PTOV1-AS1 desensitizes colorectal cancer cells to 5-FU through depressing miR-149-5p to activate the positive feedback loop with Wnt/ß-catenin pathway.

5-Fluorouracil is a commonly used chemotherapy drug for colorectal cancer. Resistance to 5-Fluorouracil remains a challenge. This research aimed to explore the mechanism of 5-Fluorouracil resistance in colorectal cancer. RT-qPCR and Western blot were used to determine the RNA and protein expression in both cells and exosome. Assays in vitro and in vivo were performed to measure the role of miR-149-5p in colorectal cancer cells. RIP, luciferase activity report, and RNA pulldown assay were applied to detect the association of PTOV1-AS1, SUV39H1, miR-149-5p, and FOXM1. MiR-149-5p was down-expressed in 5-Fluorouracil-resistant cells. MiR-149-5p enhanced the effectiveness of 5-Fluorouracil both in vitro and in vivo. Sensitive colorectal cancer cells released exosomal miR-149-5p to sensitize resistant cells to chemotherapy. Mechanistically, miR-149-5p targeted the FOXM1 to inactivate Wnt/ß-catenin pathway, and PTOV1-AS1 recruited SUV39H1 to suppress miR-149-5p transcription, in turn activating Wnt/ß-catenin pathway, and forming a positive feedback loop with FOXM1. PTOV1-AS1 inhibits miR-149-5p by a positive feedback loop with FOXM1-mediated Wnt/ß-catenin pathway, which provides insights into a potential novel target for enhancing the effectiveness of chemotherapy in colorectal cancer patients.

Established and emerging biomarkers of immunotherapy in renal cell carcinoma.

Immunotherapies, such as immune checkpoint inhibitors, have heralded impressive progress for patient care in renal cell carcinoma (RCC). Despite this success, some patients' disease fails to respond, and other patients experience significant side effects. Thus, development of biomarkers is needed to ensure that patients can be selected to maximize benefit from immunotherapies. Improving clinicians' ability to predict which patients will respond to immunotherapy and which are most at risk of adverse events - namely through clinical biomarkers - is indispensable for patient safety and therapeutic efficacy. Accordingly, an evolving suite of therapeutic biomarkers continues to be investigated. This review discusses biomarkers for immunotherapy in RCC, highlighting current practices and emerging innovations, aiming to contribute to improved outcomes for patients with RCC.

Renal cell carcinoma (RCC) is a type of kidney cancer. Treatments that target the body's immune system, called immunotherapies, are generally effective in RCC, but not all patients' cancer will respond (shrink or disappear) after receiving this treatment. Because of this, signals, called biomarkers, are needed to signal which patients' cancer will respond and which patients may experience unwanted side effects after treatment. This article highlights biomarkers that have been or are being studied for understanding immunotherapy in RCC.

The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide.

PURPOSE: HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide. EXPERIMENTAL DESIGN: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (NCT02269982, n = 118) treated with abiraterone/enzalutamide. CTC detection and HOXB13 complementary DNA (cDNA) expression was measured using a modified Adnatest, grouping patients into 3 categories: CTC 0 (undetectable); CTC+ HOXB13 CTC low (<4 copies); or CTC+ HOXB13 CTC high. The HOXB13 threshold was determined by maximally selected rank statistics for prognostic associations with overall survival (OS) and progression-free survival (PFS). RESULTS: We included 102 men with sufficient CTC HOXB13 cDNA, identifying 25%, 31%, and 44% of patients who were CTC 0, CTC+ HOXB13 low, and CTC+ HOXB13 high, respectively. Median OS were 25.7, 27.8, and 12.1 months whereas the median PFS were 9.0, 7.7, and 3.8 months, respectively. In subgroup analysis among men with CellSearch CTCs ≥5 copies/mL and adjusting for prior abi/enza treatment and Halabi clinical risk score, the multivariate HR for HOXB13 CTC detection was 2.39 (95% CI, 1.06-5.40) for OS and 2.78 (95% CI, 1.38-5.59) for PFS, respectively. Low HOXB13 CTC detection was associated with lower CTC PSA, PSMA, AR-FL, and AR-V7 detection, and more liver/lung metastases (41% vs. 25%). CONCLUSIONS: Higher CTC HOXB13 expression is associated with AR-dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC.

Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer.

PURPOSE: The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB). RESULTS: In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.

Expresión del receptor de factor de crecimiento epidérmico en cáncer de ovario / Expression of the epidermal growth factor receptor in ovarian cancer

El cáncer de ovario es una de las neoplasias más letales dentro de los cánceres ginecológicos con altos niveles de resistencia a los tratamientos habituales. La identificación de blancos tumorales para terapias biológicas responde a la necesidad de desarrollar nuevas estrategias terapéuticas contra este tipo de tumor. Diferentes estudios han demostrado que existe asociación entre la expresión del ligando de EGF, así como sus receptores y el pronóstico de las pacientes con cáncer de ovario. Altos niveles de EGFr se asocian a proliferación, invasión, metástasis y resistencia a la quimioterapia. El uso de productos anti-EGF, como la vacuna CIMAvax-EGF, podría resultar beneficioso en el tratamiento del cáncer de ovario, lo que constituye una opción terapéutica para estas pacientes(AU)

Ovarian cancer is one of the most lethal neoplasms in gynecological cancers having high levels of resistance to the usual treatments.Identifying tumor targets for biological therapies responds to the need to develop new therapeutic strategies against this type of tumor. Different studies have shown that there is an association between EGF ligand expression, as well as receptors and prognosis of patients with ovarian cancer. High levels of EGFr are associated with proliferation, invasion, metastasis and resistance to chemotherapy. High levels of EGFr are associated with proliferation, invasion, metastasis and resistance to chemotherapy.The use of anti-EGF products, such as the CIMAvax-EGF vaccine, could be beneficial in the treatment of ovarian cancer, which constitutes a therapeutic option for these patients(AU)

Cancer stem cells - the current status of an old concept: literature review and clinical approaches

As regards their morphology and biology, tumours consist of heterogeneous cell populations. The cancer stem cell (CSC) hypothesis assumes that a tumour is hierarchically organized and not all of the cells are equally capable of generating descendants, similarly to normal tissue. The only cells being able to self-renew and produce a heterogeneous tumour cell population are cancer stem cells. CSCs probably derive from normal stem cells, although progenitor cells may be taken into consideration as the source of cancer stem cells. CSCs reside in the niche defined as the microenvironment formed by stromal cells, vasculature and extracellular matrix. The CSC assays include FACS sorting, xenotransplantation to immunodeficient mice (SCID), incubation with Hoechst 33342 dye, cell culture in non-adherent conditions, cell culture with bromodeoxyuridine. CSCs have certain properties that make them resistant to anticancer therapy, which suggests they may be the target for potential therapeutic strategies.

Gliomas: marcadores tumorais e prognóstico / Gliomas: tumors biomarkers and prognosis

Os gliomas representam 30%-40% de todas as neoplasias intracranianas e aproximadamente 50% são glioblastomas. São classificados em graus pela OMS, de acordo com sua patologia. Apresentam altas taxas de mortalidade. Existem marcadores tumorais que podem auxiliar na detecção precoce e avaliar prognóstico. Realizada revisão sobre o tema marcadores tumorais por meio do site PubMed. MGMT é uma proteína que restaura o DNA, impedindo a sua alquilação. A metilação do MGMT por meio de fenômeno epigenético impede sua transcrição inibindo sua ação, tornando o tumor suscetível a fármacos. IDH e codeleção cromossômica 1p19q são marcadores tumorais e estão associados a melhor prognóstico. As neoplasias intracranianas apresentam altas taxas de mortalidade e sua detecção precoce por meio de marcadores e o conhecimento de alterações que conferem bom prognóstico podem auxiliar no tratamento dessa doença. A análise molecular auxilia na detecção e no tratamento de tumores.

Gliomas represent 30%-40% of all intracranial tumors and approximately 50% are glioblastomas. They are classified by the WHO in degrees, according to their pathology. Have high mortality rates. There are tumor markers may help in early detection and assess prognosis. Was performed a review about the topic tumor markers through PubMed. MGMT is a protein that restores the DNA, preventing its alkylation. Methylation of MGMT through epigenetic phenomenon prevents their transcription and inhibits its action, making the tumor susceptible to drugs. IDH and chromosomal deletion 1p19q are tumor markers and are associated with better prognosis. The intracranial tumors have high rates of mortality and early detection through biomarkers and knowledge of changes that confer a good prognosis can help in treating this disease. Molecular analysis allows the detection and treatment of tumors.

Uso del ganglio centinela con azul patente: y radiofármaco en pacientes con cáncer de endometrio / Use of sentinel node with patent blue: and radiopharmaceutical in patients with endometrial cancer

El objetivo del presente estudio es demostrar la factibilidad de aplicación del ganglio centinela, utilizando la combinación de radiofármaco y azul patente en pacientes con cáncer de endometrio. En 14 pacientes con cáncer de endometrio estadio I, fueron sometidas a procedimiento de ganglio centinela, utilizando una combinación de coloide marcado con tecnecio 99 y azul patente, inyectados a nivel del cuello uterino. Luego del procedimiento de ganglio centinela, las pacientes fueron sometidas a histerectomía abdominal con ooforosalpingectomía bilateral, y a disección ganglionar pélvica sistemática. El ganglio centinela fue identificado en 10 de 14 pacientes (71,4 por ciento). Se registró 1 ganglio centinela metastásico, en una paciente con un adenocarcinoma endometrioide aparente estadio IB G3, por hematoxilina-eosina. Sólo se detectó un ganglio centinela por paciente. Todos estaban localizados en la pelvis. El porcentaje de falsos negativos fue de cero. La obtención del ganglio centinela en cáncer de endometrio precoz, utilizando azul patente y radiofármaco, a través de inyección pericervical, es factible en pacientes en las que se logre su identificación, el estado ganglionar del resto de la pelvis es 100 por ciento predecible, lo que evitaría disecciones ganglionares innecesarias.

The purpose of the present study was to assess the feasibility of intraoperative sentinel node detection based on the combined use of radio colloid and patent blue labelling in patients with diagnosis of endometrial cancer. Fourteen patients with endometrial cancer classified of stage I underwent a sentinel nodes procedure based on combined technetium 99 labelled colloid and patent blue injected pericervically. After the sentinel nodes procedure, all patients underwent abdominal hysterectomy, bilateral salpingo-oophorectomy, and complete pelvic lymphadenectomy. The sentinel nodes were identified in 10 of the 14 patients (71.4 %). Metastases were detected in: One sentinel node of a patient with an endometrioide adenocarcinoma, seeming stage IB G3, by haematoxylin and eosin staining. No more than one sentinel node was detected in each patient. All were in the pelvic localised. No false negative sentinel node results were observed. Obtain of sentinel node procedure based on combination of radio colloid and patent blue injected pericervically is feasible in patients with diagnosis of early endometrial cancer. The rest of pelvic ganglions were 100 % predictable. This technique reflect the true ganglion status, avoiding an unnecessary pelvic lymphadenectomy.

Carcinoma seroso papilar primario de peritoneo: a propósito de un caso / Primary peritoneum serous papillary: a purposed case

Presentar caso de tumor epitelial raro derivado del peritoneo. Paciente femenina 62 años, quien consulta por aumento de volumen inguinal derecho de 3 meses de evolución. Examen físico: abdomen globoso por panículo adiposo, no se palpa tumor; tumor inguinal derecho de 5 cm x 4 cm. Adenopatía inguinal izquierda de 1,5 cm. Marcadores tumorales: CA 125, alfa feto proteína y CEA normales. Estudios de imágenes reportan tumor pélvico de aproximadamente 10 cm, además de adenopatías inguinales bilaterales, la mayor del lado derecho de 72 mm x 42 mm. PAAF de plastrón inguinal derecho reporta adenocarcinoma metastásico. Es llevada a intervención con diagnóstico de carcinoma de ovario estadio IV. Hallazgos operatorios incluyeron: ascitis, implantes peritoneales, tumor parauterino izquierdo y plastrones ganglionares pélvicos, para aórticos e inguinales. Se realiza cirugía estadiadora de ovario con cito reducción subóptima. El reporte de anatomía patológica concluye: carcinoma seroso papilar primario de peritoneo de origen Mülleriano vs. mesotelioma maligno. La inmunohistoquímica es positiva para citoqueratina 7,CA125, WT1 y p53; negativa para queratina 20, calretinina y TTF1. Se concluye como carcinoma seroso papilar primario de peritoneo estadio IV. Actualmente recibe tratamiento sistémico con respuesta parcial. Entidad indistinguible histológicamente de su contraparte de ovario, excepto por los criterios diagnósticos establecidos para tal fin. Se caracteriza por una afección amplia del peritoneo con ovarios normales. Se deriva del epitelio celómico del peritoneo. El tratamiento es igual al carcinoma de ovario, pero tiene peor pronóstico

We present a rare case of epithelial tumor derived from peritoneum. Is a female patient 62 years old, who consulted us with right inguinal tumor of 3 months of evolution. The physical examination for abdominal adiposity globosely, with not palpable tumor, right inguinal tumor of about 5 cm x 4 cm. Left inguinal adenopathy of about 1.5 cm size. Tumor markers: CA 125, alpha fetoprotein and normal CEA. Imaging studies reported pelvic mass of approximately 10 cm, bilateral inguinal addition, most of the right side of 72 mm x 42 mm. FNA reports plastron right inguinal of metastatic adenocarcinoma. Operating table is carried diagnosed with ovarian carcinoma stage IV (inguinal nodes). The operative findings included: ascites, peritoneal implants, tumor par-uterine left pelvic ganglion ascots, par-aortic and inguinal. Surgery is performed ovarian staging with suboptimal cyto-reduction. The pathology report concludes: Primary papillary serous carcinoma of müllerian origin vs. peritoneal malignant mesotelioma. The Immunohistochemestry is positive for cytokeratin 7, CA125, WT1 and p53; negative for keratin 20, calretinin and TTF1. It is concluded primary serous papillary carcinoma of peritoneum stage IV. Currently she receives systemic treatment with partial response. Entity histological is indistinguishable ovarian counterpart, except for the diagnostic criteria established for this purpose. It is characterized by extensive peritoneal disease with normal ovaries. It is derived from the celomic epithelium of the peritoneum. The treatment is the same as ovarian carcinoma, but has described a worse prognosis

Recentes aquisiçöes em mastologia / The recent progresses in mastology

O câncer de mama, neste final de século, em pesem os avanços diagnósticos e terapêuticos, é permanente desafio para os responsáveis pela saúde pública. Quase nada melhoraram os índices de sobrevida a longo prazo. Mas, graças à possibilidade de diagnóstico precoce e ao tratamento menos agressivo e mutilante, encaramos o futuro com certo otimismo na expectativa do aumento da incidência de casos iniciais e de melhor prognóstico. Descobriram-se fatores etiológicos genéticos e sensível evoluçao no campo da biologia molecular e no diagnóstico por imagem. Aumentou o conhecimento sobre marcadores tumorais e houve inequívoco progresso no estudo das lesoes epiteliais benignas e das neoplasias pré-invasivas. A cirurgia conservadora tem sido praticada em número cada vez maior de pacientes, em substituiçao aos procedimentos mutilantes. A radioterapia tem prática sedimentada com tecnologia e indicaçao bem definidas. O tratamento farmacológico encontra na quimioterapia e na hormonioterapia métodos de ampla utilizaçao os quais, entretanto, nao atingiram a plenitude na inocuidade e na eficiência. Os autores, passam em revista superficial os recentes avanços observados em alguns aspectos da patologia mamária acrescentando, quando oportuno, comentários sobre sua experiência pessoal.