Rhabdomyoma of the soft palate. Fine structural details of a highly differentiated muscle tumor

An adult rhabdomyoma was light and electron microscopically studied. The lesional cells presented well-known structural details, such as abundance of mitochondria and glycogen, myofilaments and myofibrils, hypertrophied Z-bands and masses of Z-band material. Triads were randomly scattered in the cytoplasm and also related to the individual sarcomeres. In sarcomeres the triads were regularly placed near to the A-I-junctions. This peculiarity of mammalian skeletal muscle fibers may yield a criterion to distinguish between cardiac and extracardiac rhabdomyomas. Circumscribed surface areas of the tumor cells were provided with elaborate infoldings of plasma membrane and basal lamina. These areas were interpreted as imitating myotendinous junctions. Satellite cells were regularly found.     

Aspiration cytology of adult rhabdomyoma

The distinct cytologic picture of a fine needle aspirate from a case of adult rhabdomyoma is described. The presence of cytoplasmic cross striations was a diagnostic feature that could be demonstrated in some tumor cells with all routine stains used (Papanicolaou, May-Grünwald-Giemsa and hematoxylin and eosin).     

Adult-type rhabdomyoma of the palate. Cytologic presentation of two cases with histologic and immunologic study

The cytologic presentations of two adult-type rhabdomyomas of the soft palate are reported. Fine needle aspiration smears of the lesions contained globular tumor cells that had striations and intracytoplasmic rod-shaped inclusions. These inclusions, corresponding to hypertrophied Z bands, were pathognomonic of rhabdomyoma tissue. The cytologic diagnosis was confirmed by histologic and immunologic studies in both cases. The cytologic preparations fixed in alcohol or air dried did not show the "spiderweb cells" observed in the histologic sections of tissue fragments fixed in formaldehyde; this clearly illustrates that the morphology of the cells of this tumor depends primarily on the specimen preparation technique used. These cases suggest that aspiration cytology can establish the diagnosis of this benign tumor of striated muscle, for which total surgical removal is usually sufficient to effect a cure. The differential diagnosis is discussed in detail.     

Tuberous sclerosis with rhabdomyoma

Tuberous sclerosis is a neurocutaneous syndrome characterized by abnormalities of both the integument and central nervous system. We present a case of tuberous sclerosis with rhabdomyoma in the heart. This was a 1½-year-old female child with infantile spasms and rhabdomyoma in heart with mother having neurocutaneous markers of tuberous sclerosis. Magnetic resonance imaging brain and electroencephalography findings were consistent with diagnosis.     

Submandibular rhabdomyoma: a case report

BACKGROUND: The cytologic diagnosis of extracardiac rhabdomyoma is frequently hampered by its rarity and resemblance to various tumors. In this regard, the infrequent occurrence has hindered its prompt and early recognition. It is also confused with other tumors because of similarities in clinical and cytologic presentations. CASE: A submandibular rhabdomyoma occurred in an otherwise-healthy, 62-year-old man. The neoplasm was firstly diagnosed by fine needle aspiration cytology (FNAC. Complete local excision without radical surgery was performed. Histologic findings confirmed the cytologic diagnosis of adult rhabdomyoma. Treatment-related complications were minimal, and there was no evidence of recurrent disease 6 years later. CONCLUSION: Helpful FNAC features and immunocytochemical results permitted an early diagnosis and spared the patient unnecessary radical surgery.     

Adult rhabdomyoma in fine needle aspirates. A report of two cases

BACKGROUND: Adult rhabdomyoma (ARh) is a rare, benign tumor arising most frequently in the head and neck region and sometimes mimicking malignant tumors clinically. Correct preoperative evaluation of this tumor is of crucial importance as its treatment is complete excision only and not radical surgery. CASES: Two patients with ARh, one tumor presenting near the submandibular gland and the other in the thyroid area, are reported. The first tumor was correctly diagnosed by fine needle aspiration cytology. The second, clinically suspected to be a colloid goiter, was preoperatively diagnosed as such cytologically as well. After the tumor was excised, reexamination of the cytologic specimen disclosed follicle cells admixed with single cells from ARh; these had been interpreted as colloid fragments at the time of primary evaluation. CONCLUSION: Fine needle aspiration evaluation of ARh may be problematic due to the rarity of the tumor and to the similarity of the tumor cells to normal striated muscle and to other tumors in which cells with abundant granular cytoplasm are characteristic. With an awareness of the cytologic features of this uncommon tumor, cytopathologists can render a correct diagnosis.     

Fine needle aspiration cytology of a rhabdomyoma of the pharynx

The fine needle aspiration (FNA) cytology of an extracardiac adult rhabdomyoma of the pharynx is documented. The smear of the aspirate contained large cells with peripherally located, uniform, round nuclei and abundant granular eosinophilic cytoplasm. In addition to these features, peripheral vacuoles were seen in sections of a cell block prepared from the aspirate. Special stains of the cell block sections and of the surgical specimen showed cross striations in some cells while electron microscopy showed the typical features of adult rhabdomyoma. The findings in this case suggest that FNA can diagnose this rare, benign neoplasm when it presents as a solitary mass in the head and neck region. Its differential diagnosis from other neoplasms that occur in that area is discussed.     

Apo-metallothionein emerging as a major player in the cellular activities of metallothionein

Observations of apo-metallothionein (apo-MT) have been made under a variety of physiologic circumstances, including zinc deficiency in cell culture and in rodents, cellular induction of MT by dexamethasone with concurrent Zn deficiency, a variety of tumors under normal Zn conditions, MT induction by Zn and Bi citrate, induction of hepatic MT after tumor cell injection into nude mice, and overexpression of cardiac MT in MT transgenic mice. Experiments demonstrating both the lability of Zn and Cu bound to MT and the cellular stability of apo-MT are described to help rationalize the widespread presence of this metal-depleted species. Finally, comparative in vitro and cellular experiments examined the relative reactivity of Zn- and apo-MT with nitric oxide species, showing that apo-MT is much more reactive chemically and that in cells it may be a principal reactive species within the MT pool.     

Inflammatory cytokines associated with cancer growth induce mitochondria and cytoskeleton alterations in cardiomyocytes

Cardiac dysfunction is often observed in patients with cancer also representing a serious problem limiting chemotherapeutic intervention and even patient survival. In view of the recently established role of the immune system in the control of cancer growth, the present work has been undertaken to investigate the effects of a panel of the most important inflammatory cytokines on the integrity and function of mitochondria, as well as of the cytoskeleton, two key elements in the functioning of cardiomyocytes. Either mitochondria features or actomyosin cytoskeleton organization of in vitro-cultured cardiomyocytes treated with different inflammatory cytokines were analyzed. In addition, to investigate the interplay between tumor growth and cardiac function in an in vivo system, immunocompetent female mice were inoculated with cancer cells and treated with the chemotherapeutic drug doxorubicin at a dosing schedule able to suppress tumor growth without inducing cardiac alterations. Analyses carried out in cardiomyocytes treated with the inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), interleukin 6 (IL-6), IL-8, and IL-1β revealed severe phenotypic changes, for example, of contractile cytoskeletal elements, mitochondrial membrane potential, mitochondrial reactive oxygen species production and mitochondria network organization. Accordingly, in immunocompetent mice, the tumor growth was accompanied by increased levels of the inflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-8, either in serum or in the heart tissue, together with a significant reduction of ventricular systolic function. The alterations of mitochondria and of microfilament system of cardiomyocytes, due to the systemic inflammation associated with cancer growth, could be responsible for remote cardiac injury and impairment of systolic function observed in vivo.     

Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells

ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin down-regulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNF-α, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNF-α-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.     

Paracrine effects of hypoxic fibroblast-derived factors on the MPT-ROS threshold and viability of adult rat cardiac myocytes

Cardiac fibroblasts contribute to multiple aspects of myocardial function and pathophysiology. The pathogenetic relevance of cytokine production by these cells under hypoxia, however, remains unexplored. With the use of an in vitro cell culture model, this study evaluated cytokine production by hypoxic cardiac fibroblasts and examined two distinct effects of hypoxic fibroblast-conditioned medium (HFCM) on cardiac myocytes and fibroblasts. Hypoxia caused a marked increase in the production of tumor necrosis factor (TNF)-alpha by cardiac fibroblasts. HFCM significantly enhanced the susceptibility of cardiac myocytes to reactive oxygen species (ROS)-induced mitochondrial permeability transition (MPT), determined by high-precision confocal line-scan imaging following controlled, photoexcitation-induced ROS production within individual mitochondria. Furthermore, exposure of cardiac myocytes to HFCM for 5 h led to loss of viability, as evidenced by change in morphology and annexin staining. HFCM also decreased DNA synthesis in cardiac fibroblasts. Normoxic fibroblast-conditioned medium spiked with TNF-alpha at 200 pg/ml, a concentration comparable to that in HFCM, promoted loss of myocyte viability and decreased DNA synthesis in cardiac fibroblasts. These effects of HFCM are similar to the reported effects of hypoxia per se on these cell types, showing that hypoxic fibroblast-derived factors may amplify the distinct effects of hypoxia on cardiac cells. Importantly, because both hypoxia and oxidant stress prevail in a setting of ischemia and reperfusion, the effects of soluble factors from hypoxic fibroblasts on the MPT-ROS threshold and viability of myocytes may represent a novel paracrine mechanism that could exacerbate ischemia-reperfusion injury to cardiomyocytes.     

Venous pseudo-aneurysm as a late complication of short-term central venous catheterisation

Background

Adrenocortical carcinoma is a rare, highly malignant tumor. Cardiac involvement of the tumor is very rare. Echocardiography facilitates the evaluation of the cardiac involvement of the tumor.

Case Presentation

We describe a patient with an adrenal tumor. Transthoracic echo showed its extension into the right atrium. Accordingly, a combined abdominal and cardiac operation was performed, monitored by transesophageal echocardiography.

Conclusion

This case highlights the importance of echocardiography in revealing the cardiac involvement by this tumor and in planning the operative procedure.     

COMPLETE RESECTION OF A PRIMARY CARDIAC RHABDOMYOSARCOMA

A case of primary cardiac rhabdomyosarcoma in a 23-year-old white man was managed by complete excision and combination chemotherapy. The pathologic features of the tumor are described. Based on a review of the English literature, the natural history of this tumor is discussed and a plan of therapy is proposed, which consists of (1) resection of the tumor if feasible, (2) chemotherapy with Actinomycin D, vincristine sulfate, and cyclophosphamide, and (3) cardiac radiation for residual unresected or locally recurrent tumor.     

A Bama miniature pig model of monoallelic TSC1 mutation for human tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a dominant genetic neurocutaneous syndrome characterized by multiple organ hamartomas. Although rodent models bearing a germline mutation in either TSC1 or TSC2 gene have been generated, they do not develop pathogenic lesions matching those seen in patients with TSC because of the significant differences between mice and humans, highlighting the need for an improved large animal model of TSC. Here, we successfully generate monoallelic TSC1-modified Bama miniature pigs using the CRISPR/Cas9 system along with somatic cell nuclear transfer (SCNT) technology. The expression of phosphorylated target ribosomal protein S6 is significantly enhanced in the piglets, indicating that disruption of a TSC1 allele activate the mechanistic target of rapamycin (mTOR) signaling pathway. Notably, differing from the mouse TSC models reported previously, the TSC1^+/− Bama miniature pig developed cardiac rhabdomyoma and subependymal nodules, resembling the major clinical features that occur in patients with TSC. These TSC1^+/− Bama miniature pigs could serve as valuable large animal models for further elucidation of the pathogenesis of TSC and the development of therapeutic strategies for TSC disease.     

Human Breast Tumor Cells Are More Resistant to Cardiac Glycoside Toxicity Than Non-Tumorigenic Breast Cells

Cardiotonic steroids (CTS), specific inhibitors of Na,K-ATPase activity, have been widely used for treating cardiac insufficiency. Recent studies suggest that low levels of endogenous CTS do not inhibit Na,K-ATPase activity but play a role in regulating blood pressure, inducing cellular kinase activity, and promoting cell viability. Higher CTS concentrations inhibit Na,K-ATPase activity and can induce reactive oxygen species, growth arrest, and cell death. CTS are being considered as potential novel therapies in cancer treatment, as they have been shown to limit tumor cell growth. However, there is a lack of information on the relative toxicity of tumor cells and comparable non-tumor cells. We have investigated the effects of CTS compounds, ouabain, digitoxin, and bufalin, on cell growth and survival in cell lines exhibiting the full spectrum of non-cancerous to malignant phenotypes. We show that CTS inhibit membrane Na,K-ATPase activity equally well in all cell lines tested regardless of metastatic potential. In contrast, the cellular responses to the drugs are different in non-tumor and tumor cells. Ouabain causes greater inhibition of proliferation and more extensive apoptosis in non-tumor breast cells compared to malignant or oncogene-transfected cells. In tumor cells, the effects of ouabain are accompanied by activation of anti-apoptotic ERK1/2. However, ERK1/2 or Src inhibition does not sensitize tumor cells to CTS cytotoxicity, suggesting that other mechanisms provide protection to the tumor cells. Reduced CTS-sensitivity in breast tumor cells compared to non-tumor cells indicates that CTS are not good candidates as cancer therapies.     

Circulation in rats with Guérin carcinoma.

After implantation of Guérin carcinoma in rats, cardiac output (by Evans-blue dilution), distribution of the organ fractions of cardiac output (by Sapirsteins's isotope indicator fractionation technique), nutritive blood flow and circulatory resistance of the organs (including the tumor) were studied. The following parameters were altered proportionately to the weight of the tumor (0.39-84.0 g): a) weight of gut and carcass diminished; b) cardiac index increased, blood pressure and total peripheral resistance decreased; c) tumor fraction of cardiac output was augmented; d) blood flow of the organs increased and their circulatory resistance decreased. Hematocrit decreased from 47.2 to 31.0% 20 days after tumor implantation. In rats with tumor the changes of blood flow may be conditioned by both anemia and the decrease in organ weight.     

Doppler echocardiographic reference values for healthy rhesus monkeys under ketamine hydrochloride sedation

Cardiac ultrasound is a noninvasive technique that is commonly used to serially evaluate cardiac structure and function. Recent advances in Doppler-Echocardiography enable the ultrasonographer to perform a sophisticated noninvasive assessment of cardiovascular physiology. The Rhesus monkey is a frequently used non-human primate animal model of human cardiovascular disease because this species closely models human anatomy and physiology. However, while this species is frequently used in cardiovascular research, standardized echocardiographic values generated from large numbers of normal Rhesus are not available. In the present study, we performed cardiac ultrasound imaging on 28 healthy Rhesus monkeys to obtain normal reference values of cardiovascular structure and function in this species. Nomograms were generated from these data by plotting parameters of cardiovascular geometry and function with body weight. These normal reference data were compared to previously reported values obtained from prior studies that used noninvasive, invasive, and morphometric techniques. Cardiac ultrasound is a noninvasive technique that is commonly used to serially evaluate cardiac structure and function. Recent advances in Doppler-Echocardiography enable the ultrasonographer to perform a sophisticated noninvasive assessment of cardiovascular physiology. The Rhesus monkey is a frequently used non-human primate animal model of human cardiovascular disease because this species closely models human anatomy and physiology. However, while this species is frequently used in cardiovascular research, standardized echocardiographic values generated from large numbers of normal Rhesus are not available. In the present study, we performed cardiac ultrasound imaging on 28 healthy Rhesus monkeys to obtain normal reference values of cardiovascular structure and function in this species. Nomograms were generated from these data by plotting parameters of cardiovascular geometry and function with body weight. These normal reference data were compared to previously reported values obtained from prior studies that used noninvasive, invasive, and morphometric techniques.     

Sex difference in distribution and iron responsiveness of the two ferritins of rat cardiac and skeletal muscle

The presence of two electrophoretically and structurally distinguishable forms of ferritin (“fast” and “slow”) in cardiac and skeletal muscle (diaphragm) of the rat was confirmed. Although the total amount of cardiac ferritin showed no difference in concentration in male and female rats, the distribution between the fast and slow species was remarkedly different in the two sexes, the fast form predominating in the cardiac muscle and diaphragm of the female. In agreement with this, the rates of synthesis and of degradation of the fast species were greater in teh female, while the opposite obtained for the male. Iron administration stimulated synthesis of each ferritin species in the cardiac muscle and diaphragm of both sexes. Induction of cardiac connective tissue hypertrophy with isoproterenol inverted the ratio of slow to fast ferritin in female rats, while iron adminsitration along with isoproterenol restored this to normal. It is concluded that the metabolism of ferritin in cardiac and skeletal muscle is sensitive both to sexual status and to iron administration.     

IL-1beta stimulates rat cardiac fibroblast migration via MAP kinase pathways

The pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are elevated following acute myocardial infarction (MI) and have been implicated in the pathophysiology of cardiac disease progression. The cardiac fibroblast represents an important effector cell target for cytokine actions. In particular, cytokine-directed cardiac fibroblast migration is likely to impact both myocardial repair following acute MI and pathological myocardial remodeling in the progression to heart failure. In the present study, we examined the migratory response of neonatal rat cardiac fibroblasts to pro-inflammatory cytokines using modified Boyden chamber assays. On the basis of the knowledge of migration in other cell types, we hypothesized that members of the mitogen-activated protein kinase (MAPK) family may regulate this process. This possibility was addressed with the use of immunoblot detection of active phosphorylated MAPK species and pharmacological inhibitors for individual members of the MAPK cascades. IL-1beta stimulated robust and concentration-dependent increases in migration (maximum, 20-fold over control cells). TNF-alpha had lesser effect (fourfold increase over control). IL-6 did not induce migration. Activation of all three MAPK subfamilies (extracellular signal-regulated kinases, c-Jun NH(2)-terminal kinases, and p38) was shown to occur in response to cytokine stimulation. Fibroblast migration was attenuated by pharmacological inhibition of each MAPK subfamily. Understanding the regulation of cardiac fibroblast migration may provide insights in the search for therapies aimed at enhancing the functional nature of the remodeling process.