Tea polyphenols induce S phase arrest and apoptosis in gallbladder cancer cells

Gallbladder cancer (GBC) is the most common malignancy in the biliary tract. Without effective treatment, its prognosis is notoriously poor. Tea polyphenols (TPs) have many pharmacological and health benefits, including antioxidant, anti-inflammatory, anti-tumor, anti-thrombotic, antibacterial, and vasodilatory properties. However, the anti-cancer effect of TPs in human gallbladder cancer has not yet been determined. Cell viability and colony formation assay were used to investigate the cell growth. Cell cycle and apoptosis were evaluated by flow cytometry analysis. Western blot assay was used to detect the expression of proteins related to cell cycle and apoptosis. Human tumor xenografts were used to examine the effect of TPs on gallbladder cancer cells in vivo. TPs significantly inhibited cell growth of gallbladder cancer cell lines in a dose- and time-dependent manner. Cell cycle progression in GBC cells was blocked at the S phase by TPs. TPs also induced mitochondrial-related apoptosis in GBC cells by upregulating Bax, cleaved caspase-3, and cleaved PARP expressions and downregulating Bcl-2, cyclin A, and Cdk2 expressions. The effects of TPs on GBC were further proven in vivo in a mouse xenograft model. Our study is the first to report that TPs inhibit GBC cell growth and these compounds may have potential as novel therapeutic agents for treating gallbladder cancer.

Effect of 4-(N,N-dimethylamino)phenethyl Alcohol on Degree of Conversion and Cytotoxicity of Photo-Polymerized CQ-Based Resin Composites

The aim of this study was to evaluate the degree of conversion (DC) and the cytotoxicity of photo-cured experimental resin composites containing 4-(N,N-dimethylamino)phenethyl alcohol (DMPOH) combined to the camphorquinone (CQ) compared with ethylamine benzoate (EDAB). The resin composites were mechanically blended using 35 wt% of an organic matrix and 65 wt% of filler loading. To this matrix was added 0.2 wt% of CQ and 0.2 wt% of one of the reducing agents tested. 5x1 mm samples (n=5) were previously submitted to DC measurement and then pre-immersed in complete culture medium without 10% (v/v) bovine serum for 1 h or 24 h at 37 °C in a humidifier incubator with 5% CO2 and 95% humidity to evaluate the cytotoxic effects of experimental resin composites using the MTT assay on immortalized human keratinocytes cells. As a result of absence of normal distribution, the statistical analysis was performed using the nonparametric Kruskal-Wallis to evaluate the cytotoxicity and one-way analysis of variance to evaluate the DC. For multiple comparisons, cytotoxicity statistical analyses were submitted to Student-Newman-Keuls and DC analysis to Tukey's HSD post-hoc test (=0.05). No significant differences were found between the DC of DMPOH (49.9%) and EDAB (50.7%). 1 h outcomes showed no significant difference of the cell viability between EDAB (99.26%), DMPOH (94.85%) and the control group (100%). After 24 h no significant difference were found between EDAB (48.44%) and DMPOH (38.06%), but significant difference was found compared with the control group (p>0.05). DMPOH presented similar DC and cytotoxicity compared with EDAB when associated with CQ.

O objetivo deste estudo foi avaliar o grau de conversão (GC) e a citotoxicidade de resinas compostas experimentais utilizando o álcool 4-(N,N-dimetilamino) fenil etílico (DMPOH) associado à canforoquinona (CQ) como sistema fotoiniciador (SF) comparado à versão comercial utilizando o benzoato de etilamina (EDAB). Para tanto, as resinas compostas experimentais foram mecanicamente misturadas utilizando (em peso): 35% de matriz orgânica e 65% em peso de partículas de carga. Posteriormente, foram adicionados 0,2% de CQ e 0,2% de um dos agentes redutores testados. Amostras de 5 x 1 mm (n=5) foram previamentes submetidas à análise de GC e posteriormente, esterilizadas e colocadas no meio de cultura completo sem soro fetal bovino estéril por 1 h ou 24 h a 37 °C em encubadora com 5% de CO2 and 95% de umidade para avaliar os efeitos citotóxicos das resinas compostas experimentais utilizando o método MTT emcélulas células humanas imortalizadas de queratinócitos. Os dados de citotoxicidade foram submetidos à análise estatística de Kruskal-Wallis e de GC à análise de variância com um fator. Em virtude da ausência de normalidade, a análise estatística da citotoxicidade foi realizada utilizando-se o teste não-paramétrico de Kruskal-Wallis. Para o GC, os dados foram submetidos à análise de variaância de 1 fator. Posteriormente para múltiplas comparações, os dados de citotoxicidade foram submetidos ao teste Student-Newman-Keuls e o GC ao teste de Tukey's HSD post-hoc (=0.05). Não foi observada diferença estatística entre o GC de DMPOH (49,9%) e EDAB (50,7%). Para os resultados de 1 h não houve diferença na viabilidade celular entre EDAB (99,26%), DMPOH (94,85%) e o grupo controle (100%). Após 24 h, nenhuma diferença estatística foi encontrada entre EDAB (48,44%) e DMPOH (38,06%), entretanto, diferença significativa foi encontrada em relação ao grupo controle (p>0,05). O DMPOH apresentou GC e citotoxicidade semelhante à EDAB quando associado à CQ.

Expression of procaspase 3 and activated caspase 3 and its relevance in hormone-responsive gallbladder carcinoma chemotherapy

BACKGROUND/AIMS: The higher incidence of gallbladder cancer (GBC) in females has been accredited to the involvement of hormones. The clinical implications of sex hormone receptors in GBC are well established. Cysteine proteases (such as caspase-3-9, etc.) are known to play a central role in the apoptotic pathway. Of these, the downstream enzyme caspase-3 is often activated in the apoptotic pathway. The aim of this work was to examine the status of apoptosis (which directly correlated with the level of active caspase-3) in hormone-responsive GBC. METHODS: We used 10 androgen receptor (AR)-positive, 14 estrogen receptor (ER)-positive, 12 HER/neu-positive, eight triple positive, and 10 triple negative malignant GBC human tissue samples. We isolated the total cellular protein from tumor tissues and carried out Western blotting using antipro-caspase-3 and anti-activated caspase-3 antibodies. RESULTS: ER and HER/neu-positive GBC exhibited high caspase-3 activity and low procaspase-3 activity, whereas AR-positive GBC showed no significant level of apoptosis. We also evaluated the apoptosis status of triple positive GBC and triple negative GBC, and found significant apoptosis in triple positive GBC. CONCLUSIONS: The results indicate that ER and HER/neu-positive GBCs had active apoptosis, whereas AR-positive GBC was highly resistant to apoptosis.

Manejo paliativo del cáncer de vesícula biliar irresecable o metastásico: Conclusiones del Consenso Latinoamericano de Manejo del Cáncer de Vesícula Biliar / Palliative treatment for locally advanced or metastatic gallbladder cancer: conclusions of the Latin American Consensus meeting for the management of gallbladder cancer

Gallbladder cancer is a rare disease in Western developed countries, but it is a highly prevalent and lethal disease in Chile and other countries in Latin America. No randomized controlled trials have been performed in gallbladder cancer to establish standard treatments. We therefore performed the first Latin American consensus meeting for the management of gallbladder cancer. In this article we present the conclusions of the panel of experts for the palliative treatment of unresectable or metastatic gallbladder cancer based on a review of the literature, the discussion of the participating experts and the opinion of the assistants. The topics reviewed included: 1.- Gallbladder Cancer and Cholangiocarcinoma -are they the same disease?; 2. - Palliative Chemotherapy: Indications, Drugs and Schedules; 3. - Palliative Radiotherapy; 4.- Palliative Surgery; 5.-Management of Malignant Biliary Obstruction.

Infusion chemotherapy with cisplatinum and fluorouracil in the treatment of locally-advanced and metastatic gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) has a poor prognosis. Chemotherapy is traditionally considered to be ineffective. The goal of the current study was to evaluate the efficacy of infusional 5-fluorouracil (5-FU) and cisplatinum (CDDP) in patients with inoperable GBC. MATERIALS AND METHODS: A total of 65 patients with inoperable GBC received palliative chemotherapy with CDDP and 5-FU. All the patients had clinically measurable disease as well as adequate bone marrow, hepatic, and renal function. Response was assessed after three cycles of chemotherapy. RESULTS: A total of 19 patients had locally advanced unresectable cancer and 46 patients had metastatic cancer. There were 39 females and 26 males, with a median age of 50 years. A total of 212 chemotherapy cycles were administered to the patients. Response evaluation after three cycles of chemotherapy revealed complete response in five patients [7.69%; 95% confidence interval (95% CI): 2.87-16.22], partial response in 17 patients (26.15%; 95% CI: 16.57-37.81), stabilization of disease in 9 patients (13.85%; 95% CI: 6.96-23.88), and progression in 21 patients (32.30%; 95% CI: 21.80-44.35). At 6 months 44.6% patients were alive and 18.5% patients were alive at 12 months. The median overall survival was 5.7 months and the median time to disease progression was 3.1 months. This chemotherapy combination was well tolerated. There were no chemotherapy-related deaths. CONCLUSIONS: Infusion chemotherapy with CDDP and 5-FU appears to have a fair amount of activity in patients of inoperable GBC, with acceptable toxicity. Tumor shrinkage following treatment with this regimen enabled surgical resection in two patients. We believe that this promising combination must be tested against gemcitabine-based combinations in patients with inoperable GBC.

Cáncer de vesícula: manejo del dolor y otros síntomas / Gallbladder cancer: pain and other symptoms management

El cáncer de vesícula es generalmente diagnosticado tardíamente, por lo cual manejar adecuadamente los síntomas y optimizar la calidad de vida es fundamental. El dolor es generalmente de origen visceral y en su manejo se privilegia la vía oral y subcutánea, según el concepto de escalera analgésica de la OMS; esto facilita el acceso de los pacientes a la analgesia opioide y a los fármacos coadyuvantes. Los métodos invasivos son: analgesia espinal y bloqueo neurolítico de plexo celíaco.Otros síntomas como náuseas y vómitos, anorexia, astenia, constipación, ictericia y prurito, edema de extremidades, ascitis, singulto y cuadros ansioso-depresivos, se tratan con diversas estrategias farmacológicas y no farmacológicas. La atención de los problemas psicosociales del paciente y su familia es también muy importante. En la experiencia del Instituto Nacional del Cáncer entre 1994 y 2001, se observa un incremento progresivo de los pacientes con cáncer de vesícula avanzado, describiéndose la incidencia, evolución y tratamiento de 120 pacientes con distintos síntomas de una patología cuya sobrevida fue entre 1 y 224 días (promedio 49.8 días) y en los cuales se aplicó un modelo de manejo integral del paciente, bajo el concepto de medicina paliativa.

Gallbladder cancer is diagnosed too late most of the time. For this reason symptomatic management and improve quality of life is essential. Pain has visceral origin and must be alleviated using the WHO analgesic ladder strategy by oral or subcutaneous route. Access of patient to different opioids and coadyuvants is mandatory. Invasive methods for analgesia includes spinal analgesia and neurolityc celiac plexus block. Other symptoms like nausea and vomits, anorexia, asthenia, constipation, jaundice and pruritus, lower limbs oedema, ascites, hiccup, and depressive states, need pharmacological and non pharmacological approach. Psychosocial intervention is advisable. Analysing "Instituto Nacional del Cáncer" experience since 1994 to 2001, a progressive increment in patients with gallbladder cancer is observed, describing the incidence, evolution and management of pain and others symptoms in 120 patients with this pathology. Mean survival of patients was between 1 and 224 days, (mean 49,8 days). An integral management of palliative medicine was applied.

A Phase II Study of Capecitabine Combined with Gemcitabine in Patients with Advanced Gallbladder Carcinoma

Capecitabine and gemcitabine are used in the treatment of a variety of solid tumors including pancreatic and biliary tract carcinomas. The authors evaluated survival, response, and toxicity associated with using a combination of capecitabine and gemcitabine to treat patients with unresectable or metastatic gallbladder adenocarcinoma (GBC). Eligible patients had histologically- or cytologically-confirmed GBC, no prior systemic therapy with capecitabine or gemcitabine, Karnofsky Performance Status 70%, serum total bilirubin up to three times normal, and measurable disease. Treatment consisted of gemcitabine 1000 mg/m2 IV on Days 1 and 8 concurrent with administration of capecitabine 1000 mg/m2 PO BID on Days 1 through 14, on a 3-week cycle. Tumor response was assessed by the response evaluation criteria in solid tumors (RECIST criteria) and survival was calculated from initiation of CapGem therapy. A total of 24 patients were enrolled. Median age at the time of diagnosis was 62 years (range, 41-78 years). Fourteen patients had undergone prior surgery. Results showed that eight patients achieved partial response (33%) with an additional 10 patients achieving stable disease (42%). The overall median time to disease progression was 6.0 months (95% CI, 3.8-8.1 months) and overall survival was 16 months (95% CI, 13.8-18.3 months). The one-year survival rate was 58%. No Grade 4 toxicity was seen. Transient Grade 3 neutropenia/ thrombocytopenia and manageable nausea, hand-foot syndrome and anorexia were the most common toxicities. Our study shows that CapGem is an active and well-tolerated chemotherapy regimen in patients with advanced GBC.

Eficacia de gemcitabina en cáncer de vesícula biliar: experiencia inicial en 4 casos / Efficacy of gemcitabine in gallbladder cancer: report of 4 cases

Surgery continues to be the only curative therapy for gallbladder cancer, but useful in very few patients. Mean survival of patients with gallbladder cancer, that are out of the reach of surgery, is 3 months. The few clinical trials of chemotherapy for this disease, report very low success rates. We report four patients with advanced gallbladder cancer, treated with gemcitabine in an intravenous dose of 1000 mg/m2, given in 30 min, once a week during three consecutive weeks, every 28 days. There was a partial response that lasted 40,3 23,2 weeks with a mean survival of 59,75 17 weeks. One patient survives without evidences of disease after 17 months of the diagnosis of an advanced cancer. In all patients, symptoms were alleviated, functional status and quality of life improved. Toxicity was mild and did not require reduction in doses or delay in therapy. Therefore, this medication deserves further investigation for the treatment of gallbladder cancer

Câncer da vesícula biliar / Carcinoma of the gallbladder

A incidência de câncer da vesícula biliar näo é bem conhecida, porém aumenta com a idade em ambos os sexos. A presença de cálculos é considerada um fator de risco importante para o cancer da vesícula. O diagnóstico prediz mau prognóstico com sobrevida em cinco anos, variando de 3 a 5 porcento na maioria das séries. A sobrevida média para pacientes que näo säo submetidos a ressecçäo varia entre dois e seis meses. Está claro, portanto, que o câncer da vesícula biliar é uma doença altamente letal e persistem controvérsias sobre o manuseio ideal. O presente estudo tem por objetivo revisar aspectos relacionados ao diagnóstico e tratamento do câncer da vesícula.(au)

Cáncer de la vesícula biliar. Incidencia en el IGBJ / Gallbladder cancer. Incidence ar the Bolivian Japanese Gastroenterologic Institute (IGBJ)

Entre julio de 1992 y agosto de 1997, se admitieron 4.006 pacientes en el IGBJ. se encontraron 10 casos de cáncer de vesícula biliar (ca-vb). La incidencia en relación a adminisiones fue el 0,25 p/c, en relación a cirugías de la vesícula el 0,75 por ciento. Ocupó el 4§ entre los cánceres del sisteme digestivo con el 7.94

Aspectos clínicos-quirúrgicos del cáncer de vesícula / Clinical surgical aspects of the gallblader neoplasms

Se presentaron 33 carcinomas primarios de la vesícula biliar. Sólo en 4 casos el diagnóstico fue operatorio. Afecta mayormente a mujeres luego de la sexta década de la vida y se calcula su frecuencia entre el 1 y el 2 por ciento de las vesículas extirpadas por litiasis. La colecistectomía simple tuvo buenos resultados en la etapa I de Nevin. En estados avanzados todos los tratamientos carecieron de eficacia. No resultaron de utilidad para prolongar la sobrevida, las resecciones ampliadas, la quimioterapia ni el tratamiento radiante

Tumores malígnos primários da vesícula biliar: estudo de 40 casos

O autor analisa 40 pacientes portadores de tumores malignos primários da vesícula biliar, do Departamento de Cirurgia (Serviço de Cirurgia Geral do Hospital Universitário Clementino Fraga Filho) da Faculdade de Medicina da Universidade Federal do Rio de Janeiro, no período de 15 de março de 1978 a 31 de dezembro de 1989, constituindo 1,9% em relação ao número de intervenções cirúrgicas sobre as vias biliares extra-hepáticas. As idades limítrofes foram de 34 a 88 anos, com uma idade média de 59,5 anos. Foram mais freqüentes no sexo feminino (39 casos - 97,5%), em brancas (31 casos-77,5%) em casadas 50,0%. O câncer da vesícula biliar e uma afecção rara e de comportamento biológico, evolução clínica e possibilidades terapêuticas pouco favoráveis. O tipo histológico mais encontrado foi o adenocarcinoma (37 casos-92,5%). Predominaram as lesões avançadas (estágio v) com 32 casos (80,0%). Os sinais e sintomas mais freqüentes foram: dor abdominal (35 casos - 87,5%), perda de peso (31 casos-77,5%) e icterícia (21 casos - 52,5%). A duração dos sintomas oscilou de dez dias a 30 anos. O diagnóstico pré-operatório de câncer da vesícula biliar, foi feito em apenas quatro casos (10,0%), os quais não foram submetidos a tratamento cirúrgico. A ultra-sonografia do abdome foi realizada em 22 casos (55,0%), a qual fez suspeição ou diagnóstico de câncer da vesícula biliar em dez casos (45,5%). A tomografia computadorizada do abdome foi de real valia, sendo que, em dois, contraindicou o tratamento cirúrgico, pelo estágio avançado da doença. A afecção associada, predominante na maioria da nossa casuística, foi a colelitíase (28 casos - 70,0%). Os procedimentos cirúrgicos utilizados foram múltiplos e variados, em função do estágio evolutivo da doença. As complicações pós-operatórias imediatas, ocorreram em 44,4% dos pacientes e tardias em 23,3%. A sobrevida dos pacientes variou de seis dias a três anos, sete meses e 22 dias,cuja sobrevida média foi significativamente baixa (5,5 meses) e a de cinco anos nula. A sobrevida global de um ano, segundo o método de KALAN & MEIER foi de 15,0%

The author analyzes 40 patients bearing primary malignant tumor of the gall’bladder, in the Surgery Department (“Serviço de Cirurgia Geral - Hospital Universitario Clementino Fraga Filho”) of the “Universidade Federal do Rio de Janeiro” Medical School, from March 15th, 1978, to December 31st, 1989, consisting of 1,9% of the number of surgical interventions on the extrahepatic biliary ducts. The ages ranged from 34 to 88 years old, with an average of 59,5 years old. They were more frequent in females (39 cases - 97.5%), white (31 cases-77, 5%) and married (50,0%). The gall’bladder cancer is a rare affection having an unfavorable biological behavior, clinical course and therapeutic possibilities. The most frequently found histological pattern was adenocarcinoma (37 cases - 92, 5%). Advanced lesions (stage V) were predominant (32 cases - 80.0%). The most frequently signs and symptoms were abdominal pain (35 cases - 87.5%), weight loss (31 cases-77, 5%) and jaundice (21 cases - 52.5%). Symptoms lasted from ten days to 30 years. Preoperative diagnosis of gall’bladder cancer was done in only four cases (10.0%), who were not subjected to surgical treatment. The abdominal ultrasonography was carried out in 22 cases (55.0%), with a suspicion or diagnosis of gall’bladder cancer in ten cases (45.5%). The abdominal computerized tomography was of real value and, in two cases, it counterindicated surgical treatment, due to the disease advanced stage. The predominant accompanying affection in our study was cholelithiasis (28 cases - 70.0%). The used surgical procedures were many and varied, according to the disease progress. Immediate post-operative complications occurred in 44.4% of patients and late ones in 23.3%. The patients survival ranged from six days to three years, seven months and 22 days, the average survival being significantly low (5.5 months) and the five year survival null. The one year global survival, according to KALAN & MEIER method, was 15.0%