RESUMO
BACKGROUND: Loss of function variants in CDH1 are the most frequent cause of hereditary diffuse gastric cancer. Endoscopy is regarded as insufficient for early detection due to the infiltrative phenotype of diffuse-type cancers. Microscopic foci of invasive signet ring cells are pathognomonic of CDH1 and precede development of diffuse gastric cancer. We aimed to assess the safety and effectiveness of endoscopy for cancer interception in individuals with germline CDH1 variants, particularly in those who declined prophylactic total gastrectomy. METHODS: In this prospective cohort study, we included asymptomatic patients aged 2 years or older with pathogenic or likely pathogenic germline CDH1 variants who underwent endoscopic screening and surveillance at the National Institutes of Health (Bethesda, MD, USA) as part of a natural history study of hereditary gastric cancers (NCT03030404). Endoscopy was done with non-targeted biopsies and one or more targeted biopsy and assessment of focal lesions. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Procedural morbidity, gastric cancer detection by endoscopy and gastrectomy, and cancer-specific events were assessed. Screening was defined as the initial endoscopy and all subsequent endoscopies were considered surveillance; follow-up endoscopy was at 6 to 12 months. The primary aim was to determine effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma. FINDINGS: Between Jan 25, 2017, and Dec 12, 2021, 270 patients (median age 46·6 years [IQR 36·5-59·8], 173 [64%] female participants, 97 [36%] male participants; 250 [93%] were non-Hispanic White, eight [3%] were multiracial, four [2%] were non-Hispanic Black, three [1%] were Hispanic, two [1%] were Asian, and one [<1%] was American Indian or Alaskan Native) with germline CDH1 variants were screened, in whom 467 endoscopies were done as of data cutoff (April 30, 2022). 213 (79%) of 270 patients had a family history of gastric cancer, and 176 (65%) reported a family history of breast cancer. Median follow-up was 31·1 months (IQR 17·1-42·1). 38 803 total gastric biopsy samples were obtained, of which 1163 (3%) were positive for invasive signet ring cell carcinoma. Signet ring cell carcinoma was detected in 76 (63%) of 120 patients who had two or more surveillance endoscopies, of whom 74 had occult cancer detected; the remaining two individuals developed focal ulcerations each corresponding to pT3N0 stage carcinoma. 98 (36%) of 270 patients proceeded to prophylactic total gastrectomy. Among patients who had a prophylactic total gastrectomy after an endoscopy with biopsy samples negative for cancer (42 [43%] of 98), multifocal stage IA gastric carcinoma was detected in 39 (93%). Two (1%) participants died during follow-up, one due to metastatic lobular breast cancer and the other due to underlying cerebrovascular disease, and no participants were diagnosed with advanced stage (III or IV) cancer during follow-up. INTERPRETATION: In our cohort, endoscopic cancer surveillance was an acceptable alternative to surgery in individuals with CDH1 variants who declined total gastrectomy. The low rate of incident tumours (>T1a) suggests that surveillance might be a rational alternative to surgery in individuals with CDH1 variants. FUNDING: Intramural Research Program, National Institutes of Health.
Assuntos
Adenocarcinoma , Carcinoma de Células em Anel de Sinete , Neoplasias Gástricas , Masculino , Humanos , Feminino , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Estudos Prospectivos , Gastrectomia/efeitos adversos , Adenocarcinoma/cirurgia , Carcinoma de Células em Anel de Sinete/diagnóstico , Carcinoma de Células em Anel de Sinete/epidemiologia , Carcinoma de Células em Anel de Sinete/genética , Mutação em Linhagem Germinativa , Predisposição Genética para DoençaRESUMO
Severe atrioventricular valve (AVV) or semilunar valve (SLV) regurgitation in the setting of a single ventricle physiology may proceed to valve replacement if repair strategies fail. Outcome data for these children are limited. We present transplant-free survival of a case series of children with single ventricle physiology undergoing either atrioventricular replacement (AVVR) or semilunar valve replacement (SLVR) from a multi-institutional, US-based registry (Pediatric Cardiac Care Consortium-PCCC). Outcomes were derived from PCCC and by linkage with the National Death Index (NDI) and Organ Procurement Transplant Network (OPTN). Fifty children with single ventricle physiology were identified to have received either AVVR (n = 38) or SLVR (n = 12). There were 17 in-hospital deaths including 8 intraoperative deaths (all intraoperative deaths were among children requiring AVVR). The in-hospital mortality was 42% and 8% for AVVR and SLVR, respectively. Among the 33 children surviving to hospital discharge, follow-up was available in 15 (46%). Death or cardiac transplant after hospital discharge occurred in 10-death in 4 (all among those requiring AVVR), cardiac transplant in 6 (2 following AVVR, 4 following SLVR). Valve replacement in children with single ventricle physiology, especially AVVR, is associated with poor outcomes. Alternative palliation strategies should be considered in children with single ventricle physiology with significant AVV or SLV regurgitations.
Assuntos
Implante de Prótese de Valva Cardíaca/métodos , Coração Univentricular/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Coração Univentricular/mortalidade , Coração Univentricular/fisiopatologiaAssuntos
Radioterapia (Especialidade) , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Anticorpos Monoclonais Humanizados , Extremidades , Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/radioterapia , Radioterapia AdjuvanteAssuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Mitotano/uso terapêutico , Cisplatino/uso terapêutico , Etoposídeo/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos Hormonais/uso terapêuticoAssuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Floxuridina , Artéria Hepática/diagnóstico por imagem , Artéria Hepática/patologia , Carcinoma Adrenocortical/diagnóstico por imagem , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Colorretais/patologia , Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Neoplasias do Córtex Suprarrenal/tratamento farmacológicoAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Estadiamento de Neoplasias , Pneumonectomia , Radiocirurgia , Medição de Risco , Resultado do TratamentoRESUMO
BACKGROUND: The goal of this study was to describe in-hospital and long-term mortality after single-stage repair of truncus arteriosus communis (TAC) and explore factors associated with these outcomes. METHODS: This was a cohort study of consecutive patients undergoing single-stage TAC repair between 1982 and 2011 reported to the Pediatric Cardiac Care Consortium registry. In-hospital mortality was obtained for the entire cohort from registry records. Long-term mortality was obtained for patients with available identifiers by matching with the National Death Index through 2020. Kaplan-Meier survival estimates were created for up to 30 years after discharge. Cox regression models estimated hazard ratios for the associations with potential risk factors. RESULTS: A total of 647 patients (51% male) underwent single-stage TAC repair at a median age of 18 days; 53% had type I TAC, 13% had interrupted aortic arch, and 10% underwent concomitant truncal valve surgery. Of these, 486 (75%) patients survived to hospital discharge. After discharge, 215 patients had identifiers for tracking long-term outcomes; 30-year survival was 78%. Concomitant truncal valve surgery at the index procedure was associated with increased in-hospital and 30-year mortality. Concomitant interrupted aortic arch repair was not associated with increased in-hospital or 30-year mortality. CONCLUSIONS: Concomitant truncal valve surgery but not interrupted aortic arch was associated with higher in-hospital and long-term mortality. Careful consideration of the need and timing for truncal valve intervention may improve TAC outcomes.
Assuntos
Coartação Aórtica , Persistência do Tronco Arterial , Criança , Humanos , Masculino , Lactente , Recém-Nascido , Feminino , Persistência do Tronco Arterial/cirurgia , Tronco Arterial/cirurgia , Estudos de Coortes , Seguimentos , Valvas Cardíacas/cirurgia , Coartação Aórtica/cirurgia , Reoperação , Resultado do TratamentoRESUMO
Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.
RESUMO
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have diverse tumor biology. Succinate dehydrogenase (SDH)-deficient GIST, comprise less than 10% of all GIST, with mutational loss of the catalytic SDHA subunit being the most common subtype. Contrary to typical GISTs harboring inactivating mutations in KIT/PDGFRA, SDH-deficient GIST has varying biology and behavior, occurring at a younger age, often metastatic on presentation and frequently refractory to conventional tyrosine kinase inhibitors (TKI). Liver and peritoneum are their most common sites of metastases, and extra-abdominal spread to the diaphragm or mediastinum has not been previously described. Case Description: Herein, we present a case of a 44-year-old female patient with a history of SDHA-deficient GISTs with multiple previous metastasectomies who presented with recurrence to the paraesophageal region and diaphragm which was identified upon routine positron emission tomography (PET) surveillance. Patient subsequently underwent a robotic assisted metastasectomy using a thoracic approach. Follow up was obtained 2 months following procedure and there was no evidence of recurrence. Conclusions: SDHA-deficient GISTs have unique tumor biology and management of metastatic lesions remains an area of debate and discovery. Overall, this report highlights the need for comprehensive knowledge of the disease, a skilled surgical team, and multi-disciplinary involvement in order to optimize care and ensure favorable outcomes in this patient population.
RESUMO
OBJECTIVE: The ideal valve substitute for surgical intervention of congenital aortic valve disease in children remains unclear. Data on outcomes beyond 10-15 years after valve replacement are limited but important for evaluating substitute longevity. We aimed to describe up to 25-year death/cardiac transplant by type of valve substitute and assess the potential impact of treatment centre. Our hypothesis was that patients with pulmonic valve autograft would have better survival than mechanical prosthetic. METHODS: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a multi-institutional US-based registry of paediatric cardiac interventions, linked with the National Death Index and United Network for Organ Sharing through 2019. Children (0-20 years old) receiving aortic valve replacement (AVR) from 1982 to 2003 were identified. Kaplan-Meier transplant-free survival was calculated, and Cox proportional hazard models estimated hazard ratios for mechanical AVR (M-AVR) versus pulmonic valve autograft. RESULTS: Among 911 children, the median age at AVR was 13.4 years (IQR=8.4-16.5) and 73% were male. There were 10 cardiac transplants and 153 deaths, 5 after transplant. The 25-year transplant-free survival post AVR was 87.1% for autograft vs 76.2% for M-AVR and 72.0% for tissue (bioprosthetic or homograft). After adjustment, M-AVR remained related to increased mortality/transplant versus autograft (HR=1.9, 95% CI=1.1 to 3.4). Surprisingly, survival for patients with M-AVR, but not autograft, was lower for those treated in centres with higher in-hospital mortality. CONCLUSION: Pulmonic valve autograft provides the best long-term outcomes for children with aortic valve disease, but AVR results may depend on a centre's experience or patient selection.
Assuntos
Valvopatia Aórtica , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Adolescente , Adulto , Valva Aórtica/cirurgia , Criança , Pré-Escolar , Feminino , Implante de Prótese de Valva Cardíaca/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Mitral valve anomalies in children are rare but frequently severe, recalcitrant, and not often amenable to primary repair, necessitating mechanical mitral valve replacement (M-MVR). This study examined outcomes of a cohort undergoing a first M-MVR at age younger than 21 years. METHODS: We queried the Pediatric Cardiac Care Consortium, a multi-institutional United States-based cardiac intervention registry, for patients undergoing first M-MVR for 2-ventricle congenital heart disease. Survival and transplant status through 2014 were obtained from Pediatric Cardiac Care Consortium and linkage with the National Death Index and the Organ Procurement and Transplantation Network. RESULTS: We identified 441 patients (median age, 4.3 years; interquartile range, 1.3 to 10.1 years) meeting study criteria. The commonest disease necessitating M-MVR was atrioventricular canal (44.3%). Early mortality (death <90 days after M-MVR) was 11.1%; there was increased risk of early death if age at M-MVR was younger than 2 years (odds ratio, 7.8; 95% confidence interval [CI], 1.1 to 56.6) and with concurrent other mechanical valve placement (odds ratio, 8.5; 95% CI, 2.0 to 35.6). In those surviving more than 90 days after M-MVR, transplant-free survival was 76% at 20 years of follow-up (median follow-up, 16.6 years; interquartile range, 11.9 to 21.3 years). Adjusted analysis in those who survived more than 90 days showed elevated risk of death/transplant for boys (hazard ratio, 1.5; 95% CI, 1.0 to 2.3), age at M-MVR younger than 2 years (10-year survival: hazard ratio, 4.3; 95% CI, 1.2 to 15.1), and nonbileaflet prosthesis placement (hazard ratio, 2.4; 95% CI, 1.3 to 4.3). CONCLUSIONS: M-MVR is a viable strategy in children with unrepairable mitral valve disease. Age younger than 2 years at the first M-MVR is associated with significant early risk of death and poorer long-term survival.