Vismodegib y sonidegib en el carcinoma de células basales localmente avanzado y metastásico: actualización acerca de los inhibidores de la vía de Hedgehog / Vismodegib and Sonidegib in Locally Advanced and Metastatic Basal Cell Carcinoma: Update on Hedgehog Pathway Inhibitors

El carcinoma de células basales (CBC) es una de las neoplasias malignas más frecuentes, por lo que se ha convertido en una importante carga asistencial. Su incidencia se incrementa anualmente, especialmente en la población con mayor edad. A pesar de que generalmente está bien localizado, el CBC tiene la capacidad de destruir tejidos y evolucionar a un CBC localmente avanzado (CBCla) o incluso, aunque de forma más rara, a un CBC metastásico (CBCm). Las opciones terapéuticas convencionales en estos casos están bien establecidas, entre las cuales se incluyen la cirugía y la radioterapia. Sin embargo, no todos los casos son elegibles para realizar un tratamiento de tipo convencional. Recientemente, los tratamientos biológicos vienen ganando una mayor atención y son objeto de diversos estudios de investigación. De este modo se ha desarrollado una terapia dirigida utilizando los inhibidores de la vía de Hedgehog (IVH), teniendo en cuenta que se trata de una vía patogénica clave tanto en el CBCla como en el CBCm. En la actualidad, para poder tratar el CBCla y el CBCm no operables existen dos IVH aprobados: el vismodegib y el sonidegib. Esta revisión busca explorar la fisiopatología de la vía del Hedgehog responsable del desarrollo del CBC y hacer una actualización en cuanto a la eficacia, así como de las propiedades farmacocinéticas de los IVH, características que los convirtieron en la opción terapéutica ideal en el CBCla o en el CBCm, ya sea en forma de monoterapia o en combinación con alguno de los tratamientos convencionales (AU)

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies (AU)

[Translated article] Vismodegib and Sonidegib in Locally Advanced and Metastatic Basal Cell Carcinoma: Update on Hedgehog Pathway Inhibitors / Vismodegib y sonidegib en el carcinoma de células basales localmente avanzado y metastásico: actualización acerca de los inhibidores de la vía de Hedgehog

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies (AU)

El carcinoma de células basales (CBC) es una de las neoplasias malignas más frecuentes, por lo que se ha convertido en una importante carga asistencial. Su incidencia se incrementa anualmente, especialmente en la población con mayor edad. A pesar de que generalmente está bien localizado, el CBC tiene la capacidad de destruir tejidos y evolucionar a un CBC localmente avanzado (CBCla) o incluso, aunque de forma más rara, a un CBC metastásico (CBCm). Las opciones terapéuticas convencionales en estos casos están bien establecidas, entre las cuales se incluyen la cirugía y la radioterapia. Sin embargo, no todos los casos son elegibles para realizar un tratamiento de tipo convencional. Recientemente, los tratamientos biológicos vienen ganando una mayor atención y son objeto de diversos estudios de investigación. De este modo se ha desarrollado una terapia dirigida utilizando los inhibidores de la vía de Hedgehog (IVH), teniendo en cuenta que se trata de una vía patogénica clave tanto en el CBCla como en el CBCm. En la actualidad, para poder tratar el CBCla y el CBCm no operables existen dos IVH aprobados: el vismodegib y el sonidegib. Esta revisión busca explorar la fisiopatología de la vía del Hedgehog responsable del desarrollo del CBC y hacer una actualización en cuanto a la eficacia, así como de las propiedades farmacocinéticas de los IVH, características que los convirtieron en la opción terapéutica ideal en el CBCla o en el CBCm, ya sea en forma de monoterapia o en combinación con alguno de los tratamientos convencionales (AU)

Management of high-risk and advanced basal cell carcinoma

Despite that basal cell carcinoma (BCC) is curative in the vast majority of cases, some patients are at high risk of recurrence and, in a few patients, lesions can progress to a point unsuitable for local therapy and prognosis is quite poor. The aim of the present work is to review clinical and pathologic characteristics as well as classical and new treatment options for high-risk, metastatic and locally advanced BCC. Surgery and radiotherapy remain the selected treatments for the majority of high-risk lesions. However, some patients are located on a blurry clinical boundary between high-risk and locally advanced BCC. Treatment of these patients is challenging and need an individualized and highly specialized approach. The treatment of locally advanced BCC, in which surgery or radiotherapy is unfeasible, inappropriate or contraindicated, and metastatic BCC has changed with new Hedgehog pathway inhibitors of which vismodegib is the first drug approved by FDA and EMA (AU)

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[New aspects of the pathogenesis and classification of basal-like breast carcinoma].

New approaches to the molecular classification of breast cancer are considered. Particular emphasis is placed on its basal-like type that belongs to the most aggressive and prognostically unfavorable forms of tumor. The origin of this type of breast cancer is the subject of intense debate in the scientific community. There are three basic theories that basal-like breast carcinoma may arise from the stem or myoepithelial cells and through dedifferentiation via epithelial-mesenchymal transformation. The theory of its origin from stem/progenitor cells is most valid and proven.

Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells.

The relationship between the cells that initiate cancer and the cancer stem-like cells that propagate tumors has been poorly defined. In a human prostate tissue transformation model, basal cells expressing the oncogenes Myc and myristoylated AKT can initiate heterogeneous tumors. Tumors contain features of acinar-type adenocarcinoma with elevated eIF4E-driven protein translation and squamous cell carcinoma marked by activated beta-catenin. Lentiviral integration site analysis revealed that alternative histological phenotypes can be clonally derived from a common cell of origin. In advanced disease, adenocarcinoma can be propagated by self-renewing tumor cells with an androgen receptor-low immature luminal phenotype in the absence of basal-like cells. These data indicate that advanced prostate adenocarcinoma initiated in basal cells can be maintained by luminal-like tumor-propagating cells. Determining the cells that maintain human prostate adenocarcinoma and the signaling pathways characterizing these tumor-propagating cells is critical for developing effective therapeutic strategies against this population.

Carcinoma basocelular con diferenciación mioepitelial / Basall cell carcinoma with myoepithelial differentiation

Presentamos un nuevo caso de carcinoma basocelular con diferenciación micepitelial en un varón de 71 años. La tumoración, de 2,5 cm, estaba localizada en el ala nasal izquierda. Se trataba de un carcinoma basocelular típico que infiltraba en profundidad, alcanzando el tejido muscular. En algunas áreas del tumor el citoplasma de las células neoplásicas se hacía homogéneo y eosinofilico, desplazando el núcleo a la periferia. Estas células eran idénticas a las llamadas células hialinas descritas en tumores mixtos y mioepiteliomas de glándula salival y piel. En el estudio inmunohistoquímico presentaban una franca positividad para la actína muscular específica (HHF35) y más débil para la desmína. Ultraestructuralmente la eosinofilia citoplasmática estaba determinada por la presencia de abundantes filamentos finos de tipo actína que desplazaban los escasos tonofilamentos a la periferia. Estas células cumplían todos los criterios para ser etiquetadas como mioepiteliales. En la literatura sólo se han descrito siete casos de carcinoma basocelular con esta peculiar diferenciación (AU)

UV induced erythema evaluated 24 h post-exposure by skin reflectance and laser Doppler flowmetry is identical in healthy persons and patients with cutaneous malignant melanoma and basal cell cancer.

Twenty-one patients with invasive cutaneous malignant melanoma and 19 patients with basal cell skin cancer and 29 healthy volunteers were phototested on non-UV exposed buttock skin to examine their 24 h reaction to a series of increasing doses of simulated sunlight with 25% dose increments. Skin pigmentation at the phototest sites was determined by skin reflectance before testing to assure an equal level of constitutive skin pigmentation in the 3 groups. Erythema reactions were scored visually 24 hours post-exposure and objective measurements of erythema were performed by skin reflectance and laser Doppler flowmetry. In adjacent non-irradiated skin the redness was also quantified to determine the increase in redness in irradiated skin compared to non-irradiated skin. Constitutional skin pigmentation correlated well to UV sensitivity (r = 0.75) and skin redness measured by skin reflectance technique correlated to laser Doppler flowmetry (r = 0.86). No significant differences in UV doses to barely perceptible erythema or to the higher erythema grades were found between the two skin tumour groups and the control group, and no significant differences were found in skin reflectance measured redness or in laser Doppler flowmetry of any erythema reactions between the 3 groups. The 24 h erythema reaction to sunlight can therefore not be used to distinguish patients with invasive cutaneous malignant melanoma or basal cell carcinoma from normal persons.

Mitotic phase distribution, mitotic activity and apoptosis in basal cell tumours of canine skin.

This study evaluates the mitotic phase distribution, mitotic activity and apoptosis in 17 basal cell tumours of canine skin. The number of mitotic and apoptotic cell/mm2 of neoplastic epithelium is counted and the volume corrected mitotic and apoptotic index, respectively, are obtained (M/V and A/V index). Transmission electron microscopy is performed on selected cases to confirm the typical features of apoptosis. The M/V index ranges from 9 to 45/mm2 of neoplastic epithelium, while the A/V index ranges from 5 to 111/mm2 of neoplastic epithelium. Even if the number of apoptotic cells is slightly higher than that of mitotic cells and vice versa, the mean values of the two parameters (mean M/ V = 20.76 +/- 10.86, mean A/V = 31.41 +/- 24.53) tend to be equal. In fact, apoptotic and mitotic index are not statistically different (P = 0.11). Furthermore, in all the samples examined, an increased proportion of metaphases (46.82%) is observed. These findings suggest that the discrepancy between apparent mitotic activity and tumour growth may be mainly due to the increased duration of the entire cell cycle rather than to the high incidence of apoptosis.