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1.
Jpn J Clin Oncol ; 50(6): 635-642, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32372090

RESUMO

BACKGROUND: Regular endoscopic surveillance for Lynch syndrome is reported to reduce colorectal cancer (CRC)-related mortality. However, the appropriate surveillance intervals are still unclear. We evaluated the adequacy of annual colonoscopy and investigated the differences in tumor occurrence rates between individual patients. METHODS: In total, 25 patients with Lynch syndrome who underwent colonoscopic surveillance between 2007 and 2016 at the Iwakuni Clinical Center were included. We retrospectively investigated the surveillance frequency and the clinical features associated with tumor development. RESULTS: Colonoscopic surveillance was performed every 397 days on average. A total of 101 tumors, including 8 intramucosal carcinomas and 15 carcinomas, were observed within the study period. Annual colonoscopy detected six malignancies, including a carcinoma requiring surgery. Tumor incidence was associated with tumor existence in the initial colonoscopies (P = 0.018). Patients with a tumor occurrence rate of 0.4 tumors per year during our observation period were significantly more likely to have malignancies detected during regular surveillance than patients who had a lower occurrence rate (P < 0.001). Malignancy occurrence rate was strongly associated with tumor occurrence rate (P < 0.001, R2 = 0.44). CONCLUSIONS: Annual colonoscopic surveillance for Lynch syndrome patients was effective in reducing the risk of CRC progression, but was insufficient to completely avoid surgery. Because the tumor occurrence rate differed substantially between individuals, more intensive surveillance was required for high-risk patients.


Assuntos
Variação Biológica da População , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/diagnóstico , Adulto , Idoso , Colonoscopia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Estudos Retrospectivos
2.
BMC Cancer ; 20(1): 191, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143595

RESUMO

BACKGROUND: This case represents the first report of malignant primary cardiac tumour in a patient with Lynch Syndrome associated with MSH2 pathogenic variant. CASE PRESENTATION: A 57-year-old woman with previous ovarian cystadenocarcinoma was admitted to the emergency room for hematic pericardial effusion. Multimodal diagnostic imaging revealed two solid pericardial vascularized masses. After pericardiectomy, the final histological diagnosis was poorly differentiated pleomorphic sarcomatoid carcinoma. During follow-up she developed an ampulla of Vater adenocarcinoma. Genetic analysis identified an MSH2 pathogenic variant. CONCLUSION: This case contributes to expand the tumour spectrum of Lynch syndrome, suggesting that MSH2 pathogenic variants cause a more complex multi-tumour cancer syndrome than the classic Lynch Syndrome. In MSH2 variant carriers, symptoms such as dyspnoea and chest discomfort might alert for rare tumours and a focused cardiac evaluation should be considered.


Assuntos
Adenocarcinoma/complicações , Ampola Hepatopancreática/patologia , Carcinoma/complicações , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Cardíacas/complicações , Proteína 2 Homóloga a MutS/genética , Derrame Pericárdico/complicações , Pericárdio/patologia , Carcinoma/cirurgia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Seguimentos , Mutação em Linhagem Germinativa , Neoplasias Cardíacas/cirurgia , Humanos , Pessoa de Meia-Idade , Linhagem , Pericardiectomia , Pericárdio/cirurgia , Resultado do Tratamento
3.
Gastroenterology ; 158(4): 895-904.e1, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31520613

RESUMO

BACKGROUND & AIMS: Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. METHODS: We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. RESULTS: We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%-43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%-36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5-46.1) than white-light endoscopy (23.4%; 95% CI 16.9-31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P < .001). CONCLUSIONS: In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.


Assuntos
Adenoma/diagnóstico , Colonoscopia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Vigilância da População/métodos , Adenoma/congênito , Adulto , Neoplasias Colorretais/congênito , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
4.
Jpn J Clin Oncol ; 50(1): 80-88, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31665498

RESUMO

BACKGROUND: The prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet. METHODS: A total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated. RESULTS: The frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that age<70 years (P = 0.04), ureter as the tumor location (P = 0.052), previous history/synchronous diagnosis of colorectal cancer (P < 0.01) and fulfillment of the criteria per the revised Bethesda guideline (P < 0.01) tended to be or were significantly associated with high-level microsatellite instability/mismatch repair loss. CONCLUSIONS: The prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Neoplasias Urológicas/epidemiologia , Neoplasias Urológicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas , Carcinoma de Células de Transição/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Detecção Precoce de Câncer/métodos , Feminino , Testes Genéticos , Humanos , Imuno-Histoquímica , Japão/epidemiologia , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Síndromes Neoplásicas Hereditárias , Prevalência , Sistema Urinário/patologia , Neoplasias Urológicas/complicações
6.
Gan To Kagaku Ryoho ; 47(13): 2257-2259, 2020 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-33468926

RESUMO

Endometrial cancer(EC)is often the sentinel cancer in women with Lynch syndrome(LS), but the actual incidence of EC as the sentinel cancer in patients with LS is not well-known in Japan. We investigated the history of malignancies and incidence of sentinel cancers in patients with LS-associated EC and their relatives. We examined 8 patients with LS-associated EC between 2005 and 2019. Five of them(63%)had suffered from a cancer other than EC, while 5(63%)had developed a cancer after EC. Seven patients(88%)had EC as the sentinel cancer, while 1(13%)developed colorectal cancer before EC. Among first-degree relatives(15 men and 23 women), 15(40%)had a history of cancer, of whom 7 were women (30%). Five women(22%)had EC, all sentinel. Among second-degree relatives(40 men, 44 women, 14 unknown), 16 (16%)had cancer. Four women(9%)had a history of cancer, of whom 2(5%)had EC, all sentinel. Although we only investigated a few LS cases, the importance of EC as the sentinel cancer was highlighted in Japanese women with LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias do Endométrio , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/epidemiologia , Feminino , Humanos , Incidência , Japão
7.
Scand J Gastroenterol ; 54(12): 1473-1480, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31829749

RESUMO

Background: Lifetime incidence of colorectal cancer (CRC) especially in carriers of MLH1 and MSH2 pathogenic germline variants in mismatch repair genes is high despite ongoing colonoscopy surveillance. Lynch syndrome (LS) registries have been criticized for not reporting colonoscopy quality adequately.Methods: Prospective follow-up data from the national registry were combined with a retrospective assessment of the colonoscopy reports from Helsinki University Hospital electronic patients records in 2004-2019.Results: Total of 366 MLH1, MSH2 and MSH6 carriers underwent 1564 colorectal endoscopies (mean 4.3 per patient, range 1-10) at a single unit. At least one subsequent examination was performed on 336 patients.Bowel preparation was suboptimal (Boston Bowel Preparation Scale 0-2) on either right or left side of the colon in 12.9% of planned surveillance examinations. Caecal intubation rate for full-length colonoscopies was 98.9%. Adenoma detection rate (ADR) was 15.8% in 2004-2014 but substantially increased (21.9%) after introduction of high-definition (HD) technology in 2015-2019 (p = .004; 18.7% across all examinations).CRCs were detected in 23 cases. Nineteen cancers were detected after 977 optimal quality colonoscopies and 4 after 151 compromised quality (BBPS <3 or non-complete examination; p = .16). Advanced neoplasias were not more frequently reported after compromised quality examinations.Conclusion: The majority of LS-associated incident CRCs were detected after colonoscopies with proper bowel preparation and complete examination. There is a considerable time trend towards higher ADR after introducing HD technology of endoscopes. The effect of time trend in ADR to CRC incidence in LS needs to be studied in larger, prospective settings.


Assuntos
Adenoma/diagnóstico , Colonoscopia/normas , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/epidemiologia , Vigilância da População , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Finlândia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sistema de Registros , Estudos Retrospectivos
8.
Tex Med ; 115(12): e1, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31800088

RESUMO

In 2016, the UT Southwestern Medical Center's Cancer Genetics Program was awarded a grant (PP160103) by the Cancer Prevention and Research Institute of Texas (CPRIT) to increase awareness of hereditary cancer syndromes, particularly Lynch syndrome (LS), and implement a population-based genetic screening program to identify those at high genetic risk for cancer.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer , Família , Testes Genéticos , Programas de Rastreamento , Anamnese , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/genética , Feminino , Humanos , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Fatores de Risco , Texas
9.
Medicine (Baltimore) ; 98(51): e18279, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860975

RESUMO

RATIONALE: Lynch syndrome (LS) is an autosomal dominant cancer predisposition condition caused by germline heterozygous mutations in mismatch repair (MMR) genes. However, as one of the MMR genes, PMS2 mutation-induced LS-associated endometrial cancer (LSAEC) was rarely reported. PATIENT CONCERNS: A 26-year-old female patient suffered from prolonged menstrual period and increased menstrual flow for 2 months. DIAGNOSES: The patient was diagnosed with cervix CIN III, endometrial cancer (EC), anemia, and LS. INTERVENTIONS: Total hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy were performed for treating EC, while ovariectomy was refused by the patient. The patient underwent postoperative chemotherapy with paclitaxel combined with carboplatin for 6 courses of treatment. Laparoscopic partial enterectomy was applied for treating colon cancer 5 years later after the surgery treatment for EC. Besides, Sanger sequencing and high-throughput genome sequencing were employed to detect the genetic status of the family that included two generations with four members. Immunohistochemistry (IHC) staining was used to identify the function of PMS2 mutation. OUTCOMES: The 26-year-old Chinese patient suffered from LSAEC and recovered well after surgery. A PMS2 germline heterozygous mutation (c.1577delA) was confirmed by gene sequencing 5 years later. In addition, PMS2 mutation was verified by IHC. The patient was followed up for 7 years. LESSONS: Carrying PMS2 germline mutation (c.1577delA) confers an extremely high susceptibility of suffering from LS-associated cancers. Thus, close clinical monitoring and prophylactic surgery are highly recommended to reduce the morbidity and mortality of LS-associated cancers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias do Endométrio/genética , Mutação em Linhagem Germinativa/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Humanos
10.
Br J Cancer ; 121(10): 869-876, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31551580

RESUMO

BACKGROUND: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. METHODS: This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. RESULTS: Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Colesterol/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/sangue , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Molécula de Adesão da Célula Epitelial/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Modelos de Riscos Proporcionais , Fatores de Risco , Triglicerídeos/sangue
11.
World Neurosurg ; 132: 219-222, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31491579

RESUMO

BACKGROUND: Lynch syndrome (LS) is a cancer-predisposing condition resulting from germline mutations in deoxyribonucleic acid mismatch repair genes. Patients are at high risk for a multitude of tumors, but no reports of undifferentiated sellar carcinomas have previously been described. CASE DESCRIPTION: A 56-year-old female with LS due to MSH2 and MSH6 mutations presented with panhypopituitarism and a sellar mass. She was initially diagnosed with pituitary apoplexy and treated nonoperatively. The mass self-resolved. The mass recurred 2 years later, and she underwent endoscopic endonasal biopsy demonstrating an undifferentiated carcinoma of the sella with MSH2 and MSH6 loss. The tumor was negative for pituitary markers and weakly positive for p63. The patient further developed lung and bone metastases and was treated with radiation and chemotherapy. CONCLUSIONS: This is the first report of an undifferentiated carcinoma of the sella. Our patient harbored a diagnosis of LS and demonstrated local tumor recurrence and aggressive systemic progression. Patients with LS should undergo close follow-up and active surveillance to detect and treat these aggressive lesions in a timely manner.


Assuntos
Carcinoma/complicações , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Hipofisárias/complicações , Neoplasias Ósseas/secundário , Carcinoma/patologia , Carcinoma/cirurgia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Terapia Combinada , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Biópsia Guiada por Imagem , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Recidiva Local de Neoplasia , Procedimentos Neurocirúrgicos/métodos , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Tomografia Computadorizada por Raios X
12.
Rev Med Liege ; 74(9): 479-483, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31486319

RESUMO

Lynch syndrome is a hereditary predisposition to several cancers. The goals of our study were to know the different mutations in our Lynch population, to evaluate the prevalence of cancers in this population and to determine the mean age of onset of those cancers. This retrospective study includes proven carriers of a MMR mutation diagnosed either by the CHU of Liège or either by the CHC Saint-Joseph in Liège, Belgium. We noted a clear majority of MSH2 mutations (50 %) in the Lynch families recorded in Liège, which is different from the main literature. In our study population (106 subjects), 65 % of subjects were affected by at least one cancer. Prevalences for colorectal and endometrial cancers are, respectively, 50 % and 27.5 %. We found no difference in the mean age of onset of cancers compared to literature. We discuss the follow-up of Lynch patients and the interest of additional exams such as hysteroscopy and cystoscopy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias do Endométrio , Predisposição Genética para Doença , Bélgica , Neoplasias Colorretais/etiologia , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/etiologia , Feminino , Humanos , Mutação , Estudos Retrospectivos
13.
Pathologe ; 40(6): 584-591, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31372733

RESUMO

BACKGROUND: Hereditary nonpolyposis colorectal cancer (Lynch/HNPCC syndrome) is based on a germline mutation inducing increased occurrence of colorectal cancer and extracolonic carcinomas in young age. The German HNPCC consortium aims to increase awareness for detection of hereditary colon cancer among patients and physicians. OBJECTIVES: Reliable detection of HNPCC patients is based on a thorough documentation of patients' medical history and on further diagnostics delivered by human genetics and surgical pathology. This manuscript presents a standardized diagnostic concept. METHODS: Relevant literature is reviewed and discussed and diagnostic parameters are outlined. In addition, operating figures of the German HNPCC consortium are presented. RESULTS: The German HNPCC consortium is based on an efficient cooperation between clinical physicians, human geneticists, and surgical pathologists. After a funding period from the Deutsche Krebshilfe, HNPCC diagnostics and preventive medical examinations were transferred into standard care in Germany. In total, 5770 families (8873 patients) were included in HNPCC diagnostics. To date, in 1296 families, mutations of the MLH1-, MSH2-, MSH6-, PMS2-, or EPCAM-gene have been detected. Furthermore, 612 pathogenic variants and 325 variants of unknown significance were found. CONCLUSIONS: Reliable detection of HNPCC patients is based on a standardized diagnostic concept, which has been established within the German HNPCC consortium.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Colo/complicações , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Alemanha , Humanos , Mutação
14.
Oncologist ; 24(11): 1416-1419, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31444293

RESUMO

Immune checkpoint blockade (ICB) is an approved therapy for advanced metastatic mismatch repair (MMR)-deficient cancer regardless of tissue of origin. Although therapy is effective initially, recurrence rates are significant, and long-term outcomes remain poor for most patients. It is not currently recommended to give sequential ICB for advanced MMR-deficient colorectal cancer (CRC) or for patients with metastatic cancer from Lynch syndrome. The need for subsequent therapy options in advanced MMR-deficient cancer beyond the first ICB regimen arises in clinical practice, and there are often no effective standard chemotherapies or other targeted therapies. We report the case of a Lynch syndrome patient with metastatic CRC and urothelial cancer who was treated sequentially with pembrolizumab (targeting PD1), atezolizumab (targeting PD-L1), brief rechallenge with pembrolizumab, and finally the combination of ipilimumab (targeting CTLA-4) and nivolumab (targeting PD1). Over a 28-month period the patient experienced prolonged disease control with each different regimen the first time it was given, including metabolic response by positron emission tomography and computed tomography scanning and tumor marker reductions. The case suggests that some patients with advanced MMR-deficient CRC may experience meaningful clinical benefit from multiple sequential ICB regimens, a strategy that can be further tested in clinical trials. KEY POINTS: The case exemplifies clinical benefit from sequential immune checkpoint blockade in a patient with Lynch syndrome with advanced metastatic colorectal cancer and urothelial cancer.Metabolic response, with decreased fluorodeoxyglucose avidity on positron emission tomography and computed tomography, and reductions in tumor markers, such as carcinoembryonic antigen, were helpful in this case to monitor disease status over a 28-month period of therapy.The concept of sequential immune checkpoint blockade in patients with advanced mismatch repair-deficient cancer merits further study to determine which patients are most likely to benefit.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Urológicas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias do Colo/complicações , Neoplasias do Colo/secundário , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Humanos , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Prognóstico , Neoplasias Urológicas/complicações , Neoplasias Urológicas/patologia
15.
Curr Treat Options Oncol ; 20(10): 75, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444655

RESUMO

OPINION STATEMENT: Research into novel therapies for gynecologic cancers is underfunded, and as a result, we are still playing catchup with other solid tumors in the realm of immune checkpoint inhibition. This is despite the fact that two of the most common gynecologic cancers in the USA have strong biologic rationales for response to these agents. Work is now underway to demonstrate safe and effective therapies for our patients. As we better understand the immune system, and more specifically the tumor microenvironment, we will be able to achieve complete responses. The immune system can learn, adapt, and provide ongoing surveillance; if only we could mimic its abilities.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/etiologia , Terapia de Alvo Molecular , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Suscetibilidade a Doenças , Feminino , Neoplasias dos Genitais Femininos/diagnóstico , Humanos , Imunoterapia , Microambiente Tumoral/efeitos dos fármacos
16.
Oral Oncol ; 97: 137-138, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31445773

RESUMO

For patients with Lynch Syndrome (LS) (formerly known as hereditary nonpolyposis colorectal cancer or HNPCC), inheritance of one of several mutated mismatch repair genes (MMR) results in an increased risk for a variety of malignancies including colon, rectal, endometrial, urinary tract, gastric, small bowel and others [1]. Confirmation of increased risk of particular malignancies for patients harboring an MMR germline mutation has typically been the result of population studies of families tracked for the development of the possible associated cancer. When cancer results from inheritance of a particular mutated MMR gene, the malignancy has a characteristic fingerprint referred to as microsatellite instability-high (MSI-H), which results from deficient expression of the inherited MMR gene product (dMMR). Therefore, if sporadic tumors of a particular tissue of origin are only rarely dMMR, identifying a tumor as dMMR in a known LS family member suggests that, in that particular family, inheritance of the mutated MMR gene does predispose to that malignancy. Here we describe a patient diagnosed with a germline mutation in the MMR gene MSH6 who developed an oral pharynx cancer. Oral pharynx cancers are not known to be associated with LS. By confirming that the tumor was not dMMR and not MSI-H, it was concluded that his oral pharynx cancer was sporadic, rather than LS-related, and other family members carrying the mutated MSH6 are unlikely to be at above-average risk for the development of oral cancers, as a result of the LS. In additional, he would not be eligible for the so-called FDA agnostic approved immunotherapy which is endorsed for dMMR or MSI-H tumors [2].


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Bucais/etiologia , Neoplasias Bucais/genética , Neoplasias de Células Escamosas/etiologia , Neoplasias de Células Escamosas/genética , Idoso , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Risco
17.
PLoS One ; 14(8): e0221419, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31469860

RESUMO

BACKGROUND: Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer. METHODS: A decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used. RESULTS: Reflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over. CONCLUSIONS: Testing for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/economia , Análise Custo-Benefício , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/economia , Adulto , Fatores Etários , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Testes Genéticos/economia , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Reflexo/genética , Reino Unido/epidemiologia
18.
Cancer Commun (Lond) ; 39(1): 42, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307542

RESUMO

BACKGROUND: The prevalence of Lynch syndrome and screening strategies for this disorder in Chinese patients with endometrial cancer have seldom been investigated. Such data would be essential for the screening, prevention, genetic counseling, and treatment of Lynch syndrome. The purpose of this prospective study was to determine the accuracy of the mismatch repair (MMR) protein immunohistochemistry (IHC), microsatellite instability (MSI) test, and clinical diagnostic criteria in screening for Lynch syndrome-associated endometrial cancer (LS-EC) in a prospective Chinese cohort. METHODS: All patients with newly diagnosed endometrial cancer (EC) were evaluated using clinical diagnostic criteria (Amsterdam II criteria and the revised Bethesda guidelines), MSI test, and IHC of MMR proteins in tumor tissues. For all patients, the screening results were compared with results of germline sequencing for pathogenic variants of MMR genes. RESULTS: Between December 2017 and August 2018, a total of 111 unselected patients with newly diagnosed EC were enrolled. Six patients (5.4%) harbored a pathogenic germline mutation of MMR genes: 1 had a mutation in MutL homolog 1 (MLH1), 2 in MutS homolog 2 (MSH2), and 3 in MutS homolog 6 (MSH6). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying LS-EC were 33.3%, 88.6%, 14.3%, and 95.9%, for the clinical criteria, 66.7%, 75.0%, 14.3%, and 97.3% for IHC of MMR proteins, 100%, 89.9%, 33.3%, and 100% for MSI test, and 100%, 72.4%, 20.0% and 100% for combined IHC and MSI test, respectively. The combination of IHC and MSI test had higher sensitivity and PPV than the clinical criteria (p = 0.030). MSI test and IHC were highly concordant for LS-EC screening (73/77, 94.8%). CONCLUSION: The accuracy of the combination of IHC of MMR proteins and MSI test for screening LS among Chinese patients with EC was superior to that of the clinical criteria. Trial registration NCT03291106. Registered on September 25, 2017.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/diagnóstico , Programas de Rastreamento/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Mutação em Linhagem Germinativa , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Estudos Prospectivos
19.
Fam Cancer ; 18(4): 399-420, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31236808

RESUMO

Lifestyle factors related to energy balance, such as excess body weight, poor diet, and physical inactivity, are associated with risk of sporadic endometrial cancer (EC) and colorectal cancer (CRC). There are limited data on energy balance-related lifestyle factors and EC or CRC risk among individuals with lynch syndrome, who are at extraordinarily higher risk of developing EC or CRC. We conducted a systematic review of evidence related to weight status, weight change, dietary habits, and physical activity on EC and CRC risk among individuals with lynch syndrome. Findings are reported narratively. We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to June 14th, 2018. In total, 1060 studies were identified and 16 were included. Three studies were related to EC and 13 to CRC. Overall, evidence suggests that weight status/weight change may not be associated with EC risk and multivitamin and folic-acid supplementation may be associated with decreased EC risk. Early-adulthood overweight/obese weight-status and adulthood weight-gain may be associated with increased CRC risk, whereas multivitamin supplementation, tea and high fruit intake, and physical activity may be associated with decreased CRC risk. Current evidence proposes that recommendations related to weight, some dietary habits, and physical activity recommended for the general public are also relevant to individuals with lynch syndrome. More research is needed, specifically prospective cohorts and randomized controlled trials, to determine if tailored recommendations are needed among individuals with lynch syndrome.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/etiologia , Neoplasias do Endométrio/etiologia , Ingestão de Energia , Estilo de Vida , Peso Corporal , Neoplasias do Endométrio/prevenção & controle , Metabolismo Energético , Exercício Físico , Comportamento Alimentar , Feminino , Ácido Fólico/farmacologia , Humanos , Masculino , Vitaminas/farmacologia
20.
Genet Med ; 21(12): 2706-2712, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31204389

RESUMO

PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias. METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level. RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women. CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/etiologia , Medição de Risco/métodos , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Mutação , Fatores de Risco
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