Investigation of vascular changes following penile vein ligation.

In an effort to characterize the changes in penile vasculature that occur following penile vein ligation, we performed pharmaco-cavernosometry and pharmaco-cavernosography on 20 patients after penile vein ligation for comparison with preoperative studies. Three patients with return of erectile function underwent repeat study: 2 were completely normal and 1 had a mild leak from the deep dorsal vein. The remaining 17 patients had continued complaints of erectile impairment. Of these studies 4 showed no evidence of venous leakage, 11 identified a new site of leakage (7 corporo-spongiosal shunts, 2 crural veins and 2 with multiple sites of involvement) and 1 revealed persistent leak through the proximal stump of the resected deep dorsal vein, while 1 patient had an iodine allergy and underwent pharmaco-cavernosometry only. A repeat study in the latter patient showed flow volumes consistent with continued venous leakage. In summary, penile vein ligation appears to be effective at correcting venous leakage noted on cavernosography. However, new sites of leakage frequently appear postoperatively. A corporo-spongiosal shunt was the most frequent site of recurrent venous leakage. A surprisingly high percentage of patients with continued complaints of erectile dysfunction following penile vein ligation demonstrate no venous leakage on subsequent pharmaco-cavernosography.

Dipyridamole-cisplatin potentiation: enhanced in vivo cytotoxicity in xenograft models of human testicular and bladder cancers.

The antitumor efficacy and host toxicity of dipyridamole (DP), methotrexate (MTX) and cisplatin (CDDP) alone and combined were evaluated in a nude mouse supported human bladder cancer model. Single agent post treatment tumor volume growth ratio [TGR] values of DP, MTX and CDDP were 97%, 65% and 49% of control. While the MTX/DP combination produced only mild cytotoxic enhancement, CDDP/DP and CDDP/MTX/DP reduced TGR to 20% and 17%, respectively. A second multi-dose evaluation of CDDP/DP using human testicular carcinoma in this model also showed a CDDP dose-dependent response with achievable complete tumor regression. Host toxicity was not substantially increased by DP. DP would appear to be effective in vivo as a chemosensitizer of CDDP; it may enhance the therapeutic efficacy of CDDP in a variety of tumors.

Characterization of a new model of human prostatic cancer: the multicellular tumor spheroid.

Multicellular tumor spheroids (MTS) provide a closer in vitro correlate to in vivo malignancy than do conventional monolayer cultures; while simulating many parameters of in vivo growth, MTS systems provide those perquisites (i.e., experimental control, economy, expediency) associated with in vitro evaluation of preclinical therapeutic strategies. For these reasons, we exploited the proclivity of the highly metastatic human prostatic carcinoma subline I-LN-PC3-IA to spontaneously assume a spheroid morphology under routine culture conditions. I-LN spheroids demonstrate salient features described in other spheroid systems and exhibit histologic characteristics of human prostate carcinoma. Cells encompassed in the I-LN spheroid format demonstrated functional divergence from their monolayer counterparts with respect to immunoreactivity for prostatic acid phosphatase, positional dependence of prostate-restricted p40 antigen expression, and chemotherapeutic drug response. This new in vitro-in vivo transition model of human prostatic carcinoma should provide a valuable in vitro context to expediently evaluate in vivo correlates of oncolytic protocols on a malignancy that remains refractive to therapy.

Enhanced in vivo cytotoxicity of recombinant human tumor necrosis factor with etoposide in human renal cell carcinoma. Evaluation in a pre-clinical model.

The combination of tumor necrosis factor (TNF) and etoposide (ETP) was evaluated for potential cytotoxic efficacy against a human renal cell carcinoma xenograft using an in vivo assay employing an athymic mouse host with tumor implanted a the subrenal capsule site. Both antitumor efficacy (relative survival or RTS) and toxicity (weight loss) of TNF and ETP alone and in combination were evaluated. While TNF and ETP alone were mildly inhibitory (RTS 90% and 71%, respectively), the combination caused marked tumor inhibition (45% of controls). Host toxicity encountered with the combination did not exceed the toxicity associated with ETP alone, suggesting that the therapeutic index may have been augmented. It is concluded that enhanced antitumor activity without substantial augmentation of toxicity is observed with this combination, providing a rationale for further evaluation of tumor necrosis factor-based regimens for the treatment of advanced renal carcinoma.

Effect of edema and height on bronchial diameter and shape in excised dog lung.

Mechanical interactions among the artery, bronchus, and lung parenchyma cause the bronchus to be pulled from a circular cross-section in such a way that the largest diameter of the bronchus ( Db2 ) lies along a line joining the centers of bronchus and artery. To effect these interactions, the peribronchovascular interstitial space must transmit stresses from the lung parenchyma to the artery and bronchus. To test how interstitial edema affects the interdependence between the artery and the bronchus, we measured orthogonal diameters ( Db2 , Db1 ) from tantulum bronchograms as a function of edema formation at a fixed transpulmonary pressure (Ptp). As lobe weight increased to three times normal, Db2 / Db1 decreased from 1.08 to 1.0 at a Ptp of 6 and 25 cm H2O. Cross-sectional area decreased only at a Ptp of 6 cm H2O. We conclude (1) that peribronchovascular interstitial (Pi) pressure became more uniform with edema present, causing the bronchus to assume a more circular shape, and (2) that it increased, causing bronchial cross-sectional area to decrease at a Ptp of 6 cm H2O. To determine whether Pi is uniform with height, in a separate group of lungs we measured Db1 as a function of height in two configurations: hilus-dependent, Db1 (d) and then inverted or hilus-nondependent, Db1 (nd). Db1 was unaffected by lobe inversion at 25, 10, 6 and 4 cm H2O Ptp. At a Ptp of 2 cm H2O, the difference Db1 (d) - Db1 (nd) was positive near the hilus, decreased to zero in the lung periphery, and increased with edema. This bronchial distortion due to lobe inversion was consistent with the effect of gravitational forces on lung parenchyma as modeled by a finite-element analysis, as was opposite to that predicted by a vertical hydrostatic gradient in Pi.