Iron deficiency during first-line chemotherapy in metastatic cancers: a prospective epidemiological study.

PURPOSE: Anemia is common in oncology and negatively impacts quality of life. However, there is lack of knowledge about iron deficiency (ID) epidemiology. The aim of this study was to prospectively assess iron status in patients with locally advanced or metastatic cancer beginning chemotherapy. METHODS: In this prospective, multicenter cohort study, anemia and ID were evaluated in patients with locally advanced or metastatic solid tumors and lymphoma before starting chemotherapy. Blood samples were collected at inclusion (W0), 6 weeks (W6), and 12 weeks (W12). Prevalence was evaluated in the general population, according to tumor location and was correlated with tumor response. RESULTS: One hundred twenty-nine patients were enrolled between 2013 and 2015; 119 had solid tumors and 10 lymphomas. At W0, there were no significant difference between locations with a prevalence around 50-60% (range 47.2-70.4%) and only a trend for colorectal cancer (70.4%, P = 0.069) due to a higher prevalence of absolute ID (18.5%). Prevalence of ID+ decreased between W0 and W6 and remained stable until W12 due to the proportion of patients with ID and without anemia. However, anemia prevalence increased during W0 and W6 and remained stable to W6 from W12 due to patients with anemia but without ID. A significant correlation between tumor response and ID prevalence was found (P = 0.036). CONCLUSIONS: We confirm the high prevalence of ID and anemia in cancer patients. ID status is correlated to tumor response providing a strong rationale for iron monitoring during cancer management.

Sporadic Retroperitoneal Hemangioblastoma: Report of a Case and Review of the Literature.

We report a case of sporadic isolated hemangioblastoma arising from the retroperitoneum and provide a review of the scarce literature regarding this very rare tumor. Furthermore, we thoroughly describe the pathologic features and the broad differential diagnosis that should always be included in the study of any retroperitoneal soft tissue mass to arrive at the final diagnosis.

A symptomatic de novo pheochromocytoma 23 years after liver transplantation: a case report and review of the literature.

We report a case of subacute onset of headaches and tremors with a newly discovered adrenal pheochromocytoma 23 years after an orthotopic liver transplantation and provide a review of the scarce literature regarding endocrine malignancies in liver transplant recipients. We describe the clinical presentation, diagnostic work-up, and management. This is the second case report in the literature of a de novo pheochromocytoma after solid organ transplantation. It shows that new-onset common symptoms in transplant recipients are always challenging and deserve a very thorough work-up until the cause of the symptoms is elucidated. A broad differential diagnosis should always be included in the study of any abnormalities in this patient population.

Intra-articular fibroma of tendon sheath of the shoulder joint: synovial fibroma.

The case of a 30-year-old woman with multiple loose bodies in the shoulder joint is presented. The patient complained of discomfort of her right shoulder. Conventional radiographs failed to reveal any abnormality of the shoulder. On MRI numerous loose bodies were detected that resembled synovial chondromatosis. Histologically, the loose bodies were composed of a benign fibroblastic lesion with diagnostic features of fibroma of tendon sheath, each surfaced by synoviocytes. The clinicopathologic features of intra-articular fibroma of tendon sheath are reviewed. We propose using the term "synovial fibroma" for tumors with histopathologic features of fibroma of tendon sheath arising in the synovium of joints.

Hypertrophic phenotype of cardiac calcium/calmodulin-dependent protein kinase II is reversed by angiotensin converting enzyme inhibition.

Calcium-dependent mechanisms and the renin angiotensin system (RAS) are critically involved in the hypertrophic growth of the myocardium. The calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator in calcium signaling and modulates calcium handling and growth mechanisms in cardiomyocytes. Here we present data on expression of cardiac isoforms of CaMKIIdelta, the dominant form in the myocardium, in compensatory hypertrophy of stroke-prone spontaneously hypertensive rats (SHRSP) compared to the normotensive Wistar-Kyoto (WKY) control strain. Cardiac hypertrophy in SHRSP was documented by an increased heart weight/body weight ratio (HW/BW) of 31% (p < 0.05) and a more than six-fold elevated atrial natriuretic factor (ANF) transcript level (p < 0.05). Compensatory hypertrophic growth in SHRSP produced a specific phenotype of CaMKIIdelta isoforms characterized by increased transcript levels of the embryonic/neonatal isoform delta4 (48%, p < 0.05) and the isoform delta9 (31%, p < 0.05) with no changes in delta2 and delta3. Inhibition of angiotensin converting enzyme (ACE) by cilazapril completely regressed myocardial hypertrophy, normalized ANF transcript levels, and restored the normal phenotype of CaMKIIdelta by reducing transcripts for delta4 and delta9 to levels present in WKY controls. Our data suggest the importance of specific changes in the CaMKII isoform composition for growth processes in the myocardium.

Expression of Ca2+/calmodulin-dependent protein kinase II delta-subunit isoforms in rats with hypertensive cardiac hypertrophy.

Myocardial hypertrophy is characterized by abnormal intracellular Ca2+ handling and decreased contractile performance. Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates numerous Ca2+ handling proteins and thus can regulate intracellular Ca2+ homeostasis directly. We therefore investigated whether differential expression of CaMKII isoforms occurs with cardiac hypertrophy which might promote an abnormal intracellular Ca2+ homeostasis. We further investigated the potential influence of angiotensin (Ang) II on CaMKII expression levels. Hearts from adult Spontaneously Hypertensive Rats (SHR) and hearts from two transgenic rat models with Ang II-dependent hypertension were studied. The expression of the cardiac CaMKII isoforms delta2, delta3, delta4 and delta9 was determined by RT-PCR and immunoblot methods. Rats transgenic for the mouse Ren-2 gene (mrTGR), SHR and controls were studied at the age of 6 months and rats transgenic for the human renin-angiotensin system (hrTGR) from postnatal day 1 to week 8. SHR and mrTGR had an increased heart/body weight ratio (26 and 25%) compared with controls (p < 0.05). SHR hearts showed significantly increased mRNA levels of delta4 and delta9 (p < 0.05) with no change for delta2 and delta3. mrTGR hearts had a significantly increased delta4 and a significantly decreased delta3 transcript level (p < 0.05) with no change for delta2 and delta9. hrTGR hearts developed severe hypertrophy (42%) after postnatal day 14. The neonatal delta2, delta3 and delta4 isoform expression levels were higher (30-100%) compared with SD controls. The levels decreased with increasing age and equalized to controls at week 8, except for delta4 which started to increase after week 4 (p < 0.05). CaMKIIdelta protein levels of all cardiac hypertrophy models were increased in sarcoplasmic reticulum preparations (50-120%) compared with controls (p < 0.05) while the cytosolic levels remained unchanged. Thus, CaMKIIdelta isoforms are differentially expressed in cardiac hypertrophy. The fetal delta4 isoform was constantly expressed. CaMKIIdelta adopts the fetal phenotype independent of the type of hypertrophic stimulus. The observed alterations of CaMKIIdelta isoform patterns may affect intracellular Ca2+ homeostasis and thus contribute to the abnormal contractile phenotype of cardiac hypertrophy.

Cheyne-Stokes respiration as an additional risk factor for pulmonary hypertension in a boy with trisomy 21 and atrioventricular septal defect.

Central ventilation disorders(1) and airway obstruction(2) with chronic hypoxemia are causally related to cor pulmonale. Pulmonary vascular resistance is often reversible, and hypoxic pulmonary hypertension often responds to treatment with supplemental oxygen. Oxygen therapy during sleep may be useful as a temporary palliative treatment in children with obstructive sleep apnea syndrome (3) and Cheyne-Stokes respiration (CSR) in congestive heart failure(4). This type of sleep-related breathing disorder is characterized by periodic crescendo-decrescendo alterations in tidal volume. Proposed mechanism include an increased central nervous system sensitivity to changes in arterial PCO2 and PO2, a decrease in total body stores of CO2 and O2 with resulting instability in arterial blood gas tensions in response to changes in ventilation, and an increased circulatory time. Clinical features of obstructive and central sleep-related breathing disorders include daytime somnolence, unusual breathing patterns, failure to thrive, and cyanosis masquerading as cyanotic congenital heart disease(2). Down syndrome is often associated with cardiac malformations, left to right shunt, and the development of pulmonary hypertension(5). However, this may be exacerbated by sleep-related breathing disorders, as illustrated in the following case report.

Bilateral diaphragmatic paralysis after cardiac surgery: ventilatory assistance by nasal mask continuous positive airway pressure.

The case of an 8-month-old boy with bilateral diaphragmatic paralysis after surgical reoperation for congenital heart disease is presented. In order to avoid repeated intubation and long-term mechanical ventilation or tracheotomy, we used nasal mask continuous positive airway pressure (CPAP) as an alternative method for assisted ventilation. Within 24 hours the boy accepted the nasal mask and symptoms such as dyspnea and sweating disappeared. Respiratory movements became regular and oxygen saturation increased. Nasal mask CPAP may serve as an alternative treatment of bilateral diaphragmatic paralysis in infants, thereby avoiding tracheotomy or long-term mechanical ventilation.

Central apnoea and endogenous prostaglandins in neonates.

AIM: Central apnoeas without an identifiable precipitating cause frequently occur in the neonatal period. Serious apnoeas should be treated with ventilation-enhancing methylxanthines. Drugs such as opioids or prostaglandins (PGE2) are known to induce apnoea. PGE2 is an endogenous hormone that plays an important role in the regulation of neural activity and a relationship between PGE2 and central apnoeas has been postulated. METHODS: In order to test the hypothesis that the incidence of central apnoeas in preterm infants is related to endogenous PGE concentration, we measured the urinary concentration of PGE2 and PGE-M and determined the number of central apnoeas >10 s/12 h in overnight polygraphy in 18 preterm infants with apnoeas, bradycardias and desaturations, and 18 normal controls. RESULTS: We found 80.6 (SE 6.9) central apnoeas in the study group, and 52.9 (SE 4.1) in the control group (p = 0.002). Urinary PGE2 concentration was 25.9 (SE 6.1) ng/h/1.73 m2 in the control, 31.2 (SE 15.8) ng/h/1.73 m2 in the study group (p = n.s.), PGE-M concentration was 486 (SE 35) ng/h/1.73 m2 in the control and 1132 (SE 131) ng/h/1.73 m2 in the study group (p < 0.0001). There was a significant correlation between the number of central apnoeas and the PGE-M concentration in the study group (r = 0.68, p < 0.0001). CONCLUSION: Our results suggest a relationship between PGE and the respiratory system and open potential therapeutic options for the treatment of central apnoeas in neonates.

delta-Ca(2+)/calmodulin-dependent protein kinase II expression pattern in adult mouse heart and cardiogenic differentiation of embryonic stem cells.

delta-isoforms of the Ca(2+)/calmodulin-dependent protein kinase type II (CaMKII) are considered to substantially influence cardiac functions. However, no data exist on the expression of these isoforms in the mouse heart. We analyzed the transcript pattern of non-neuronally expressed delta-isoforms in heart and skeletal muscle of adult mice by RT-PCR. For members of the delta-CaMKII subclass with both variable domains (subclass II), weak transcriptional expression of isoforms delta(2) and delta(3) was found in the heart. In skeletal muscle no delta(3)-specific transcript was detectable. In cardiac tissue, stronger signals result from amplifications of delta(9) and from members of the subclass I lacking the second variable domain. Western blotting was performed using a subclass II-specific antibody. In murine cardiac and skeletal muscle tissue a delta-CaMKII protein pattern was obtained similar to that described for rat. To gain insight into the expression of delta-CaMKII during the earliest steps of cardiogenic differentiation, we analyzed the transcript pattern of murine embryonic stem cell-derived cardiomyocytes in various differentiation stages. Reproducible RT-PCR signals could be obtained for delta(6) and delta(10), both belonging to the delta-CaMKII subclass I. Transcripts for delta(6) were ubiquitously expressed, whereas transcripts for delta(10) were detectable in increasing amounts after 7-10 days of the onset of cardiogenic differentiation. Our results point to a differentiation-dependent expression of the two delta-CaMKII subclasses, and also to differences in the expression of individual members of subclass I during the early stages of cardiogenic differentiation.

Neonatal urinary prostanoid excretion.

Urinary excretion of prostanoids prostaglandin E2 (PGE2), PGE-M (7alpha-hydroxy-5,11-diketo-2,3,4,5,20-penta-19-carboxyprostano ic acid), 6-keto-PGF1alpha, 2,3-dinor-6-keto-PGF1alpha, thromboxane B2 (TxB2) 2,3-dinor-TxB2 and 11-dehydro-TxB2 was determined by gas chromatography/mass spectrometry in preterm and term infants to show that there is an age-dependent excretion rate of the above prostanoids in infants this young. Group I included premature children with normal postnatal development, Groups II and III included term children who were admitted in the neonatal period for observation because of feeding problems but who were subsequently found to be completely healthy. We present normal data of three primary prostanoids and four prostanoid metabolites. In Group I, excretion rates of 2,3-dinor-TxB2 were significantly lower than in Group II (P = 0.04) and in Group III (P = 0.05). Furthermore, the excretion rate of 11-dehydro-TxB2 in group I was significantly lower than in Group II (P = 0.05). We found no significant age-dependent differences between the three groups in excretion rates of PGE2, PGE-M, 6-keto-PGF1alpha, 2,3-dinor-6-keto-PGF1alpha, and TxB2.

Reduced prostacyclin to thromboxane A2 ratio is correlated with central apneas in preterm infants.

Prostacyclin has a vasodilating effect on pulmonary vessels, whereas thromboxane A2 results in vasoconstriction. This study was designed to test the hypothesis that recurrent central apneas in preterm infants are correlated with a reduced prostacyclin to thromboxane A2 ratio. Twelve preterm infants with clinical events of apneas were matched with 12 control infants. Urinary concentration of 2,3-dinor-6-keto-PGF1alpha and 2,3-dinor-TxB2 was determined, and the ratio correlated with the number of central apneas (>20s) measured in overnight polygraphy. The number of central apneas >20s/12h was 97.4 (SE 7.8) in the study group, and 47.3 (SE 6.6) in the control group (p = 0.001). There was a significant correlation between the number of central apneas and the 2,3-dinor-6-keto-PGF1alpha/2,3-dinor-TxB2-ratio in all infants combined (r = -0.72, p < 0.0001) as well as in the two subject groups. Central apneas in premature infants are correlated with an decreased prostacyclin to thromboxane A2 ratio. The underlying pathomechanism may be increased intrapulmonary shunts with reflexive central apneas due to reduced pulmonary oxygenation.

Developmental changes in isoform expression of Ca2+/calmodulin-dependent protein kinase II delta-subunit in rat heart.

In the heart, Ca2+/calmodulin-dependent protein kinase II is critically involved in the regulation of Ca2+ homeostasis. Previously the predominant expression of a subclass of Ca2+/calmodulin-dependent protein kinase II delta-subunit, containing a second variable domain, was demonstrated in cardiac tissue. Here we report on the expression pattern of the non-neuronal members of this delta-subunit subclass, delta 2, delta 3, delta 4, and delta 9 in the developing heart of the rat. By semiquantitative RT-PCR isoform delta 3 was shown to be typically expressed in the heart, whereas delta 4 was expressed in skeletal muscle of adult rat. From embryonic day 14 up to the adult state of rat ventricular muscle, amounts of delta 9 transcripts remained unchanged, transcript levels of isoforms delta 2 and delta 3 were significantly increased, whereas level of delta 4 transcript was significantly decreased. Immunoblotting, using an antibody recognizing specifically those delta-isoforms containing the second variable domain, revealed three separated protein signals at about 59 kDa, 58 kDa, and 56 kDa. The immunoreaction at about 59 kDa, corresponding to the predicted molecular mass of delta 4, was dramatically diminished, whereas a significant increase in the signal at about 58 kDa was assumed to represent an increase in isoform delta 3. The protein signal at about 56 kDa, close to the predicted molecular mass of isoform delta 2, was high in the embryonic heart and significantly decreased after birth. Our data suggest the predominant expression of isoform delta 2 in the embryonic heart, establish delta 3 to be the typical isoform in the adult heart and define the skeletal muscle form delta 4 to be characteristic for fetal and neonatal stages of the heart.

Identification and expression of delta-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium.

Despite its importance for the regulation of heart function, little is known about the isoform expression of the multifunctional Ca2+/calmodulin-dependent protein kinase (CaMKII) in human myocardium. In this study, we investigated the spectrum of CaMKII isoforms delta2, delta3, delta4, delta8, and delta9 in human striated muscle tissue. Isoform delta3 is characteristically expressed in cardiac muscle. In skeletal muscle, specific expression of a new isoform termed delta11 is demonstrated. Complete sequencing of human delta2 cDNA, representing all common features of the investigated CaMKII subclass, revealed its high homology to the corresponding rat cDNA. Comparative semiquantitative reverse transcription-polymerase chain reaction analyses from left ventricular tissues of normal hearts and from patients suffering from dilated cardiomyopathy showed a significant increase in transcript levels of isoform delta3 relative to the expression of glyceraldehyde-3-phosphate dehydrogenase in diseased hearts (101. 6+/-11.0% versus 64.9+/-9.9% in the nonfailing group; P<0.05, n=6). Transcript levels of the other investigated cardiac CaMKII isoforms remained unchanged. At the protein level, by using a subclass-specific antibody, we observed a similar increase of a delta-CaMKII-specific signal (7.2+/-1.0 versus 3.8+/-0.7 optical density units in the nonfailing group; P<0.05, n=4 through 6). The diseased state of the failing hearts was confirmed by a significant increase in transcript levels for atrial natriuretic peptide (292. 9+/-76.4% versus 40.1+/-3.2% in the nonfailing group; P<0.05, n=3 through 6). Our data characterize for the first time the delta-CaMKII isoform expression pattern in human hearts and demonstrate changes in this expression pattern in heart failure.

Different patterns of sighs in neonates and young infants.

To examine the prevalence and clinical assessment of sighs in neonates, we observed three different patterns of sighs: (A) sighs in the absence of apneic pause; (B) sighs with instantly following apneic pause >2 s, and (C) sighs with apneic pause >2 s following 1-3 normal breaths. We investigated preterm and term infants with 12 h nocturnal polygraphic recording. Sighs were more frequent in preterm than in term infants and more so during REM sleep than non-REM sleep. The part of sighs B of total number of sighs increased with gestational age. During REM sleep sighs without apnea were predominant, whereas apnea-associated sighs were mainly found during non-REM sleep.

Four-year-old girl with Goldenhar-sequence and severe obstructive sleep apnea, symptoms, diagnosis and therapy.

Recently sleep related breathing disorders in children have received considerable attention. Unfortunately, cardiorespiratory polygraphy is expensive and time-consuming, and up until now today only a few pediatric hospitals have complete facilities for all-night cardiorespiratory polygraphy. Nevertheless, the prevalence of sleep related breathing disorders in children is higher than has previously been thought. To show the importance of proper diagnosis of sleep related breathing disorders, we report a case of a 4-year-old girl with severe obstructive sleep apnea caused by Goldenhar-sequence (facio-auriculo-vertebral dysplasia). Despite some treatment efforts to correct the aplastic right mandible, the symptoms of obstructive sleep apnea were not immediately recognized and remained untreated. Untreated obstructive sleep apnea led to growth and mental retardation. After polygraphic confirmation of obstructive sleep apnea and appropriate interdisciplinary treatment, the 4-year-old girl made rapid advances in growth and mental development.

[Obstructive sleep apnea in the child: an interdisciplinary treatment concept with special reference to craniofacial changes]. / Obstruktive schlafbezogene Atmungsstörungen beim Kind: Ein interdisziplinäres Behandlungskonzept unter besonderer Berücksichtigung kraniofazialer Veränderungen.

Diagnosis and therapy of obstructive sleep-related breathing disturbances SRBD in adults may not be applied without hesitation to children. SRBD in newborn and infants are often due to craniofacial disturbances (Pierre Robin syndrome, Goldenhars syndrome etc.), obesity is of minor importance. More than 30 infants with SRBD and craniofacial changes have been diagnosed and successfully treated over a 2-year period. Conservative therapy starts immediately after birth. The first step in newborn with Pierre Robin syndrome, for instance, is prone position for protrusion of tongue and mandible and mandibular growth stimulation. Intermediate nightly nasopharyngeal tubes are an alternative to nCPAP-/BiPAP treatment. Conventional orthopaedic/orthodontic treatment should not be neglected, even if it takes years to become effective. Surgical therapies are able to support, sometimes to replace or at least to shorten conservative methods. In rare cases when prone position in combination with palatal plates in cases of Robin syndrome, for instance, are not fully effective, mandibular extension is indicated. Aplasia or defects demand adequate surgical reconstruction, even if this does not necessarily mean abolishment of SRBD. In contrast to adults adenotonsillectomy is highly effective in infants and does not only reduce SRBD, but also improves nasal breathing and thus positively influences facial growth. A relatively new method is gradual mandibular distraction osteogenesis according to Ilizarov, which also enhances soft tissue growth. Maxillary and mandibular advancement osteotomies should not be considered before the termination of facial growth. Thanks to this refined treatment concept we were able to avoid tracheotomies in children during the past few years.

Differentiation-dependent expression of cardiac delta-CaMKII isoforms.

Despite their important role in controlling the cardiac Ca2+ homeostasis, presence and functions of individual isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in the heart are not well studied. Here we report on expression of isoforms of the delta class in two differentiation states of the embryonic rat heart-derived cell line H9c2 compared to adult rat heart. Reverse transcription coupled polymerase chain reaction analysis revealed specific expression patterns of four variants of the delta class (delta B, delta C, delta 4, delta 9) in adult rat heart, H9c2 myoblasts, and skeletal muscle-like H9c2 myotubes. delta C was identified as a common isoform with higher amounts in H9c2 cells and the prominent one in myoblasts. In contrast, expression of delta 9 accompanied cardiac as well as skeletal muscle differentiation. Expression of delta B, however, was representative for differentiated cardiac muscle, whereas delta 4 expression coincided with differentiation into the skeletal muscle-like state. Our results demonstrate differentiation-dependent isoform expression of the delta class of the multifunctional Ca2+/calmodulin-dependent protein kinase of muscle. The identification of cardiac target proteins for this kinase, e.g. the alpha 1-subunit of the L-type Ca2+ channel, the sarcoplasmic reticulum Ca(2+)-ATPase, phospholamban and the ryanodine receptor define H9c2 myoblasts as a suitable model system for further functional characterization of the identified cardiac delta isoforms.

cAMP-dependent reversal of opioid- and prostaglandin-mediated depression of the isolated respiratory network in newborn rats.

1. Membrane potential (Vm) and resistance (Rm) of ventral respiratory group (VRG) neurons were measured in the isolated brainstem-spinal cord from newborn rats during bath application of the opioid receptor agonists fentanyl or [D-Ala2, D-Leu5]-enkephalin (Ala-Leu-Enk) and of the prostaglandin E1 (PGE1). 2. PGE1 (0.1-3 microM) and fentanyl or Ala-Leu-Enk (1-50 microM) produced depression and, at higher doses, block of inspiratory nerve activity and respiration-related postsynaptic potentials. This apnoea was associated with hyperpolarization and Rm fall in 25% of thirty-two VRG neurons tested, whereas resting Vm and Rm were not changed in the other cells. 3. The selective mu- and delta-receptor blockers naloxonazine (10-20 microM) and naltrindole (50-100 microM) antagonized the effects of 5 microM fentanyl and 50 microM Ala-Leu-Enk, respectively. 4. Opioid- and PGE1-evoked respiratory depression was reversed upon elevation of endogenous cAMP levels by stimulating adenylyl cyclase with 100 microM forskolin, activating dopamine D1 receptors with 50-100 microM 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2, 3,4,5-tetrahydro-1H-3-benzazepine (6-chloro-APB) or preventing cAMP breakdown with 50-100 microM isobutylmethylxanthine. 5. The results indicate that opioid- or prostaglandin-induced respiratory depression is due to a fall in cAMP levels in cells responsible for generation of rhythm or providing a tonic drive to the respiratory network. 6. We suggest that elevation of cAMP levels is an effective antidote in neonates against such forms of respiratory depression.