Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.

BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Randomized, double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC).

OBJECTIVES: Adding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population. METHODS: 66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60 mg/m(2), subsequent cycles: 80 mg/m(2) in the absence of any hematological toxicity ≥ grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80 mg/m(2) i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n=34) or placebo patches (arm B, n=32) were administered once daily from day -3 to day 2 of each cycle and were removed about 12h after administration. One nitroglycerin patch contained 25mg nitroglycerin. RESULTS: Median age was 62.5 (33-82) years. In the overall population (n=66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0-39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8-69.7), a median time to progression (TTP) of 4.8 months (n=58; 95%CI: 3.4-5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9-13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥ 3 were moderate with no significant differences between the two treatment arms. CONCLUSIONS: Overall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients.

[Hypertrophic pulmonary osteoarthropathy as a cue for NSCLC: four cases in the light of the current literature]. / Das Marie-Bamberger-Syndrom als Fingerzeig auf ein NSCLC: vier Fälle im Lichte der aktuellen Literatur.

Hypertrophic pulmonary osteoarthropathy (often referred to as Marie-Bamberger syndrome) occurs in 1 - 5 % of all patients with non-small cell lung cancer (NSCLC) as a paraneoplastic syndrome. The complete syndrome is characterised by clubbing of the fingers and toes (often without hypoxia) and pain in the joints and tubular bones. On the basis of four clinical cases, this article shows that this syndrome can precede tumour-specific symptoms and that it is still often overlooked by physicians. An early suspicion of this syndrome is of great clinical value because it can lead to a diagnosis of NSCLC at an earlier tumour stage. In addition to the case reports, the current literature on hypertrophic pulmonary osteoarthropathy is reviewed in this article, with special reference to pathogenetic concepts und to therapeutic options.

Acute effects of tobacco smoke on human airway dendritic cells in vivo.

Airway dendritic cells (DCs) play a key role in smoke-related lung diseases; however, the acute effects of tobacco smoke on human airway DCs in vivo are unknown. A total of 16 smokers underwent bronchoalveolar lavage at two time-points: directly after a 4-h period of nonsmoking (no smoke exposure); and directly after a 4-h period during which eight cigarettes were smoked (acute smoke exposure). Using flow cytometry, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), as well as function-associated surface molecules on mDCs, were analysed in bronchoalveolar lavage fluid (BALF) and in blood. The numbers of macrophages, lymphocytes, neutrophils, eosinophils and pDCs were unchanged in BALF following acute smoke exposure, as compared to no smoke exposure. In contrast, there was a strong increase in mDC number in BALF and a concomitant decrease in mDC number in blood following acute smoke exposure. In addition, acute smoke exposure led to an increase in the expression of the surface molecules blood dendritic cell antigen 1 and 4 and a decrease in the expression of the lung homing receptor, CC chemokine receptor 5, on mDCs in BALF. Acute tobacco smoke inhalation results in an immediate and selective recruitment of mDCs into human airways, which might reflect the very early reaction of the adaptive immune system to smoke exposure.

[Fetal juvenile granulosa cell tumor with hermaphroditism verus - prenatal diagnosis, management and outcome]. / Fetaler juveniler Granulosazelltumor mit Hermaphroditismus verus - pränatale Diagnostik, Management und postnatales Outcome.

Fetal ovarian cysts are common during pregnancy and after delivery. Most of these cysts are simple cysts that involute during pregnancy or in the first months of life. However, complicated cyst with a heterogeneous structure and also possible and can result in various complications: rupture, hemorrhage, ascites, edema of the labia, compression of other viscera, and ovarian torsion. In this case report we describe rare diagnosis of a complicated fetal ovarian cyst with edema of the labia and moderate ascites. The neonate had ambiguous genitalia with clitoromegaly. The newborn underwent surgery with oophorectomy. During the operation a uterus with fallopian tubes was found. The pathological findings showed a juvenile granulosa cell tumor FIGO Ia. Karyotyping revealed a mosaic of 45, X/ 46, X mar (Y) in the peripheral blood as well as in the granulosa cell tumor. Because of a right side inguinal hernia, the child underwent a second surgery. Specimen taken from the abdominal gonad and the inguinal region showed testicular and dysplastic ovarian tissue. There were elevated levels of androgens in the child's peripheral blood due to the granulosa cell tumor. In summary, this case report describes a fetus with true hermaphroditism and a juvenile granulosa cell tumor diagnosed as a complicated ovarian cyst in the 32 (nd )week of pregnancy.

Airway dendritic cell phenotypes in inflammatory diseases of the human lung.

Airway dendritic cells (DCs) are key regulators of pulmonary immune responses. However, information is limited regarding the characteristics of airway DCs in human lung diseases. Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were analysed using four-colour flow cytometry in bronchoalveolar lavage fluid (BALF) from nonsmoking controls and patients with sarcoidosis, idiopathic pulmonary fibrosis (IPF) and pneumonia (in the presence or absence of immunosuppression). Compared with controls, immunocompetent patients with pneumonia displayed strongly enhanced pDC counts in BALF. In contrast, pDC counts in BALF from immunocompromised patients with pneumonia were even lower than in controls. This discrepancy was not explained by a different chemotactic milieu in the airways; all patients with pneumonia were characterised by strongly increased concentrations of the pDC-attracting chemokine, CXC chemokine ligand 10, in BALF. Patients with IPF were characterised by normal percentages of DC subtypes. However, the mDCs of patients with IPF were not as mature (CD83-positive) as those of controls. Patients with sarcoidosis displayed a unique increase in CD1a-negative mDCs in the airways. In addition, there was altered expression of costimulatory molecules (increased CD80 and decreased CD86 expression) on mDCs in patients with sarcoidosis. These data suggest that inflammatory diseases of the human lung are associated with a differential phenotype and recruitment of airway dendritic cells.

The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC).

The polymorphic variants at codon 72 of the p53 gene were shown to be functionally distinct in vitro, whereby the arginine (arg) variant induces apoptosis more efficiently than the proline (pro) variant. From the evidence that the DNA mismatch repair system and p53 interact to maintain genomic integrity, we hypothesized that the codon 72 variation may influence the age of onset of disease in HNPCC patients. We tested 538 patients for p53 codon 72 variants, including 167 unrelated patients with pathogenic germline mutations in MSH2 or MLH1 and colorectal carcinoma as first tumour, 126 patients with sporadic microsatellite stable colorectal cancers, and 245 healthy controls. The median age of onset was 41, 36, and 32 years for MSH2 or MLH1 mutation carriers with arg/arg, arg/pro, and pro/pro genotypes, respectively. The log rank test revealed significant differences in the age of onset between arg/arg and pro/pro individuals (p = 0.0002) and in arg/pro versus arg/arg and pro/pro individuals (p = 0.0026 and p = 0.0217, respectively). A Cox regression model indicated an additive mode of inheritance. No significant differences in age of onset were observed among different genotype carriers with microsatellite stable tumours. Our results suggest that p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a mismatch repair deficient background in a dose dependent manner. These findings may be relevant for preventive strategies in HNPCC.

[Pneumological disease in pregnancy]. / Pneumologische Erkrankungen in der Schwangerschaft. Bleibt genügend Luft für den Nachwuchs?

The age at manifestation of numerous diseases affecting the lungs is appreciably lower than the average age for other internistic diseases. 7-10% of women of child-bearing age suffer from asthma, and are in need of adequate management during their pregnancy. Other diseases affecting the lungs, such as pneumonia, occur as acute conditions and, despite their dramatic aspects, should be treated only with certain selected antibiotics, so as not to put the unborn child at risk. Apart from TB, cystic fibrosis, HIV and restrictive pulmonary illnesses, there are a number of less common pneumological diseases that require special attention during a pregnancy.

The role of connexin-mediated cell-cell communication in breast cancer metastasis.

Gap junctional intercellular communication (GJIC) is a form of cell-cell communication mediating the exchange of small molecules between neighboring cells. Gap junctions (GJs) are formed by connexins (Cxs), and are subject to tight and dynamic regulation. They are involved in the cell cycle, differentiation, and cell signaling. The loss of Cxs and GJs is a hallmark of carcinogenesis, while their induction in cancer cells leads to a reversal of the cancer phenotype, induction of differentiation, and regulation of cell growth. On the basis of the observations about Cx loss in breast cancer, this review examines Cxs' involvement in breast cancer metastasis. Previous work indicates that Cx expression is inversely correlated to metastatic potential. This is probably because of the loss of cooperation between neighboring cells, leading to cell heterogeneity and cell dissociation in the tumor. The possible involvement of Cx activity during metastasis will be discussed.

Coronary artery compression caused by a large pseudoaneurysm of the mitral-aortic intervalvular fibrosa.

An unusual late complication of bacterial endocarditis is described. Four years after diagnosis and treatment, a patient is seen with coronary artery compression caused by a large pseudoaneurysm of the mitral-aortic intervalvular fibrosa. The utility of transesophageal echocardiography in diagnosis and surgical management is emphasized.

Acute cardiogenic pulmonary edema: clinical and noninvasive evaluation.

Left ventricular echocardiograms performed within ninety-six hours of admission were prospectively correlated with the clinical course in 87 consecutive patients admitted with acute pulmonary edema. Patients were stratified into four groups based on their two-dimensional echocardiogram: hyperdynamic, normal, mildly reduced, and severely reduced. Echocardiographic estimates of left ventricular function were compared with their ejection fraction measured by the gated radioisotope technique. The authors found that 48% of the patients were either normal or hyperdynamic (38% and 10% respectively). Patients in these two groups had a greater incidence of left ventricular hypertrophy (wall thickness greater than 13 mm) (66% vs 39%, p less than .05), hypertension on admission (BP greater than 160/100) (66% vs 41%, p = .05), and smaller end-diastolic dimension (p less than .05) than those with decreased left ventricular function. The authors conclude that echocardiography is a good screening test of left ventricular function in patients presenting with pulmonary edema. Patients with normal or increased left ventricular systolic function should be evaluated for correctable or treatable causes of acute pulmonary edema.

Time variation of mitral regurgitant flow in patients with dilated cardiomyopathy.

Angiographic results in patients with mitral regurgitation suggest that up to 50% of the regurgitant volume occurs during the preejection period. This contrasts markedly with the electromagnetic measurements of mitral regurgitant flow in anesthetized dogs, which suggest that only 5% of mitral regurgitant flow occurs during the preejection period. Therefore, we used two-dimensional and Doppler echocardiography to quantify mitral regurgitation during aortic ejection and in the preejection and postejection periods in eight patients with severe heart failure. Mitral regurgitant volume (RV) was calculated as the difference between total stroke volume (by two-dimensional echocardiography) and forward aortic flow (by pulsed Doppler). Regurgitant velocity (V) and time (RT) were measured by continuous-wave Doppler, and the mean regurgitant area (RAm) was calculated from the RT and mean regurgitant velocity (Vm): RAm = (RV/RT)/Vm. As a first approximation, the RA was assumed to be constant during systole, and the regurgitant volume during aortic ejection and during the preejection and postejection periods was calculated from: RVi = (Vmi) (RTi) (TAm), where Ti represents the duration of the appropriate period. Percentages of total regurgitant volume occurring during the preejection, ejection, and postejection periods were 13 +/- 4%, 79 +/- 5%, and 8 +/- 5%, respectively. Thus, in contrast to previously reported angiographic studies, mitral regurgitation occurs predominantly during the aortic ejection period. These results were not substantially changed by assuming a 20% reduction in effective regurgitant orifice area between the preejection and ejection periods and are consistent with data from chronically instrumented dogs with mitral regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamics of mitral regurgitation during nitroglycerin therapy: a Doppler echocardiographic study.

Seven patients with decompensated chronic heart failure and functional mitral regurgitation were studied before and during administration of nitroglycerin at a mean dose of 42 micrograms/min (range 20 to 90 micrograms/min). Forward aortic flow obtained by pulsed Doppler increased significantly from 35 +/- 8 to 45 +/- 9 ml/beat (p less than 0.001) and correlated well with the cardiac output measured by thermodilution technique (r = 0.8). Whereas regurgitant mitral volume calculated from the difference between echocardiographic total stroke volume and forward aortic flow decreased significantly from 19 +/- 9 to 3 +/- 3 ml/beat (p less than 0.001), peak velocity of mitral regurgitant flow increased from 4.1 +/- 0.9 to 4.4 +/- 1.0 m/sec (p less than 0.05). The decrease in effective mitral regurgitation area derived from a modified Gorlin formula average 80%. Accordingly, in patients with decompensated chronic heart failure and functional mitral regurgitation, nitroglycerin decreases mitral regurgitant area substantially, and thus almost abolishes mitral regurgitation despite an increase in systolic pressure gradient between left ventricle and atrium. Moreover, the increase in forward flow can be entirely accounted for by the reduction in mitral regurgitant flow.

Endocarditis of a tricuspid prosthesis causing valvular stenosis and shunting through a patent foramen ovale.

A young intravenous drug user presented with Staphylococcus aureus endocarditis involving the tricuspid valve, which was replaced with a Hancock bioprosthesis. She presented again with fever and dyspnea five months later and was found to be cyanotic. Recurrent endocarditis involving the prosthesis with right-to-left shunting through a patent foramen ovale was documented by echo and confirmed at autopsy.

Improvement in forward cardiac output without a change in ejection fraction during nitroglycerin therapy in patients with functional mitral regurgitation.

Left ventricular volumes and forward aortic flow were measured using combined two-dimensional echocardiography and doppler cardiography in seven patients with decompensated congestive heart failure and functional mitral regurgitation prior to and during intravenous administration of nitroglycerin. Total stroke volume was calculated from the difference between end-diastolic and end-systolic volumes, and regurgitant mitral volume from the difference between total stroke volume and forward aortic flow. Regurgitant mitral volume fell from 19 +/- 9 to 3 +/- 3 mL/beat (p less than 0.001), while forward stroke volume increased from 35 +/- 8 to 45 +/- 9 mL/beat (p less than 0.001). The changes were well correlated (r = 0.8, p less than 0.001). Total stroke volume decreased from 54 +/- 12 to 48 +/- 6 mL/beat (p less than 0.05), and ventricular end-diastolic volume from 173 +/- 66 to 158 +/- 66 mL (p less than 0.05). Left ventricular ejection fraction did not change significantly: 33 +/- 9% vs 32 +/- 9% (NS). Thus, in patients with severe congestive heart failure and functional mitral regurgitation, intravenous nitroglycerin redistributes blood flow within the heart by decreasing mitral regurgitation and increasing forward aortic flow, without affecting left ventricular ejection fraction.

Atrial contraction is an important determinant of pulmonary venous flow.

Pulmonary venous flow has two phases (systolic and diastolic) in normal subjects when studied by pulsed Doppler echocardiography. Only one phase of pulmonary venous flow (diastolic) was observed in six patients without synchronous atrial contraction (four patients with atrial fibrillation and two with complete atrioventricular [AV] block). This pattern reversed to normal (biphasic) when AV synchrony was reestablished by cardioversion to sinus rhythm in patients with atrial fibrillation and by AV sequential pacing in patients with complete AV block. Thus, both atrial and ventricular contraction and relaxation are important determinants of pulmonary venous flow.