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BACKGROUND: Trastuzumab deruxtecan (T-DXd) demonstrated unprecedented efficacy in patients with pretreated HER2+ metastatic breast cancer (mBC). However, few data are available about its efficacy in routine clinical practice. In this multicenter retrospective study, we examined effectiveness and safety of T-DXd in a real-world population. METHODS: Clinico-pathological information about patients with HER2+ mBC who received T-DXd were collected from 12 Italian hospitals. HER2 status was determined locally. Patients who received at least one administration of T-DXd, as any therapy line for advanced disease were included in the analysis. The primary endpoint was real-word PFS (rwPFS). RESULTS: One hundred and forty-three patients were included. Median age was 66 (range: 37-90), and 4 men were included. Hormone receptor (HR) status was positive in 108 (75%) patients and negative in 35(25%). T-DXd was administered as first, second, third, or subsequent lines in 4 (3%), 16 (11%), 42 (29%), and 81 (57%) patients, respectively. Among 123 patients with measurable disease, the ORR was 68%, and the DCR was 93% (9 CRs, 74 PRs, and 30 SD). Nine (7%) patients had a primary resistance to T-DXd. With a median follow-up of 12 months, the median rwPFS was 16 months. RwPFS was 84%, 59%, and 39% at 6, 12, and 18 months, respectively. A favorable trend in rwPFS was reported in patients receiving T-DXd as I/II line versus further lines (17 vs. 15 months; Pâ =â .098). Any-grade toxicity was registered in 84 patients (59%). Most common adverse events (AEs) reported were nausea (33%), neutropenia (21%), and asthenia (21%). Liver toxicity and diarrhea were uncommon (5% and 1%). Severe toxicities was registered in 18% of patients, and the most frequent were neutropenia, nausea/vomiting, and ILD observed in 15, 2, and 3 patients. AEs led to dose reduction in 37 patients (26%). Dose reduction and AEs do not affect patients' response and survival outcomes. CONCLUSIONS: Efficacy and safety of T-DXd were confirmed in an unselected real-world population of HER2+ mBC. These results are consistent with the results of known findings, and no new safety concerns were reported.
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Neoplasias da Mama , Camptotecina/análogos & derivados , Imunoconjugados , Neutropenia , Masculino , Humanos , Idoso , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Trastuzumab/efeitos adversos , Náusea , Receptor ErbB-2/genéticaRESUMO
INTRODUCTION: There is little evidence regarding the safety and efficacy of the combination of abemaciclib plus radiotherapy (RT). The majority of studies investigated the combination of RT with palbociclib or ribociclib reporting that hematological toxicity is common. Given the unique toxicity profile of abemaciclib with greater gastrointestinal toxicity compared to hematological toxicity, we wanted to evaluate the toxicity of the combination with RT in metastatic breast cancer (BC) patients. METHODS: Patients with histologically proven metastatic or locally advanced BC treated with RT and concurrent abemaciclib were selected. Toxicity was assessed according to the NCI-CTCAE V4.0. RESULTS: Thirty-two metastatic sites were treated in 19 patients and analyzed. All patients received abemaciclib during the RT course. A total of 68% of patients received a full dose of abemaciclib during RT. Also, 71.9% of patients received a palliative intent (median dose = 30 Gy, range = 8-30 Gy), and 26.3% were treated for 9 oligo-metastatic or oligo-progressive sites of disease with stereotactic body RT (median dose = 30 Gy, range 21-30 Gy, given in 3-5 fractions). Overall, the rate of G3 toxicity was 15.7%. The rate of G3 hematological toxicity was 10.6% (2/19 patients, one G3 neutropenia and one G3 anemia). No patient presented diarrhea, including those treated for RT sites close to the bowel. One patient developed G3 skin toxicity. Pain significantly improved after RT (mean value NRS pre-RT = 3.9, SD = 3.07; mean value NRS after RT = 0.9, SD = 0.46; p < 0.0001). CONCLUSION: Abemaciclib and concomitant RT seem well tolerated showing acceptable toxicity.
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BACKGROUND: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. METHODS: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. FINDINGS: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037). INTERPRETATION: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality. FUNDING: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.
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COVID-19 , Neoplasias , Humanos , Feminino , Masculino , SARS-CoV-2 , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/prevenção & controle , Teste para COVID-19 , Neoplasias/epidemiologia , Neoplasias/terapia , Progressão da DoençaRESUMO
BACKGROUND: Breast cancer (BC) metastasis, which often occurs in bone, contributes substantially to mortality. MicroRNAs play a fundamental role in BC metastasis, although microRNA-regulated mechanisms driving metastasis progression remain poorly understood. METHODS: MiRome analysis in serum from BC patients was performed by TaqMan™ low-density array. MiR-662 was overexpressed following MIMIC-transfection or lentivirus transduction. Animal models were used to investigate the role of miR-662 in BC (bone) metastasis. The effect of miR-662-overexpressing BC cell conditioned medium on osteoclastogenesis was investigated. ALDEFLUOR assays were performed to study BC stemness. RNA-sequencing transcriptomic analysis of miR-662-overexpressing BC cells was performed to evaluate gene expression changes. RESULTS: High levels of hsa-miR-662 (miR-662) in serum from BC patients, at baseline (time of surgery), were associated with future recurrence in bone. At an early-stage of the metastatic disease, miR-662 could mask the presence of BC metastases in bone by inhibiting the differentiation of bone-resorbing osteoclasts. Nonetheless, metastatic miR-662-overexpressing BC cells then progressed as overt osteolytic metastases thanks to increased stem cell-like traits. CONCLUSIONS: MiR-662 is involved in BC metastasis progression, suggesting it may be used as a prognostic marker to identify BC patients at high risk of metastasis.
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Neoplasias Ósseas , Neoplasias da Mama , MicroRNAs , Animais , Neoplasias Ósseas/patologia , Neoplasias da Mama/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , HumanosRESUMO
Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume (p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed.
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Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Mutação , Osso e Ossos/patologia , Reparo do DNA/genéticaRESUMO
BACKGROUND: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. METHODS: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. RESULTS: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288). CONCLUSIONS: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1 , Estudos RetrospectivosRESUMO
In metastatic renal cell carcinoma (mRCC) patients, cardiac metastases are a rare and often a post-mortem finding. Clinical manifestations of cardiac metastases have a late onset and include pericardial effusions, heart failure and embolic phenomena. Treatment of cardiac metastasis is not yet standardized, and few data are available about the efficacy of TKI on treatment of cardiac metastases in mRCC patients. In this report, we describe the case of a 66-year-old male who presented with mRCC with lung and cardiac metastases treated with cabozantinib, a multikinase inhibitor that was administered in second line after disease progression with sunitinib. To date, there are no data about the safety and efficacy of cabozantinib in mRCC with cardiac metastasis. In a real word analysis, cabozantinib demonstrated to be associated to a modest risk of developing left ventricular heart failure. It is unknown if this risk is higher in mRCC population with cardiac metastases. We report the first evidence of efficacy and safety of cabozantinib in cardiac mRCC patients, probably due to its specific inhibition of several molecular intracellular pathways. Additional molecular and clinical studies are needed before well tolerated and efficacy of cabozantinib treatment for these patients can be fully understood.
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Anilidas/uso terapêutico , Carcinoma de Células Renais/patologia , Neoplasias Cardíacas/tratamento farmacológico , Neoplasias Cardíacas/secundário , Neoplasias Renais/patologia , Piridinas/uso terapêutico , Idoso , Anilidas/efeitos adversos , Humanos , Masculino , Piridinas/efeitos adversosRESUMO
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a worldwide sanitary emergency. The viral biology is only partially known, with some aspects in common with other coronaviruses, and the damage observed in the most severe cases is due to intense inflammation. Immunotherapy restores immunological activity against cancer cells and it has become a standard treatment for several cancers. We carried out an examination of available data on the effects exerted by both SARS-CoV-2 and the most widespread immunotherapy treatments on the immune system in order to hypothesize mechanisms underlying potential and mutual interaction. We provided an analysis of laboratory, clinical and therapeutic data related with severe acute respiratory syndrome coronavirus. We finally focused on implications of immunotherapy treatments in clinical practice.
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Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Imunoterapia/métodos , Neoplasias/terapia , Pneumonia Viral/terapia , COVID-19 , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Interleucina-6/antagonistas & inibidores , Neoplasias/patologia , Pandemias , Pneumonia Viral/patologia , SARS-CoV-2RESUMO
BACKGROUND: The expression of human equilibrative nucleoside transporter 1 (hENT1), the major gemcitabine transporter into cells, has been thoroughly investigated as a predictive marker of response to gemcitabine in pancreatic cancer and biliary tract cancers. Since gemcitabine is widely used in the treatment of leiomyosarcoma and angiosarcoma, we investigated the correlation between hENT1 expression and gemcitabine efficacy in these sarcoma subtypes. METHODS: We retrospectively identified 71 patients affected by advanced angiosarcoma (26) or leiomyosarcoma (45) treated within five Italian referral centres for sarcoma; among them, 49 patients (15 angiosarcoma, 34 leiomyosarcoma) were treated with gemcitabine. All tumour samples were analysed for hENT1 expression by real-time PCR. Median 2-ΔCt value was used as the cutoff to dichotomise patients into 'high' expression and 'low' expression groups. Kaplan-Meier analysis was performed to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: We found a significant association between high hENT1 expression levels and favourable outcome in terms of PFS and OS compared to cases with low hENT1 expression in leiomyosarcoma treated with gemcitabine (PFS: 6.8 vs 3.2 months, P=0.004; OS: 14.9 vs 8.5 months, P=0.007). In addition, hENT1 overexpression correlated with a significant improvement in PFS (9.3 vs 4.5 months; P=0.02) and OS (20.6 vs 10.8 months; P=0.001) in angiosarcoma patients treated with gemcitabine. CONCLUSIONS: Our study suggests that higher hENT1 expression are associated to gemcitabine efficacy both in patients with advanced leiomyosarcoma and angiosarcoma.
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Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Hemangiossarcoma/genética , Leiomiossarcoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Expressão Gênica , Hemangiossarcoma/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , GencitabinaRESUMO
The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed. In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs. The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient.
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Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Serina-Treonina Quinases TOR/genética , Carcinoma de Células Renais/patologia , Everolimo , Regulação Neoplásica da Expressão Gênica , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Bisphosphonates (BPs) are approved as standard therapy in breast cancer for the treatment of bone metastases, since they were demonstrated to reduce the prevalence of skeletal-related events including fractures and hypercalcemia. In the adjuvant setting, BPs can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. In this article we will review the mechanisms through which BPs have been demonstrated to prevent premetastatic niche formation and cell proliferation in bone lesions. Moreover, preclinical evidence of antitumoral effects of BPs will be presented and results from the most important clinical trials will be described critically. BPs may clearly play a clinically important role in early breast cancer in a postmenopausal adjuvant setting.
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Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Animais , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , HumanosRESUMO
INTRODUCTION: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting. AREAS COVERED: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development. EXPERT OPINION: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.
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Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Denosumab/farmacologia , Denosumab/uso terapêutico , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Taxa de Sobrevida , Microambiente TumoralRESUMO
Gastrointestinal (GI) events have been described with sorafenib, sunitinib and pazopanib in cancer patients. We performed an up-to-date meta-analysis to determine the incidence and relative risk (RR) in patients with cancer treated with these agents. PubMed databases were searched for articles published till May 2013. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 6,447 patients were available for the meta-analysis; 2,260 had renal cell carcinoma (RCC) and 4,187, 1,691 non-small cell lung cancers, 599 hepatocellular cancers, 1,066 breast cancers, 165 neuroendocrine tumors, 304 gastrointestinal stromal tumors and 362 soft tissue sarcomas. Diarrhea was the most common GI event. When stratified by tumor type (RCC vs. non-RCC), the difference among the incidences of GI events was significant for diarrhea (p < 0.001) and vomiting (p = 0.006), that resulted higher in RCC patients. In RCC patients, sorafenib registered the lower incidence and RR of all grades GI events. The difference was statistically significant for sorafenib versus sunitinib-related all and high-grade events (p < 0.001) and for sorafenib versus pazopanib all grades GI events (p < 0.001) and high-grade anorexia (p < 0.001). Treatment with VEGFR TKIs sorafenib, sunitinib and pazopanib is associated with a significant increase in the risk of GI events in patients with cancer, and frequent clinical monitoring should be emphasized when managing these three and newer VEGFR TKIs.
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Gastroenteropatias/induzido quimicamente , Trato Gastrointestinal/efeitos dos fármacos , Indóis/efeitos adversos , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Sulfonamidas/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos como Assunto , Diarreia/induzido quimicamente , Humanos , Incidência , Indazóis , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Sorafenibe , Sunitinibe , Vômito/induzido quimicamenteRESUMO
The development of bone metastases requires multistep and multicellular machinery consisting not only of processes shared with any type of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to the particular bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). MiRNAs are highly conserved, small RNAs molecules that regulate gene expression. The functional consequence of miRNA deregulation lies in the mRNA targets whose expression is altered. MiRNA networks acting as upstream regulators of these genes interfere with the initial steps of tumor local invasion and cancer cell intravasation, mainly by regulating the epithelial-mesenchymal transition, the motility, invasiveness and survival abilities of these cells. The miRNA-mediated regulation on the steps of bone tropism, anchorage, homing and finally bone colonization is more tissue specific, being dependent on the expression pattern of target miRNAs in bone marrow sinusoids, bone cells and microenvironment. In that, miRNA specific expression signatures that can distinguish between primary tumors from their corresponding bone metastases might be determinants of clinical aggressiveness. In this review, we focus on the current advances on functions and molecular mechanisms by which miRNAs exert their biological roles in regulating bone metastases development.
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Neoplasias Ósseas , RNA Neoplásico , Microambiente Tumoral , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , RNA Neoplásico/genética , RNA Neoplásico/metabolismoRESUMO
BACKGROUND: Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy. METHODS: Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS). RESULTS: The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL's potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features. CONCLUSION: These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.
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Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Ligante RANK , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Ligante RANK/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Adulto , Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , PrognósticoRESUMO
BACKGROUND: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, radiological, and pathological aspects of bone metastases. METHODS: We included studies that evaluated the use of AI applications in patients affected by bone metastases. Two reviewers performed a digital search on 31 December 2023 on PubMed, Scopus, and Cochrane library and extracted authors, AI method, interest area, main modalities used, and main objectives from the included studies. RESULTS: We included 59 studies that analyzed the contribution of computational intelligence in diagnosing or forecasting outcomes in patients with bone metastasis. Six studies were specific for spine metastasis. The study involved nuclear medicine (44.1%), clinical research (28.8%), radiology (20.4%), or molecular biology (6.8%). When a primary tumor was reported, prostate cancer was the most common, followed by lung, breast, and kidney. CONCLUSIONS: Appropriately trained AI models may be very useful in merging information to achieve an overall improved diagnostic accuracy and treatment for metastasis in the bone. Nevertheless, there are still concerns with the use of AI systems in medical settings. Ethical considerations and legal issues must be addressed to facilitate the safe and regulated adoption of AI technologies. The limitations of the study comprise a stronger emphasis on early detection rather than tumor management and prognosis as well as a high heterogeneity for type of tumor, AI technology and radiological techniques, pathology, or laboratory samples involved.
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Objective: The objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy. Methods: Data were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER <1%), progesterone receptor (PgR <1%) and human-epidermal growth factor receptor-2 (HER2 0, 1+, 2+ ISH-not amplified) according to standard ASCO-CAP criteria. Demographic and clinical characteristics were collected. Premedication, dose modifications and treatment schedule were based on the approved label of the product. Adverse events (AEs) were assessed according to NCI-CTCAE v5.0. Results: Fifty-seven eligible patients who received sacituzumab govitecan for mTNBC were included. Median age was 53 years (range 25-75). Approximately 70% of patients had an initial diagnosis of TNBC. Median time from the diagnosis of metastatic BC to start of sacituzumab govitecan was 17 months (range 0-97) and median number of previous therapies was 3 (range 1-7). The most common sites of metastasis were lymph nodes (63.1% of patients), lung (57.9%), bone (50.8%) and liver (38.6%). Eight (14.0%) patients had a disease-free interval ≤12 months. A total of 32 (56.1%) deaths were observed and the median overall survival (OS) was 12.43 months (95% CI, 7.97 months-not reached). At a median follow-up of 10.6 months, 45 patients (78.9%) had progression and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-7.1 months). Partial tumour response was observed in 19 patients (33.3%), stable disease in 16 (28.1%) and disease progression in 22 patients (38.6%). The most common treatment-related AEs were anemia (66.6% of patients), alopecia (66.6%), neutropenia (59.6%), nausea (42.1%) and diarrhea (38.6%). Neutropenia was the most common serious treatment-related AE: 21.0% and 8.7% of patients experienced grade 3 or 4 neutropenia, respectively. Twenty-two patients (38.6%) reduced the dose and 5.3% permanently discontinued treatment. Conclusion: The results of this real-world analysis showed that both safety and efficacy of sacituzumab govitecan in mTNBC patients are consistent with that previously reported in regulatory trials. The use of premedication and supportive measures was associated with a satisfactory toxicity profile.
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Guidelines historically recommended mono-chemotherapy for the 1st line treatment of elderly patients with non-small cell lung cancer (NSCLC) and poor performance status (PS). Nowadays, there is no clear indication whether chemo-immunotherapy (chemo-IO) combinations can be effectively delivered in this population. We collected induction chemotherapy data in consecutive patients with advanced NSCLC treated with carboplatin-based chemotherapy regimens plus pembrolizumab, to compute the received dose intensity (RDI) from standard regimens or patient-tailored regimens modified due to age, comorbidities and PS. Comorbidities were stratified according to the comorbidity-polypharmacy score (CPS). The established cut-off of ≥85% for RDI was used to define adequate delivery. 116 pts were treated from Feb-20 to July-23, of whom 96 and 20 with non-squamous and squamous NSCLC, treated with carboplatin-pemetrexed or carboplatin-paclitaxel doublets plus pembrolizumab, respectively. The majority of patients were aged ≥ 70 years (52.6%), the median CPS was 5, with 58.6% having a CPS ≥5, whilst 47.4%, 44.8% and 7.8% had an Eastern Cooperative Oncology Group (ECOG) - PS of 0, 1 and 2, respectively. PD-L1 TPS were <1% in 31.9% and 1-49% in 65.4%. Overall, 47.4% received a priori modified regimens due to poor PS, age, or comorbidities. Among patients with non-squamous NSCLC, median received doses of carboplatin and pemetrexed were 1.37 AUC/week and 138.8 mg/m2/week, with RDIs of 86% and 75% (p < 0.01) for patients treated with standard or modified regimens, respectively. Of note, the RDI was 57.9% among patients with ECOG-PS 2. However, patients treated with modified regimens experienced similar toxicities as those treated with standard regimens, despite being older (p < 0.01), with higher PS (p < 0.01) and more comorbid (p = 0.03). Patients treated with modified regimens achieved a shorter survival (7.1 vs 13.9 months), which is comparable to IO-free historical controls. Among patients with squamous NSCLC, 90% received modified regimens upfront, with median received doses of carboplatin and paclitaxel of 1.19 AUC/week and 40 mg/m2/week, and an overall RDI of 73.5%. Although regimen modifications ensure a safe administration of chemotherapy plus pembrolizumab in frail patients, the RDI seems to be subtherapeutic, especially in those with squamous histology. Dedicated trials are needed to implement combination strategies in this population.
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Tumour-associated Macrophages (TAM) present two different polarizations: classical (M1) characterized by immunostimulation activity and tumour suppression; alternative (M2) characterized by tumour promotion and immune suppression. In this retrospective study, we evaluated the correlation between the two forms of TAM with survival time in radically resected gastric cancer patients. A total of 52 chemo- and radio-naive patients were included. Two slides were prepared for each patient and double-stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five representative high-power fields per slide were evaluated for TAM count. The median value of the two macrophage populations density and the median value of M1/M2 ratio were used as cut-off. Twenty-seven patients with M1 density above-the-median had a significantly higher survival compared to those below the median. Twenty-six patients with M1/M2 ratio above the median showed median OS of 27.2 months compared to 15.5 months of the patients below the median. No association between M2 macrophage density and patient's outcome was found. In multivariate analysis, M1/M2 was a positive independent predictor of survival. The M1 macrophage density and M1/M2 ratio, as confirmed in multivariate analysis, are factors that can help in predicting patients survival time after radical surgery for gastric cancer.
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Macrófagos/fisiologia , Neoplasias Gástricas/mortalidade , Polaridade Celular , Feminino , Gastrectomia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
PURPOSE: Published data demonstrated that zoledronic acid (ZOL) exhibits antiangiogenetic effects. A promising tool for monitoring antiangiogenic therapies is the measurement of circulating endothelial cells (CECs) and circulating endothelial precursor cells (CEPs) in the peripheral blood of patients. Our aim was to investigate the effects of ZOL on levels of CECs and CEPs in localized prostate cancer. METHODS: Ten consecutive patients with a histologic diagnosis of low-risk prostate adenocarcinoma were enrolled and received an intravenous infusion of ZOL at baseline (T0), 28 days (T28) and 56 days (T56). Blood samples were collected at the following times: T0 (before the first infusion of ZOL), T3 (72 h after the first dose), T28, T56 (both just before the ZOL infusion) and T84 (28 days after the last infusion of ZOL) and CEC/CEP levels were directly quantified by flow cytometry at all these time points. RESULTS: Our analyses highlighted a significant reduction of mean percentage of CECs and CEPs after initiation of ZOL treatment [p = 0.014 (at day 3) and p = 0.012 (at day 84), respectively]. CONCLUSION: These preliminary results demonstrate that ZOL could exert an antiangiogenic effect in early prostate cancer through CEP and CEC modulation.