RESUMO
BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of â¼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. PATIENTS AND METHODS: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. RESULTS: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. CONCLUSIONS: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Paclitaxel , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Projetos Piloto , GencitabinaRESUMO
BACKGROUND: Response assessment in advanced pancreatic cancer (APC) is difficult and predictive markers are needed. There are insufficient data on the value of carbohydrate antigen 19-9 (CA 19-9) and cytostatic-targeted therapies. Axitinib, a selective vascular endothelial growth factor (VEGF) receptors 1, 2, 3 inhibitor, may increase overall survival (OS) in APC. METHODS: We assessed serum CA 19-9, clinical outcomes and diastolic blood pressure (dBP) in APC patients receiving gemcitabine plus axitinib (Gem+A) or gemcitabine alone. RESULTS: In the total population (N=95), median OS was significantly longer in patients with baseline CA 19-9 values at or below the median than in those with values above it (12.2 months [95% confidence interval (CI), 8.6-16.6%] vs 5.0 months [95% CI, 3.9-5.7%]; P<0.0001). This also reached significance in the Gem+A arm (median OS, 12.5 months [95% CI, 8.6-16.6%] vs 4.9 months [95% CI, 3.6-5.6%]; P<0.0001). Patients with any dBP>90 mmHg had significantly longer OS than those who did not. However, there was no predictive significance of CA 19-9. CONCLUSION: Baseline CA 19-9 levels had prognostic value for OS, but caution is advised in interpreting CA 19-9 as a predictive biomarker for novel cytostatic agents such as VEGF-targeted therapies in phase II studies.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Desoxicitidina/análogos & derivados , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Axitinibe , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Diástole , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , GencitabinaAssuntos
Quimioembolização Terapêutica , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/terapia , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Progressão da Doença , Humanos , Neoplasias Hepáticas/radioterapia , Radioterapia AdjuvanteRESUMO
Loss of chromosome 18q21 is well documented in colorectal cancer, and it has been suggested that this loss targets the DCC, DPC4/SMAD4, and SMAD2 genes. Recently, the importance of SMAD4, a downstream regulator in the TGF-beta signaling pathway, in colorectal cancer has been highlighted, although the frequency of SMAD4 mutations appears much lower than that of 18q21 loss. We set out to investigate allele loss, mutations, protein expression, and cytogenetics of chromosome 18 copy number in a collection of 44 colorectal cancer cell lines of known status with respect to microsatellite instability (MSI). Fourteen of thirty-two MSI(-) lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts). Of the 18 MSI(-) cancers with retained SMAD4 expression, four harbored missense mutations in the 3' part of the gene and showed allele loss. The remaining 14 MSI(-) lines had no detectable SMAD4 mutation, but all showed allele loss at SMAD4 and/or DCC. SMAD4 mutations can therefore account for about 50-60% of the 18q21 allele loss in colorectal cancer. No MSI(+) cancer showed loss of SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or DCC, although many of these MSI(+) lines did carry TGFBIIR changes. Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI(+) and MSI(-) pathways diverge. Thus, MSI(+) cancers may diverge first, followed by CIN(+) (chromosomal instability) cancers, leaving other cancers to follow a CIN(-)MSI(-) pathway.
Assuntos
Adenocarcinoma/genética , Cromossomos Humanos Par 18/genética , Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Repetições de Microssatélites , Proteínas de Neoplasias/genética , Transativadores/genética , Western Blotting , Transformação Celular Neoplásica/genética , Deleção Cromossômica , Análise Mutacional de DNA , Proteínas de Ligação a DNA/biossíntese , Deleção de Genes , Perfilação da Expressão Gênica , Genes DCC , Humanos , Perda de Heterozigosidade , Mutação , Proteínas de Neoplasias/biossíntese , Ploidias , Polimorfismo Conformacional de Fita Simples , Transdução de Sinais , Proteína Smad4 , Fatores de Tempo , Transativadores/biossíntese , Fator de Crescimento Transformador beta/fisiologia , Células Tumorais CultivadasRESUMO
The functional effects of APC (adenomatous polyposis coli gene) germ-line mutations on crypt fission and cell proliferation were investigated in the normal intestine of human familial adenomatous polyposis (FAP) and multiple intestinal neoplasia (MIN) mice. Compared with controls, there was a 19-fold increase in the proportion of crypts in fission in FAP colon [95 per cent confidence interval (CI): 11-32, P < 0.0001], and a 75 and 61 per cent increase in MIN colon (95 per cent CI: 1.08-2.82, P < 0.02) and small bowel, respectively (95 per cent CI: 1.31-1.99, P < 0.001). In marked contrast, no significant differences in intra-cryptal epithelial cell proliferation or mitotic distribution were seen. Furthermore, 10.9 per cent of crypts in FAP were in asymmetrical fission as opposed to only 1 per cent in controls (P = 0.001). The largest relative increases in MIN crypt fission were in the colon (proximal and distal colon:190 per cent, P = 0.02 and 83 per cent, P = 0.01), suggesting that Apc mutations exert their maximal influence site-specifically. However, sites with the highest relative increases were also those with the largest eventual tumour sizes, but not the highest polyp counts. Three-dimensional serial section reconstruction analysis corroborated that FAP adenomas enlarge by crypt fission, which was frequently both asymmetrical and atypical. It is proposed that the absence of an increase in intestinal cell division infers that APC regulates intestinal crypt differentiation, specifically through the crypt cycle. This role appears analogous to the control of axis re-duplication in embryonic development, when downstream targets of APC are over-expressed. It is concluded that in vivo, the major defect in pre-neoplastic intestine harbouring APC mutations is elevated rates of crypt fission, and that this is also the mode by which micro-adenomas enlarge.
Assuntos
Polipose Adenomatosa do Colo/genética , Genes APC , Mutação em Linhagem Germinativa , Mucosa Intestinal/patologia , Adenoma/patologia , Polipose Adenomatosa do Colo/patologia , Adulto , Animais , Divisão Celular , Colo , Epitélio/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Modelos BiológicosRESUMO
Significant differences in colon cancer incidence worldwide have led to the hypothesis that this variation can be explained largely by environmental, notably dietary influences. Although a positive correlation between dietary fat intake and incidence is suggested from some human epidemiological and rodent carcinogenesis studies, a direct association remains contentious. Using a spontaneous mouse tumor model of multiple intestinal neoplasia, we demonstrate that there is a generalized increase in tumor counts, in both the large and small bowel with higher dietary fat [standard (3%) fat versus high (15%) fat diet (mean +/- SD) 1.59 +/- 1.46 vs. 3.85 +/- 2.37 P < 0.001 and 21.36 +/- 7.4 vs. 31.3 +/- 9.7, respectively, P < 0.001]. Increasing dietary fat also increases polyp size in the small bowel. These changes appear independent of total calorific intake as assessed by body weights. Halving the crude fiber intake together with an increase in dietary fat from 3% to 10% did not have as marked an effect on tumor counts as an increase of fat alone to 15%, which also decreased survival (P < 0.05). These results demonstrate that increasing dietary fat intake from weaning can have a significant adverse effect on polyp numbers in mice genetically predisposed to intestinal tumor development. A further understanding of the biology of this interaction may provide novel strategies aimed at both colonic polyp prevention and treatment.
Assuntos
Gorduras na Dieta/farmacologia , Neoplasias Intestinais/genética , Pólipos Intestinais/genética , Neoplasias Primárias Múltiplas/genética , Animais , Colo/patologia , Feminino , Neoplasias Intestinais/patologia , Pólipos Intestinais/patologia , Intestino Delgado/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , FenótipoAssuntos
Teratoma/cirurgia , Neoplasias Testiculares/cirurgia , alfa-Fetoproteínas/metabolismo , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hepatite Alcoólica/etiologia , Hepatite Alcoólica/metabolismo , Humanos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Neoplasia Residual/cirurgia , Orquiectomia , Período Pós-Operatório , Teratoma/tratamento farmacológico , Teratoma/metabolismo , Teratoma/secundário , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/metabolismo , Toracotomia , Resultado do TratamentoAssuntos
Consumo de Bebidas Alcoólicas/sangue , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Teratoma/sangue , alfa-Fetoproteínas/análise , Adulto , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Dactinomicina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Masculino , Metotrexato/administração & dosagem , Orquiectomia , Teratoma/tratamento farmacológico , Toracotomia , Vincristina/administração & dosagemRESUMO
A patient with primary adenocarcinoma with yolk sac and trophoblastic differentiation occurring in Barrett's esophagus is reported. Yolk sac differentiation at this site has not been described previously. The diagnosis of germ cell differentiation initially was suggested by the finding of elevated serum tumor marker levels. The patient experienced disease remission after cytotoxic chemotherapy. Germ cell differentiation may be difficult to identify in small biopsy samples, which may not be representative of the tumor as a whole. The finding of germ cell differentiation defines therapy and predicates for a relatively good prognosis, which is contrast to adenocarcinoma. Because of the significance of germ cell differentiation in the selection of appropriate therapy, immunostaining for germ cell tumor markers is suggested in all patients with adenocarcinoma who are younger than 50 years.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Coriocarcinoma/patologia , Tumor do Seio Endodérmico/patologia , Neoplasias Esofágicas/patologia , Neoplasias Primárias Múltiplas , Biomarcadores Tumorais/sangue , Transformação Celular Neoplásica , Gonadotropina Coriônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , alfa-Fetoproteínas/análiseRESUMO
In advanced disease, androgen deprivation remains the usual treatment. The completion of current trials is awaited to confirm whether total androgen blockade will prolong survival. To make further advances in treatment the fundamental biology of the prostate cell, benign or malignant, and its relationship to endocrine manipulation, must be understood. This may then lead to an understanding of clonal escape mechanisms in transformed cells and the clinical correlate of escape, relapse.