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1.
Oncotarget ; 13: 686-693, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574217

RESUMO

BACKGROUND: Non-small cell lung cancer is the leading cause of cancer death worldwide. New strategies in molecular therapies are being explored to detect and target genetic mutations in NSCLC. Therefore, it is also important to understand the interaction between these mutations and other therapies. This study focuses on possible correlations between the KRAS-G12C mutation and response of patients treated with immunotherapy. METHODS: Twenty-two patients with stage IV NSCLC undergoing immunotherapy were divided into two groups treated with first- and second-line therapy, respectively. KRAS-G12C mutation was detected by liquid biopsy Idylla KRAS assay. RESULTS: In first-line treated patients, there was no significant increase in PFS in patients with the KRAS mutation (20 months versus 14.5 months, HR = 1.31; CI 95% = 0.25-6.71; p value = 0.76) and no difference in OS (OS = 21 months, HR = 1; CI 95% = 0.17-6.2; p value > 0.99). In the second group, KRAS G12C mutated patients had a median PFS of 23 months compared with a median PFS of only 5 months among nonmutated patients (HR = 3.28; CI 95% = 0.86-12.5; p value = 0.03). CONCLUSION: The results of this study do not reveal a clear correlation between mutation and response to immunotherapy. The mechanism regulating immune system activity in the tumor microenvironment remains unclear.

2.
EBioMedicine ; 79: 104010, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35477069

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2- metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR+/HER2- mBC. METHODS: Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR+/HER2- mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67. FINDINGS: The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p<0.0001 and p<0.05, respectively). In particular, the effector Treg subset (CD4+CD25+FOXP3highCD45RA-) was strongly reduced (p<0.0001). The decrease in Treg levels was significantly greater in responder patients than in non-responder patients. Conversely, CDK4/6i treatment was associated with increased levels of CD4+ T cells and anti-tumour CD137+CD8+ T cells (p<0.05). INTERPRETATION: CDK4/6i treatment results in downregulation of Tregs, M-MDSCs, and PMN-MDSCs, thus weakening tumour immunosuppression. This decrease is associated with response to treatment, highlighting the importance of unleashing immunity in cancer treatment efficacy. These results suggest a novel mechanism of immunomodulation in mBC and provide valuable information for the future design of novel treatments combining CDK4/6i with immunotherapy in other cancer settings. FUNDING: Sapienza University of Rome.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Feminino , Fatores de Transcrição Forkhead , Humanos , Leucócitos Mononucleares , Estudos Prospectivos
3.
Cancers (Basel) ; 14(3)2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35159069

RESUMO

Liquid biopsies have shown that, in RAS mutant colorectal cancer, the conversion to RAS wild-type * status during the course of the disease is a frequent event, supporting the concept that the evolutionary landscape of colorectal cancer can lead to an unexpected negative selection of RAS mutant clones. The aim of the present study was to clarify whether the negative selection of RAS mutation in plasma might be drug-dependent. For this purpose, we used liquid biopsy to compare the rate of conversion from RAS mutant to RAS wild-type * in two groups of originally RAS mutant mCRC patients: the first treated with chemotherapy alone, while the second was treated with chemotherapy combined with bevacizumab. Serial liquid biopsies were performed at 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4) after starting first line treatments. We found that the only independent variable significantly associated to RAS status conversion was the use of bevacizumab. RAS conversion was not found associated to tumor burden reduction, although bevacizumab-treated patients who converted to RAS wild-type * had a significantly longer PFS compared to patients who remained RAS mutant. The appearance of a "RAS wild-type * window", mainly in bevacizumab-treated patients, might present them as candidates for second line treatment with anti-EGFR, which was otherwise precluded.

4.
Anticancer Res ; 42(2): 991-1000, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35093899

RESUMO

BACKGROUND/AIM: To compare clinical outcomes following intensified total neoadjuvant therapy (TNT) and intensified neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Of the 79 patients with LARC admitted to our department, 51 received intensified neoadjuvant CRT (CRT group) and 28 received intensified TNT (TNT group). Intensified TNT was defined as multi-agent chemotherapy, including FOLFOXIRI regimen plus bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) followed by oxaliplatin-5-fluorouracil-based CRT and surgery. Kaplan-Meier and Log rank test were used for survival analysis. Survival rates of the two groups were compared using propensity score matching. RESULTS: Data from 28 TNT patients and 28 CRT patients were analyzed after a 1:1 propensity matching with replacement. Kaplan-Meier curve showed that overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates with TNT were comparable to those with CRT. The 5-year DMFS rates for TNT and CRT were 61.5% versus 63.0% (p=0.82), respectively. In the TNT group, 32.1% patients (n=9) achieved pathological complete response (pCR), whereas 21.4% patients (n=6) achieved pCR with CRT (p=0.37). CONCLUSION: Intensified TNT and CRT resulted in similar survival outcomes, while intensified TNT led to higher pCR, albeit not statistically significant.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Terapia Neoadjuvante/métodos , Neoplasias Retais/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/métodos , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Invasividade Neoplásica , Pontuação de Propensão , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Análise de Sobrevida , Adulto Jovem
6.
Abdom Radiol (NY) ; 47(2): 763-770, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34919160

RESUMO

PURPOSE: The Vesical Imaging-Reporting and Data System (VI-RADS) criteria are expanding, providing fine differentiation of bladder wall layers involvement. We aimed to explore the feasibility of a novel categorical scoring, the Neoadjuvant chemotherapy VI-RADS (nacVI-RADS) for radiologic assessment of response (RaR), to define the spectrum of treatment response among patients with muscle invasive bladder cancer (MIBC). METHODS: Ten consecutive patients diagnosed with non-metastatic MIBC were prospectively enrolled and addressed to NAC and underwent mpMRI before staging resection and after the chemotherapy cycles. The follow-up MRI assessment was performed using the nacVI-RADS algorithm for evaluation of response to therapy. NacVI-RADS categorically define complete RaR, based on prior VI-RADS score, presence of residual disease, tumor size, and infiltration of the muscularis propria. RESULTS: NacVI-RADS categories were able to match all the final radical cystectomy pathology both for complete pT0 responders and for the patients defined as partial or minimal responders, who only showed some RaR inter-scoring class downstaging. CONCLUSION: This report is the preliminary evidence of the feasibility of nacVI-RADS criteria. These findings might lead to possible paradigmatic shifts for cancer-specific survival risk assessment and to possibly drive the therapeutic decision through active surveillance programs, bladder-sparing modalities, or to the standard of care.


Assuntos
Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Bexiga Urinária , Cistectomia , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológico
8.
Cancers (Basel) ; 13(24)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944975

RESUMO

BACKGROUND: Sarcopenia is a condition characterized by loss of skeletal muscle mass associated with worse clinical outcomes in cancer patients. Data on sarcopenia in patients undergoing immune checkpoint inhibitors (ICI) therapy are still limited. The aim of this prospective observational study was to investigate the relationship between sarcopenia, ICI treatment response and immunological profile, in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-seven stage IV NSCLC patient candidates for starting ICI, were enrolled from the Policlinico Umberto I outpatient Oncology. Patients underwent baseline blood test, inflammatory markers, cytokine assessment and body composition with dual-energy X-ray absorptiometry (DXA). Sarcopenia was defined with appendicular skeletal muscle mass over height2 (ASM/heigh2). RESULTS: Overall, 19/47 patients (40.4%) results were sarcopenic. Sarcopenic patients showed significantly shorter PFS than non-sarcopenic ones (20.3 weeks, 95% CI 7.5-33.1 vs. 61 weeks, 95% CI 22.5-99.4, p = 0.047). Specifically, they had an 8.1 times higher risk of progression disease (PD) than non-sarcopenic patients (OR 8.1, 95%, p = 0.011). CONCLUSIONS: Sarcopenic patients showed worse PFS and had a higher risk of PD compared to non-sarcopenic ones. Therefore, sarcopenia may reflect the increased metabolic activity of more aggressive tumors, which involves systemic inflammation and muscle wasting and could be considered a negative predictive factor for ICI response.

9.
Diagnostics (Basel) ; 11(12)2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34943432

RESUMO

Although molecular profiling at diagnosis has traditionally relied on direct sampling of neoplastic tissue, cancer clonal evolution represents a critical obstacle to use primary tissue biopsies to guide clinical decision-making at the time of progressive disease. Liquid biopsies might offer enormous advantages over tissue biopsies, tracking in real-time temporal-based tumor dynamics following each line of treatment. Here, we compared two liquid biopsy assays, specifically real-time polymerase chain reaction and next-generation sequencing, to track the KRAS G12C mutation at onset of progression from previous lines of therapy. The KRAS G12C mutation was acquired at the time of progressive disease in 24% of patients. Furthermore, all patients with KRAS G12C mutation-positive tissue became negative in ctDNA at progressive disease. The presence of other somatic mutations in all these samples confirmed the tumor origin of the circulating DNA. This pilot study suggests that in the assessment of the plasma KRAS G12C mutation as a druggable target, real-time PCR assay Idylla might be a suitable approach to better match patients to interventional biomarker-targeted therapies.

10.
Sci Rep ; 11(1): 13770, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215766

RESUMO

In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2-positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Prognóstico , Receptor ErbB-2/genética , Ado-Trastuzumab Emtansina/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores de Progesterona/genética
11.
Tumori ; : 3008916211004733, 2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33818208

RESUMO

BACKGROUND: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses. OBJECTIVE: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC). METHODS: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic. RESULTS: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0). CONCLUSIONS: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

12.
J Transl Med ; 19(1): 119, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757546

RESUMO

BACKGROUND: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. METHODS: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. RESULTS: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn't (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p < 0.0001; median OS, 4 months vs. 35 months, HR 1.60, 95% CI 1.26-2.02, p < 0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥ 1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden. DISCUSSION: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. CONCLUSIONS: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Analgésicos Opioides/uso terapêutico , Humanos , Imunoterapia , Estudos Retrospectivos
13.
Cancer Biother Radiopharm ; 36(5): 391-396, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33769088

RESUMO

Background: The retrospective studies that have so far described the outcomes of the sequential use of life-prolonging agents (LPAs) did not include metastatic castration-resistant prostate cancer (mCRPC) patients who received radium-223 (223Ra) as part of their treatment. Consequently, it is not known whether including 223Ra in the therapeutic sequence has an impact on cumulative survival. The aim of this study was to evaluate this impact by comparing the cumulative overall survival (OS) in two series of mCRPC patients sequentially treated with two or three LPAs after first-line docetaxel (DOC), including 223Ra and not. Materials and Methods: The authors retrospectively reviewed the records of mCRPC patients with bone involvement alone who received two or three LPAs (including 223Ra) after first-line DOC. The control group was a contemporary series of mCRPC patients with bone involvement alone treated with sequences of two or three LPAs other than 223Ra after first-line DOC. Results: Median cumulative OS was 40.6 months in the 223Ra group of 78 patients and 36.2 months in the non-223Ra group of 186 patients (p = 0.08). OS outcomes were significantly influenced by the number of treatment lines, and baseline Eastern Cooperative Oncology Group performance status (PS) and prostate-specific antigen levels. Conclusions: To the best of the authors' knowledge, this is the first study designed to evaluate the impact of introducing 223Ra in the treatment sequences for mCRPC patients, and the results show that its use does not negatively affect cumulative OS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/terapia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Compostos Radiofarmacêuticos/uso terapêutico , Rádio (Elemento)/uso terapêutico , Acetato de Abiraterona/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Benzamidas/administração & dosagem , Neoplasias Ósseas/secundário , Terapia Combinada , Docetaxel/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem
14.
Clin Cancer Res ; 27(12): 3443-3455, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33785482

RESUMO

PURPOSE: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. EXPERIMENTAL DESIGN: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. RESULTS: We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15-2.69; P = 0.008). CONCLUSIONS: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2- aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2- aBC.


Assuntos
Neoplasias da Mama , Everolimo , Androstadienos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Glicemia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Fosfatidilinositol 3-Quinases , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos
15.
Cancer Lett ; 507: 89-96, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33744389

RESUMO

The paucity of targeted treatments available in patients with RAS mutant colorectal cancers contributes to the poor prognosis of this patient group compared to those with RAS wild-type disease. Recent liquid biopsy-driven studies have demonstrated that RAS mutant clones might disappear in plasma during the clonal evolution of the disease, opening new unforeseen perspectives for EGFR blockade in these patients. Nevertheless, the lack of detection of RAS mutations in plasma might depend on the low amount of released circulating tumor DNA (ctDNA), making it necessary a more accurate selection of patients with true RAS mutation conversions. In this liquid biopsy-based study, we assessed RAS mutational status in initially RAS-mutant patients at the time of progressive disease from any line of therapy and investigated the incidence of true conversions to plasma RAS wild-type, comparing a colon cancer specific methylation profile with a mutational signature of ctDNA. Globally, considering either mutational panel or methylation profile as reliable tests to confirm or exclude the presence of ctDNA, the percentage of "true RAS converters" was 37.5%. In our series we observed a trend toward a better PFS in patients who received anti-EGFR as second or subsequent treatment lines compared to those who did not.


Assuntos
DNA Tumoral Circulante/genética , Neoplasias Colorretais/genética , Metilação de DNA , GTP Fosfo-Hidrolases/genética , Perfilação da Expressão Gênica , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Transcriptoma , Adulto , Idoso , Antineoplásicos/uso terapêutico , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Intervalo Livre de Progressão
16.
Transl Oncol ; 14(5): 101044, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33621741

RESUMO

Locally advanced rectal cancer requires a multidisciplinary management, traditionally based on neo-adjuvant (chemo) radiotherapy, conservative surgery with total mesorectal excision and adjuvant chemotherapy. Despite effective in term of local control, this strategy is linked to a high risk of distant metastasis (up to 30%). In this context, recent published randomized phase III clinical trials have tested the potential benefits with a different sequencing and/or intensification of the standard components of the trimodal therapy. Here, we briefly assess the efficacy and discuss the clinical relevance of total neoadjuvant treatment with a focus on indications and results in the short-course radiotherapy followed by chemotherapy use for this setting of patients. Long term results and additional prospective studies are necessary to more accurately estimate the clinical benefit and further establish the role of total neoadjuvant therapy in locally advanced rectal cancer disease.

17.
Future Oncol ; 17(7): 807-815, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33508980

RESUMO

Background: Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Results: Median overall survival (OS) from the start of first-line treatment was 39.8 months, with the patients who completed all six planned courses of RA223 having a longer OS than those who did not (53.2 vs 29.5 months; p < 0.0001). Conclusions: Our study confirms the activity of RA223 regardless of the treatment line in which it is administered and suggests that patient selection plays a central role in maximizing this activity.


Assuntos
Antagonistas de Receptores de Andrógenos/administração & dosagem , Neoplasias Ósseas/terapia , Neoplasias de Próstata Resistentes à Castração/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Rádio (Elemento)/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Quimiorradioterapia/métodos , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Seleção de Pacientes , Prostatectomia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
19.
Recenti Prog Med ; 111(12): 761-768, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33362173

RESUMO

INTRODUCTION: Pemetrexed maintenance significantly improved progression-free survival (PFS) and overall survival (OS) in advanced nonsquamous non-small-cell lung cancer (NSCLC) patients not progressing after induction chemotherapy. OBJECTIVES: This study is aimed at examine the association of various clinical factor and survival in a real-world cohort analysis. MATERIALS AND METHODS: One hundred ninety-four patients were included and classified as "PM" cohort ("Pemetrexed Maintenance", including patients given with pemetrexed maintenance after induction chemotherapy, n=112), and "noPM" cohort ("no Pemetrexed Maintenance" including those discontinuing pemetrexed, n=82). RESULTS: The median PFS was 8.8 and 5.4 months in the PM and noPM cohorts, respectively (p=0.001). The median OS was 19.6 months in the "PM" cohort and 13.2 months in the "noPM" cohort (p<0.02). In the multivariate analysis, ECOG Performance Status (PS) 0 and maintenance therapy were independently associated with improved PFS and OS. A longer median PFS was reported in patients given ≥5 cycles of pemetrexed maintenance (p<0.01). DISCUSSION: These results further confirm the survival benefit of pemetrexed maintenance in a real-word population. All eligible advanced NSCLC patients should be strongly considered for at least 5 of pemetrexed maintenance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Pemetrexede/uso terapêutico , Resultado do Tratamento
20.
J Exp Clin Cancer Res ; 39(1): 279, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33302999

RESUMO

BACKGROUND: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. METHODS: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. RESULTS: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively). CONCLUSIONS: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/deficiência , Ado-Trastuzumab Emtansina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Células Tumorais Cultivadas
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