND: Incidence of human papillomavirus (HPV)-related oropharyngeal carcinomas is increasing worldwide. The purpose of this study was to report the incidence in our region, and to determine the influence of HPV status on survival among a heavy smoking population. METHODS: p16 expression was analyzed in 102 patients with stage II to IV treated with chemoradiation. Overall survival (OS), locoregional control, and disease-free survival (DFS) were compared for HPV+ and HPV- status. RESULTS: The majority of patients were smokers (86%). p16 positivity was found in 26.7%. Patients who were HPV+ were younger (56 vs 59 years old; p = .052). No differences were observed regarding tumor stage, sex, or smoking between HPV+ and HPV-. Three-year OS was 67.4% for patients who were HPV+ versus 49.7% for HPV- (hazard ratio [HR], 0.55; p = .095). CONCLUSION: Incidence of HPV-related oropharyngeal carcinoma in Spain is similar to that reported in other European countries. In this sample of heavy smokers, we observed a nonsignificant trend for better outcomes in patients who were HPV+.

Biological markers of cisplatin resistance in advanced testicular germ cell tumours.

INTRODUCTION: Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course. RESULTS: The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival. CONCLUSIONS: Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.

Impact of epidermal growth factor receptor expression on disease-free survival and rate of pelvic relapse in patients with advanced cancer of the cervix treated with chemoradiotherapy.

OBJECTIVES: To determine the impact of the expression of epidermal growth factor receptor (EGFR) on disease-free survival (DFS) and on pelvic relapse in patients with advanced cancer of the cervix receiving concurrent chemoradiotherapy. METHODS: In 112 consecutive patients with advanced cancer of the cervix (11 stage IB2-IIA, 25 IIB, 63 IIIB, 13 IVA) treated with chemoradiotherapy between December 1994 and September 2004, the expression of EGFR using histoimmunochemistry was measured and used in univariate and multivariate analysis, along with variables such as age, International Federation of Gynecology and Obstetrics Staging System for Epithelial Ovarian Cancer (FIGO) stage, histology, Eastern Cooperative Oncology Group (ECOG), tumor size, and ganglia involvement diagnosed with computerized axial tomography, treatment with cisplatin to evaluate its impact on DFS and pelvic relapse. RESULTS: Of the 112 biopsies, 32 (28.6%) were negative or slightly positive (EGFR±) and 80 (71.4%) were moderate or intensely positive (EGFR++/+++). The overexpression of EGFR (++/+++) was significantly associated with an epidermoid histology (P < 0.0001), with a higher rate of pelvis relapse and a decreased DFS (hazard ratio [HR]: 2.31 [1.08-4.96]; P = 0.03). Overall, treatment with cisplatin increased DFS (HR: 0.51 [0.26-0.97]; P = 0.04). CONCLUSIONS: Patients with tumors of the cervix and overexpression of the EGFR++/+++ show a higher probability of pelvic relapses and a decreased disease-free survival. The poor prognosis of these tumors may be a consequence of an increase in radio-resistance.

Expression of EGFR, HER-2/neu and KIT in germ cell tumours.

BACKGROUND: Germ cell tumours (GCTs) represent an extraordinarily chemosensitive malignancy. However, 20-30% of patients with advanced disease cannot be cured by currently available treatments. The role of tyrosine kinase receptors has been widely studied in other malignancies. Yet, limited information is available on GCTs. METHODS: One hundred and nine paraffin-embedded GCTs in 84 patients were assessed by immunohistochemistry for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2)/neu and KIT (CD117) expression. Univariate and multivariate analyses were performed to evaluate their role as predictive and/or prognostic factors. RESULTS: EGFR and HER-2/neu staining was detected in 28% and 13% of tumours, respectively, predominantly in nonseminomatous GCTs. KIT protein was almost universally expressed in seminomas (97%), being virtually absent in choriocarcinoma and teratocarcinoma subtypes. EGFR expression showed inverse association with tumour response of borderline significance. With a median follow-up of 10.6 years, no significant association was observed between the expression of any of these markers and relapse-free or overall survival. CONCLUSIONS: EGFR, HER-2/neu and KIT have differential patterns of expression in GCTs according to histological subtypes. The expression of these markers in our series had no prognostic or predictive significance.

Cisplatin-based radiochemotherapy improves the negative prognosis of c-erbB-2 overexpressing advanced cervical cancer.

OBJECTIVES: To determine the impact of c-erb-B2 overexpression on disease-free survival (DFS) and local relapse in patients with advanced cervical cancer (CC) receiving concurrent chemoradiotherapy treatment. METHODS: A total of 136 patients with advanced CC (FIGO stage: IB2-IIA [12]; IIB [34]; IIIB [71]; IVA [19]; including both epidermoid [86] and adenocarcinoma [14]) were analyzed to determine c-erb-B2 levels by immunohistochemistry (c-erb-B2 antibody; Dako, Glostrup, Denmark). Only c-erb-B2+++ biopsies were considered positive. All patients received pelvic radiotherapy, brachytherapy, and concurrent chemotherapy with 2 different regimens: 48 patients were treated with tegafur (800 mg/d orally) and 88 with tegafur (same doses) plus 5 cycles of weekly cisplatin 40 mg/m/wk intravenously. RESULTS: A total of 32 (23.5%) biopsies were considered c-erb-B2-positive. Three-year and 5-year DFS were 61% and 58% for c-erb-B2-negative patients and 36% and 36% for c-erB2-positive patients, respectively (P = 0.02). Patients were stratified in 4 groups according to their c-erb-B2 status and whether they received cisplatin. The group of patients with c-erb-B2 overexpression that did not receive platinum treatment had a higher rate of pelvic relapse (P < 0.0001), associated with a decreased DFS (P = 0.0014). CONCLUSIONS: c-erb-B2 overexpression may imply a poor prognosis for patients with advanced CC. Treatment with cisplatin-based radiochemotherapy improved outcome in these patients.

Negative prognostic impact of the coexpression of epidermal growth factor receptor and c-erbB-2 in locally advanced cervical cancer.

OBJECTIVE: The objective was to determine the impact of the coexpression of epidermal growth factor receptor (EGFR) and tumor marker c-erbB-2 on disease-free survival (DFS) and pelvic relapse-free survival (PRFS) in patients with locally advanced cervical cancer (LACC) receiving concurrent chemoradiotherapy. METHODS: The expression of EGFR and c-erbB-2 was assessed by immunohistochemistry, which was centralized and blinded to outcome. Univariate and multivariate analyses were used to evaluate the impact of EGFR and c-erbB-2 on DFS and PRFS. RESULTS: 170 patients with LACC were included and received concurrent chemoradiotherapy. 25 (15%) biopsies were considered EGFR and c-erbB-2 positive; 100 (59%) were either EGFR or c-erbB-2 positive, and 45 (26%) were EGFR and c-erbB-2 negative. The 3- and 5-year DFS was 39% each for EGFR- and c-erbB-2-positive patients, 54 and 49%, respectively, for EGFR- or c-erbB-2-positive patients, and 76 and 72%, respectively, for EGFR- and c-erbB-2-negative patients (p = 0.006). EGFR- and c-erbB-2-positive tumors were significantly associated with a decrease in PRFS (hazard ratio, HR, 3.99; 95% confidence interval, CI, 1.44-11.05, p = 0.007), and DFS (HR 2.9; 95% CI, 1.26-6.66, p = 0.01). CONCLUSION: Patients with LACC coexpressing EGFR and c-erbB-2, and treated with concurrent chemoradiotherapy, had a worse clinical prognosis with shorter DFS and PRFS.

Susceptibility of pRb-deficient epidermis to chemical skin carcinogenesis is dependent on the p107 allele dosage.

Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. However, only a reduced spectrum of tumors displays inactivation of the Rb gene. This can be attributed, at least partially, to the possible overlapping functions carried out by the related retinoblastoma family members p107 and p130. We observed that loss of pRb in epidermis, using the Cre/LoxP technology, results in proliferation and differentiation defects. These alterations are partially compensated by the elevation in the levels of p107. Moreover, epidermis lacking pRb and p107, but not pRb alone, develops spontaneous tumors, and double deficient primary keratinocytes are highly susceptible to Ha-ras-induced transformation. Two-stage chemical carcinogenesis experiments in mice lacking pRb in epidermis revealed a reduced susceptibility in papilloma formation and an increase in the malignant conversion. We have now explored whether the loss of one p107 allele, inducing a decrease in the levels of p107 up to normal levels could restore the susceptibility of pRb-deficient skin to two-stage protocol. We observed partial restoration in the incidence, number, and size of tumors. However, there is no increased malignancy despite sustained p53 activation. We also observed a partial reduction in the levels of proapoptotic proteins in benign papillomas. These data confirm our previous suggestions on the role of p107 as a tumor suppressor in epidermis in the absence of pRb.

Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas.

The down-regulation of the catalytic subunit of the mitochondrial H+-ATP synthase (beta-F1-ATPase) is a hallmark of most human carcinomas. This characteristic of the cancer cell provides a proteomic signature of cellular bioenergetics that can predict the prognosis of colon, lung, and breast cancer patients. Here we show that the in vivo tumor glucose uptake of lung carcinomas, as assessed by positron emission tomography in 110 patients using 2-deoxy-2-[18F]fluoro-d-glucose as probe, inversely correlates with the bioenergetic signature determined by immunohistochemical analysis in tumor surgical specimens. Further, we show that inhibition of the activity of oxidative phosphorylation by incubation of cancer cells with oligomycin triggers a rapid increase in their rates of aerobic glycolysis. Moreover, we show that the cellular expression level of the beta-F1-ATPase protein of mitochondrial oxidative phosphorylation inversely correlates (P < 0.001) with the rates of aerobic glycolysis in cancer cells. The results highlight the relevance of the alteration of the bioenergetic function of mitochondria for glucose capture and consumption by aerobic glycolysis in carcinomas.

Sarcoma sinovial intramandibular. A propósito de un caso / Synovial sarcoma of the mandible. A case report

Introducción: El sarcoma sinovial es un tumor de partes blandas poco frecuente en cabeza y cuello y excepcional en la mandíbula. Presentación del caso: Presentamos un caso de un paciente de 74 años previamente diagnosticado y tratado de osteosarcoma mandibular, que muestra una tumoración en el remanente mandibular con extensión infratemporal. El diagnóstico con microscopía óptica, técnicas inmunohistoquímicas y ultraestructura fue de sarcoma sinovial monofásico. Se realizó estudio genético para la traslocación t (x;18) que resultó positiva, confirmándose el diagnóstico de recidiva local por sarcoma sinovial. La biopsia previa estaba erróneamente diagnosticada. Conclusiones: El sarcoma sinovial monofásico requiere diagnóstico diferencial con otras entidades. Es una tumoración que recidiva en más de la mitad de los casos y presenta un riesgo elevado de metástasis. Su diagnóstico exacto necesita un buen procesamiento tisular, técnicas inmunohistoquímicas, ultraestructurales y estudio genético

Introduction: Synovial sarcoma is an unusual soft tissue tumour of the head and neck. It is extremely rare on the mandible. Case presentation: We present here a case of a 74 year-old man previously diagnosed and treated of jaw osteosarcoma. Five years later the patient showed a neoplasm recurrence on the remaining mandibular condyloid, extending to the temporal bone. The diagnosis with light microscopy, immunohistochemical staining, and ultrastructure was monophasic synovial sarcoma. The characteristic chromosomal translocation t(x;18) was founded on the cytogenetic study, confirming the diagnosis of local recurrence of synovial sarcoma. The previous biopsy was misdiagnosed. Conclusions: The monophasic synovial sarcoma needs a differential diagnosis with other neoplasms. More than 50% of the cases shows recurrence and have a high rate of distant metastases. Adequate tissue sampling, immunohistochemical, ultraestructural and characteristic chromosomal translocation findings are necessary for diagnosis

Sarcoma sinovial intramandibular. A propósito de un caso / Synovial sarcoma of the mandible. A case report

Introducción: El sarcoma sinovial es un tumor de partes blandas poco frecuente en cabeza y cuello y excepcional en la mandíbula. Presentación del caso: Presentamos un caso de un paciente de 74 años previamente diagnosticado y tratado de osteosarcoma mandibular, que muestra una tumoración en el remanente mandibular con extensión infratemporal. El diagnóstico con microscopía óptica, técnicas inmunohistoquímicas y ultraestructura fue de sarcoma sinovial monofásico. Se realizó estudio genético para la traslocación t (x;18) que resultó positiva, confirmándose el diagnóstico de recidiva local por sarcoma sinovial. La biopsia previa estaba erróneamente diagnosticada. Conclusiones: El sarcoma sinovial monofásico requiere diagnóstico diferencial con otras entidades. Es una tumoración que recidiva en más de la mitad de los casos y presenta un riesgo elevado de metástasis. Su diagnóstico exacto necesita un buen procesamiento tisular, técnicas inmunohistoquímicas, ultraestructurales y estudio genético

Introduction: Synovial sarcoma is an unusual soft tissue tumour of the head and neck. It is extremely rare on the mandible. Case presentation: We present here a case of a 74 year-old man previously diagnosed and treated of jaw osteosarcoma. Five years later the patient showed a neoplasm recurrence on the remaining mandibular condyloid, extending to the temporal bone. The diagnosis with light microscopy, immunohistochemical staining, and ultrastructure was monophasic synovial sarcoma. The characteristic chromosomal translocation t(x;18) was founded on the cytogenetic study, confirming the diagnosis of local recurrence of synovial sarcoma. The previous biopsy was misdiagnosed. Conclusions: The monophasic synovial sarcoma needs a differential diagnosis with other neoplasms. More than 50% of the cases shows recurrence and have a high rate of distant metastases. Adequate tissue sampling, immunohistochemical, ultraestructural and characteristic chromosomal translocation findings are necessary for diagnosis

Primary papillary serous carcinoma of the peritoneum: report of a case with diagnosis by fine needle aspiration and immunocytochemistry.

BACKGROUND: Primary papillary serous carcinoma (PPSC) of the peritoneum is a rare neoplasm, histologically indistinguishable from papillary serous carcinoma of the ovary, which diffusely involves the peritoneum but spares or minimally invades the ovaries. To the best of our knowledge, the preoperative and the fine needle aspiration diagnosis of this disorder have not been reported before. CASE: A woman developed an extensive peritoneal neoplasm 4 years after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Fine needle aspiration of the tumor was performed, and the cytologic and immunocytochemical findings were consistent with papillary serous carcinoma. A diagnosis of PPSC of the peritoneum was rendered because review of all slides from previous surgical specimens showed no evidence of carcinoma and no other primary tumors were found elsewhere. CONCLUSION: Fine needle aspiration cytology coupled with immunocytochemical and clinical data allows an unequivocal preoperative diagnosis of papillary serous carcinoma (primary peritoneal or with an ovarian origin). The sole limitation to establish a primary peritoneal origin before surgery is the requirement to histologically study the ovaries. Based on this fact, the preoperative fine needle aspiration cytology diagnosis of PSCP should be restricted to oophorectomized patients.

Myxoinflammatory fibroblastic sarcoma: report of a case with fine needle aspiration cytology.

BACKGROUND: Myxoinflammatory fibroblastic sarcoma (MFS) is a distinct neoplasm that usually arises in the acral zones of distalextremities. We report, for the first time, the preoperative fine needle a,spiration cytology (FNAC) findings of an MFS case that was confirmed after surgical excision. CASE: An 81-year-old woman presented with a multinodular tumor in the distal right extremity that had been present for 1 year. FNA C of the lesion was performed and followed by local excision. The fine needle aspiration smears contained 2 of the 3 types of neoplastic cells that have been observed in MFS: spindled and ganglionlike cells. The background was myxoid, with a prominent inflammatory infiltrate. Histopathologic examination of the surgical specimen confirmed the diagnosis of MFS. CONCLUSION: Although the cytologic diagnosis was "pleomorphic sarcoma," MFS was considered and local excision recommended, given the reported low grade nature of this entity. However, the need for extreme caution in the diagnosis of soft tissue lesions on cytologic grounds alone cannot be overemphasized.

Prognostic value of KIT expression in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a very aggressive disease, with poor survival rates despite standard treatment with combination chemotherapy with or without radiotherapy. Further insights into the molecular biology of this malignant tumour are needed to improve the therapeutic approaches and outcome. KIT protein is expressed in SCLC, and its kinase activity has been implicated in the pathophysiology of many tumours, including SCLC. The purpose of this study was to evaluate the prevalence of KIT expression in patients with SCLC and its prognostic value. METHODS: We performed an inmunohistochemical analysis of 204 SCLC samples to determine KIT protein expression. The relationship between KIT expression and clinicopathological parameters was evaluated. Univariate and multivariate analyses were performed to define its prognostic significance. RESULTS: KIT expression was observed in 149 of 204 tumour tissues (73%). KIT expression was associated with advanced disease and with decreased incidence of bone metastases. No significant differences were observed for time to disease progression (TTP) (9.1% versus 6.2% at 3 years, p=0.6) or overall survival (OS) (10.7% versus 6.9% at 3 years, p=0.37) among patients with KIT positive versus negative tumours, respectively. Multivariate analysis showed that sex, tumour stage, albumin levels and response to therapy were the only independent predictors for survival. CONCLUSION: KIT protein is expressed in a high percentage of SCLC tumours. In our study population, however, the expression of KIT had no significant impact on survival.

Unexpected roles for pRb in mouse skin carcinogenesis.

The mouse skin carcinogenesis represents one of the best models for the understanding of malignant transformation, including the multistage nature of tumor development. The retinoblastoma gene product (pRb) plays a critical role in cell cycle regulation, differentiation, and inhibition of oncogenic transformation. In epidermis, Rb-/- deletion leads to proliferation and differentiation defects. Numerous evidences showed the involvement of the retinoblastoma pathway in this model. However, the actual role of pRb is still unknown. To study the possible involvement of pRb in keratinocyte malignant transformation, we have carried out two-stage chemical skin carcinogenesis on Rb(F19/F19) (thereafter Rb+/+) and Rb(F19/F19);K14Cre (thereafter Rb-/-) animals. Unexpectedly, we found that Rb-/- mice developed fewer and smaller papillomas than the Rb+/+ counterparts. Moreover, the small size of the pRb-deficient tumors is associated with an increase in the apoptotic index. Despite this, pRb-deficient tumors display an increased conversion rate to squamous cell carcinomas. Biochemical analyses revealed that these characteristics correlate with the differential expression and activity of different pathways, including E2F/p19arf/p53, PTEN/Akt, c-jun NH2-terminal kinase/p38, and nuclear factor-kappaB. Collectively, our findings show unexpected and hitherto nondescribed roles of pRb during the process of epidermal carcinogenesis.

Mixofibroma odontogénico: presentación de un caso y revisión de los conocimientos actuales / Odontogenic myxofibroma: report of a case and review of the literature

El mixofibroma odontogénico es un tumor infrecuentede origen controvertido que de forma típica aparece en lamandíbula o el maxilar superior. Presentamos el caso de unamujer de 23 años sometida a una hemimaxilectomía izquierdapor un mixofibroma odontogénico de 7 × 6,5 × 4 cmde tamaño. Microscópicamente el tumor estaba constituidopor una proliferación de células estrelladas o fusiformes dispuestasde forma dispersa en una matriz mixoide. La inmunohistoquímicademostró una intensa positividad paravimentina y positividad heterogénea para actina músculoliso-específica (1A4), actina muscular específica (HHF-35)y calponina, mientras que la desmina, caldesmón, proteínaS-100, HBME-1 y las panqueratinas (AE1-AE3) fuerontodas ellas negativas. El microscopio electrónico reveló laexistencia de células ultraestructuralmente similares a miofibroblastos.El conjunto de los resultados obtenidos sugiereun origen miofibroblástico para esta lesión, como ya ha sidoreferido en la literatura. Se discute el diagnóstico diferencial

Background: Odontogenic myxofibroma is a rare benignneoplasm of controversial origin, typically developing in jawbones.Patients and Methods: A 23-year-old female subjectedto left hemimaxillectomy for a maxillary myxofibroma isreported. The tumor measured 7 × 6,5 × 4 cm in diameter.Results: Microscopically, the tumor consisted of a few uniformstar-shaped or spindle-shaped cells in a myxoidmatrix. A prominent positivity for vimentin and scatteredimmunoreactivity for alpha smooth muscle actin (1A4),common muscle actin (HHF-35) and calponin was found.Desmin, caldesmon, S-100 protein, HBME-1 and cytokeratinsAE1-AE3 were negative. By electron microscopy onlycells with myofibroblastic morphologic features werefound. Conclusion: These results suggest a myofibroblasticorigin for this neoplasm as described in previous reports.Differential diagnostic possibilities are also discussed

Miliary brain metastases presenting as rapidly progressive dementia.

We report the case of a 79-year-old woman who developed a rapidly progressive dementia (RPD) with severe memory impairment, early visual hallucinations and extrapyramidal signs. Symptoms started suddenly after hip replacement surgery following an accidental fall. Motor epileptic seizures appeared at the end of the illness. Dementia worsened gradually leading to akinetic mutism. She died five and a half months after the onset of symptoms. MRI showed cerebral atrophy but failed to detect any other lesion. Results of all laboratory tests performed were negative. After the most frequent treatable diseases were excluded, the diagnosis of dementia with Lewy bodies was initially considered. CJD was also suggested based on the rapid evolution of the disease and the positivity of 14-3-3 protein in CSF. Neuropathological examination revealed an extensive miliary metastatic dissemination from an unknown primary adenocarcinoma. Pulmonary origin was suggested according to the immunohistochemical profile. Histopathological changes of Alzheimer's disease were also observed in the cerebral cortex and hippocampus. Neither Lewy bodies nor PrP deposits were found. The sudden onset of the dementia just after the hip replacement surgery raises the possibility of a pathological fracture with secondary tumoral microembolic dissemination. Despite its rarity, this entity should be included in the differential diagnosis of RPD. This case illustrates the definite importance of neuropathological post-mortem examination in order to elucidate the different types of dementia.

Prognostic value of the epidermal growth factor receptor (EGRF) and p53 in advanced head and neck squamous cell carcinoma patients treated with induction chemotherapy.

We measured the expression of the p53 nuclear protein and epidermal growth factor receptor (EGFR) in 46 biopsy samples from patients with advanced head and neck cancer treated with induction combination chemotherapy of 5-fluorouracil, cisplatin, and paclitaxel. Tumour expression of p53 protein was analysed with the monoclonal D07 antibody and EGFR with monoclonal H11 antibody. The overall response, defined as complete (CR) and partial response (PR) rates to treatment, was 88%. p53 positive staining was significantly more frequent in patients who did not respond to the induction treatment. EGFR expression failed to show any correlation with the response rate. Multivariate analysis indicated that a tumour location in the oral cavity together with p53 expression combined with moderate-to-high EGFR staining were independent prognostic factors of a shorter disease-free survival (DFS). Location of the tumour in the oral cavity and EGFR expression had independent prognostic value for overall survival (OS). We conclude that the EGFR status and an oral cavity location of the tumour have independent prognostic value in patients with advanced head and neck carcinoma treated with induction chemotherapy. The p53 status appears to be a determinant of the tumour chemo-sensitivity in advanced head and neck squamous cell carcinoma (HNSCC). The presence in the tumour of a p53-positive stain and moderate-to-high staining of EGFR is associated with a shorter DFS and time to treatment failure (TTF) probably reflecting a more aggressive tumour phenotype.