RESUMEN
The immune response to cancer serves an important role in disease progression and patient prognosis. For triple-negative breast cancer showing aggressive behavior, immunotherapy has a good efficacy because of the potent immunogenicity of this type of cancer. However, the dominant subtype, luminal human epidermal growth factor receptor-2 (HER2)-negative breast cancer, is less immunogenic. To determine whether luminal HER2-negative cancer reacts to the anticancer immune response, the present study analyzed the status and prognostic value of the principal immunological biomarkers of breast cancer, including tumor-infiltrating lymphocytes (TILs), CD8+ T lymphocytes, the major histocompatibility complex and programmed cell death ligand-1 (PD-L1). The biomarkers were compared between patients with luminal HER2-negative breast cancer and those with immunogenic subtypes including triple-negative and HER2-overexpressed breast cancer. A total of 71 patients with primary breast cancer were classified into the immunogenic non-luminal (n=23) and less immunogenic luminal HER2-negative groups (n=48) based on immunogenicity. In the luminal HER2-negative group, compared with patients with low TIL levels, those with high TIL levels were at an advanced stage of cancer (P=0.024) and showed worse relapse-free survival (P=0.057); however, the remaining biomarkers exhibited no association with cancer progression or prognosis. In the non-luminal group, patients with high TIL levels showed significantly better RFS than those with low TIL levels (P=0.014). Compared with non-luminal patients negative for PD-L1, those positive for PD-L1 exhibited better overall survival (P=0.064). Notably, TIL status was found to exhibit contrasting prognostic predictions based on immunogenicity. In conclusion, TILs are a strong candidate for prognostic prediction in breast cancer, regardless of the subtype. PD-L1 is a potential candidate for prognostic prediction in immunogenic breast cancers, but not in the luminal HER2-negative subtype.
RESUMEN
BACKGROUND: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression. METHODS: TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high-throughput quantitative fluorescence in situ hybridization using a previously reported cohort comprising 1434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma, hepatocellular carcinoma, and renal cell carcinoma (RCC), which are known cancers with a statistically significantly low incidence of alternative lengthening of telomeres. Cases were divided into 2 groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis was analyzed. RESULTS: There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC, and RCC. CONCLUSIONS: Longer telomeres are associated with worse prognosis in ADC, SCC, and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma de Células Renales , Carcinoma de Células Escamosas , Neoplasias Renales , Neoplasias Hepáticas , Humanos , Fibroblastos Asociados al Cáncer/patología , Hibridación Fluorescente in Situ , Pronóstico , Acortamiento del Telómero , Telómero , Carcinoma de Células Escamosas/patología , Neoplasias Hepáticas/patología , Homeostasis del TelómeroRESUMEN
Recent evidence indicates that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in tumor formation in a telomere-independent manner. Non-canonical function of hTERT has been considered as a therapeutic target for cancer therapy. We have previously shown that hTERT phosphorylation at threonine 249 (p-hTERT), which promotes RdRP activity, is an indicator of an aggressive phenotype and poor prognosis in liver and pancreatic cancers, using two cohorts with small sample sizes with polyclonal p-hTERT antibody. To clarify the clinical relevance of p-hTERT, we developed a specific monoclonal antibody and determined the diagnostic and prognostic value of p-hTERT in cancer specimens using a large cohort. A monoclonal antibody for phosphorylated hTERT (p-hTERT) at threonine 249 was developed and validated. The antibody was used for the immunohistochemical staining of formalin-fixed, paraffin-embedded specimens from 1523 cases of lung, colon, stomach, pancreatic, liver, breast, and kidney cancers. We detected elevated p-hTERT expression levels in cases with a high mitotic activity, high pathological grade, and high nuclear pleomorphism. Elevated p-hTERT expression was an independent prognostic factor for lung, pancreatic, and liver cancers. Furthermore, p-hTERT expression was associated with immature and aggressive features, such as adenosquamous carcinoma (lung and pancreas), invasive type of cancer (lung), high serum alpha-fetoprotein level (liver), and triple-negative status (breast). In conclusion, RdRP activity indicated by p-hTERT expression predicts aggressive cancer phenotypes in various types of cancer. Thus, p-hTERT is a novel biomarker for the diagnosis of aggressive cancers with a poor prognosis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Asunto(s)
Neoplasias , Telomerasa , Anticuerpos Monoclonales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/genética , Neoplasias/patología , Fosforilación , Pronóstico , ARN Polimerasa Dependiente del ARN , Telomerasa/genética , Treonina/metabolismoRESUMEN
Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually treated with chemotherapy. Treatment of older patients with TNBC, however, should be decided carefully because of the side effects of chemotherapy in this population. Some forms of TNBC are associated with a favorable prognosis and do not require chemotherapy. To optimize the treatment of older patients with TNBC, it is important to know the clinicopathological characteristics and a prognostic marker. In this study, classic clinicopathological factors, immunohistochemical characteristics (androgen receptor [AR], cytokeratin 5/6 [CK5/6], epidermal growth factor receptor), tumor-infiltrating lymphocytes (TILs), and the clinical outcome based on the status of each biomarker were compared among a consecutive series of female patients with TNBC aged ≥75 years (n = 75) and among those aged 55-64 years matched for the pathological stage (n = 47) who underwent surgery without neoadjuvant therapy. TNBC with special histology (particularly apocrine carcinoma, pleomorphic invasive lobular carcinoma, and metaplastic carcinoma) was more frequent in the older group than in the younger group (35/75, 57% versus 11/47, 23%, P = 0.010). The AR positivity rate was higher in older patients than in younger patients, whereas TILs and CK5/6 exhibited the opposite results. In multivariate analyses, AR positivity was an independent predictor of a favorable outcome in older patients (lower recurrence rate), whereas the high level of TILs was favorable in younger patients (lower recurrence and mortality rates). AR positivity or apocrine morphology was frequent and predicts a favorable clinical outcome in older patients with TNBC, suggesting the importance of AR examination in this population.
Asunto(s)
Neoplasias de la Mama Triple Negativas/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Receptores Androgénicos/metabolismoRESUMEN
We report 4 female patients with metastatic breast cancer who were administered TS-1 as a late-line treatment and showed favorable outcomes. Their average age was 66.3. The patients, all of whom had undergone prior treatment with both anthracyclines and taxanes, showed intrinsic Luminal A or B subtypes. After administration of TS-1 in the lines of 2 to 9 in metastatic settings, all patients showed a long progression-free survival with a favorable quality of life.
Asunto(s)
Neoplasias de la Mama , Silicatos/uso terapéutico , Titanio/uso terapéutico , Anciano , Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Calidad de Vida , Taxoides , Resultado del TratamientoRESUMEN
Febrile neutropenia(FN)is a frequent adverse event observed in cancer patients undergoing chemotherapy that may cause life-threatening infections. However, reducing the dose of anti-cancer drugs for breast cancer in adjuvant settings to prevent FN has been reported to adversely affect patient survival. Therefore, it is important to administer therapeutic agents as per their prescheduled regimens without delays or reductions in the dosage. From April 2015 to September 2017, pegfilgrastim was administered to 24 patients with breast cancer(primary prevention in 11 patients and secondary prevention in 13 patients)to prevent FN during chemotherapy in either adjuvant or metastatic settings. We were able to reduce the incidence of FN through prophylactic administration of pegfilgrastim without encountering serious adverse events. The inclusion of pegfilgrastim is considered essential for the safe administration of chemotherapy according to a preplanned schedule. Here, we discuss the indications, efficacy, and safety of the drug.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Filgrastim , Neutropenia , Polietilenglicoles , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Filgrastim/uso terapéutico , Factor Estimulante de Colonias de Granulocitos , Humanos , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Polietilenglicoles/uso terapéutico , Proteínas RecombinantesRESUMEN
Bevacizumab (BV), an inhibitor of vascular endothelial growth factor, is used in combination with paclitaxel (PTX) to treat advanced breast cancer. Hypertension and proteinuria are characteristic adverse events of BV therapy. We assessed the potential of these adverse events as predictors of BV treatment responses. Our results revealed that groups that developed hypertension and proteinuria early (by day 56) had a stronger antitumor response (Fisher's exact test p<0.05). However, no significant difference was observed in progression-free survival (the Kaplan-Meier method and Log-rank test). As a reference, age, the treatment line, subtypes, liver and renal function, diabetes mellitus and hyperlipidemia history, body mass index, influencing concomitant medicine, average relative dose intensity and hematotoxicity did not significantly differ between groups with or without hypertension and with or without proteinuria. These results indicate the potential of the development of hypertension and proteinuria as predictors of improved outcomes with PTX plus BV therapy in patients with breast cancer. However, since both adverse events may preclude the continuation of treatment, their earlier management may be required.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hipertensión/inducido químicamente , Proteinuria/inducido químicamente , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Bevacizumab/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Since breast cancer shows diversity in clinical behaviors, a standard therapy does not always lead to favorable outcomes. MATERIALS AND METHODS: The expression statuses of candidate markers, including topoisomerase-II alpha (TOP2A), beta-tubulin (B-tub), and tissue inhibitor of metalloprotease-1 (TIMP-1), were immunohistochemically evaluated in 70 breast cancer tissues from 68 patients with advanced breast cancers receiving chemotherapy. RESULTS: The response rates to anthracycline and taxane were 70.5% and 67.2%, respectively. Overall, 25.1% ± 29.7%, 8.32% ± 10.1%, and 16.37% ±17.5% of cancer cells in the tumors studied were positive for B-tub, TOP2A, and TIMP-1 expressions, respectively. However, positive molecule expression did not differ between patients who did and did not exhibit clinical responses to treatment. The proportion of TOP2A-positive cancer cells was significantly higher among anthracycline responders than among nonresponders in HR-negative cancer (15.4% ±17.5% vs. 2.0% ± 2.4%, respectively, P = 0.048), whereas TOP2A and TIMP-1 expression statuses did not differ in HR-positive cancer. When patients were stratified according to B-tub, TOP2A, or TIMP-1 expression statuses (B-tub ≥10% vs. <10%, TOP2A ≥5% vs. <5%, TIMP-1 ≤20% vs. >20%, respectively), the proportion of patients with ≥10% B-tub-positive cancer cells was significantly higher in taxane responders than in nonresponders (72.4% vs. 37.5%, respectively, P = 0.016). Anthracycline responders showed a trend to have a higher proportion of patients with either ≥5% TOP2A-positive cancer cells or ≤20% TIMP-1-positive cancer cells compared to nonresponders (86.7% vs. 61.5%, respectively, P = 0.066). CONCLUSION: Immunohistochemical TOP2A, TIMP-1, and B-tub expression analyses are expected to be useful for predicting tumor responses to chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adulto , Anciano , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/administración & dosificación , ADN-Topoisomerasas de Tipo II/metabolismo , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Pronóstico , Receptor ErbB-2/metabolismo , Taxoides/administración & dosificación , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: The dendritic cell (DC)-based vaccine targeting the highly immunogenic tumor antigen, MUC1, has been promising for a cancer immunotherapy; however, predictive biomarkers for beneficial clinical responses of the vaccine remain to be determined. METHODS: DCs loaded with MUC1-derived peptide were subcutaneously administered to patients with MUC1-positive non-small cell lung cancer (NSCLC) that was refractory to standard anticancer therapies, every 2 weeks. The effectiveness and tolerability of the vaccine were evaluated, and predictive biomarkers of clinical responses were explored. RESULTS: Between August 2005 and May 2015, 40 patients received the vaccines. The median survival time (MST) after the initial vaccination was 7.4 months, and the 1-year survival rate was 25.0%. The MST for patients who received more than six vaccinations was 9.5 months, and the 1-year survival rate was 39.3%. In this cohort, patients who experienced immune-related adverse events, including skin reactions at the vaccination site and fever, had significantly longer survival times compared with patients without those immune-related adverse events (12.6 versus 6.7 months, p = 0.042). Longer survival times were also observed in patients whose peripheral white blood cells contained >20.0% lymphocytes (12.6 versus 4.5 months; p = 0.014). MUC1-specific cytotoxic immune responses were achieved in all of seven patients analyzed who received six vaccinations. CONCLUSION: The MUC1-targeted DC-based vaccine induced an antitumor immune response that promoted prolonged survival of patients with refractory NSCLC. The occurrence of immune-related adverse events and having a higher percentage of peripheral lymphocytes were predictive biomarkers of a beneficial clinical response during cancer immunotherapy for NSCLC.
RESUMEN
The survival of patients with metastatic breast cancer (MBC) has not improved, despite recent advances in therapeutic strategies. This is mainly due to the fact that cytotoxic agents cannot be administered over a long period, even if they exhibit favorable activity, due to treatment-related side effects or acquisition of tumor resistance to the administered agents. Thus, the development of therapeutic strategies that may be used over a long time period is required to improve survival. We assessed the availability and clinical outcomes of metronomic chemotherapy, which is defined as continuous or frequent treatment with low doses of cytotoxic drugs. A total of 80 patients with MBC received chemotherapy in the metastatic setting, and the clinicopathological factors and clinical outcomes were retrospectively compared between 52 patients who received metronomic regimens and 28 patients who received other cytotoxic regimens. As regards clinical outcomes, the median time-to-treatment failure (TTF) and overall survival (OS) were significantly longer in the metronomic group compared with those in the non-metronomic group (TTF, 15 vs. 4 months, P=0.0001; and OS, 53 vs. 28 months P=0.0012, respectively). In the metronomic group, none of the 18 patients who responded to the regimen had triple-negative (TN) cancer (17 had luminal-type tumors and 1 had a human epidermal factor receptor 2-type tumor). Furthermore, TTF and OS were significantly longer in patients with non-TN cancer compared with those in patients with TN cancer in the metronomic group (TTF, 16 vs. 7 months, P=0.0014; and OS, 108 vs. 20 months, P=0.000007, respectively). The proportion of patients who experienced treatment-related adverse events was significantly lower in the metronomic group compared with that in the non-metronomic group (36.5 vs. 61.5%, respectively; P=0.038). In conclusion, metronomic chemotherapy is a viable option for luminal-type MBC in terms of effectiveness and minimal toxicity, regardless of metastatic sites or prior treatment. However, an alternative treatment is required for TN cancer.
RESUMEN
BACKGROUND: Although survival of patients with metastatic breast cancer (MBC) has been significantly prolonged over the past decade due to improvement of anti-cancer therapeutics, only a few patients survive for more than 10 years. It has not been determined which patients can have long-term survival with treatment. METHODS: To determine prognostic factors responsible for long-term survival, we retrospectively compared clinicopathologic factors of patients with MBC who survived for 50 months or more after diagnosis with patients who did not. Of 70 patients with MBC who received chemotherapy between November 2005 and September 2011, 23 patients who survived for 50 months or more after diagnosis and 28 patients who died within 50 months after diagnosis were assessed for their clinicopathologic factors and outcomes. RESULTS: The proportion of patients with hormone receptor-positive (HR+) tumors was significantly higher and the proportion of patients with triple negative tumors (TN) was lower in long-term survivors than in non-long-term survivors (HR+: 87% versus 28.6%, P=0.000037; TN: 13.1% versus 53.6%, P=0.0028). Metastatic site, number of disease sites, prior chemotherapeutic regimens and human epidermal growth factor receptor-2 (HER2) status did not differ between the two groups. The proportion of patients who received metronomic regimens was significantly higher in long-term survivors than in non-long-term survivors (65.2% versus 35.7%, P=0.034) when the most effective regimen among regimens that were received in metastatic settings was compared between the two groups. Overall response rate was significantly higher (82.6% versus 17.9%, P<0.00001) and time to treatment failure after receiving the most effective regimen was longer in long-term survivors than in non-long-term survivors (26 versus 5 months, P=0.0001). The number of chemotherapeutic regimens for breast cancer and that for MBC did not differ between the two groups. CONCLUSIONS: Patients with luminal-type MBC who benefit at least once from chemotherapy including metronomic regimens, or patients who continued to receive the most effective regimen for more than two years can be expected to have long-term survival after diagnosis of MBC, regardless of the number of chemotherapeutic regimens they had received.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
The high level of transforming growth factorß (TGFß) in tumor tissue, which is primarily released from tumor cells, helps maintain their metastatic nature and exacerbates the creation of a pro-tumor microenvironment. Although the strategy of targeting TGFß in cancer therapy has shown promise, its effects remain limited. In the present study, we focused on tumor cells as sources of TGFß release, and hypothesized that inhibition of their TGFß release could suppress their epithelial-mesenchymal transition (EMT)-associated metastatic nature and inactivate the induction of suppressor immune cells. To investigate this hypothesis, LLC1 cells, a mouse lung cancer cell line, were cultured with the TGFß release inhibitor tranilast and the motility of LLC1 cells was examined. Furthermore, to examine whether inhibition of TGFß release influences the induction of regulatory T (Treg) cells, spleen cells from normal mice were cultured in medium in which LLC1 cells had been cultured with tranilast. The results showed that tranilast inhibited the release of TGFß1 from LLC1 cells without affecting their proliferation. Inhibition of TGFß1 release suppressed the invasive activity of LLC1 cells, but enhanced their activity to adhere. mRNA levels of Slug and Twist were decreased in LLC1 cells, whereas levels of Ecadherin were recovered. Treg cells were less frequently induced by medium in which LLC1 cells had been cultured with tranilast. Taken together, inhibition of TGFß1 release dampens the metastatic nature of LLC1 cells through the downregulation of EMT and possesses the possibility to improve antitumor immune responses through suppression of Treg cell induction. These findings provide a new rationale for development of TGFßtargeted molecular immunotherapy against cancer.
Asunto(s)
Transición Epitelial-Mesenquimal/fisiología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Cadherinas/genética , Cadherinas/metabolismo , Procesos de Crecimiento Celular/fisiología , Línea Celular , Línea Celular Tumoral , Movimiento Celular/fisiología , Regulación hacia Abajo , Transición Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Ratones , ARN Mensajero/genética , Factores de Transcripción de la Familia Snail , Bazo/metabolismo , Bazo/fisiología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismoRESUMEN
PURPOSE: Simultaneous activation of T helper 1 (Th1) cell function has crucial roles in induction of potent cytotoxic T lymphocyte (CTL) responses in cancer immunotherapy. Here, we investigated whether dendritic cell (DC)-based vaccines loaded with both tumor-associated antigen (TAA)-derived MHC class I and pan-MHC class II peptides could elicit more potent CTL responses through simultaneous activation of Th1 function and reduction in CD4(+) regulatory T (Treg) cell proliferation. METHODS: C57BL/6 mice bearing LLC1, a mouse Lewis lung cancer cell line, were subcutaneously administered DCs loaded with both LLC-derived MHC class I (MUT1&2) and LLC-unrelated pan-MHC class II (PADRE) peptides (DC-MUT1&2-PADRE). In assays using samples from advanced lung cancer patients, peripheral blood mononuclear cells were stimulated with autologous DCs loaded with both MUC1 MHC class I and PADRE peptides (DC-MUC1-PADRE) in vitro. Subsequently, TAA-specific CTL responses and the population of CD4(+) Treg cells were analyzed. RESULTS: The population of spleen CD4(+) PADRE-specific cells producing interferon-gamma (IFNγ) was significantly increased by DC-MUT1&2-PADRE administration. Vaccinations with DC-MUT1&2-PADRE decreased the population of CD4(+) Treg cells in spleen and augmented CTL responses, effectively leading to suppression of tumor growth. In assays with human samples, CD4(+) Treg cells were induced less frequently, and MUC1-specific cytotoxicity was enhanced by stimulation with DC-MUC1-PADRE compared with that by stimulation with DC-MUC1 alone. CONCLUSIONS: Simultaneous activation of Th1 function by DCs loaded with both TAA-derived MHC class I and PADRE peptides augments TAA-specific CTL responses while reducing Treg cell proliferation.
Asunto(s)
Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Neoplasias/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Vacunas contra el Cáncer/inmunología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Antígenos de Histocompatibilidad Clase II/química , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunoterapia , Interferón gamma/biosíntesis , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ratones , Neoplasias/terapia , Péptidos/inmunología , Péptidos/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/inmunología , Células TH1/inmunologíaRESUMEN
After injection of green fluorescent protein-positive (GFP(+)) bone marrow (BM) cells into lethally irradiated wild-type mice, the organs of the recipient mice [BM transplantation (BMT) mice] were regenerated; however, irradiation of the cecum or spleen (only) blocked their regeneration with loss of injected BM cells. These results suggest that the donor cells first enter the BM and then migrate to the peripheral organs. The maintenance of epithelial structure and function is controlled by interactions between stromal cells and the epithelia; the organ is stable only if the stroma is functioning normally. In BMT mice, intestinal GFP(+) stromal cells were regenerated fairly rapidly although GFP(+) cells were observed only rarely in the intestinal epithelium even if it passes several weeks or months post BMT, indicating that BM-derived stromal cells play a pivotal role in epithelial renewal and are crucial for maintaining organ structure and function. BM-derived cells in the periphery possess a special key to return to the BM and then to migrate to various organs to become resident cells.
Asunto(s)
Células de la Médula Ósea/citología , Trasplante de Médula Ósea , Diferenciación Celular , Especificidad de Órganos , Regeneración/fisiología , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de la radiación , Diferenciación Celular/efectos de la radiación , Movimiento Celular/efectos de la radiación , Epitelio/patología , Epitelio/efectos de la radiación , Citometría de Flujo , Proteínas Fluorescentes Verdes/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Recuento de Linfocitos , Linfocitos/metabolismo , Linfocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Especificidad de Órganos/efectos de la radiación , Parabiosis , Regeneración/efectos de la radiación , Células del Estroma/citología , Células del Estroma/metabolismo , Células del Estroma/efectos de la radiación , Factores de Tiempo , Rayos XRESUMEN
We assessed the clinical usefulness of human epidermal growth factor receptor-2 extracellular domain (HER2ECD) as a biomarker for detecting cancer and monitoring disease status and for predicting the efficacy of anticancer treatment in breast cancer. Five-hundred and eighty serum samples from 252 patients with breast cancer were examined for the concentration of HER2ECD to compare with conventional tumor markers (CEA, CA15-3, NCC-ST439 and BCA225). Also, in 19 patients with HER2-overexpressed advanced or recurrent breast cancer who were treated with trastuzumab, clinical outcomes were evaluated retrospectively to determine whether their serum HER2ECD levels predict clinical responses. The proportion of patients with elevated HER2ECD levels was 15.1%, which was compatible with those with elevated conventional marker levels. In patients with HER2-overexpressed breast cancer, the positive rate of HER2ECD was significantly higher (24.1%) than those of conventional markers (7.4-12.9%), suggesting the usefulness of HER2ECD for detecting cancer in this population. HER2-overexpressed patients responding to trastuzumab (12 of 19 patients) showed significantly higher serum HER2ECD level (p = 0.033) and longer time to progression (TTP) (p = 0.039) and overall survival (OS) (p = 0.031) than did patients not responding (seven patients). Furthermore, higher response rates were observed in patients with elevated HER2ECD levels than in patients without elevated HER2ECD levels (91.3% vs. 14.3%, p = 0.032), whereas there was no difference in survival between the two groups. The results suggest that HER2ECD is a useful biomarker not only for detecting breast cancer recurrence but also for predicting tumor responses to trastuzumab.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Carcinoma Ductal de Mama/sangre , Recurrencia Local de Neoplasia/sangre , Receptor ErbB-2/sangre , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Capecitabina , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Docetaxel , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Paclitaxel/administración & dosificación , Estructura Terciaria de Proteína , Receptor ErbB-2/química , Taxoides/administración & dosificación , Trastuzumab , Resultado del TratamientoRESUMEN
The objective of treatment for metastatic breast cancer (MBC) is to control the disease or disease-related symptoms. Prolonged survival has also often been achieved by chemotherapeutic regimens in this setting. Long-term administration of one therapeutic regimen is essential for prolonging survival as well as for maintaining quality of life in these patients. In this study, we focused on time to treatment failure (TTF) as a parameter that predicts patient survival and we retrospectively compared clinical outcomes of patients with MBC who showed TTF of ≥12 months (26 patients) and <12 months (29 patients). The proportion of hormone receptor-positive tumors and the number of prior chemotherapy regimens for MBC were significantly higher and tumor grade was lower in patients with TTF ≥12 months compared to those with TTF <12 months. With regard to clinical outcomes, the objective response rate (ORR) in patients with TTF ≥12 months was significantly higher and median time to progression (TTP) and overall survival (OS) were longer compared to those with TTF <12 months. Of note, the proportion of patients who received metronomic regimens was significantly higher in patients with TTF ≥12 months compared to those with TTF <12 months (80.8 vs. 24.1%, P=0.00003). To assess the clinical benefit of metronomic regimens, the efficacy in patients receiving metronomic and those receiving non-metronomic regimens was compared. Although there was no difference in ORR between the two groups, median TTP and OS were significantly longer in the metronomic compared to the non-metronomic group (TTP: 30 vs. 4 months, P=0.0017; OS: 68 vs. 28 months, P=0.0005). The results suggested that metronomic chemotherapy is useful for palliative care and also improved clinical outcomes as a regimen for which long-term administration may be expected.
RESUMEN
OBJECTIVE: Immunohistochemistry (IHC) and Fluorescent In Situ Hybridization (FISH) are important technologies to examine the protein expression and gene amplification of human epidermal growth factor receptor type 2/neu (HER-2/neu), respectively, in breast cancer tumors; however, tumor samples are not always available for examination. Therefore, an easy and sensitive examination to detect HER2-overexpressed tumors should be developed. The extracellular domain of HER-2/neu protein (HER2ECD) has been reported to be observed in the serum of many patients with metastatic breast cancer. In this study we assessed the clinical usefulness of serum HER2ECD (sHER2ECD) as a biological marker in breast cancer. METHOD: We measured sHER2ECD levels in 108 patients with breast cancer using the ADVIA Centaur assay system, and conventional tumor markers, i.e. CEA and CA15-3, using enzyme or chemiluminescent immunoassay. The sHER2ECD levels were compared with the levels of tumor markers and clinical characteristics. RESULTS: Patients with primary breast cancer who had four or more lymph nodes involved (n=6) showed significantly higher sHER2ECD values than those with no nodes involved (n=57, p<0.05) and those with 1 to 3 nodes involved (n=15, p<0.01). In the IHC-positive group, the positive rate of sHER2ECD was higher than those of CA15-3 or CEA. In metastatic breast cancer, the combination of sHER2ECD and CA15-3 showed the highest positive rate (81.5%). In all 3 patients with HER2-overexpressed cancer showing a partial response (PR) or complete response (CR) to trastuzumab therapy, sHER2ECD levels declined after treatment (39.9 to 58.7%). CONCLUSION: The sHER2ECD assay by the CLIA method may be useful for the diagnosis and monitoring of metastatic/recurrent breast cancer.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , Inmunoensayo/métodos , Receptor ErbB-2/sangre , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/diagnóstico , Juego de Reactivos para Diagnóstico , Sensibilidad y Especificidad , TrastuzumabRESUMEN
Skin-sparing mastectomy (SSM) is one of the available operation methods for breast cancer. We discuss here indications for SSM for primary breast cancer. We carried out SSM for 28 patients with breast cancer. Their clinical features were compared with those in patients who underwent breast-conserving treatment (BCT). Fifteen of the 28 patients received SSM according to schedule. The remaining 13 patients who were scheduled to undergo BCT received SSM because of involvement of the surgical margin. Clinical features indicating suitability for SSM included extensive intraductal cancer growth and multicentricity. The length of intraductal cancer growth in these patients was significantly greater than that in 24 patients who received BCT (2.28 versus 0.571 cm; P = 0.000078). Tumor size and tumor-nipple distance were not indicating factors for this treatment. SSM, which is advantageous in terms of aesthetic outcome and oncologic safety, may be widely indicated after careful evaluation by magnetic resonance imaging or pathologic examination.
Asunto(s)
Neoplasias de la Mama/cirugía , Mastectomía/métodos , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Escisión del Ganglio Linfático , Imagen por Resonancia Magnética , Mamografía , Mastectomía Segmentaria , Persona de Mediana Edad , Pezones , Receptor ErbB-2/metabolismoRESUMEN
Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptor-alpha (ERalpha) promote the proliferation of breast cancer cells. Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription. Here, we show that menin expressed in breast cancer cell line MCF-7 is colocalized with ERalpha and functions as a direct coactivator of ER-mediated transcription in breast cancer cells. In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner. Cells knocked down for ERalpha exhibited impaired ERE-luciferase activity induced by menin. Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ERalpha. These results indicate that menin is a direct activator of ERalpha function. Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7. In a clinical study with 65 ER-positive breast cancer samples-all of which had been treated with tamoxifen for 2-5 years as adjuvant therapies--menin-positive tumors had a worse outcome than menin-negative ones. These indicated that menin can function as a transcriptional regulator of ERalpha and is a possible predictive factor for tamoxifen resistance.
Asunto(s)
Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Estradiol/metabolismo , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Tamoxifeno/uso terapéutico , Animales , Sitios de Unión , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Células COS , Línea Celular Tumoral , Quimioterapia Adyuvante , Chlorocebus aethiops , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Nucleares/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas/genética , Interferencia de ARN , Proteínas Recombinantes de Fusión/metabolismo , Factores de Tiempo , Activación Transcripcional , Transfección , Técnicas del Sistema de Dos HíbridosRESUMEN
A 38-year-old male was admitted to our hospital with epigastric pain, and he was confirmed to have acute exudative pancreatitis. After the episode of acute pancreatitis subsided, laboratory investigation revealed increased serum calcium (12.0 mg/dl), decreased serum phosphorus (2.7 mg/dl), and increased serum parathyroid hormone (intact) levels (131 pg/ml). A computed tomography (CT) scan of the neck did not reveal any mass lesions in the parathyroid gland. However, (99m)Tc sestamibi scintigraphy revealed that there was one functioning parathyroid gland in the upper mediastinum. Combined (99m)Tc sestamibi scintigraphy and CT scan confirmed the diagnosis of primary hyperparathyroidism in the mediastinum. Microscopic examination revealed the presence of a parathyroid adenoma (1.3 x 0.4 cm(2)) adjacent to the atrophic parathyroid gland in right thymus gland. We report the case of a patient diagnosed with primary hyperparathyroidism due to an ectopic mediastinal parathyroid adenoma. An ectopic mediastinal parathyroid adenoma may manifest as an episode of acute pancreatitis. Preoperative investigation to determine the exact location of an adenoma should include two types of imaging studies, preferably (99m)Tc sestamibi scintigraphy and CT of the neck and chest.