Reverse Mismatch Research Articles

172 P - Inhibition of BCL-2 by antisense oligonucleotides reduces tumor size and reduces chemotesistance of human melanoma in SCID mice

Malignant melanoma, a prime example for poor response to various treatment modalities including chemotherapy, expresses bcl-2 in up to 90% of all cases. The anti-apoptosis gene bcl-2 belongs to a new category of oncogenes capable of regulating programed cell death. Induction of programed cell death has been proposed recently as the mechanism of action for a variety of chemotherapeutic agents. In the present study we could show a sequence specific downregulation of bcl-2 protein by phosphorothioate antisense oligonucleotides in human melanoma under in vitro conditions. In addition, we established a SCID-hu xenotransplantation melanoma model and evaluated the role of bcl-2 in the biology and chemoresistance of human melanoma in vivo by using the same antisense approach. We could demonstrate that antisense induced downregulation ofthe bcl-2 gene product of human melanoma grown in SCID mice results in a statistically significant decrease in tumor weight. Bcl-2 antisense treatment also reduced the chernoresislance of human melanoma rendering animals without detectable tumors after a combined bel-2 antisense-dacarbazine treatment. Reverse controls and mismatch phosphorothioate oligonucleotides had no such effects. These results strongly suggest an antisense mode of action, but this has yet to be confirmed at the RNA level. Our findings stress the notion that downregulation of bcl-2 in human melanoma may be a novel approach to overcome chemoresistance in this type of malignancy.

Regional alterations in lung ventilation in end-stage primary pulmonary hypertension: correlation between CT and scintigraphy.

The purpose of this study was to correlate scintigraphic findings of regional alterations in lung ventilation and perfusion with regional variations in CT attenuation in patients with primary pulmonary hypertension. Chest CT scans and ventilation-perfusion scans obtained within 24 hr of each other in 18 patients with primary pulmonary hypertension referred for lung transplantation were reviewed. The lungs were divided into eight regions (left/right, superior/inferior relative to the carina, and anterior/posterior relative to the trachea). CT scans were evaluated and areas of parenchymal inhomogeneities were tabulated for the eight regions. Areas of reverse mismatch (perfusion without ventilation) were established by blinded analysis of planar scintigraphic studies in six projections using 99mTc-labeled DTPA-aerosol and macroaggregated albumin for the eight regions and then were correlated with the CT findings. Abnormal findings on ventilation scans and reverse ventilation-perfusion mismatches indicating an inadequate hypoxic vasoconstriction reflex were found in 91 regions in all 18 patients. Nonuniform parenchymal CT density was found in 12 patients. There was a significant correlation (p = .009) of scintigraphic reverse mismatches with abnormal CT density in 38 regions in 11 patients. In one patient, there was no scintigraphic correlation with abnormal CT attenuation. The specificity of abnormal CT density for scintigraphic reverse mismatches was 81%, with a sensitivity of 42%. Scintigraphic reverse mismatches indicate a high prevalence of significant pulmonary arterial shunting in patients with ventilatory defects. Increased relative CT attenuation in areas of impaired ventilation as shown on the ventilation scans is amplified in primary pulmonary hypertension by an inadequate hypoxic vasoconstriction reflex. This finding does not signify underlying infiltrative lung disease and correlates with regions with reverse mismatches.

Scintigraphic Appearances in Patients With Pulmonary Infection and Lung Scintigrams of Intermediate or Low Probability for Pulmonary Embolism

Out of 294 patients with lung scintigrams of low or intermediate probability for pulmonary embolism, the appearances in 54 patients with a final diagnosis of pulmonary infection were reviewed. The most common finding was a matched defect in ventilation and perfusion occurring in 40 patients (76%). Regional reverse mismatch occurred in 13 patients (24%) and both appearances were found in one patient (2%). Reverse mismatch was also present in a further seven patients, four of whom had bronchial obstruction. Although occurring less frequently than matched defects, 81% of regional reverse mismatched defects were because of chest infection. The presence of regional reverse mismatch in patients investigated for pulmonary embolism suggests the alternative diagnosis of chest infection.

Large Reverse Mismatch Associated With Pulmonary Embolism

Because alveolar hypoxia causes reflex vasoconstriction, areas of absent ventilation on lung scans usually are accompanied by matching perfusion defects. Perfusion of nonventilated lung, or reverse mismatch, has been described in a variety of conditions, including bronchial obstruction, atelectasis, and pneumonia (1-3), but not in pulmonary embolism. In this patient, a reverse mismatch involving almost the entire left lung was associated with extensive emboli to the opposite lung. It is likely that the increased vascular resistance produced by the emboli forced blood flow into the left lung, overcoming hypoxic vasoconstriction

Generation of Parametric Images during Routine Tc-99m PYP lnhalationlTc-99m MAA Perfusion Lung Scintigraphy

A simple technique is described for generating ventilation/perfusion ratio and perfusion/ventilation ratio images from the posterior Tc-99m PYP aerosol inhalation and Tc-99m MAA perfusion images obtained during routine lung scintigraphy. These images highlight areas of ventilation/perfusion incongruence--mismatch or reverse mismatch--that may sometimes be difficult to detect on conventional images.

PEEP and “Reverse Mismatch”: A Case Where Less PEEP is Best

A V/Q lung scan was obtained in a patient with LLL collapse who was receiving IPPV and PEEP. This revealed absent ventilation and hyperperfusion to the collapsed lobe. After a reduction in PEEP from 12 to 5 cm H2O, a repeat V/Q scan showed a more even distribution of pulmonary perfusion. Arterial hypoxemia improved.

Reverse Radioaerosol/Radioperfusion Distribution in Pulmonary Endobronchial Obstruction

A characteristic image pattern of diminished radioaerosol penetration and reduced radioparticle perfusion has been observed in endobronchial obstruction. This reverse mismatch has a variety of etiologies, with the most common being mucus plugging. The regional hypoxia created by the obstruction causes the blood to shunt from the affected lung. Eleven patients from a group of 178 patients referred with a working diagnosis of pulmonary embolism showed the reversed mismatch. All presented with sudden dyspenea, chest pain and hypoxia. Bronchoscopy was recommended from the image results and nine patients demonstrated mucus plugs that were subsequently aspirated, one patient had a partially obstructing endobronchial carcinoma and one patient had a traumatic fractured bronchus that became occluded with healing granulation tissue. All improved following bronchoscopy. The incompleteness of the airway obstruction accounted for the variations of the perfusion images. Because of the radioaerosol's ability to sharply image the pulmonary airway distribution in contrast to the poor resolution of the radiogases such as xenon-133, it is recommended that radioaerosol lung imaging be substituted for radiogas ventilation imaging since it can accurately detect endobronchial obstruction as well as pulmonary embolism.

The incidence and etiology of the ventilation/perfusion reverse mismatch defect.

Kr-81m ventilation and Tc-99m perfusion images of 392 patients were examined retrospectively for the incidence and etiology of the reverse mismatch defect, which is characterized by a region of lung where the perfusion defect exceeds the ventilation defect. Forty-six patients (11.7%) showed such defects. The most frequent causes were pneumonia (15%), atelactasis (15%), pleural effusions (15%), chronic obstructive airway disease (24%), and bronchial obstruction (31%). The significance of the reverse mismatch defect is discussed.