Chemotherapy-Induced Neuronal Maturation in Sinonasal Teratocarcinosarcoma—a Unique Observation

Sinonasal teratocarcinosarcoma (SNTCS) is a rare and highly malignant tumour with combined features of a teratoma and carcinosarcoma. We report the first case of a SNTCS in 23 year old male treated with neo-adjuvant chemotherapy followed by cranio-facial resection. The resection specimen displayed cellular maturation in the neuroectodermal component. The patient presented with a short history of nasal obstruction, epistaxis and headache. On imaging, a bone destroying lesion of left paranasal sinuses and nasal cavity was identified. The diagnosis of SNTCS could be offered only on the third biopsy which showed heterogeneous admixture of primitive neuroectodermal, epithelial and mesenchymal elements. An adequate sampling with high index of suspicion is needed to catch hold this rare tumor. Tumor was excised after 4 cycles of neo-adjuvant chemotherapy. On microscopic examination, it showed similar epithelial and mesenchymal components as the pretreatment biopsies. However, the primitive neuroectodermal component displayed extensive neuronal maturation. The undifferentiated neuroectodermal cells were completely absent in the post chemotherapy specimen. This case throws light on the morphologic evidence of chemotherapy induced maturation in the neuroectodermal component within SNTCS, an event hitherto not reported in the literature in case of SNTCS

Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)

Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments

Disparate In Vivo Efficacy of FTY720 in Xenograft Models of Philadelphia Positive and Negative B-lineage Acute Lymphoblastic Leukemia

Most patients with acute lymphoblastic leukemia (ALL) respond well to standard chemotherapy-based treatments. However a significant proportion of patients, particularly adult patients, relapse with the majority dying of leukemia. FTY720 is an immunosuppressive drug that was recently approved for the treatment of multiple sclerosis and is currently under pre-clinical investigation as a therapy for a number of hematological malignancies. Using human ALL xenografts in NOD/SCIDγc−/− mice, we show for the first time that three Ph+ human ALL xenografts responded to FTY720 with an 80±12% (p = 0.048) reduction in overall disease when treatment was commenced early. In contrast, treatment of mice with FTY720 did not result in reduced leukemia compared to controls using four separate human Ph− ALL xenografts. Although FTY720 reactivated PP2A in vitro, this reactivation was not required for death of Ph− ALL cells. The plasma levels of FTY720 achieved in the mice were in the high nanomolar range. However, the response seen in the Ph+ ALL xenografts when treatment was initiated early implies that in vivo efficacy may be obtained with substantially lower drug concentrations than those required in vitro. Our data suggest that while FTY720 may have potential as a treatment for Ph+ ALL it will not be a useful agent for the treatment of Ph− B-ALL

Hamartomas, teratomas and teratocarcinosarcomas of the head and neck: Report of 3 new cases with clinico-pathologic correlation, cytogenetic analysis, and review of the literature

<p>Abstract</p> <p>Background</p> <p>Germ-cell tumors (GCT) are a histologically and biologically diverse group of neoplasms which primarily occur in the gonads but also develop at different extragonadal sites in the midline of the body. The head and neck region including the upper respiratory tract is a very rare location for such tumors in both children and adults, which can cause diagnostic and therapeutic difficulties.</p> <p>Methods</p> <p>We describe here two new cases of multilineage tumors including sinonasal teratocarcinosarcoma [SNTCS], and congenital oronasopharyngeal teratoma (epignathus) and compare their features with those of a new case of a rare salivary gland anlage tumor [SGAT], an entity for which the pathogenesis is unclear (i.e. hamartoma versus neoplasm). We correlate their presenting clinico-pathological features and compare histologic and cytogenetic features in an attempt to elucidate their pathogenesis and biologic potentials.</p> <p>Results and discussion</p> <p>Cytogenetic analysis revealed chromosomal abnormalities only in the case of SNTCS that showed trisomy 12 and 1p deletion. Both cytogenetic abnormalities are characteristically present in malignant germ cell tumors providing for the first time evidence that this rare tumor type indeed might represent a variant of a germ cell neoplasm. The SGAT and epignathus carried no such cytogenetic abnormalities, in keeping with their limited and benign biologic potential.</p> <p>Conclusion</p> <p>The comparison of these three cases should serve to emphasize the diversity of multilineage tumors (hamartomas and GCT) of the upper respiratory tract in regards to their biology, age of presentation and clinical outcomes. Malignant tumors of germ cell origins are more likely to affect adults with insidious symptom development, while benign tumors can nevertheless cause dramatic clinical symptoms which, under certain circumstances, can be fatal.</p

The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

In Ph-positive (Ph+) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph+ acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγnull (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G0 cells in the CD34+CD38− population compared with the CD34+CD38+ and CD34− populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34+CD38− population than in the other populations. Although slow-cycling G0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34+CD38− population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34+ cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph+ leukemia due to quiescence

Identification of Hepatic Niche Harboring Human Acute Lymphoblastic Leukemic Cells via the SDF-1/CXCR4 Axis

In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis

Quality of life and treatment satisfaction in adults with Type 1 diabetes: A comparison between continuous subcutaneous insulin infusion and multiple daily injections

Aims: The aim of this case-control study was to compare quality of life (QoL) and treatment satisfaction in adults with Type 1 diabetes (T1DM) treated with either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). Methods: Consecutive patients aged between 18 and 55 years, and attending diabetes clinics for a routine visit, completed the Diabetes-Specific Quality-of-Life Scale (DSQOLS), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the SF-36 Health Survey (SF-36). Case (CSII) and control subjects (MDI) were recruited in a 1 : 2 ratio. Results: Overall, 1341 individuals were enrolled by 62 diabetes clinics; 481 were cases and 860 control subjects. Cases had a longer diabetes duration and were more likely to have eye and renal complications. Age, school education, occupation and HbA1c were similar. Of control subjects, 90% followed glargine-based MDI regimens and 10% used NPH-based MDI regimens. On multivariate analysis, after adjusting for socioeconomic and clinical characteristics, scores in the following areas of the DSQOLS were higher in cases than control subjects: diet restrictions (β = 5.96; P &lt; 0.0001), daily hassles (β = 3.57; P = 0.01) and fears about hypoglycaemia (β = 3.88; P = 0.006). Treatment with CSII was also associated with a markedly higher DTSQ score (β = 4.13; P &lt; 0.0001) compared with MDI. Results were similar when CSII was compared separately with glargine- or NPH-based MDI regimens. Conclusions: This large, non-randomized, case-control study suggests quality of life gains deriving from greater lifestyle flexibility, less fear of hypoglycaemia, and higher treatment satisfaction, when CSII is compared with either glargine-based or NPH-based MDI regimens. © 2008 The Authors

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway