Association of early changes in arterial carbon dioxide with acute brain injury in adult patients with extracorporeal membrane oxygenation: A ten-year retrospective study in a German tertiary care hospital.

PURPOSE: To assess the association between fluctuations of arterial carbon dioxide early after start of extracorporeal membrane oxygenation (ECMO) with intracranial hemorrhage (ICH) or ischemic stroke (IS). MATERIALS AND METHODS: This single-center retrospective study included patients who required ECMO for circulatory or respiratory failure between January 2011 and April 2021 and for whom a cerebral computed tomography (cCT) scan was available. Multivariable logistic regression models were fitted to evaluate the association between the relative change of arterial carbon dioxide (RelΔPaCO2) and ICH, IS or a composite of ICH, IS, and mortality. RESULTS: In 618 patients (venovenous ECMO: n = 295; venoarterial ECMO: n = 323) ICH occurred more frequently in patients with respiratory failure (19.0%) compared with patients with circulatory failure (6.8%). Conversely, the incidence of IS was higher in patients with circulatory failure (19.2%) compared with patients with respiratory failure (4.7%). While patients with ECMO for respiratory failure were more likely to have ICH (OR 3.683 [95% CI: 1.855;7.309], p < 0.001), they had a lower odds for IS (OR 0.360 [95%CI: 0.158;0.820], p = 0.015) compared with patients with circulatory failure. There was no significant association between RelΔPaCO2 and ICH or IS. CONCLUSIONS: Irrespective of the indication for ECMO, we did not find a significant association between the relative change in PaCO2 early after ECMO initiation and acute brain injury. Aside from early PaCO2 decline at cannulation, future studies should address fluctuations of PaCO2 throughout the course of ECMO support and their effect on acute brain injury.

[Onboarding in intensive care and emergency medicine in Germany]. / Einarbeitung in der Intensiv- und Notfallmedizin in Deutschland.

BACKGROUND: The treatment of acute life-threatening conditions in intensive care and emergency medicine requires in-depth training and education, with initial training playing a key role. RESEARCH QUESTION: What is the structure and quality of the initial training of physicians and nurses in intensive care units and emergency departments in Germany? METHODS: With the help of survey software, an online questionnaire comprising 40 questions in German on the aforementioned topic was designed. It was distributed via the website of the German Society for Internal Intensive Care and Emergency Medicine (DGIIN) and via pertinent social media channels. RESULTS: In total, 103 nurses and 125 physicians participated in the survey. The average work experience of the participating nurses and physicians was 8.5 ± 5.1 and 3.0 ± 3.1 years, respectively. The majority of participants worked primarily in intensive care units (59%) or in emergency departments (22%). On average, the initial training lasted 45 ± 27 and 13 ± 13 days for nurses and physicians, respectively. Only 20% of the initial training comprised seminars or hands-on workshops taught outside of routine clinical care. In all, 47% of the participants stated that they were not able to complete the entire initial training period. Only 49% had been officially certified for usage of the technical equipment in their department. A total of 35% reported feeling confident or somewhat confident in handling predictable tasks after initial training, but only 15% in handling acute emergencies. DISCUSSION: The present study revealed that initial training in intensive care and emergency medicine is frequently incomplete, unstructured, as well as inadequate and bears both safety and liability risks. New concepts are needed to improve the initial training across clinics.

Resetting thermal limits: 10-year-old white sturgeon display pronounced but reversible thermal plasticity.

While many ectotherms improve thermal tolerance in response to prolonged thermal stress, little is known about the lasting effects of warm acclimation after returning to cooler temperatures. Furthermore, thermal stress may disproportionately impact threatened and endangered species. To address this, we repeatedly measured critical thermal maxima (CTmax; °C) and associated stress responses (hematocrit, hemoglobin concentration, plasma cortisol) of endangered subadult white sturgeon (Acipenser transmontanus) in response to control temperature (pre-acclimation; 14°C), after 1 month at either control or warm temperature (acclimation; 14°C or 20°C), and after one smonth following return to control temperature (post-acclimation; 14°C). While control fish demonstrated fairly repeatable thermal tolerance (interclass correlation coefficient = 0.479), warm-acclimated fish experienced a ∼3.1°C increase in thermal tolerance and when re-acclimated to control temperature, decreased thermal tolerance ∼1.9°C. Hematocrit, hemoglobin concentration, and final splenic somatic index (spleen mass relative to whole body mass, collected after post-acclimation CTmax) were not significantly different between control and treatment fish, suggesting no effects of warm acclimation on aerobic capacity. Plasma cortisol was significantly higher in control fish after pre-acclimation and post-acclimation CTmax trials, but importantly, acclimation temperature did not affect this response. Strikingly, final hepatosomatic index (relative liver size) was 45% lower in treatment fish, indicating warm acclimation may have lasting effects on energy usage and metabolism, even after reacclimating to control temperature. To our knowledge, these 10-year-old subadult sturgeon are the oldest sturgeon experimentally tested with regards to thermal plasticity and demonstrate incredible capacity for thermal acclimation relative to other fishes. However, more research is needed to determine whether the ability to acclimate to warm temperature may come with a persistent cost.

[Routine computed tomography body composition analysis-experience in intensive care patients]. / Routinecomputertomographie zur Analyse der Körperzusammensetzung ­ Erfahrungen bei Intensivpatient:innen.

The assessment of the nutritional status of patients in the intensive care unit is recommended in current guidelines and should include the assessment of muscle status. A suitable method is the analysis of routine computed tomography (CT) scans, which are frequently performed in critically ill patients. With the help of special software, individual CT slices are processed and various parameters such as muscle area, muscle density or even the percentage of adipose tissue are displayed and quantified. It has been shown that cross-sectional acquisition of skeletal muscle in the lumbar spine correlates very well with total body muscle. There are defined, albeit population-based, cut-off values that can be used to establish diagnosis of sarcopenia. Monitoring of individualized nutritional therapy can be accomplished by assessment of repetitive CT examinations. The steadily growing body of data confirms that the method can make a valuable contribution to the assessment of body composition in intensive care medicine. Most of the currently available software requires time-consuming processing of the CT. Automated programs, which are now occasionally available and eliminate the need for most manual processing, may make the method even more attractive in the future. Ultimately, the risk of intensive transport to the CT or radiation exposure may be only justified for medical indications. Nevertheless, whenever CT is available for medical reasons, it should also be exploited for composition analysis.

Molecular Subgroups of Diffuse Large B Cell Lymphoma: Biology and Implications for Clinical Practice.

PURPOSE OF REVIEW: Genomic analyses have immensely advanced our conception of the heterogeneity of diffuse large B cell lymphoma (DLBCL), resulting in subgroups with distinct molecular profiles. In this review, we summarize our current knowledge of the biology of DLBCL complexity and discuss the potential implications for precision medicine. RECENT FINDINGS: During the last two decades, gene expression profiling, copy number analysis, and high throughput sequencing enabled the identification of molecular subclasses of DLBCL that are biologically and clinically meaningful. The resulting classifications provided novel prospects of diagnosis, prognostication, and therapeutic strategies for this aggressive disease. The molecular characterization of DLBCL offers unprecedented insights into the biology of these lymphomas that can guide precision medicine. The knowledge of the molecular setup of an individual DLBCL patients enables prognostication of patients and will be useful to stratify patients in clinical trials. Future direction should focus to implement the molecular classifications of DLBCL in the clinical practice to evaluate their significance and scope using real-world data.

Parallel evaluation of cell­based phage display panning strategies: Optimized selection and depletion steps result in AML blast­binding consensus antibodies.

Phage display technology (PD) is a powerful technique for the generation of tumor­targeting antibodies. However, there are a number of different selection methods established in different laboratories around the world. Cell­based PD panning methods using primary tumor cells are particularly heterogeneous between laboratories, which can lead to inconsistent results. Therefore, the present study evaluated different cell­based PD selection methods regarding their potential to generate acute myeloid leukemia (AML) blast­binding antibodies. In addition to this evaluation, the present study improved the PD procedure by optimizing selection as well as depletion strategies. To the best of our knowledge, the current study demonstrated for the first time that antigen diversity during the depletion step is of importance for the enrichment of tumor­targeting phage antibodies. It is demonstrated that medium levels of depletion antigen diversity led to the most promising antibody candidates. In addition, it was determined that purification of blast cells from patients with AML by immunomagnetic separation ameliorated the selection of AML­binding phages during panning. Furthermore, suggesting a common design­related mechanism using a 'single­pot' PD library, such as the well­known Tomlinson single­chain fragment variable (scFv) library, the present study identified specific binding consensus phage particles in independent panning procedures. By means of these optimized strategies, four promising AML blast­binding phage particles were isolated and soluble scFv­Fc (scFv cloned to a fragment crystallizable of an IgG2a mouse antibody) fusion proteins were produced. These scFv­Fc antibodies bound the surface of AML blasts and were successfully internalized into their cytoplasm, indicating that they are potential immunoconjugate candidates for AML immunotherapy.

Epidemiology, clinical characteristics, and outcome of candidemia in critically ill patients in Germany: a single-center retrospective 10-year analysis.

BACKGROUND: Despite advances in the management of bloodstream infections (BSI) caused by Candida spp., the mortality still remains high in critically ill patients. The worldwide epidemiology of yeast-related BSI is subject to changing species distribution and resistance patterns, challenging antifungal treatment strategies. The aim of this single-center study was to identify predictors of mortality after 28 and 180 days in a cohort of mixed surgical and medical critically ill patients with candidemia. METHODS: Patients, who had been treated for laboratory-confirmed BSI caused by Candida spp. in one of 12 intensive care units (ICU) at a University hospital between 2008 and 2017, were retrospectively identified. We retrieved data including clinical characteristics, Candida species distribution, and antifungal management from electronic health records to identify risk factors for mortality at 28 and 180 days using a Cox regression model. RESULTS: A total of 391 patients had blood cultures positive for Candida spp. (incidence 4.8/1000 ICU admissions). The mortality rate after 28 days was 47% (n = 185) and increased to 60% (n = 234) after 180 days. Age (HR 1.02 [95% CI 1.01-1.03]), a history of liver cirrhosis (HR 1.54 [95% CI 1.07-2.20]), septic shock (HR 2.41 [95% CI 1.73-3.37]), the Sepsis-related Organ Failure Assessment score (HR 1.12 [95% CI 1.07-1.17]), Candida score (HR 1.25 [95% CI 1.11-1.40]), and the length of ICU stay at culture positivity (HR 1.01 [95% CI 1.00-1.01]) were significant risk factors for death at 180 days. Patients, who had abdominal surgery (HR 0.66 [95% CI 0.48-0.91]) and patients, who received adequate (HR 0.36 [95% CI 0.24-0.52]) or non-adequate (HR 0.31 [95% CI 0.16-0.62]) antifungal treatment, had a reduced mortality risk compared to medical admission and no antifungal treatment, respectively. CONCLUSIONS: The mortality of critically ill patients with Candida BSI is high and is mainly determined by disease severity, multiorgan dysfunction, and antifungal management rather than species distribution and susceptibility. Our results underline the importance of timely treatment of candidemia. However, controversies remain on the optimal definition of adequate antifungal management.

Physical Activity Counseling in Primary Care in Germany-An Integrative Review.

Physical activity counseling in primary health care is regarded as a useful complementary preventive and therapeutic measure and is advocated by leading public health institutions. This integrative review summarizes the available data on physical activity counseling in primary care in Germany. A systematic literature search in various databases (peer reviewed and grey literature) was carried out for quantitative and qualitative studies on physical activity counseling and use of "Exercise on Prescription". The 25 studies included show a very high methodological diversity and, in some cases, considerable risks of bias, with limited comparability across studies. Counseling was provided in all studies by physicians. They report frequent physical activity counseling, which is partly confirmed and partly refuted by patient data. The use of "Exercise on Prescription" is at a very low level. Information on the frequency of physical activity counseling in Germany varies depending on data source and is sometimes contradictory. Our review provides a synthesis of various perspectives on routine physical activity counseling in primary care in Germany. Future studies using standardized and validated instruments in representative samples are needed to further knowledge on counseling and to be able to establish trends in prevalence. Strengthening the topics of physical activity and health and physical activity counseling in medical curriculum is strongly recommended.

Advanced organ support (ADVOS) in the critically ill: first clinical experience in patients with multiple organ failure.

BACKGROUND: Prevalence of multiple organ failure (MOF) in critically ill patients is increasing and associated mortality remains high. Extracorporeal organ support is a cornerstone in the management of MOF. We report data of an advanced hemodialysis system based on albumin dialysis (ADVOS multi device) that can regulate acid-base balance in addition to the established properties of renal replacement therapy and albumin dialysis systems in critically ill patients with MOF. METHODS: 34 critically ill patients with MOF received 102 ADVOS treatment sessions in the Department of Intensive Care Medicine of the University Medical Center Hamburg-Eppendorf. Markers of metabolic detoxification and acid-base regulation were collected and blood gas analyses were performed. A subgroup analyses were performed in patients with severe acidemia (pH < 7.2). RESULTS: Median number of treatment sessions was 2 (range 1-9) per patient. Median duration of treatment was 17.5 (IQR 11-23) hours per session. Treatment with the ADVOS multi-albumin dialysis device caused a significant decrease in bilirubin levels, serum creatinine, BUN and ammonia levels. The relative elimination rate of bilirubin was concentration dependent. Furthermore, a significant improvement in blood pH, HCO3- and PaCO2, was achieved during ADVOS treatment including six patients that suffered from severe metabolic acidosis refractory to continuous renal replacement therapy. Delta pH, HCO3- and PaCO2 were significantly affected by the ADVOS blood flow rate and pH settings. This improvement in the clinical course during ADVOS treatments allowed a reduction in norepinephrine during ADVOS therapy. Treatments were well tolerated. Mortality rates were 50% and 62% for 28 and 90 days, respectively. CONCLUSIONS: In this case series in patients with MOF, ADVOS was able to eliminate water-soluble and albumin-bound substances. Furthermore, the device corrected severe metabolic and respiratory acid-base disequilibrium. No major adverse events associated with the ADVOS treatments were observed.

Quality of Voice and Prognostic Markers for the Recovery of Vocal Fold Paralysis After Thyroid Surgery.

OBJECTIVES: This study is set to analyze clinicopathological factors predicting the recovery of unilateral vocal fold paralysis (UVP) in patients after thyroid gland surgery. The quality of voice was additionally assessed in these patients. METHODS: The charts and videolaryngostroboscopy (VLS) examinations of 84 consecutive patients with a complete UVP after surgery of the thyroid gland were retrospectively reviewed. Patients were divided into 2 groups: patients who fully recovered from vocal fold paralysis and those who failed to recover after a follow-up of 12 months. The quality of voice was analyzed among other things by determining the Voice Handicap Index (VHI). RESULTS: The UVP fully recovered in 52 of 84 (61.9%) patients. Positive mucosal waves (pMWs) on the paralyzed side, a minimal glottic gap <3 mm seen at the first postoperative VLS, age ≤50 years, and surgery duration ≤120 minutes were associated factors for a complete recovery of nerve function. The voice parameters improved independently from recovery of the paralysis in 90% of the patients. CONCLUSIONS: For patients with a poor prognosis of a UVP, early intervention may be beneficial. Thus, predicting factors for a full recovery of vocal fold motion would be a valuable tool. In our cohort, about 60% of recoveries could have been predicted using the above-mentioned parameters. Good quality of voice was independently reached in 90% of the cases.

Switching of bacterial adhesion to a glycosylated surface by reversible reorientation of the carbohydrate ligand.

The surface recognition in many biological systems is guided by the interaction of carbohydrate-specific proteins (lectins) with carbohydrate epitopes (ligands) located within the unordered glycoconjugate layer (glycocalyx) of cells. Thus, for recognition, the respective ligand has to reorient for a successful matching event. Herein, we present for the first time a model system, in which only the orientation of the ligand is altered in a controlled manner without changing the recognition quality of the ligand itself. The key for this orientational control is the embedding into an interfacial system and the use of a photoswitchable mechanical joint, such as azobenzene.

UV-mediated tuning of surface biorepulsivity in aqueous environment.

While it is well-known that oligoethylene glycol (OEG) terminated self-assembled monolayers (SAMs) can be deteriorated by UV irradiation in air, we now report that the analogous modification can also be performed in water, opening the opportunity for in situ tuning of biorepulsive properties. Surprisingly, this deterioration also takes place even in the absence of molecular oxygen, resulting in a very selective process.

Direct grafting of anti-fouling polyglycerol layers to steel and other technically relevant materials.

Direct grafting of hyperbranched polyglycerol (PG) layers onto the oxide surfaces of steel, aluminum, and silicon has been achieved through surface-initiated polymerization of 2-hydroxymethyloxirane (glycidol). Optimization of the deposition conditions led to a protocol that employed N-methyl-2-pyrrolidone (NMP) as the solvent and temperatures of 100 and 140 °C, depending on the substrate material. In all cases, a linear growth of the PG layers could be attained, which allows for control of film thickness by altering the reaction time. At layer thicknesses >5 nm, the PG layers completely suppressed the adhesion of albumin, fibrinogen, and globulin. These layers were also at least 90% bio-repulsive for two bacteria strains, E. coli and Acinetobacter baylyi, with further improvement being observed when the PG film thickness was increased to 17 nm (up to 99.9% bio-repulsivity on silicon).

Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts.

Nonsteroidal anti-inflammatory drugs (NSAIDs; 1) are widely recommended for several acute and chronic conditions. For example, both indomethacin and aspirin are taken for pain relief. Aspirin is also used for prevention of myocardial infarction, and indomethacin can be administered orally or as a suppository for patients with rheumatoid disease and other chronic inflammatory states. However, use of NSAIDs can cause damage to the mucosal barrier surrounding the gastrointestinal (GI) tract, increasing the risk of ulcer formation. While microencapsulation of NSAIDs has been shown to reduce upper GI injury, sustained release in the lower GI tract and colon may cause epithelial erosion due to increased acidification. The use of suppositories has also been linked to rectal and lower GI bleeding. In this study, we investigated the role of NSAIDs aspirin and indomethacin on Na⁺/H⁺ exchanger (NHE) activity in rat colonic crypts. By comparing average rates of pH recovery between control and NSAID perfusion runs, we were able to determine that both aspirin and indomethacin increase hydrogen extrusion into the colonic lumen. Through treatment with 5-ethylisopropyl amiloride (EIPA), amiloride, and zoniporide dihydrochloride, we further demonstrated that indomethacin specifically enhances proton excretion through regulation of apical NHE-3 and NHE-2 and to a lesser extent on basolateral NHE-1 and NHE-4. Our results suggest that clinical exposure to NSAIDs may affect colonic tissue at the site of selected NHE isoforms, resulting in modulation of transport and barrier function.

ß-cell metabolic alterations under chronic nutrient overload in rat and human islets.

The aim of this study was to assess multifactorial ß-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of lipid droplets in ß-cells in a time- and concentration-dependent manner. Glucose and FFAs synergistically stimulated the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1). A potent mTORC1 inhibitor, rapamycin (25 nM), significantly reduced triglyceride accumulation in rat islets. Importantly, lipid droplets accumulated only in ß-cells but not in α-cells in an mTORC1-dependent manner. Nutrient activation of mTORC1 upregulated the expression of adipose differentiation related protein (ADRP), known to stabilize lipid droplets. Rat islet size and new DNA synthesis also increased under nutrient overload. Insulin secretion into the culture medium increased steadily over a 4-day period without any significant difference between glucose (10 mM) alone and the combination of glucose (10 mM) and FFAs (240 µM). Insulin content and insulin biosynthesis, however, were significantly reduced under the combination of nutrients compared with glucose alone. Elevated nutrients also stimulated lipid droplet formation in human islets in an mTORC1-dependent manner. Unlike rat islets, however, human islets did not increase in size under nutrient overload despite a normal response to nutrients in releasing insulin. The different responses of islet cell growth under nutrient overload appear to impact insulin biosynthesis and storage differently in rat and human islets.

Bacteria-repulsive polyglycerol surfaces by grafting polymerization onto aminopropylated surfaces.

The formation of hydrogels on surfaces is a frequently used strategy to render these surfaces biorepulsive. Hyperbranched polyglycerol layers are a promising alternative to the frequently used polyethyleneglycol layers. Here, we present a strategy to covalently graft polyglycerol layers onto surfaces by first depositing an aminopropylsiloxane layer, which then acts as initiator layer for the ring-opening polymerization of 2-(hydroxymethyl)oxirane (glycidol). For silicon surfaces, the resulting polyglycerol layers start being biorepulsive for E. coli at a thickness of 2 nm and reach their highest bacterial repulsion (98%) at thicknesses of 7 nm or larger. This deposition strategy promises general applicability because the formation of aminopropylsiloxane layers has already been described for many materials.

Chromosomal genotype in breast cancer progression: comparison of primary and secondary manifestations.

The purpose of this study was to compare the chromosomal genotype between breast cancers with and without secondary manifestations and between primary tumors and their secondary manifestations. Eighty six breast cancers, twenty lymph node metastases, ten distant metastases and ten local recurrences were analyzed by comparative genomic hybridization. Tumors with local recurrences showed significant more frequent losses at 2q32 than the tumors without recurrences. Lymph node positive cases showed significant more frequent losses at 9p21 than node negative cases. Lymph node metastases exhibited significant more frequent losses at 7q11, 14q24.3-q31 and 17q22-q24 than their primary tumors. In cases with distant metastases, losses at 5q23 were more frequent than in those without, but not reaching the significance level. The distant metastases showed significant more frequent losses at 5p15, 12q24 and 17q22-q24 than the primary tumors. These results reveal strong evidence that the potential for progression is determined in the primary tumor and that different ways of the development of local recurrences, lymph node and distant metastases exist. After confirmation of the results by interphase FISH on tissue micro arrays, the detection of these specific chromosomal imbalances may contribute to a more individual prediction of prognosis in breast cancer.

Timing and extent of surgery in patients with familial medullary thyroid carcinoma/multiple endocrine neoplasia 2A-related RET mutations not affecting codon 634.

In hereditary medullary thyroid carcinoma (MTC), recommendations regarding timing and extent of surgery are mainly based on the data of patients with the codon 634 RET mutation, which is the most often affected codon. Little is known about whether these recommendations may also be applied to patients with less common RET mutations. We ascertained the data from 140 patients with FMTC/MEN2A-related RET mutation not affecting codon 634 who have been treated at three specialized centers. The several RET mutations found affected codons 611 (n = 17), 618 (n = 22), 620 (n = 17), 768 (n = 9), 790 (n = 24), 791 (n = 21), 804 (n = 23), and 891 (n = 7). For each codon, the age of the youngest patient with MTC only (41, 7, 18, 29, 13, 47, 20, and 15 years, respectively), MTC with lymph node metastases (46, 24, 21, 34, 46, 47, 50, and 76 years, respectively), and MTC with distant metastases (52, 69, 43, 68, 57, - , - , and 75 years, respectively) was determined. All patients with lymph node metastases had elevated basal calcitonin levels. Based on these data, a more individual recommendation regarding timing and extent of surgery can be given. Because neither gender nor the type of nucleotide substitution for a specific codon appeared to have a significant influence on the age of onset, this recommendation should be based on the affected codon, the age of the patient, and the calcitonin level. Recurrent laryngeal nerve palsy (n = 6) and hypoparathyroidism (n = 3) were rather rare and were found only in patients older than 30 and 43 years, respectively, giving evidence that surgery in young patients can be performed safely.

RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple endocrine neoplasia type 2A syndrome?

BACKGROUND: In patients with multiple endocrine neoplasia type 2A syndrome, prophylactic thyroidectomy is generally recommended at the age of 5 to 6 years. Whether this recommendation is justified for exon 13 mutations is unknown. METHODS: We analyzed the clinical data from 40 patients harboring RET codon 790/791 mutations (exon 13) who had been treated in 4 specialized centers. RESULTS: Mean age was 35.2 +/- 21.6 years (range, 5.1-69.0 years). Thirteen patients were index patients (mean age, 57.7 +/- 11.3 years), 27 patients were screening patients (mean age, 24.4 +/- 16.5 years). In the index group, pT-category was: T0, n = 2; T1, n = 6; T2, n = 2; T3, n = 1; and T4, n = 2. Lymph node metastases were found in 5 patients and distant metastases in 1 patient. Postoperatively, 69% of index patients were biochemically cured. In the screening group, pT-category was: T0, n = 19; T1, n = 7; and T2, n = 1. Lymph node metastases were found in 2 patients. Postoperatively, 93% of screening patients were biochemically cured. The youngest patient with medullary thyroid carcinoma was 13.8 years, the youngest patient with lymph node metastases was 46.4 years. CONCLUSIONS: Patients with RET codon 790/791 mutations seemed to have a less aggressive clinical course compared with patients with classic multiple endocrine neoplasia type 2A syndrome. Still, index patients had a lower biochemic cure rate in comparison with screening patients. Timely total thyroidectomy including lymph node dissection is warranted.