RESUMEN
BACKGROUND: Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary. METHODS: We established a classifier of cancer type based on the microarray DNA methylation signatures (EPICUP) in a training set of 2790 tumour samples of known origin representing 38 tumour types and including 85 metastases. To validate the classifier, we used an independent set of 7691 known tumour samples from the same tumour types that included 534 metastases. We applied the developed diagnostic test to predict the tumour type of 216 well-characterised cases of cancer of unknown primary. We validated the accuracy of the predictions from the EPICUP assay using autopsy examination, follow-up for subsequent clinical detection of the primary sites months after the initial presentation, light microscopy, and comprehensive immunohistochemistry profiling. FINDINGS: The tumour type classifier based on the DNA methylation profiles showed a 99·6% specificity (95% CI 99·5-99·7), 97·7% sensitivity (96·1-99·2), 88·6% positive predictive value (85·8-91·3), and 99·9% negative predictive value (99·9-100·0) in the validation set of 7691 tumours. DNA methylation profiling predicted a primary cancer of origin in 188 (87%) of 216 patients with cancer with unknown primary. Patients with EPICUP diagnoses who received a tumour type-specific therapy showed improved overall survival compared with that in patients who received empiric therapy (hazard ratio [HR] 3·24, p=0·0051 [95% CI 1·42-7·38]; log-rank p=0·0029). INTERPRETATION: We show that the development of a DNA methylation based assay can significantly improve diagnoses of cancer of unknown primary and guide more precise therapies associated with better outcomes. Epigenetic profiling could be a useful approach to unmask the original primary tumour site of cancer of unknown primary cases and a step towards the improvement of the clinical management of these patients. FUNDING: European Research Council (ERC), Cellex Foundation, the Institute of Health Carlos III (ISCIII), Cancer Australia, Victorian Cancer Agency, Samuel Waxman Cancer Research Foundation, the Health and Science Departments of the Generalitat de Catalunya, and Ferrer.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Neoplasias Primarias Desconocidas/genética , Receptores ErbB/genética , Femenino , Humanos , Masculino , Neoplasias Primarias Desconocidas/clasificación , Neoplasias Primarias Desconocidas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas p21(ras)/genética , Estudios RetrospectivosRESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse event. Nutritional status can become impaired in cancer patients, potentially contributing to neuropathy's evolution. Our aim was to evaluate serum micronutrients and prealbumin in a cohort of 113 solid-cancer patients receiving platinum and taxane compounds during the development and recovery of neuropathy, up to 1 year after finishing treatment. CIPN was graded according to Total Neuropathy Score(©) and NCI.CTCv3 at T0 (baseline), T1 (1-3 months), and T12 (12 months) after chemotherapy. CIPN was classified as asymptomatic (< grade 2) or symptomatic (≥2). CIPN recovery was defined as ≥1 grade improvement at T12. Symptomatic CIPN developed in 52% of patients. Symptomatic patients presented a higher increase in TNSc (p < 0.001), in TNSr(©) (p < 0.001), and decrease in sural (p < 0.001) and radial nerve conduction (p < 0.001). No significant differences with any of the micronutrients were observed along T0-T1 period between severity or chemotherapy groups. By T12, symptomatic patients without recovery had a decrease in vitamin E levels (p = 0.019) and prealbumin (p = 0.062) compared with those symptomatic that improved. A correlation between the variation of vitamin E and prealbumin at T0-T1 (r = 0.626, p = 0.001) and T1-T12 (r = 0.411, p = 0.06) was observed. After chemotherapy treatment, the improvement of patients displaying symptomatic neuropathy is related to vitamin E and prealbumin serum levels. Our results suggest that nutritional status can play a role in CIPN recovery.
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Antineoplásicos/efectos adversos , Micronutrientes/sangre , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Prealbúmina/metabolismo , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND: To evaluate whether the addition of bevacizumab (BVZ) to capecitabine-based chemoradiotherapy in the preoperative treatment of locally advanced rectal cancer (LARC) improves efficacy measured by the pathological complete response (pCR) rate. METHODS: A phase II two-step design was performed. Patients received four cycles of therapy consisting of: BVZ 10 mg/kg in first infusion on day 1 and 5 mg/kg on days 15, 29, 43, capecitabine 1800 mg/m(2)/day 5 days per week during radiotherapy, which consisted of external-beam irradiation (45 Gy in 1.8 Gy dose per session over 5 sessions/week for 5 weeks). Six to eight weeks after completion of all therapies surgery was undergone. To profile the biological behaviour during BVZ treatment we measured molecular biomarkers before treatment, during BVZ monotherapy, and during and after combination therapy. Microvessel density (MVD) was measured after surgery. RESULTS: Forty-three patients were assessed and 41 were included in the study. Three patients achieved a pathological complete response (3/40: 7.5%) and 27 (67.5%) had a pathological partial response, (overall pathological response rate of 75%). A further 8 patients (20%) had stable disease, giving a disease control rate of 95%. Downstaging occurred in 31 (31/40: 77.5%) of the patients evaluated. This treatment resulted in an actuarial 4-year disease-free and overall survival of 85.4 and 92.7% respectively. BVZ with chemoradiotherapy showed acceptable toxicity. No correlations were observed between biomarker results and efficacy variables. CONCLUSION: BVZ with capecitabine and radiotherapy seem safe and active and produce promising survival results in LARC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00847119 . Trial registration date: February 18, 2009.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Capecitabina/administración & dosificación , Quimioradioterapia Adyuvante/métodos , Neoplasias del Recto/terapia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Capecitabina/uso terapéutico , Fraccionamiento de la Dosis de Radiación , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Neoplasias del Recto/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the behavior of 11 CXC chemokines in the blood of 104 mCRC patients undergoing first-line oxaliplatin-based treatment to pinpoint predictive and prognostic markers. Serum samples were collected before treatment, at response evaluation (EVAR), and at disease progression or last follow-up. Chemokines were assessed in all samples using a Luminex® custom panel. CXCL13 levels increased at EVAR in responders, while in non-responders it decreased. Increasing levels of CXCL13 at EVAR, independently correlated with improved progression-free survival (PFS) and overall survival (OS). Nanostring® analysis in primary tumor samples showed CXCL13 gene expression's positive correlation not only with gene profiles related to an immunogenic tumor microenvironment, increased B cells and T cells (mainly CD8+) but also with extended OS. In silico analysis using RNAseq data from liver metastases treated or not with neoadjuvant oxaliplatin-based combinations, and deconvolution analysis using the MCP-counter algorithm, confirmed CXCL13 gene expression's association with increased immune infiltration, improved OS, and Tertiary Lymphoid Structures (TLSs) gene signatures, especially in neoadjuvant-treated patients. CXCL13 analysis in serum from 36 oxaliplatin-treated patients from the METIMMOX study control arm, reported similar findings. In conclusion, the increase of CXCL13 levels in peripheral blood and its association with the formation of TLSs within the metastatic lesions, emerges as a potential biomarker indicative of the therapeutic efficacy in mCRC patients undergoing oxaliplatin-based treatment.
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Biomarcadores de Tumor , Quimiocina CXCL13 , Neoplasias Colorrectales , Oxaliplatino , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Oxaliplatino/uso terapéutico , Oxaliplatino/farmacología , Masculino , Quimiocina CXCL13/sangre , Femenino , Anciano , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Anciano de 80 o más Años , Supervivencia sin Progresión , Microambiente Tumoral , PronósticoRESUMEN
Cancer of unknown primary site (CUP) is defined as a heterogeneous group of tumors that appear as metastases, and of which standard diagnostic work-up fails to identify the origin. It is considered a separate entity with a specific biology, and nowadays molecular characteristics and the determination of actionable mutations may be important in a significant group of patients. In this guide, we summarize the diagnostic, therapeutic, and possible new developments in molecular medicine that may help us in the management of this unique disease entity.
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Neoplasias Primarias Desconocidas , Humanos , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/terapiaRESUMEN
INTRODUCTION: To date, we do not know the best therapeutic scheme in locally advanced rectal cancer when patients are older or have comorbidities. METHODS: In 2009, we established a prospective treatment protocol that included short-course preoperative radiotherapy (RT) with standard surgery +/- chemotherapy in frail patients, mostly older than 80 years or with comorbidities. RESULTS: We included 87 patients; the mean follow-up was 43.5 months (0.66-106.3). Disease-specific survival and disease-free survival at 36 months were 86.3% and 82.8%; at 60 months, they were 78.2% and 78%, respectively, with a local recurrence rate of 2.5%. The rate of late radiotoxicity was 9% in the form of sacral insufficiency fracture and small bowel obstruction with one death. The interval before surgery varied according to the involvement of the mesorectal fascia, but it was less than 2 weeks in 45% of cases. The rate of R0 was 95%. Surgical complications included abdominal wound dehiscence (3.5%), anastomotic leak (2.4%), and reoperations (11.5%). Downstaging was observed in 51% of the cases, regardless of the interval before surgery. DISCUSSION: Therapeutic outcomes in our group of elderly patients and/or patients with comorbidities with neoadjuvant short-course RT are such as those of the general population treated with neoadjuvant RT-chemotherapy, all with acceptable toxicity. Therefore, this treatment scheme, with short-course preoperative RT, would be the most appropriate in this group of patients.
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Adenocarcinoma/terapia , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/epidemiología , Radioterapia Conformacional , Neoplasias del Recto/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Comorbilidad , Supervivencia sin Enfermedad , Anciano Frágil , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Proctectomía , Estudios Prospectivos , Planificación de la Radioterapia Asistida por Computador , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Recto/diagnóstico por imagen , Recto/patología , Recto/efectos de la radiación , Recto/cirugía , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
INTRODUCTION: The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B). RESULTS: Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment. CONCLUSIONS: In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC.
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Antineoplásicos/uso terapéutico , Axitinib/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Quimioterapia de Mantención/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/mortalidad , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Supervivencia sin ProgresiónRESUMEN
An LV infuser consists of an infusion pump which can administer medicines via various methods: intravenous, epidural, subdural, o subcutaneous. Its usefulness is based on the administration of medicines such as oncological drugs and/or analgesic by means of a continuous infusion.
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Analgesia Controlada por el Paciente/instrumentación , Elastómeros , Prótesis de la Rodilla , Diseño de Equipo , Humanos , Consentimiento InformadoRESUMEN
BACKGROUND: To assess if surgical manipulation increases peripheral blood cancer cells dissemination in early stage (I and II) breast cancer patients. PATIENTS AND METHODS: We analyzed 64 patients using RT-PCR for cytokeratin-19 as a marker for peripheral blood breast cancer cell dissemination. Peripheral blood was obtained at 4 different time-points (24 hours before and after surgery, one week and one month later). RESULTS: RT-PCR was positive in 14 (24%) out of 59 evaluable patients. Circulating cells were detected in 4 out of 14 patients before surgery (7%) while in the remaining 10, the positivity was observed after surgery (17%). The percentage of patients with occult breast cancer cells increased significantly after surgery (p = 0.01). CONCLUSION: 1) 7% of early breast cancer patients had circulating tumor cells before surgery. 2) After surgery tumor cells were detected in 17% of patients. 3) Surgery significantly increased the presence of occult breast cancer cells. 4) The clinical significance of occult breast cancer cells should be tested within a larger clinical trial trying to assess their role as an independent prognostic factor.
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Neoplasias de la Mama/sangre , Neoplasias de la Mama/cirugía , Queratinas/genética , Siembra Neoplásica , Células Neoplásicas Circulantes/metabolismo , ARN Mensajero/sangre , Procedimientos Quirúrgicos Operativos/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Humanos , Queratinas/sangre , Persona de Mediana Edad , Estadificación de Neoplasias , Células Neoplásicas Circulantes/patología , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
PURPOSE: This study analyzes the results of a follow-up policy in colorectal cancer at our institution and evaluates the possible benefit provided by each test performed. PATIENTS AND METHODS: Six hundred nineteen patients who had radical surgery and adjuvant treatment for colorectal cancer were followed up with a protocol that included carcinoembryonic antigen testing and clinical examination every three months for the first two years, every four months in the third year, and every six months in the fourth and fifth years. Chest X-ray and colonoscopy were performed yearly for five years and abdominal ultrasound was done every six months for the first three years and yearly afterward. Abdominopelvic computerized tomography was performed yearly for the first two years in cases with rectal cancer. If relapse was detected, all operable cases underwent surgery if possible. RESULTS: Between 1993 and 1999, 619 patients were followed-up. Mean follow-up was 66.9 months. Two hundred eight relapses were detected, 83.6 percent in the first three years and 73 (35.1 percent) underwent surgical resection. Carcinoembryonic antigen testing detected 44.2 percent of recurrences and 31.9 percent of them were operated on. Imaging techniques detected a lower percentage of recurrences (18.7 percent) but were more often resectable: 52 percent and 60 percent of the recurrences detected by computerized tomography and chest X-ray, respectively, underwent surgery. Median overall survival of patients with resected relapse was 62 months, significantly higher than those who were not operable (12.4 months). CONCLUSION: Imaging techniques in the surveillance of resected colorectal cancer contribute to early detection of relapse with a high proportion of operable metastatic disease.