Mary Maluccio

Cyclosporine induces cancer progression by a cell-autonomous mechanism

Malignancy is a common and dreaded complication following organ transplantation,,,. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipients immune-surveillance system,,,,. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation,, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-β (TGF-β). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID–beige mice; anti-TGF-β monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the hosts immune cells, and that cyclosporine-induced TGF-β production is involved in this.

Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy.

Background. Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient’s immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine. Methods. A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kip1, cyclin D1) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum. Results. Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kip1, reduced cyclinD1, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells. Conclusions. Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

The Use of Computed Tomography for the Diagnosis of Acute Appendicitis in Children Does Not Influence the Overall Rate of Negative Appendectomy or Perforation

BACKGROUNDnComputed tomography (CT) has been used more frequently to diagnose acute appendicitis in children. The purpose of this study was to determine whether the use of CT has any influence on negative appendectomy or perforation rates.nnnMETHODSnReview of a prospective database of children having appendectomy for suspected acute appendicitis. Negative appendectomy and perforation rates were determined by correlation with final pathology reports.nnnRESULTSnEighty-five consecutive patients underwent appendectomy for the suspicion of acute appendicitis. The overall negative appendectomy rate was 17.6%, being 19.4% in females and 16.6% in males (p = 0.75). The overall accuracy, sensitivity and positive predictive value of CT were 75%, 91%, and 81%, respectively. Patients that had CT did not have a significantly lower rate of negative appendectomy (17.9% vs. 19.3%, p > 0.99) or perforation (26% vs. 17%; p = 0.53).nnnCONCLUSIONSnThe use of CT for the diagnosis of appendicitis in children does not change the negative appendectomy rate. Results of studies performed in adults may not be extrapolated to the evaluation of children with suspected acute appendicitis.

A Prospective Evaluation of the Use of Emergency Department Computed Tomography for Suspected Acute Appendicitis

BACKGROUNDnComputed tomography (CT) is used increasingly to evaluate suspected cases of acute appendicitis (AA) in the emergency department (ED). This prospective study was performed to test the hypothesis that the evaluation of AA by CT in the ED remains suboptimal and that erroneous interpretation diminishes its utility.nnnMETHODSnConsecutive patients 18 years of age or older were enrolled prospectively if AA was among the first three differential diagnoses listed in the record of patients undergoing evaluation of abdominal pain in the ED. Imaging of the abdomen and pelvis was obtained at the discretion of the ED staff or consultant surgeon. Initial CT interpretation was by a radiology resident or fellow along with the surgical staff, but final review by an attending radiologist occurred later. Age, gender, presenting symptoms, white blood cell (WBC) count, final CT results, and final pathology (for patients undergoing operation) were recorded. X +/- SEM, p < 0.05 by chi(2), ANOVA, or MANOVA was used for statistical analysis as appropriate.nnnRESULTSnA CT scan was performed in 104 patients (83% of those meeting entry criteria), 35 of whom were male (mean age, 37 +/- 2 years) and 69 of whom were female (mean age, 39 +/- 3 years). Thirty-five patients had pathologically proved appendicitis, 28 of whom were diagnosed prospectively by CT. There were seven false-negative scans. Sensitivity, specificity, and positive predictive value for the initial CT reading were 80%, 91%, and 82%, respectively. Gender (p < 0.03), WBC count (p < 0.0002), and a positive initial CT reading (p < 0.0001) correlated with operative management. However, although final CT interpretation did correlate with pathologic confirmation of AA (p < 0.0001), initial CT interpretation did not correlate with the presence of AA (p = 0.52).nnnCONCLUSIONnThe ability of CT to predict AA is dependent on the interpretative skill of the individual interpreting the images. Widespread use of CT in the evaluation of patients for AA should be implemented with caution until institution-specific protocols are validated.

Dendritic cells armed with anti-CD3 mAbs reduce pulmonary metastases, prolong survival, and engender antitumor effector cells demonstrable by adoptive transfer.

AbstractBackground: Dendritic cells (DCs) pulsed with tumor cells or peptides are effective antitumor agents in a number of tumor models. In light of our earlier demonstration that T-cell signaling via the CD3 proteins induces cytolytic activity and constrains tumor progression, we equipped DCs pulsed with tumor cells with anti-CD3 mAbs and tested their antitumor efficacy in a murine renal cell cancer pulmonary metastasis model.n Methods: We investigated the antitumor efficacy of DCs pulsed with whole irradiated tumor cells (DC/R) or DCs pulsed with irradiated tumor cells and armed with anti-CD3 mAbs (DC/R/anti-CD3 mAbs). Experimental end points included the number of pulmonary metastases and survival of tumor-inoculated mice.n Results: Our studies demonstrate that arming tumor-pulsed DCs with anti-CD3 mAbs results in a superior outcome compared to that from tumor-pulsed DCs alone in terms of reduction in the number of pulmonary metastases and survival times. Furthermore, adoptive transfer experiments revealed that the splenocytes from DC/R/anti-CD3 mAbs-treated mice are superior to splenocytes from DC/R-treated mice in reducing renal cancer pulmonary metastases in severe combined immunodeficient (SCID) beige mice.n Conclusion: Our data suggest that the therapeutic efficacy of DCs pulsed with tumor cells can be augmented by arming them with anti-CD3 mAbs. DC-based treatment regimens that currently are being pursued in clinical trials might be improved by equipping such cells with anti-CD3 mAbs.