"Exuberant" neuronal growth after brain damage in adult rats: the essential role of behavioral experience

Wilms tumor can be explained only partially by the "two hit" model that was originally developed for retinoblastoma. Heterogeneity of two kinds operates. The first is that four other primary tumors are regularly observed in children, and the second is that Wilms tumor itself appears to represent more than one genetic entity. All five of these primary renal tumors arise from primary or secondary mesenchyme, renal blastema, or renal epithelium. Mesoblastic nephroma, and possibly clear cell sarcoma, may have some genetic affinity with Wilms tumor, but rhabdoid tumor of the kidney and renal carcinoma do not. At least three different genes seem to be important in the origin of Wilms tumor. One, WT1, whose mutations may be associated with aniridia, may follow the "two hit" model in that there are cases in which both copies of the gene are defective or lost, as expected for a tumor suppressor gene. A second gene, which is associated with Beckwith-Wiedemann Syndrome (BWS) and which has not been cloned, appears to be imprinted in females, and may have an oncogene function. It is evidently activated by gain of a paternal allele or by loss of the inactive, but possibly trans-sensing, maternal allele. Activation of the insulin-like growth factor II gene may be a final common pathway for mutation in both WT1 and BWS. A third gene is unlinked to either of the other two, but its location and function are unknown. It shares with WT1 specificity for Wilms tumor, which is not true of the BWS gene.     

Obesity as a pleiotropic effect of gene action

Obesity, an easily detected and quantifiable phenotypic endpoint, is often considered, colloquially, as a disease. However, the study of obesity in rodents suggests that it is merely a convenient indicator of diverse underlying metabolic and physiologic dysregulations, rather than a disease entity in itself. To illustrate this concept, the differences between the murine Lepob/Lepob and Avy/- "obesity" syndromes are delineated. In both syndromes, pleiotropic effects of single mutations play a major role in altering the homeostatic regulation of energy metabolism and a myriad of extra- and intracellular processes in a diversity of tissues and cell types. The Lepob/Lepob syndrome mimics juvenile-onset obesity, whereas the Avy/- syndrome resembles maturity-onset obesity. The Avy/- syndrome has its basis in overabundance of agouti protein, whereas the Lepob/Lepob syndrome results from a lack of active leptin hormone. Lepob/Lepob mice have a smaller lean body mass, whereas Avy/- mice have a larger lean body mass than their respective lean siblings. Lepob/Lepob mice have fewer lung and mammary tumors than their lean Lep/- littermates, and Avy/- develop more mammary and lung tumors than their lean A/- or a/a siblings. Lepob/Lepob mice are infertile or sterile, whereas Avy/- mice are fertile. Thus, although adult Lepob/Lepob and Avy/- mice are both obese, many of the other morphologic and physiologic attributes of one mutant are diametrically opposite to those of the other.     

Bronchial carcinoid tumors

Bronchial carcinoid tumors, termed (incorrectly) "bronchial adenomas" in the past, are uncommon pulmonary neoplasms. These tumors are currently classified as neuroendocrine in origin because of their potential to form and sometimes secrete a variety of chemical substances. Overall, approximately 75% of bronchial carcinoid tumors arise in the lobar bronchi, 10% occur in the main-stem bronchi, and 15% originate in the periphery of the lung. Well-differentiated carcinoid tumors constitute almost 90% of all bronchial carcinoids. Atypical carcinoid tumors have a higher malignant potential than do typical bronchial carcinoids. The carcinoid syndrome is rarely, if ever, associated with carcinoids limited to the tracheobronchial tree. Occasionally, Cushing's syndrome due to ectopic hormone production is caused by bronchial carcinoid tumors. More than 75% of bronchial carcinoids are detected on conventional posteroanterior chest roentgenograms. Computed tomography may help disclose small neoplasms that are occult on conventional roentgenography, particularly in the assessment of patients who have Cushing's syndrome due to ectopic hormone production. Pulmonary resection is the treatment of choice for bronchial carcinoids. The prognosis is related to the pathologic grade and stage of the tumor.     

Perceived motivational climate and cognitive and affective correlates among Norwegian athletes

CONCLUSION: The diagnosis of a pancreatic carcinoid should be based on the measurement of serotonin in serum or its demonstration in the tumor and/or by the measurement of its derivative (5-HIAA) in urine. Carcinoid of the pancreas is a rare but definite entity; usually having metastasized by the time of diagnosis. The term "serotonin-producing tumor of the pancreas" has been suggested as an alternative designation for "pancreatic carcinoid." BACKGROUND: The literature on carcinoid tumors of the pancreas is confusing because much of it preceded the development of the more specific immunological, chemical and staining techniques currently available. METHODS: 43 case reports were collected from the world's literature, based on a demonstrable pancreatic neuroendocrine tumor plus a positive finding of at least one of the following without another dominant hormone being demonstrated: elevation of 5-Hydroxytryptamine (5-HT) (serotonin) in the serum or detected in tumor tissue, and/or elevation of 5-Hydroxyindole acetic acid (5-HIAA) in the urine. In addition to these two hormone-specific assays, information was collected on the silver-staining properties of the tumor; properties which have traditionally been associated with carcinoid tumors. Positive silver staining in tumor cells (argyrophilic and/or argentaffin reaction) is strongly indicative of the carcinoid tumor but the findings are less specific than the hormone assays and immunohistologic stains. RESULTS: In this review of 43 cases, including two current ones, the pancreatic carcinoid tumor has the following important features: 1. It is a rare tumor that is usually diagnosed late when the tumor is large and has metastasized. Thirty-eight (88.4%) have been malignant. They are, therefore, associated with a high incidence of the "carcinoid syndrome." 2. To date, prognosis in therapy is poor, based on delayed diagnosis, a resultant low incidence of resectability, and an uncertain duration of survival after resection. 3. Pancreatic carcinoid tumors remain difficult to differentiate from other endocrine tumors. The measurement of urinary 5-HIAA excretion or the demonstration of elevated serotonin level in the tumor or in serum is essential to its distinction. Silver staining of the tumor, although of historic importance, has been superceded by the hormone-specific studies. 4. To distinguish it from other endocrine tumors of the pancreas, the terms "pancreatic serotoninoma" or "serotonin-producing tumor of the pancreas" have been suggested as possible alternatives. Its growth characteristics may be related more to its cell of origin than to its extent of hormone secretion. Not all of the tumors result in recognizable hyperserotoninemia.     

Simultaneous occurrence of a supra- and an infratentorial glioma in a patient with Ollier's disease: more evidence for non-mesodermal tumor predisposition in multiple enchondromatosis

A case is presented in which two neuro-ectodermal tumors, an infra- and a supratentorial glioma, developed in a young man with multiple enchondromatosis of Ollier's disease. This is the third such case of multifocal low-grade glioma in Ollier's disease, suggesting a predisposition for non-mesodermal tumors in Ollier's disease. The related condition of multiple enchondromatosis and hemangiomas (Maffucci's syndrome) is well known for its malignant potential, developing both mesodermal and non-mesodermal tumors. Along with other authors, we support the concept of two variants of the same disease with a predisposition to development of tumors from various germ layers.     

Use of octreotide acetate for control of symptoms in patients with islet cell tumors

Gut tumor syndromes are rare, occurring in less than two cases per million population per year: Insulinomas are most common and gastrinomas are less common; all the others are extremely rare. Conventional treatment of the symptoms caused by these tumors has included surgery, hepatic arterial embolization, and chemotherapy; some patients with Zollinger-Ellison syndrome (ZES) have been treated with specific agents such as gastric antisecretory drugs. The development of octreotide, a synthetic, long-acting analogue of the natural peptide somatostatin, has offered an alternative to such therapies. Octreotide has a half life of > 100 minutes and inhibits both physiological- and tumor release of many peptides. It also has direct effects on the gut that modify secretion and motility. Octreotide has been shown to be particularly useful for the symptoms of tumors producing vasoactive intestinal peptide (VIP), and of the carcinoid syndrome. It is also useful in patients with glucagonomas, with growth hormone-releasing hormone producing tumors, and in some patients with Cushing's syndrome and unresectable insulinomas. Octreotide is effective in patients with ZES, but alternative therapies such as omeprazole are more effective, safer, and more convenient for those patients. Side effects of octreotide have not been troublesome in these patients, but the incidence of long term effects is still not entirely clear. Octreotide has proved to be a significant advance in the treatment of patients with islet cell tumors.     

Vasopressin receptors modulate the pharmacological phenotypes of Cushing's syndrome

We have examined the expression profiles of the different vasopressin receptors (V1, V2, V3) that can be expressed in the three different types of tumors associated with Cushing's syndrome. V3 (V1b) receptor cDNA was cloned from a pituitary tumor responsible for Cushing's disease. We show that it is overexpressed in these tumors and can respond to DD-AVP. High expression of the V3 receptor on highly differentiated, ACTH-secreting, bronchial carcinoid tumors explain why these non-pituitary tumors occasionally respond to vasopressin, mimicking a "pituitary-like" behavior. A retrospective analysis showed that vasopressin induced an ACTH-independent cortisol rise in 27% of the adrenocortical tumors responsible for Cushing's syndrome. V1 mRNA was detected in normal adrenal cortex and in all tumors. Adenomas had significantly higher levels than carcinomas. V1 mRNA levels were higher in responders than in non-responders. One adenoma which had a brisk cortisol response in vivo, also had in vitro cortisol responses that were inhibited by a specific V1 antagonist. In situ hybridization showed the presence of V1 mRNA in the normal human adrenal cortex where the signal predominated in the compact cells of the zona reticularis. A positive signal was also present in the tumors with high V1 mRNA levels determined by RT-PCR; its distribution pattern was heterogeneous and showed preferential association with compact cells. High-and not ectopic-expression of the V1 receptor occurs in a minority of adrenal cortical tumors which become directly responsive to vasopressin stimulation.     

Malignant neoplasms in cyclosporin A-induced autoimmunity (CyA-AI)

Lethally X-irradiated LEW rats reconstituted with syngeneic bone marrow and given low-dose Cyclosporine A (CyA) for 5 weeks develop, after withdrawal of CyA, symptoms of disease resembling graft-vs.-host disease (GVHD) as seen after allogeneic bone-marrow transplantation. Symptoms of disease may include acute dermatitis and chronic disease resembling scleroderma. Since anti-class II MHC cytotoxic lymphocytes are generated in this model, it has been proposed as an anti-tumor regimen in humans. We now report that LEW rats treated according to this protocol may, after cessation of CyA administration, paradoxically develop malignant neoplasms. Of 48 experimental animals, 31 developed rapidly progressive subcutaneous and/or intracutaneous tumors commencing at 6 weeks, 13 weeks and 6 months after cessation of CyA. Tumors were of mesenchymal origin, usually high-grade sarcoma, adenocarcinoma or both mesenchymal and epithelial tumors. Such tumor incidence exceeded the incidence of tumor growth in X-irradiated controls, and in rats subjected to thymectomy prior to X-irradiation and CyA administration. CyA by itself induced no tumors. Our results show that total body X-irradiation is required for tumor development but that the presence of CyA-induced autoimmune disease increases the incidence significantly.     

Determinants of the willingness to endorse assisted suicide. A survey of physicians, nurses, and social workers

The cancer cachexia syndrome is clinically characterized by anorexia, wasting, weight loss, weakness, fatigue, poor performance status, and impaired immune function, which are unresolved by forced caloric intake. Diminished nutritional intake, maladaptive metabolic processes, and increased metabolic expenditure all play roles in the development of this syndrome. Multiple mediators of both tumor and host cell origin are mechanistic in its etiology. Treatment is not entirely satisfactory and should be directed toward improvement in the quality of life of the patient and should often include nutritional counseling. It should take into consideration both disease and treatment related factors as well as the cachexia syndrome itself. Use of progestogens (megesterol acetate, medroxyprogesterone), corticosteroids (decadron, prednisone), metoclopramide, tetrahydrocannabinol (dronabinol), and possibly anabolic steroids (nandrolone decanoate, oxandrolone), melatonin, and eicosapentaenoic acid, may yield therapeutic benefit.     

Anesthesia for patients with carcinoid syndrome

Carcinoid syndrome, although rare, can create serious problems to the anesthetist, both by the nature and variability of clinical manifestations and by the complications that can occur peroperatively. Recent research has led to a better understanding of the pathophysiology of the disease process. However, modern medicine is far from unraveling the precise nature and physiological effects of all the peptide mediators produced by these tumors. The severity of symptoms does not predict the severity of perioperative complications, so that patients with minor preoperative symptoms may have significant intraoperative complications. While urinary 5-HIAA levels provide a good indicator of disease progression, they cannot predict the degree or type of physiological response to intraoperative tumor manipulation. Indeed, urinary 5-HIAA may be normal both in the presence of a clinical diagnosis of carcinoid syndrome and in the face of a peroperative carcinoid crisis. The keys to successful anesthetic management of patients with carcinoid syndrome are good communication between endocrinologist, anesthetist, and surgeon and preoperative optimization of the patient. This includes appropriate investigation and treatment of the effects of carcinoid peptides and the prevention of their release from tumors. If possible, advice should be sought from centers with experience at managing this group of patients. Octreotide has largely replaced the use of other drugs both for symptomatic control and acute treatment of the symptoms associated with carcinoid syndrome. However, other drugs, such as aprotinin, still have a significant place in the symptomatic control and treatment of peroperative complications, as serotonin is only one of a large variety of peptides responsible for the clinical effects of this disease. Anesthetic technique should be aimed at minimizing carcinoid mediator release, in response to stress it induction of anesthesia and tracheal intubation and during tumor manipulation. It is equally important to prepare for carcinoid crisis by, for example, ordering drugs, which are otherwise uncommonly used in the theater setting, ahead of time. Cardiovascular instability, particularly hypotension, is common, so that full monitoring and vigilance is vital to predict its onset. The current surgical view of management is that, while curative resection of carcinoid tumors less than 2 cm in diameter with no evidence of invasion or metastatic spread is appropriate, patients with disseminated disease should be medically managed unless symptom control is poor. The exceptions to this are those patients with early and correctable carcinoid cardiac disease and those who require palliative procedures such as defunctioning obstructed bowel. Survival rates in patients following excision of gastric and appendical carcinoid tumors approach those of the general population as a whole and the chance of metastasis is extremely low. Only two series have been published in the anesthetic literature on anesthesia for patients with carcinoid syndrome, although there are many single-case reports. Despite the rarity of this syndrome, further formal studies into the anesthetic management of this condition should be encouraged.     

Direct anti-atherosclerosis-related effects of garlic

Leydig cell tumors are very rarely seen testicular tumors and can be difficult to distinguish from testicular tumors of the adrenogenital syndrome. Testicular tumors of the adrenogenital syndrome are confined to patients with congenital adrenal hyperplasia. The authors report a case of a patient with malignant Leydig cell tumor and a history of congenital adrenal hyperplasia (adrenogenital syndrome). To the authors' knowledge, this has not been reported previously.     

Primary cardiac gastrinoma causing Zollinger-Ellison syndrome

Primary cardiac tumors are rare, and there are no reports of patients with a functional gastroenteropancreatic tumor syndrome caused by such a tumor. This case report describes a patient with a cardiac gastrinoma causing Zollinger-Ellison syndrome. Evidence is presented that this tumor represents a primary cardiac tumor. The exact identification of this gastrinoma in an extra-abdominal site was facilitated by the use of [111In-DTPA-DPhe1]octreotide scanning for somatostatin receptors, which these tumors characteristically possess in high numbers. The recent availability of this novel localization method may facilitate identification of extra-abdominal sites in an increasing proportion of patients with gastrinomas and related neuroendocrine functional tumors in which no intra-abdominal primary tumor is currently found.     

Nitric oxide-induced blood-brain barrier dysfunction is not mediated by inhibition of mitochondrial respiratory chain activity and/or energy depletion

The six reported cases were separated into 2 groups: 1) the tumors of sporadic type, carcinoids (n = 2) and neuro-endocrine carcinomas (n = 2); 2) the gastrin-promoted tumors (n = 2). The purpose of this retrospective study was to review for each group of tumors, the clinicopathologic characteristics, prognosis factors and optimal management. In the first group, patients with a small and well differentiated tumor revealed by digestive bleeding, were treated by wedge excision and are alive and well 24 and 22 years later; the patients with large, invasive and poorly differentiated tumors were treated by subtotal (n = 1) and total (n = 1) gastrectomy, and died 1 year and 3 years later with metastases. In the second group, one patient with a small asymptomatic carcinoid tumor revealing chronic atrophic gastritis, was treated by endoscopic resection, without recurrence 3 years later; another patient with asymptomatic multifocal carcinoid tumors (about 100) associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1, was treated by total gastrectomy and is alive and well 7 years later. No patient had carcinoid syndrome. Synaptophysin was the most sensitive marker and secretion of serotonine was detected in 2 tumors. Conclusion: Sporadic carcinoids serotonin and neuro-endocrine carcinomas are life-threatening tumors and need aggressive surgical therapy: their prognosis depends on tumors size, histological differentiation and mostly on tumor extension. In contrast, gastrin-promoted carcinoids do not result in disseminated disease and death, and a rather conservative approach seems appropriate.     

Long-term medical treatment of ectopic ACTH syndrome

BACKGROUND: The morbidity of hypercortisolemia due to ectopic production of ACTH by various tumors may be greater than the morbidity of the tumor itself. METHODS: We report three cases of long-term treatment of ectopic ACTH syndrome due to metastatic bronchial carcinoid, islet cell carcinoma, and malignant thymoma tumors. Clinical and biochemical eucortisolemia was achieved in each case and was sustained from 24 to 55 months. We review the therapeutic options and their reported efficacy. RESULTS: Cessation of therapy resulted in recurrence of hypercortisolemia in each case, showing the effectiveness of therapy. CONCLUSION: Long-term treatment of ectopic ACTH-induced hypercortisolemia by blocking adrenal steroidogenesis is clinically effective and well tolerated.     

Cowden's disease with a defined genetic alteration--chromosomal duplication at 15q11-q13

Cowden's disease, multiple hamartoma syndrome, is a dominantly inherited disorder characterized by multiple hamartomas of ectodermal, endodermal, and mesodermal origin and also by a high incidence of malignant tumors. Despite many efforts to identify the genetic alterations responsible for the syndrome, the molecular mechanism remains unclear. We report a case of Cowden's disease in which karyotype analysis revealed a small duplication (about 1 Mb) at 15q11-q13. This part of the genome is a region that is deleted in the Prader-Willi/Angelman syndrome and is a "hot spot" of chromosomal duplication.     

Germ cell neoplasms of the testis

Testicular germ cell neoplasia, a disease predominantly of young men, is, for unknown reasons, increasing in incidence. Cryptorchidism, a prior testicular germ cell tumor, a family history of testicular germ cell tumors, and somatosexual ambiguity syndromes remain well-established risk factors. Intratubular germ cell neoplasia of the unclassified type represents the common precursor to the great majority of testicular germ cell tumors, and its identification in testicular biopsies reliably identifies those patients who will often progress to an invasive lesion. Seminoma appears to represent the invasive derivative of intra-tubular germ cell of neoplasia of the unclassified type; problematic variants include seminomas with tubular, granulomatous, and edematous patterns. Spermatocytic seminoma is an essentially nonmetastasizing neoplasm unless complicated by the rare development of a sarcomatous component. Embryonal carcinomas usually occur admixed with other germ cell tumor types. The combination of positivity for placental alkaline phosphatase and negativity for epithelial membrane antigen can assist in the distinction of embryonal carcinomas from somatic carcinomas. The treatment of clinical stage I patients with nonseminomatous germ cell tumor with "surveillance only" may be contraindicated depending on features that include the proportion of embryonal carcinoma and the presence of lymphovascular invasion in the orchiectomy specimen. It is important to be aware that pure, mature teratomas in postpubertal patients may be associated with metastases of teratomatous or nonteratomatous type Yolk sac tumor is characterized by numerous patterns including glandular, myxomatous, sarcomatoid, hepatoid, and parietal variants. Choriocarcinomas classically have a biphasic pattern of syncytiotrophoblast and cytotrophoblast; trophoblastic proliferations lacking a biphasic pattern also occur but are difficult to classify unless this category is broadened. Mixed germ cell tumors, consisting of two or more different elements, are quite common. The polyembryoma is a distinctive, well-organized form of mixed germ cell tumor consisting of embryonal carcinoma and yolk sac tumor.     

Studies of malformation syndromes of man XXIX: the Wiedemann-Beckwith syndrome. Clinical, genetic and pathogenetic studies of 12 cases

This report describes 12 patients with the Wiedemann-Beckwith syndrome (WBS), including 6 familial cases from 2 families. The clinical manifestations do not allow for a differentiation between familial and sporadic cases. Consistent morphologic features include organomegaly, cytomegaly and nucleomegaly. The pathogenetic process may involve few or many organs and tissues and may represent a nuclear/mitotic dysfunction. Clinically, the manifestations are hyperplasia, hypoplasia, dysplasia, neoplasia and defects in differentiation. Secondary functional disturbances are at times prominent. The differential diagnosis of the WBS includes 1) the Wilm's tumor (WT)-aniridia syndrome: 2) the "tumor-hypertrophy syndrome" which includes WT, adenocortical tumors or hepatoblastoma; 3) the WT-pseudohermaphroditism syndrome; and 4) the "tumor-nevus syndrome" with or without malformations (particularly duplications) of the urinary tract. The latter two conditions are apparently not associated with hemihypertrophy. Familial occurrence suggests that some cases of the WBS may be due to delayed mutation. Carriers of the premutated allele appear to belong to two classes: those with a high risk of producing affected offspring and those who transmit the premutated allele but have no affected offspring.     

Regulating angiogenesis: a new therapeutic strategy

Angiogenesis is the proliferation of endothelial and smooth muscle cells to form new blood vessels. Largely muted after adolescence, angiogenesis may be reignited by cancerous cells. Neoangiogenesis plays a primary role in tumor growth and metastases. Antiangiogenic therapy to limit and even reverse the growth of tumors are under investigation and showing promise. A derivative of fumagillin, TNP 470, is the first angiogenesis inhibitor to be given to humans. Surprisingly, several potent inhibitors are derived from tumors themselves. Researchers nowc recognize that stimulation of angiogenesis may have a place in the treatment of cardiovascular disease. Reestablishing blood flow to ischemic tissue through angiogenesis may provide a biologic "bypass" for patients with ischemic heart disease. The same applies to the treatment of peripheral vascular disease.     

Sex cord-stromal and steroid cell tumors of the ovary

Gonadal cell types that derive from the coelomic epithelium (sex cords) or mesenchymal cells of the embryonic gonads include granulosa cells, theca cells, fibroblasts, Leydig cells, and Sertoli cells. Ovarian tumors of these cell types are called sex cord-stromal tumors. This group of tumors represents approximately 8% of ovarian neoplasms and affects all age groups. The more common types are granulosa cell tumors (GCTs), fibrothecomas, and Sertoli-Leydig cell tumors. Sex cord-stromal tumors are of interest partly because of their hormonal effects, which are rare for other ovarian neoplasms. These effects include estrogenic effects (pseudoprecocious puberty, endometrial bleeding, endometrial hyperplasia and carcinoma) and virilization. The variety of gross appearances of these tumors, ranging from large multicystic masses to small solid masses, would appear to preclude a specific radiologic diagnosis. However, in many patients, both clinical and radiologic clues can suggest the diagnosis, including predominantly fibrous content at ultrasound or magnetic resonance imaging (fibrothecoma), large hemorrhagic multicystic mass in a child with pseudoprecocious puberty (juvenile GCT), and associated syndromes such as Peutz-Jeghers syndrome (sex cord tumor with annular tubules) or Ollier disease and Maffucci syndrome (juvenile GCT).     

Bromocriptine therapy for "nonfunctioning" pituitary tumors

Bromocriptine therapy may cause regression of prolactinomas, but its effect on nonsecretory pituitary tumors is uncertain. Conventional treatment for such "functionless" tumors is surgery and/or radiotherapy, but recurrences pose a therapeutic dilemma. We describe a patient with such a tumor treated by surgery and radiotherapy who presented with recurrent disease 14 days later. On treatment with bromocriptine, 20 mg daily for 25 months, the intrasellar tumor recurrence had diminished in size and a suprasellar extension had almost disappeared. Bromocriptine therapy may therefore benefit some patients with nonsecretory pituitary tumors considered unsuitable for surgery or radiotherapy.