Evaluation of medical decision support systems (DDX generators) using real medical cases of varying complexity and origin.

BACKGROUND: Medical decision support systems (CDSSs) are increasingly used in medicine, but their utility in daily medical practice is difficult to evaluate. One variant of CDSS is a generator of differential diagnoses (DDx generator). We performed a feasibility study on three different, publicly available data sets of medical cases in order to identify the frequency in which two different DDx generators provide helpful information (either by providing a list of differential diagnosis or recognizing the expert diagnosis if available) for a given case report. METHODS: Used data sets were n = 105 cases from a web-based forum of telemedicine with real life cases from Afghanistan (Afghan data set; AD), n = 124 cases discussed in a web-based medical forum (Coliquio data set; CD). Both websites are restricted for medical professionals only. The third data set consisted 50 special case reports published in the New England Journal of Medicine (NEJM). After keyword extraction, data were entered into two different DDx generators (IsabelHealth (IH), Memem7 (M7)) to examine differences in target diagnosis recognition and physician-rated usefulness between DDx generators. RESULTS: Both DDx generators detected the target diagnosis equally successfully (all cases: M7, 83/170 (49%); IH 90/170 (53%), NEJM: M7, 28/50 (56%); IH, 34/50 (68%); differences n.s.). Differences occurred in AD, where detection of an expert diagnosis was less successful with IH than with M7 (29.7% vs. 54.1%, p = 0.003). In contrast, in CD IH performed significantly better than M7 (73.9% vs. 32.6%, p = 0.021). Congruent identification of target diagnosis occurred in only 46/170 (27.1%) of cases. However, a qualitative analysis of the DDx results revealed useful complements from using the two systems in parallel. CONCLUSION: Both DDx systems IsabelHealth and Memem7 provided substantial help in finding a helpful list of differential diagnoses or identifying the target diagnosis either in standard cases or complicated and rare cases. Our pilot study highlights the need for different levels of complexity and types of real-world medical test cases, as there are significant differences between DDx generators away from traditional case reports. Combining different results from DDx generators seems to be a possible approach for future review and use of the systems.

Clinical outcome and global gene expression data support the existence of the estrogen receptor-negative/progesterone receptor-positive invasive breast cancer phenotype.

The presence or absence of estrogen and progesterone steroid hormone receptor expression (ER, PR) is an essential feature of invasive breast cancer and determines prognosis and endocrine treatment decisions. Among the four ER/PR receptor phenotypes, the ER-/PR+ is infrequent, and its clinical relevance has been controversially discussed. Thus, we investigated its clinical significance and gene expression pattern in large datasets. In a retrospective clinical study of 15,747 breast cancer patients, we determined the ER/PR subtype survival probabilities using Kaplan-Meier and Cox regression analyses. From The Cancer Genome Atlas (TCGA) breast cancer dataset, PAM50 expression signature and pathway analyses were performed to test for distinct molecular features. In our cohort, the ER-/PR+ phenotype has been observed at a frequency of 4.1 % and was associated with an improved 10-year survival for stage I cancers compared to the ER+/PR+ reference subtype (median; 95 % CI 88.1 %; 83-93 vs. 84.3 %; 82-86 %, P = 0.024) as was confirmed by multivariate analysis over the entire follow-up (HR 0.59, 95 % CI 0.38-0.92, P = 0.021). This association lacked significance when including all stages. ER-/PR+ patients treated with antihormonal agents (34.5 %) had shorter survival compared to their non-treated counterparts (Log-rank P = 0.0001). PAM50 signatures suggest a distinct configuration for the ER-/PR+ phenotype. This specific phenotype has been further separated by a set of 59 uniquely expressed genes. Our study supports the notion of the existence of an ER-/PR+ phenotype with clinical and molecular features distinct from the large group of ER+/PR+ patients.

Severe thrombocytopenia in hantavirus-induced nephropathia epidemica.

Nephropathia epidemica is a milder form of hemorrhagic fever with renal syndrome, caused by Puumala virus. The clinical picture is characterized by a rapid loss of renal function (acute kidney injury) and thrombocytopenia. The purpose of the current analysis was to compare the clinical course of patients presenting with or without severe thrombocytopenia. In 47 out of 456 patients with acute nephropathia epidemica, the nadir count of thrombocytes was available for the acute course of the disease. The clinical course of these patients was further analyzed. No major bleeding (e.g., intracranial bleeding or gastrointestinal bleeding) occurred in either group. Creatinine peak levels were higher and proteinuria was more frequently present in the severely thrombocytopenic group. In conclusion, severe thrombocytopenia is common in nephropathia epidemica and is associated with a more severe course of the disease; however, bleeding complications are rare.

A typical Wegeners granulomatosis -- but not pauci-immune!

We present a the case of 58-year old man who was admitted to hospital with typical clinical features (bloody nasal discharge, arthralgia, acute kidney injury with a nephritic syndrome) consisting with Wegeners granulomatosis (WG). CT-scan showed pulmonary nodules and antineutrophil cytoplasmatic antibodies (ANCA) were elevated. A kidney biopsy showed a crescentic glomerulonephritis, but not pauci-immune-immune with a histopathological staining of a mesangioproliferative IgA-glomerulonephritis. The patient was put on prednisolone and i.v. cyclophosphamid (CYCLOPS-protocol (1). The anti-proteinase-3 antibody titer decreased and the CT-scan showed decreased activity of Wegener's granulomatosis (BVAS 26 dropped to 2) and the patient`s serum creatinine level was stable. The exact nosological relation of mesangial IgA-nephropathy to WG is still unclear. This case underlines that knowledge of renal histology is essential in the management of patients with renal disease, especially in patients with hematuria and/or proeinuria with positive ANCA.

[Cardiorenal syndrome]. / Kardiorenales Syndrom.

The cardiorenal syndrome describes the frequent clinical situation in which therapy of a patient with acute cardiac decompensation is limited by a decline of renal function. This is frequently associated with preexisting chronic renal insufficiency. It is important to be aware of this potentially fatal constellation and perform diuretic therapy slowly and carefully in order to avoid inadequate volume depletion. This may require surveillance in an intensive care unit. Ultrafiltration is an alternative to diuretic therapy which may permit greater fluid loss when beginning therapy and better control of volume reduction once heart failure symptoms improve. The individual treatment of patients with cardiorenal syndrome requires a close cooperation between cardiologists and nephrologists.

[Salt appetite, cramps and palpitations in a 21-year old medical secretary]. / Salzhunger, Krämpfe und Palpitationen bei einer 21-jährigen Arzthelferin.

Hypokalemia is a common finding. The clinical presentation can be paralyses and cardiac arrhythmias. We present a normotensive young woman with salt appetite, cramps and palpitations. In our case report the patient shows a positive family history for hypopotassemia, a metabolic alkalosis with hypotension, and hypocalciuria with an increased urinary potassium loss. The levels of renin and aldosterone were elevated. After a negative testing for metabolites of diuretics, we obtained a positive result of the suspected SLC12A3 genetic test. This mutation leads to a failure of the thiazide-sensitive sodium-2-chloride-cotransporter, the so called Gitelman syndrome, which presents similar to a chronic thiazide therapy. The Gitelman syndrome is a rare disease with renal potassium loss and hypotension. Especially in young patients around the age of twenty or in patients with chronic intractable hypopotassemia a Gitelman syndrome should be considered.

[Metabolic acidosis : Diagnosis and treatment]. / Metabolische Azidose : Diagnostik und Therapie.

Acid-base disorders and in particular metabolic acidosis are very common in critically ill patients and contribute significantly to morbidity and mortality. We shed light on the most common causes, the pathophysiology and treatments. Particular attention will be paid to the common practice of substituting sodium bicarbonate in the light of recent study results.

Fibrogenic growth factors in encapsulating peritoneal sclerosis.

BACKGROUND: Increased local levels of fibrogenic growth hormones contribute substantially to the process of encapsulating peritoneal sclerosis (EPS) in animal models. METHODS: We analyzed probes from patients with normal kidney function (n = 10), with normal kidney function and inflammation (n = 10), on PD without (n = 10) and with EPS (n = 9). We investigated the degree of fibrosis and the number of vessels and vasculopathy. Additionally, we investigated the expression of NFkappaB, TGFbeta1, TGFbeta1 receptor, TGFbeta2, TGFbeta2 receptor, FGF-BP, CTGF and VEGF by immunohistochemistry. RESULTS: In EPS, we found an exclusive upregulation of VEGF (normal 0, appendicitis 1.0 +/- 1.2, PD 1.7 +/- 1.8 and EPS 5.7 +/- 4.4; p < 0.0001), whereas in PD, CTGF was significantly increased (normal 6.0 +/- 2.8, appendicitis 7.3 +/- 2.5, PD 10.0 +/- 1.8 and EPS 7.3 +/- 2.1; p = 0.0059). The results for the TGFbeta system and NFkappaB were not uniform, in EPS no increases were demonstrable. Vasculopathy was significantly more pronounced in EPS (normal 0.4 +/- 0.5, appendicitis 0.2 +/- 0.3, PD 1.0 +/- 0.7 and EPS 1.6 +/- 1.2; p < 0.0001) than in PD or inflammation (normal 30 +/- 16, appendicitis 82 +/- 48, PD 1,936 +/- 952 and EPS 2,613 +/- 1,209; p < 0.0001), whereas the density of vessels were decreased (normal 125 +/- 114, appendicitis 817 +/- 347, PD 81 +/- 57 and EPS 36 +/- 33; p < 0.0001). CONCLUSIONS: The process of EPS was associated with increased VEGF in the peritoneum. The reduced density of vessels compared with marked fibrosis could point to hypoxia as an inducer.

Renal complications of cancer therapies.

Cancer patients often exhibit preexisting renal impairment and are simultaneously at risk for developing further kidney injury due to direct or indirect complications of oncological therapies. The nature of kidney injury is highly dependent on the therapy regimen used, and the spectrum of possible kidney stressors has widened as a result of the development of new therapeutic modalities such as molecular therapy or immunotherapy. Indirect renal complications are often due to volume depletion or other therapy-related side effects. Direct toxicity from "classic" chemotherapy treatments such as cisplatin usually leads to acute tubular necrosis, whereas treatment with protein kinase inhibitors is more likely to cause disorders such as thrombotic microangiopathy. Immunotherapy often affects kidneys through the development of acute interstitial nephritis. Because of the high risk of nephrological complications in oncological patients, close monitoring of renal function and the early involvement of a nephrologist are strongly recommended.

Risk prediction of acute kidney injury by [TIMP-2]•[IGFBP7].

Acute kidney injury (AKI) is a common syndrome with increased mortality, a heavy burden of illness and high cost. The Kidney Disease Improving Global Outcomes (KDIGO) criteria for staging of AKI have been validated in large patient cohorts and classify AKI into three stages. In order to achieve prevention or early therapy, the focus of scientific interest is early detection and risk prediction of AKI. The combination of the two cell cycle arrest markers [TIMP-2]·[IGFBP7] in the urine shows good results in the risk prediction of AKI in different clinical settings (intensive care medicine, sepsis, cardiac surgery, emergency department). Clinical use is currently being tested in different randomized intervention studies.

[Hypertension due to aortic coarctation--a missed clinical diagnosis]. / Hypertonie bei Aortenisthmusstenose--eine übersehene klinische Diagnose.

HISTORY AND FINDINGS: A 30-year-old woman presented to our emergency department with severe headaches, dizziness and uncontrolled hypertension. She had arterial hypertension and a known heart murmur since adolescence. Previous medical work up did not reveal any cause for secondary hypertension. Recently her blood pressure had been difficult to control. A systolic murmur as well as absent inguinal and feet pulses were notable at the physical examination. INVESTIGATIONS: When performing doppler ultrasound the closing pressures of the dorsalis pedis arteries were only 70 mm Hg compared to a blood pressure reading of 160 mm Hg on the upper arms. Thoracic magnetic resonance imaging showed subtotal aortic coarctation causing the differences in blood pressures. Echocardiography and cardiac catheterization additionally revealed a moderately stenosed bicuspid aortic valve, the pressure gradient across the coarctation was 30 mm Hg. THERAPY AND COURSE: Despite the severity of the coarctation an interventional approach was favoured instead of a classical operative therapy. Balloon dilatation with stent implantation was performed without complications. Since the intervention blood pressure have remained normotensive, the coarctation gradient being markedly reduced. CONCLUSIONS: In young patients with arterial hypertension, as well as in cases of severe and refractory hypertension, causes of secondary hypertension must be looked for and excluded. Especially when hypertension occurs in adolescence, aortic coarctation should be taken into account, in addition to renal or endocrine causes. A thorough physical examination with cardiac auscultation and checking of all peripheral pulses is the crucial step to the diagnosis.

[A 65-year-old man with history of claudication, palpable purpura and livedo reticularis]. / Claudicatio intermittens, palpable Purpura und Livedo reticularis bei einem 65-jährigen Patienten.

HISTORY AND ADMISSION FINDINGS: A 65-year-old man was admitted with history of claudication symptoms and painful skin lesions of the lower legs. Physical examination showed palpable purpura of the lower legs and livedo reticularis, most marked at the forefoot and toes. INVESTIGATIONS: Computed tomography (CT) showed an aortic mass 2 cm above the bifurcation. This was treated after angiography with a covered stent. Biopsy of the skin lesions showed no sign of vasculitis and no cholesterol crystals. TREATMENT AND COURSE: The patient was discharged and remained symptom-free for 9 months. He was readmitted at that time with recurrent complaints. CT revealed a subtotal stenosis of the aortic stent. A skin biopsy showed CD31-positive tumor cells in small arteries. Biopsy of a new osteolytic lesion in the ileum confirmed the diagnosis of angiosarcoma of the aorta. The patient decided in favor of palliative care and was discharged from the hospital. CONCLUSION: Primary tumors of the aorta, although they are rare, should be considered in the presence of an intravascular mass with stenosis to blood flow. A skin biopsy is easy to conduct and often leads to the final diagnosis.

The impact of thyroid disease on the regulation, expression, and function of ABCB1 (MDR1/P glycoprotein) and consequences for the disposition of digoxin.

The impact of thyroid dysfunction on the regulation, expression, and function of ABCB1 remains unclear. We therefore investigated ABCB1 mRNA expression and function in patients with thyroid dysfunction and studied the disposition of the ABCB1 substrate digoxin before and after treatment for thyroid disease. In patients with hypothyroidism, normalization of thyroid function was associated with a 1.8-fold increase in mRNA expression and a 26% increase in rhodamine efflux from CD56(+) cells. In hypothyroidism, digoxin clearance was significantly decreased, whereas bioavailability, volume of distribution, half-life time, and protein binding were unaltered. In hyperthyroidism, ABCB1 mRNA expression, rhodamine efflux, and disposition of digoxin were not significantly affected other than in relation to renal clearance. Experiments using the LS174T cell line indicated that the gene is a direct target of thyroid hormone receptors. In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein.

Clinical impacts of histological subtyping primary breast cancer.

BACKGROUND: Treatment decisions in breast cancer depend on TNM classification and the assessment of additional variables with have an impact on survival. We examined whether histological subtyping breast cancer as either ductal or lobular is related to disease outcome. PATIENTS AND METHODS: We examined a large data base of 14198 breast cancer patients. RESULTS: Histological sub-classification of invasive breast cancer as either ductal or lobular is not correlated with disease outcome. However, the data further showed that invasive lobular carcinomas have a higher probability of being oestrogen receptor (ER)- and progesterone receptor (PR)-positive and a lower probability of being c-erbB2-positive. They also showed a higher average age at the time of diagnosis in comparison with invasive ductal carcinoma. Local recurrence rates were lower in invasive lobular carcinoma in comparison with invasive ductal carcinoma (3.5% vs. 6.2%; p = 0.031). The multivariable Cox regression analysis showed that ER, PR, nodal status, grade and tumour size predicted disease outcome with statistical significance, while the histological subtype (invasive ductal or lobular) was not a significant predictor of disease outcome. CONCLUSION: Histological sub-classification of invasive breast cancer as either ductal or lobular is not correlated with disease outcome. On the other hand our data gives some indication that lobular and ductal breast cancer appear to be different biological entities.