RESUMO
BACKGROUND: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. METHODS: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. FINDINGS: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). INTERPRETATION: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. FUNDING: Roche and Amgen.
Assuntos
Neoplasias Colorretais , Hipertensão , Neoplasias Hepáticas , Neutropenia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Bevacizumab , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico , Panitumumabe/uso terapêutico , Leucovorina , Proteínas Proto-Oncogênicas B-raf/genética , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fluoruracila , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Hipertensão/induzido quimicamente , Neutropenia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. METHODS: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified. RESULTS: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD -0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10-14.49; miR-194-5p OR 0.91, 95% CI 0.83-0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Irinotecano/administração & dosagem , Irinotecano/farmacologia , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Estudos ProspectivosRESUMO
AIMS: Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main metabolizing enzyme of docetaxel in the liver, a potential drug-drug interaction may occur. In this prospective randomized pharmacokinetic cross-over study we investigated docetaxel exposure with concomitant prednisone, compared to docetaxel monotherapy in men with metastatic prostate cancer. METHODS: Patients scheduled to receive at least 6 cycles of docetaxel (75 mg/m2 ) and who gave written informed consent were randomized to receive either the 1st 3 cycles, or the last 3 consecutive cycles with prednisone (twice daily 5 mg). Pharmacokinetic blood sampling was performed during cycle 3 and cycle 6. Primary endpoint was difference in docetaxel exposure, calculated as area under the curve (AUC0-inf ) and analysed by means of a linear mixed model. Given the cross-over design the study was powered on 18 patients to answer the primary, pharmacokinetic, endpoint. RESULTS: Eighteen evaluable patients were included in the trial. Docetaxel concentration with concomitant prednisone (AUC0-inf 2784 ng*h/mL, 95% confidence interval 2436-3183 ng*h/mL) was similar to the concentration of docetaxel monotherapy (AUC0-inf 2647 ng*h/mL, 95% confidence interval 2377-2949 ng*h/mL). Exploratory analysis showed no toxicity differences between docetaxel monotherapy and docetaxel cycles with prednisone. CONCLUSION: No significant difference in docetaxel concentrations was observed. In addition, we found similar toxicity profiles in absence and presence of prednisone. Therefore, from a pharmacokinetic point of view, docetaxel may be administrated with or without prednisone.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Docetaxel/farmacologia , Prednisona/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/uso terapêutico , Docetaxel/uso terapêutico , Interações Medicamentosas , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
Tivozanib hydrochloride monohydrate (tivozanib; formerly KRN-951, AV-951) is a potent pan-VEGF receptor tyrosine kinase inhibitor. The biological activity of tivozanib seems to outstand that of other VEGF tyrosine kinase inhibitors. In Phase I studies, observed side effects are generally mild, with hypertension being the most common adverse event. In single-agent Phase II and III studies in patients with advanced or metastatic renal cell carcinoma, tivozanib has demonstrated convincing clinical activity. Further clinical trials of tivozanib combined with various cytotoxic drug regimens as well as other classes of target-specific anticancer agents (e.g., mTOR inhibitors) for other indications are underway. Tivozanib has not yet been approved for regular use.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Quinolinas/química , Quinolinas/farmacologiaRESUMO
We present a 77-year-old woman with suspicion of hepatogenic and lymphogenic metastatic coloncarcinoma who developed a rapidly expanding subcutanaeous emphysema and hematoma formation. Computerized tomography (CT) pelvis with contrast revealed extensive free air in abdomen and leg compatible with fasciitsnecroticans. Blood cultures came out positive for Clostridium septicum. Despite intravenous antibiotics her condition deteriorated rapidly and she passed away.
Assuntos
Enfisema , Enfisema Pulmonar , Feminino , Humanos , Idoso , Dor Abdominal/etiologia , Abdome , Tomografia Computadorizada por Raios X , Enfisema/diagnóstico por imagemRESUMO
Multiple prognostic biomarkers, including circulating tumour cell (CTC) counts, exist in metastatic castration-resistant prostate cancer (mCRPC) patients, but none of them have been implemented into daily clinical care. The modified fast aneuploidy screening test-sequencing system (mFast-SeqS), which yields a genome-wide aneuploidy score, is able to reflect the fraction of cell-free tumour DNA (ctDNA) within cell-free DNA (cfDNA) and may be a promising biomarker in mCRPC. In this study, we investigated the prognostic value of dichotomized aneuploidy scores (< 5 vs. ≥ 5) as well as CTC counts (< 5 vs. ≥ 5) in 131 mCRPC patients prior to treatment with cabazitaxel. We validated our findings in an independent cohort of 50 similarly treated mCRPC patients. We observed that, similar to the dichotomized CTC count [HR: 2.92; 95% confidence interval (CI);1.84-4.62], dichotomized aneuploidy scores (HR: 3.24; CI: 2.12-4.94) significantly correlated with overall survival in mCRPC patients. We conclude that a dichotomized aneuploidy score from cfDNA is a prognostic marker for survival in mCRPC patients within our discovery cohort and in an independent mCRPC validation cohort. Therefore, this easy and robust minimally-invasive assay can be readily implemented as a prognostic marker in mCRPC. A dichotomized aneuploidy score might also be used as a stratification factor in clinical studies to account for tumour load.
Assuntos
DNA Tumoral Circulante , Células Neoplásicas Circulantes , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Prognóstico , Biomarcadores Tumorais/genética , Células Neoplásicas Circulantes/patologia , DNA Tumoral Circulante/genética , AneuploidiaRESUMO
BACKGROUND: The number of people with cancer will increase in the Netherlands. Further concentration and network care is pursued. The aim of this study was to explore how long medical oncology patients are willing to travel for their cancer care. METHOD: A flashmob study into patients' willingness to travel for cancer care was conducted in 65 Dutch hospitals. Patients completed a questionnaire about willingness to travel and any experienced issues with traveling. RESULTS: A total of 4337 medical oncology patients completed the questionnaire. Of the patients, 20% were willing to travel more than 1 hour (one-way) for their current treatment, and more willing to travel for treatment in a hospital more experienced in their specific type of cancer (44% more than 1 hour). Willingness to travel longer was higher among patientsagedv40 years or younger, those with higher education, with better physical functioning and with a rare cancer. Willingness to travel longer was lowest among patients aged 75 or older. Approximately 30% of all patients experienced issues with traveling, especially those with comorbidities or with decreased physical functioning. CONCLUSION: In this flashmob study, 15% of patients were willing to travel up to 30 minutes (one-way) and 44% more than 1 hour for treatment and follow-up in a hospital more experienced in their specific type of cancer. Patients aged 75 years or older were less willing to travel longer. Thirty percent of patients experienced issues with travelling. It is important to take this into account in the future organization of cancer care.
Assuntos
Oncologia , Neoplasias , Humanos , Países Baixos , Neoplasias/terapia , Pacientes , EtnicidadeRESUMO
Background: FOLFIRINOX chemotherapy is the current Dutch standard of care for locally advanced (LAPC) and metastatic pancreatic cancer (PDAC) patients with good performance status. The objective of this study was to evaluate real-world response rates and survival in advanced PDAC and to assess conditional survival after FOLFIRINOX. Methods: A multicenter, retrospective cohort study was conducted in four hospitals in the Netherlands. Consecutive patients with LAPC or metastatic PDAC, treated with FOLFIRINOX, were included. Results: Between 2012 and 2018, 284 patients were included: n = 136 with LAPC and n = 148 with metastatic PDAC. Objective response rates were similar in both the groups: 14.0% in LAPC and 18.2% in metastatic patients. The disease control rate was higher in LAPC patients (77.2%) compared to metastatic PDAC (51.4%, P < 0.001). Median overall survival (OS) in LAPC patients was 12.7 months (95% CI 11.4-14.1 months). Their 2-year survival probability increased from 14% to 26% one year after the completion of FOLFIRINOX. Median OS in metastatic PDAC patients was 8.1 months (95% CI 6.5-9.6 months); 2-year survival probability increased from 10% to 29% after one year. Discussion. Our study provides real-world estimates of response rates, survival, and conditional survival in patients with advanced PDAC treated with FOLFIRINOX. These results are useful for patient counseling and clinical decision making.
RESUMO
Background: Biomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS). Methods: Serum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (n=83) of all disease stages. Overall, 34 circulating cytokines were analyzed with a multiplex immunoassay. In addition, changes in peripheral blood immune cell counts were determined by flow cytometry to correlate with differences in cytokine levels. Chemotherapy response was determined by CT scans with the RECIST 1.1 criteria, as disease control (n=64) or progressive disease (n=19) within eight cycles of FOLFIRINOX. Results: Patients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25, P=0.040). Increase of circulating IL-1RA concentrations correlated with increase of total, classical (CD14+CD16-), and non-classical monocytes (CD14-CD16+), and dendritic cells. In multivariable cox regression, including the variables chemotherapy response outcome and baseline CA19-9 level, serum concentrations of IL-7 (HR 2.14, P=0.010), IL-18 (HR 2.00, P=0.020), and MIP-1ß (HR 0.51, P=0.025) after one cycle of FOLFIRINOX showed correlations with OS. Conclusions: Circulating IL-1RA, IL-7, IL-18, and MIP-1ß concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Quimiocina CCL4 , Citocinas/uso terapêutico , Fluoruracila , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-18 , Interleucina-7 , Irinotecano , Leucovorina , Oxaliplatina , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients with positive AR-V7 expression in their circulating tumour cells (CTCs) rarely derive benefit from abiraterone and enzalutamide. DESIGN: We performed a prospective, multicenter, single arm phase II clinical trial (CABA-V7) in mCRPC patients previously treated with docetaxel and androgen deprivation therapy. OBJECTIVE: In this trial, we investigated whether cabazitaxel treatment resulted in clinically meaningful PSA response rates in patients with positive CTC-based AR-V7 expression and collected liquid biopsies for genomic profiling. RESULTS: Cabazitaxel was found to be modestly effective, with only 12% of these patients obtaining a PSA response. Genomic profiling revealed that CTC-based AR-V7 expression was not associated with other known mCRPC-associated alterations. CTC-based AR-V7 status and dichotomised CTC counts were observed as independent prognostic markers at baseline. CONCLUSIONS: AR-V7 positivity predicted poor overall survival (OS). However, cabazitaxel-treated AR-V7 positive patients and those lacking AR-V7 positivity, who received cabazitaxel as standard of care, appeared to have similar OS. Therefore, despite the low response rate, cabazitaxel may still be an effective treatment in this poor prognosis, AR-V7 positive patient population.
Assuntos
Células Neoplásicas Circulantes , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/uso terapêutico , Isoformas de Proteínas/genética , Células Neoplásicas Circulantes/patologia , Nitrilas/uso terapêuticoRESUMO
BACKGROUND: Adult-type hypolactasia is caused by genetic lactase non-persistence. It is the most common cause of lactose intolerance, which results in gastrointestinal symptoms after ingestion of dairy products. Currently, lactose intolerance is investigated by the hydrogen breath test (HBT), which is considered the preferred diagnostic test. Adult-type hypolactasia may also be diagnosed by genotyping. The single nucleotide polymorphism -13910C>T, which is located upstream of the lactase gene (LCT), is tightly associated with lactase persistence. Several other variants, mostly in non-European populations, can also lead to lactase persistence. This study investigated the accuracy of a modified, recently proposed algorithm which includes genotyping for the diagnosis of adult-type hypolactasia in a patient population with unexplained abdominal complaints. METHODS: In 126 patients with unexplained abdominal symptoms or who were suspected to have adult-type hypolactasia, LCT genotyping by melting curve analysis on a LightCycler was performed. Those patients with CC(-13910) genotype (indicating loss of lactase expression) were directly referred to a dietician for a lactose-free diet. Those identified as CT(-13910) or TT(-13910) genotype underwent a HBT. Those who tested positive for hydrogen were also referred to a dietician for a lactose-free diet. The response to diet modification was recorded. RESULTS: Genotype prevalences were: CC(-13910): 43 (34.1%); CT(-13910): 48 (38.1%); TT(-13910): 33 (26.2%); TG-13915: 2 (1.6%). Eleven of 48 (23%) patients with CT(-13910)-genotype and 1/33 (3%) patients with TT(-13910)-genotype had a positive hydrogen breath test. They all improved after a lactose-free diet. Four of 43 (9%) patients with CC(-13910)-genotype still had symptoms after a lactose-free diet. CONCLUSIONS: The results show that lactase-genotype testing can be used as a first step to diagnose lactose intolerance in a patient population with unexplained abdominal complaints. It accurately identifies the group of patients sensitive to lactose, those who need further breath testing and those in whom adult-type hypolactasia can be excluded with high probability without performing a HBT. This algorithm would save hydrogen breath testing in more than 50% of the patients who present with unexplained abdominal symptoms.
Assuntos
Dor Abdominal/etiologia , Intolerância à Lactose/complicações , Intolerância à Lactose/diagnóstico , Adulto , Genótipo , Humanos , Intolerância à Lactose/genética , Intolerância à Lactose/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). METHODS: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control (n = 30) or progressive disease (n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. RESULTS: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40-79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31-37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6-6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6-17.4 months). CONCLUSION: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
RESUMO
BACKGROUND: We conducted a multicentre phase II trial to investigate feasibility and antitumor activity of sequential FOLFIRINOX and Stereotactic Body Radiotherapy (SBRT) in patients with locally advanced pancreatic cancer (LAPC), (LAPC-1 trial). METHODS: Patients with biopsy-proven LAPC treated in four hospitals in the Netherlands between December 2014 and June 2017. Patients received 8 cycles of FOLFIRINOX followed by SBRT (5 fractions/8â¯Gy) if no tumour progression after the FOLFIRINOX treatment was observed. Primary outcome was 1-year overall survival (OS). Secondary outcomes were median OS, 1-year progression-free survival (PFS), treatment-related toxicity, and resection rate. The study is registered with ClinicalTrials.gov, NCT02292745, and is completed. FINDINGS: Fifty patients were included. Nineteen (38%) patients did not receive all 8 cycles of FOLFIRINOX, due to toxicity (nâ¯=â¯12), disease progression (nâ¯=â¯6), or patients' preference (nâ¯=â¯1). Thirty-nine (78%) patients received the SBRT treatment. The 1-year OS and PFS were 64% (95% CI: 50%-76%) and 34% (95% CI: 22%-48%), respectively. Thirty grade 3 or 4 adverse events were observed during FOLFIRINOX. Two (5%) grade 3 or 4 adverse events after SBRT were observed. Two (5%) patients died due to a gastro-intestinal bleeding within three months after SBRT were observed. Six (12%) patients underwent a resection, all resulting in a complete (R0) resection. Two patients had a complete pathological response. INTERPRETATION: FOLFIRINOX followed by SBRT in patients with LAPC is feasible and shows relevant antitumor activity. In 6 (12%) patients a potentially curative resection could be pursued following this combined treatment, with a complete histological response being observed in two patients.
RESUMO
PURPOSE: To prospectively compare three strategies of magnetic resonance colonography (MRC) with fecal tagging. MATERIALS AND METHODS: Three strategies were compared: (S1) gadolinium as oral tagging agent and a gadolinium-water mixture for rectal filling (bright lumen), (S2) oral barium and water rectally, and (S3) oral barium and air rectally. In S2 and S3 (both dark lumen) gadolinium was injected intravenously. Three-dimensional (3D) T1-weighted and two-dimensional (2D) T2-weighted sequences were used. Two observers scored diagnostic confidence and image quality (contrast, homogeneity, artifacts), analyzed by chi-squared and Fisher's exact test. Patient experience and preference were determined by questionnaire (Mann-Whitney test). RESULTS: A total of 45 patients were included, 15 were randomly assigned per strategy. Diagnostic confidence of S1 and S3 is significantly better than for S2. S1 has the additional advantage of showing significantly better contrast between bowel wall and lumen, and showing significantly better homogeneity on both T1- and T2-weighted sequences, but with significantly more artifacts on the T1-weighted sequences. S3 showed significantly better contrast and homogeneity than S2 on the T2-weighted sequences. Bowel preparation of S1 was rated significantly better. Patient preference was comparable. CONCLUSION: Image quality was best using the bright lumen strategy or the dark lumen strategy using air for rectal filling. Although bowel preparation was rated best using the bright lumen strategy, patient preference was comparable.
Assuntos
Sulfato de Bário , Pólipos do Colo/diagnóstico , Meios de Contraste/administração & dosagem , Gadolínio , Imageamento por Ressonância Magnética/métodos , Idoso , Colo , Colonoscopia , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos ProspectivosRESUMO
PURPOSE: To prospectively evaluate participants' experience and preference of magnetic resonance (MR) colonography with limited bowel preparation compared with full-preparation colonoscopy in participants at increased risk for colorectal cancer. MATERIALS AND METHODS: This study had institutional review board approval; all participants gave written informed consent. In this multicenter study, consecutive participants undergoing conventional colonoscopy because of a personal or family history of colorectal cancer or adenomatous polyps underwent MR colonography 2 weeks prior to colonoscopy. They all followed a low-fiber diet and were given lactulose and an oral contrast agent (fecal tagging with gadolinium) 2 days before colonography. Before imaging, spasmolytics were administered intravenously, and a water-gadolinium chelate mixture was administered rectally for distention of the colon. Breath-hold T1- and T2-weighted sequences were performed in the prone and supine positions. Participant experience in terms of, for example, pain and burden was determined by using a five-point scale and was evaluated with a Wilcoxon signed rank test; participant preference was determined by using a seven-point scale and was evaluated with the chi2 statistic after dichotomizing. RESULTS: Two hundred nine participants (77 women, 132 men; mean age, 58 years; range, 23-84 years) were included. One hundred forty-eight participants received sedatives (midazolam) and/or analgesics (fentanyl) during colonoscopy. Participants rated the MR colonography bowel preparation as less burdensome (P<.001) compared with the colonoscopy bowel preparation (10% and 71% of participants rated the respective examinations moderately to extremely burdensome). Participants also experienced less pain at MR colonography (P<.001) and found MR colonography less burdensome (P<.001). Immediately after both examinations, 69% of participants preferred MR colonography, 22% preferred colonoscopy, and 9% were indifferent (P<.001, 69% vs 22%). After 5 weeks, 65% preferred MR colonography and 26% preferred colonoscopy (P<.001). CONCLUSION: Participants preferred MR colonography without extensive cleansing to colonoscopy immediately after both examinations and 5 weeks later. Experience of the bowel preparation and of the procedure was rated better.
Assuntos
Colonoscopia , Fármacos Gastrointestinais/farmacologia , Imageamento por Ressonância Magnética/métodos , Aceitação pelo Paciente de Cuidados de Saúde , Pólipos Adenomatosos/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Catárticos/administração & dosagem , Neoplasias Colorretais/diagnóstico , Feminino , Gadolínio , Humanos , Lactulose/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
PURPOSE: To prospectively evaluate the diagnostic performance of magnetic resonance (MR) colonography by using limited bowel preparation in patients with polyps of 10 mm or larger in diameter in a population at increased risk for colorectal cancer, with optical colonoscopy as the reference standard. MATERIALS AND METHODS: The institutional review boards of all three hospitals approved the study. All patients provided written informed consent. In this multicenter study, patients undergoing colonoscopy because of a personal or family history of colorectal cancer or adenomatous polyps were included. Two blinded observers independently evaluated T1- and T2-weighted MR colonographic images obtained with limited bowel preparation (bright-lumen fecal tagging) for the presence of polyps. The limited bowel preparation consisted of a low-fiber diet, with ingestion of lactulose and an oral gadolinium-based contrast agent (with all three major meals) starting 48 hours prior to imaging. Results were verified with colonoscopic outcomes. Patient sensitivity, patient specificity, polyp sensitivity, and interobserver agreement for lesions of 10 mm or larger were calculated for both observers individually and combined. RESULTS: Two hundred patients (mean age, 58 years; 128 male patients) were included; 41 patients had coexistent symptoms. At colonoscopy, 12 patients had 22 polyps of 10 mm or larger. Per-patient sensitivity was 58% (seven of 12) for observer 1, 67% (eight of 12) for observer 2, and 75% (nine of 12) for both observers combined for polyps of 10 mm or larger. Per-patient specificity was 95% (178 of 188) for observer 1, 97% (183 of 188) for observer 2, and 93% (175 of 188) for both observers combined. Per-polyp sensitivity was 55% (12 of 22) for observer 1, 50% (11 of 22) for observer 2, and 77% (17 of 22) for both observers combined. Interobserver agreement was 93% for identification of patients with lesions of 10 mm or larger. CONCLUSION: In patients at increased risk for colorectal cancer, specificity of MR colonography by using limited bowel preparation was high, but sensitivity was modest.