Vestibular schwannoma : the evolution of hearing and tumor size in natural course and after treatment by Linac stereotactic radiosurgery

Objectif : D'analyser l'évolution naturelle de la taille de la tumeur et de l'audition chez 151 patients avec schwannome vestibulaire (VS) en suivi et d'évaluer les mêmes paramètres pour une partie du group traité par Radiochirurgie Stéréotaxique Linac (SRS). Méthodes: Etude prospective des patients bilantés par IRM et tests audio-vestibulaires à l'inclusion, pendant la période du suivi et après SRS. L'audition a été gradé selon l'échelle de Gardner-Robertson (GR) et la taille tumorale selon l'échelle de Koos. L'analyse statistique inclut l'analyse de survie de Kaplan-Meier, analyse multivariée avec régression linéaire et logistique. Les patients avec une audition utile ont étés spécifiquement analysés. Résultats: Pendant la période du suivi (moyenne 24 mois, déviation 6-96), le risqué annuel de dégradation de la classe GR était 6% pour les patients GRI et 15% pour les GRII. La perte auditive comme symptôme initial était un facteur signifïcativement prédictif pour une aggravation auditive ultérieure (p=0.003). La croissance tumorale était de 25% à la dernière observation pendant le suivi. Pour les patients traités par Linac, la préservation d'une audition utile était 51% à 1 an et 36% à 3 ans. Le contrôle tumoral était 94 % and 91% respectivement. Conclusion: Chez les patients avec VS, la perte auditive déjà présente au diagnostique est un facteur prédictif négatif pour l'évolution de l'audition. La Radiochirurgie Stéréotaxique Linac est efficace pour le contrôle tumoral. Les patients ayant préservés leur status auditif prétraitement présentent un rythme annuel de perte auditive diminué après SRS compare à celle-ci avant le traitement. Cette constatation suggère un effet protectif potentiel de la SRS, à condition que la fonction cochléaire soit préservée.

Reduction of the Ant Mandible Gap Range After Biotic Homogenization Caused by an Ant Invasion (Hymenoptera: Formicidae)

After most of the native ant species are displaced by the Argentine ant invasion, it is probable that some ecological processes carried out by natives are not replaced. In some cases this could be due to a morphological difference between the Argentine ant and the displaced native ants. The significant decrease in ant richness after the invasion (only two species detected in the invaded zones vs. 25 species in surrounding non-invaded zones) implies a drastic reduction in the ant mandible gap range (the mandible gap spectra of all the ant species in a community) in the invaded zones. This reduction could explain why some roles that were previously carried out by the displaced native species are not performed by the invasive species. This could be due to a functional inability to carry out these activities. The mandible gap waspositively correlated with the ant body mass in the 26 ant species considered. The functional inability hypothesis could be applied to other invasive ants as well as to the Argentine ant

Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle

Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hall- mark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM (the calcein acetoxymethyl-ester) on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phos-phate pathway was significantly altered. To elucidate whe-ther these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.

Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors.

Decrease in the diversity of pyrrolizidine alkaloids of Senecio pterophorus after invasion

Pyrrolizidine alkaloids (PAs) are N-based plant secondary metabolites that function as chemical defenses against vertebrate and invertebrate herbivores. PAs can be highly variable at intraspecific level, both in their absolute and relative concentrations. Changes in the chemical composition of exotic plants when they invade a new environment have been poorly explored. Here we studied the biogeographical variation on PAs in Senecio pterophorus (Asteraceae) in the native region in Eastern South Africa, an expanded region in Western South Africa, and two introduced regions in Australia and Europe. PAs in S. pterophorus were represented by the highly toxic 1,2-unsaturated PAs and the less toxic 1,2-saturated PAs. Our results show a change in the plant chemical composition after invasion. Total PAs concentrations were highest in Australia compared to any other region. Plants from Europe contained the highest relative concentrations of 1,2-saturated PAs. The positive correlation between the chemical and the genetic distances estimated between populations suggests that the chemical profiles in the non-native regions were related to the plant dispersal routes. The decrease in the chemical diversity and the change in the absolute PAs concentrations in S. pterophorus after invasion may have consequences in the interactions between plants and herbivores in the novel habitats.

Chemical modifications of a natural xanthone and antimicrobial activity against multidrug resistant Staphylococcus aureus and cytotoxicity against human tumor cell lines

A series of 15 ω-aminoalkoxylxanthones containing methyl, ethyl, propyl, tert-butylamino and piperidinyl moieties were synthesized from a natural xanthone isolated from a lichen species. These compounds were tested for their in vitro antibacterial properties against Gram-positive and Gram-negative bacteria and cytotoxicity against a number of human tumor cell lines was too evaluated. The newly synthesized derivatives revealed selective activity against Staphylococcus aureus (Gram-positive), and the most promising results are for a multidrug resistant strain, for which six of these compounds showed good activity (MICs 4 µg/mL). Many derivatives inhibited tumor cells growth and most compounds were active on multiple lines.

Novel Players in the Integrin Signaling Orchestra: TCPTP and MDGI

Metastases are the major cause of cancer deaths. Tumor cell dissemination from the primary tumor utilizes dysregulated cellular adhesion and upregulated proteolytic degradation of the extracellular matrix for progeny formation in distant organs. Integrins are transmembrane adhesive receptors mediating cellcell and cellmatrix interactions that are crucial for regulating cell migration, invasion, proliferation, and survival. Consequently, increased integrin activity is associated with augmented migration and invasion capacity in several cancer types. Heterodimeric integrins consist of an alpha - and beta-subunit that are held together in a bent conformation when the receptor is inactive, but extension and separation of subdomains is observed during receptor activation. Either inside-out or outside-in activation of receptors is possible through the intracellular molecule binding to an integrin cytoplasmic domain or extracellular ligand association with an integrin ectodomain, respectively. Several regulatory binding partners have been characterized for integrin cytoplasmic beta-domains, but the regulators interacting with the cytoplasmic alpha-domains have remained elusive. In this study, we performed yeast two-hybrid screens to identify novel binding partners for the cytoplasmic integrin alpha-domains. Further examination of two plausible candidates revealed a significant coregulatory role of an integrin alpha-subunit for cellular signaling processes. T-cell protein tyrosine phosphatase (TCPTP) showed a specific interaction with the cytoplasmic tail of integrin alpha1. This association stimulated TCPTP phosphatase activity, leading to negative regulation of epidermal growth factor receptor (EGFR) signaling and diminished anchorage-independent growth. Another candidate, mammary-derived growth inhibitor (MDGI), exhibited binding to several different integrin cytoplasmic alpha-tails through a conserved GFFKR sequence. MDGI overexpression in breast cancer cells altered EGFR trafficking and caused a remarkable accumulation of EGFR in the cytoplasm. We further demonstrated in vivo that MDGI expression induced a novel form of anti-EGFR therapy resistance. Moreover, MDGI binding to α-tails retained integrin in an inactive conformation attenuating integrin-mediated adhesion, migration, and invasion. In agreement with these results, sustained MDGI expression in breast cancer patients correlated with an increased 10-year distant disease-free survival. Taken together, the integrin signaling network is far from a complete view and future work will doubtless broaden our understanding further.

Functional Study of Oncogenic Transcription Factor ERG and its Signaling in Prostate Cancer

TMPRSS2–ERG is the most frequent type of genomic rearrangement present in prostate tumors, in which the 5- prime region of the TMPRSS2 gene is fused to the ERG oncogene. TMPRSS2, containing androgen response elements (AREs), is regulated by androgens in the prostate. The truncated TMPRSS2-ERG fusion transcript is overexpressed in half of the prostate cancer patients. The formation of TMPRSS2-ERG transcript is an early event in prostate carcinogenesis and previous in vivo and in vitro studies have shown ectopic ERG expression to be associated with increased cell invasion. However, the molecular function of ERG and its role in cell signaling is poorly understood. In this study, genomic rearrangement of ERG with TMPRSS2 was studied by using comparative genomic hybridization (CGH) in prostate cancer samples. The biological processes associated with the ERG oncogene expression in prostate epithelial cells were studied, and the results were compared with findings observed in clinical prostate tumor samples. The gene expression data indicated that increased WNT signaling and loss of cell adhesion were a characteristic of TMPRSS2- ERG fusion positive prostate tumor samples. Up- regulation of WNT pathway genes were present in ERG positive prostate tumors, with frizzled receptor 4 (FZD4) presenting with the highest association with ERG overexpression, as verified by quantitative reverse transcription-PCR, immunostaining, and immunoblotting in TMPRSS2-ERG positive VCaP prostate cancer cells. Furthermore, ERG and FZD4 silencing increased cell adhesion by inducing active β1-integrin and E-cadherin expression in VCaP cells. Furthermore, we found a novel inhibitor, 4-(chloromethyl) benzoyl chloride which inhibited the WNT signaling and induced similar phenotypic effects as observed after ERG or FZD4 down regulation in VCaP cells. In conclusion, this work deepens our understanding on the complex oncogenic mechanisms of ERG in prostate cancer that may help in developing drugs against TMPRSS2-ERG positive tumors.

Molecular markers for progression of squamous cell carcinoma of the skin

Incidence of nonmelanoma skin cancer (NMSC) is increasing. Ultraviolet (UV) –light is a major risk factor for the development of cutaneous SCC. Cutaneous SCCs that develop to chronic ulcers are known to progress and metastasize more easily than UV-induced SCCs. Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes which are suggested to have a role in cancer growth and invasion. The molecular background for progression of cutaneous SCC was examined by immunohistochemistry (IHC) using tissue samples of recessive dystrophic epidermolysis bullosa (RDEB) –associated SCC, sporadic UV-induced SCC, and SCC precursors. IHC studies using tissue microarray (TMA) technique revealed overexpression of MMP-7 and MMP-13 in SCC tumor cells. MMP-7 expression was enhanced especially in the SCC tumor cells of the RDEB –associated SCCs. Studies with SCC cell lines showed that tumor cell derived MMP-7 activated heparin binding epidermal growth factor –like growth factor (HB-EGF) which enhanced the growth of SCC tumor cells. Further, it was shown that type VII collagen (COL7) is expressed in sporadic SCC tumor cells. Interestingly, it was shown that SCC –associated MMP-13 is capable of cleaving COL7 in vitro. COL7 cleavage may have a role in the progression of cutaneous SCC. Studies on serine proteinase inhibitor gene family using SCC tumor cell gene array, quantitative real-time PCR, SCC cell lines, normal human epidermal keratinocytes and IHC of TMA samples showed that serine proteinase inhibitor clade A, member 1 (serpinA1, alpha-1-antitrypsin) is expressed and produced by human SCC tumor cells but not by normal keratinocytes. Moreover, serpinA1 expression was shown to correlate with the progression of cutaneous SCC using transformed HaCaT-cell lines and mouse chemically induced skin SCC model. SerpinA1 may serve as a novel biomarker for the progression of cutaneous SCC. This study elucidated putative mechanisms of the progression of cutaneous SCC and revealed novel biomarker candidates for the progression of SCC of the skin.

Conduta terapêutica atual no adenocarcinoma da cárdia e da junção esofagogástrica

Adenocarcinomas of the cardia and gastroesophageal junction are peculiar entities with three different origins, which differ somewhat from other adenocarcinomas of the stomach in their clinical presentation and pathogenesis, and have a poorer prognosis. In this article the authors reviewed definitions, incidence and epidemiology, etiologic factors, genetic implications, clinical presentation, diagnosis, staging and treatment, with emphasis on the surgical approach, discussing the current management of these cancers. The prognostic factors related specifically to the cardia cancers are: esophageal invasion greater than 3cm, microscopic residual tumor and wall penetration (>T2). Preoperative workup should include computed tomography, and endoscopic ultrasonography and laparoscopy when available. Preoperative recognition of T3/ T4/N2 lesions should indicate inclusion in neo-adjuvant protocols whenever possible. The authors present the results of 46 resected cases of adenocarcinomas of the cardia and GE junction of the Instituto Nacional do Câncer- Brazil (1981-1995). Cure was intended in 29 and palliation in 17 patients. The most common type of resection was total gastrectomy with abdominal esophagectomy (28 cases). Morbidity (major and minor) occurred in 50% of the patients. The main causes were of respiratory origin and fistulas (19.6% each). Death occurred in 44% of the patients with fistula. Postoperative death until the 30th day occurred in 17.24% of the curative cases and in 23.52% of the palliative ones. The median survival time was 68.5 months for stage I, 25 months for stage II, 31 months for stage III and 12.5 months for stage IV diseases. The median survival time was 8 months for palliation and 28.5 months for cure. No long-term survival was obtained with the palliative group, whereas 25% survived five years of more in the curative group. The authors conclude that the surgical approach should be the one the surgeon feels more comfortable with. Complete removal of the disease proved by frozen section, splenectomy and D2 lymphadenectomy should be the standard therapy with curative intent.

Tumor do saco vitelino primário em retroperitônio

A case of primary extragonadal yolk sac tumor in the retroperitoneum of a young adult male is reported. The symptoms were melena and weakness for two months. Radiologic studies suggested a retroperitoneal tumor infiltrating the duodenum, artery aorta and vein cava, was found. Partial resection was performed, remaining tumor around the vessels. Microscopic examination disclosed a yolk sac tumor infiltrating the duodenum. The patient was managed unsuccessfully with radiotherapy, but good results were actived with chemotherapy. Few cases like that were reported in the literature.

Metástase cervical de carcinoma epidermóide com tumor primário desconhecido

Revisamos nossa experiência com carcinoma epidermóide metastático (CEM) para o pescoço com tumor primário desconhecido com a intenção de evidenciar quando o tratamento radioterápico exclusivo ou o tratamento cirúrgico seguido de radioterapia teriam impacto positivo sobre a sobrevida. Este é um estudo retrospectivo de 54 pacientes com CEM tratados na Seção de Cirurgia de Cabeça e Pescoço do Hospital do Câncer/INCa entre 1986 e 1992. Quarenta e oito pacientes (89%) eram do sexo masculino, a idade média foi de 54 anos. Quarenta pacientes tinham metástase para linfonodos cervicais da cadeia jugular interna alta (nível 2). Utilizamos a classificação TNM da UICC de 1992 para estagiar os pacientes, onde oito pacientes foram classificados como N1, vinte como N2, 22 como N3, sendo que quatro pacientes permaneceram não classificados. Todos foram submetidos a endoscopia do trato aerodigestivo superior e raio X de tórax. Trinta e cinco pacientes foram submetidos a biópsia de aspiração com agulha fina. Trinta e oito pacientes tiveram tratamento com intenção curativa e 1.6 tiveram tratamento paliativo com radioterapia. Dos pacientes tratados com intenção curativa, dez foram submetidos a esvaziamento cervical e 28 tiveram tratamento exclusivo com radioterapia. Os 16 pacientes tratados com intenção paliativa foram excluídos dos cálculos de sobrevida e análise das recidivas. As recidivas cervicais foram analisadas usando o método do qui-quadrado, e as curvas de sobrevida foram comparadas usando-se o teste de Wilcoxon. A biópsia aspirativa com agulha fina alcançou o diagnóstico em 85% dos casos. Oito pacientes (15%) apresentaram metástase à distância. O tumor primário foi identificado subseqüentemente em 9% dos pacientes. Dezoito pacientes (64%) tratados com radioterapia exclusiva tiveram recidivas no pescoço, e três pacientes (33%) tratados com cirurgia + radioterapia tiveram recidivas no pescoço. (p=0,05) Os pacientes classificados como N2/N3 tratados com cirurgia + radioterapia tiveram melhores resultados do que os tratados com radioterapia exclusiva (respectivamente p=0,05 e p=0,09). Os pacientes Nl tiveram melhor sobrevida livre de doença do que os pacientes N2/N3 (respectivamente p=0,007 e p=0,OO7). A sobrevida livre de doença em cinco anos foi de 69% para os pacientes Nl, 11 % para os pacientes N2 e 15% para os pacientes N3. A sobrevida livre de doença para todos os estágios foi de 28%. A biópsia aspirativa com agulha fina é um bom meio para diagnóstico e deve ser usada rotineiramente.

Metástase cervical de tumor primário oculto: estudo de 107 casos

Foram avaliados retrospectivamente 107 pacientes com metástases cervicais de tumor primário oculto, atendidos entre 1977 e 1995 no Hospital Heliópolis. Considerou-se a influência de fatores epidemiológicos e características clínicas na recorrência da doença e sobrevida. O carcinoma epidermóide foi o tipo histológico mais freqüente, acometendo predominantemente as cadeias júgulo-carotídeas alta e média (níveis II e III). Noventa e três por cento dos pacientes apresentavam doença avançada (estadiamento N2 ou N3). A sobrevida livre de doença (SLD) aos 5 anos foi de 24%, sendo 40% para os pacientes com 55 anos ou menos e 8% para aqueles com mais de 55 anos (p = 0,01). Todos os pacientes com doença na cadeia júgulo-carotídea baixa (nível IV) apresentaram recidiva nos primeiros 12 meses após o tratamento. Os tumores indiferenciados apresentaram recidiva mais precocemente. Na análise multivariada os fatores idade, tipo de tratamento e estadiamento foram significativos (p<0,05).

Tumor estromal gastrointestinal de intestino delgado

Stromal tumors of the gastrointestinal tract (gists) represent relatively rare lesions that arise from connective tissue elements located along the entire length of the gut. They were initially identified by immunohistochemical investigation, proving their origin from nondifferentiated mesenchymal cells. Only a minority of this lesions, mainly those confined to the esophagus and rectum, have been shown to correspond to mature, well-differentiated types of neoplasms such as leiomyoma or leiomyosarcoma. The majority of gists corresponds to a heterogeneous group of lesions that have as their common denominator an immature proliferation of epithelioid or spindle cells arising from its muscle layers, or between them, showing partial or incomplete myoide, neural, ganglionic, or mixed features of differentiation. This case report intends to show a gist of small bowel in a male, 46 years old, with a two-year of evolution.