Cytogenetically Cryptic Acute Promyelocytic Leukemia: A Diagnostic Challenge.

Cytogenetically cryptic acute promyelocytic leukemia (APL) is rare, characterized by typical clinical and morphological features, but lacks t(15;17)(q24;q21)/PML::RARA translocation seen in conventional karyotyping or FISH. The prompt diagnosis and treatment of APL are critical due to life-threatening complications associated with this disease. However, cryptic APL cases remain a diagnostic challenge that could mislead the appropriate treatment. We describe four cryptic APL cases and review reported cases in the literature. Reverse transcriptase polymerase chain reaction (RT-PCR) is the most efficient diagnostic modality to detect these cases, and alternative methods are also discussed. This study highlights the importance of using parallel testing methods to diagnose cryptic APL cases accurately and effectively.

The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: A survey of LGG Fellowship Program Directors.

Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model. Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time. The data were collected, and the responses were aggregated for each question. Results: All of the responding PDs had started training at least 1 LGG fellow. PDs noted challenges with funding, staff shortages, molecular/cytogenetics content integration, limited total training time, increased remote work, increased sendout testing, and a lack of prior cytogenetics knowledge among incoming fellows. Conclusion: This survey attempted to assess the challenges that LGG PDs have been facing in offering and integrating clinical molecular genetics and clinical cytogenetics fellowship training. Common challenges between programs were noted, and a set of 6 concluding comments are provided to facilitate future discussion.

Adult acute myeloid leukemia patients with NUP98 rearrangement have frequent cryptic translocations and unfavorable outcome.

Acute myeloid leukemia (AML) with NUP98 rearrangement (AML-NUP98) has been uncommonly reported in adults, and its incidence in our institution is ∼2.5%. There were four men and five women with a median age of 49 years, among which six cases were de novo AML and three were therapy-related. Five cases were AML with minimal differentiation or without maturation, followed by four with monocytic differentiation. NUP98 rearrangement was confirmed in all cases by FISH, and five cases showed cryptic translocations. The median overall survival (OS) was 13 months, shorter than that of AML-NPM1 (p < 0.05), and similar to that in AML-KMT2A patients in our institution. The unfavorable OS was further confirmed by comparing to AML patients in TCGA database. In conclusion, adult AML-NUP98 is associated with cryptic translocations and an unfavorable outcome. Our study suggests that incorporating the NUP98 probe into AML FISH panels are warranted to improve clinical management.

Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia due to mutations causing haploinsufficiency of RUNX2, an osteoblast transcription factor specific for bone and cartilage. The classic form of CCD is characterized by delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Clinical reports suggest that a subset of patients with CCD have skeletal changes which mimic hypophosphatasia (HPP). Mutations in RUNX2 are detected in approximately 65% of cases of CCD, and microdeletions occur in 13%. We present clinical and radiological features in a 6-year-old child with severe CCD manifested by absence of the clavicles marked calvarial hypomineralization, osteoporosis and progressive kyphoscoliosis. HPP features included Bowdler spurs, severe osteopenia, and low alkaline phosphatase. Following negative mutation analysis of RUNX2, comparative genomic hybridization (CGH) microarray was performed. The result revealed a microdeletion in RUNX2, disrupting the C-terminal part of the gene.

Genomic instability after targeted irradiation of human lymphocytes: evidence for inter-individual differences under bystander conditions.

Environmental (222)radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET alpha-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single (3)He(2+) particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype.

Single nucleotide polymorphism genomic arrays analysis of t(8;21) acute myeloid leukemia cells.

Translocation of chromosomes 8 and 21, t(8;21), resulting in the AML1-ETO fusion gene, is associated with acute myeloid leukemia. We searched for additional genomic abnormalities in this acute myeloid leukemia subtype by performing single nucleotide polymorphism genomic arrays (SNP-chip) analysis on 48 newly diagnosed cases. Thirty-two patients (67%) had a normal genome by SNP-chip analysis (Group A), and 16 patients (33%) had one or more genomic abnormalities including copy number changes or copy number neutral loss of heterozygosity (Group B). Two samples had copy number neutral loss of heterozygosity on chromosome 6p including the PIM1 gene; and one of these cases had E135K mutation of Pim1. Interestingly, 38% of Group B and only 13% of Group A samples had a KIT-D816 mutation, suggesting that genomic alterations are often associated with a KIT-D816 mutation. Importantly, prognostic analysis revealed that overall survival and event-free survival of individuals in Group B were significantly worse than those in Group A.

Detection of copy number alterations in metastatic melanoma by a DNA fluorescence in situ hybridization probe panel and array comparative genomic hybridization: a southwest oncology group study (S9431).

PURPOSE: Gene copy number alteration (CNA) is common in malignant melanoma and is associated with tumor development and progression. The concordance between molecular cytogenetic techniques used to determine CNA has not been evaluated on a large set of loci in malignant melanoma. EXPERIMENTAL DESIGN: A panel of 16 locus-specific fluorescence in situ hybridization (FISH) probes located on eight chromosomes was used to identify CNA in touch preparations of frozen tissue samples from 19 patients with metastatic melanoma (SWOG-9431). A subset (n = 11) was analyzed using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH) of DNA isolated directly from touch-preparation slides. RESULTS: By FISH, most samples showed loss near or at WISP3/6p21, CCND3/6q22, and CDKN2A/9p21 (>75% of samples tested). More than one third of CDKN2A/9p21 losses were biallelic. Gains of NEDD9/6p24, MET/7q31, and MYC/8q24 were common (57%, 47%, and 41%, respectively) and CNA events involving 9p21/7p12.3 and MET were frequently coincident, suggesting gain of the whole chromosome 7. Changes were confirmed by aCGH, which also uncovered many discreet regions of change, larger than a single BAC. Overlapping segments observed in >45% of samples included many of the loci analyzed in the FISH study, in addition to other WNT pathway members, and genes associated with TP53 pathways and DNA damage response, repair, and stability. CONCLUSIONS: This study outlines a set of CNAs at the gene and regional level, using FISH and aCGH, which may provide a benchmark for future studies and may be important in selection of individual therapy for patients with metastatic malignant melanoma.

Applications of molecular neuro-oncology - a review of diffuse glioma integrated diagnosis and emerging molecular entities.

Insights into the molecular underpinnings of primary central nervous system tumors have radically changed the approach to tumor diagnosis and classification. Diagnostic emphasis has shifted from the morphology of a tumor under the microscope to an integrated approach based on morphologic and molecular features, including gene mutations, chromosomal copy number alterations, and gene rearrangements. In 2016, the World Health Organization provided guidelines for making an integrated diagnosis that incorporates both morphologic and molecular features in a subset of brain tumors. The integrated diagnosis now applies to infiltrating gliomas, a category that includes diffusely infiltrating astrocytoma grades II, III, and IV, and oligodendroglioma, grades II and III, thereby encompassing the most common primary intra-axial central nervous system tumors. Other neoplasms such as medulloblastoma, embryonal tumor with multilayered rosettes, certain supratentorial ependymomas, and atypical teratoid/rhabdoid tumor are also eligible for integrated diagnosis, which can sometimes be aided by characteristic immunohistochemical markers. Since 2016, advances in molecular neuro-oncology have resulted in periodic updates and clarifications to the integrated diagnostic approach. These advances reflect expanding knowledge on the molecular pathology of brain tumors, but raise a challenge in rapidly incorporating new molecular findings into diagnostic practice. This review provides a background on the molecular characteristics of primary brain tumors, emphasizing the molecular basis for classification of infiltrating gliomas, the most common entities that are eligible for an integrated diagnosis. We then discuss entities within the diffuse gliomas that do not receive an integrated diagnosis by WHO 2016 criteria, but have distinctive molecular features that are important to recognize because their clinical behavior can influence clinical management and prognosis. Particular attention is given to the histone H3 G34R/G34V mutant astrocytomas, an entity to consider when faced with an infiltrating glioma in the cerebral hemisphere of children and young adults, and to the group of histologically lower grade diffuse astrocytic gliomas with molecular features of glioblastoma, an important category of tumors to recognize due to their aggressive clinical behavior.

Na+/Ca2+ exchanger subtype (NCX1, NCX2, NCX3) protein expression in the rat hippocampus following 3 min and 8 min durations of global cerebral ischemia.

There is increasing evidence that the sodium-calcium exchanger (NCX) subtypes, NCX1, NCX2 and NCX3 play an important role in intracellular calcium homeostasis/dysregulation following cerebral ischemia. In the present study we examined NCX1, NCX2 and NCX3 protein levels in the rat hippocampus at 3, 6, 12, 18, 24 and 48 h following a 3 min and 8 min duration of global cerebral ischemia. We observed that NCX1 protein levels were significantly increased by 22.3% and 20.6% at the 6 and 12 h respective time points following a 3 min duration of global ischemia, while NCX2 and NCX3 protein levels remained relatively constant. Following a 8 min duration of global ischemia, NCX1 protein levels remained relatively constant, while NCX2 protein levels were down-regulated by 6.9%, 10.8%, 14.4% and 10.3% at the 6, 18, 24 and 48 h respective time points, and NCX3 protein levels were up-regulated by 22.1% at the 18 h time point. Taken together, our results show that NCX subtype protein expression is sensitive to cerebral ischemia, and indicates that changes in NCX activity may be playing an important role in calcium maintenance and neuronal outcome following ischemia.

MYC immunohistochemical and cytogenetic analysis are required for identification of clinically relevant aggressive B cell lymphoma subtypes.

Accurate subclassification of aggressive B cell lymphomas (ABCLs) requires integration of morphologic, immunohistochemical (IHC), and cytogenetic information. Optimal strategies have not been well defined for diagnosis of high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBLwR) and double expressor lymphomas with MYC and BCL2 protein overexpression. One hundred and eighty seven ABCLs were investigated with complete IHC and FISH analysis. Morphologic and IHC analysis was insufficient to identify clinically relevant HGBLwR. Approximately, 75% of cases classified as HGBLwR showed conventional DLBCL morphologic features. Fourteen percent of MYC-rearranged cases were negative by IHC. Conversely, 60% of cases positive for MYC by IHC did not demonstrate a MYC rearrangement. Analysis by FISH without MYC and BCL2 IHC would miss 41 cases of double expressor lymphoma. Complete IHC and FISH analysis is recommended in the evaluation of all ABCLs.

Challenges in array comparative genomic hybridization for the analysis of cancer samples.

PURPOSE: To address some of the challenges facing the incorporation of array comparative genomic hybridization technology as a clinical tool, including archived tumor tissue, tumor heterogeneity, DNA quality and quantity, and array comparative genomic hybridization platform selection and performance. METHODS: Experiments were designed to assess the impact of DNA source (e.g., archival material), quantity, and amplification on array comparative genomic hybridization results. Two microdissection methods were used to isolate tumor cells to minimize heterogeneity. These data and other data sets were used in a further performance comparison of two commonly used array comparative genomic hybridization platforms: bacterial artificial chromosome (Roswell Park Cancer Institute) and oligonucleotide (Agilent Technologies, Santa Clara, CA). RESULTS: Array comparative genomic hybridization data from as few as 100 formalin-fixed, paraffin-embedded cells isolated by laser capture microdissection and amplified were remarkably similar to array comparative genomic hybridization copy number alterations detected in the bulk (unamplified) population. Manual microdissection from frozen sections provided a rapid and inexpensive means to isolate tumor from adjacent DNA for amplification and array comparative genomic hybridization. Whole genome amplification introduced no appreciable allele bias on array comparative genomic hybridization. The array comparative genomic hybridization results provided by the bacterial artificial chromosome and Agilent platforms were concordant in general, but bacterial artificial chromosome array comparative genomic hybridization showed far fewer outliers and overall less technical noise, which could adversely affect the statistical interpretation of the data. CONCLUSIONS: This study demonstrates that copy number alterations can be robustly and reproducibly detected by array comparative genomic hybridization in DNA isolated from challenging tumor types and sources, including archival materials, low DNA yield, and heterogeneous tissues. Furthermore, bacterial artificial chromosome array comparative genomic hybridization offers the advantage over the Agilent oligonucleotide platform of presenting fewer outliers, which could affect data interpretation.

Non-random distribution of instability-associated chromosomal rearrangement breakpoints in human lymphoblastoid cells.

Genomic instability is observed in tumors and in a large fraction of the progeny surviving irradiation. One of the best-characterized phenotypic manifestations of genomic instability is delayed chromosome aberrations. Our working hypothesis for the current study was that if genomic instability is in part attributable to cis mechanisms, we should observe a non-random distribution of chromosomes or sites involved in instability-associated rearrangements, regardless of radiation quality, dose, or trans factor expression. We report here the karyotypic examination of 296 instability-associated chromosomal rearrangement breaksites (IACRB) from 118 unstable TK6 human B lymphoblast, and isogenic derivative, clones. When we tested whether IACRB were distributed across the chromosomes based on target size, a significant non-random distribution was evident (p<0.00001), and three IACRB hotspots (chromosomes 11, 12, and 22) and one IACRB coldspot (chromosome 2) were identified. Statistical analysis at the chromosomal band-level identified four IACRB hotspots accounting for 20% of all instability-associated breaks, two of which account for over 14% of all IACRB. Further, analysis of independent clones provided evidence within 14 individual clones of IACRB clustering at the chromosomal band level, suggesting a predisposition for further breaks after an initial break at some chromosomal bands. All of these events, independently, or when taken together, were highly unlikely to have occurred by chance (p<0.000001). These IACRB band-level cluster hotspots were observed independent of radiation quality, dose, or cellular p53 status. The non-random distribution of instability-associated chromosomal rearrangements described here significantly differs from the distribution that was observed in a first-division post-irradiation metaphase analysis (p=0.0004). Taken together, these results suggest that genomic instability may be in part driven by chromosomal cis mechanisms.

Bystander-mediated genomic instability after high LET radiation in murine primary haemopoietic stem cells.

Communication between irradiated and unirradiated (bystander) cells can result in responses in unirradiated cells that are similar to responses in their irradiated counterparts. The purpose of the current experiment was to test the hypothesis that bystander responses will be similarly induced in primary murine stem cells under different cell culture conditions. The experimental systems used here, co-culture and media transfer, are similar in that they both restrict communication between irradiated and bystander cells to media borne factors, but are distinct in that with the media transfer technique, cells can only communicate after irradiation, and with co-culture, cells can communication before, during and after irradiation. In this set of parallel experiments, cell type, biological endpoint, and radiation quality and dose, were kept constant. In both experimental systems, clonogenic survival was significantly decreased in all groups, whether irradiated or bystander, suggesting a substantial contribution of bystander effects (BE) to cell killing. Genomic instability (GI) was induced under all radiation and bystander conditions in both experiments, including a situation where unirradiated cells were incubated with media that had been conditioned for 24h with irradiated cells. The appearance of delayed aberrations (genomic instability) 10-13 population doublings after irradiation was similar to the level of initial chromosomal damage, suggesting that the bystander factor is able to induce chromosomal alterations soon after irradiation. Whether these early alterations are related to those observed at later timepoints remains unknown. These results suggest that genomic instability may be significantly induced in a bystander cell population whether or not cells communicate during irradiation.

Spontaneous and radiation-induced genomic instability in human cell lines differing in cellular TP53 status.

Structural chromosomal rearrangements are commonly observed in tumor karyotypes and in radiation-induced genomic instability. Here we report the effects of TP53 deficiency on karyotypic stability before and after irradiation using related cells and clones differing in cellular TP53 status. The parental cell line, TK6, is a TP53 wild-type human B-lymphoblastoid line with a highly stable karyotype. In the two TK6 derivatives used here, TP53 has been inactivated by biochemical means (expression of HPV16 E6; TK6-5E) or genetic means (allelic inactivation; NH32). Biochemical inactivation of TP53 (TK6-5E) had little effect on the spontaneous karyotype, whereas allelic inactivation of TP53 (NH32) resulted in a modest increase in spontaneous karyotypic instability. After 2 Gy gamma irradiation, the number of unstable clones derived from TP53-deficient cells was significantly elevated compared to the TP53 wild-type counterpart. Extensively destabilized clones were common after irradiation in the set of clones derived from NH32 cells, and one was observed in the set of TK6-5E clones; however, they were never observed in TK6-derived clones. In two of the irradiated NH32 clones, whole chromosomes or chromosome bands were preferentially involved in alterations. These results suggest that genomic instability may differ both quantitatively and qualitatively as a consequence of altered TP53 expression. Some of the results showing repeated and preferential chromosome involvement in aberrations support a model in which instability may be driven by cis mechanisms.

Genomic instability in human lymphocytes irradiated with individual charged particles: involvement of tumor necrosis factor alpha in irradiated cells but not bystander cells.

Exposure to ionizing radiation can increase the risk of cancer, which is often characterized by genomic instability. In environmental exposures to high-LET radiation (e.g. 222Ra), it is unlikely that many cells will be traversed or that any cell will be traversed by more than one alpha particle, resulting in an in vivo bystander situation, potentially involving inflammation. Here primary human lymphocytes were irradiated with precise numbers of 3He2+ ions delivered to defined cell population fractions, to as low as a single cell being traversed, resembling in vivo conditions. Also, we assessed the contribution to genomic instability of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFA). Genomic instability was significantly elevated in irradiated groups (> or = two-fold over controls) and was comparable whether cells were traversed by one or two 3He2+ ions. Interestingly, substantial heterogeneity in genomic instability between experiments was observed when only one cell was traversed. Genomic instability was significantly reduced (60%) in cultures in which all cells were irradiated in the presence of TNFA antibody, but not when fractions were irradiated under the same conditions, suggesting that TNFA may have a role in the initiation of genomic instability in irradiated cells but not bystander cells. These results have implications for low-dose exposure risks and cancer.

The New Equivocal: Changes to HER2 FISH Results When Applying the 2013 ASCO/CAP Guidelines.

OBJECTIVES: Human epidermal growth factor receptor 2 (HER2, ERBB2) testing is an important prognostic/predictive marker in breast cancer management, especially in selecting HER2-targeted treatment. American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines address HER2 status and were recently revised in 2013, replacing the 2007 version. For in situ hybridization interpretation, 2013 guidelines return to the prior threshold of a HER2/CEP17 ratio of 2.0 or greater for positive and eliminate 1.8 to 2.2 as the equivocal range. Also, the HER2 signal/nucleus ratio is accounted for, with 6.0 or greater for positive and 4.0 to less than 6.0 for equivocal, even in cases with a HER2/CEP17 ratio less than 2.0. METHODS: With institutional review board approval, we reviewed our 2006 to 2012 HER2 fluorescence in situ hybridization (FISH) results and classified them according to both the 2007 and 2013 guidelines as negative, positive, or equivocal. RESULTS: Of 717 HER2 FISH results, 55 (7.7%) changed category when reassessed by 2013 guidelines. Nineteen of 25 results in the 2007 equivocal category were reassigned as positive (n = 13) or negative (n = 6). Thirty-five previously negative cases became equivocal in the 2013 scheme, 12 of these with 1+ immunohistochemistry. The positive category increased from 71 to 85. CONCLUSIONS: The 2013 ASCO/CAP guidelines increased the number of HER2 FISH positive and equivocal results. The equivocal group is substantially different, posing a dilemma for clinical management.

Intravenous administration of magnesium is only neuroprotective following transient global ischemia when present with post-ischemic mild hypothermia.

We hypothesized that post-ischemic hypothermia plays an important role in magnesium mediated neuroprotection following global cerebral ischemia. To test this hypothesis, we subjected rats to 8 min of global cerebral ischemia and magnesium treatment with and without post-ischemic body temperature maintenance. In Group 1, rats received an intravenously administered loading dose (LD) of 360 micromol/kg MgSO4 immediately before ischemia followed by a 48-h intravenous infusion (IVI) at either 60, 120 or 240 micromol/kg/h. Animal body temperature was kept at 37+/-0.2 degrees C during ischemia and between 36.6 and 37.8 degrees C for 6 h after ischemia. In Group 2, rats received a 360 micromol/kg MgSO4 LD followed by a 48-h IVI of either 120 or 240 micromol/kg/h MgSO4. In this group, body temperature following ischemia was monitored but not regulated. Control animals in Groups 1 and 2 received normal saline. Seven days after ischemia, hippocampal CA1 neurons were histologically examined. All Group 1 MgSO4-treated and control animals demonstrated less than 6% hippocampal CA1 neuronal survival. In Group 2, the rectal temperature of MgSO4-treated and control animals spontaneously dropped as low as 35.4 degrees C during the 6-h post-ischemia monitoring period. In addition, Group 2 animals that received the LD followed by an IVI of 120 or 240 micromol/kg/h MgSO4 demonstrated 34% (p<0.05) and 20% (p=0.936) CA1 neuronal survival, respectively. The CA1 neuronal survival in saline-treated control animals in both groups was less than 6%. Our data demonstrate only the combination of MgSO4 treatment and post-ischemic mild hypothermia is neuroprotective following global ischemia.

Spontaneous mutation in Big Blue mice from fetus to old age: tissue-specific time courses of mutation frequency but similar mutation types.

Transgenic mouse mutation detection systems permit rapid determination of the frequency and type of mutations allowing direct examination of mutational markers for aging, neurodegeneration, and cancer. The Big Blue transgenic mouse mutation detection system was used to determine the frequency and nature of spontaneous mutations versus age in multiple tissue types. Nuclear DNA was extracted from whole fetus at 13.5 days postcoitus (dpc) and from six tissues postbirth (cerebellum, forebrain, thymus, liver, adipose tissue, and male germline) of Big Blue transgenic mice at four ages: 10 days and at 3, 10, and 25 months postbirth. Forty million total plaque-forming units (pfu) were screened. The time course of mutation frequency with age had a significantly different shape in different tissues (P < 10(-6)). By 13.5 dpc, the whole fetus mutation frequency had already started increasing from the theoretical zero at conception to a value that was about one-half the mid-adulthood (3-10 months) average. From 10 days to 3 months, mutation frequency increased significantly in liver (P = 0.007) and showed an increasing trend in cerebellum, forebrain, and thymus. From 3 to 10 months, there was no significant change in mutation frequency in any tissue examined. From 10 to 25 months, the mutation frequency increased significantly in liver (P < 10(-6)) and adipose tissue (P = 0.002), but not in the other tissues examined (cerebellum, forebrain, and male germline). It is of interest that the mutation frequency in the male germline is consistently the lowest, remaining essentially unchanged in old age. The spectrum of mutation types was unaltered with age, tissue type and gender, although, as previously reported, tandem GG-->TT mutations are tissue specific and show significant increases with age and certain hotspots (Buettner VL et al. [1999]: Environ Mol Mutagen 33:320-324; Hill KA et al. [2003]: Mutat Res 534:173-186). The spectrum of mutation types was generally the same for all tissue types, despite the tissue-specific increases in mutation frequency with age. These data provide a useful reference for future studies of endogenous and exogenous mutagenesis.

Interrelationships amongst radiation-induced genomic instability, bystander effects, and the adaptive response.

Over the past two decades, our understanding of radiation biology has undergone a fundamental shift in paradigms away from deterministic "hit-effect" relationships and towards complex ongoing "cellular responses". These responses include now familiar, but still poorly understood, phenomena associated with radiation exposure such as bystander effects, genomic instability, and adaptive responses. All three have been observed at very low doses, and at time points far removed from the initial radiation exposure, and are extremely relevant for linear extrapolation to low doses; the adaptive response is particularly relevant when exposure is spread over a period of time. These are precisely the circumstances that are most relevant to understanding cancer risk associated with environmental and occupational radiation exposures. This review will provide a synthesis of the known, and proposed, interrelationships amongst low-dose cellular responses to radiation. It also will examine the potential importance of non-targeted cellular responses to ionizing radiation in setting acceptable exposure limits especially to low-LET radiations.

Mammary analog secretory carcinoma of salivary glands: a report of 2 cases in the lips.

OBJECTIVE: This study presents 2 cases of labial mammary analog secretory carcinoma (MASC) including diagnostic criteria and a review of literature. MASC has not been previously described in the dental literature. DESIGN: Two cases of MASC and 1 case of acinic cell carcinoma (ACC) of the lips were reviewed for their microscopic and immunohistochemical features. Fluorescence in situ hybridization (FISH) for the ETV6-NTRK3 translocation was performed. The clinical features of 65 cases previously described in the medical literature are reviewed. RESULTS: MASCs had hematoxylin and eosin features similar to those of ACC but demonstrated larger, globular periodic acid-Schiff positive deposits, whereas ACC had finer granular deposits. MASCs were strongly positive for S100, vimentin, and mammaglobin, whereas ACC was negative for S100 and vimentin and only focally mammaglobin positive. FISH demonstrated that MASCs were positive for ETV6 disruption. CONCLUSION: MASCs are newly described, can occur in a wide age range, favor males, and can be misinterpreted as ACC or adenocarcinoma not otherwise specified by routine microscopy.