Is nonangiogenesis a novel pathway for cancer progression? A study using 3-dimensional tumour reconstructions

The nonangiogenic lung tumour is characterized by neoplastic cells co-opting the pre-existent vasculature and filling the alveoli space. 3-Dimensional reconstruction of the tumour reveals that this particular tumour progresses without neovascularization and there is no major destruction of the lung's architectural integrity

Clonal karyotype evolution involving ring chromosome 1 with myelodysplastic syndrome subtype RAEB-t progressing into acute leukemia

s Karyotypic evolution is a well-known phenomenon in patients with malignant hernatological disorders during disease progression. We describe a 50-year-old male patient who had originally presented with pancytopenia in October 1992. The diagnosis of a myelodysplastic syndrome (MDS) FAB subtype RAEB-t was established in April 1993 by histological bone marrow (BM) examination, and therapy with low-dose cytosine arabinoside was initiated. In a phase of partial hernatological remission, cytogenetic assessment in August 1993 revealed a ring chromosome 1 in 13 of 21 metaphases beside BM cells with normal karyotypes {[}46,XY,r(1)(p35q31)/46,XY]. One month later, the patient progressed to an acute myeloid leukemia (AML), subtype M4 with 40% BM blasts and cytogenetic examination showed clonal evolution by the appearance of additional numerical aberrations in addition to the ring chromosome{[}46,XY,r(1),+8,-21/45,XY,r(1),+8,-21,-22/46, XY]. Intensive chemotherapy and radiotherapy was applied to induce remission in preparation for allogeneic bone marrow transplantation (BMT) from the patient's HLA-compatible son. After BMT, complete remission was clinically, hematologically and cytogenetically (normal male karyotype) confirmed. A complete hematopoietic chimerism was demonstrated. A relapse in January 1997 was successfully treated using donor lymphocyte infusion and donor peripheral blood stem cells (PB-SC) in combination with GM-CSF as immunostimulating agent in April 1997, and the patient's clinical condition remained stable as of January 2005. This is an interesting case of a patient with AML secondary to MDS. With the ring chromosome 1 we also describe a rare cytogenetic abnormality that predicted the poor prognosis of the patient, but the patient could be cured by adoptive immunotherapy and the application of donor's PB-SC. This case confirms the value of cytogenetic analysis in characterizing the malignant clone in hernatological neoplasias, the importance of controlling the quality of an induced remission and of the detection of a progress of the disease. Copyright (c) 2006 S. Karger AG, Basel

Respiratory chain complex III deficiency due to mutated BCS1L : a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

Background: Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. Results: A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient's platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. Conclusions: We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.Peer reviewe

Female genital mutilation of a karyotypic male presenting as a female with delayed puberty

BACKGROUND: Female genital mutilation (FGM) is commonly practiced mainly in a belt reaching from East to West Africa north of the equator. The practice is known across socio-economic classes and among different ethnic, religious, and cultural groups. Few studies have been appropriately designed to measure the health effects of FGM. However, the outcome of FGM on intersex individuals has never been discussed before. CASE PRESENTATION: The patient first presented as a female with delayed puberty. Hormonal analysis revealed a normal serum prolactin level of 215 Mu/L, a low FSH of 0.5 Mu/L, and a low LH of 1.1 Mu/L. Type IV FGM (Pharaonic circumcision) had been performed during childhood. Chromosomal analysis showed a 46, XY karyotype and ultrasonography verified a soft tissue structure in the position of the prostate. CONCLUSION: FGM pose a threat to the diagnosis and management of children with abnormal genital development in the Sudan and similar societies

Panel 7: Otitis media: treatment and complications

Objective. We aimed to summarize key articles published between 2011 and 2015 on the treatment of (recurrent) acute otitis media, otitis media with effusion, tympanostomy tube otorrhea, chronic suppurative otitis media and complications of otitis media, and their implications for clinical practice.Data Sources. PubMed, Ovid Medline, the Cochrane Library, and Clinical Evidence (BMJ Publishing).Review Methods. All types of articles related to otitis media treatment and complications between June 2011 and March 2015 were identified. A total of 1122 potential related articles were reviewed by the panel members; 118 relevant articles were ultimately included in this summary.Conclusions. Recent literature and guidelines emphasize accurate diagnosis of acute otitis media and optimal management of ear pain. Watchful waiting is optional in mild to moderate acute otitis media; antibiotics do shorten symptoms and duration of middle ear effusion. The additive benefit of adenoidectomy to tympanostomy tubes in recurrent acute otitis media and otitis media with effusion is controversial and age dependent. Topical antibiotic is the treatment of choice in acute tube otorrhea. Symptomatic hearing loss due to persistent otitis media with effusion is best treated with tympanostomy tubes. Novel molecular and biomaterial treatments as adjuvants to surgical closure of eardrum perforations seem promising. There is insufficient evidence to support the use of complementary and alternative treatments.Implications for Practice. Emphasis on accurate diagnosis of otitis media, in its various forms, is important to reduce over-diagnosis, overtreatment, and antibiotic resistance. Children at risk for otitis media and its complications deserve special attention.</p

Binomial Mitotic Segregation of MYCN-Carrying Double Minutes in Neuroblastoma Illustrates the Role of Randomness in Oncogene Amplification

BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids, indicating that they do not bind to specific positional elements in human chromosomes. Scoring DM copy-numbers in ana/telophase cells revealed that DM segregation could be closely approximated by a binomial random distribution. Colony-forming assay demonstrated a strong growth-advantage for NB cells with high DM (MYCN) copy-numbers, compared to NB cells with lower copy-numbers. In fact, the overall distribution of DMs in growing NB cell populations could be readily reproduced by a mathematical model assuming binomial segregation at cell division combined with a proliferative advantage for cells with high DM copy-numbers. CONCLUSION: Binomial segregation at cell division explains the high degree of MYCN copy-number variability in NB. Our findings also provide a proof-of-principle for oncogene amplification through creation of genetic diversity by random events followed by Darwinian selection

Multipolar Spindle Pole Coalescence Is a Major Source of Kinetochore Mis-Attachment and Chromosome Mis-Segregation in Cancer Cells

Many cancer cells display a CIN (Chromosome Instability) phenotype, by which they exhibit high rates of chromosome loss or gain at each cell cycle. Over the years, a number of different mechanisms, including mitotic spindle multipolarity, cytokinesis failure, and merotelic kinetochore orientation, have been proposed as causes of CIN. However, a comprehensive theory of how CIN is perpetuated is still lacking. We used CIN colorectal cancer cells as a model system to investigate the possible cellular mechanism(s) underlying CIN. We found that CIN cells frequently assembled multipolar spindles in early mitosis. However, multipolar anaphase cells were very rare, and live-cell experiments showed that almost all CIN cells divided in a bipolar fashion. Moreover, fixed-cell analysis showed high frequencies of merotelically attached lagging chromosomes in bipolar anaphase CIN cells, and higher frequencies of merotelic attachments in multipolar vs. bipolar prometaphases. Finally, we found that multipolar CIN prometaphases typically possessed γ-tubulin at all spindle poles, and that a significant fraction of bipolar metaphase/early anaphase CIN cells possessed more than one centrosome at a single spindle pole. Taken together, our data suggest a model by which merotelic kinetochore attachments can easily be established in multipolar prometaphases. Most of these multipolar prometaphase cells would then bi-polarize before anaphase onset, and the residual merotelic attachments would produce chromosome mis-segregation due to anaphase lagging chromosomes. We propose this spindle pole coalescence mechanism as a major contributor to chromosome instability in cancer cells

A case of Cornelia de Lange syndrome from Sudan

BACKGROUND: Brachmann de Lange syndrome (BDLS) is a multiple congenital anomaly syndrome characterized by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioral problems, and malformations of the upper extremities. CASE PRESENTATION: Here we present for the first time a case of BDLS from Sudan, a 7-month-old female infant, who was referred as a case of malnutrition. The patient was from a Sudanese western tribe. Clinical investigation showed that the child was a classical case of BDLS, but with some additional clinical findings not previously reported including crowded ribs and tied tongue. CONCLUSION: Reporting BDLS cases of different ethnic backgrounds could add nuances to the phenotypic description of the syndrome and be helpful in diagnosis

Stabilization of Dicentric Translocations through Secondary Rearrangements Mediated by Multiple Mechanisms in S. cerevisiae

The gross chromosomal rearrangements (GCRs) observed in S. cerevisiae mutants with increased rates of accumulating GCRs include predicted dicentric GCRs such as translocations, chromosome fusions and isoduplications. These GCRs resemble the genome rearrangements found as mutations underlying inherited diseases as well as in the karyotypes of many cancers exhibiting ongoing genome instabilityThe structures of predicted dicentric GCRs were analyzed using multiple strategies including array-comparative genomic hybridization, pulse field gel electrophoresis, PCR amplification of predicted breakpoints and sequencing. The dicentric GCRs were found to be unstable and to have undergone secondary rearrangements to produce stable monocentric GCRs. The types of secondary rearrangements observed included: non-homologous end joining (NHEJ)-dependent intramolecular deletion of centromeres; chromosome breakage followed by NHEJ-mediated circularization or broken-end fusion to another chromosome telomere; and homologous recombination (HR)-dependent non-reciprocal translocations apparently mediated by break-induced replication. A number of these GCRs appeared to have undergone multiple bridge-fusion-breakage cycles. We also observed examples of chromosomes with extensive ongoing end decay in mec1 tlc1 mutants, suggesting that Mec1 protects chromosome ends from degradation and contributes to telomere maintenance by HR.HR between repeated sequences resulting in secondary rearrangements was the most prevalent pathway for resolution of dicentric GCRs regardless of the structure of the initial dicentric GCR, although at least three other resolution mechanisms were observed. The resolution of dicentric GCRs to stable rearranged chromosomes could in part account for the complex karyotypes seen in some cancers

NuMA Overexpression in Epithelial Ovarian Cancer

Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon