RESUMEN
Undifferentiated sarcomas characterized by a primitive monomorphic round to spindle cell phenotype and often non-specific immunoprofile remain difficult to subclassify outside molecular analysis. The increased application of RNA sequencing in clinical practice led to significant advances and discoveries of novel gene fusions that furthered our understanding and refined classification of otherwise undifferentiated neoplasms. In this study, we report an undifferentiated round to spindle cell sarcoma arising in the femur of a 34-year-old female. The round to spindle tumor cells were arranged in short fascicles, with focal rosette formation, within a hyalinized stroma. The tumor immunoprofile included diffuse reactivity for CD99, SATB2, and TLE1 and patchy positivity for Cyclin D1, Keratin AE1/AE3, synaptophysin, and chromogranin. Other markers, such as EMA, SMA, desmin, S100, ERG, and WT1, were negative. Fluorescence in situ hybridization analysis for EWSR1 gene alterations showed a break-apart signal and targeted RNA sequencing revealed an EWSR1::SSX3 gene fusion. The patient received neoadjuvant chemotherapy followed by surgery and subsequently relapsed in less than a year with lung metastasis. Larger series are needed to determine if this fusion defines a novel subset of undifferentiated tumors or represents a genomic variant of already existing primitive round cell sarcoma categories, such as Ewing sarcoma or synovial sarcoma.
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Sarcoma de Ewing , Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Adulto , Hibridación Fluorescente in Situ , Sarcoma/genética , Sarcoma/patología , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Factores de Transcripción/genética , Neoplasias de los Tejidos Blandos/genética , Fusión Génica , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genéticaRESUMEN
BACKGROUND: Histopathological and molecular features have been proposed to hold prognostic information, but few have been validated. The aim of this retrospective study was to validate the Genetic And Morphological Evaluation ('GAME') score and assess the impact of histological characteristics on the prognosis in patients with colorectal liver metastases. METHODS: Data were collected from 176 patients with metastatic colorectal cancer undergoing liver resection at Hospital de la Santa Creu i Sant Pau. Patients were classified into Genetic And Morphological Evaluation score groups and relapse-free survival and overall survival were calculated. Histopathological changes in colorectal liver metastases were documented and prognostic variables were selected to create a post-surgery score, called the Histopathological, Clinical, And Molecular ('HICAM') score. RESULTS: Regarding the Genetic And Morphological Evaluation score, the high-risk group had a median relapse-free survival of 8.8 months, compared with 20.5 months for the low-risk group (P = 0.005), and the high-risk group had a median overall survival of 37.8 months, compared with 67.0 months for the low-risk group (P = 0.005). Histological examination of 144 liver samples showed that the desertic immune phenotype was associated with worse overall survival in the multivariable analysis (P = 0.020). The Histopathological, Clinical, And Molecular score variables were age at diagnosis, tumour burden score, carcinoembryonic antigen levels greater than or equal to 20â ng/ml, primary tumour resection, TNM stage at diagnosis, molecular status, histopathological growth patterns, and immune phenotypes of the liver. The high-risk group had a median relapse-free survival of 8.4 months, compared with 20.4 months for the low-risk group (P < 0.001), and a median overall survival of 30.4 months, compared with 105.0 months for the low-risk group (P < 0.001). CONCLUSION: The Genetic And Morphological Evaluation score was validated as a preoperative prognostic tool to predict candidacy for liver resection. The Histopathological, Clinical, And Molecular score could be useful to assess adjuvant treatment after hepatic resection.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Estudios Retrospectivos , Neoplasias Colorrectales/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , HepatectomíaRESUMEN
BACKGROUND: Endometrial cancers with more than one molecular feature-POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'. OBJECTIVE: To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. METHODS: Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. RESULTS: Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%. CONCLUSIONS: The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing.
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Thyroid nodules are commonly encountered in clinical practice, affecting up to 50% of the population. The large majority of thyroid lumps are benign incidental findings detected by imaging, while approximately 5-15% harbor malignancy. For a target patient's care, it is of paramount importance to identify and treat thyroid malignancy, while preventing unnecessary invasive surgery in patients with benign lesions. Although fine needle aspiration (FNA) associated with cytological examination provides malignant risk information, 20-30% of diagnoses fall into the "indeterminate thyroid nodule" (ITN) category. ITN clinical management remains a challenging issue for physicians since the ITN risk of malignancy varies from 5% to 40% and most thyroid nodules undergo overtreatment with surgery procedures. ITN molecular testing may better define malignant risk in the single nodule and is able to discriminate with accuracy benign from malignant nodules. Nowadays there are different technologies and different molecular panels, each with its own specificity, sensitivity and predictive values. In view of widespread introduction of molecular testing , some outstanding questions remain and are addressed in the present review such as the presence of molecular panels acting as "rule in" or "rule out" tools, the effective impact of testing results in the clinical decision-making process, and the prohibitive cost of commercial assays associated with the lack of test reimbursement in national health systems.
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Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Toma de Decisiones Clínicas , Técnicas de Diagnóstico MolecularRESUMEN
OBJECTIVE: To compare the risk class attribution with molecular classification unknown to those with molecular classification known, according to the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) 2020 guidelines on endometrial cancer, with a focus on risk group migration. Additionally, to evaluate the capability of a novel molecular analysis algorithm to reduce the number of required tests. METHODS: We conducted a retrospective study including all consecutive patients with endometrial cancer undergoing surgery and comprehensive molecular analyses between April 2019 and December 2021. Molecular analyses including immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were performed to classify tumors as POLE-mutated (POLE), MMR-deficient (MMR-d), p53 abnormal (p53abn), or non-specific molecular profile (NSMP). The two risk classifications of the ESGO/ESTRO/ESP 2020 guidelines were compared to estimate the proportion of patients in which the molecular analysis was able to change the risk class attribution. We developed a novel algorithm where the molecular analyses are reserved only for patients in whom incorporation of the molecular classification could change the risk class attribution. RESULTS: A total of 278 patients were included. Molecular analyses were successful for all cases, identifying the four subgroups: 27 (9.7%) POLE, 77 (27.7%) MMR-d, 49 (17.6%) p53abn, and 125 (45.0%) NSMP. Comparison of risk class attribution between the two classification systems demonstrated discordance in the risk class assignment in 19 (6.8%, 95% CI 4.2% to 10.5%) cases. The application of our novel algorithm would have led to a reduction in the number of POLE sequencing tests by 67% (95% CI 61% to 73%) and a decrease of p53 immunohistochemistry by 27% (95% CI 22% to 33%), as compared with the application of molecular classification to all patients. CONCLUSION: Molecular categorization of endometrial cancer allows the reallocation of a considerable proportion of patients in a different risk class. Furthermore, the application of our algorithm enables a reduction in the number of required tests without affecting the risk classification.
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Background: Homologous recombination repair (HRR) is the main mechanism of repair of DNA double-strand breaks. Its deficiency (HRD) is a common feature of epithelial ovarian cancers (EOCs). BRCA1/2 mutations and/or other aberrations in genes of HRR are well known causes of HRD and genomic instability. Poly ADP-ribose polymerase inhibitors (PARPi) have revolutionized the management of BRCA mutant EOCs and demonstrated activity in HRD tumor cells. Determining HRD status can provide informations on the magnitude of benefit for PARPi therapy. Myriad MyChoice CDx is a next generation sequencing- based in vitro diagnostic test that assesses the Genomic Instability Score (GIS) which is an algorithmic measurement of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens. However Myriad MyChoice CDx, is a centrally performed and costly assay, with no reimbursement scheduled, at least in Italy. Methods: In this report, we described our experience in performing the HRD Focus AmoyDx (Amoy Diagnostics Ltd, Xiamen, Fujian, China) on the same samples of EOCs evaluated with Myriad MyChoiceCDx assay. Results: The overall percent agreement between AmoyDx and Myriad was 87.8% (65 of 74 tumors tested). All the 36 AmoyDx negative cases were confirmed to be negative by Myriad (negative predictive value, 100%). Conclusions: The concordance of the results with the gold standard Myriad MyChoice CDx assay suggest the feasibility and reliability of HRD testing in diagnostic laboratories with high-throughput NGS platforms and qualified personnel.
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Proteína BRCA2 , Neoplasias Ováricas , Adenosina Difosfato Ribosa , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/genética , Estudios de Factibilidad , Femenino , Formaldehído , Inestabilidad Genómica , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Reparación del ADN por Recombinación/genética , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The breast cancer genome dynamically evolves during malignant progression and recurrence. We investigated the genomic profiles of primary early-stage breast cancers and matched relapses to elucidate the molecular underpinnings of the metastatic process, focusing on potentially actionable alterations in the recurrences. METHODS: A mono-institutional cohort of 128 patients with breast cancers (n = 68 luminal B HER2, n = 6 luminal B HER2+, n = 1 HER2+ non-luminal, n = 56 triple negative) and at least one recurrence in a timeframe of 17 years was evaluated. Next-generation sequencing comprehensive genomic profiling was performed on 289 formalin-fixed paraffin-embedded (FFPE) samples, including primary tumors and matched relapses. Correlations of genomic aberrations with clinicopathologic factors and time to breast cancer relapse were analyzed. RESULTS: Genomic data were available for 188 of 289 FFPE samples that achieved the sequencing quality parameters (failure rate 34.9%), including 106 primary tumors and 82 relapses. All primary and relapse samples harbored at least one genomic alteration, with a median number of six alterations per sample (range 1-16). The most frequent somatic genomic alterations were mutations of TP53 (primary tumors = 49%, relapses = 49%) and PIK3CA (primary tumors = 33%, relapses = 30%). Distinctive genomic alterations of primary tumors were significantly associated with molecular subtypes. TP53, PIK3R1, and NF1 somatic alterations were more frequently detected in triple negative tumors (p value < 0.05); CCND1, FGF3, and FGFR1 copy number gains were recurrently identified in luminal cases (p value < 0.05). Moreover, TP53 mutations and MYC amplification were significantly and independently associated with a shorter time to relapse (p value < 0.05). Molecular subtype changes between primary tumors and relapses were seen in 10 of 128 (7.8%) cases. Most driver genomic alterations (55.8%) were shared between primary tumors and matched recurrences. However, in 39 of 61 cases (63.9%), additional private alterations were detected in the relapse samples only, including 12 patients with potentially actionable aberrations. CONCLUSIONS: Specific genomic aberrations of primary breast cancers were associated with time to relapse. Primary tumors and matched recurrences showed a core of shared driver genomic aberrations but private actionable alterations have been identified in the relapses.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Genómica/métodos , Terapia Molecular Dirigida/métodos , Mutación , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Fosfatidilinositol 3-Quinasa Clase I/genética , Resistencia a Antineoplásicos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
PURPOSE: We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00. METHODS: A matched case-control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence. RESULTS: Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88-5.92), though this difference was not statistically significant (p = 0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy. CONCLUSIONS: Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.
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Biomarcadores de Tumor , Mutación , Neoplasias de la Mama Triple Negativas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Oportunidad Relativa , Pronóstico , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Carga Tumoral , Adulto JovenAsunto(s)
Carcinoma Basocelular , Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Cutáneas , Neoplasias de los Tejidos Blandos , Humanos , Proteínas Hedgehog , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
AIMS: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology. METHODS AND RESULTS: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E-cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2-STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2-STAT6 fusion variant (exon 4-exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified. CONCLUSIONS: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours.
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Adenofibroma/genética , Receptor alfa de Estrógeno/biosíntesis , Neoplasias Pulmonares/genética , Proteínas Represoras/genética , Factor de Transcripción STAT6/genética , Adenofibroma/metabolismo , Adenofibroma/patología , Anciano , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Captura por Microdisección con Láser , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/biosíntesis , Proteínas de Fusión Oncogénica/genéticaRESUMEN
INTRODUCTION AND HYPOTHESIS: Uterosacral ligament suspension at the time of primary prolapse repair represents a well-established surgical option. Our aim was to compare the effectiveness, complications rate, and functional results of modified McCall culdoplasty and Shull suspension. METHODS: Patients who underwent vaginal hysterectomy and cuff suspension for pelvic organ prolapse were retrospectively analyzed. McCall culdoplasty (group A) or Shull suspension (group B) were performed according to surgeon choice based on age and sexual activity. Perioperative data, objective, and subjective cure rate were noted. RESULTS: A total of 339 patients (215 in group A and 124 in group B) completed follow-up. Operating time and blood loss were slightly higher in group B. The complications rate was similar in the two groups. Anatomical outcomes in terms of recurrence and reoperation rate did not show any statistically significant differences. POP-Q items analysis revealed only a different total vaginal length between groups (8 mm longer in group B). Functional outcomes were similar in the two groups as was patient satisfaction. CONCLUSION: Both uterosacral ligament suspension procedures were shown to be safe and effective. There were no clinically significant differences with regard to surgical data, complications, anatomical, functional, and subjective outcomes between modified McCall culdoplasty and Shull suspension.
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Culdoscopía/métodos , Histerectomía Vaginal/métodos , Prolapso de Órgano Pélvico/cirugía , Procedimientos de Cirugía Plástica/métodos , Vagina/cirugía , Anciano , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Tempo Operativo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: To assess the association between CT features and EGFR, ALK, KRAS mutations in non-small cell lung cancer. METHODS: Patients undergoing chest CT and testing for the above gene mutations were included. Qualitative evaluation of CTs included: lobe; lesion diameter; shape; margins; ground-glass opacity; density; cavitation; air bronchogram; pleural thickening; intratumoral necrosis; nodules in tumour lobe; nodules in non-tumour lobes; pleural retraction; location; calcifications; emphysema; fibrosis; pleural contact; pleural effusion. Statistical analysis was performed to assess association of features with each gene mutation. ROC curves for gene mutations were drawn; the corresponding area under the curve was calculated. P-values <0.05 were considered significant. RESULTS: Of 285 patients, 60/280 (21.43 %) were positive for EGFR mutation; 31/270 (11.48 %) for ALK rearrangement; 64/240 (26.67 %) for KRAS mutation. EGFR mutation was associated with air bronchogram, pleural retraction, females, non-smokers, small lesion size, and absence of fibrosis. ALK rearrangements were associated with age and pleural effusion. KRAS mutation was associated with round shape, nodules in non-tumour lobes, and smoking. CONCLUSIONS: This study disclosed associations between CT features and alterations of EGFR (air bronchogram, pleural retraction, small lesion size, absence of fibrosis), ALK (pleural effusion) and KRAS (round lesion shape, nodules in non-tumour lobes). KEY POINTS: Air bronchogram, pleural retraction, small size relate to EGFR mutation in NSCLC. Pleural effusion and younger age relate to ALK mutation. Round lesion shape, nodules in non-tumour lobes relate to KRAS mutation.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Genes ras/genética , Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Tirosina Quinasas Receptoras/genética , Anciano , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Femenino , Reordenamiento Génico/genética , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Derrame Pleural/diagnóstico por imagen , Derrame Pleural/genética , Curva ROC , Fumar/genética , Tomografía Computarizada por Rayos XAsunto(s)
Artritis/etiología , Cirugía Bariátrica , Dermatitis/etiología , Femenino , Fiebre , Humanos , Persona de Mediana Edad , MialgiaRESUMEN
Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.
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Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/análogos & derivados , Tumores Neuroendocrinos/tratamiento farmacológico , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/toxicidad , Dacarbazina/farmacocinética , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Dacarbazina/toxicidad , Humanos , TemozolomidaRESUMEN
INTRODUCTION: We describe the clinical features, outcome and incidence of druggable targets of lung cancers in patients ≤ 40 years old. MATERIALS & METHODS: Young patients were compared with two other groups (41-64 and ≥ 65 years). Neuroendocrine tumors, adenocarcinoma and non-adenocarcinoma/unspecified non-small-cell lung cancer were analyzed separately. Molecular characteristics of adenocarcinoma were evaluated in a subset of young patients. RESULTS: Of 2847 patients with lung cancer, 100 were ≤ 40 years old. The young group contained more women, never-smokers and patients presenting with advanced disease. The commonest tumor in young patients was adenocarcinoma. In total, 19 of 34 young patients with adenocarcinoma had tumors with specific molecular alterations. CONCLUSION: Lung cancers in young patients have distinctive features but outcomes similar to those in older patients.
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Adenocarcinoma/genética , Tumor Carcinoide/genética , Carcinoma de Células Grandes/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Receptores ErbB/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Receptor ErbB-2/genética , Tasa de Supervivencia , Factores de Transcripción/genética , Adulto Joven , Proteínas ras/genéticaRESUMEN
BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sirolimus/análogos & derivados , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Everolimus , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Humanos , Niacinamida/efectos adversos , Niacinamida/farmacocinética , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Sirolimus/efectos adversos , Sirolimus/farmacocinética , Sirolimus/uso terapéutico , Sorafenib , Proteínas ras/antagonistas & inhibidoresRESUMEN
Poor long-term survival in localized high-risk soft tissue sarcomas (STSs) of the extremities and trunk highlights the need to identify new prognostic factors. CXCR4 is a chemokine receptor involved in tumor progression, angiogenesis, and metastasis. The aim of this study was to evaluate the association between CXCR4 expression in tumor tissue and survival in STSs patients treated with neoadjuvant therapy. CXCR4 expression was retrospectively determined by immunohistochemical analysis in serial specimens including initial biopsies, tumors post-neoadjuvant treatment, and tumors after relapse. We found that a positive cytoplasmatic expression of CXCR4 in tumors after neoadjuvant treatment was a predictor of poor recurrence-free survival (RFS) (p = 0.003) and overall survival (p = 0.019) in synovial sarcomas. We also found that positive nuclear CXCR4 expression in the initial biopsies was associated with poor RFS (p = 0.022) in undifferentiated pleomorphic sarcomas. In conclusion, our study adds to the evidence that CXCR4 expression in tumor tissue is a promising prognostic factor for STSs.