RESUMO
Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B-/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B-/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes, and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses. ⢠Doxorubicin activates the G2/M cell cycle checkpoint in acute lymphoblastic leukemia (ALL) cells. ⢠ALL cells respond to doxorubicin-induced DNA damages by activating the ATR-CHK1 pathway. ⢠The inhibition of the ATR-CHK1 pathway synergizes with doxorubicin in the induction of cytotoxicity in ALL cells. ⢠The inhibition of ATR-CHK1 pathway induces aberrant chromosome segregation and mitotic spindle defects in doxorubicin-pretreated ALL cells.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Quinases , Humanos , Proteínas Quinases/metabolismo , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Doxorrubicina/farmacologia , Dano ao DNA , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50-60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification.
Assuntos
Fibrossarcoma , Histiocitoma Fibroso Maligno , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/genética , Neoplasias de Tecidos Moles/patologia , Extremidades/patologia , GenômicaRESUMO
BACKGROUND: Neuroendocrine neoplasias (NENs) are a rare group of tumors with different prognosis and response to therapy. Their heterogeneity is dependent on the site of origin, morphology, and Ki67. Temozolomide (TEM) appears to be active in metastatic NENs (mNENs) but there is limited evidence about its efficacy in gastrointestinal NENs. We analyzed "real-world" data on the use of TEM alone or in association with capecitabine (CAPTEM) in patients with mNENs. PATIENTS AND METHODS: One hundred consecutive patients with advanced NENs treated with TEM or CAPTEM between 2009 and 2019 were included. A pretreatment tumor growth rate (TGR0) was calculated. Overall survival (OS), progression-free survival (PFS), tolerance, objective response rate (ORR), and disease control rate (DCR) were analyzed. A propensity score analysis and inverse probability of treatment weights for Cox regression models were used. RESULTS: TEM-based therapy was administered to 95 patients (26.3% CAPTEM and 83.7% TEM) with a median age of 59 years (range 26-85) years. ECOG performance status was 0-2. Carcinoid syndrome was reported in 12 (12.6%) patients. Twenty (21.1%) patients with grade (G) 3 neuroendocrine carcinoma (NEC) and 9 (9.4%) with G3 neuroendocrine tumors (NETs) were included in the analysis. Median PFS of the entire group was 10.4 months (95% confidence interval [CI]: 6.0-11.5). In multivariate analysis, a higher risk of progression was observed for NEC G3 patients (hazard ratio [HR] 2.70, 95% CI: 1.25-5.84) and for a TGR ≥19.55 (HR: 2.53, 95% CI: 1.45-4.40). Median OS was 23.4 months (95% CI: 17.0-29.0) and was similar in both treatment groups (23.9 vs. 20.5 months for TEM and CAPTEM, respectively, p = 0.585). In multivariate analysis, TGR ≥19.55 was associated with a higher risk of death (HR: 2.18, 95% CI: 1.16-4.11) than TGR <19.55, as was NEC G3 (HR: 2.42, 95% CI: 1.04-5.59) with respect to NETs. No differences in terms of mPFS or mOS were seen in relation to the primary site of disease. In the 86 patients evaluable for response, ORR was 44.1% and the DCR was 70.9%. Mild adverse events (grade I-II) included anemia, neutropenia, and headache. Rare cases of G 3 neutropenia and thrombocytopenia were recorded. CONCLUSIONS: TEM-based regimens are associated with a high DCR and a relatively tolerable toxicity profile in NENs of pancreatic, intestinal, and lung origin. Further investigation of these specific NETs is warranted in prospective clinical trials.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina/farmacologia , Tumores Neuroendócrinos/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Temozolomida/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Temozolomida/administração & dosagem , Temozolomida/efeitos adversosRESUMO
Adult rhabdomyosarcoma (RMS) represents an uncommon entity with an incidence of less than 3% of all soft tissue sarcomas (STS). Consequently, the natural history and the clinical management of this disease are infrequently reported. In order to fill this gap, we investigated the molecular biology of an adult RMS case series. The expression of epithelial mesenchymal transition-related gene and chemoresistance-related gene panels were evaluated. Moreover, taking advantage of our STS translational model combining patient-derived primary culture and 3D-scaffold, the pharmacological profile of an adult head and neck sclerosing RMS was assessed. Furthermore, NGS, microsatellite instability, and in silico analyses were carried out. RT-PCR identified the upregulation of CDH1, SLUG, MMP9, RAB22a, S100P, and LAPTM4b, representing promising biomarkers for this disease. Pharmacological profiling showed the highest sensitivity with anthracycline-based regimen in both 2D and 3D culture systems. NGS analysis detected RAB3IP-HMGA2 in frame gene rearrangement and FGFR4 mutation; microsatellite instability analysis did not detect any alteration. In silico analysis confirmed the mutation of FGFR4 as a promising marker for poor prognosis and a potential therapeutic target. We report for the first time the molecular and pharmacological characterization of rare entities of adult head and neck and posterior trunk RMS. These preliminary data could shed light on this poorly understood disease.
Assuntos
Rabdomiossarcoma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Genômica/métodos , Humanos , Masculino , Instabilidade de Microssatélites , Mutação/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Regulação para CimaRESUMO
BACKGROUND: Patients undergoing chemotherapy are at risk of toxicity, especially of haematological origin. Granulocyte depletion, although often underestimated, can lead to the occurrence of an event defined as febrile neutropenia (FN). Neutropenic fever syndromes are dangerous because they cause major complications in around 25%-30% of patients and have a mortality rate of up to 11%. Treatment for FN was limited to antibiotics and supportive therapies until filgrastim was approved for use in the 1990s. OBJECTIVES: The present systematic review focuses on the efficacy and safety of this haematopoietic growth factor. DATA SOURCES AND METHODS: For this review, a systematic literature search of electronic databases and references from recent reviews up to December 2018 was carried out to identify clinical trials, observational studies and case reports evaluating filgrastim efficacy and safety. English language was defined as a restriction. Published randomised controlled trials (RCTs), case reports and reviews analysing the effects of filgrastim on severe neutropenia and its limits were considered. Four review authors independently selected the studies, assessed the risk of bias and extracted study data. RESULTS: As reported in ASCO guidelines, the efficacy of filgrastim with respect to placebo or no treatment in RCTs is based on its prevention of FN. A recent meta-analysis analysed nine RCTs with 2197 patients, revealing a reduction in the incidence of FN with filgrastim (risk ratio [RR] 0.63, 95% CI 0.53-0.75). These findings were further confirmed in two observational studies. Bone pain is the most commonly reported adverse event with filgrastim, while other toxicities are associated with filgrastim efficacy and with an increased neutrophil count. KEY FINDINGS: In conclusion, our findings attest to the previous results on the efficacy and safety of filgrastim.
Assuntos
Filgrastim/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fármacos Hematológicos/uso terapêutico , Neutropenia/prevenção & controle , Antibacterianos/uso terapêutico , Humanos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The use of patient-derived primary cell cultures in cancer preclinical assays has increased in recent years. The management of resected tumor tissue remains complex and a number of parameters must be respected to obtain complete sample digestion and optimal vitality yield. We provide an overview of the benefits of correct primary cell culture management using different preclinical methodologies, and describe the pros and cons of this model with respect to other kinds of samples. One important advantage is that the heterogeneity of the cell populations composing a primary culture partially reproduces the tumor microenvironment and crosstalk between malignant and healthy cells, neither of which is possible with cell lines. Moreover, the use of patient-derived specimens in innovative preclinical technologies, such as 3D systems or bioreactors, represents an important opportunity to improve the translational value of the results obtained. In vivo models could further our understanding of the crosstalk between tumor and other tissues as they enable us to observe the systemic and biological interactions of a complete organism. Although engineered mice are the most common model used in this setting, the zebrafish (Danio rerio) species has recently been recognized as an innovative experimental system. In fact, the transparent body and incomplete immune system of zebrafish embryos are especially useful for evaluating patient-derived tumor tissue interactions in healthy hosts. In conclusion, ex vivo systems represent an important tool for cancer research, but samples require correct manipulation to maximize their translational value.
Assuntos
Técnicas de Cultura de Células/métodos , Neoplasias/patologia , Animais , Reatores Biológicos , Humanos , Pesquisa Translacional Biomédica , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
PURPOSE: Anthracycline and ifosfamide-based chemotherapy represents a widely used regimen both in early and advanced settings in soft tissue sarcoma (STS). Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. The aim of this study was to assess the efficacy and safety of biosimilar G-CSF in these patients. METHODS: Between 2003 and 2013, 67 patients with soft tissue tumors under epirubicin and ifosfamide (EI) treatment receiving biosimilar filgrastim (Zarzio®), originator filgrastim (Granulokine®, Neupogen®), and lenograstim (only originator Myelostim®) as primary prophylaxis for a total of 260 cycles of therapy were retrospectively analyzed. Baseline patient characteristics were summarized in a propensity score (PS). RESULTS: The incidence of febrile neutropenia (FN) was 44.0 % in biosimilar filgrastim, 40.0 % in originator filgrastim, and 45.5 % in the lenograstim groups (p = 0.935). All grade and G4 neutropenia were similar in the three groups with the same safety profile. The use of biosimilar filgrastim achieved cost savings of 225.25 over originator filgrastim and 262.00 over lenograstim. CONCLUSION: Biosimilar G-CSF was effective in preventing FN and in reducing the need for hospitalization in STS patients undergoing EI treatment. It also proved comparable to its reference products from both a clinical and cost-effective standpoint.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/prevenção & controle , Filgrastim/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/etiologia , Epirubicina/efeitos adversos , Feminino , Fármacos Hematológicos/uso terapêutico , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Lenograstim , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Sarcoma/sangueRESUMO
Although bone metastases represent a major challenge in the natural history of breast cancer (BC), the complex interactions involved have hindered the development of robust in vitro models. The aim of this work is the development of a preclinical model of cancer and bone stromal cells to mimic the bone microenvironment. We studied the effects on osteoclastogenesis of BC cells and Mesenchymal stem cells (MSC) cultured alone or in combination. We also analyzed: (a) whether the blockade of the Epithelial Growth Factor Receptor (EGFR) pathway modified their influence on monocytes towards differentiation, and (b) the efficacy of bone-targeted therapy on osteoclasts. We evaluated the osteoclastogenesis modulation of human peripheral blood monocytes (PBMC) indirectly induced by the conditioned medium (CM) of the human BC cell line SCP2, cultured singly or with MSC. Osteoclastogenesis was evaluated by TRAP analysis. The effect of the EGFR blockade was assessed by treating the cells with gefitinib, and analyzed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western Blot (WB). We observed that SCP2 co-cultured with MSC increased the differentiation of PBMC. This effect was underpinned upon pre-treatment of the co-culture with gefitinib. Co-culture of SCP2 with MSC increased the expression of both the bone-related marker Receptor Activator of Nuclear Factor κB (RANK) and EGFR in BC cells. These upregulations were not affected by the EGFR blockade. The effects of the CM obtained by the cells treated with gefitinib in combination with the treatment of the preosteoclasts with the bone-targeted agents and everolimus enhanced the inhibition of the osteoclastogenesis. Finally, we developed a fully human co-culture system of BC cells and bone progenitor cells. We observed that the interaction of MSC with cancer cells induced in the latter molecular changes and a higher power of inducing osteoclastogenesis. We found that blocking EGFR signaling could be an efficacious strategy for breaking the interactions between cancer and bone cells in order to inhibit bone metastasis.
Assuntos
Neoplasias da Mama/metabolismo , Comunicação Celular/efeitos dos fármacos , Receptores ErbB , Células-Tronco Mesenquimais/metabolismo , Monócitos/metabolismo , Proteínas de Neoplasias , Osteoclastos/metabolismo , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe , Humanos , Células-Tronco Mesenquimais/patologia , Monócitos/patologia , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Osteoclastos/patologiaRESUMO
Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal neoplasm with no specific line of differentiation. Eribulin, a novel synthetic microtubule inhibitor, has shown anticancer activity in several tumors, including soft tissue sarcomas (STS). We investigated the molecular biology of UPS, and the mechanisms of action of this innovative microtubule-depolymerizing drug. A primary culture from a patient with UPS was established and characterized in terms of gene expression. The activity of eribulin was also compared with that of other drugs currently used for STS treatment, including trabectedin. Finally, Western blot analysis was performed to better elucidate the activity of eribulin. Our results showed an upregulation of epithelial mesenchymal transition-related genes, and a downregulation of epithelial markers. Furthermore, genes involved in chemoresistance were upregulated. Pharmacological analysis confirmed limited sensitivity to chemotherapy. Interestingly, eribulin exhibited a similar activity to that of standard treatments. Molecular analysis revealed the expression of cell cycle arrest-related and pro-apoptotic-related proteins. These findings are suggestive of aggressive behavior in UPS. Furthermore, the identification of chemoresistance-related genes could facilitate the development of innovative drugs to improve patient outcome. Overall, the results from the present study furnish a rationale for elucidating the role of eribulin for the treatment of UPS.
Assuntos
Biomarcadores Tumorais/genética , Furanos/administração & dosagem , Cetonas/administração & dosagem , Cultura Primária de Células , Sarcoma/tratamento farmacológico , Idoso , Antineoplásicos/administração & dosagem , Proteínas Reguladoras de Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Dioxóis/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pacientes , Sarcoma/genética , Sarcoma/patologia , Tetra-Hidroisoquinolinas/administração & dosagem , TrabectedinaRESUMO
Metastatic bone disease has a major impact on morbidity of breast cancer (BC) patients. Alterations in mTOR signaling are involved both in cancer progression and in osteoclast differentiation. The purpose of this study was to assess the role of mTOR inhibitor Everolimus (Eve) on osteoclastogenesis induced by triple negative BC cells. To this aim, we developed an in vitro human model of osteoclastogenesis from peripheral blood monocytes co-cultured with the triple negative SCP2 and the hormonal receptor positive MCF7 cell lines. Osteoclastogenesis was evaluated by TRAP staining, evaluation of F actin rings and Calcitonin Receptor expression. Eve significantly reduced differentiation induced by cancer cells and resulted more effective when evaluated in combination with Denosumab and Zoledronic Acid (Zol). Combination with Zol showed a total abrogation of osteoclast differentiation induced by the triple negative cell line, not by MCF7. Finally, we observed that Eve was active in the inhibition of the crosstalk between cancer cells and osteoclasts reproduced by our model, highlighting a new therapeutic choice for the subsetting of triple negative BC patients. We observed a difference in the response to bone-targeted therapy with respect to BC subtypes. Our model may represent a valid platform for preclinical trials on bone-targeted drugs and for the study of the interplay of BC with bone stromal cells.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Everolimo/farmacologia , Osteoclastos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Western Blotting , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Diferenciação Celular/genética , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Denosumab/farmacologia , Difosfonatos/farmacologia , Expressão Gênica/genética , Humanos , Imidazóis/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Células MCF-7 , Modelos Biológicos , Osteoclastos/citologia , Osteonectina/genética , Ligante RANK/metabolismo , Receptores CXCR4/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ácido ZoledrônicoRESUMO
Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF) embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231). The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT), revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient's medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/complicações , Modelos Animais de Doenças , Animais , Feminino , Xenoenxertos , Humanos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
Eribulin mesylate is a novel, non-taxane, synthetic microtubule inhibitor showing antitumor activity in a wide range of tumors including soft tissue sarcomas (STS). Eribulin has been recently approved for the treatment of metastatic liposarcoma (LPS) patients previously treated with anthracyclines. This work investigated the mechanism of action of this innovative antitubulin agent in well-differentiated/dedifferentiated LPS (ALT/DDLPS) which represents one of the most common adipocytic sarcoma histotypes. A primary culture of ALT/DDLPS from a 54-year-old patient was established. The anticancer activity of eribulin on the patient-derived primary culture was assessed by MTT and tunel assays. Eribulin efficacy was compared to other drugs approved for the treatment of STS. Cell migration and morphology were examined after exposure to eribulin to better understand the drug mechanism of action. Finally, Western blot analysis of apoptosis and migration proteins was performed. The results showed that eribulin exerts its antiproliferative effect by the arrest of cell motility and induction of apoptosis. Our results highlighted the activity of eribulin in the treatment of ALT/DDLPS patients.
Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Cetonas/farmacologia , Lipossarcoma/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Transformação Celular Neoplásica , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipossarcoma/patologia , Pessoa de Meia-Idade , Cultura Primária de Células , Células Tumorais CultivadasRESUMO
BACKGROUND: Leiomyosarcoma (LMS) is an aggressive soft tissue sarcoma derived from smooth muscle cells typically of uterine, gastrointestinal or soft tissue origin. The prognosis for this tumor is poor, with survival rates among the lowest of all soft tissue sarcomas. Surgery is the best approach for localized disease. The principal role of chemotherapy is prevalently in the treatment of metastatic disease. Trabectedin, a promising new DNA-damaging agent with a mechanism of action that differs from that of traditional alkylating agents, has been approved in Europe for the treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, CASE PRESENTATION: We report the case of a 53-year-old woman with metastatic well differentiated uterine leiomyosarcoma refractory to multiple treatments who underwent 22 cycles of trabectedin over 30 months, obtaining a partial response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with good tolerability, and maintaining the response for 10 months after trebectedin withdrawal. CONCLUSION: This very prolonged response, which persisted after drug discontinuation, suggests that trabectedin exerts an oncostatic effect rather than the cytotoxic one produced by other chemotherapeutic agents. Our experience also raises the question of the best way to evaluate trabectedin efficacy.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Trabectedina , Resultado do TratamentoRESUMO
Gastrointestinal stromal tumors are rare malignancies characterized by c-kit and PDGFR-α mutations targeted by imatinib. Pleural effusion is a very rare side effect of imatinib treatment. A 65-year-old female with metastatic gastrointestinal stromal tumor developed electrolyte imbalance, severe peripheral edema and progressively worsening dyspnea 2 months after starting imatinib. Having excluded cardiovascular and pulmonary disorders, imatinib was discontinued and prednisone 25 mg orally daily was begun. The patient's condition improved substantially over the next 48 h with a progressive decrease in dyspnea and a reduction in pleural effusion and peripheral edema. All side effects had resolved within 1 month. In view of the partial response obtained, the patient re-started imatinib after a 1-week interruption. Prednisone was maintained and there was no further toxicity.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Neoplasias Gastrointestinais/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Piperazinas/uso terapêutico , Derrame Pleural Maligno/diagnóstico por imagem , Pirimidinas/uso terapêutico , Idoso , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/secundário , Humanos , Mesilato de Imatinib , Derrame Pleural Maligno/tratamento farmacológico , Radiografia , Resultado do TratamentoRESUMO
Malignant tumors of the lacrimal gland are rare, and single bone metastases from lacrimal gland carcinoma are an exceptional event. We present the case of a 71-year-old man with a history of lumbar pain and left exophthalmos. Surgical resection of the lacrimal lesion and a bone biopsy gave a final histopathological diagnosis of primary ductal adenocarcinoma of the lacrimal gland with bone metastasis. The pathological tissue from both procedures was positive for androgen receptor expression. The patient underwent embolization and radiotherapy in association with total androgen blockade. After 20 months, the patient is still asymptomatic and has maintained the partial response at L1 with no progression to other sites. Our patient would appear to have a better prognosis and the disease a more indolent clinical course than the other cases of ductal adenocarcinoma of the lacrimal gland reported in the literature.
Assuntos
Adenocarcinoma/patologia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Neoplasias Oculares/patologia , Aparelho Lacrimal/patologia , Idoso , Biópsia , Neoplasias Ósseas/radioterapia , Humanos , Vértebras Lombares/patologia , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga TumoralRESUMO
Immunotherapy has emerged as promising treatment in sarcomas, but the high variability in terms of histology, clinical behavior and response to treatments determines a particular challenge for its role in these neoplasms. Tumor immune microenvironment (TiME) of sarcomas reflects the heterogeneity of these tumors originating from mesenchymal cells and encompassing more than 100 histologies. Advances in the understanding of the complexity of TiME have led to an improvement of the immunotherapeutic responsiveness in sarcomas, that at first showed disappointing results. The proposed immune-classification of sarcomas based on the interaction between immune cell populations and tumor cells showed to have a prognostic and potential predictive role for immunotherapies. Several studies have explored the clinical impact of immune therapies in the management of these histotypes leading to controversial results. The presence of Tumor Infiltrating Lymphocytes (TIL) seems to correlate with an improvement in the survival of patients and with a higher responsiveness to immunotherapy. In this context, it is important to consider that also immune-related genes (IRGs) have been demonstrated to have a key role in tumorigenesis and in the building of tumor immune microenvironment. The IRGs landscape in soft tissue and bone sarcomas is characterized by the connection between several tumor-related genes that can assume a potential prognostic and predictive therapeutic role. In this paper, we reviewed the state of art of the principal immune strategies in the management of sarcomas including their clinical and translational relevance.
Assuntos
Imunoterapia , Linfócitos do Interstício Tumoral , Sarcoma , Microambiente Tumoral , Humanos , Sarcoma/terapia , Sarcoma/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Animais , Pesquisa Translacional Biomédica , PrognósticoRESUMO
Soft tissue sarcomas represent an heterogeneous group of rare mesenchymal tumors comprising 1% of all solid malignancies. Among them, liposarcoma is one of the most common histotypes with atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma (ALT/WDLPS and DDLPS) as the major sub-entities. The unavailability of predictive, prognostic and druggable biomarkers makes the management of these lesions challenging. In recent years CDK4 and its inhibitors have emerged as potential agents for these lesions especially for ALT/WDLPS and DDLPS but the results are not conclusive and need to be elucidated. This study involved 21 ALT/WDLPS and DDLPS patients. Histological analyses of MDM2 and CDK4 were carried out. Moreover, a DDLPS patient-derived cancer model was established in vitro and in vivo assessing the efficacy of palbociclib in combination and sequential treatment. Finally, in silico analyses on CDK4 expression were carried out. The results showed a higher expression of CDK4 and MDM2 in DDLPS compared to ALT/WDLPS. Moreover, no correlation between MDM2 expression and CDK4 was observed. Next, in vitro analysis of CDK4 inhibitor palbociclib showed an antagonistic effect when combined to other chemotherapeutics, while it exhibited a significant synergy when administered in sequential schedule with lenvatinib. Next, in vivo analysis on DDLPS xenotransplanted embryos assessing the efficacy and safety profile of the in vitro tested schedules confirmed the observed data. This proof-of-concept study sheds light on the natural history of ALT/WDLPS and DDLPS and provides the rationale for the clinical applicability of sequential treatment with palbociclib in the management of DDLPS.