Tumor progression, oncogenes and the evolution of metastatic phenotypic diversity.
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Cell Transformation, Neoplastic↗
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Metastatic phenotype of human prostate tumor cells in athymic nude mice: alteration by exposure to ethyl methanesulfonate and "reversion" by 5-azacytidine.
The human prostate tumor subline 1-LN-PC-3-1A (1-LN) is reproducibly metastatic in adult athymic nude mice. Cells surviving a brief in vitro exposure to ethyl methanesulfonate (EMS) exhibited a profound decrease in capacity for experimental lung metastasis in nude mice. Thirty days after EMS treatment, 1 X 10(6) uncloned EMS-treated 1-LN cells (1-LN-EMS-10) were injected IV into groups of 6 to 8-week-old male athymic nude mice (BALB/cAnBOM). A median of 8.5 colonies/lung was observed among 20 1-LN-EMS-10-injected mice, which was significantly different from the median of 51 colonies/lung produced among 14 1-LN-injected mice (P = 0.0002). This altered phenotype remained stable during 150 days of continuous culture. However, the 1-LN-EMS-10 cells were tumorigenic in 10/10 nude mice injected SC. Single lung tumor colonies recovered from 1-LN-EMS-10-injected mice and reinjected IV into nude mice produced medians of 32-63 colonies/lung. The altered metastatic phenotype resulting from treatment of 1-LN with EMS was reversed by exposure to a noncytotoxic dose of 5-azacytidine, but unaffected by a second exposure to EMS. Collectively these data demonstrate that the metastatic phenotype of these human tumor cells in athymic nude mice can be heritably altered by in vitro exposure to EMS and 5-azacytidine. Analysis of the mechanisms underlying these phenotypic changes may provide insight into parts of the complex process of tumor cell evolution.
Animals↗
Prerequisites for fetal neurosurgery: management of central nervous system anomalies toward the 21st century.
With the dramatic technical advances in neuroimaging, it has become possible to diagnose central nervous system (CNS) anomalies in the fetus in utero with more precise morphological analysis. A new technique, high-resolution magnetic resonance (MR) imaging using heavily T2-weighted fast spin echo sequences, has been reported to solve motion artifact of the fetus. However, it has also been recognized that the morphological fetal CNS findings detected in early development are not always the final features: occasionally they may not be determined in diagnosis and may change developmentally or chronologically during the fetal life in utero. Certain factors of the fetal chronology of CNS anomalies can cause irreversible changes during fetal life. These include: (1) significant delay in the neuronal maturation process in fetal hydrocephalus developed in clinicoembryological stage II in the Perspective Classification of Congenital Hydrocephalus (PCCH), (2) secondary neural injury in the intactly developing spinal cord above the neural placode in fetus with spina bifida aperta (myeloschisis), (3) histological "evolution" of tumors or dysgenetic CNS, and (4) deformity of the normally developed intracranial or intraspinal CNS structures. Considering the current status of fetal surgery in general and technical advances promising improved outcomes, fetal neurosurgery can also be applied in the above-mentioned progressive pathology or pathophysiology in the fetal CNS. However, since the failure of the first trial of fetal neurosurgery in the 1980s, the prerequisites have still not been clarified. In order to use advanced neurosurgery techniques in the management of fetal CNS anomalies, these prerequisites have to be established.
Journal Article↗
Thalamic tumors: clinical presentation.
INTRODUCTION: Thalamic tumors (TTs) account for approximately 1% of all intracranial neoplasms. TTs are seen predominantly in children and young adults. Most childhood neoplasms in this location are of glial lineage, a large proportion being low-grade tumors. The evolution of symptoms before diagnosis is characteristically shorter in children than in adults. CLINICAL PRESENTATION: Clinical features of TTs reflect the pressure of the mass on the cerebrospinal fluid pathways, the pyramidal tracts, the thalamic nuclei and the optic radiations. In this paper, we review the clinical data of 20 children with TTs seen at our hospital and compare the findings with those in the current literature. An acute presentation is not rare and was encountered in 20% of our patients, although most individuals had a subacute or slow evolution. Symptoms and signs of raised intracranial pressure (65%), motor deficits (40%), and seizures (35%), alone or in combination, were the most frequent manifestations of TTs. Behavioral and mental changes are not uncommon in TTs and were found in 25% of our patients. Involuntary movements (10%) and the classic thalamic syndrome (5%) were quite exceptional. Infants and young children with TTs may present with macrocephaly, psychomotor delay, and failing vision or disorders of ocular movements.
Adolescent↗
Diagnosis, outcome, and management of fetal abnormalities: fetal hydrocephalus.
INTRODUCTION: It has been recognized that the morphological fetal CNS findings detected in early development are not always the final features: occasionally they may not be determined in diagnosis and may change developmentally or chronologically during the fetal life in utero. DISCUSSION: Certain factors of the fetal chronology of CNS anomalies can cause irreversible changes during fetal life. These include: significant delay in the neuronal maturation process in fetal hydrocephalus developed in clinico-embryological stage II of the Perspective Classification of Congenital Hydrocephalus (PCCH), secondary neural injury in the intactly developing spinal cord above the neural placode in fetuses with spina bifida aperta (myeloschisis), histological "evolution" of tumors or dysgenetic CNS, and deformity of the normally developed intracranial or intraspinal CNS structures. Considering the current status of fetal surgery in general and technical advances promising improved outcomes, fetal neurosurgery can also be applied to the above-mentioned progressive pathology or pathophysiology in the fetal CNS. However, since the failure of the first trial of fetal neurosurgery in the 1980s, the prerequisites have still not been clarified. In order to use advanced neurosurgery techniques in the management of fetal CNS anomalies, these prerequisites have to be established.
Animals↗
Evolution of cystic and adnexal tumors identified by echography.
The authors present their experience in detecting volume and echostructure alterations of the ovary in 14,525 women examined echographically and clinically. They analyzed 499 adnexal tumors and observed after clinical follow-up and echography that 60.6% of the cystic-septa tumors had involuted spontaneously. Percentage of spontaneous resolution was higher in small-diameter tumors, avoiding unnecessary surgery.
Adenoma↗
Chronic myelogenous leukemia in the monosomic cell line of a fertile Turner syndrome mosaic (45,X/46,XX).
Malignancy in patients with constitutional chromosome abnormality is of interest not only because it permits insights into the relationship between the chromosome abnormality and cancer, but also because it provides opportunities to address such questions as the clonality and evolution of tumors. We report Ph1-positive chronic myelogenous leukemia (CML) in a 50-year-old mosaic (45,X/46,XX) Turner syndrome patient whose leukemia was restricted to the monosomic cell line. Our extensive cytogenetic studies of this patient demonstrated that non-leukemic normal cells persisted in the marrow and were able to proliferate during a period of temporary suppression of the leukemic clone following aggressive treatment.
Blood Cells↗
Genetic instability of cancer. Why a metastatic tumor is unstable and a benign tumor is stable.
It is theorized that tumors may be initiated by two methods: by an error affecting one or several oncogenes, or by an error affecting one or several of the genes controlling the stability of the genome. The majority of cells that misexpress an oncogene(s) and that later form a tumor probably form nonevolving benign tumors. A minority of these cells with an activated oncogene(s) (or one of the descendant cells) may also come to misexpress a stability gene(s). A normal cell that misexpresses only a stability gene(s) may form an evolving and genetically unstable cell line that may later misexpress an oncogene(s). A cell or cell line that misexpresses both an oncogene(s) and a stability gene(s) may form a genetically unstable tumor that creates diverse variants, allowing for extensive tumor cell evolution and the acquisition of malignant and metastatic properties.
Humans↗
NO2/NO3 and cytokine plasma profiles under different postoperative parenteral nutrition regimens.
Both nitric oxide and cytokines are considered mediators of the acute-phase response in humans, and their early postoperative period plasma levels have been found to be of prognostic value. On the other hand, it has been suggested that the fatty emulsions used in total parenteral nutrition (TPN) may induce changes in macrophage function. In the present study we investigated the postoperative evolution of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and nitrate/nitrite plasma levels under three different TPN regimens. Twenty-one patients diagnosed with upper digestive tract neoplasm, without preoperative TPN, and having undergone radical surgery, were randomly assigned to three groups: Group I, all nonprotein calories supplied by hypertonic glucose solution: Group II, 55% of the nonprotein calories supplied by glucose and 45% by 20% long-chain triacylglycerides emulsion (LCT) (Intralipid 20%, Kabi-Pharmacia); Group III, same as Group II, but a 20% emulsion of a mixture of medium-chain and long-chain triacylglycerides (MCT/LCT) (Lipofundina MCT/LCT 20%, B. Braun) was used instead of LCT. Blood samples were obtained on postoperative Days 1-5 and 10, 3 h after ending the lipid infusion. In all the three groups IL-1, IL-6, and TNF-alpha levels rose after surgery, peaking at Day 2, whereas NO2/NO3 levels had their peak at Day 3. Day-to-day comparison of plasma levels of cytokines and NO2/NO3 between the investigated groups did not show any statistical significance. Differences between group means were not found when the areas under the curve over the first 5 postoperative days were compared (1.72 +/- 0.25, Group I; 1.88 +/- 0.34, Group II; and 2.52 +/- 0.50, Group III, for TNF-alpha; 1.79 +/- 0.12, Group I; 1.92 +/- 0.18, Group II; and 1.50 +/- 0.12, Group III, for NO2/NO3). We conclude that the different parenteral nutrition regimens studied do not evoke alterations in cytokine and NO2 + NO3 levels in the patient groups investigated in this study.
Cytokines↗
Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.
Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin. In contrast to bulk studies, wellDR-seq enabled the study of subclone-level gene-dosage relationships, which showed near-linear correlations in large chromosomal segments and extensive variation at the single-gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes as well as sporadic copy-number aberrations in non-cancer cells. Overall, these data reveal complex relationships between copy number and gene expression in single cells, improving our understanding of breast cancer progression.
Breast Neoplasms↗
Mutational analysis of gene families in human cancer.
The completion of the human genome project has marked a new beginning in biomedical sciences. Human cancer is a genetic disease and, accordingly, the field of oncology has been one of the first to be impacted by this historic revolution. Knowledge of the sequence and organization of the human genome facilitates the systematic analysis of the genetic alterations underlying the origin and evolution of tumors. Recent mutational analyses in colorectal and other cancers have focused on examination of gene families involved in signal transduction, such as kinases and phosphatases. This approach has been successful in identifying mutations in a variety of different genes, including the identification of PI3KCA as one of the most commonly mutated oncogenes in human cancer. Such genomic analyses have already demonstrated their utility in basic and clinical cancer research, and are expected to have an important impact on future diagnostic and therapeutic strategies.
Colorectal Neoplasms↗
Thyroid alar cartilage graft in paediatric laryngotracheal reconstruction.
OBJECTIVE: To evaluate the potential indications of thyroid alar cartilage (TAC) graft in the paediatric laryngotracheal reconstruction (LTR) population based on observations obtained in a case series of 27 consecutive infants referred to our tertiary care center. METHODS: Thyroid alar cartilage grafting was performed for limited Myer grade II and grade III subglottic stenosis requiring a single-stage laryngoplasty and for laryngeal enlargement after translaryngotracheal resection of endolaryngeal tumors. The evolution of the grafted area was evaluated prospectively during endoscopic follow-up. RESULTS: Twenty-five patients (92.5%) were successfully extubated after a mean of 5.1 days. No perioperative or postoperative complications were observed. The mean duration of graft harvesting was 7.7 min. Follow-up of the grafted area revealed one case of partial necrosis without prolapse into the lumen. The mean duration of graft epithelialization was 18.1 days (range: 12-30 days). Development of granulation tissue was observed in eight patients (32%) with a mean duration of granulation tissue persistence of 61.5 days (range: 7-155 days). Endoscopic follow-up did not demonstrate any pharyngolaryngeal asymmetry or feeding difficulties. CONCLUSION: This study demonstrated that the use of thyroid alar cartilage grafting is feasible for pediatric laryngotracheal reconstruction. The indications of thyroid alar cartilage graft should be reserved for moderated subglottic stenosis. The use of TAC reduced the operative time and cosmetic sequelae significantly. The healing of the grafted area was similar to those obtained with other types of graft. The TAC removal did not induce laryngeal deformation but longer follow-up is necessary to confirm this.
Adolescent↗
Characterization of microsatellite markers to diagnose ADPKD.
Autosomal dominant polycystic kidney disease (ADPKD) maps to chromosome 16p13.3 (PKD1) and to chromosome 4q21-23 (PKD2), with the likelihood of a third unmapped locus. The size and genomic complexity of the PKD1 gene make it impractical to detect mutations for prenatal diagnosis. Therefore, pedigree-based linkage analysis remains useful for diagnosis of ADPKD. Since, the complete genome sequences of chromosome 16p13.3 and 4q21-23 including PKD1 and PKD2, respectively, were reported very recently, in order to do more precise diagnosis of ADPKD, we tried to find microsatellite markers. We performed database searches of 2000 kb of genome sequence across the 16p13.3 and the 4q21-23. To determine the distribution of alleles and the degree of polymorphism of the microsatellites, genotyping experiments were performed on 48 Korean individuals. We found novel 14 microsatellite markers around ADPKD that are more polymorphic and closer to PKD1 or PKD2 than the known markers. The novel microsatellite markers were applied to diagnose ADPKD families. These novel microsatellite markers are not only useful for presymptomatic and prenatal diagnosis of ADPKD, but also applicable in the study of positional cloning, human evolution and tumor biology.
Chromosomes, Human, Pair 4↗
Cancers of new appearance in liver transplant recipients: incidence and evolution.
OBJECTIVE: To investigate the incidence, time of appearance, treatment, and evolution of tumors appearing in liver transplant recipients at our hospital. MATERIAL AND METHODS: We undertook a retrospective analysis of our series of liver transplants between 1990 and 2005. Patients who died during the immediate postoperative period were excluded. RESULTS: Of the 515 patients, 25 died during the immediate postoperative period and therefore had no occasion to develop neoplasms. Of the remaining 490, 32 developed cancers (6.5%). The average age was 55.4 +/- 7.17 years. The reasons for transplant were alcoholic cirrhosis (n = 15), hepatitis C virus (2), hepatitis B virus (n = 1), alcoholic and viral cirrhosis (n = 7), primary biliary cirrhosis (n = 1), and cryptogenic cirrhosis (n = 1). Four patients developed multiple neoplasms. Most of the tumors were cutaneous: nine basal cell and six squamous cell carcinomas. Other locations were the lung, urothelium, stomach, thyroid, and brain. Eight patients presented metastasis at the time of diagnosis. The average tumor-free period was 3.36 years. Nine patients died as a result of the tumor. DISCUSSION: Patients with a liver transplant have a high risk of developing cancers as a result of the immunosuppression treatment, which is lifelong. Nevertheless, other factors can be involved, such as infection by cytomegalovirus or the original diagnosis leading to transplantation. The risk for developing cancers is significantly greater than in the general population, with a higher tendency to recurrence and later development of second neoplasms.
Adult↗
Optical coherence tomography of choroidal osteoma.
PURPOSE: To examine the cross-sectional structure of a choroidal osteoma using optical coherence tomography. METHODS: Observational case report. A choroidal osteoma in the right eye of a 22-year-old woman was studied with fluorescein and indocyanine green fundus angiograms and optical coherence tomography. RESULTS: The optical coherence tomography showed that a creamy-white lesion in the tumor had an increased reflectivity with a cavernous structure, whereas an orange lesion showed less reflectivity beneath the apparently intact retinal pigment epithelium. The area of less-intense whiteness in the creamy-white lesion showed higher reflectivity at the level of the retinal pigment epithelium, which precluded our viewing the deeper structure of the tumor. CONCLUSION: Optical coherence tomography can demonstrate the cavernous structure of a choroidal osteoma at a selective stage of a tumor's evolution, namely, when the retinal pigment epithelium is atrophied and the ossification is premature.
Adult↗
Modification of lymphocyte responsiveness by hormone used in the treatment of urologic malignancies.
Recognition that the immune system may be important in regulating the clinical evolution of tumors and that corticosteroids suppress immune responses lends relevance to determining the concentrations in which sex hormones, currently used in the treatment of urologic malignancies exert immunosuppressive effects. We have investigated the effects of the sex hormones, diethylstilbestrol, diethylstilbestrol diphosphate, testosterone and progesterone, on in vitro lymphocyte blastogenesis as determined by 3H thymidine incorporation after stimulation with phytomitogens and alloantigens, and compared their effects to the effects of cortisol. Compared to cortisol these sex hormones are relatively weak suppressors of lymphocyte blastogenesis (cortisol 10(-7) M, progesterone 5 times 10(-6) M, testosterone 5 times 10(-5) M, diethylstilbestrol 5 times 10(-5) M and diethylstilbestrol diphosphate 10(-3) M) and probably are not significantly immunosuppressive in commonly used pharmacologic dosages. Similar results were observed with the T lymphocyte mitogens, phytohemagglutinin and concanavalin A, and in the combined T and B cell mitogen pokeweed. The fact that alloantigen-stimulated lymphocyte blastogenesis also was suppressed by diethylstilbestrol indicates that sex hormones exert their effects on the lymphocytes and not on the mitogens. Furthermore, sex hormones were not found to be cytotoxic to lymphocytes. It is postulated that the sex hormones tested act by suboptimal binding to glucocorticoid receptors in the lymphocytes and that the relative immunosuppressive potency of a given hormone is related to its affinity for the glucocorticoid receptor.
Diethylstilbestrol↗
[Testicular neoplasms. Evaluation of the experience during 25 years in a military hospital].
OBJECTIVES: The testicular tumors are frequent in the young adult, coinciding with the incorporation to the Military Service. The objective of our work is to evaluate the tumoral characteristic, its evolution with the time and the result of the treatments used in our center for this type of tumors. MATERIAL AND METHODS: We carried out a retrospective longitudinal study in a cohort of 98 patients with an average age of 28.6 years, subjected to orchiectomy for testicular tumor in our center between 1979 to 2004. In the study, we collected data referred to the age of the patients, the tumoral characteristic, the outcome of the treatment and the evolution of the tumor. RESULTS: In 61% of the cases, the affected testicle was the right (significant differences). The most common histologyc type was the non seminomatous germ cell tumors (NSGCT) (65.3%). Followed by the pure seminomas (27.6%), and non germinal cell tumors (NGC) (7.1%). The NSGCT was diagnosed to a average age (23.2 years) significantly smaller that the other two types. The stage I was the most frequent (58%). The seminomas presented a stage I in a significantly bigger frequency (80%) that the others tumors. The data picked up during the 25 years didn't show a significant variation regarding the tumoral characteristic. The survival análisis indicated that the tumoral characteristic with better pronostic regarding the probability of tumoral recurrences were the seminomas and the tumoral stages I and II. CONCLUSIONS: The non seminomatous germ cell tumors (NSGCT) are the most frequent testicular tumors in young adults. Most of the tumors are diagnosed in initial stages, and their pronostic is better in the case of the seminomas and in the stages I and II.
Adult↗
[Clear-cell carcinoma of the larynx: review of the literature apropos of a case].
Clear cell carcinoma of the larynx is exceptional. Only six cases are described in the literature. We report a new case occurring in a 58-year-old man. The treatment consisted of a total laryngectomy with lymph node dissection followed by adjuvant irradiation. Local and regional recurrence occurred after 5 months. The patient died from the tumor's evolution 12 months after the diagnosis. The prognosis of clear cell carcinoma of the larynx is similar to the clear cell carcinoma of the lung and is unfavorable.
Adenocarcinoma, Clear Cell↗