Intracerebral cystic rhabdoid meningioma

A 36-year-old woman presented to our hospital with a short history of intermittent headaches. An MRI of the brain revealed a left temporal intracerebral cystic lesion with rim enhancement. Histopathology showed a malignant tumour with features of rhabdoid differentiation. Immunohistochemistry revealed that vimentin, epithelial membrane antigen and S-100 were positive, and that glial fibrillary acidic protein and the chromosome deletion 1p/19q were negative. The patient was diagnosed as having an intracerebral cystic rhabdoid meningioma. She was treated with surgery and post-operative radiotherapy. Cystic intracerebral rhabdoid meningiomas are rare. We discuss the clinical picture of this patient with reference to the published literature on this uncommon diagnosis.     

Electron arc therapy for bilateral chest wall irradiation: treatment planning and dosimetric study

Aims

The treatment of patients with synchronous bilateral breast cancer is a challenge. We present a report of dosimetric data of patients with bilateral chest walls as the target treated with electron arc therapy.

Materials and methods

Ten consecutive patients who had undergone electron arc therapy to the bilateral chest wall for breast cancer were analysed. After positioning and immobilisation, patients underwent computed tomography scans from the neck to the upper abdomen. Electron arc plans were generated using the PLATO RTS (V1.8.2 Nucletron) treatment planning system. Electron energy was chosen depending upon the depth and thickness of the planning target volume (PTV). For all patients, the arc angle ranged between 80 and 280° (start angle 80°, stop angle 280°). The homogeneity index, coverage index and doses to organs at risk were evaluated. The patient-specific output factor and thermoluminescence dosimetry (TLD) measurements were carried out for all patients. The total planned dose to the PTV was 50 Gy/25 fractions/5 weeks.

Results

The mean PTV (± standard deviation) was 568.9 (±116) cm³. The mean PTV coverage was 89 (±5.8)% of the prescribed dose. For the right lung, the mean values of D₁ and D₁₀ were 46 (±7.6) and 30 (±9) Gy, respectively. For the left lung, the mean values of D₁ and D₁₀ were 45 (±7) and 27 (±8) Gy, respectively. For the heart, the mean values of D₁, D₅ and D₁₀ were 21 (±15), 13.5 (±12) and 9 (±9) Gy, respectively. The mean values of TLD at various pre-specified locations on the chest wall surface were 1.84, 1.82, 1.82, 1.89 and 1.78 Gy, respectively

Conclusion

The electron arc technique for treating the bilateral chest wall is a feasible and pragmatic technique. This technique has the twin advantages of adequate coverage of the target volume and sparing of adjacent normal structures. However, compared with other techniques, it needs a firm quality assurance protocol for dosimetry and treatment delivery.     

Unusual objects in the root canal of deciduous teeth: a report of two cases

Accidental foreign body ingestion or aspiration is a common problem in children. Children often have a habit of inserting objects into their mouth. Some of these objects can be accidentally ingested or even aspirated which can be frightening and a stressful experience. But the presence of foreign objects in the teeth are rare. The foreign objects in the teeth may act as a potential source of infection and pain. In most of the cases, children avoid informing their parents due to fear of punishment. This paper presents two cases of foreign objects embedded in the deciduous teeth. In both the cases, parents were not aware of foreign body ingestion by their children.     

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor,induces pleiotropic anti‐myeloma activity in vitro and in vivo

This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine‐induced osteoclast differentiation more potently (9‐ to 10‐fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G₀‐G₁ cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti‐MM therapies. Significant tumour growth reduction in AS703026‐ vs. vehicle‐treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC‐induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti‐MM agents, to improve patient outcome.     

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-β family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox–5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.     

Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis

Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells, even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 down-regulates the expression/secretion of osteoclast (OC)-activating factors from MM cells and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF-kappaB (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM.     

Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma

Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.     

Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

Introduction

Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.

Methods

We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.

Results

Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.

Conclusion

Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.     

Feasibility of using MRI alone for 3D radiation treatment planning in brain tumors

OBJECTIVE: The aim of this study was to establish whether radiation treatment planning using MRI alone could replace CT-based planning for brain tumors while retaining the dosimetric accuracy. This would help to provide a single imaging modality for both target delineation as well as treatment planning, thus saving time and resources. METHODS: Twenty-five patients with brain tumors were scanned on a spiral CT scanner and 1.5 T MRI scanner. Three treatment plans were generated for all patients. The first plan was generated using the CT scan images with inhomogeneity correction (CT + IC); the second plan used the CT scan without inhomogeneity correction (CT-IC) and the third plan was generated using the MRI scan (MRI alone). RESULTS: The maximum distortion in the MRI phantom study was less than 1 mm. There were no statistically significant differences in any of the target coverage parameters analysed in this study. Similarly, the maximum antero-posterior and lateral dimensions for the CT-based and MRI-based planning did not show any statistical difference. CONCLUSION: MRI-based treatment planning for brain lesions is feasible and gives equivalent dosimetric results compared to CT-based treatment planning.     

Radiotherapy-induced depigmentation in a patient with breast cancer

Vitiligo is a common dermatological disorder. A middle-aged woman with preexisting vitiligo was diagnosed with breast carcinoma. After surgery and chemotherapy she received regional radiotherapy. Six months after the completion of radiotherapy she developed depigmentation in the irradiated area. This article discusses the etiology for this phenomenon and the literature in this regard.