RESUMO
The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Neoplasias/diagnóstico , Processamento Alternativo , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial , Neoplasias/genéticaRESUMO
OBJECTIVE: To measure association between endometrial carcinoma ER and PR status and endometrial cancer (EC) survival, accounting for inter-observer variation. METHODS: The intensity and proportion of tumor cell expression of ER and PR in ECs were assessed independently and semi-quantitatively by two pathologists using digital images of duplicate tumor tissue microarrays (TMAs). Cases with inconsistent initial assessment were reviewed and final scoring agreed. The association between overall and EC-specific survival and hormone receptor expression (intensity, proportion and combined) was assessed using Cox regression analysis. The C-index was used to evaluate model discrimination with addition of ER and PR status. RESULTS: Tumor ER and PR analysis was possible in 659 TMAs from 255 patients, and in 459 TMAs from 243 patients, respectively. Initial ER and PR scoring was consistent in 82% and 80% of cases, respectively. In multivariate analyses decreased ER and PR expression was associated with increased tumor-related mortality. Associations reached statistical significance for ER proportion score (P=0.05), ER intensity score (P=0.003), and PR combined score (P=0.04). Decreased expression of combined ER/PR expression was associated with poorer EC-specific survival than decreased expression of either hormone receptor alone (P=0.005). However, hormone receptor status did not significantly improve mortality prediction in individual cases. CONCLUSION: ER and PR expression combined, using cut-points that capture variation in scoring and across cores, is significantly associated with EC-specific survival in analyses adjusting for known prognostic factors. However, at the individual level, ER and PR expression does not improve mortality prediction.
Assuntos
Carcinoma Endometrioide/mortalidade , Neoplasias do Endométrio/mortalidade , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-IdadeRESUMO
Robotic right hemicolectomy (RRC) may have technical advantages over the conventional laparoscopic right colectomy (LRC) due to higher degrees of rotation, articulation, and tri-dimensional imaging. There is growing literature describing advantages of RRC compared to LRC; however, there is a lack of evidence about safety, oncologic quality of surgery and cost. This study aimed to analyse complication rates, length of stay and nodal harvest in patients undergoing minimally invasive right hemicolectomy for colon cancer from a prospective Australasian colorectal cancer database. This was a retrospective cohort study using nearest neighbour matching. The Binational Colorectal Cancer Audit (BCCA) provided the data for analysis. The primary outcome was length of stay. Secondary outcomes were harvested lymph node count, anastomotic leak, postoperative haemorrhage, abdominal abscess, postoperative ileus, wound infections and non-surgical complications. 4977 patients who underwent robotic (n = 146) or laparoscopic (n = 4831) right hemicolectomy for right-sided colon cancer were included. For RRC, LOS was shorter (5 vs 6.9 days, p = 0.01) and nodal harvest was higher (22 vs 19, p = 0.04). For RRC, surgical complications (5.9% vs 14.2%, p < 0.004) and non-surgical complications (4.6% vs 11.7%, p = 0.007) were lower though there was no difference in return to theatre or inpatient death. Robotic right hemicolectomy is associated shorter LOS and marginally higher lymph node count, though this may reflect anastomotic technique rather than surgical platform. Longer term studies are required to establish differences in overall survival, incisional hernia rates and cost effectiveness.
Assuntos
Neoplasias do Colo , Laparoscopia , Procedimentos Cirúrgicos Robóticos , Anastomose Cirúrgica/métodos , Colectomia/efeitos adversos , Colectomia/métodos , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Tempo de Internação , Duração da Cirurgia , Estudos Prospectivos , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: Pancreatic panniculitis is a rare manifestation of benign and malignant pancreatic disease. The presentation of pancreatic panniculitis is non-specific and thus diagnosis is often delayed. When associated with malignancy, pancreatic panniculitis confers a poor prognosis. This case demonstrates the successful surgical management of this paraneoplastic phenomenon following resection of the underlying pancreatic acinar cell carcinoma and associated liver metastasis. PRESENTATION OF CASE: A 71-year-old female with debilitating subcutaneous lower limb lesions had a delayed diagnosis of pancreatic panniculitis. A formal diagnosis of pancreatic acinar cell carcinoma with liver metastasis was established and the disease was determined to be resectable. Pre-operatively, serum lipase measured 10,825 U/L. The patient proceeded to an open left hemihepatectomy and radical distal pancreatectomy with complete resection of malignant disease. Six days post-operatively the serum lipase levels normalised, and the panniculitis began to settle. The patient proceeded to adjuvant FOLFORINOX chemotherapy. Twenty months post-surgery, the patient remains disease-free and without any evidence of panniculitis. DISCUSSION: Due to the rarity of pancreatic acinar cell carcinoma, guidelines based on prospective data do not exist. Most management is based on retrospective analyses. A survival benefit may be achieved with more aggressive surgical management compared to other pancreatic cancer types. Pancreatic acinar cell carcinoma may show a slower rate of disease progression, an increased likelihood of resectability of disease at presentation and is more likely to undergo potentially curative resection. CONCLUSION: Aggressive surgical management of resectable metastatic pancreatic acinar cell carcinoma can treat pancreatic panniculitis and provide sustained disease-free survival from pancreatic cancer.