Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo.

PURPOSE: In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo. MATERIALS AND METHODS: The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice. RESULTS: The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF. CONCLUSION: Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.     

Epidermal growth factor receptor tyrosine kinase inhibitor does not improve paclitaxel effect in an orthotopic mouse model of lung cancer.

PURPOSE: The purpose is to evaluate whether inhibition of epidermal growth factor receptor (EGFR) activation by PKI166, an EGFR-tyrosine kinase inhibitor, affects growth of human lung cancer implanted orthotopically into the lungs of nude mice. EXPERIMENTAL DESIGN: Lungs of mice were injected with NCI-H358 human bronchioloalveolar cancer cells. In three experiments, groups of mice (n = 10 per group) were randomized 7 days after tumor implantation to receive one of the following treatments: i.p. paclitaxel 100 or 200 microg (4 or 8 mg/kg) once per week, oral PKI166 100 or 200 mg/kg three times per week, paclitaxel plus PKI166, or i.p. saline and oral PKI166-vehicle (control) for 5 weeks. Mice were killed 6.5 to 8 weeks after tumor implantation. The experiments were repeated with PC14PE6 human lung adenocarcinoma cells to assess effect on survival. RESULTS: Immunohistochemical analyses revealed the expression and phosphorylation of EGFR in the growing tumors. Treatment with PKI166 alone or in combination with paclitaxel diminished activation of EGFR on tumor cells, yet maximal therapeutic effect was observed in mice treated with paclitaxel alone. Activated mitogen-activated protein kinase and basic fibroblast growth factor expression were similar in all treatment groups. Survival in mice treated with the combination of paclitaxel and PKI166 was shorter than in those treated with paclitaxel alone. CONCLUSIONS: Our results suggest that concurrent administration of EGFR-tyrosine kinase inhibitor and chemotherapy is equivalent and may indeed be inferior to chemotherapy alone, even if EGFR is functional and its phosphorylation effectively inhibited. Our data show that the interaction of EGFR-TKIs and chemotherapy is complex and suggest that other growth factors may activate the downstream signaling events.     

The effect of intensive care on in-hospital survival

Intensive Care Units (ICU) are one of the most powerful and expensive technologies within inpatient care. However, its effect on survival is still an issue under discussion. The objective of this paper is to assess the effect of General ICU on in-hospital survival. We assessed the effect of ICU on survival using Linear and Probit regressions. Since admission to IC is not random and depends on unobserved (to the researcher) heterogeneity, we reassessed the IC effect by Instrumental Variables (IV) and Bivariate Probit techniques, using crowding in the IC unit as an instrument. The results show that a simple Probit of the IC effect on survival is 7–10 percentage-points (pts). The IV estimate of the IC effect on survival is 21–34 pts, and the Bivariate Probit estimate is 17–21 pts. We conclude that although admitted patients are at lower risk of death, as determined by their observable (to the researcher) characteristics, controlling for observable differences, those with a higher unobserved risk of mortality are more likely to be admitted. The implications for an optimal admission policy are discussed.     

Feedback and feedforward adaptation to visuomotor delay during reaching and slicing movements

It has been suggested that the brain and in particular the cerebellum and motor cortex adapt to represent the environment during reaching movements under various visuomotor perturbations. It is well known that significant delay is present in neural conductance and processing; however, the possible representation of delay and adaptation to delayed visual feedback has been largely overlooked. Here we investigated the control of reaching movements in human subjects during an imposed visuomotor delay in a virtual reality environment. In the first experiment, when visual feedback was unexpectedly delayed, the hand movement overshot the end‐point target, indicating a vision‐based feedback control. Over the ensuing trials, movements gradually adapted and became accurate. When the delay was removed unexpectedly, movements systematically undershot the target, demonstrating that adaptation occurred within the vision‐based feedback control mechanism. In a second experiment designed to broaden our understanding of the underlying mechanisms, we revealed similar after‐effects for rhythmic reversal (out‐and‐back) movements. We present a computational model accounting for these results based on two adapted forward models, each tuned for a specific modality delay (proprioception or vision), and a third feedforward controller. The computational model, along with the experimental results, refutes delay representation in a pure forward vision‐based predictor and suggests that adaptation occurred in the forward vision‐based predictor, and concurrently in the state‐based feedforward controller. Understanding how the brain compensates for conductance and processing delays is essential for understanding certain impairments concerning these neural delays as well as for the development of brain–machine interfaces.     

Long-term efficacy and safety of interferon α-2a therapy in severe refractory ophthalmic Behcet’s disease

Ophthalmic involvement is the most debilitating complication of Behcet’s disease (BD). The aim of the current study is to report on the efficacy and safety of a long-term use of interferon alpha-2a (IFNα-2a) in the treatment of refractory ophthalmic BD in the Azari population of Iran. We retrospectively analyzed the clinical data of 12 patients with ophthalmic BD who were under IFNα-2a therapy. All these patients had previously been treated unsuccessfully with corticosteroid and at least one conventional immunosuppressive drug. IFNα-2a was administered at a daily dose of 6 million IU (MIU). After controlling the symptoms, a dose of 6 MIU three times per week was applied for 8–12 weeks, and then, a dose of 3 MIU was administered three times per week as a subcutaneous injection. Visual acuity and total inflammatory activity index (TIAI) were used in order to assess the response to the treatment. Response to the treatment and complete eye remission were obtained in 10 (83.3 %) and 7 (58.3 %) patients, irrespectively. Improvement or stabilization of visual acuity was observed in 18 (81.8 %) out of 22 eyes. After a mean period of 29.6 months, the use of IFNa-2a was discontinued in eight (66.7 %) patients. Unaltered vision for 2 years after IFNa-2a discontinuation happened in eight (100 %) patients. IFNa-2a is probably effective and safe in the treatment of refractory sight-threatening ophthalmic BD in the Azari population of Iran.     

Intrahepatic cholangiocarcinoma: current management and emerging therapies

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify ‘target-able’ molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients.

Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies.

Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies.     

Particulate vs. block bone grafts: Three-dimensional changes in graft volume after reconstruction of the atrophic maxilla,a 2-year radiographic follow-up

BackgroundExtensive alveolar bone resorption in the maxilla limits the possibility of successful placement and osseointegration of endosseous implants for future prosthetic rehabilitation. Autogenous bone from the iliac crest may be used as lateral onlays in the atrophic maxilla, both as block and particulate bone. To our knowledge, there is no three-dimensional 2-year follow-up study measuring the volumetric reduction of the augmented areas comparing particulate and block bone grafts.PurposeThe aim of this study was to conduct a radiographic 2-year follow-up study, using computed tomographic (CT) images in order to evaluate and compare the extent of bone graft resorption in the frontal maxillae augmented by particulate (test) and block bone (control).Material and methodsEleven patients treated with iliac bone grafts and oral implants in the maxilla were followed with CT examinations directly post grafting and after 2 years.ResultThe volumetric changes after 6 months were extensive. Additionally, the changes in particulate bone tended to be larger after 2 years compared to block bone, using this protocol. However, the difference was not statistically significant.ConclusionThe present follow-up study showed that there is radiographically complete integration and embedding of implants installed in grafted bone despite extensive initial graft resorption. There was no significant difference in the amount of volumetric reduction between particulate bone and block bone grafts.