RESUMO
BACKGROUND/AIM: Current treatment strategies for advanced melanoma require serial assessment of disease status in affected patients. In this study, we sought to examine the relationship between radiographic tumour burden and blood borne biomarkers including plasma cfDNA, serum LDH, plasma VEGF, PD-L1 and IFN-γ in advanced melanoma patients receiving immunotherapy. We hypothesized that a combination of these explanatory variables in a suitable regression analysis model may predict changes in tumour burden during patient treatment. MATERIALS AND METHODS: We extracted and quantified circulating cfDNA, LDH, VEGF, PD-L1, and IFN-γ from thirty patients with stage IV melanoma at baseline and at six months. All participating patients were evaluated with paired blood sample collection and CT scan assessments during treatment. RESULTS: Changes in radiographic tumour burden correlated with changes in levels of cfDNA (p≤0.001), LDH (p≤0.001), VEGF (p≤0.001), and PD-L1 (p<0.05) during treatment. Multiple regression analysis consisting of the follow-up to baseline assessment ratios of cfDNA, LDH, VEGF and PD-L1 explained changes in tumour burden (F (4, 23)=32.05, p<0.001); with an R2 of 0.8479 (Y=ß0+ß1*B+ß2*C+ß3*D+ß4*E). CONCLUSION: A quantitative measure of cfDNA, LDH, VEGF and PD-L1 may complement current methods of assessing tumour burden in advanced melanoma patients.
Assuntos
Melanoma/sangue , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Feminino , Humanos , Imunoterapia , Interferon gama/sangue , L-Lactato Desidrogenase/sangue , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Análise de Regressão , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Importance: Obesity, particularly visceral obesity and sarcopenia, are poor prognostic indicators in colon cancer. Objectives: To explore the association between body composition profiles and 5-year colon cancer outcomes and delineate the associated underlying inflammatory processes. Design, Setting, and Participants: This multicenter translational cohort study included patients with nonmetastatic colon cancer who did not have underlying chronic inflammatory disorders and were not receiving anti-inflammatory drugs referred to tertiary cancer centers from 2009 to 2015. Preoperative acute phase proteins (white cell count, C-reactive protein, and albumin), cytokines (interleukin [IL]-1b, IL-2, IL-6, IL-10, interferon γ, and tumor necrosis factor α), vascular endothelial growth factor (VEGF), and cell surface receptor expression levels (CD11b and CD14) were measured. All patients underwent follow-up for at least 5 years. Data were analyzed in December 2020. Exposure: Nonmetastatic colon cancer. Main Outcomes and Measures: The associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality were analyzed using Mantel Cox log-rank test and Kaplan-Meier curves. Results: A total of 28 patients were included (median [interquartile range] age, 67 [58-72] years; 22 [78.6%] men). Low skeletal muscle area (SMA) and high visceral to total fat ratio were associated with poor clinical and oncological outcomes, including increased 5-year recurrence (low SMA: hazard ratio [HR], 2.30 [95% CI, 1.41-2.89]; P = .04; high visceral to total fat ratio: HR, 5.78 [95% CI, 3.66-7.95]; P = .02). High visceral to total fat ratio was associated with increased 5-year disease-specific mortality (HR, 5.92 [95% CI, 4.04-8.00]; P = .02). Patients with low SMA who developed a cancer recurrence, compared with those who did not, had higher C-reactive protein (mean [SD], 31.24 [6.95] mg/dL vs 8.11 [0.58] mg/dL; P = .003), IL-6 (mean [SD], 1.93 [1.16] ng/mL vs 0.88 [0.14] ng/mL; P = .004), VEGF (mean [SD], 310.03 [122.66] ng/mL vs 176.12 [22.94] ng/mL; P = .007), and CD14 (mean [SD], 521.23 [302.02] ng/mL vs 322.07 [98.35] ng/mL; P = .03) expression and lower albumin (mean [SD], 3.8 [0.6] g/dL vs 43.50 [3.69] g/dL; P = .01), IL-2 (mean [SD], 0.45 [0.25] ng/mL vs 0.94 [0.43] ng/mL; P < .001), IL-10 (mean [SD], 8.15 [1.09] ng/mL vs 16.32 [4.43] ng/mL; P = .004), and interferon γ (mean [SD], 2.61 [1.36] ng/mL vs 14.87 [3.43] ng/mL; P = .02) levels. Patients with high visceral to total fat ratio who developed recurrence had higher levels of IL-6 (mean [SD], 5.26 [7.05] ng/mL vs 2.76 [3.11] ng/mL; P = .03) and tumor necrosis factor α (mean [SD], 5.74 [4.53] ng/mL vs 4.50 [1.99] ng/mL; P = .03). Conclusions and Relevance: These findings suggest that low SMA and high visceral to total fat ratio were associated with worse colon cancer outcomes and with increased expression of proinflammatory cytokines and VEGF and inhibition of anti-inflammatory cytokines.
Assuntos
Composição Corporal , Neoplasias do Colo/mortalidade , Neoplasias do Colo/fisiopatologia , Tecido Adiposo/fisiopatologia , Idoso , Proteína C-Reativa/análise , Antígeno CD11b/sangue , Neoplasias do Colo/cirurgia , Citocinas/sangue , Feminino , Humanos , Inflamação , Gordura Intra-Abdominal/fisiopatologia , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Receptores de Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/fisiopatologia , Período Pré-Operatório , Modelos de Riscos Proporcionais , Albumina Sérica/análise , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Morphine has been used in the treatment of pain for centuries. It is commonly used by oncology in terminal cancer cases and by surgery perioperatively for oncology surgery. Its extra-analgesic effects on cancer have been described extensively but conflicting results abound. It has been shown to have varying effects on tumour progression, cell proliferation, tumour invasion, angiogenesis, immune function, and metastatic potential. In vivo studies on the effects of morphine and the mu-opioid receptor on tumours are discussed below. Mechanisms involved are also discussed, drawn from a combination of both in vivo and in vitro methods. At present, no consensus can be drawn from data collected, and further studies are necessary to elicit the safest method and agent for analgesia in oncology patients.
Assuntos
Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Morfina/uso terapêutico , Analgésicos Opioides/farmacologia , Animais , Dor do Câncer/metabolismo , Dor do Câncer/patologia , Humanos , Morfina/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Receptores Opioides mu/metabolismoRESUMO
The optimal duration and treatment strategies involving adjuvant endocrine therapy in early breast cancer remained largely undetermined. As data emerge on the various modalities of treatment in both pre- and postmenopausal groups, debates, and discussions continue. Most studies to date focused on the 5-year duration of treatment consisting of mainly tamoxifen. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) study demonstrated that anastrozole is superior to tamoxifen and has become the mainstream treatment in postmenopausal women with early breast cancer, although the duration was arbitrarily set for 5 years, analogous to tamoxifen treatment. Several clinical trials, however, have emerged to support extended endocrine therapy as it becomes clear that the recurrence risk of breast cancer does not decrease beyond the initial 5 years of treatment. The advent of molecular signatures also plays an important role in the breast cancer profiling, and where available should be incorporated in the overall decision-making. Furthermore, side effects and noncompliance pose another issue in achieving an optimal treatment benefit. The decision-making as regards to extended endocrine treatment should therefore focus not only on the cancer biology alone but also include treatment side effects, assessment of risk of recurrence and patients' preference. In this review, we present an overview of the published studies to date as well as ongoing studies on the topic to better refine the options for adjuvant hormonal therapy.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Nitrilas/administração & dosagem , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagem , Anastrozol , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Esquema de Medicação , Feminino , HumanosRESUMO
BACKGROUND: Body composition is an important predictor of drug toxicity and outcome. Ipilimumab (Ipi), a monoclonal antibody used to treat metastatic melanoma, has specific toxicities. No validated biomarkers that predict Ipi toxicity and efficacy exist. Also, the impact of Ipi on body composition has not been established. METHODS: Patients with metastatic melanoma treated with Ipi between 2009 and 2015 were included. Body composition was assessed by computed tomography at baseline and after four cycles of Ipi. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Event V.4.0). RESULTS: Eighty-four patients were included in this study (62% male, median age 54 years). At baseline, 24% were sarcopenic and 33% had low MA. On multivariate analysis, sarcopenia and low MA were significantly associated with high-grade AEs (OR=5.34, 95% CI: 1.15-24.88, P=0.033; OR=5.23, 95% CI: 1.41-19.30, P=0.013, respectively), and low MA was associated with high-grade irAEs (OR=3.57, 95% CI: 1.09-11.77, P=0.036). Longitudinal analysis (n=59) revealed significant reductions in skeletal muscle area (SMA), total body fat-free mass, fat mass (all P<0.001) and MA (P=0.030). Mean reduction in SMA was 3.3%/100 days (95% CI: -4.48 to -1.79%, P<0.001). A loss of SMA ⩾7.5%/100 days (highest quartile) was a significant predictor of overall survival in multivariable Cox regression analysis (HR: 2.1, 95% CI: 1.02-4.56, P=0.046). CONCLUSIONS: Patients with sarcopenia and low MA are more likely to experience severe treatment-related toxicity to Ipi. Loss of muscle during treatment was predictive of worse survival. Treatments to increase muscle mass and influence outcome warrant further investigation.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Composição Corporal/fisiologia , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Composição Corporal/efeitos dos fármacos , Feminino , Humanos , Ipilimumab , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Sarcopenia/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Focused exploration (FE) and bilateral parathyroid exploration (BE) are the standard surgical options for patients with primary hyperparathyroidism. However, the relative risk of recurrence, persistence, overall failure, reoperation, and any complications associated with either surgical approach is unclear. This study compared the outcomes and complication rates after FE and BE for patients with primary hyperparathyroidism. METHODS: PubMed and Embase were searched for studies comparing these outcomes between FE and BE. A meta-analysis was performed using RevMan 5.3 software. Published data were pooled using the DerSimonian random-effect model, and results were presented as odds ratio (OR) or mean difference with 95% confidence interval (CI). RESULTS: A total of 12,743 patients from 19 studies were included in this meta-analysis. In comparison with BE, the FE arm had comparable rates of recurrence (OR 1.08; 95% CI 0.59-2.00; p = 0.80; n = 9 studies), persistence (OR 0.89; 95% CI 0.58-1.35; p = 0.58; n = 13), overall failure (OR 0.88; 95% CI 0.58-1.34; p = 0.56; n = 13), and reoperation (OR 1.05; 95% CI 0.25-4.32; p = 0.95, n = 4). The operative time was significantly shorter (mean difference = -39.86; 95% CI -53.05 to -26.84; p < 0.01, n = 9), with a lower overall complication rate in the FE arm (OR 0.35; 95% CI 0.15-0.84; p = 0.02; n = 12). The latter was attributed predominantly to a lower risk of transient hypocalcemia (OR 0.36; 95% CI 0.14-0.90; p = 0.03; n = 9). There was a significant heterogeneity among these studies for all outcomes except for disease recurrence. CONCLUSIONS: Compared with BE, FE has similar recurrence, persistence, and reoperation rates but significantly lower overall complication rates and shorter operative time.
Assuntos
Hiperparatireoidismo Primário/cirurgia , Glândulas Paratireoides/cirurgia , Paratireoidectomia , Humanos , Duração da Cirurgia , Prognóstico , ReoperaçãoRESUMO
To analyse the patient demographics, tumour characteristics and follow-up data of patients with recurrence of melanoma following a negative sentinel lymph node biopsy. A retrospective review of a prospectively maintained melanoma database was conducted. Melanoma patients who had a negative sentinel lymph node were identified and we performed statistical analysis on their respective demographics, tumour histology characteristics and follow-up data. Of 164 patients studied, 40 (24%) had a recurrence of melanoma at a median of 39.5 months following diagnosis (range 1-92 months). Distant metastases were the most common form of disease recurrence (40% of all recurrences). Increasing tumour thickness was an independent predictor of recurrence on multivariate analysis while nodular histology approached significance. Median survival of 6 months was seen following disease recurrence (range 1-126 months). In the setting of a negative sentinel lymph node biopsy, there remains a risk of melanoma recurrence. Distant metastases were the most common form of recurrence. Disease recurrence occurred more frequently in those with thick primary tumours. Recurrences occurred at long intervals from diagnosis indicating the need to consider prolonged patient follow-up.
Assuntos
Melanoma/epidemiologia , Melanoma/patologia , Recidiva Local de Neoplasia/epidemiologia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Idoso , Reações Falso-Negativas , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaAssuntos
Ceratodermia Palmar e Plantar/induzido quimicamente , Ceratodermia Palmar e Plantar/terapia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Adulto , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Clobetasol/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Oximas/efeitos adversos , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Thyroid drains following thyroid surgery are routinely used despite minimal supportive evidence. Our aim in this study is to determine the impact of routine open drainage of the thyroid bed postoperatively on ultrasound-determined fluid accumulation at 24 hours. METHODS: We conducted a prospective randomised clinical trial on patients undergoing thyroid surgery. Patients were randomly assigned to a drain group (n = 49) or a no-drain group (n = 44) immediately prior to wound closure. Patients underwent a neck ultrasound on day 1 and day 2 postoperatively. After surgery, we evaluated visual analogue scale pain scores, postoperative analgesic requirements, self-reported scar satisfaction at 6 weeks and complications. RESULTS: There was significantly less mean fluid accumulated in the drain group on both day 1, 16.4 versus 25.1 ml (P-value = 0.005), and day 2, 18.4 versus 25.7 ml (P-value = 0.026), following surgery. We found no significant differences between the groups with regard to length of stay, scar satisfaction, visual analogue scale pain score and analgesic requirements. There were four versus one wound infections in the drain versus no-drain groups. This finding was not statistically significant (P = 0.154). No life-threatening bleeds occurred in either group. CONCLUSIONS: Fluid accumulation after thyroid surgery was significantly lessened by drainage. However, this study did not show any clinical benefit associated with this finding in the nonemergent setting. Drains themselves showed a trend indicating that they may augment infection rates. The results of this study suggest that the frequency of acute life-threatening bleeds remains extremely low following abandoning drains. We advocate abandoning routine use of thyroid drains. TRIAL REGISTRATION: ISRCTN94715414.
Assuntos
Drenagem , Complicações Pós-Operatórias , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adolescente , Adulto , Feminino , Seguimentos , Doença de Graves/etiologia , Doença de Hashimoto/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/patologia , Fatores de Tempo , Ultrassom , Adulto JovemRESUMO
BACKGROUND: The status of resected lymph nodes in colon cancer determines prognosis and further treatment. The American Joint Committee on Cancer staging system has designated extramural nodules as nonnodal disease and classified them as extensions of the T category in the sixth edition and as site-specific tumor deposits in the seventh edition. Extracapsular lymph node extension is an established poor prognostic indicator in many cancers. Its significance in colon cancer has not been extensively investigated. OBJECTIVE: This study aimed to determine the prognostic significance of extramural nodules and extracapsular lymph node extension in colon cancer. DESIGN: A pathological review of 114 stage III and 80 stage II colon cancers was undertaken to analyze for p-T stage, p-N stage (using the fifth, sixth, and seventh editions), and the size and contour of nodal and extramural deposits. Multivariate Cox regression models were used to determine the prognostic significance of clinicopathological parameters on survival estimates. RESULTS: According to the sixth and seventh editions of the guidelines, extramural deposits were present in 29% and 31% of patients with stage III colon cancer and in 5% of patients with stage II colon cancer. Extracapsular lymph node invasion was present in 68% of cases. Multivariate analysis demonstrated that lymph node ratio, extracapsular lymph node extension, and adjuvant chemotherapy were independent prognostic factors affecting 5-year disease-free survival. The same 3 variables, in addition to extramural deposits, were independent prognostic factors affecting overall survival. The presence of extramural deposits was associated with an 11% 5-year survival, and extracapsular lymph node invasion was associated with a 33% 5-year survival. CONCLUSIONS: Instead of extramural nodules being included as part of the T category or as site-specific tumor deposits, they should perhaps be classified in the metastasis category. This has major prognostic implications and may broaden the application of a number of adjuvant agents.
Assuntos
Neoplasias do Colo/patologia , Guias de Prática Clínica como Assunto , Idoso , Neoplasias do Colo/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Cardiopulmonary bypass results in ischemia/reperfusion (I/R)-induced endotoxemia. We conducted a prospective randomized trial to investigate the effect of taurolidine, an antiendotoxin agent with antioxidant and membrane-stabilizing properties, on patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 60 patients undergoing CABG were randomized into 4 groups. St Thomas' Hospital cold crystalloid cardioplegia was used in groups A and B, and cold blood cardioplegia in groups C and D. Groups A and C received a placebo infusion of normal saline, whereas groups B and D were administered intravenous taurolidine. Arrhythmias induced by pro- and anti-inflammatory cytokines (interleukin [IL]-6 and IL-10), and I/R were assessed perioperatively. RESULTS: Administration of taurolidine in crystalloid cardioplegia patients resulted in a significant decrease in serum IL-6 and an increase in serum IL-10 at 24 hours postaortic unclamping compared to placebo (P < .0001). Although not statistically significant, this trend in serum IL-6 decrease was mirrored in the blood cardioplegia patients (P = .068). Taurolidine treatment also significantly decreased I/R-induced arrhythmias compared to placebo in the crystalloid cardioplegia patients (P < .003). There were fewer I/R-induced arrhythmias compared to placebo in the blood cardioplegia patients; the difference, however, was marginal and not statistically significant (P = .583). CONCLUSION: This study demonstrates that administration of taurolidine in CABG patients induces a potent anti-inflammatory response that is associated with a significant decrease in arrhythmias.
Assuntos
Ponte de Artéria Coronária/métodos , Endotoxinas/efeitos adversos , Traumatismo por Reperfusão/prevenção & controle , Taurina/análogos & derivados , Taurina/metabolismo , Idoso , Antioxidantes/uso terapêutico , Ponte Cardiopulmonar/métodos , Constrição , Ponte de Artéria Coronária/efeitos adversos , Endotoxinas/uso terapêutico , Feminino , Parada Cardíaca Induzida/métodos , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Fagocitose/fisiologia , Placebos , Traumatismo por Reperfusão/etiologia , Explosão Respiratória/fisiologia , Taurina/uso terapêuticoRESUMO
BACKGROUND AND DESIGN: Taurolidine consists of two taurinamide rings derived from the naturally occurring amino acid taurine. It has been utilized to prevent adhesions, as an antimicrobial, and as an anti-inflammatory agent. More recently, it has been found to exert antineoplastic activity. We reviewed the literature regarding taurolidine and its role in cancer treatment. RESULTS AND CONCLUSION: Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate proinflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine's tumoricidal action. Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine's potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Taurina/análogos & derivados , Tiadiazinas/uso terapêutico , Animais , Humanos , Taurina/uso terapêuticoRESUMO
BACKGROUND: The surgical insult induces an inflammatory response that activates P38 MAP kinases and solid tumours can also release cytokines. Therfore inhibition of these pathways may reduce tumour growth We set out to examine the effects of P38-MAPK inhibition on apoptosis, proliferation, VEGF release and cell cycle effects in-vitro and on primary tumour growth in-vivo. METHODS: 4T-1 cells (2 x 105 cells/well) were incubated, in 24 well plates with control, 25, 50 or 100 ng/ml of SB-202190 for 24 hours. Cells were subsequently asessed for apoptosis, proliferation, VEGF release and cell cycle analysis. Balb-c mice each received 1 x 106 4T 1 cells subcutaneously in the flank and were then randomised to receive control or SB202190 (2.5 microM/kg) by intraperitoneal injection daily. Tumour size was measured alternate days and at day 24 animals were sacrificed and serum VEGF assessed. RESULTS: P38-MAPK inhibition in-vitro resulted in a significant reduction in proliferation (75.2 +/- 8.4% vs. 100 +/- 4.3%, p < 0.05) and G1 cell cycle phase(35.9 +/- 1.1% vs. 32.5 +/- 0.6%, p < 0.05) but no significant changes in apoptosis or VEGF levels. In-vivo, P38-MAPK inhibition resulted in an increase in primary tumour growth (155.6 +/- 34.9 vs. 86.7 +/- 18.2 mm3, p < 0.05). P38-MAPK inhibition also lowered circulating VEGF levels but this difference was not significant (101.9 +/- 27.1 etag/ml compared to 158.6 +/- 27.1 etag/ml) CONCLUSION: These findings demonstrate that P38-MAPK inhibition in-vitro reduces proliferation and G1 cell cycle phase as well as promoting primary tumour growth in-vivo. These effects would appear to be independent of VEGF.
Assuntos
Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Animais , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Feminino , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: P38 mitogen activated protein kinase (p38 MAPK) is a critical mediator of the inflammatory response, which makes it a suitable candidate as a novel therapeutic strategy for inflammatory conditions. In this study, we set out to examine the precise role of both protein kinase C (PKC) and P38 MAPK signaling kinases in bacterial lipoprotein (BLP) induced nuclear factor-kappa B (NFkappaB) activation and tumor necrosis factor-alpha (TNFalpha) release in THP-1 monocytic cell line. MATERIALS AND METHODS: THP-1 cells were incubated with BLP(0-1000 ng/mL), phorbol myristate acetate (PMA; 0-100 microg/mL) or a combination of both for 6 and 24 h, with or without pretreatment with SB202190, a specific inhibitor of p38 MAPK and bisindolylmaleimide I, a specific inhibitor of PKC (0-200 microm). Cell supernatants were analyzed for TNF-alpha release and apoptosis. NFkappaB activity was analyzed by electromobility supershift assay. RESULTS: BLP induced TNF-alpha release was significantly reduced by pretreatment with SB202190 at all concentrations (428.7 +/- 5.9 versus 51 +/- 0.8 rhog/mL, P < 0.05). Pretreatment with bis I significantly inhibited TNF-alpha release at higher concentrations (200 microM) (429.7 +/- 5.9 versus 194.9 +/- 42.68 rhog/mL, P < 0.05) but this was much less effective than SB202190. PMA induced TNF-alpha release was not inhibited at 6 h by either SB202190 or bis I, but was significantly so at 24 h (148.5 +/- 9.8 versus 24 +/- 1.7 and 25.1 +/- 4.4 rhog/mL, P < 0.05). BLP or lipopolysaccharide (LPS) did not result in apoptosis in THP-1 cells (P > 0.05) with PMA inducing apoptosis in a time- and dose-dependent manner. In combination with BLP (1000 ng/mL) but not LPS (1000 ng/mL), low dose PMA resulted in a significant increase in apoptosis, 6% +/- 0.5% (Control) versus 9.2% +/- 0.3% (P < 0.05) and 7% +/- 2.2% (Control) versus 7.7% +/- 0.3% (P > 0.05), respectively. This synergistic effect was inhibited by bisindolylmaleimide 100 nm, 8.9% +/- 0.9% (Control) versus 9.8% +/- 0.2% (P > 0.05). PMA and BLP induced rapid nuclear translocation of NFkappaB, which was inhibited by pretreatment with both SB-202190 and bis I, and SB202190 but not bis I, respectively. CONCLUSIONS: P38 is a critical mediator of BLP induced TNF-alpha release and NFkappaB activation, whereas PKC is only partially responsible for its response. P38 and PKC are both critical mediators of PMA induced TNF-alpha release and NFkappaB activation.
Assuntos
Apoptose/efeitos dos fármacos , Lipoproteínas/efeitos adversos , Monócitos/metabolismo , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas de Bactérias/efeitos adversos , Proteínas de Bactérias/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Inflamação/etiologia , Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Lipoproteínas/farmacologia , Maleimidas/farmacologia , Monócitos/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Piridinas/farmacologia , Transdução de Sinais/fisiologia , Acetato de Tetradecanoilforbol/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
BACKGROUND: Nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK) are critical intracellular signal transduction pathways that mediate the systemic inflammatory response syndrome. Antibiotics induce bacterial lysis, which also contributes to cytokine production and the inflammatory response by activating NF-kappaB and p38 kinase. In this study, we set out to examine the effects of inhibition of p38 MAPK and NF-kappaB translation in in vivo models of sepsis. MATERIALS AND METHODS: Intraperitoneal lipopolysaccharide (30 mg/kg), tail vein injection of bacteria (Staphylococcus aureus + Salmonella Typhimurium, 5 x 10(7) colony forming units/kg) and cecal ligation and puncture (CLP) with or without antibiotics (Augmentin, 100 mg/kg) were the septic models used. Animals received control, SB-202190 (a p38 inhibitor), or SN-50 (an NF-kappaB inhibitor), and mortality was assessed by log-rank analysis. Blood was collected at different time points for cytokine analysis, and splenic tissue was used for cytoplasmic protein extraction to assess kinase activation. RESULTS: SB-202190 and SN-50 resulted in significant survival benefit in the lipopolysaccharide model (P = 0.0006) but not bacterial or CLP models (P = 0.9 and 0.3, respectively). SB-202190 and SN-50, in combination with antibiotic, resulted in a significant survival benefit in the CLP model (P = 0.0001 and 0.006, respectively). Circulating levels of both tumor necrosis factor-alpha and interleukin-6 were significantly reduced at 2 h (P = 0.047 and 0.036, respectively) and Western blot demonstrated down-regulation of p38 kinase 2 h after CLP in animals treated with p38MAPK and SN-50 inhibitors in combination with antibiotics. CONCLUSIONS: We have demonstrated that p-38 and NF-kappaB inhibition improve survival in endotoxin shock, whereas the survival benefit in polymicrobial sepsis requires coexistent antibiotic treatment.
Assuntos
Imidazóis/uso terapêutico , NF-kappa B/antagonistas & inibidores , Peptídeos/uso terapêutico , Piridinas/uso terapêutico , Sepse/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antibacterianos/uso terapêutico , Western Blotting , Ceco/lesões , Quimioterapia Combinada , Ensaio de Desvio de Mobilidade Eletroforética , Endotoxinas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Interleucina-6/metabolismo , Ligadura , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: We aimed to identify mechanisms driving local recurrence in a model of breast-conserving surgery (BCS) for breast cancer. BACKGROUND: Breast cancer recurrence after BCS remains a clinically significant, but poorly understood problem. We have previously reported that recurrent colorectal tumours demonstrate altered growth dynamics, increased metastatic burden and resistance to apoptosis, mediated by upregulation of phosphoinositide-3-kinase/Akt (PI3K/Akt). We investigated whether similar characteristics were evident in a model of locally recurrent breast cancer. METHODS: Tumours were generated by orthotopic inoculation of 4T1 cells in two groups of female Balb/c mice and cytoreductive surgery performed when mean tumour size was above 150 mm(3). Local recurrence was observed and gene expression was examined using Affymetrix GeneChips in primary and recurrent tumours. Differential expression was confirmed with quantitative real-time polymerase chain reaction (qRT-PCR). Phosphorylation of Akt was assessed using Western immunoblotting. An ex vivo heat shock protein (HSP)-loaded dendritic cell vaccine was administered in the perioperative period. RESULTS: We observed a significant difference in the recurrent 4T1 tumour volume and growth rate (p < 0.05). Gene expression studies suggested roles for the PI3K/Akt system and local immunosuppression driving the altered growth kinetics. We demonstrated that perioperative vaccination with an ex vivo HSP-loaded dendritic cell vaccine abrogated recurrent tumour growth in vivo (p = 0.003 at day 15). CONCLUSION: Investigating therapies which target tumour survival pathways such as PI3K/Akt and boost immune surveillance in the perioperative period may be useful adjuncts to contemporary breast cancer treatment.
Assuntos
Neoplasias da Mama/patologia , Modelos Animais de Doenças , Recidiva Local de Neoplasia/diagnóstico , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Medula Óssea/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Perfilação da Expressão Gênica , Proteínas de Choque Térmico/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
We report here how a heterotopic penetrating peptic ulcer progressed to cause small bowel obstruction in a patient with multiple previous negative investigations. The clinical presentation, radiographic features and pathological findings of this case are described, along with the salient lessons learnt. The added value of wireless capsule endoscopy (WCE) in such circumstances is debated.
Assuntos
Coristoma/diagnóstico , Obstrução Intestinal/diagnóstico , Doenças do Jejuno/diagnóstico , Divertículo Ileal , Úlcera Péptica/diagnóstico , Idoso , Coristoma/patologia , Diagnóstico Diferencial , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/patologia , Masculino , Úlcera Péptica/complicações , Úlcera Péptica/patologiaRESUMO
BACKGROUND: The aim of this study was to analyze the factors that influence the advancement and the career choices of doctors and medical students. METHODS: Using the combined databases of the iformix and surgent websites, 450 doctors and medical students were invited to complete an internet-based survey. Surgent (http://www.surgent.ie) and iformix (http://www.iformix.com) are two free internet services administered by the authors. Surgent is a medical educational website, while iformix facilitates the online submission of abstracts to surgical and medical conferences across Britain and Ireland. The combined database of these two websites is approximately 4500 entries. Four hundred and fifty users represented a 10% sample based on an expected 40%-45% response rate. This was anticipated to yield between 180 and 202 respondents, statistically sufficient to analyze the data. A detailed Likert scale assessed the importance of "academic," "clinical," and "lifestyle" factors in determining career choice and progression. Analysis included descriptive statistics and inferential testing. RESULTS: Fifty percent (N = 222) of surveys were returned; 142 men and 78 women. Thirty-seven percent of respondents were Irish, 28% British, and 35% non-European. Fifteen percent were undergraduates, 4% interns, 12% had 2-4 years of clinical experience, while 69% had completed more than 4 years. Fifty-six percent had decided upon a career in general surgery. Overall, the most important factors for career choice were intellectual challenge (95%), academic opportunities (61%), and research opportunities(54%). Doctors with more than 4 years of experience deemed duration of training (p = 0.002), lifestyle during training (p = 0.02), and stress (0.005) as less important factors when considering career choice. Correlation analyses demonstrated that prestige (p = 0.002), patient relationships (p = 0.006), and advice from friends or family (p = 0.01) were more important influencing factors for interns. In terms of career advancement, 66% of non-Europeans considered family contacts important as opposed to 20% of British and 45% of Irish doctors (p < 0.001). In addition, 47% of females felt gender was important for career advancement as opposed to 31% of males (p = 0.01). CONCLUSIONS: Academic and clinical factors play an important role in career choice. However, it is clear that lifestyle factors predominate in determining an individual's career decisions in surgery.
Assuntos
Escolha da Profissão , Mobilidade Ocupacional , Cirurgia Geral , Adulto , Feminino , Cirurgia Geral/economia , Humanos , Renda , Irlanda , Estilo de Vida , Masculino , Médicas/estatística & dados numéricos , Reino UnidoRESUMO
BACKGROUND: Intuitively, vascular procedures performed by high-volume vascular subspecialists working at high-volume institutions should be associated with improved patient outcome. Although a large number of studies assess the relationship between volume and outcome, a single contemporary compilation of such studies is lacking. METHODS: A review of the English language literature was performed incorporating searches of the Medline, EMBASE, and Cochrane collaboration databases for abdominal aortic aneurysm repair (elective and emergent), carotid endarterectomy, and arterial lower limb procedures for any volume outcome relationship. Studies were included if they involved a patient cohort from 1980 onwards, were community or population based, and assessed health outcomes (mortality and morbidity) as a dependent variable and volume as an independent variable. RESULTS: We identified 74 relevant studies, and 54 were included. All showed either an inverse relationship of variable magnitude between provider volume and mortality, or no volume-outcome effect. The reduction in the risk-adjusted mortality rate (RAMR) for high-volume providers was 3% to 11% for elective abdominal aortic aneurysm (AAA) repair, 2.5 to 5% for emergent AAA repair, 0.7% to 4.7% carotid endarterectomy, and 0.3% to 0.9% for lower limb arterial bypass procedures. Subspeciality training also conferred a considerable morbidity and mortality benefit for emergent AAA repair, carotid endarterectomy, and lower limb arterial procedures. CONCLUSION: High-volume providers have significantly better outcomes for vascular procedures both in the elective and emergent setting. Subspeciality training also has a considerable impact. These data provide further evidence for the specialization of vascular services, whereby vascular procedures should generally be preformed by high-volume, speciality trained providers.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Doenças das Artérias Carótidas/cirurgia , Hospitais/estatística & dados numéricos , Doenças Vasculares Periféricas/cirurgia , Especialidades Cirúrgicas/estatística & dados numéricos , Procedimentos Cirúrgicos Vasculares/estatística & dados numéricos , Carga de Trabalho/estatística & dados numéricos , Aneurisma da Aorta Abdominal/mortalidade , Doenças das Artérias Carótidas/mortalidade , Certificação , Educação de Pós-Graduação em Medicina , Procedimentos Cirúrgicos Eletivos/estatística & dados numéricos , Serviços Médicos de Emergência/estatística & dados numéricos , Endarterectomia das Carótidas/estatística & dados numéricos , Tamanho das Instituições de Saúde , Mortalidade Hospitalar/tendências , Humanos , Extremidade Inferior/irrigação sanguínea , Doenças Vasculares Periféricas/mortalidade , Medição de Risco , Especialidades Cirúrgicas/educação , Análise de Sobrevida , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/educaçãoRESUMO
BACKGROUND: Surgical removal remains the principal treatment modality in the management of lung cancer. Our aim is to characterize the effects of tumor removal on subsequent tumor recurrence at both local and systemic levels. METHODS: C57/BL6 mice [10/group] underwent a mammary fat pad inoculation of 3LL cells [5 x 10(5)/animal] and were divided into two groups. Group 1 served as control while mice in group 2 were further subdivided into groups 2A and 2B. After 2 weeks, all mice in 2A were killed, and primary tumors and lungs were excised. At 2 weeks, primary tumors were excised completely for all mice in group 2B. These mice were then recovered and recurrent tumor growth evaluated for a further 2 weeks. Four weeks from the onset of the study, all remaining primary tumors and lungs were excised from groups 1 and 2. RESULTS: After 4 weeks undisturbed growth, primary tumors in group 1 reached a mean size of 2.85 +/- 0.33 cm. After 2 weeks growth, primary tumors in groups 2A and 2B were comparable at 1.36 +/- 0.44 m and 1.53 +/- 0.29 cm, respectively. Two weeks after primary tumor excision, recurrent tumors in group 2B had reached a mean size of 2.65 +/- 0.74 cm. Moreover, for several animals, recurrent tumors rapidly reached similar volumes to that of primary tumors in group 1. Primary tumors were typically encapsulated and nonadherent. In contrast, recurrent tumors were locally invasive and adherent to chest wall and wound. Interestingly, pulmonary metastatic burden was increased in group 2B relative to group 1. Histologic examination revealed increased mitosis in recurrent tumors when compared with primary tumors. CONCLUSIONS: Tumor removal is followed by accelerated growth of locally recurrent tumors and metastases. Moreover, recurrent tumors are more locally invasive than primary tumors. These findings strongly indicate that resection may be followed by tumor progression in residual disease.