Rational thresholding of circulating tumor DNA concentration for improved surveillance of metastatic breast cancer.

BACKGROUND: The use of circulating tumor DNA (ctDNA) concentration for metastatic cancer surveillance is promising, but uncertainty remains about cut-offs with clinical validity. MATERIALS AND METHODS: This observational study recruited 136 subjects with advanced metastatic breast cancer (irrespective of ERBB2/hormone receptor status) for sequencing of their primary tumor in search for PIK3CA hotspot variants amenable for monitoring by droplet digital PCR (ddPCR). The study analyzed 341 on-treatment samples from 19 patients with PIK3CA variants H1047R or E545K enrolled for long-term (median 85 weeks, range 13-125 weeks), frequent (every 3-5 weeks, median of 14 time points per subject, range 2-29) blood sampling for ctDNA quantification by ddPCR, orthogonally validated by deep sequencing. The diagnostic accuracy of ctDNA versus cancer antigen 15-3 (CA15-3) concentrations to predict disease progression within 12 weeks was investigated using receiver operating characteristic (ROC) analysis. Likelihood ratios were used for rational selection of ctDNA result intervals. RESULTS: ctDNA [area under the ROC curve (AUC) 0.848, 95% confidence interval (CI) 0.791-0.895] showed superior diagnostic performance than CA15-3 (AUC 0.670, 95% CI 0.601-0.735, P < 0.001) to predict clinical progression within 12 weeks. ctDNA levels below 10 mutant allele copies/ml had high negative predictive value (88%), while levels above 100 copies/ml detected 64% of progressions 10 weeks earlier versus standard of care. Logistic regression analysis indicated complementary value of ctDNA and the presence of two consecutive CA15-3 rises, resulting in a model with 86% (95% CI 74% to 93%) positive predictive value and a clinically meaningful result in 89% of blood draws. CONCLUSIONS: Intensive ctDNA quantification improves metastatic breast cancer surveillance and enables individualized risk-based scheduling of clinical care.

PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment.

PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium.

Abdominal pain in covid times: time to think twice.

We report a case of abdominal pain followed by acute systolic heart failure due to multisystem inflammatory syndrome in children (MIS-C). This multisystem disease typically appears several weeks after infection with COVID-19 in children and young adults. There is a wide spectrum of presentation with MIS-C: some present with features of shock, others with a condition that has overlapping characteristics with Kawasaki disease (KD), and others with more non-specific features. Very often the symptoms include gastrointestinal symptoms. Our 17-year-old patient presented with fever, abdominal pain and inflammatory laboratory results. Rapidly after admission he developed acute heart failure with biopsy-confirmed myocarditis. The diagnostic criteria of MIS-C were met. This case emphasizes the changing diagnostic landscape. However rare, we want to raise awareness for MIS-C in children and young adults presenting with abdominal pain. Because of the risk of rapid clinical deterioration, early recognition and a multidisciplinary approach can be life-saving.

Isolated amyloidosis of the gastro-intestinal tract.

Amyloidosis is a very rare condition, which, due to its rarity, is often missed or diagnosed in an advanced stage of the disease, causing significant morbidity and mortality. In this review we describe the existing types of amyloidosis focusing on the gastro-intestinal tract. Amyloidosis occurs when abnormal protein fibrils (amyloid) deposit in the muscularis mucosae. This can cause an array of symptoms ranging from (in order of occurrence): gastro-intestinal bleeding, heartburn, unintentional weight loss, early satiety, constipation, diarrhea, nausea, vomiting and fecal incontinence (1). Treatment is focused on the underlying condition (if any) causing the production and deposition of the abnormal fibrils, in combination of symptomatic treatment.

Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study.

INTRODUCTION: Quantitative methylation specific PCR (qMSP) is a frequently used technique to assess MGMT gene promoter methylation in glioblastoma patients. The optimal technical cut-off value to distinguish methylated from unmethylated samples is nevertheless still undetermined. In literature, a "grey zone" of diagnostic uncertainty has been described. METHODS: We performed a retrospective analysis of newly diagnosed glioblastoma patients treated according to the Stupp protocol. Epidemiological data were gathered from the individual patient files. MGMT gene promoter methylation status was determined on stored tumour samples using qMSP. A strong, weak or absent promoter methylation was determined based on Cq values (quantification value) of the MGMT and ACTB primers as well as a positive control sample. RESULTS: In total, 181 patient files were reviewed and included for statistical analysis. MGMT promoter hypermethylation was detected in 38.7% of glioblastoma patients. The median overall survival of unmethylated and strongly methylated patients was 10.1 months and 19.7 months respectively. Furthermore, 11% of the total patient cohort had a weak MGMT gene promoter methylation. The median OS in this subgroup was 15.4 months, significantly better compared to the unmethylated cohort (P < 0.001). Multivariate Cox regression analysis showed weak MGMT promoter methylation as an independent prognostic parameter for overall survival. CONCLUSION: Glioblastoma patients with weak promoter methylation show a statistically significant longer overall survival when compared to clearly unmethylated patients. Patients with grey zone qMSP test results should receive additional molecular analysis in future to further direct individual therapy strategies.

Bilateral adrenal masses as the sole clinical key for diagnosing a Histoplasma capsulatum infection.

We describe a case of a 52-year-old man presenting with bilateral adrenal masses. A Histoplasma capsulatum infection was diagnosed on the basis of culture, pathological findings, Histoplasma antigen detection and molecular testing. The patient was treated with itraconazole and initially showed a good response. However, after discontinuation of one year of therapy, a relapse was seen and therapy was restarted. This case illustrates that histoplasmosis should be considered in the differential diagnosis of patients presenting with bilateral adrenal enlargement. Of all the diagnostic tests that are available, serology and antigen detection are the only rapid and non-invasive tests. Antigen detection can also be used for further follow-up of the disease.

Histopathology of the parathyroid glands.

The paper describes the histology of the normal parathyroid gland and the histopathology of parathyroid adenoma, hyperplasia and carcinoma. The possibilities and limitations of intraoperative frozen sections are discussed. Finally the use of immunochemistry and other special studies in parathyroid pathology is mentioned.