Screening for distress and needs: Findings from a multinational validation of the Adolescent and Young Adult Psycho-Oncology Screening Tool with newly diagnosed patients.

OBJECTIVE: Adolescents and young adults (AYAs) diagnosed with cancer commonly experience elevated psychological distress and need appropriate detection and management of the psychosocial impact of their illness and treatment. This paper describes the multinational validation of the Distress Thermometer (DT) for AYAs recently diagnosed with cancer and the relationship between distress and patient concerns on the AYA-Needs Assessment (AYA-NA). METHODS: AYA patients (N = 288; 15-29 years, Mage  = 21.5 years, SDage  = 3.8) from Australia (n = 111), Canada (n = 67), the UK (n = 85) and the USA (n = 25) completed the DT, AYA-NA, Hospital Anxiety Depression Scale (HADS) and demographic measures within 3 months of diagnosis. Using the HADS as a criterion, receiver operating characteristics analysis was used to determine the optimal cut-off score and meet the acceptable level of 0.70 for sensitivity and specificity. Correlations between the DT and HADS scores, prevalence of distress and AYA-NA scores were reported. RESULTS: The DT correlated strongly with the HADS-Total, providing construct validity evidence (r = 0.65, p < 0.001). A score of 5 resulted in the best clinical screening cut-off on the DT (sensitivity = 82%, specificity = 75%, Youden Index = 0.57). Forty-two percent of AYAs scored at or above 5. 'Loss of meaning or purpose' was the AYA-NA item most likely to differentiate distressed AYAs. CONCLUSIONS: The DT is a valid distress screening instrument for AYAs with cancer. The AYA-POST (DT and AYA-NA) provides clinicians with a critical tool to assess the psychosocial well-being of this group, allowing for the provision of personalised support and care responsive to individuals' specific needs and concerns.

Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens.

For young adults with acute lymphoblastic leukemia, pediatric-based regimens are likely to provide the following when compared to hyper-CVAD regimens: better disease control, less hospitalization time, diminished acute toxicities, decreased financial cost, more quality-adjusted life years, and fewer adverse late effects, such as infertility, myelodysplasia, and second malignant neoplasms. There are also reasons to expect less cardiac and cognitive dysfunction after pediatric regimens. The improved quality and quantity of life associated with pediatric regimens renders them preferable to hyper-CVAD regimens for the treatment of Philadelphia-negative B-precursor or T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma in young adults.

Fallacy of attributing the U.S. firearm mortality epidemic to mental health.

BACKGROUND: Annual global data on mental disorders prevalence and firearm death rates for 2000-2019, enables the U.S. to be compared with comparable counties for these metrics. METHODS: The Institute for Health Metrics and Evaluation (IHME) Global Health Burden data were used to compare the prevalence of mental disorders with overall, homicide and suicide firearm death rates including homicides and suicides, in high sociodemographic (SDI) countries. RESULTS: Overall and in none of the nine major categories of mental disorders did the U.S. have a statistically-significant higher rate than any of 40 other high SDI countries during 2019, the last year of available data. During the same year, the U.S. had a statistically-significant higher rate of all deaths, homicides, and suicides by firearm (all p<<0.001) than all other 40 high SDI countries. Suicides accounted for most of the firearm death rate differences between the U.S. and other high SDI countries, and yet the prevalence of mental health disorders associated with suicide were not significantly difference between the U.S. and other high SDI countries. CONCLUSION: Mental disorder prevalence in the U.S. is similar in all major categories to its 40 comparable sociodemographic countries, including mental health disorders primarily associated with suicide. It cannot therefore explain the country's strikingly higher firearm death rate, including suicide. Reducing firearm prevalence, which is correlated with the country's firearm death rate, is a logical solution that has been applied by other countries.

Retrospective evidence for pediatric benefit of U.S. assault weapons ban as rationale for implementing an even more effective ban.

BACKGROUND: With data available since 1981, firearm death rates in American children and adolescents can be evaluated for trends during the 13 years before, the decade of, and during 16 years since the United States (U.S.) 1994-2004 Federal Assault Weapons Ban (FAWB). METHODS: National and regional firearm mortality trends in the U.S. during 1981-2020 were assessed with joinpoint regression applied to Centers for Disease Control and Prevention data. RESULTS: After increasing exponentially before the FAWB, the national firearm death rate in 0-14 year-olds promptly reversed course and declined throughout the FAWB and then reversed again after the FAWB and resumed an exponential increase (all phases p<0.001). The reduction in firearm death rate occurred within 1-3 years of the start of the FAWB, in both sexes, in all four census regions of the U.S., and in all four major race/ethnicity subgroups, especially non-Hispanic blacks. No other form of violence in 0-14 year-olds had this temporal relationship with the FAWB. The firearm mortality reduction during the FAWB is strongly-highly correlated with the concomitant reduction in handgun manufacturing in 91 % of 24 sex, race/ethnicity and region subsets analyzed, These FAWB-related trends were also apparent in older adolescents and young adults and less so in older persons. CONCLUSIONS: Firearm death rates in 0-14 year-olds before, during, and after the FAWB, and no other type of injury, implicate the FAWB as having had a beneficial effect. Legislation to mitigate firearm mortality and injury inclusive of a FAWB should be especially beneficial to children and young adolescents, and regardless of sex, race/ethnicity or region in the U.S.

Increasing Rate of Unintentional Firearm Deaths in Youngest Americans: Firearm Prevalence and Covid-19 Pandemic Implication.

BACKGROUND: The United States has had, by far, the world's greatest civilian ownership of firearms. An even greater ownership occurred during the Covd-19 pandemic, mostly of handguns and including many new owners. The U.S. has also had the least progress of the 41 highest sociodemographic countries ranked by the Institute for Health Metrics and Evaluation in reducing the unintentional firearm mortality rate in young children. This study characterized the unintentional firearm mortality trends in American 1-4 year-olds by sex and race/ethnicity and evaluated the trends in the context of firearm prevalence in the U.S. METHODS: Mortality data for 1999-2018 were obtained from the U.S. Centers for Disease Control and Prevention and the Institute for Health Metrics and Evaluation, firearm injury and mortality data for 2016-2020 from Everytown for Gun Safety #NotAnAccident database, firearm background check data for 1999-2020 from the National Instant Criminal Background Check System, and civilian firearm prevalence for 2017 from the Small Arms Survey. RESULTS: In American 1-4 year-olds, the rate of unintentional firearm deaths during 1999-2018 increased exponentially at an average annual percent rate of 4.9 (p < 0.001) and was greatest in non-Hispanic black children. Unintentional firearm deaths had the most rapid increase of all evaluable causes of death in the age group. The unintentional firearm death rate increase was correlated with the concurrent rate of firearm background checks and handgun permits issued (each p < 0.001) and in non-Hispanic white children with handgun prevalence in their families (p = 0.03). Globally, the unintentional firearm death rate was also correlated with firearm prevalence (p = 0.02). CONCLUSIONS: An increase in fatal firearm accidents in the United States death rate among 1-4 year-olds is directly associated with the steadily increasing prevalence of firearms. The acceleration of firearm deaths and injuries among young Americans, especially among non-Hispanic black children, requires urgent solutions to address firearm prevalence and access. The problem is expected to become even more urgent as a result of the record high firearm sales that occurred in the United States during the 2020 coronavirus pandemic.

Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference.

One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials.

Premature carotid artery disease in pediatric cancer survivors treated with neck irradiation.

BACKGROUND: While carotid artery disease and strokes have been documented in adult cancer patients treated with neck irradiation, little information is available on pediatric patients. The purpose of this study is to determine if carotid disease is more prevalent among pediatric cancer survivors treated with neck irradiation than among healthy controls. PROCEDURE: Thirty pediatric cancer survivors who received neck irradiation (2,000-6,660 cGy) and 30 healthy subjects underwent bilateral carotid ultrasounds. Study outcome measures were common carotid intima-media thickness (IMT) and plaque (present or absent). Multivariate methods were used to compare cases and controls and to identify risk factors related to carotid disease in childhood cancer survivors. RESULTS: IMT was greater for cancer survivors than controls (0.46 mm (SD 0.12) vs. 0.41 mm (SD 0.06), P < 0.001). Plaque was present in 18% of irradiated vessels and 2% of non-irradiated vessels (P < 0.01). Among cancer survivors, IMT was positively associated with female gender (P < 0.05), non-white ethnicity (P < 0.01), positive family history of stroke/heart attack (P < 0.05), BMI (P < 0.001), total cholesterol (P < 0.01), cancer relapse (P < 0.001), and years off treatment (P < 0.0001). Plaque was positively associated with relapse (P < 0.05) and C-reactive protein (P < 0.01). There was no significant relationship between radiation dose at levels >or=2,000 cGy and IMT or plaque. CONCLUSIONS: Carotid artery disease was more prevalent among cancer survivors treated with neck irradiation than among controls. Due to the high risk of stroke associated with advanced carotid disease, larger prospective studies are needed to better define disease risk in these long-term survivors.

Expression in childhood primary brain tumors of NY-ESO-1, a cancer/testis antigen: an immunohistochemical study.

BACKGROUND: NY-ESO-1 is a human gene that codes for antigens that are expressed in malignancies of various histological types, but not in normal tissues, except the testes. The expression of NY-ESO-1 in intracranial brain tumors including astrocytomas (ASTRs) and medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs) was examined since the expression of NY-ESO-1 has only previously been explored in depth in neuroblastomas. MATERIALS AND METHODS: During our immunohistochemical study, a sensitive, four-step, alkaline phosphatase-conjugated antigen detection technique was employed. The expression of NY-ESO-1 was thereby examined in 6 cases of MED/PNET and 14 cases of ASTR. RESULTS: All 6 MED/PNET cases demonstrated high levels of immunoreactivity (overexpression) with the highest immunostaining intensity grades A and B. In the astrocytic tumors of various subtypes examined, the level of NY-ESO-1 expression was not as strong as that in MEDs/PNETs. However, there was a significant increase in expression level when comparing low-grade pilocytic ASTRs to high-grade anaplastic ASTRs and glioblastomas. CONCLUSION: As evidenced by our results, NY-ESO-1 overexpression increases as the malignancy grade of the astrocytic tumors increases. These data suggest that antigen-directed immunotherapy of primary brain tumors could target cancer/testis antigens (CTAs), especially those expressed at higher frequency such as NY-ESO-1.

Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review.

Importance: The incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adolescent and young adult (AYA) patients (age range, 15-39 years) in the United States is increasing at a greater rate than in younger or older persons. Their optimal treatment has been increasingly debated as pediatric regimens have become more widely used in the age group. This review compares the basic features of pediatric and adult chemotherapy regimens for ALL and LBL, recognizes and describes the challenges of the pediatric regimen, and suggests strategies to facilitate its adoption for AYAs with ALL and LBL. Observations: All but 2 of 25 published comparisons of outcomes with pediatric and adult regimens for ALL and LBL in AYAs and 1 meta-analysis favor the pediatric regimen. After more than a half-century of clinical trials of the pediatric regimens, including at least 160 phase 3 trials in the United States, the pediatric regimens have become far more complex than most adult regimens. Asparaginase, a critical component of the pediatric regimens, is more difficult to administer to AYAs (and older patients) but nonetheless has a favorable benefit to toxicity ratio for AYAs. A dramatic reduction in outcome of ALL and LBL during the AYA years (the "survival cliff") is coincident with similar reductions in proportions of AYAs referred to academic centers and enrolled on clinical trials (the "accrual cliff" and "referral cliff"). Conclusions and Relevance: The accumulating data increasingly support treating AYAs with ALL and LBL with a pediatric-inspired regimen or an approved institutional or national clinical trial tailored for this patient group. A need to develop clinical trials specifically for AYAs and to encourage their participation is paramount, with a goal to improve both the quantity and quality of survival.

Prevalence and correlates of fatigue in long-term survivors of childhood leukemia.

PURPOSE: To estimate the prevalence of fatigue, identify the factors associated with fatigue, and to explore the relationship between fatigue and quality of life (QOL) in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: One hundred sixty-one ALL survivors diagnosed at Childrens Hospital Los Angeles (Los Angeles, CA) before age 18 years and between January 1, 1975 and December 31, 1995, participated in a structured telephone interview. Participants were aged 18 to 41 years and off treatment for an average of 14 years. Four measures of fatigue, including the Revised-Piper Fatigue Scale, were used to assess fatigue; depression was assessed using the Center for Epidemiological Studies Depression Scale. Multivariate logistic regression models were developed to identify factors associated with fatigue and depression. RESULTS: Prevalence of fatigue (30%) fell within the general population normal limits. Fatigue and depression were highly correlated (Pearson r = 0.75). Fatigue was associated with marriage (OR = 0.11; 95% CI, 0.02 to 0.50), having children (OR = 5.80; 95% CI, 1.30 to 25.82), sleep disturbances (OR = 6.15; 95% CI, 2.33 to 16.22), pain (OR = 5.56; 95% CI, 2.13 to 14.48), obesity (OR = 3.80; 95% CI, 1.41 to 10.26), cognitive impairment (OR = 2.56; 95% CI, 1.02 to 6.38), and exercise-induced symptoms (OR = 2.98; 95% CI, 1.11 to 8.02). Four factors associated with fatigue were also associated with depression: sleep disturbances, pain, obesity, and cognitive impairment. Fatigue was inversely related to QOL. CONCLUSION: Some survivors of childhood ALL experience fatigue many years after treatment. Fatigued survivors represent a high-risk subgroup as they report more depression and poorer QOL than non-fatigued survivors and their peers.

Up-regulation of VEGF expression and related neo-angiogenesis in childhood high-grade gliomas: implications for anti-angiogenic anti-neoplastic therapy.

Vascular endothelial growth factor (VEGF) is a homodimeric, disulfide-linked glycoprotein which exhibits endothelial cell-specific mitogenic properties. VEGF is also a potent inducer of vascular permeability. There is considerable experimental evidence that VEGF isoforms are strongly involved in provoking neoangiogenesis of neoplastic cells and, consequently, the growth and progression of primary neoplasms (i.e., astrocytic gliomas), including the formation of an invasive and metastatic immunophenotype (IP). During this immunohistochemical study, the presence and tissue localization of VEGF121 was observed in anaplastic, high-grade astrocytomas (AAs) and in glioblastoma multiforme (GBMs) employing the specific monoclonal antibody against it. A sensitive, four-step, alkaline phosphatase-conjugated antigen detection technique was used. The immunoreactivity demonstrated a cytoplasmic, cell surface and extracellular matrix localization pattern in more than 90% of the tumor cells, with high intensity immunoreactivity (++++, A,B) in every high-grade astrocytic glioma tissue. VEGF121 expression was identified mostly within the cytoplasm of tumor cells, suggesting an embryonic, undifferentiated and more malignant cellular IP of high-grade gliomas. Tumor-related neo-angiogenesis and endothelial cell proliferation were also present. The great majority of high-grade astrocytic gliomas are incurable with the three classic therapeutic modalities. In the future, the development of targeted anti-neoplastic treatment strategies, adapted to individual patients, will require molecular identification of the different classes of neoplasm (including subtypes of astrocytomas) according to their stages, biology, prognosis and therapeutic options.

Cyclooxygenase-2 (COX-2) overexpression in childhood brain tumors.

The overexpression of COX enzymes has been demonstrated in human neoplasms at various sites, including the colon, gastrointestinal tract, lung, skin and recently in brain tumors. In this study, COX-2 receptor overexpression in primary childhood brain tumors was determined and the distribution pattern of COX-2 receptors was examined. A sensitive, 4-step, alkaline phosphatase conjugated antigen detection technique was used and a specific monoclonal antibody for medulloblastomas/ primitive neuroectodermal tumors (MEDs/PNETs), anaplastic, high-grade astrocytomas (ASTRs) and in glioblastoma multiformes (GMs) was employed. All of the 14 MEDs/PNETs observed demonstrated high levels of immunoreactivity (overexpression), with the highest immunostaining intensity (grades A and B). However, of the 14 subtypes of astrocytic tumors examined, the COX-2 receptor expression level did not even approach those of the MEDs/PNETs levels. However, significant differences were found when comparing low grade pilocytic ASTRs to high grade anaplastic ASTRs and glioblastomas. In two low grade pilocytic ASTRs, the expression level never exceeded 20%, while in high grade glial tumors (6 anaplastic ASTRs and 6 GMs) 30 to 50% of the tumor cells overexpressed COX-2 receptors, documenting an increase in COX-2 receptor overexpression with the increasing grade of the astrocytic tumor. In view of these findings, it would appear likely that COX-2 inhibitors may represent a chemo-preventive tool in treating childhood brain tumors, which are the leading cause of solid tumor cancer death in children under the age of 20.

Immunocytochemical detection of members of the caspase cascade of apoptosis in childhood medulloblastomas.

During the process of programmed cell death (PCD), the cell disintegrates into small, membrane-bound apoptotic bodies. Caspase-3 is ubiquitously expressed in normal and neoplastically-transformed human cells and serves as an executioner in the apoptotic or PCD pathway. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase-conjugated antigen detection technique was employed. The results demonstrated the presence of apoptotic activity within the cellular microenvironment of childhood medulloblastoma/primitive neuroectodermal tumor. The observations identified the cytoplasmic presence of caspase-3 in more than 20% of neoplastic cells. The immunocytochemical expression pattern demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells in about 5% of the tumor cells. Caspase-3 presence was also detected in the tumor infiltrating lymphocytes (TILs), representing the host's immune, mostly CD8+, cytotoxic, tumor-associated antigen (TAA)-directed effector cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that the grade and intensity of apoptosis may not only have diagnostic and prognostic significance, but could also play a leading role in the biological (fourth modality) antineoplastic treatment of these highly malignant, neuroectodermal brain tumors.

Epidermal growth factor receptor (EGFR) expression in childhood brain tumors.

Overactivation of epidermal growth factor receptor (EGFR) signaling has been recognized as an important step in the pathogenesis and progression of multiple forms of cancer of epithelial origin. Reports regarding EGFR family members in brain tumors are sparse and, thus, the significance of EGFR expression in childhood brain tumors is unclear. In this study, the expression of the EGFR family members was analyzed in 22 medulloblastomas. During the immunohistochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results demonstrated the presence of c-erbB-2 (HER-2) and c-erbB-4 (HER-4) in 10 to 50% of the neoplastic cells of high-grade glial tumors with high immunoreactivity, while c-erbB-3 (HER-3) was only detected in less than 10% of the neoplastically-transformed cells. In a follow-up, 70% of children, usually under 4 years of age, with c-erbB-2 (HER-2)-positive MEDs/PNETs, succumbed to the cancer. The Kaplan-Meier estimation revealed a significant correlation between c-erbB-2 expression and survival (p = 0.002), suggesting that c-erbB-2 (HER-2) is probably a prognostic marker for limited survival. Medulloblastoma is the most common malignant brain tumor that occurs during childhood. Multimodality treatment regimens have substantially improved survival in this disease; however, the tumor is incurable in about one-third of patients with medulloblastoma, and the current treatment has a detrimental effect on long-term survivors. As such, the results of this study further support the idea that targeting EGFR alone, or in combination with its downstream mediators, represents a promising new approach for the management of childhood brain tumors. Moreover, c-erbB-2 (HER-2) expression may also be of use in better classifying brain tumors.

Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961).

BACKGROUND: Glutamine (Gln) deamination by asparaginase (ASNase) appears to contribute in the decrease of serum asparagine (Asn) levels and enhance leukemic cell apoptosis. The pharmacodynamic (PD) rationale is based on the role of Gln as the main amino group donor for Asn synthesis from aspartate by the enzyme asparagine synthetase (AS). MATERIALS AND METHODS: Relationships between ASNase enzymatic activity and Asn or Gln levels were examined in 274 pairs of pre- and post-ASNase serum specimens from 200 high-risk acute lymphoblastic leukemia (ALL) patients from the Children's Cancer Group (CCG-1961). Data were analyzed according to a novel PD model based on previous best-fit projections (NONMEM) from the CCG-1962 standard-risk ALL study. RESULTS: The PD results from high-risk and standard-risk ALL patients were superimposable. The percentages of Asn and Gln deamination were predicted by ASNase activity in patients' sera. Pharmacodynamic analyses strongly suggested that > 90% deamination of Gln must occur before optimal Asn deamination takes place in vivo. Asparaginase activity > or = 0.4 IU/ml yielded mean Gln and Asn % deamination values of 90%. Lower ASNase concentrations yielded lower Gln or Asn % deamination. This ASNase concentration coincides with the in vitro determined IC50 value on CEM/0 human T-lymphoblastic leukemia cells. CONCLUSION: Asparaginase activity of > or = 0.4 IU/ml provided optimal Asn and Gln deamination in high-risk ALL patients. Deamination of Gln correlates with enhanced serum Asn deamination in vivo. Therefore, deamination of Gln may enhance the antileukemic effect of ASNase.

MAGE-1, a cancer/testis-antigen, expression in childhood astrocytomas as an indicator of tumor progression.

During the last decade, the aberrant expression of normal testicular proteins in neoplastically transformed cells became common knowledge. Cancer/testis-antigens (CTAs) represent a novel family of immunogenic proteins. The MAGE genes were initially analyzed from melanomas and turned out to have an almost exclusively neoplasm-specific expression pattern. This expression pattern might contribute to the genetic instability of neoplastically transformed cells. In normal adult tissues, most 23 human MAGE genes are expressed only in the testis, but only in the mitotic spermatogonia (germ cells) and in the primary spermatocytes. The immunocytochemistry was carried out on routine, formalin-fixed, paraffin-wax-embedded 3 to 4 mm thick astrocytoma (ASTR) tissue sections. A four step, indirect, biotin-streptavidin based method was employed with alkaline phosphatase enzyme conjugation. Immunocytochemical presence and cellular localization of the MAGE-1 CT-antigen, employing anti-MAGE-1 MoAB was observed only in anaplastic, high-grade ASTRs (100%), certainly including glioblastomas, in this study. The immunoreactivity was always heterogeneous, showing a cytoplasmic pattern and loosely grouped cells with similar staining characteristics being detected within the cellular and hormonal microenvironment of the ASTRs. We never identified MAGE-1, CT-antigen expression in the lowest grade, pilocytic ASTRs. The MAGE-1 CTA expression levels may also be used to evaluate the malignant and dedifferentiation tendencies of low-grade ASTRs and predict the likelihood of mutations of the genome and further dedifferentiation towards even more malignant anaplastic ASTR and glioblastoma multiforme IPs.

Restoration of the thymic cellular microenvironment following autologous bone marrow transplantation.

Mammalian thymic histogenesis can be morphologically divided into three consecutive stages: 1) epithelial; 2) lymphopoietic or lympho-epithelial; and 3) differentiated cellular microenvironmental, with formation of Hassall's bodies (HBs). The marked reduction of the thymic cellular microenvironment (TCM) is a well-controlled physiological process and is presumably under both local and global regulation by the cells of the RE meshwork and by the neuroendocrine axis, respectively. In humans, the age-related decline of facteur thymique sérique (FTS) levels in blood begins after 20 years of age and FTS completely disappears between the 5th and 6th decade of life. In contrast, serum levels of thymosin-alpha 1 and thymopoietin seem to decline earlier, starting as early as 10 years of age. The influences of other hormones on the thymic involution have also been characterized: testosterone, estrogen and hydrocortisone treatment results in marked involution, cortisone and progesterone administration causes slight to moderate, while use of desoxycorticosterone has no effect. Since the thymus is the primary T-lymphopoietic organ during mammalian ontogenesis, its age-related involution with the typical immunomorphological alterations can be held responsible only for a decline in antigen-specific T-lymphocyte immune functions. Thymic involution and diminished T-lymphocyte proliferation can be partially restored by thymic tissue transplantation or administration of thymic hormones. The stimulus for thymic cell proliferation and differentiation is genetically determined within the organ implant. The only partial reconstitution of CD4+ T-helper-lymphocyte subset after anti-neoplastic chemotherapy and autologous BTM represents a significant, therapy-complicating, clinical problem. After high-dose chemotherapy, the restoration of thymus-dependent CD4+ T-lymphocyte genesis was reported only in children. Our radiation, stem cell transplantation, and hormone treatment experiments in animals resulted in age- and time-dependent regeneration of the cytoarchitecture of the TCM, as well as intrathymic lymphopoiesis.

Antigen presentation by dendritic cells and their significance in antineoplastic immunotherapy.

Dendritic cells (DCs) are present in essentially every mammalian tissue, where they operate at the interface of innate and acquired immunity by recognizing pathogens and presenting pathogen-derived peptides to T lymphocytes. According to the research group of Shortman, experimental results suggest a "dual" DC differentiation model, demonstrating the existence of both myeloid-derived (with characteristic IF: CD11b+, CD11c+, CD8alpha- and DEC205+) and lymphoid-derived DCs (showing CD11b- CD11c-, CD8alpha+ and DEC205+ IF). DCs, including interdigitating cells (IDCs) and Langerhans cells (LCs), are characterized by dendritic morphology, high migratory mobility and are the most effective, "professional" cells for antigen presentation in primary immune responses. Most of the DCs express immunocytochemically detectable antigens like: S-100, CD1a, CD40 receptor, adhesion molecules (ICAM-1 or CD54, LFA-1 and LFA-3), integrins (CD11a, CD11c and CD18), CD45, CD54, co-stimulatory molecules (B7-1 or CD80, B7-2 or CD86), F418, MHC class I and II and DEC-205, multilectin receptor, immunostimulatory cytokine (IL-12) and, of course, Fc and complement receptors. Following recognition and uptake of antigens, mature dendritic cells (DCs) migrate to the T lymphocyte rich area of draining lymph nodes, display an array of antigen-derived peptides on the surface of major histocompatibility complex (MHC) molecules and acquire the cellular specialization to select and activate naive antigen-specific T lymphocytes. Immunotherapeutic ideas are based on the ability of the mammalian immune system to recognize neoplastically transformed cells. Immunotherapy of human neoplasms has always represented a very attractive fourth-modality therapeutic approach, especially in light of the many shortcomings of conventional surgical, radiation and chemotherapies in the management of neoplastically transformed cells. The cancer vaccine approach to therapy is based on the notion that the immune system could possibly mount a rejection strength response against the neoplastic cell conglomerate. The efficiency of DCs for T lymphocyte stimulation moved a number of research groups to develop DC- based immunotherapy approaches. The failure of cancer vaccines may be attributed to the relationship between host and neoplasm: through a natural selection process, the host facilitates the selective enrichment of clones with highly aggressive neoplastically transformed cells, being in various stages of differentiation and only during certain stages express neoplastic cell specific molecules.

Racial differences in childhood tumors.

The purpose of this brief review is to inform the reader of the appearance of childhood neoplasms along racial and ethnic lines. The Lag time, general aspects and specific tumors, such as astrocytomas, medulloblastomas and those of the skin, including cases affecting the face and mouth, are discussed. Other tumors discussed are melanomas, those of the nasopharynx, liver, bone, Hodgkin's disease and especially leukemias as primary forms. Special emphasis was put on the racial and other variabilities producing various combinations and specific responses to treatment.

Survivin expression in childhood medulloblastomas: a possible diagnostic and prognostic marker.

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in embryonic tissues during human ontogenesis and most human malignancies, but it is not present in the majority of normal adult tissues. Survivin is also a chromosomal passenger protein required for physiological cell divison. Survivin blocks apoptosis, via its BIR domain, by either directly or indirectly blocking the function of the members of the caspase cascade. The expression of this apoptosis inhibitor protein in medulloblastomas (MEDs) was examined for the first time. During the immunohistochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results did, in fact, demonstrate the presence of survivin in 10 to 50 per cent of medulloblastoma (MED) cells with medium intensity immunoreactivity (++, B) in this neuroectodermal brain tumor. These results indicate that survivin is probably not only a diagnostic marker, but also an important prognostic marker for MEDs/PNETs and may be useful in the future grading of malignancy in MEDs, much as grading is done today for astrocytomas (ASTRs). Furthermore, the almost exclusive neoplastic expression of survivin will allow development of new antineoplastic, immunotherapeutic strategies.