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1.
BMC Gastroenterol ; 21(1): 67, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579196

RESUMO

BACKGROUND: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions. METHODS: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power. DISCUSSION: TC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy. TRIAL REGISTRATION: Clinical Trials: NCT04180033, November 27, 2019, https://clinicaltrials.gov/ct2/show/NCT04180033 .

2.
Am J Epidemiol ; 190(2): 230-238, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524116

RESUMO

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.

4.
Cancer Epidemiol ; 69: 101809, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32947154

RESUMO

BACKGROUND: Persons with Lynch syndrome (LS) have an increased risk of developing colorectal tumors (CRTs). Adherence to diet quality indices associated with colorectal cancer (CRC) risk in the general population has not been studied before in LS. METHODS: Dietary habits of 490 participants with LS from a prospective cohort study was collected using a food frequency questionnaire. The Dutch Healthy Diet index 2015 (DHD15-index) and Dietary Approaches to Stop Hypertension (DASH) were used to score food-based diet quality. Diet quality scores were divided into tertiles where a higher tertile reflects a higher diet quality. Multivariable Cox proportional hazard regression models were used to estimate the association between the DHD15-index, DASH score and CRT risk. RESULTS: During a median follow-up time of 53.4 months, 210 participants (42.9%) developed CRTs. The DHD-index and DASH score were not associated with CRT risk; hazard ratios for highest vs. lowest tertile were 1.00 (95% Confidence Interval (CI): 0.67-1.48) and 1.11 (95% CI: 0.74-1.69), respectively. No linear trends across the DHD-index and DASH score tertiles were observed (P-trend = 0.97 and 0.83 respectively). CONCLUSION: In contrast to observations in the general population, no evidence for an association between the food-based DHD15-index or DASH score and CRT risk was observed in persons with LS. Further studies are needed investigating the association between diet quality and mechanisms leading to the development of LS-associated tumors.

5.
Am J Epidemiol ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32803246

RESUMO

Persons with Lynch syndrome (LS - carrying a pathogenic mutation in a DNA mismatch repair gene) have an increased colorectal cancer (CRC) and endometrial cancer (EC) risk. A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for LS. We aimed to investigate the association between height and CRC and EC for persons with LS using two large studies. Information of 1,213 men and 1,636 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch cohort study (2006-2017) was harmonized. We used weighted Cox proportional hazard regression models with age on the time-axis to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for each 5 cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation and 171 women were diagnosed with EC during 39,227 person-years of observation. Height was not associated with CRC for men (HR 1.00 per 5 cm, 95%CI: 0.91, 1.11) or women (HR 1.01 per 5 cm, 95%CI: 0.92, 1.11). Nor was height associated with EC (HR 1.08 per 5 cm, 95%CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC for persons with LS.

6.
Lancet Oncol ; 21(8): e386-e397, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32758476

RESUMO

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.


Assuntos
Síndromes Neoplásicas Hereditárias , Neoplasias Gástricas , Humanos
7.
Fam Cancer ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770331

RESUMO

A cancer diagnosis is suggested to be associated with changes in dietary and lifestyle habits. Whether this applies to persons with familial cancer, such as Lynch syndrome (LS) is unknown. We investigated whether a colorectal neoplasm (CRN) diagnosis in persons with LS is associated with changes in dietary and lifestyle habits over time. We used data of confirmed LS mutation carriers from the GEOLynch study, a prospective cohort study. Information on dietary intake and lifestyle habits was collected with a validated semi-quantitative food frequency questionnaire and a general questionnaire administered at baseline (2006-2008) and follow-up (2012-2017). Participants' medical records were used to identify CRN diagnoses. Changes in dietary and lifestyle habits in the CRN and the no-CRN group were compared using multivariable linear regression models for continuous variables and cross-tables with percentage change at follow-up compared with baseline for categorical variables. Of the 324 included participants, 146 developed a CRN (CRN group) between baseline and follow-up, while 178 did not (no-CRN group). Smoking cessation was more often reported in the CRN than in the no-CRN group (41.4% vs. 35.0%). There were no differences in changes of energy intake, alcohol, red meat, processed meat, dairy, fruit, vegetables and dietary fiber consumption, BMI, physical activity and NSAID use. Apart from a potentially higher likelihood of smoking cessation, we found little evidence that a CRN diagnosis is associated with changes in lifestyle habits in persons with LS.

8.
Gastrointest Endosc ; 92(1): 166-172, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32105713

RESUMO

BACKGROUND AND AIMS: Endoscopic resection is often feasible for submucosal invasive colorectal cancers (T1 CRCs) and usually judged as complete. If histology casts doubt on the radicality of resection margins, adjuvant surgical resection is advised, although residual intramural cancer is found in only 5% to 15% of patients. We assessed the sensitivity of biopsy specimens from the resection area for residual intramural cancer as a potential tool to estimate the preoperative risk of residual intramural cancer in patients without risk factors for lymph node metastasis (LNM). METHODS: In this multicenter prospective cohort study, patients with complete endoscopic resection of T1 CRC, scheduled for adjuvant resection due to pathologically unclear resection margins, but absent risk factors for LNM, were asked to consent to second-look endoscopy with biopsies. The results were compared with the pathology results of the surgical resection specimen (criterion standard). RESULTS: One hundred three patients were included. In total, 85% of resected lesions were unexpectedly malignant, and 45% were removed using a piecemeal resection technique. Sixty-four adjuvant surgical resections and 39 local full-thickness resections were performed. Residual intramural cancer was found in 7 patients (6.8%). Two of these patients had cancer in second-look biopsy specimens, resulting in a sensitivity of 28% (95% confidence interval, <58%). The preoperative risk of residual intramural cancer in the case of negative biopsy specimens was not significantly reduced (P = .61). CONCLUSIONS: The sensitivity of second-look endoscopy with biopsies for residual intramural cancer after endoscopic resection of CRC is low. Therefore, it should not be used in the decision whether or not to perform adjuvant resection. (Clinical trial registration number: NCT02328664.).

9.
Gut ; 69(1): 112-121, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981990

RESUMO

BACKGROUND AND AIMS: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1-2 years. However, yearly surveillance likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies. METHODS: Between 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance. RESULTS: We followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%[95% CI 0% to 3.2%]). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, p<0.001). Most patients were recommended a 2-year interval, and those recommended a 2-year interval were not at increased risk of AN: AN incidence after a 2-year recommendation was 15.6% compared with 24.4% after a 1-year recommendation (OR 0.57, p=0.08). CONCLUSION: Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance. TRIAL REGISTRATION NUMBER: The study was registered on http://www.trialregister.nl; trial-ID NTR4609.


Assuntos
Polipose Adenomatosa do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/cirurgia , Idoso , Estudos de Coortes , Colonoscopia/métodos , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Sobremedicalização/prevenção & controle , Sobremedicalização/estatística & dados numéricos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Vigilância da População/métodos , Prevalência , Estudos Prospectivos , Fatores de Risco , Espanha/epidemiologia
10.
Eur J Gastroenterol Hepatol ; 31(3): 340-344, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30520764

RESUMO

OBJECTIVES: Serrated polyposis syndrome (SPS) is a relatively new and under-recognized colorectal cancer (CRC) predisposition syndrome. Previous studies have reported miss-rates of SPS diagnosis varying from 40 to 82%. As SPS patients and their first-degree relatives have an increased risk of CRC, early recognition is important. We aimed to determine the miss-rate of SPS and to determine the reasons for missed diagnosis. PATIENTS AND METHODS: We retrospectively identified all patients diagnosed with at least one colorectal polyp or carcinoma detected at our tertiary referral center between January 1986 and July 2013 using the nationwide pathology registry. On the basis of cumulative polyp count with size and location, SPS patients were identified. We checked whether the SPS diagnosis was made in the medical files and, if not, what might have been the reason for missing the diagnosis. RESULTS: We randomly assessed 5000 patients, of whom 25 patients fulfilled the WHO criteria for SPS. In six patients, no previous SPS diagnosis had been made, leading to a miss-rate of 24.0% (95% confidence interval: 7.3-40.7). The reasons for missed diagnosis were polyps removed before establishment of the WHO criteria, unavailable pathology reports, and failure to apply the criteria by the clinician. CONCLUSION: The miss-rate for the diagnosis of SPS is considerable, even during longer follow-up with repeated colonoscopies. A preventable reason for missing SPS cases is failure to apply the WHO criteria. Awareness of this CRC predisposition syndrome needs to be raised to decrease the miss-rate of SPS.


Assuntos
Polipose Adenomatosa do Colo/patologia , Carcinoma/patologia , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Erros de Diagnóstico , Polipose Adenomatosa do Colo/cirurgia , Carcinoma/cirurgia , Pólipos do Colo/cirurgia , Neoplasias Colorretais/cirurgia , Humanos , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária
11.
Cancer ; 125(6): 990-999, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30561773

RESUMO

BACKGROUND: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors. METHODS: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis. RESULTS: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001). CONCLUSIONS: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered.


Assuntos
Pólipos do Colo/epidemiologia , Neoplasias Colorretais/epidemiologia , Doença de Hodgkin/radioterapia , Procarbazina/uso terapêutico , Idoso , Sobreviventes de Câncer , Estudos de Coortes , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
12.
Gastrointest Endosc ; 87(2): 397-404.e2, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28455161

RESUMO

BACKGROUND AND AIMS: The aim of this study was to determine the yield of endoscopic screening in first-degree relatives (FDRs) of CDH1-negative hereditary diffuse-type gastric cancer (HDGC) patients. METHODS: In this retrospective observational cohort study, in 2 expert centers in the Netherlands data were collected on FDRs from families fulfilling the international HDGC criteria that underwent endoscopic screening. Extensive inspection of the stomach was performed by gastroscopy, taking random and/or targeted stomach biopsy specimens to identify diffuse-type gastric cancer. RESULTS: Between 2004 and 2016, 90 persons (40% men; mean age, 48 years) from 40 families were offered endoscopic screening. The mean number of endoscopies per person was 3. The mean follow-up time was 46 months and mean endoscopic interval 20 months. Signet ring cell carcinoma foci restricted to the mucosa (pT1a) were identified in 4 persons (4%) from 1 family, which afterward was diagnosed with a germline CTNNA1 mutation. Advanced poorly cohesive gastric carcinoma was diagnosed in 1 person from another family. Intestinal metaplasia was diagnosed in 38 persons (42%) and low-grade dysplasia in 4 persons (4%). Additionally, in 40 persons (44%) scar tissue was observed in the gastric mucosa, which can hinder the endoscopic detection of small white lesions typical for HDGC. CONCLUSIONS: Endoscopic screening in HDGC families without a pathogenic CDH1 mutation may be reasonable, as we detected signet ring cell carcinomas in 6% of persons screened. However, the criteria and frequency of screening may have to be reconsidered.


Assuntos
Carcinoma de Células em Anel de Sinete/diagnóstico por imagem , Carcinoma de Células em Anel de Sinete/patologia , Gastroscopia , Metaplasia/patologia , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Adulto , Idoso , Antígenos CD , Biópsia , Caderinas/genética , Carcinoma de Células em Anel de Sinete/genética , Detecção Precoce de Câncer/métodos , Feminino , Mucosa Gástrica/patologia , Mutação em Linhagem Germinativa , Humanos , Masculino , Metaplasia/diagnóstico por imagem , Pessoa de Meia-Idade , Linhagem , Estudos Retrospectivos , Neoplasias Gástricas/genética , Adulto Jovem , alfa Catenina/genética
13.
BMC Cancer ; 17(1): 112, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28173773

RESUMO

BACKGROUND: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. METHODS/DESIGN: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived ≥8 years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. DISCUSSION: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. TRIAL REGISTRATION: Registered at the Dutch Trial Registry (NTR): NTR4961 .


Assuntos
Adenoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/economia , Doença de Hodgkin/tratamento farmacológico , Segunda Neoplasia Primária/diagnóstico , Procarbazina/efeitos adversos , Projetos de Pesquisa , Adenoma/induzido quimicamente , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos Antineoplásicos , Colonoscopia , Neoplasias Colorretais/induzido quimicamente , Análise Custo-Benefício , DNA de Neoplasias/análise , Detecção Precoce de Câncer/métodos , Fezes/química , Doença de Hodgkin/radioterapia , Humanos , Imunoquímica , Pessoa de Meia-Idade , Segunda Neoplasia Primária/induzido quimicamente , Procarbazina/uso terapêutico , Estudos Prospectivos , Sobreviventes , Adulto Jovem
14.
Pharmacogenet Genomics ; 27(3): 83-88, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27926584

RESUMO

OBJECTIVE: Proton pump inhibitors (PPIs) are effective drugs for the treatment of gastric acid-related disorders. Serious adverse events are rare for PPIs, but recent data suggest that PPIs cause hypomagnesemia. The aim of this study was to estimate the frequency of PPI-induced hypomagnesemia and to define the risk factors for its development. MATERIALS AND METHODS: A total of 133 chronic users of PPIs were enrolled and patients were distinguished on the basis of their serum Mg concentrations. Common single nucleotide polymorphisms (SNPs) in the candidate gene, transient receptor potential melastatin type 6 (TRPM6), were screened. RESULTS: Seventeen out of 133 patients had PPI-induced hypomagnesemia. The duration of PPI use was longer in those with hypomagnesemia (7.7 vs. 5.2 years). Two common SNPs in TRPM6 (rs3750425 and rs2274924) increased the risk for PPI-induced hypomagnesemia by 5.8-fold. CONCLUSION: We found hypomagnesemia in 13% of PPI users. SNPs in TRPM6 drive the risk of developing hypomagnesemia during chronic PPI use.


Assuntos
Deficiência de Magnésio/induzido quimicamente , Magnésio/sangue , Polimorfismo de Nucleotídeo Único , Inibidores da Bomba de Prótons/administração & dosagem , Canais de Cátion TRPM/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Deficiência de Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Adulto Jovem
15.
Cancer Immunol Immunother ; 65(10): 1249-59, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27060000

RESUMO

Microsatellite instability (MSI), the somatic accumulation of length variations in repetitive DNA sequences called microsatellites, is frequently observed in both hereditary and sporadic colorectal cancer (CRC). It has been established that defects in the DNA mismatch repair (MMR) pathway underlie the development of MSI in CRC. After the inactivation of the DNA MMR pathway, misincorporations, insertions and deletions introduced by DNA polymerase slippage are not properly recognized and corrected. Specific genomic regions, including microsatellites, are more prone for DNA polymerase slippage and, therefore, more susceptible for the introduction of these mutations if the DNA MMR capacity is lost. Some of these susceptible genomic regions are located within the coding regions of genes. Insertions and deletions in these regions may alter their reading frame, potentially resulting in the transcription and translation of frameshift peptides with c-terminally altered amino acid sequences. These frameshift peptides are called neoantigens and are highly immunogenic, which explains the enhanced immunogenicity of MSI CRC. Neoantigens contribute to increased infiltration of tumor tissue with activated neoantigen-specific cytotoxic T lymphocytes, a hallmark of MSI tumors. Currently, neoantigen-based vaccination is being studied in a clinical trial for Lynch syndrome and in a trial for sporadic MSI CRC of advanced stage. In this Focussed Research Review, we summarize current knowledge on molecular mechanisms and address immunological features of tumors with MSI. Finally, we describe their implications for immunotherapeutic approaches and provide an outlook on next-generation immunotherapy involving neoantigens and combinatorial therapies in the setting of MSI CRC.


Assuntos
Antígenos de Neoplasias/metabolismo , Neoplasias Colorretais/terapia , Imunoterapia/métodos , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Neoplasias Colorretais/imunologia , Reparo do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Imunoterapia/tendências , Ativação Linfocitária , Mutação/genética , Linfócitos T Citotóxicos/transplante
16.
Gut ; 65(6): 963-70, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-25753029

RESUMO

OBJECTIVE: Accurate endoscopic differentiation would enable to resect and discard small and diminutive colonic lesions, thereby increasing cost-efficiency. Current classification systems based on narrow band imaging (NBI), however, do not include neoplastic sessile serrated adenomas/polyps (SSA/Ps). We aimed to develop and validate a new classification system for endoscopic differentiation of adenomas, hyperplastic polyps and SSA/Ps <10 mm. DESIGN: We developed the Workgroup serrAted polypS and Polyposis (WASP) classification, combining the NBI International Colorectal Endoscopic classification and criteria for differentiation of SSA/Ps in a stepwise approach. Ten consultant gastroenterologists predicted polyp histology, including levels of confidence, based on the endoscopic aspect of 45 polyps, before and after participation in training in the WASP classification. After 6 months, the same endoscopists predicted polyp histology of a new set of 50 polyps, with a ratio of lesions comparable to daily practice. RESULTS: The accuracy of optical diagnosis was 0.63 (95% CI 0.54 to 0.71) at baseline, which improved to 0.79 (95% CI 0.72 to 0.86, p<0.001) after training. For polyps diagnosed with high confidence the accuracy was 0.73 (95% CI 0.64 to 0.82), which improved to 0.87 (95% CI 0.80 to 0.95, p<0.01). The accuracy of optical diagnosis after 6 months was 0.76 (95% CI 0.72 to 0.80), increasing to 0.84 (95% CI 0.81 to 0.88) considering high confidence diagnosis. The combined negative predictive value with high confidence of diminutive neoplastic lesions (adenomas and SSA/Ps together) was 0.91 (95% CI 0.83 to 0.96). CONCLUSIONS: We developed and validated the first integrative classification method for endoscopic differentiation of small and diminutive adenomas, hyperplastic polyps and SSA/Ps. In a still image evaluation setting, introduction of the WASP classification significantly improved the accuracy of optical diagnosis overall as well as SSA/P in particular, which proved to be sustainable after 6 months.


Assuntos
Adenoma/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/diagnóstico , Imagem de Banda Estreita , Adenoma/classificação , Colonoscopia/métodos , Neoplasias Colorretais/classificação , Humanos , Imagem de Banda Estreita/métodos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
J Nucl Med ; 57(3): 480-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26678613

RESUMO

UNLABELLED: Small and flat adenomas are known to carry a high miss-rate during standard white-light endoscopy. Increased detection rate may be achieved by molecular fluorescence endoscopy with targeted near-infrared (NIR) fluorescent tracers. The aim of this study was to validate vascular endothelial growth factor A (VEGF-A) and epidermal growth factor receptor (EGFR)-targeted fluorescent tracers during ex vivo colonoscopy with an NIR endoscopy platform. METHODS: VEGF-A and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples--48 sessile serrated adenomas/polyps, 70 sporadic high-grade dysplastic adenomas, and 19 hyperplastic polyps--and tissue derived from patients with Lynch syndrome--78 low-grade dysplastic adenomas, 57 high-grade dysplastic adenomas, and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116(luc) tumors received intravenous bevacizumab-800CW (anti-VEGF-A), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW, or sodium chloride. Three days later, 8 resected HCT116(luc) tumors (2-5 mm) were stitched into 1 freshly resected human colon specimen and followed by an ex vivo molecular fluorescence colonoscopy procedure. RESULTS: Immunohistochemistry showed high VEGF-A expression in 79%-96% and high EGFR expression in 51%-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions, compared with the adjacent normal colon crypts. During ex vivo molecular fluorescence endoscopy, all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing, respectively, stromal and cell membrane fluorescence. CONCLUSION: VEGF-A is a promising target for molecular fluorescence endoscopy because it showed a high protein expression, especially in sessile serrated adenomas/polyps and Lynch syndrome. We demonstrated the feasibility to visualize small tumors in real time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field red-flag technique for adenoma detection. Clinical studies are currently being performed in order to provide in-human evaluation of our approach.


Assuntos
Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Endoscopia Gastrointestinal/métodos , Imagem Molecular/métodos , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Colonoscopia/métodos , Receptores ErbB/metabolismo , Fluorescência , Corantes Fluorescentes , Humanos , Imuno-Histoquímica , Camundongos , Reprodutibilidade dos Testes
18.
Endoscopy ; 47(11): 1043-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26126164

RESUMO

BACKGROUND AND STUDY AIMS: The most frequently cited prevalence for serrated polyposis syndrome (SPS) is 1 in every 3000 people screened, but this value is debated. Additionally, changes in 2010 in the World Health Organization (WHO) diagnostic criteria for SPS might affect reported prevalence. An updated estimate of SPS prevalence is necessary to predict the number of cases in screening programs. PATIENTS AND METHODS: A systematic literature search was conducted in the PubMed, EMBASE, and Web of Science databases up to February 2014. Studies reporting the prevalence of SPS, as defined by WHO criteria, in screening populations were selected. RESULTS: Six studies reported prevalence of SPS in screening populations, varying from 0 to 0.66 %. The highest prevalences (0.34 % and 0.66 %) were seen in studies from screening programs with patients pre-selected by fecal blood test. Primary colonoscopy-based screening programs, that have the lowest risk of bias, reported SPS prevalences ranging from 0 to 0.09 %. Across studies, 56 patients were diagnosed with SPS of whom 3 presented with synchronous colorectal cancer at index endoscopy. CONCLUSION: The true prevalence of SPS is unclear because of the risk of bias across studies, but is likely to be below 0.09 % as derived from primary colonoscopy screening programs. The prevalence in pre-selected screening populations after positive fecal testing is higher, with reported values of 0.34 % and 0.66 %. Large and high quality primary colonoscopy screening studies, reporting SPS prevalence in adequately described populations, are necessary for better estimation of the true prevalence of SPS in average-risk patients.


Assuntos
Polipose Intestinal/epidemiologia , Colonoscopia , Europa (Continente)/epidemiologia , Humanos , Polipose Intestinal/diagnóstico , Prevalência , Síndrome , Estados Unidos/epidemiologia
19.
J Med Genet ; 52(6): 361-74, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25979631

RESUMO

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.


Assuntos
Caderinas/genética , Mutação em Linhagem Germinativa , Heterozigoto , Neoplasias Gástricas/genética , Antígenos CD , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Detecção Precoce de Câncer/métodos , Feminino , Aconselhamento Genético , Testes Genéticos/métodos , Humanos , Vigilância da População , Guias de Prática Clínica como Assunto , Gravidez , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia
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