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BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
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OBJECTIVES: Hearing voices is a common experience for people with schizophrenia. Perceived voices are in most cases a source of great distress for patients. This experience also exists in the general population and is considered as "non-clinical". Much research has focused on the psychological and neuropsychological mechanisms behind the emergence of voices. With regard to voice persistence factors, the acceptance of the voice-hearing phenomenon is still relatively unexplored. In addition, there are few standardized tools that specifically assess this dimension of voice experience. The Voices Acceptance and Actions Scale (VAAS) is the only validated tool to address voice acceptance in individuals with schizophrenia. However, to date, there is no French version. The objective of this research was to validate the VAAS in a French speaking population. METHOD: Our sample consisted of individuals with schizophrenia (N=65) and voice hearers from the general population (N=321). For the clinical population, individuals with schizophrenia and auditory hallucinations were assessed using the VAAS scale in its two abbreviated versions (9 and 12 items). In order to validate the measure in French, we administered psychopathology scales (BPRS) and voice belief scales (BAVQ-R) for convergent and divergent validity. For the non-clinical population, we administered the VAAS scale online (via LimeSurvey), accompanied by a brief sociodemographic questionnaire (age, sex, country of origin, existence of medical or psychological follow-up). RESULTS: The psychometric properties of the VAAS scale were satisfactory and similar to the original English-language tool for both versions, with a slight advantage for the one with 9-items. The convergent validity measured with the BAVQ-R scale, and the divergent one measured with the BPRS depression subscale, were found to be satisfactory. In addition, the re-test performed 6 weeks after the first test (N=30) was satisfactory for both scales, with a Pearson correlation index greater than 70 (r=0.70; P<0.001 for the VAAS 9 items) and (r=0.79; P<0.001 for the 12 item version). In individuals with schizophrenia (clinical population), the level of voice acceptance was low and strongly correlated with depression. This point seems to corroborate the current data in the field suggesting that voice hearing in this population is associated with significant distress and has a significant impact on their lives. Conversely, the level of acceptance obtained from the non-clinical population was much higher, reflecting a higher level of acceptance in this population. People from the non-clinical population seemed to accept and experience their voices with less distress than people from the clinical population in this study. CONCLUSION: To date, a paucity of studies have investigated the acceptance of auditory hallucinations. Our results support the psychometric validity of the French version of the VAAS, particularly the 9-item version. Furthermore, our study supports the need to continue studying voice acceptance, as it appears to be strongly linked to depression in people with psychiatric disorders such as schizophrenia. In addition, our study is novel in that it also explored, with a standardized tool, the level of voice acceptance in a non-clinical population and found people to be more accepting of the voices they hear and better at living with them. These data provide new evidence to better understand the links between the level of acceptance of voices, their experiences, and depression. Clinically, it seems essential to conduct more systematic and regular evaluations of the level of voice acceptance in those hearing voices. Finally, in terms of rehabilitation, voice acceptance can become a therapeutic target in order to improve the psychological and behavioral functioning of the person.
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Transtornos Mentais , Esquizofrenia , Alucinações/diagnóstico , Humanos , Psicometria , Esquizofrenia/diagnóstico , Inquéritos e QuestionáriosRESUMO
Background: Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population. Patients and methods: Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator's choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria. Results: About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75-91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT). Conclusion: Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Taxa de SobrevidaRESUMO
Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656.
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Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Neoplasias Colorretais/sangue , Neoplasias Hepáticas/sangue , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA/métodos , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto JovemRESUMO
BACKGROUND: Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients. PATIENTS AND METHODS: Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR). RESULTS: From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%). CONCLUSION: In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2. CLINICALTRIALSGOV: NCT00303771.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Análise Multivariada , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
A total of 350 samples were analyzed to estimate zebu gene proportions into two different taurine cattle breeds of Burkina Faso (Lobi and N'Dama) using 38 microsatellites and various statistical methodologies. West African and East African zebu samples were sequentially used as reference parental populations. Furthermore, N'Dama cattle from Congo, the composite South African Bonsmara cattle breed and a pool of European cattle were used successively as second parental populations. Independently of the methodology applied: (a) the use of West African zebu samples gave higher admixture coefficients than the East African zebu; (b) the higher zebu proportions were estimated when the European cattle was used as parental population 2; and (c) the use of the N'Dama population from Congo as parental population 2 gave the more consistent zebu proportion estimates for both the Lobi and the N'Dama breeds. In any case, the zebu admixture proportions estimated were not negligible and were always higher in the N'Dama cattle than in the Lobi cattle of Burkina Faso. This suggested that the introgression of Sahelian zebu genes into the taurine cattle of Southern West Africa can follow a complex pattern that can depend on local agro-ecological features. The current research pointed out that the estimation of admixture coefficients is highly dependent on both the assumptions underlying the methodologies applied and the selection of parental populations. Our analyses suggest that either too high or nil genetic identity between the parental and the expectedly derived populations must be avoided.
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Cruzamento , Bovinos/genética , Repetições de Microssatélites/genética , Seleção Genética , Animais , Burkina Faso , Doenças dos Bovinos/genéticaRESUMO
INTRODUCTION: Supported employment programs are highly effective in helping people with severe mental illness obtain competitive jobs quickly. However, job tenure is often a problem for many. Of the various obstacles to job tenure documented, dysfunctional beliefs regarding the workplace and one's own abilities has been proposed as a therapeutic target. OBJECTIVES: The purpose of this article is threefold: (1) to describe the development and the content of a novel group cognitive behavioral intervention designed to increase job tenure for people receiving supported employment services; (2) to present the feasibility and acceptability of the intervention; and (3) to investigate some preliminary data regarding employment outcomes. A group CBT intervention offered during 8 sessions over the course of one month, in order to respect the rapid job search principle of IPS (individual placement and support), was developed. The content was tailored to facilitate the learning of skills specific to the workplace, such as recognizing and managing one's stressors at work, determining and modifying dysfunctional thoughts (e.g. not jumping to conclusions, finding alternatives, seeking facts), overcoming obstacles (e.g. problem solving), improving one's self-esteem as a worker (recognizing strengths and qualities), dealing with criticism, using positive assertiveness, finding coping strategies (for symptoms and stress) to use at work, negotiating work accommodations and overcoming stigma. A trial is currently underway, with half the participants receiving supported employment as well as CBT-SE and the other half receiving only supported employment. METHODS: A subsample of the first 24 participants having completed the 12-month follow-up were used for the analyses, including 12 having received at least 3 sessions out of the 8 group sessions and 12 receiving only supported employment. Feasibility and acceptability were determined by the group therapists' feedback, the participants' feedback as well as attendance to group sessions. The work outcomes looked at with the preliminary sample only included the 12-month follow-up and involved: obtaining a competitive job, number of hours worked per week as well as number of weeks worked at the same job (>24hours). RESULTS: In terms of feasibility and acceptability, therapists and participants all mentioned appreciating the group, finding it useful and helpful, some even mentioning feeling grateful to have had the opportunity to receive the intervention. The only negative feedback received pertained to the frequency of the meetings, which could be brought down to one meeting per week of two hours instead of two one-hour sessions per week. Participation was very good, with the average number of sessions attended being of 6/8. In terms of work outcomes, 50 % of all participants in both conditions found competitive work. Out of those working competitively, the number of participants working more than 24hours per week at the 12-month follow-up was higher in the CBT-SE group compared to the control condition (75 % vs. 50 %). Similarly, there was a trend towards the number of consecutive weeks worked at the same job being slightly superior at the 12-month follow-up for those who had received the CBT-SE intervention (22.5 weeks vs. 18.3 weeks). DISCUSSION: The preliminary results support previous studies where on average 50 % of people registered in supported employment programs obtain competitive work. We confirmed that the intervention was feasible and acceptable. Preliminary data suggest that the CBT-SE intervention might help people with severe mental illness use skills and gain the needed confidence enabling them to work longer hours and consecutive weeks. These results should be considered with caution given that only 24 participants were looked at whereas the final sample size will be of 160 participants. Nonetheless, these preliminary results are promising. Furthermore, additional information regarding the impact of the CBT-SE intervention on the capacity to overcome obstacles at work, self-esteem as a worker, as well as other work-related variables have been collected but have not been investigated here. Once the study is completed, the results should enlighten us regarding the usefulness of offering CBT-SE not only in terms of work outcomes but also in improving various psychosocial domains linked to workplace satisfaction.
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Terapia Cognitivo-Comportamental/métodos , Readaptação ao Emprego , Transtornos Mentais/reabilitação , Psicoterapia de Grupo/métodos , Adulto , Terapia Combinada , Estudos de Viabilidade , Seguimentos , Esperança , Humanos , Transtornos Mentais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde , Quebeque , Ajustamento Social , Responsabilidade Social , Avaliação da Capacidade de TrabalhoRESUMO
BACKGROUND: Prior trials validated triplet chemotherapy (Tri-CT) with bevacizumab as first line treatment for metastatic colorectal cancer (mCRC) but real-world data are scarce and practices remain heterogeneous. AIMS: To evaluate Tri-CT +/- bevacizumab efficacy and safety, and to identify factors influencing treatment decisions. METHODS: The COLOTRIP retrospective study enrolled mCRC patients treated from 2014 to 2019 in 14 French centers. RESULTS: Of 299 patients (81% PS 0-1, 58% RAS-mutated and 19% BRAF-mutated), 51% received Tri-CT and 49% Tri-CT + bevacizumab. Metastatic disease was classified as resectable (6.5%), potentially resectable (40%), and unresectable (54%). Bevacizumab use was associated with primary tumor location, mutational status and number of metastases. Median overall survival was 33.5 months in the Tri-CT group and 23.9 months in the Tri-CT + bevacizumab group, with median progression-free survival being 14.5 and 11.4 months. After adjusting for initial characteristics, no difference in survival was noted. Around 30% of patients experienced grade ≥3 adverse events. CONCLUSIONS: This study highlights several factors influencing Tri-CT use +/- bevacizumab decision and confirms the real-world good oncological outcomes and tolerability of these regimens in mCRC patients. Our results suggest that Tri-CT alone may by an appropriate option for specific subgroups of patients.
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BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. METHODS: Expression of HER2, ß-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. RESULTS: We obtained samples from 63 SBA patients (tumour stages: I-II: 30%; III: 35%; IV: 32%; locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of ß-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9-72.2). For all patients, in univariate analysis, stages I-II (P<0.001), WHO PS 0-1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0-1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0-1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS. CONCLUSION: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.
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Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/metabolismo , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Idoso , Anticorpos Monoclonais/imunologia , Sequência de Bases , Biomarcadores Tumorais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Receptores ErbB/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Análise de Sequência de DNARESUMO
Irinotecan is a powerful anticancer drug with severe systemic side effects that limit its clinical application. Drug-targeted delivery with noninvasive methods is required to enhance the drug concentration locally and to reduce these undesirable events. Microbubble-assisted ultrasound has become a promising method for noninvasive targeted drug delivery. The aim of this study is to evaluate the therapeutic effectiveness of in vitro and in vivo irinotecan delivery based on the combination of ultrasound and microbubbles. In the present study, in vitro results showed that the irinotecan treatment with microbubble-assisted ultrasound induced a significant decrease in cell viability of human glioblastoma cells. Moreover, using subcutaneous glioblastoma xenografts, the in vivo preclinical study in nude mice demonstrated that this therapeutic protocol led to a decrease in tumor growth and perfusion and an increase of tumor necrosis. The conclusions drawn from this study demonstrate the promising potential of this therapeutic approach for the anticancer targeted therapy.
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Camptotecina/análogos & derivados , Microbolhas , Ultrassom , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Humanos , Irinotecano , Masculino , Camundongos NusRESUMO
BACKGROUND: Precision medicine trials disrupted the paradigm of randomized controlled trials in large populations. Patient selection may be based on molecular alterations rather than on primary tumor location. In small patient populations, the growth modulation index (GMI) has been developed to evaluate treatment efficacy by using each patient as its own control. The FFCD 0307 randomized phase III trial compared two sequences of chemotherapy in advanced gastric cancer, which represents a unique opportunity to evaluate the relevance of the GMI. PATIENTS AND METHODS: In the FFCD 0307 trial, patients with advanced gastric cancer were randomized between two chemotherapy sequences [ECX followed by FOLFIRI at disease progression (arm A) versus FOLFIRI followed by ECX (arm B)]. GMI was defined as the ratio of the progression-free survival on second treatment (PFS2) to the time to progression on first treatment (TTP1). Sequence benefit was defined as a GMI exceeding 1.3 (GMI-high). GMI was correlated with overall survival (OS). OS1 and OS2 were measured from first randomization and second-line failure to death. RESULTS: Four hundred and sixteen patients were randomized (209 in arm A, 207 in arm B). One hundred and seventy-five patients (42%) received the two sequences and were assessable for GMI (97 in arm A, 79 in arm B). The median GMI was higher in arm A than in arm B (0.62 versus 0.47, P = 0.04). Patients with a high GMI had a longer OS1 (median 14.9 versus 11.5 months, NS). Median OS2 was doubled in the GMI-high group (3.4 versus 1.6 months, NS). CONCLUSION: GMI analyses suggest that ECX followed by FOLFIRI might represent a better therapeutic strategy than FOLFIRI followed by ECX. High GMI was associated with prolonged survival.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Although malnutrition is known to be frequent in cancer patients, it has not been described in a selected population of patients with gastrointestinal malignancies under chemotherapy only. Physician judgment about malnutrition and risk factors for malnutrition were also evaluated. All consecutive in- and outpatients of 11 centers were prospectively enrolled in a cross-sectional 14-day period study and classified according to the French health recommendations [Haute Autorité de Santé (HAS)]. Among 313 patients enrolled in 11 centers (mean age = 63 yr; range = 21-93; 67% male) mainly with colorectal (58%), pancreatic (15%), gastric (11%), and hepatobiliary (10%) primary tumors, the prevalence of malnutrition was 52%. Moderate and severe malnutrition was present in 27% and 25% of cases, respectively. Physicians considered it in 36% and 6% of cases, respectively, thereby misclassifying 134 patients (43%). The agreement between the HAS definition and the physicians' judgment was very low (κ = 0.30). Most of the patients who were identified as severely malnourished received no nutritional support. Performance status and pancreatic and gastric cancers were independently associated with malnutrition. Malnutrition levels are high, around 50%, unequally distributed according to the primitive tumor. It is still underestimated by physicians. Weight loss remains a clinically relevant, simple, and reliable marker of malnutrition.
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Neoplasias Gastrointestinais/epidemiologia , Desnutrição/epidemiologia , Estado Nutricional , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Neoplasias Gastrointestinais/fisiopatologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Avaliação Nutricional , Apoio Nutricional/métodos , Pacientes Ambulatoriais , Prevalência , Estudos Prospectivos , Fatores de Risco , Redução de Peso , Adulto JovemRESUMO
"The Accept Voices© is a useful intervention for the management and acceptance of auditory verbal hallucinations in people with schizophrenia. This study aims at determining if the clinical effects remained at six- and 12-month follow-ups. Results show that participants (N = 22) maintained a decrease in auditory hallucinations, at the six and 12 months follow ups for severity and acceptance of Voices, anxiety and depression. Accept Voices© shows promise as a potential treatment for people with schizophrenia struggling with Voices.
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Esquizofrenia , Voz , Humanos , Psicologia do Esquizofrênico , Alucinações/etiologia , Alucinações/terapia , Esquizofrenia/complicações , Esquizofrenia/terapia , Ansiedade/terapiaRESUMO
BACKGROUND: Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce. PATIENTS AND METHODS: All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study. RESULTS: Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX. CONCLUSIONS: This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Duodenais/tratamento farmacológico , Neoplasias do Íleo/tratamento farmacológico , Neoplasias do Jejuno/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cisplatino/administração & dosagem , Neoplasias Duodenais/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Neoplasias do Íleo/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Irinotecano , Neoplasias do Jejuno/patologia , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Peritoneais/secundário , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Cancer is characterized by multiple somatic genetic and epigenetic alterations that could be useful as molecular markers for detecting tumor DNA in different bodily fluids. In patients with various diseases as well as in healthy subjects, circulating plasma and serum carry small amounts of non-cell-bound DNA. In this free circulating DNA, tumor-associated molecular alterations can be detected in patients who have cancer. In many instances, the alterations identified are the same as those found in the primary tumor tissue, thereby suggesting tumor origin from a fraction of the circulating free DNA. In fact, various types of DNA alterations described in colorectal cancer have been detected in the circulating free DNA of patients with colorectal cancer. These alterations include KRAS2, APC and TP53 mutations, DNA hypermethylation, microsatellite instability (MSI) and loss of heterozygosity (LOH). Also, advances in polymerase chain reaction (PCR)-based technology now allow the detection and quantification of extremely small amounts of tumor-derived circulating free DNA in colorectal cancer patients. The present report summarizes the literature available so far on the mechanisms of circulating free DNA, and on the studies aimed at assessing the clinical and biological significance of tumor-derived circulating free DNA in colorectal cancer patients. Thus, tumor-derived circulating free DNA could serve as a marker for the diagnosis, prognosis and early detection of recurrence, thereby significantly improving the monitoring of colorectal cancer patients.
Assuntos
Neoplasias Colorretais/sangue , DNA de Neoplasias/sangue , Biomarcadores/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Genes Supressores de Tumor , Humanos , Mutação , Oncogenes/genética , Valor Preditivo dos Testes , PrognósticoRESUMO
AIM OF THE STUDY: The objective of this study was to evaluate the potential impact of a third wave CBT group intervention for the management of auditory hallucinations in patients with schizophrenia. METHOD: 38 patients with schizophrenia presenting with auditory hallucinations, followed in mental health services, participated in six sessions of a group based on acceptance and engagement therapy (ACT). The study followed a repeated single case experimental design (type A-B-A) based on the principle of a control phase followed by an intervention phase and a follow-up phase of similar duration. The various measurements were administered during the control phase, at pre-/post-group and six weeks after the last group session. RESULTS: The results show a significant decrease in auditory hallucinations, as measured by the PSYRATS scale, during the treatment and follow-up phase, compared to the control phase. In addition, the participants saw significant reductions in depressive and anxious symptomatology (assessed with CDSS and SEAS), and increases in coping and acceptance in regards to voices (assessed using a study scale and VAAS). The level of Malevolence beliefs about voices (measured with BAVQ-R) also decreased significantly. CONCLUSIONS: A brief group intervention based acceptance show promise in the reduction of the intensity of auditory hallucinations, depression and anxiety in patients with schizophrenia, while improving their acceptance.
Assuntos
Terapia Cognitivo-Comportamental/métodos , Gerenciamento Clínico , Alucinações/psicologia , Alucinações/terapia , Esquizofrenia/terapia , Psicologia do Esquizofrênico , Adaptação Psicológica/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicoterapia de Grupo/métodos , Inquéritos e QuestionáriosRESUMO
The prevalence, clinical profiles and management of gastroenteropancreatic endocrine tumours (GEP) in France are not known. From August 1, 2001 to September 1, 2002, standardized records on patients with GEP were prospectively completed in 87 participating centres. The total group amounted to 668 patients (median age: 56 years, range: 12-89). WHO performance status was 0/1 for 80.2% of patients. The primary sites were the small bowel and colon (288), pancreas (211), unknown (77), stomach (33), non-digestive primary sites (24), appendix (20), rectum-anus (12), and oesophagus or cardia (3). GEP were functional in 260 patients (39%). Most pancreatic tumours were non-functional (72%). Metastatic disease was observed in 73.4% of cases. Most tumours (85.8%) were well or moderately differentiated. Somatostatin receptor scintigraphy was performed in only 55% of patients. The following treatment modalities were employed: resection of primary tumour: 66%; systemic chemotherapy: 41%; somatostatin analogues: 44 and 26% for GEP of small intestine and pancreas, respectively; interferon: 12%, and intra-arterial hepatic (chemo)embolization in 23 and 15% of GEP arising from the midgut and pancreas, respectively. Despite their low prevalence, well-differentiated GEP represent a significant and heterogeneous clinical group, which warrants improved medical education, referral to expert centres at an early stage, and the design of prospective therapeutic trials.
Assuntos
Neoplasias Gastrointestinais/epidemiologia , Tumores Neuroendócrinos/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , França , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/terapia , Cintilografia , Fatores de TempoRESUMO
BACKGROUND: Individuals with psychosis are known to have a lower self-esteem compared to the general population, in part because of social stigma, paternalistic care, long periods of institutionalization and negative family interactions. This study aimed at assessing the efficacy of a self-esteem enhancement program for individuals with severe mental illness and at analyzing the results in their European context. METHOD: A randomized cross-over study including 54 outpatients with a diagnosis of schizophrenia from Geneva, Switzerland, was conducted. Twenty-four were recruited from an outpatient facility receiving traditional psychiatric care whereas 30 came from an outpatient facility with case-management care. Psychosocial, diagnostic and symptom measures were taken for all the subjects before treatment, after treatment, and at 3-months' follow-up. RESULTS: Results indicated significant positive self-esteem module effects on self-esteem, self-assertion, active coping strategies and symptom for the participants receiving case-management care. Results were not significant for those receiving traditional care. However, 71% of all participants expressed satisfaction with the module. CONCLUSION: Individuals with schizophrenia appear to be benefit from the effects of the self-esteem module, particularly when they are involved in a rehabilitation program and followed by a case manager who liaises with the other partners of the multidisciplinary team. This encourages reconsidering the interventions' format and setting in order to ensure lasting effects on the environment and in turn on coping, self-esteem and overall empowerment.