Abnormal mismatch repair and other clinicopathologic predictors of poor response to progestin treatment in young women with endometrial complex atypical hyperplasia and well-differentiated endometrial adenocarcinoma: a consecutive case series.

OBJECTIVE: To report the response to progestin therapy in young women with endometrial complex atypical hyperplasia (CAH) or FIGO grade 1 endometrial adenocarcinoma (FIGO 1 EAC) based on clinicopathologic features, including abnormal DNA mismatch repair (MMR) by immunohistochemistry (IHC). DESIGN: Consecutive case series. SETTING: Olive View-UCLA Medical Center in Sylmar, CA, USA, and Cedars-Sinai Medical Center in Los Angeles, CA, USA. POPULATION: Women ≤55 years old with CAH or FIGO 1 EAC. METHODS: Response to progestin therapy in 84 consecutive patients was assessed based on clinicopathologic factors, including age, body mass index (BMI), initial histology, and IHC staining for MMR proteins. MAIN OUTCOME MEASURES: Rates of abnormal MMR protein expression and response to progestin therapy were determined. RESULTS: Six (7%) patients had abnormal IHC staining, of whom five (83%) had FIGO 1 EAC at initial diagnosis. Following progestin treatment, none of the endometrial lesions in patients with abnormal IHC for MMR proteins had resolution of hyperplasia or malignancy, in contrast to 41 (53%) with normal staining (P = 0.028). Age ≤40 years and initial lesion (CAH versus FIGO 1 EAC) were predictors of response to progestin; BMI was not. CONCLUSIONS: In this cohort, 7% of women ≤55 years of age with CAH or FIGO 1 EAC had loss of MMR proteins by IHC. These patients had a higher incidence of invasive cancer and a lower incidence of resolution with progestin therapy. TWEETABLE ABSTRACT: Abnormal MMR protein expression predicts poor response to progestins in young women with CAH or FIGO 1 EAC.

Field-induced quantum criticality and universal temperature dependence of the magnetization of a spin-1/2 heisenberg chain.

High-precision dc magnetization measurements have been made on Cu(C4H4N2) (NO3)2 in magnetic fields up to 14.7 T, slightly above the saturation field Hs=13.97 T, in the temperature range from 0.08 to 15 K. The magnetization curve and differential susceptibility at the lowest temperature show excellent agreement with exact theoretical results for the spin-1/2 Heisenberg antiferromagnet in one dimension. A broad peak is observed in magnetization measured as a function of temperature, signaling a crossover to a low-temperature Tomonaga-Luttinger-liquid regime. With an increasing field, the peak moves gradually to lower temperatures, compressing the regime, and, at Hs, the magnetization exhibits a strong upturn. This quantum critical behavior of the magnetization and that of the specific heat withstand quantitative tests against theory, demonstrating that the material is a practically perfect one-dimensional spin-1/2 Heisenberg antiferromagnet.

Bacteriophage gene targeting vectors generated by transplacement.

A rate-determining step in gene targeting is the generation of the targeting vector. We have developed bacteriophage gene targeting vectorology, which shortens the timeline of targeting vector construction. Using retro-recombination screening, we can rapidly isolate targeting vectors from an embryonic stem cell genomic library via integrative and excisive recombination. We have demonstrated that recombination can be used to introduce specific point mutations or unique restriction sites into gene targeting vectors via transplacement. Using the choline/ethanolamine kinase alpha and beta genes as models, we demonstrate that transplacement can also be used to introduce specifically a neo resistance cassette into a gene targeting phage. In our experience, the lambdaTK gene targeting system offers considerable flexibility and efficiency in TV construction, which makes generating multiple vectors in one week's time possible.

IL-5 production by peripheral blood Th cells of adult asthma patients in response to Candida albicans allergen.

Cytokines produced by T cells are involved in chronic asthma. Relevant antigens for nonatopic asthma are still mostly unknown. Peripheral blood mononuclear cells (PBMCs) were obtained from adult asthmatic donors and incubated with Candida albicans extract. Proliferation response and cytokine production were analyzed. IL-2 and IL-5 were detectable in the cultures incubated with C. albicans extract, whereas IL-4 was undetectable. PBMCs obtained from some nonatopic asthma patients produced IL-5 upon stimulation of C. albicans extract. C. albicans allergen may be involved in the airway eosinophilic inflammation through the induction of IL-5 production by Th cells.

Structure and characterization of the genes for murine choline/ethanolamine kinase isozymes alpha and beta.

Choline/ethanolamine kinase (CK/EK) is the first enzyme in phosphatidylcholine/phosphatidylethanolamine biosynthesis in all animal cells. The highly purified CKs from mammalian sources and their recombinant gene products so far were all shown to have EK activity also, indicating that both activities reside on the same protein. CK/EK in most animal cells exists as several isoforms, for two of which (alpha and beta) their cDNAs have been cloned from both the rat and mouse, and they are found to be separate gene products. The physiological significance for the existence of more than one CK/EK enzyme, however, remains to be clarified. In this study, we isolated mouse genes encoding both types of CK/EK isozyme and determined their entire structure. The 5'-flanking promoter regions were found to have quite different features from each other, indicating that their expression could be under distinct control. Comparison of the nucleotide sequence between the corresponding coding exons showed the best homology (75%) residing on exon VIII. A search of the database resulted in the possible existence of 17 different origins of eukaryotic CK and/or EK, each of which presumably contained the entire amino acid sequence. Multialignment of their putative amino acid sequences led to an identification of the novel consensus sequence possibly required for the expression of either CK or EK activity, which corresponded to the sequence within exons VII and VIII of CK/EK-alpha and -beta genes from the mouse. This sequence was localized in close proximity to the C-terminal region of the general (Brenner's) phosphotransferase concensus sequence which was also completely conserved in all of the putative eukaryotic CK/EK proteins. The results demonstrated that, while both CK/EK-alpha and -beta genes were composed of 11 major exons, the size of their genes was quite different: 40 kb for CK/EK-alpha, whereas it was only 3.5 kb for CK/EK-beta.

Molecular cloning of mouse choline kinase and choline/ethanolamine kinase: their sequence comparison to the respective rat homologs.

Complementary DNAs homologous to a rat 42-kDa choline/ethanolamine kinase [C. Aoyama et al., Biochim. Biophys. Acta 1390 (1998) 1-7] and to a 50-kDa choline kinase [T. Uchida and S. Yamashita, J. Biol. Chem. 267 (1992) 10156-10162] were isolated from a 17-day post coitum mouse embryo cDNA library and their sequences were compared with the two murine species, respectively. The nucleotide sequence homology (within the coding sequence) between mouse and rat 50-kDa choline kinases (96.0%) was considerably higher than that between their 42-kDa choline/ethanolamine kinases (92.4%). Northern blot and RT-PCR studies on several rat tissues demonstrated that both isozymes are expressed ubiquitously with the highest level in testis.

Complementary DNA sequence for a 42 kDa rat kidney choline/ethanolamine kinase.

By means of peptide sequence information, several cDNA clones encoding a 42 kDa choline/ethanolamine kinase were isolated from a rat kidney cDNA library. Eight clones were sequenced with all of them resulting in identical overlapping nucleotide sequences. Four of them possessed entire open reading frame which could encode 394 amino acids with a calculated molecular size of 45 100. The predicted amino acid sequence contained all of the internal peptide fragment sequences derived from the purified 42 kDa enzyme. When the open reading frame was introduced into pGEX-2T vector and transfected into E. coli cells, a significant choline/ethanolamine kinase activity did appear in the cell lysate. A homology comparison with the previously reported choline kinase cDNAs (CKR1 and CKR2) from rat liver showed 66%-68% in entire nucleotide sequences and 57%-59% in amino acid sequences, indicating that the cloned cDNA here must be a novel CK/EK gene product. (c) 1998 Elsevier Science B. V.

Uterine cervical dysplasia and cancer: identification of c-myc status by quantitative polymerase chain reaction.

The c-myc oncogene status was determined in patients with nondysplasia (ND; 9 patients), low-grade squamous intraepithelial lesion (LGSIL; 12 patients), high-grade squamous intraepithelial lesion (HGSIL; 21 patients) and invasive squamous cell carcinoma (ISCC; 20 patients) of uterine cervix using fluorescent quantitative polymerase chain reaction (PCR). In the same paraffin-embedded specimens, other potential risk factors were also screened: human papillomavirus (HPV) infection, Ha-ras codon 12 mutation, DNA aneuploidy. Gene amplification, identified as c-myc copy numbers greater than the mean value +2 SD of patients with ND, was seen in 44% patients with LGSIL, 76% patients with HGSIL, and 67% patients with ISCC. These data indicate that c-myc amplification is one of the critical early events in the progression of uterine cervical lesions. HPV infection of various subtypes was identified in 0% patients with ND, 55% patients with LGSIL, 95% patients with HGSIL, and 84% patients with ISCC. No codon 12 mutation of the Ha-ras gene was found in this series. Aneuploid DNA pattern was seen in 0% patients with ND, 58% patients with LGSIL, 90% patients with HGSIL, and 80% patients with ISCC. There was a significant correlation between HPV infection and DNA aneuploidy. However, no relationship was seen between c-myc status and other factors in this series. Patients with HGSIL and ISCC almost always (95%) had multiple risk factors, whereas more than half of the patients with LGSIL had no or only one risk factor (P = 0.0001).

Pleuropulmonary blastoma in childhood. A tumor of divergent differentiation.

Pleuropulmonary blastoma (PPB) is a rare and highly aggressive tumor in children and is distinct from ordinary pulmonary blastoma or carcinosarcoma of the lung. This report describes the phenotypical characteristics of seven PPB tumors. The patients were five females and two males, all diagnosed in their third year of life. Five tumors were located within the pulmonary parenchyma, one in the mediastinum, and one involved both lung and mediastinum. Two children are alive and five have died of disease. Histologically, PPB showed a diffuse proliferation of undifferentiated blastemal cells with additional areas of chondroblastic foci (six tumors), storiform pattern (three tumors), alveolar pattern (one tumor), and lipoblastic differentiation (one tumor). Immunohistochemically, tumor cells were positive for vimentin in five of five tumors, histiocytic markers (A1AT and A1ACT, four of six cases; lysozyme, two of six; KP1, three of five) and myogenic markers (desmin, four of six; HHF35, five of six). S-100 was expressed in the chondroblastic areas (in three of four cases). Epithelial membrane antigen and cytokeratin were positive only in epithelial or mesothelial cells entrapped in the tumor. Ultrastructural examination demonstrated a similarity between the proliferating cells in PPB and those seen in malignant fibrous histiocytoma; that is, PPB tumor was mainly composed of a mixture of primitive, fibroblastic, myofibroblastic, histiocytoid, and fibrohistiocytoid cells. Also identified were cells with rhabdomyoblastic differentiation (two tumors) showing thick and thin filaments with Z-discs. In conclusion, PPB showed phenotypical diversity and was composed of MFH-type cells and cells with more specific mesenchymal differentiation.

Interpretative views on Hispanics' perinatal problems of low birth weight and prenatal care.

From a public health perspective, there is a need to recognize that Hispanics, and in particular Mexican Americans, are a very heterogeneous group. They represent all shades of acculturation, education, income, and citizenship status. As this minority group continues to increase in numbers, pertinent information about their perinatal health problems in the context of their sociocultural characteristics will be required. This review examines critically the recent literature related to low birth weight and prenatal care and suggests alternative ways to address these perinatal health issues. Low birth weight is examined in the context of the problem of intrauterine growth retardation and the potential mechanisms and consequences of different types of growth limitation in utero which have not been studied in this population. The use of prenatal care by Mexican American women and its association with birth weight is examined as an indication of maternal behavior or as a health care intervention. The implications for public health policy are discussed in relation to the identification, interpretation, and evaluation of these perinatal health issues in this minority population.

Undifferentiated (embryonal) sarcoma of the liver. A tumor of uncertain histogenesis showing divergent differentiation.

Pathologic features of eight cases of undifferentiated (embryonal) sarcoma of the liver (USL) in childhood were studied. Light microscopic examination showed a diffuse growth of spindle cells with occasional polygonal cells and multinucleated giant cells and also revealed focal areas of storiform pattern in four tumors, cambium layer formation in one tumor, and alveolar arrangement in one tumor. Immunohistochemical study showed positive staining of proliferating cells for suggestive histiocytic markers (A1AT in 6/6, A1ACT in 5/6, lysozyme in 4/6, and KP1 in 4/6) and for muscle markers (desmin in 4/6 and HHF35 in 3/6). Ultrastructural examination demonstrated that the individual tumors were composed of a mixture of cells having fibroblastic, histiocytoid, fibrohistiocytoid, myofibroblastic, and undifferentiated (primitive mesenchymal) morphologies. Also identified were cells with definite myoblastic morphology in three tumors: leiomyoblastic in one and rhabdomyoblastic in two. In conclusion, the tumor cells in USL show phenotypical diversity comparable to those of malignant fibrous histiocytoma with or without additional rhabdomyosarcomatous or leiomyosarcomatous differentiation.

Histopathologic features of composite ganglioneuroblastoma. Immunohistochemical distinction of the stromal component is related to prognosis.

Histopathologic features of 18 cases of composite ganglioneuroblastoma (CGNB) were studied with immunohistochemical staining techniques using antibodies against S-100 protein (S-100), ferritin (FER), and leukocytic common antigen (LCA). Cases of CGNB were divided on the basis of the morphologic features of neuroblastic elements into three prognostic subgroups: "Type A Intermixed," having individual microscopic nests of neuroblasts (N = 4, 100% survival); "Type B Intermixed," having microscopic aggregates of multiple neuroblastic nests (N = 6, 67% survival); and "Nodular," having grossly visible nodule(s) of neuroblastic proliferation (N = 8, 0% survival). Survival rates are significantly different for the prognostic subgroups (P less than 0.025). Each prognostic subgroup demonstrated an immunohistochemically distinct pattern of stromal cell composition in the neuroblastic elements: Type A Intermixed had numerous S-100 cells and no FER cells, Type B Intermixed contained many S-100 cells and a moderate number of FER cells, and Nodular had few S-100 cells with many FER cells. The S-100 and FER scores, determined by counting the positive cells through a line sampling method, differed significantly between these prognostic subgroups. Lymphocytic aggregations in tumor tissue evaluated by volumetric assessment with LCA staining, on the other hand, showed no contribution in predicting the outcome of the patients. There was also an inverse relationship between S-100 and FER score, suggesting a relationship between the relative predominance of these stromal cell types, tumor histopathologic features, and the biologic behavior of CGNB.

Pathologic features of extraosseous Ewing's sarcoma: a report from the Intergroup Rhabdomyosarcoma Study.

Eighty-four cases of extraosseous Ewing's sarcoma (EOE) were found during the pathology review of the Intergroup Rhabdomyosarcoma Study I and II. Patients commonly presented during or after adolescence with the most common primary sites including the trunk, extremities, and retroperitoneum. Males were slightly more affected. Histologic sections of 74 tumors in the pathology repository were re-reviewed with attention to rosette formation (positive in 18 cases) and glycogen deposition (++ in 21, + in 36, +/- in 11, and - in 2 of 70 cases examined). Fourteen tumors (7 with rosettes and 7 without) were selected for immunohistochemical and ultrastructural studies, and 13 showed single or multiple neural markers (neuron-specific enolase in 8, S-100 protein in 6, and neurosecretory-type granules in 9). These possible cases of neural EOE could be divided into three subgroups: tumor with bidirectional neuroblastic and schwannian differentiation (5 cases), tumor with monodirectional neuroblastic differentiation (7 cases), and tumor with monodirectional schwannian differentiation (1 case). EOE with a neural nature may be categorized into a spectrum of peripheral primitive neuroectodermal tumors. Clinical, histopathologic, and biologic differences between this disease and conventional sympathetic neuroblastoma are discussed.

Prognostic subgroups for undifferentiated neuroblastoma: immunohistochemical study with anti-S-100 protein antibody.

Pathologic prognostic factors in 36 undifferentiated neuroblastomas were studied by an immunohistochemical staining technique with anti-S-100 protein antibody. Nuclear abnormalities of neuroblastic cells (mitosis and karyorrhexis/5,000 cells [MKI]), the incidence of S-100 protein-positive cells in the supportive stroma, and the age of the patients at diagnosis were analyzed both individually and in combination. Based on the evaluation of these factors, two prognostic subgroups were identified for these tumors. Tumors for which the prognosis was good (all nine patients alive) occurred in younger patients (younger than 1.5 years), showed low (less than 100) or intermediate (100 to 200) MKI, and had positive to intensely positive staining for S-100 protein. Cases in which the prognosis was poor (7 per cent survival) had single or multiple factors of high (greater than 200) MKI and/or absent or weak staining for S-100 protein and/or older age (older than 1.5 years) at diagnosis. These results were compared with other clinical information.