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PubMed2005

[Antimicrobial agents in pediatric cancer patients with hepatic or renal impairment].

Antimicrobial agents are among the most frequently prescribed therapeutics in the supportive care of children and adolescents with cancer or following hematopoietic stem cell transplantation. Most of these agents are cleared from the body by elimination of unchanged drug by the kidney and/or metabolism by the liver. Impaired renal and hepatic function may have profound effects on the pharmacokinetics and pharmacodynamics of antimicrobial agents, necessitating modification of the dosage regimen in order to avoid toxicity through accumulation of the parent and/or its metabolites. Key to minimize such toxicities is a thorough understanding of the antimicrobial drug armamentarium and a careful evaluation of benefits and risks of antimicrobial interventions. This article reviews the mechanisms of renal and hepatic drug clearance in the normal state and in the state of functional impairment, their implications for antimicrobial therapy and dosage recommendations for pediatric cancer patients with impaired renal or hepatic function.

Adolescent↗
PubMed2006

Genetics and biology of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment.

Animals↗
PubMed1996

Why do stem cells exist?

Self-renewing tissues have a differentiation hierarchy such that the stem cells are the only permanent residents of the tissue, and it is in these cells that most cancerous mutations arise. The progeny of the stem cells either remain stem cells or enter a transient proliferating cell population that differentiates to produce the functional cells of the tissue. The reason that this differentiation hierarchy exists has not been established. We show here that alternative hierarchies, in which there would be no stem cells, are feasible and biologically plausible. We show that current evidence from somatic mutation frequencies at both transgenic and endogenous loci implicates cell division in the origin of most somatic mutations. We suggest, therefore, that the existence of stem cells is an evolutionary consequence of a selective pressure to avoid cancer by reducing the number of somatic mutations. The stem cell hierarchy reduces the number of cell divisions of those cells that reside permanently in the tissue, which reduces the number of somatic mutations and thus minimizes the cancer rate. In the small intestine, the existence of stem cells reduces the mutant frequency in the stem cells by about one order of magnitude. Since two or more mutations are required to transform a cell, the protective effect may be 100-fold or more. Similar factors may be expected in other tissues.

Age Factors↗
PubMed1988

Cancer "cures" in children, adolescents and young adults versus general cancer cure failure after 50 years of age.

Cancer cure has principally concerned stem cell or embryonic cell tumors in children, adolescents and adults under 50 years of age. Cancers that are termed "curable" are those in which the patient survival curve rapidly becomes parallel to the normal life expectancy curve--a plateau in children--and "almost curable" those in which this phenomenon appears later on and/or which is not completely parallel to the normal life expectancy curve. The failure to cure cancer patients over 50 years of age by chemotherapy suggests that although cytostatics are able to reduce the neoplastic cell number to a level that can be eradicated by the lato sensu immunologic functions of the organism before that age, this is not the case in older patients in which even a low number of neoplastic cells cannot be destroyed in this manner. Experimental and clinical data on preventive and curative effects of immuno-restoration/stimulation after the age of 50 are presented and discussed, as well as both reduced cancer patient survival rate and decreased immunity which follows peri-surgical radiotherapy.

Adolescent↗
PubMed2002

Stem-cell origin of metastasis and heterogeneity in solid tumours.

An explanation for the inherently metastatic and heterogeneous nature of cancers may be their derivation from distinct stem cells. The type of stem cell from which a neoplasm arises determines both the metastatic potential and the phenotypic diversity of that neoplasm. Hence, tumours originating from an early stem cell or its progenitor cells metastasise readily and have a more heterogeneous phenotype, whereas tumours originating from a later stem cell or its progenitor cells have limited metastatic potential and a more homogeneous phenotype. Further investigation of the role of stem cells in the development of cancer may lead to the discovery of novel diagnostic tools, prognostic markers, and therapeutic targets in the battle against cancer.

Biomarkers, Tumor↗
PubMed2006

Evolutionarily conserved role of nucleostemin: controlling proliferation of stem/progenitor cells during early vertebrate development.

Nucleostemin (NS) is a putative GTPase expressed preferentially in the nucleoli of neuronal and embryonic stem cells and several cancer cell lines. Transfection and knockdown studies indicated that NS controls the proliferation of these cells by interacting with the p53 tumor suppressor protein and regulating its activity. To assess the physiological role of NS in vivo, we generated a mutant mouse line with a specific gene trap event that inactivates the NS allele. The corresponding NS(-/-) embryos died around embryonic day 4. Analyses of NS mutant blastocysts indicated that NS is not required to maintain pluripotency, nucleolar integrity, or survival of the embryonic stem cells. However, the homozygous mutant blastocysts failed to enter S phase even in the absence of functional p53. Haploid insufficiency of NS in mouse embryonic fibroblasts leads to decreased cell proliferation. NS also functions in early amphibian development to control cell proliferation of neural progenitor cells. Our results show that NS has a unique ability, derived from an ancestral function, to control the proliferation rate of stem/progenitor cells in vivo independently of p53.

Animals↗
PubMed1990

Circulating hematopoietic progenitors in patients with primary lung cancer.

The levels of circulating hematopoietic progenitors were measured in 28 patients with primary lung cancer. The average numbers of progenitors per milliliter of blood were 33 (range 0-360) for colony-forming unit-granulocyte macrophage (CFU-GM), 23 (range 0-140) for burst-forming unit-erythrocyte (BFU-E), and 4 (range 0-50) for colony-forming unit-mixed lineages (CFU-mix). No significant influence of age, sex, histological type, or clinical stage of the tumor on the progenitor levels was detected. After cytoreductive chemotherapy of the patients by treatment with cisplatin plus etoposide, the cells showed 6- to 50-fold rebound overshoots, but no rebound was observed after treatment with cisplatin alone, cisplatin plus mitomycin C or cisplatin plus vindesine plus mitomycin C, or in 4 of 5 patients treated with cyclophosphamide plus adriamycin plus vincristine. Peripheral blood hematopoietic progenitors should be useful as an alternative source of stem cells for lung cancer patients treated with marrow ablative chemotherapy.

Adult↗
PubMed2003

Decreased expression of stem cell factor in esophageal and gastric mucosa after esophagogastric anastomosis for cancer: potential relevance to motility.

BACKGROUND: Esophageal replacement with gastric tube is a well-established reconstruction of the alimentary tract after esophagectomy in cancer patients. The resulting molecular events in the transposed gastric tube and residual esophagus have yet to be investigated. Stem cell factor (SCF) was recently shown to be critical for signaling in gastrointestinal motility. SCF expression is here correlated with changes in mucosal morphology, acid and biliary reflux, and motility in the residual esophagus and gastric tube. METHODS: Thirteen patients surgically resected for squamous esophageal carcinoma with gastric tube replaced by esophagogastric anastomosis underwent upper endoscopy, esophageal manometry, 24-hour pH monitoring, and bile reflux detection. Esophageal and gastric mucosa samples were examined for SCF expression by immunohistochemical and semiquantitative reverse transcriptase-polymerase chain reaction analysis and for SCF serum levels by enzyme-linked immunosorbent assay. RESULTS: All patients showed severe residual esophagus hypoperistalsis and no gastric tube motor activity. The 24-hour pH monitoring was positive in most; 24-hour bile detection was mostly negative. SCF levels in the residual esophageal and gastric tube mucosa were dramatically decreased compared with those of normal subjects. The correlation between SCF and slow-wave activity was positive. CONCLUSIONS: Hypomotility of the residual esophagus and gastric tube seems closely associated with disruption of the SCF/c-kit signaling pathway. However, the absence of notable relations between mucosal changes after chronic exposure to acid, biliary gastric content, and SCF expression indicates that this analysis cannot be considered part of endoscopic follow-up.

Adult↗
PubMed2002

History of haematopoietic stem-cell transplantation.

After fifty years of investigations into the use of pluripotent haematopoietic stem-cell transplantation for cancer therapy, this procedure has progressed from one that was thought to be plagued with insurmountable complications to a standard treatment for many haematological malignancies. How have these hurdles been overcome, and how can the therapy be expanded to include patients who are too old or medically infirm to tolerate conventional transplant approaches?

Hematologic Neoplasms↗
PubMed2006

Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks.

BACKGROUND: Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation-induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. METHODS: To extend the model to radiation-induced leukemias, we analyzed--in addition to cellular initiation, inactivation, and proliferation--a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors who were subjected to much lower radiation doses. RESULTS: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110,000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 to 1.9). CONCLUSIONS: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, with reasonable accuracy, risks for radiation-induced leukemia associated with exposure to therapeutic doses of radiation.

Adult↗
PubMed2006

A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer.

PURPOSE: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56(bright) natural killer (NK) cells, the CD34+ NK cell precursor, and CD4+ CD25+ regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56(bright) NK cells from CD34+ hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study. EXPERIMENTAL DESIGN: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m2/d for 8 weeks with 5 or 10 microg/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer. RESULTS: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m2/d of IL-2 and 5 microg/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline. CONCLUSIONS: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.

Adult↗
PubMed2006

The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention.

The breast attains its maximum development during pregnancy and lactation. After menopause the breast regresses in both nulliparous and parous women containing lobular structures that have been designated lobules type 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women, indicates that Lobules type 1 in these two groups of women might be biologically different, or exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that the Lobule type 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and therefore susceptible to undergo neoplastic transformation, these cell are called Stem cells 1, whereas Lobules type 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the other hand, are composed of an epithelial cell population that is refractory to transformation called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the "genomic signature" that differentiates the Lobule type 1 from the early parous women from that of the nulliparous women by shifting the Stem cell 1 to a Stem cell 2 that is refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full term pregnancy. The identification of a putative breast stem cell (Stem cell 1) has reached in the last decade a significant impulse and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although still more work needs to be done in order to better understand the role of the Stem cell 2 and its interaction with the genes that confer it a specific signature, collectively, the data presently available provides evidence that pregnancy, through the process of cell differentiation, shifts the Stem cell 1 to Stem cell 2, cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis.

Animals↗
PubMed2006

Stem cell transplantation: risk factors for psychiatric morbidity.

The aim of this study was to determine the risk factors for psychiatric disorder in haematological cancer patients during hospitalization for stem cell transplantation. In this 3-year prospective study, 220 patients received stem cell transplantation at a single institution. Structured psychiatric interviews applying standardized diagnostic criteria were performed at hospital admission and weekly during hospitalization until discharge or death, yielding a total of 1,062 interviews. Psychiatric disorder (any depressive, anxiety, or adjustment disorder) prevalence at the time of hospital admission was 21% and psychiatric disorder incidence during post-admission follow-up was 22%. After adjusting for multiple confounders in multivariate logistic regression analyses, we found that younger age, women, a past psychiatric history, lower functional status, pain, smoking cessation, and higher regimen-related toxicity were significantly associated with psychiatric disorder risk. Our study findings may help to improve identification of the patients most at risk for psychiatric disturbances during hospitalization for stem cell transplantation.

Adolescent↗
PubMed2004

Initiation of colorectal cancer: where do the two hits hit?

It is widely believed that stem cells are of special importance for colorectal cancer initiation. The earliest event being the inactivation of both alleles of the Adenomatous Polyposis Coli (APC) gene, it is thought that the stem cells are the most likely target for these two first hits. Indeed, at the first glance, short-lived differentiated cells cannot sustain a mutation long enough for the second hit to occur, because of the constant apoptosis/renewal process in epithelial tissues. Using a straightforward calculation, we show that this intuitive argument is incorrect. Our model based on the conventional view of colon crypt architecture, suggests that at least one of the two hits may occur in the migrating compartment. We suggest that a possible role of differentiating cells in cancer initiation cannot be discarded simply based on the fact that they are short-lived. More evidence is needed to understand the cellular origins of cancer and to identify whether or not a double hit in a daughter cell can be "immortalizing". In this study we discuss several scenarios and propose some experiments which can shed light on these questions.

Cell Differentiation↗
PubMed2006

Clinical study for management of supportive treatment for high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for intractable testicular tumor.

The side effects of high-dose anti-cancer drug chemotherapy with peripheral blood stem cell transplantation (PBCST) for the treatment of intractable testicular tumor are very serious. In particular, agranulocytosis in bone marrow suppression may be life threatening. In this study, we examined opportunistic infectious diseases and preventive counter measures in the compromised conditions of anti-cancer drug chemotherapy. The patients underwent anti-cancer drug chemotherapy with PBCST for the treatment of intractable testicular tumors at Kobe University Hospital from September 1996 to September 2002. The high-dose chemotherapy regimen consisted of total doses per course of 1,250 mg/m2 carboplatin, 1,500 mg/m2 etoposide, and 7,500 mg/m2 ifosfamide. Twenty-four men (median age, 30 years; range, 18-70 years) received 50 courses of chemotherapy in total. The nadir of peripheral leukocyte counts was less than 1,000/mm3 in all courses, and the mean period was for 7.1 days. None of these patients developed critical sepsis leading to disseminated intravascular coagulation or treatment-related death. Our detailed data show that we can perform high-dose anti-cancer drug chemotherapy with PBSCT for intractable testicular tumors without serious infectious complications if we take sufficient preventive countermeasures for infectious diseases.

Adolescent↗
PubMed2005

Purmorphamine activates the Hedgehog pathway by targeting Smoothened.

Hedgehog (Hh) signaling is an important regulator of embryonic patterning, tissue regeneration, stem cell renewal and cancer growth. A purine derivative named purmorphamine was previously found to activate the Hh pathway and affect osteoblast differentiation through an unknown mechanism. We demonstrate here that purmorphamine directly targets Smoothened, a critical component of the Hh signaling pathway.

Animals↗
PubMedDate not supplied

Development of a clinical grade procedure for generation of mRNA transfected dendritic cells from purified frozen CD34(+) blood progenitor cells.

Enriched CD34(+) peripheral blood progenitor cells (PBPC) are frequently used as stem cell support in cancer patients following high dose therapy. Since precursor dendritic cells (DCs) originate from haematopoietic progenitor cells, purified CD34(+) cells might also serve as starting cells for ex- vivo production of DC. In the present study we developed a clinical grade procedure for ex- vivo production of DC derived from enriched CD34(+) cells. Different concentrations of CD34(+) cells were grown in gas-permeable Teflon bags with different serum-free and serum-containing media supplemented with GM-CSF, IL-4, TNF-alpha, SCF, Flt-3L and INF-alpha. Serum-free CellGroSCGM medium for 7 days followed by CellGroDC medium in 7 days gave the same results as serum-containing medium. After incubation the cultured cells containing immature DCs were concentrated and transfected with tumour mRNA from human prostate cancer cell lines employing a highly efficient electroporation procedure. Thawed transfected DCs were able to elicit primary T-cell responses in vitro against antigens encoded by the prostate cancer mRNA as shown by ELISPOT assay using mock-transfected DCs as control. Our results show that frozen enriched CD34(+) cells can be an alternative and efficient source for production of DCs for therapeutic purpose.

Antigens, CD34↗