Novel Oral mTORC1/2 Inhibitor TAK-228 Has Synergistic Antitumor Effects When Combined with Paclitaxel or PI3Kα Inhibitor TAK-117 in Preclinical Bladder Cancer Models.

Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro, and reduced tumor growth and angiogenesis in vivo. Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects in vitro and in vivo. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911). IMPLICATIONS: Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer.

Cell and tissue interactions of Treponema pallidum in primary and secondary syphilitic skin lesions: an ultrastructural study of serial sections.

There are limited reports on the ultrastructure of syphilis skin lesions. The aim of this study has been to perform an electron microscopic investigation of the morphology and the tissue distribution of treponemes in primary and secondary cutaneous lesions. Three cases of primary syphilitic chancre and one case of secondary syphilis were included. Prominent epidermal abnormalities in the primary chancre and a perivascular inflammatory infiltrate in the secondary lesion were found by light microscopy. Ultrastructurally, spirochetes were located mainly in the blood vessel walls and dermal tissue of the chancre lesions. In the secondary syphilis case, spirochetes were more abundant between epidermal keratinocytes. Most of them adjusted to the intercellular spaces. Occasionally, the electron microscopy images were highly suggestive of an intracellular location. Both the ultrastructural and immunohistochemical examination of the primary and secondary syphilis lesions showed a paradoxical distribution of the causative microorganisms compared to the light microscopic changes. In addition, the ultrastructural findings strongly suggest that Treponema pallidum subspecies pallidum invades tissues, not only through an intercellular, but also through a transcellular pathway.

Treponema pallidum distribution patterns in mucocutaneous lesions of primary and secondary syphilis: an immunohistochemical and ultrastructural study.

To study the different patterns of Treponema pallidum distribution in primary and secondary syphilis, 34 biopsy specimens of 8 patients with primary and 26 with secondary syphilis were assessed. Histopathological features, silver stain, and immunohistochemical T pallidum polyclonal antibody expression were investigated. The number and distribution of spirochetes were evaluated, and ultrastructural studies were performed. Spirochetes were identified with Warthin-Starry stain in 17 specimens (4/8 primary and 13/26 secondary syphilis), whereas immunohistochemical analysis disclosed spirochetes in 29 (8/8 primary and 21/26 secondary syphilis). In secondary syphilis, an epitheliotropic pattern characterized by abundant spirochetes in the lower mucosa/epidermis in an intercellular distribution was observed. In contrast, primary syphilis exhibited a mixed epitheliotropic and vasculotropic pattern further manifested by treponemes surrounding the vascular walls. These differences were statistically significant. Ultrastructural examination confirmed these results. Immunohistochemistry shows greater sensitivity when compared with Warthin-Starry staining. The immunohistochemical pattern of T pallidum distribution may permit the diagnostic differentiation of primary from secondary syphilis.

[Acquired male urethra diverticula. Report of seven cases. Bibliographic review]. / Divertículos adquiridos de uretra masculina. A propósito de siete casos. Revisión de la literatura.

OBJECTIVES: To report our personal experience in a rare urethral pathology in relation with iatrogenic sequelae from surgical treatment of lower urinary tract pathologies. METHODS: We analyze the causes, type of presentation, and surgical treatment of seven cases of urethral diverticula, which account for 2.18% of the urethral procedures performed in our department, this latter representing 2.3% of a total of 11,845 surgical procedures in a period of 25 years. RESULTS/CONCLUSIONS: Male urethra diverticula go unnoticed because their initial symptoms are very similar to other lower urinary tract entities. But there is a definitive sign once the case is advanced: the appearance of a "lump" in the ventral side of the anterior urethra, the compression of which empties urinary content, sometimes fetid; or also the feeling of having a bag with stones if they host lithiasis. Surgical reconstructive treatment is very important to guarantee the absence of an obstacle distal to the cavity as well as to achieve a consistent ventral floor for the urethra to avoid recurrence, and that, as we will see, maybe obtained by various procedures. The attention to the original disease which indirectly had been the cause of the problem completes the therapeutic scheme for each case.

Divertículos adquiridos de uretra masculina. A propóstio de siete casos. Revisión de la literatura / Acquired male urethra diverticula. Report of seven cases. Bibliographic review

Objetivo: Presentar la experiencia personal en una patología uretral rara en relación con la actividad yatrogénica derivada de los tratamientos quirúrgicos de patologías del aparato urinario inferior. Métodos: Se analizan las causas, forma de aparición y tratamiento quirúrgico de 7 casos, de divertículos uretrales, lo que supone el 2,18% de las cirugías uretrales realizadas en nuestro Servicio que, a su vez, representan el 2,3% del total de 11.845 procedimientos quirúrgicos en un periodo de 25 años. Resultado/Conclusiones: Los divertículos de la uretra masculina pueden pasar desapercibidos ya que su sintomatología inicial no se diferencia mucho de otros procesos del aparato urinario inferior. Pero hay un hecho que, ya avanzados los casos, es definitorio: la formación de un «bulto» en la cara ventral del trayecto de la uretra anterior cuya expresión da lugar, al vaciado de un contenido urinario a veces maloliente, o también la sensación de una bolsa llena de «cantos rodados», si están habitados por litiasis. En el tratamiento quirúrgico reconstructor es muy importante asegurar la ausencia de obstáculo distal a la cavidad como también la de conseguir un suelo ventral de la uretra «consistente» para evitar la recidiva y que, como veremos, puede conseguirse con diversos procedimientos. La atención a la patología original que indirectamente haya sido la causante del problema completará el esquema terapeútico a aplicar en cada caso (AU)

Objectives: To report our personal experience in a rare urethral pathology in relation with iatrogenic sequelae from surgical treatment of lower urinary tract pathologies. Methods: We analyze the causes, type of presentation, and surgical treatment of seven cases of urethral diverticula, which account for 2.18% of the urethral procedures performed in our department, this latter representing 2.3% of a total of 11.845 surgical procedures in a period of 25 years. Results/Conclusions: Male urethra diverticula go unnoticed because their initial symptoms are very similar to other lower urinary tract entities. But there is a definitive sign once the case is advanced: the appearance of a «lump» in the ventral side of the anterior urethra, the compression of which empties urinary content, sometimes fetid; or also the feeling of having a bag with stones if they host lithiasis. Surgical reconstructive treatment is very important to guarantee the absence of an obstacle distal to the cavity as well as to achieve a consistent ventral floor for the urethra to avoid recurrence, and that, as we will see, maybe obtained by various procedures. The attention to the original disease which indirectly had been the cause of the problem completes the therapeutic scheme for each case (AU)