Extra-mandibular Osteoradionecrosis after the Treatment of Head and Neck Cancer.

AIMS: Osteoradionecrosis (ORN) is a serious toxicity of head and neck radiotherapy. It predominantly affects the mandible. Extra-mandibular ORN is rare. The aim of this study was to report the incidence and outcomes of extra-mandibular ORNs from a large institutional database. MATERIALS AND METHODS: In total, 2303 head and neck cancer patients were treated with radical or adjuvant radiotherapy. Of these, extra-mandibular ORN developed in 13 patients (0.5%). RESULTS: Maxillary ORNs (n = 8) were a consequence of the treatment of various primaries (oropharynx = 3, sinonasal = 2, maxilla = 2, parotid = 1). The median interval from the end of radiotherapy to the development of ORN was 7.5 months (range 3-42 months). The median radiotherapy dose in the centre of the ORN was 48.5 Gy (range 22-66.5 Gy). Four patients (50%) healed in 7, 14, 20 and 41 months. All temporal bone ORNs (n = 5) developed after treatment to the parotid gland (of a total of 115 patients who received radiotherapy for parotid gland malignancy). The median interval from the end of radiotherapy to the development of ORN was 41 months (range 20-68 months). The median total dose in the centre of the ORN was 63.5 Gy (range 60.2-65.3 Gy). ORN healed in only one patient after 32 months of treatment with repeated debridement and topical betamethasone cream. CONCLUSION: Extra-mandibular ORN is a rare late toxicity and this current study provides useful information on its incidence and outcome. The risk of temporal bone ORN should be considered in the treatment of parotid malignancies and patients should be counselled. More research is required to determine the optimal management of extra-mandibular ORN, particularly on the role of the PENTOCLO regimen.

Iatrogenic T-Cell Lymphoma with Associated Hemophagocytic Lymphohistiocyotsis in a Patient with Long-Standing Rheumatoid Arthritis.

Patients with rheumatoid arthritis are at increased risk of hematological malignancies, especially when exposed to immunosuppressive therapy. The mechanisms of lymphomagenesis remain poorly understood but factors implicated include high disease activity, exposure to antitumoral necrosis factor medications, and Epstein-Barr virus infection. Lymphoid malignancies of T-cell origin are uncommon in patients with rheumatoid arthirits. Clinical presentation with associated hemophagocytic lymphohistiocyotsis is rare and confers a poor prognosis. This case report illustrates a case of a patient with long-standing rheumatoid arthritis and an iatrogenic peripheral T-cell lymphoma with secondary hemophagocytic lymphohistiocytosis who achieved a complete response after intensive chemotherapy.

Perinucleolar compartment prevalence has an independent prognostic value for breast cancer.

The perinucleolar compartment (PNC) is a multicomponent nuclear structure enriched with RNAs transcribed by RNA pol III and RNA binding proteins. Studies in cultured cells showed an association between PNC and transformed phenotype. To evaluate the relationship between structure and malignancy in vivo, we examined PNC prevalence (the percentage of cells containing at least one PNC) in normal and cancerous paraffin-embedded breast tissues using immunohistochemistry against a PNC-associated protein. Five hundred nuclei in the most active area of each sample were scored for PNC prevalence. The results show that PNC prevalence significantly correlates with the progression of breast cancer (by the criteria of staging). PNC prevalence in primary tumors, lymph nodes, and distant metastases shows a stepwise increase from a median of 23% in primary tumors to approximately 100% in distant metastases. In addition, univariate and multivariate (controlling for tumor size and grade) analyses show that early-stage patients with invasive ductal carcinomas containing a higher PNC prevalence have a significantly poorer prognosis. These findings link PNC prevalence with the progression of breast cancer in vivo and suggest that PNC-containing cells have metastatic advantages. These findings also show the potential of PNC prevalence as a prognostic marker for breast cancer.

Serine phosphorylation of STATs.

Tyrosine phosphorylation regulates the dimerization of STATs as an essential prerequisite for the establishment of a classical JAK-STAT signaling path. However, most vertebrate STATs contain a second phosphorylation site within their C-termini. The phosphorylated residue in this case is a serine contained within a P(M)SP motif, and in the majority of situations its mutation to alanine alters transcription factor activity. This review addresses recent advances in understanding the regulation of STAT serine phosphorylation, as well as the kinases and other signal transducers implied in this process. The biochemical and biological consequences of STAT serine phosphorylation are discussed. Oncogene (2000).

GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression.

Gamma interferon activation site (GAS) elements are short stretches of DNA, originally defined as a requirement for the rapid transcriptional induction of genes in response to interferon-gamma (IFN-gamma). The protein complex binding to GAS sequences in IFN-gamma-treated cells, the gamma interferon activation factor (GAF), is a dimer of Stat1, the prototype of a family of cytokine-responsive transcription factors, the signal transducers and activators of transcription. To date, seven different Stats are known (excluding alternatively spliced or processed forms), six of which recognize the same small palindromic consensus sequence TTCN2-4 GAA that defines a GAS element. Because one or several Stats take part in nuclear signaling in response to most cytokines or growth factors, the GAS sequence has changed from being viewed as a specific site for IFN-activated GAF to becoming the general nuclear end of the Jak-Stat signaling pathways. This review focuses on the identification and definition of GAS elements, their interaction with Stat transcription factors, and their contribution to the specificity of cytokine-induced gene expression.

Detection of EBV DNA in the cord blood donor for a patient developing Epstein-Barr virus-associated lymphoproliferative disorder following mismatched unrelated umbilical cord blood transplantation.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been well described as a complication following allogeneic stem cell transplantation but has only recently been reported following umbilical cord blood (UCB) transplant. We report the case of a child transplanted with unrelated mismatched UCB for juvenile chronic myelogenous leukemia (JCML) who developed EBV-associated PTLD, which was confirmed pathologically, 139 days following stem cell infusion. There was no clinical response to reduction of immune suppression, high-dose acyclovir, or alpha interferon. The patient died 160 days after transplantation. EBV was detected by polymerase chain reaction in the cord blood unit used for transplantation. This case demonstrates that EBV-associated PTLD can occur following mismatched unrelated UCB transplant and may be related to transmission of EBV infection by donor lymphocytes.

Hand mirror variant of adult acute lymphoblastic leukemia. Evidence for a mixed leukemia.

Blast cells from a female patient with acute lymphoblastic leukemia-hand mirror variant were examined using various techniques, including light and ultrastructural morphologic examination, cytochemical analysis, surface antigen characterization, cytogenetic analysis, and gene rearrangement studies. The blast cells were found to be pre-B cells (CD19+ and Tdt+) that also expressed the myeloid antigens CD13 and CD33 and demonstrated a heavy chain immunoglobulin gene rearrangement. Cytogenetic studies revealed a t(11;19) translocation previously described in biphenotypic leukemias. A subset of acute lymphoblastic leukemia-hand mirror cells has been previously defined and includes predominately female patients with an indolent course. The authors' findings place this case, a mixed leukemia, within that subgroup. The possibility of mixed lineage should be considered in future cases of hand mirror variants of adult acute lymphoblastic leukemia. Furthermore, hand mirror morphologic features in any case of acute leukemia should alert the hematopathologist/hematologist to the possibility of mixed lineage.

Analysis of tamoxifen and its metabolites in synthetic gastric fluid digests and urine samples using high-performance liquid chromatography with electrospray mass spectrometry.

We report on the transformation of tamoxifen at 37 degrees C in synthetic gastric fluid as studied by high-performance liquid chromatography with triple quadrupole mass spectrometry. The major transformation products detected were (E)-isomer of tamoxifen, metabolite D, and several unidentified components having m/z 404. Addition of pepsin to the gastric fluid inhibited formation of all of these products. We analyzed several urine samples from breast cancer patients undergoing tamoxifen treatment. Metabolite D was identified in the urine samples and in the gastric fluid digest at a retention time of 22.0 min eluting from a reversed-phase HPLC column. Although several metabolites were found in all the urine samples of patients, some metabolites were detected in one sample but not others, suggesting tamoxifen metabolism varies in patients.

Histological characterization of the thyroglossal tract: implications for surgical management.

OBJECTIVES: In the current report, we characterized the relationship between the central hyoid bone and the thyroglossal tract and determined the prevalence of ectopic thyroid follicles in the adjacent soft tissues. STUDY DESIGN: Retrospective pathological analysis. METHODS: The resected specimens from 104 patients who underwent a modified Sistrunk procedure with wide-field dissection were retrospectively analyzed. Under light microscopy, serial sections were examined to determine whether the thyroglossal tract passed anterior to, posterior to, or within the hyoid bone. Specimens were also examined for the presence of thyroid follicles in the periductal and pericystic soft tissues. RESULTS: In 50 cases (48%), the tract position in relation to the hyoid bone could not be identified secondary to extensive arborization, marked inflammation, specimen fragmentation or a combination of these. Thyroid follicles were observed in 9 (18%) of these specimens. In the remaining 54 cases (52%) the tract was located anterior to the central arch of the hyoid bone in 39 (72%) and posterior to it in 15 (28%). Thyroid tissue was observed in 46% of specimens (P =.004), regardless of whether the tract was anterior or posterior. CONCLUSIONS: These results demonstrate that tract position often cannot be defined, but when a portion is dominant, it is likely to be anterior to the hyoid bone. Ectopic thyroid tissue can be found in almost 50% of specimens when the tract position is identifiable. With appropriate surgical management, a recurrence rate of less than 4% can be expected, despite the presence of ductule multiplicity, marked inflammation, tract position posterior to the hyoid bone, and ectopic thyroid follicles.

Heparin-induced thrombocytopenia: use of indirect immunofluorescence.

Sera from 14 patients who developed heparin-induced thrombocytopenia were tested by an indirect platelet immunofluorescent test in an attempt to characterize the serologic reactions between platelets, heparin, and the antibody. Positive results were observed in seven cases with variable patterns of reactions in the tests when performed in the presence or the absence of the offending drug. It was possible to absorb out the antibody in the presence of heparin and recover the antibody in the eluate. Neither complement nor the presence of immune complexes were found to play a role in the thrombocytopenia induced by heparin.

Gastric spiral bacteria in small felids.

Nine small cats, including one bobcat (Felis rufus), one Pallas cat (F. manul), one Canada lynx (F. lynx canadensis), two fishing cats (F. viverrina), two margays (F. wiedii), and two sand cats (F. margarita), necropsied between June 1995 and March 1997 had large numbers of gastric spiral bacteria, whereas five large cats, including one African lion (Panthera leo), two snow leopards (P. uncia), one Siberian tiger (P. tigris altaica), and one jaguar (P. onca), necropsied during the same period had none. All of the spiral organisms from the nine small cats were histologically and ultrastructurally similar. Histologically, the spiral bacteria were 5-14 microm long with five to nine coils per organism and were located both extracellularly within gastric glands and surface mucus, and intracellularly in parietal cells. Spiral bacteria in gastric mucosal scrapings from the Canada lynx, one fishing cat, and the two sand cats were gram negative and had corkscrewlike to tumbling motility when viewed with phase contrast microscopy. The bacteria were 0.5-0.7 microm wide, with a periodicity of 0.65-1.1 microm in all cats. Bipolar sheathed flagella were occasionally observed, and no periplasmic fibrils were seen. The bacteria were extracellular in parietal cell canaliculi and intracellular within parietal cells. Culture of mucosal scrapings from the Canada lynx and sand cats was unsuccessful. Based on morphology, motility, and cellular tropism, the bacteria were probably Helicobacter-like organisms. Although the two margays had moderate lymphoplasmacytic gastritis, the other cats lacked or had only mild gastric lymphoid infiltrates, suggesting that these organisms are either commensals or opportunistic pathogens.

Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins.

The seven mammalian members of the signal transducer and activator of transcription (STAT) family share a common core structure which reflects their shared mechanism of activation, dimerization, and DNA binding. By contrast, the STAT C termini containing the sequences required for transcriptional activation are much less homologous, suggesting different ways by which individual STATs activate their target genes. This paper describes several important discoveries linked to mechanistic aspects of STAT transcription factor function. These include regulated serine phosphorylation of the transactivating domain, promoter-dependent interactions of STATs with each other, or of STATs with other transcription factors, and with transcriptional co-activators. The basis, background, and implications of these molecular events will be summarized and discussed.

[Aorto-esophageal fistula as a complication of peptic esophageal ulcer (author's transl)]. / Aortoösophageale Fistel als Folge eines perforierten Ulcus pepticum oesophagi.

An unusual complication of a peptic esophageal ulcer is presented. Developing near the cardiac border, its origin from dystopic gastric mucosa is under discussion. The literature on aorto-esophageal fistulas has been discussed.

[Diagnostic accuracy of fiber endoscopy in esophageal and gastric carcinoma. Attempt at error analysis]. / Zur diagnostischen Treffsicherheit der Fiberendoskopie beim Karzinom der Speiseröhre und des Magens. Versuch einer Fehleranalyse.

A retrospective analysis was performed in 332 cases with cancer of the upper gastrointestinal tract. A limit of one month was set for delayed and missed bioptically verified endoscopic diagnosis. Malignant cycle in ulcerated lesions and the size of elevated processes were the probable causes of delayed diagnosis in 7 out of 37 cases with early cancer. In advanced gastric cancer missed diagnosis was probably caused by the indication for endoscopy made too late in an unknown number of cases or patient's refusal to undergo controls. However, failure of the endoscopist to recognize a malignant process must be considered too. The percentage of endoscopist's mistakes was below 2% in our series.

Stat1 combines signals derived from IFN-gamma and LPS receptors during macrophage activation.

Complete activation of macrophages during immune responses results from stimulation with the activating cytokine interferon-gamma (IFN-gamma) and a second stimulus, usually a microbial product. Bacterial infection of macrophages, or treatment with bacterial lipopolysaccharide (LPS), resulted in rapid Stat1 phosphorylation on Ser727 (S727) independently of concomitant tyrosine phosphorylation. IFN-gamma also caused rapid phosphorylation of S727. In both situations, S727 phosphorylation was reduced by pre-treatment of cells with the serine kinase inhibitor H7. When macrophages were treated sequentially or simultaneously with LPS and IFN-gamma, the pool of molecules phosphorylated on both Tyr701 (Y701) and S727 was strongly increased. Consistently, Stat1-dependent transcription in response to IFN-gamma was significantly enhanced if the cells were pre-treated with bacterial LPS. The relative amount of S727-phosphorylated Stat1 in the non-tyrosine phosphorylated fraction was considerably smaller than that in the tyrosine-phosphorylated fraction. No evidence was found for an effect of S727 phosphorylation on the phosphorylation of Y701 by IFN-gamma. Thus, serine and tyrosine phosphorylation of Stat1 are caused independently of each other, but the serine kinase may recognize tyrosine-phosphorylated Stat1 preferentially in the course of an IFN-gamma response. The data suggest Stat1 to be a convergence point for immunological stimuli in a macrophage proinflammatory response.

Non-methylated islands in fish genomes are GC-poor.

In the vertebrate genomes studied to date the 5' end of many genes are associated with distinctive sequences known as CpG islands. CpG islands have three properties: they are non-methylated; the dinucleotide CpG occurs at the frequency predicted by base composition; and they are GC-rich. Unexpectedly we have found that CpG islands in certain fish only have the first two properties; that is, their GC-content is not elevated compared to bulk genomic DNA. Based on this finding, we speculate that the GC-richness of CpG islands in vertebrates other than fish is a passive consequence of a higher mutation rate in regions of open chromatin under conditions where the nucleotide precursor pools are biased.

RPG1: an essential gene of saccharomyces cerevisiae encoding a 110-kDa protein required for passage through the G1 phase.

In Saccharomyces cerevisiae cells a number of genes are required for progression through, or else to pass beyond, the G1 phase. We characterized a novel gene, RPG1, which is also involved in this phase. RPG1 is an essential gene encoding a 110-kDa evolutionarily conserved protein. Elutriated or alpha-factor-synchronized cells of the rpg1-1 temperature-sensitive mutant were arrested in the first cell cycle when shifted to a non-permissive temperature. The cells remained unbudded and neither grew nor duplicated DNA. rpg1-1 cells synchronized in S phase completed mitosis and arrested as unseparated G1 cells after a shift to a non-permissive temperature. Similarly, the asynchronous rpg1-1 cells accumulated in G1 at the non-permissive temperature, but mother and daughter cells did not separate. A bulk of Calcofluor-stained material was localized in the region adjacent to the cell septum. Our data show that Rpg1p is required for passage through the G1 phase and may be involved in growth control. Data published recently indicate that Rpg1p exhibits significant sequence similarity to a subunit of the mammalian translation initiation factor 3.