ABSTRACT
Thymic epithelial tumors are rare malignancies with an incidence of 1.7 cases per million people per year. They pose significant management challenges due to their association with autoimmune disorders. In this case report, we present the 21-year history of a patient diagnosed with advanced B2/B3 thymoma and Good's syndrome. The patient achieved a complete and durable response after receiving only two cycles of the immune checkpoint inhibitor Nivolumab. However, this positive outcome was accompanied by the development of severe immune-related myocarditis complicated by reactivation of cytomegalovirus. Moreover, the patient developed a highly uncommon subdiaphragmatic pararectal dissemination of the thymic tumor, which is a condition rarely described in the literature. Despite the success in achieving complete and durable response with immune checkpoint inhibitors, the emergence of immune-related adverse events highlights the potential challenges associated with these treatments, emphasizing the need for careful monitoring and a comprehensive understanding of the intricate interplay between cancer, immune system dysregulations and immunotherapy.
Subject(s)
Immune Checkpoint Inhibitors , Thymus Neoplasms , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Thymus Neoplasms/immunology , Thymus Neoplasms/therapy , Thymus Neoplasms/drug therapy , Thymoma/immunology , Thymoma/therapy , Nivolumab/therapeutic use , Nivolumab/adverse effects , Male , Immunotherapy/methods , Immunotherapy/adverse effects , Myocarditis/etiology , Myocarditis/immunology , Myocarditis/therapy , Myocarditis/drug therapy , Treatment Outcome , Middle Aged , Neoplasms, Glandular and EpithelialABSTRACT
INTRODUCTION: Thymic epithelial tumors (TETs) are rare neoplasms often associated with immune-related disorders. Patients with Good's syndrome (GS), an adult-acquired TET-related immunodeficiency, are at a high risk of mortality due to infectious diseases. This study aims to examine COVID-19 occurrence and severity in TET patients, with or without GS. METHODS: Clinical records of TET patients referred to the Regional Coordinating Center for Rare Tumors of Campania Region were retrospectively collected. During the observation period, elapsing from March 2020 to April 2023, the following data were collected: occurrence of SARS-CoV-2 infection; COVID-19 severity, according to the National Institute of Health (NIH) illness categories; COVID-19 treatment. COVID-19 occurrence and severity were assessed in the overall population and correlated with the presence of GS and/or other immune-related dysregulations. RESULTS: Overall, 47 TET patients were included in the study; 27 of these (57.4%) had GS. All participants had received a full cycle of mRNA vaccine for SARS-CoV2., Thirty-one patients (66.0%) experienced COVID-19, of whom 18 (58.0%) had previously received a diagnosis of GS. No significant association of GS and/or other immune-related dysregulations with SARS-CoV-2 infection occurrence was detected (Fisher's exact test p = 1 and p = 0.3587, respectively). Among patients with GS, 8 (45.0%) reported a COVID-19 severity score of ≥ 3; whereas, only 1 of the 13 patients without GS (7.7%) had a severity score of ≥ 3. The correlation between presence of GS and COVID-19 severity (score 1 or 2 vs. ≥ 3) was statistically significant (p = 0.0448). No statistically significant association between COVID-19 severity and other immune-related syndromes were found (p = 1). Of note, all the hospitalized patients for NIH 4 and 5 COVID-19 had GS. CONCLUSIONS: Our data suggest that TET patients, especially those with GS, require a careful multidisciplinary monitoring for SARS-CoV-2 infection, in order to establish tailored treatments and prophylactic protocols.
Subject(s)
COVID-19 , Neoplasms, Glandular and Epithelial , Thymus Neoplasms , Humans , COVID-19/complications , COVID-19/epidemiology , COVID-19/immunology , Thymus Neoplasms/complications , Thymus Neoplasms/epidemiology , Thymus Neoplasms/immunology , Male , Retrospective Studies , Female , Middle Aged , Aged , Adult , Neoplasms, Glandular and Epithelial/virology , Neoplasms, Glandular and Epithelial/pathology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Primary Immunodeficiency Diseases/complications , Primary Immunodeficiency Diseases/epidemiology , Aged, 80 and over , Italy/epidemiologyABSTRACT
Treatment duration with checkpoint inhibitors must be optimized to prevent unjustified toxicity, but evidence for the management of cutaneous squamous cell carcinoma is lacking. A retrospective study was performed to evaluate the survival of patients with cutaneous squamous cell carcinoma (CSCC) who discontinued cemiplimab due to different causes and without progression. Among 95 patients with CSCC who received cemiplimab, 22 (23%) patients discontinued immunotherapy due to causes other than progression, such as comorbidities, toxicity, complete response or lack of compliance (group that discontinued before censoring [DBC]), then 73 patients had standard treatment scheduled (STS). The overall survival was 25.2 months (95% CI: 8.9-29.4) in STS group and 28.3 months (95% CI: 12.7-28.3) in the DBC group; deaths for all causes were 11/22 (50%) in the DBC group and 34/73 (46.6%) in the STS group (p = 0.32). 10/22 (45.4%) subjects died due to CSCC in the DBC after discontinuation and 34/73 (46.6%) in the STS group, and the difference between groups was not significant (p = 0.230). Duration of treatment was significantly lower in subjects with stable disease versus those with complete or partial response (16.9, 30.6 and 34.9 months, respectively; p = 0.004). Among the 22 STS patients, 12 received cemiplimab for less than 12 months (10 [83%] died) and 10 for at least 12 months (1 [10%] died). Our observation, finding no outcome difference between DBC and STS groups, suggests that ICI treatment after one year might expose patients to further treatment related events without efficacy advantages.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Male , Female , Skin Neoplasms/drug therapy , Skin Neoplasms/mortality , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/mortality , Aged , Retrospective Studies , Middle Aged , Aged, 80 and over , Treatment Outcome , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Adult , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effectsABSTRACT
BACKGROUND: Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. METHODS: A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb-IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. RESULTS: The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFß2, a marker of the N2 neutrophils with immunosuppressive activity. CONCLUSIONS: These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.
Subject(s)
Melanoma , Neutrophils , Humans , Prognosis , Retrospective Studies , Immunotherapy , Melanoma/genetics , Melanoma/therapyABSTRACT
Background: Thymic epithelial tumors (TETs) are rare malignancies with heterogeneous clinical manifestations. The high frequency of autoimmune paraneoplastic disorders observed in such patients requires caution when using COVID-19 vaccines. Furthermore, TETs are often associated with severe immunodeficiency, making it difficult to predict vaccine immunization. Therefore, we aimed to evaluate immune response to COVID-19 vaccine in patients with TETs. Methods: We conducted a prospective study enrolling patients who underwent the SARS-Cov-2 mRNA full vaccine cycle (two doses plus a booster after 6 months of BNT162b2). All patients were enrolled before receiving 1st vaccine dose and were followed over the vaccination cycle for up to 6 months after the booster dose to i) assess humoral and cellular responses, ii) define biomarkers predictive of effective immunization, and iii) evaluate the safety of the vaccine. Results: At the end of the full vaccine cycle, 27 (61.4%) patients developed humoral and 38 (86.4%) cellular responses (IFN γ release by stimulated cells) and showed an increase in activated TH1 and TH17 cells, particularly significant after the booster dose. The number of B and T lymphocytes at baseline was predictive of humoral and cellular responses, respectively. Patients with no evidence of tumor lesions had a higher probability of achieving a humoral response than those with evidence of the disease. Furthermore, the percentage of patients with immune-related disorders (75%), particularly Good's syndrome (47.7%) and myasthenia gravis (29.5%), did not change over the entire vaccine cycle. Overall, 19 of the 44 enrolled patients (43.2%) had COVID-19 during the observation period; none required hospitalization or oxygen support, and no fatalities were observed. Conclusion: SARS-Cov-2 mRNA vaccine determines the immune responses in patients with TET, particularly after the booster dose, and in patients with no evidence of tumor lesions. Preliminary analysis of B and T lymphocytes may help identify patients who have a lower probability of achieving effective humoral and cellular responses and thus may need passive immunization. The vaccine prevented severe COVID-19 infection and is safe.
Subject(s)
Autoimmune Diseases , COVID-19 , Neoplasms, Glandular and Epithelial , Humans , COVID-19 Vaccines/adverse effects , BNT162 Vaccine , Prospective Studies , COVID-19/prevention & control , SARS-CoV-2 , ImmunityABSTRACT
INTRODUCTION: Thymic epithelial tumors (TETs) are rare malignancies associated with dysregulation of the immune system and humoral- and cell-mediated immunity abnormalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is effective in preventing coronavirus disease 2019 morbidity and mortality. The aim of this study was to evaluate the seroconversion in patients with TET after two doses of mRNA vaccine. METHODS: This is a prospective study in which consecutive patients with TET were enrolled before receiving the first dose of SARS-CoV-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding immunoglobulin (Ig)G antibody serologic levels were analyzed at different time points, including before first vaccine dose (T0), 1 month after the second dose (T2), and 3 months after the second dose (T3). RESULTS: Overall, 39 patients were included in the analysis. All patients had negative antibody titer results at T0. There were 19 patients (48.7%) in the follow-up with no residual tumor lesion/s (referred as no evidence of disease), and 20 (51.3%) had evidence of disease (ED) and were receiving systemic treatment. Dysregulations of the immune system were diagnosed in 29 patients (74.4%) with Good syndrome (GS) being the most frequent immune disorder (48.7%). At univariate analysis, lack of seroconversion at T2 was significantly associated with ED (p < 0.001) and with GS (p = 0.043). A significant association with impaired seroconversion was confirmed at multivariate analysis for ED (p = 0.00101) but not for GS (p = 0.625). CONCLUSIONS: Our data revealed that patients with TET with ED had substantially higher probability of impaired seroconversion after SARS-CoV-2 mRNA vaccine as compared with patients with no evidence of disease.
Subject(s)
COVID-19 Vaccines , COVID-19 , Lung Neoplasms , Neoplasms, Glandular and Epithelial , Humans , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Prospective Studies , SARS-CoV-2 , Seroconversion , Vaccines , mRNA VaccinesABSTRACT
Sarcomas of the thoracic cavity are rare entities that predominantly affect children and young adults. They can be very heterogeneous encompassing several different histological entities. Ewing Sarcoma (ES) can potentially arise from every bone, soft tissue, or visceral site in the body. However, it represents an extremely rare finding when it affects the thoracic cavity. It represents the second most frequent type of thoracic sarcoma, after chondrosarcoma. ES arises more frequently in sites that differ from the thoracic cavity, but it displays the same biological features and behavior of extra-thoracic ones. Current management of ES often requires a multidisciplinary treatment approach including surgery, radiotherapy, and systemic therapy, as it can guarantee local and distant disease control, at least transiently, although the long-term outcome remains poor. Unfortunately, due to the paucity of clinical trials purposely designed for this rare malignancy, there are no optimal strategies that can be used for disease recurrence. As a result of its complex biological features, ES might be suitable for emerging biology-based therapeutic strategies. However, a deeper understanding of the molecular mechanisms driving tumor growth and treatment resistance, including those related to oncogenic pathways, epigenetic landscape, and immune microenvironment, is necessary in order to develop new valid therapeutic opportunities. Here, we provide an overview of the most recent therapeutic advances for ES in both the preclinical and clinical settings. We performed a review of the current available literature and of the ongoing clinical trials focusing on new treatment strategies, after failure of conventional multimodal treatments.
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Background: Ewing sarcoma (ES) represents the second most common malignant bone tumor in children and young adults. ES is not a frequent finding in sites different from the skeletal. Common sites of appearance of ES are lower extremities, the pelvis, paravertebral spaces and head and neck. Primary extraskeletal ES located in the anterior mediastinum are very rare. These neoplasms should be discussed in specialized contests with a high volume of patients treated. Here, we present an uncommon mediastinal mass challenging in its characterization and management. Case description: A thirty-year-old woman performed a thoracic CT scan for dyspnea and persistent cough. Imaging showed a solid mass of 14 x 11 cm involving the left thorax with mediastinal deviation to the right side. Patient underwent an en bloc resection of the mass. Initial histological examination was suggestive for B3 thymoma/thymic carcinoma. Patient was then referred to our rare tumor reference center where a histological review excluded the diagnosis of thymic/thymoma neoplasms meanwhile a third revision assessed a diagnosis of ES. Patient refused adjuvant chemotherapy due to her desire of maternity and radiation therapy was not indicated because surgery was performed too many months earlier. A close follow-up was considered. After a few months the patient relapsed and first line chemotherapy was proposed. She reached a complete response at the first evaluation maintained also at the end of the protocol. In order to consolidate the obtained response, high dose chemotherapy followed by autologous stem cell transplantation (HDCT/ASCT) was suggested and the patient agreed. Conclusions: This case underlined that, potentially, ES can arise from any soft tissue site in the body, even in rare sites such as mediastinum. The evaluation of expert centers was critical to establish a correct diagnosis and therapeutic approach in this complex case. Taking into account the time lasting from the diagnosis and the aggressiveness of this kind of neoplasm, frequently relapsing, the patient after a multidisciplinary discussion was a candidate for a multimodal treatment.
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BACKGROUND: Prognostic factors for initial response of advanced cutaneous squamous cell carcinoma to cemiplimab treatment are lacking. Il-6 has been found to affect immune cell populations which impact tumor development. The aim was to investigate the prognostic significance of IL-6 serum levels before and during treatment. METHODS: Serum levels of IL-6 were correlated with clinical outcomes in a retrospective study. RESULTS: Overall, 39 patients were enrolled. High serum levels of IL-6 (> 5.6 pg/ml) were associated with poorer survival (45.1% vs 0 deaths; OS: 16.1 ± 1.5 vs 20.8 ± 0 months, 95% CI 13,046 to 19,184) and shorter PFS (10.3 ± 1.9 vs 18.9 ± 1.5 months; 95% CI 3433 to 10,133) in patients with advanced CSCC treated with cemiplimab. In addition, patients whose IL-6 level increased after treatment with cemiplimab, independently of the basal level, had a poorer response to treatment than patients whose level was reduced or stable after immunotherapy. CONCLUSIONS: Serum levels of IL-6 at baseline and changes after cemiplimab immunotherapy may have a prognostic significance in patients with advanced cutaneous squamous cell carcinoma.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Interleukin-6 , Prognosis , Retrospective StudiesABSTRACT
Gastric cancer (GC) is a lethal disease and the diagnosis in the young population is a major challenge from both individual and social point of views. Early-onset GC accounts for â¼5% of GC; among them, 3% are part of a hereditary syndrome and the majority are sporadic. However, even if the early-onset forms were less frequent in the past, the increasing number in the last decades has improved the interest and awareness of them in the society and in the scientific community. In particular, the different behaviour and characteristics of early-onset GC suggest that it is a completely different entity, which requires a tailored and personalized management. Here we provide an updated overview about non-hereditary early-onset GC, which is an unmet clinical need today, along with future perspectives in this field.
Subject(s)
Stomach Neoplasms , Humans , Age of Onset , Stomach Neoplasms/diagnosis , Stomach Neoplasms/genetics , Stomach Neoplasms/therapy , Early Detection of Cancer , Genetic Predisposition to DiseaseABSTRACT
Background: Thymic epithelial tumors (TETs) are frequently accompanied by Good Syndrome (GS), a rare immunodeficiency, characterized by hypogammaglobulinemia and peripheral B cell lymphopenia. TETs can be also associated to other immunological disorders, both immunodeficiency and autoimmunity. Methods: In this study, we enrolled TET patients with GS to address differences between patients with or without associated autoimmune diseases (AD). We analyzed the immunophenotype from peripheral blood of these patients focusing on selected immune cell subsets (CD4+T cells, CD8+T cells, T regulatory cells, NK cells, B-cells, monocytes, eosinophils, basophils, neutrophils) and serum levels of cytokines, chemokines and growth factors. Results: We observed higher number of leucocytes, in particular lymphocytes, B lymphopenia and lower number of T regulatory cells in TET patients with associated AD compared to TET patients without AD. In the group of TET patients with AD, we also observed increased serum levels of IL-15, VEGF, IP-10, GM-CSF, IL-6, and MIP-1α. Thus, we identified considerable differences in the lymphocyte profiles of TET patients with and without ADs, in particular a reduction in the numbers of B lymphocytes and T-regulatory cells in the former, as well as differences in the serum levels of various immune modulators. Conclusions: Although the pathogenic mechanisms are still unclear, our results add new knowledge to better understand the disease, suggesting the need of surveilling the immunophenotype of TET patients to ameliorate their clinical management.
Subject(s)
Autoimmune Diseases , Lymphopenia , Neoplasms, Glandular and Epithelial , Primary Immunodeficiency Diseases , Thymus Neoplasms , Autoimmune Diseases/pathology , CD4-Positive T-Lymphocytes , Humans , Lymphopenia/pathology , Neoplasms, Glandular and Epithelial/complications , Neoplasms, Glandular and Epithelial/pathology , Thymus Neoplasms/complicationsABSTRACT
Prostate cancer (PCa) treatment involves multiple strategies depending on the disease's stage. Androgen deprivation therapy (ADT) remains the gold standard for advanced and metastatic stages. Sleep quality has been suggested as being additionally influenced also by local radiotherapy, prostatectomy and androgen-receptor (AR)-targeted agents. We performed a systematic review exploring the landscape of studies published between 1 January 1990 and 31 July 2021, investigating sleep disturbances in PCa patients receiving active treatments, including the influence of hormonal therapy on sleep quality as a factor affecting their quality of life. Out of 45 articles identified, 16 studies were selected, which recruited patients with PCa, undergoing active treatment in either a prospective longitudinal or cross-sectional study. Development of sleep disorders or changes in sleep quality were reported in 14 out of 16 trials included. Only five trials included objective measurements such as actigraphy, mostly at one time point and without a baseline assessment. Limitations to be addressed are the small number of existing trials, lack of randomized trials and heterogeneity of methodologies used. This systematic review outlines the lack of prospective trials investigating sleep disorders, with a rigorous methodology, in homogeneous cohorts of PCa patients. Future trials are needed to clarify the prevalence and impact of this side effect of PCa treatments.
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Objective: The aim of this review is to analyze feasibility and toxicities of high-dose chemotherapy (HDCT) in comparison to standard dose chemotherapy (SDCT) in patients affected by mediastinal germ cell tumors (MGCTs), discussing factors that may affect therapeutic choices, such as: management of residual disease, early response predictors for chemotherapeutic efficacy and determinants of chemotherapeutic resistance. In this review, we discuss the main clinical experiences with HDCT and SDCT in germ cell tumor (GCT) patients specifically in those affected by MGCT. Background: MGCTs represent a very small subset characterized by a poor prognosis, despite improvements in their clinical management and in understanding their biology. From early 1970s, HDCT has become an alternative to SDCT for both first-line and salvage therapeutic settings in advanced GCT patients. Several HDCT schedules-either cisplatin or carboplatin-based-have been tested so far, both in clinical randomized trial and in single-center experiences, with divergent results in terms of clinical outcomes and tolerability. Moreover, the majority of these studies included, but were not exclusively designed for, advanced MGCT patients, making difficult to infer data for this specific subset. Methods: an extended review of literature through PubMed was conducted using the keywords "mediastinal germinal cell tumors", "standard dose chemotherapy" and "high dose chemotherapy". Conclusions: HDCT regimens could not be considered to date a standard option as first-line therapy in advanced MGCT patients, whilst they could be an alternative to SDCT regimens in relapsed tumors after proper patient selection.
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Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most popular unconventional therapy is represented by the somatostatin analog octreotide, which can be used alone or with prednisone. The in vivo expression of somatostatin receptors documented by imaging with indium-labeled octreotide or gallium-68 Dotapeptides, the successful use of octreotide and prednisone in a chemo-refractory patient, and, thereafter, the experiences from a case series have enforced the idea that this treatment merits consideration-as proved by its inclusion in the National Comprehensive Cancer Network guidelines. In the present review, we analyze the preclinical basis for the therapeutic use of somatostatin and prednisone in refractory thymic tumors and discuss the available studies looking at future perspectives.
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Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva and vagina). To date, there is no consensus about the optimal management strategy of MM. Furthermore, the clinical rationale of molecular tumor characterization regarding BRAF, KIT or NRAS, as well as the therapeutic value of immunotherapy, chemotherapy and targeted therapy, has not yet been deeply explored and clearly established in MM. In this overview, focused on anorectal and genital MM as models of rare melanomas deserving of a multidisciplinary approach, we highlight the need of referring these patients to centers with experts in melanoma, anorectal and uro-genital cancers treatments. Taking into account the rarity, the poor outcomes and the lack of effective treatment options for MM, tailored research needs to be promptly promoted.
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Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRß expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRß was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.
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Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.
Subject(s)
Epigenesis, Genetic , Melanoma/genetics , Skin Neoplasms/genetics , Antineoplastic Agents/therapeutic use , Chromatin Assembly and Disassembly , DNA Methylation , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic/drug effects , Humans , Melanoma/pathology , Melanoma/therapy , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Skin Neoplasms/pathology , Skin Neoplasms/therapyABSTRACT
The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.
Subject(s)
Genes, p53 , Neoplasms, Germ Cell and Embryonal/metabolism , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Drug Resistance, Neoplasm , Humans , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/secondary , Tumor Suppressor Protein p53/geneticsABSTRACT
Gastric cancer (GC) is the third cause of cancer-related death worldwide; the prognosis is poor especially in the case of metastatic disease. Liver, lymph nodes, peritoneum, and lung are the most frequent sites of metastases from GC; however, bone metastases from GC have been reported in the literature. Nevertheless, it is unclear how the metastatic sites may affect the prognosis. In particular, knowledge about the impact of bone metastases on GC patients' outcome is scant, and this may be related to the rarity of bone lesions and/or their underestimation at the time of diagnosis. In fact, there is still a lack of specific recommendation for their detection at the diagnosis. Then, the majority of the evidences in this field came from retrospective analysis on very heterogeneous study populations. In this context, the aim of this narrative review is to delineate an overview about the evidences existing about bone metastases in GC patients, focusing on their incidence and biology, the prognostic role of bone involvement, and their possible implication in the treatment choice.
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As widely acknowledged, 40-50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS-RAF-MEK-ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.