In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival.

BACKGROUND: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. METHODS: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX). For each cell line, IC(50) levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC(50) correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. RESULTS: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway ('Transcription/CREB pathway') was associated with OVCA overall survival. CONCLUSION: The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.

NTRK-1 fusion in endocervical fibroblastic malignant peripheral nerve sheath tumor marking eligibility for larotrectinib therapy: A case report.

•<1% of cervical cancers are sarcomas.•Data on neurofibrosarcoma management is scarce.•Larotrectinib is approved for NTRK1 gene fusion tumors without acquired resistance.•Targeted therapy of tumor genes may expand treatment for a rare cervical sarcoma.

Simulation of cell rolling and adhesion on surfaces in shear flow: general results and analysis of selectin-mediated neutrophil adhesion.

The receptor-mediated adhesion of cells to ligand-coated surfaces in viscous shear flow is an important step in many physiological processes, such as the neutrophil-mediated inflammatory response, lymphocyte homing, and tumor cell metastasis. This paper describes a calculational method which simulates the interaction of a single cell with a ligand-coated surface under flow. The cell is idealized as a microvilli-coated hard sphere covered with adhesive springs. The distribution of microvilli on the cell surface, the distribution of receptors on microvilli tips, and the forward and reverse reaction between receptor and ligand are all simulated using random number sampling of appropriate probability functions. The velocity of the cell at each time step in the simulation results from a balance of hydrodynamic, colloidal and bonding forces; the bonding force is derived by summing the individual contributions of each receptor-ligand tether. The model can simulate the effect of many parameters on adhesion, such as the number of receptors on microvilli tips, the density of ligand, the rates of reaction between receptor and ligand, the stiffness of the resulting receptor-ligand springs, the response of springs to strain, and the magnitude of the bulk hydrodynamic stresses. The model can successfully recreate the entire range of expected and observed adhesive phenomena, from completely unencumbered motion, to rolling, to transient attachment, to firm adhesion. Also, the method can generate meaningful statistical measures of adhesion, including the mean and variance in velocity, rate constants for cell attachment and detachment, and the frequency of adhesion. We find a critical modulating parameter of adhesion is the fractional spring slippage, which relates the strain of a bond to its rate of breakage; the higher the slippage, the faster the breakage for the same strain. Our analysis of neutrophil adhesive behavior on selectin-coated (CD62-coated) surfaces in viscous shear flow reported by Lawrence and Springer (Lawrence, M.B., and T.A. Springer 1991. Cell. 65:859-874) shows the fractional spring slippage of the CD62-LECAM-1 bond is likely below 0.01. We conclude the unique ability of this selectin bond to cause neutrophil rolling under flow is a result of its unique response to strain. Furthermore, our model can successfully recreate data on neutrophil rolling as function of CD62 surface density.

The inflatable penile prosthesis, reoperation and patient satisfaction: a comparison of statistics obtained from patient record review with statistics obtained from intensive followup search.

Of 179 patients who received the inflatable penile prosthesis 43 per cent have required reoperation, 60 per cent of which were performed for mechanical failure. An attempt to evaluate the adequacy of chart review in assessing current function and patient satisfaction was made by comparing reports obtained by chart review to those obtained by direct patient interview. Results showed that if chart review alone was used malfunction would have been underestimated by 13 per cent and patient satisfaction overestimated by 21 per cent. The importance of direct followup in evaluating patients with the inflatable penile prosthesis is demonstrated.

Statistics of cell adhesion under hydrodynamic flow: simulation and experiment.

Adhesion under hydrodynamic flow is a step in many complicated physiological processes such as the neutrophil-mediated inflammatory response and cancer cell metastasis. We use a combination of computer simulation and experiment to explore how a population of cells interacts with a ligand-coated substrate under shear flow. To simulate the binding of a single cell to a surface, we use a microvilli-hard sphere model in which receptor-ligand bonds are treated as springs, and the net motion of the cell is determined from a force balance involving hydrodynamic, bonding, and colloidal forces. We show that the adhesive phenotype of a cell depends strongly on the fractional spring slippage of receptor-ligand bonds, which relates the extension of a bond to its rate of breakage; a lower spring slippage indicates bonds can withstand a great deal of extension without a significant increase in the breakage rate, and hence leads to more strongly adherent cells. We construct the behavior of a population of cells by simulating many cells using this algorithm. We show that a homogeneous population of cells with identical numbers of receptors, modeled with parameters suitable to recreate neutrophil rolling, will display a distribution of translational velocities. In addition, we calculate the average velocity for a heterogeneous population of cells which has a Gaussian distribution in receptor number. As the standard deviation of this distribution increases, the average observed velocity for the population increases. Although the homogeneous and heterogeneous populations have the same average number of receptors (10(5)) per cell, there is a significant difference in their average velocity when the standard deviation of receptor number in the heterogeneous population is as little as 25% of the average receptor number. We also present experimental evidence that not all cells exhibit the slow rolling characteristic of neutrophil-endothelial interaction, but rather appear to exist in a "binary" state in which cells are either adherent or noninteracting. We have developed an experimental model system for studying adhesion under hydrodynamic flow, using the rat basophilic leukemia (RBL) derivatized polyacrylamide gels in a flow chamber. Cells are injected into a portion of the flow chamber in which the substrate is not coated with antigen, and allowed to flow over the antigen-coated portion of the gel. We have measured the spatial distribution of cell binding for a population of cells at different flow rates, and have shown that cell binding decreases as shear rate increases.(ABSTRACT TRUNCATED AT 400 WORDS)

Respiratory failure from metastatic choriocarcinoma: a survivor of mechanical ventilation.

A patient with respiratory failure from metastatic choriocarcinoma was treated with mechanical ventilation while receiving chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine. The patient recovered from respiratory failure with the assistance of standard mechanical ventilation using low tidal volumes. The patient has sustained clinical remission with normal respiratory function. Mechanical ventilation with low tidal volumes and a pressure-targeted approach should be considered in the patient who develops early respiratory failure from metastatic choriocarcinoma.

Endometrial carcinoma associated with pregnancy: A report of three cases and review of the literature.

Endometrial carcinoma associated with pregnancy is uncommon. In case 1, a 40-year-old gravida 2, para 2, was diagnosed with focal well-differentiated papillary adenocarcinoma 4 months postpartum. In case 2, a 35-year-old gravida 1, para 0, was diagnosed with a well-differentiated papillary adenocarcinoma of the endometrium after a D&C for an incomplete abortion at 7 weeks gestation. In case 3, a 32-year-old gravida 2, para 1, was diagnosed with a moderately differentiated adenocarcinoma with squamous metaplasia 4 months postpartum. All are without evidence of disease more than 2 years after therapy. A literature review shows 24 previous cases of pregnancy associated with endometrial cancer. These cases demonstrate the importance of endometrial sampling for abnormal postpartum bleeding despite the protective effects of pregnancy.