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.

MECCIAS trial: Metabolic consequences of continuous veno-venous hemofiltration on indirect calorimetry.

BACKGROUND: and aims: Caloric prescription based on resting energy expenditure (REE) measured with indirect calorimetry (IC) improves outcome and is the gold standard in nutritional therapy of critically ill patients. Until now continuous renal replacement therapy (CRRT) precluded the use of IC due to several mechanisms. We investigated the impact of CRRT on V̇CO2, V̇O2 and REE to facilitate indirect calorimetry during CRRT. METHODS: In 10 critically ill ventilated patient in need of continuous veno-venous hemofiltration (CVVH) using citrate predilution we performed IC in 4 different states: baseline, high dose, baseline with NaCl predilution and without CVVH. CO2 content of effluent fluid was measured by a point of care blood gas analyzer. Carbon dioxide production (V̇CO2) measured with IC was adapted by adding the CO2 flow of effluent and deducing CO2 flow in postdilution fluid to calculate a true V̇CO2. True REE was calculated with the Weir equation using the true V̇CO2. RESULTS: CO2 removal in effluent during baseline, high dose and NaCl predilution was respectively 24 mL/min, 38 mL/min and 23 mL/min. Together with the CO2 delivery by the postdilution fluid this led to an adaptation of REE respectively by 34 kcal/d or 2% (p = 0,002), 44 kcal/d or 3% (p = 0,002) and 33 kcal/d or 2% (p = 0,002). Compared to the true REE during baseline of 1935 ± 921 kcal/d, true REE during high dose was 1723 ± 752 kcal/d (p = 0.65), during NaCl predilution it was 1604 ± 633 kcal/d (p = 0.014) and without CRRT it was 1713 ± 704 kcal/d (p = 0.193). CONCLUSIONS: CO2 alterations due to CVVH are clinically of no importance so no correction factor of REE is needed with or without CVVH. IC must be performed during CVVH as CVVH seems to alter metabolism. These changes may be mainly explained by the use of citrate predilution.

One-step reconstruction with a 3D-printed, biomechanically evaluated custom implant after complex pelvic tumor resection.

Resection of a pelvic tumor is challenging because of its complex three-dimensional (3D) anatomy and deep-seated location with nearby vital structures. The resection is technically demanding if a custom implant is used for reconstruction of the bone defect as the surgeon needs to ensure the resection margin is sufficiently wide and the orientation of intended resection planes must match that of the custom implant. We describe a novel workflow of performing a partial acetabular resection in a patient with pelvic chondrosarcoma and reconstruction with a custom pelvic implant in a one-step operation. A multi-planar bone resection was virtually planned. A computer-aided design implant that both matched the bone defect and biomechanically evaluated was prefabricated with 3D printing technology. The 3D-printed patient-specific instruments (PSIs) were used to reproduce the same planned resection. The histology of the tumor specimen showed a clear resection margin. The errors of the achieved resection and implant position were deviating (1-4 mm) from the planned. The patient could walk unaided with a good hip function. No tumor recurrence and implant loosening were noted at 11 months after surgery. The use of this novel CT-based method for surgical planning, the engineering software for implant design and validation, together with 3D printing technology for implant and PSI fabrication makes it possible to generate a personalized, biomechanically evaluated implant for accurate reconstruction after a pelvic tumor resection in a one-step operation. Further study in a larger population is needed to assess the clinical efficacy of the workflow in complex bone tumor surgery.

Does tranexamic acid stabilised fibrin support the osteogenic differentiation of human periosteum derived cells?

Fibrin sealants have long been used as carrier for osteogenic cells in bone regeneration. However, it has not been demonstrated whether fibrin's role is limited to delivering cells to the bone defect or whether fibrin enhances osteogenesis. This study investigated fibrin's influence on the behaviour of human periosteum-derived cells (hPDCs) when cultured in vitro under osteogenic conditions in two-dimensional (fibrin substrate) and three-dimensional (fibrin carrier) environments. Tranexamic acid (TEA) was used to reduce fibrin degradation after investigating its effect on hPDCs in monolayer culture on plastic.TEA did not affect proliferation nor calcium deposition of hPDCs under these conditions. Expression profiles of specific osteogenic markers were also maintained within the presence of TEA, apart from reduced alkaline phosphatase (ALP) expression (day 14). Compared to plastic, proliferation was upregulated on 2D fibrin substrates with a 220% higher DNA content by day 21. Gene expression was also altered, with significantly (p<0.05) decreased Runx2 (day 7) and ALP (day 14) expression and increased collagen I expression (day 14 and 21). In contrast to plastic, mineralisation was absent on fibrin substrates. Inside fibrin carriers, hPDCs were uniformly distributed. Moderate cell growth and reduced osteogenic marker expression was observed inside fibrin carriers. After 2 weeks, increased cell death was present in the carrier's centre. In conclusion, fibrin negatively influences osteogenic differentiation, compared to culture plastic, but enhanced proliferation (at least in 2D cultures) for hPDCs cultured in osteogenic conditions. TEA maintained the integrity of fibrin-based constructs, with minor effects on the osteogenic differentiation of hPDCs.

Ultrasound-guided puncture of the gallbladder for acute cholecystitis.

In 18 high-risk patients with acute cholecystitis and severe concurrent disease, we aspirated the gallbladder by using a percutaneous technique under ultrasound guidance. 17 of the 18 improved after aspiration, the only complication being local pain in 2. 13 of the 17 who improved remained free from biliary infections during a mean follow-up period of 14 months. 4 had an uncomplicated cholecystectomy 6-10 weeks later for recurrent cholecystitis. Percutaneous transhepatic gallbladder aspiration is a safe and effective procedure in critically ill patients with acute cholecystitis.

[Surgery of acute cholecystitis in patients 80 years of age or older]. / Chirurgie de la cholécystite aiguë au-delà de 80 ans.

In 17 Belgian surgical centers, 324 operations have been performed for acute cholecystitis in patients 80 years of age or older. In this group of patients: 1. The incidence of acute cholecystitis is hardly higher in women than in men. 2. The patients were operated within 24 hours of admission in 38% of cases. The main bile duct was surgically explored in 1/3 of patients. Cholecystostomy or simple drainage were used in 1/10 of cases only. 3. Operative mortality was 19%. It was higher for patients operated as emergencies than for delayed operations and higher also when the cholecystectomy was associated with an exploration of the bile duct. The ideal treatment for such patients should thus be a cholecystectomy with an endoscopic sphincterotomy.