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1.
Cancers (Basel) ; 16(14)2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-39061244

RESUMEN

Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.

2.
Cancer Treat Rev ; 128: 102752, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38772170

RESUMEN

Surgery is a standard treatment for early-stage gastrointestinal cancers, often preceded by neoadjuvant chemo(radio)therapy or followed by adjuvant therapy. While leading to cure in a proportion of patients, it has some drawbacks such as intra/post-operative complications, mutilation and life-long functional sequelae. Further to the unprecedented efficacy data from studies of immune checkpoint inhibitors for advanced mismatch repair deficient/microsatellite instable (dMMR/MSI-H) tumours, a strong interest has recently emerged for the investigation of such agents in the neoadjuvant setting. Although limited by the exploratory design and small sample size, trials of neoadjuvant immune checkpoint inhibitors for early-stage dMMR/MSI-H gastrointestinal cancers have consistently reported complete response rates ranging from 70 % to 100 %. As a result, the question has arisen as to whether surgery is still needed or organ-preserving strategies should be offered to this especially immuno-sensitive population. In this article, we discuss the available evidence for neoadjuvant immune checkpoint inhibitors in dMMR/MSI-H gastrointestinal cancers and analyse opportunities and challenges to the implementation of non-operative management approaches in this setting.


Asunto(s)
Neoplasias Gastrointestinales , Inhibidores de Puntos de Control Inmunológico , Terapia Neoadyuvante , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/terapia , Terapia Neoadyuvante/métodos , Inestabilidad de Microsatélites , Reparación de la Incompatibilidad de ADN
3.
J Pers Med ; 14(5)2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38793102

RESUMEN

BACKGROUND: Arterial hypertension is regarded as a possible biomarker of treatment efficacy in colorectal cancer. Also, extended anti-angiogenic use in the metastatic treatment of the colorectal neoplasm may result in elevated blood pressure. We carried out a systematic review and meta-analysis to assess the clinical outcome of colorectal cancer patients with concomitant hypertension (HTN). METHODS: We conducted a systematic search on Embase, Web of Science, Scopus, PubMed (Medline), the Cochrane Library, and CINAHL from inception until October 2023 for articles that addressed the relationship between HTN and progressive free survival (PFS), overall survival (OS), and overall response rate (ORR) for the first and second line of systemic therapy in patients with metastatic colorectal cancer. RESULTS: Eligibility criteria were met by 16 articles out of 802 screened studies. Pooled analysis showed that HTN was associated with significantly improved PFS (HR: 0.507, 95% CI: 0.460-0.558, p ≤ 0.001) and OS (HR: 0.677, 95% CI: 0.592-0.774, p ≤ 0.001) in patients with metastatic colorectal cancer. In addition, the pooled RR of HTN for the ORR (RR: 1.28, 95% CI: 1.108-1.495, p = 0.001) suggests that HTN could be a predictive factor of ORR in patients with metastatic colorectal cancer. CONCLUSIONS: Elevated blood pressure is associated with better clinical outcomes in patients with metastatic colorectal cancer.

4.
Expert Opin Pharmacother ; 25(4): 371-382, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38568032

RESUMEN

INTRODUCTION: Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC). AREAS COVERED: Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. EXPERT OPINION: Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.


Asunto(s)
Benzofuranos , Neoplasias Colorrectales , Metástasis de la Neoplasia , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Benzofuranos/uso terapéutico , Benzofuranos/farmacología , Quinazolinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antineoplásicos/uso terapéutico , Animales
5.
Front Immunol ; 15: 1288045, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38629065

RESUMEN

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.


Asunto(s)
Miastenia Gravis , Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Adulto , Humanos , Autoinmunidad , Neoplasias del Timo/complicaciones , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Glandulares y Epiteliales/complicaciones , Microambiente Tumoral
6.
Cancer Treat Rev ; 123: 102676, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38160535

RESUMEN

Surgery with or without adjuvant chemotherapy is the standard treatment for early-stage colon cancer. However, evidence has recently emerged for neoadjuvant chemotherapy, with the results of randomised clinical trials sparking debates within multidisciplinary teams and splitting the gastrointestinal oncology community. Further to a systematic search of the literature, we provide a thorough and in-depth analysis of the findings from these trials, highlighting the advantages and disadvantages of neoadjuvant chemotherapy. We conclude that, while there is a potential value of moving systemic therapy from the post-operative to the pre-operative setting, the available evidence does not justify a shift in the treatment paradigm of early-stage colon cancer, and surgery with or without adjuvant chemotherapy should remain the standard approach for these patients.


Asunto(s)
Neoplasias del Colon , Terapia Neoadyuvante , Humanos , Terapia Neoadyuvante/métodos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Quimioterapia Adyuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
7.
Cancers (Basel) ; 15(23)2023 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-38067278

RESUMEN

Thymic epithelial tumors (TETs) comprise a rare group of thoracic cancers, classified as thymomas and thymic carcinomas (TC). To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory tumors. Unlike other solid cancers, the development of targeted biologic and/or immunologic therapies in TETs remains in its nascent stages. Moreover, since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology, which can confer susceptibility to autoimmune diseases and ultimately influence the risk-benefit balance of immunotherapy, especially for patients with thymoma. Indeed, early results from single-arm studies have shown interesting clinical activity, albeit at a cost of a higher incidence of immune-related side effects. The lack of knowledge of the immune mechanisms associated with TETs and the absence of biomarkers predictive of response or toxicity to immunotherapy risk limiting the evolution of immunotherapeutic strategies for managing these rare tumors. The aim of this review is to summarize the existing literature about the thymus's immune biology and its association with autoimmune paraneoplastic diseases, as well as the results of the available studies with immune checkpoint inhibitors and cancer vaccines.

8.
Cancers (Basel) ; 15(24)2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38136368

RESUMEN

Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58-2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28-2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39-2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29-2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56-4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64-6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52-4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted.

9.
Int J Mol Sci ; 24(15)2023 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-37569532

RESUMEN

The therapeutic landscape in locally advanced rectal cancer (LARC) has undergone a significant paradigm shift in recent years with the rising adoption of total neoadjuvant treatment (TNT). This comprehensive approach entails administering chemotherapy and radiation therapy before surgery, followed by optional adjuvant chemotherapy. To establish and deliver the optimal tailored treatment regimen to the patient, it is crucial to foster collaboration among a multidisciplinary team comprising healthcare professionals from various specialties, including medical oncology, radiation oncology, surgical oncology, radiology, and pathology. This review aims to provide insights into the current state of TNT for LARC and new emerging strategies to identify potential directions for future research and clinical practice, such as circulating tumor-DNA, immunotherapy in mismatch-repair-deficient tumors, and nonoperative management.


Asunto(s)
Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Neoplasias del Recto/patología , Quimioradioterapia , Recto/patología , Quimioterapia Adyuvante , Estadificación de Neoplasias
11.
Front Oncol ; 13: 1190123, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37324004

RESUMEN

Introduction: Regorafenib is a tyrosine kinase inhibitor (TKI) approved in metastatic gastrointestinal stromal tumor (GIST), colorectal cancer, and hepatocarcinoma. Anyway, the toxicity profile of Regorafenib standard schedule is associated with poor compliance and a high rate of discontinuation. For this reason, there is a growing need for a Regorafenib personalized schedule emerging from the scientific community. Objective: The aim of this case series was to describe the experience of our sarcoma referral center with the continuous administration of Regorafenib as an alternative regimen to treat metastatic GIST patients. Methods: We retrospectively collected clinical, pathological, and radiological data of patients with metastatic GIST treated with daily personalized Regorafenib at a single tertiary referral center from May 2021 to December 2022. Results: We identified three patients fulfilling the inclusion criteria. The average follow-up since the start of Regorafenib was 19.1 months (12-25 months). All three patients had started a standard third-line Regorafenib schedule according to guidelines. The reasons for switching to a continuous schedule were as follows: exacerbation of symptoms during week-off treatment in the first patient, a serious adverse event (AE) in the second patient, and a combination of both conditions in the third. After switching, none of the patients reported severe AEs, and they improved control of tumor-related symptoms. Two of the patients experienced disease progression after 16 months (9 months of which is continuous schedule) and 12 months (8.1 months of which is continuous schedule) of Regorafenib, respectively; the third patient is still receiving continuous Regorafenib at the time of writing, with a progression-free survival of 25 months (14 months after the modified schedule start). Conclusion: With a similar efficacy and lower toxicities, a daily, personalized Regorafenib schedule seems to be a promising alternative to the standard regimen for metastatic GIST patients, including the frail ones. Further prospective analyses are needed to confirm the safety and efficacy of such regimen.

12.
Expert Opin Pharmacother ; 23(8): 929-946, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35508368

RESUMEN

INTRODUCTION: The paucity of the therapeutic armamentarium currently available for patients with malignant mesothelioma clearly represents a huge unmet need. Over the last years, based on new advances in understanding the biology of mesothelioma, new therapeutic approaches have been investigated. AREAS COVERED: In this manuscript, the literature data regarding the advances in drug treatment for patients with mesothelioma are critically reviewed, focusing particularly on immunotherapy and targeted therapy. EXPERT OPINION: The latest findings on immunotherapy and targeted therapy are changing the therapeutic armamentarium for mesothelioma. However, mesothelioma comprises genomically different subtypes and the phenotypic diversity combined with the rarity of this disease represents a major criticality in developing new effective therapies. Although the first clinical data are encouraging, the treatment's stratification by molecular characteristics for mesothelioma is only at the beginning. Luckily, the rapid improvement of understanding the biology of mesothelioma is producing new opportunities in discovering new therapeutic targets to test in pre-clinical settings and to transfer in the clinical setting. In this evolving scenario, the future perspectives for mesothelioma patients seem really promising.


Asunto(s)
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Inmunoterapia , Neoplasias Pulmonares/patología , Mesotelioma/tratamiento farmacológico , Mesotelioma Maligno/tratamiento farmacológico , Neoplasias Pleurales/terapia
13.
Expert Rev Cardiovasc Ther ; 12(7): 873-84, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24849323

RESUMEN

Several studies have demonstrated the beneficial effect of cardiac resynchronization therapy (CRT) in patients with drug-refractory heart failure. A variable proportion, up to 30%, of CRT patients do not benefit from treatment. The lack of response to CRT has a variety of potential causes. The implantation process is fundamental to the success of CRT, since little can subsequently be done to improve the CRT response. The authors reviewed all the geometrical and electrical parameters that could guide the CRT implant and predict its response.


Asunto(s)
Terapia de Resincronización Cardíaca , Desfibriladores Implantables , Insuficiencia Cardíaca/terapia , Electrocardiografía , Insuficiencia Cardíaca/fisiopatología , Humanos , Resultado del Tratamiento
14.
Am J Pathol ; 177(4): 2011-21, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20724594

RESUMEN

Stem cells isolated from human amniotic fluid are gaining attention with regard to their therapeutic potential. In this work, we investigated whether these cells contribute to tubular regeneration after experimental acute kidney injury. Cells expressing stem cell markers with multidifferentiative potential were isolated from human amniotic fluid. The regenerative potential of human amniotic fluid stem cells was compared with that of bone marrow-derived human mesenchymal stem cells. We found that the intravenous injection of 3.5 × 10(5) human amniotic fluid stem cells into nonimmune-competent mice with glycerol-induced acute kidney injury was followed by rapid normalization of renal function compared with injection of mesenchymal stem cells. Both stem cell types showed enhanced tubular cell proliferation and reduced apoptosis. Mesenchymal stem cells were more efficient in inducing proliferation than amniotic fluid-derived stem cells, which, in contrast, were more antiapoptotic. Both cell types were found to accumulate within the peritubular capillaries and the interstitium, but amniotic fluid stem cells were more persistent than mesenchymal stem cells. In vitro experiments demonstrated that the two cell types produced different cytokines and growth factors, suggesting that a combination of different mediators is involved in their biological actions. These results suggest that the amniotic fluid-derived stem cells may improve renal regeneration in acute kidney injury, but they are not more effective than mesenchymal stem cells.


Asunto(s)
Lesión Renal Aguda/prevención & control , Líquido Amniótico/citología , Células Madre Mesenquimatosas/citología , Rabdomiólisis/prevención & control , Trasplante de Células Madre , Células Madre/citología , Lesión Renal Aguda/etiología , Adulto , Animales , Apoptosis , Western Blotting , Médula Ósea/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rabdomiólisis/etiología
15.
Cytotherapy ; 11(5): 534-47, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19548144

RESUMEN

BACKGROUND AIMS: Amniotic fluid (AF) contains stem cells with high proliferative and differentiative potential that might be an attractive source of multipotent stem cells. We investigated whether human AF contains mesenchymal stem cells (MSC) and evaluated their phenotypic characteristics and differentiation potential in vitro. METHODS: AF was harvested during routine pre-natal amniocentesis at 14-16 weeks of pregnancy. AF sample pellets were plated in alpha-minimum essential medium (MEM) with 10% fetal bovine serum (FBS). We evaluated cellular growth, immunophenotype, stemness markers and differentiative potential during in vitro expansion. Neural progenitor maintenance medium (NPMM), a medium normally used for the growth and maintenance of neural stem cells, containing hFGF, hEGF and NSF-1, was used for neural induction. RESULTS: Twenty-seven AF samples were collected and primary cells, obtained from samples containing more than 6 mL AF, had MSC characteristics. AF MSC showed high proliferative potential, were positive for CD90, CD105, CD29, CD44, CD73 and CD166, showed Oct-4 and Nanog molecular and protein expression, and differentiated into osteoblasts, adypocytes and chondrocytes. The NPMM-cultured cells expressed neural markers and increased Na(+) channel density and channel inactivation rate, making the tetrodotoxin (TTX)-sensitive channels more kinetically similar to native neuronal voltage-gated Na(+) channels. CONCLUSIONS: These data suggest that AF is an important multipotent stem cell source with a high proliferative potential able to originate potential precursors of functional neurons.


Asunto(s)
Líquido Amniótico/citología , Células Madre Mesenquimatosas/citología , Células Madre Multipotentes/citología , Neuronas/citología , Neuronas/metabolismo , Canales de Sodio/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular , Separación Celular , Forma de la Célula , Células Cultivadas , Medios de Cultivo , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunofenotipificación , Activación del Canal Iónico , Células Madre Mesenquimatosas/metabolismo , Células Madre Multipotentes/metabolismo , Embarazo
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