Curative potential of multimodality therapy for locally recurrent rectal cancer

OBJECTIVE: To assess the results of multimodality therapy for patients with recurrent rectal cancer and to analyze factors predictive of curative resection and prognostic for overall survival. SUMMARY BACKGROUND DATA: Locally recurrent rectal cancer is a difficult clinical problem, and radical treatment options with curative intent are not generally accepted. METHODS: A total of 394 patients underwent surgical exploration for recurrent rectal cancer. Ninety were found to have unresectable local or extrapelvic disease and 304 underwent resection of the recurrence. The latter patients were prospectively followed to determine long-term survival and factors influencing survival. RESULTS: Overall 5-year survival was 25%. Curative, negative resection margins were obtained in 45% of patients; in these patients a 5-year survival of 37% was achieved, compared to 16% (P <.001) in patients with either microscopic or gross residual disease. In a logistic regression analysis, initial surgery with end-colostomy and symptomatic pain (both univariate) and increasing number of sites of the recurrent tumor fixation in the pelvis (multivariate) were associated with palliative surgery. Overall survival was significantly decreased for symptomatic pain (P <.001) and more than one fixation (P =.029). Survival following extended resection of adjacent organs was not different from limited resection (28% vs. 21%, P =.11). Patient demographics and factors related to the initial rectal cancer did not affect outcome. Perioperative mortality was only 0.3%, but significant morbidity occurred in 26% of patients, with pelvic abscess being the most common complication. CONCLUSIONS: This study demonstrates that many patients with locally recurrent rectal cancer can be resected with negative margins. Long-term survival can be achieved, especially for patients with no symptoms and minimal fixation of the recurrence in the pelvis, provided no gross residual disease remains.     

Baboons undergoing orthotopic concordant cardiac xenotransplantation surviving more than 300 days: effect of immunosuppressive regimen

OBJECTIVE: We reviewed long-term survival among hosts in 3 consecutive series of a rhesus monkey-baboon orthotopic cardiac xenotransplantation model with reference to host immune response, including the effectiveness in preventing rejection and limiting toxicity concerning infection, to evaluate specific immunosuppressive regimens for long-term outcomes. METHODS: Six juvenile baboons surviving more than 300 days after transplantation were reviewed. Regimen A consisted of splenectomy, FK506, methotrexate, and antilymphocyte globulin. Regimen B consisted of pretransplantation and chronic maintenance with cyclosporine A (INN: ciclosporin), methotrexate, and antithymocyte globulin. Regimen C was the same as regimen B plus pretransplantation total lymphoid irradiation and intraoperative donor bone marrow cell infusion. Rejections were detected by means of echocardiography. RESULTS: Long-term survivors in 3 groups were followed for a range of 332 to 515 days (mean, 436 days). Rejection frequency in regimens A, B, and C was 0.35, 0.58, and 0.18 per month, and rescue therapy days were 23 (4.8%), 123 (9.5%), and 20 (2.4%), respectively (P <.0001). Infection frequency was 0.58, 0.56, and 0.19 per month, and therapy days were 192 (38.2%), 164 (12.6%), and 7 (0.9%), respectively (P <.0001). Concerning the host immune response, interleukin 2-activated T cells of all groups during rejection-free periods showed lower numbers compared with those of control animals (P <.0005), and regimen C was the lowest among 3 groups (P <.01). The production of xenoantibody was sufficiently attenuated in all groups. CONCLUSION: Regimen C leads to long-term survival with fewer rejection and infection episodes by means of suppression of the interleukin 2 pathway and xenoantibody production.     

Endoscopic laser imaging of tissue perfusion: new instrumentation and technique

BACKGROUND AND OBJECTIVES: New instrumentation, based on a previously established laser speckle perfusion imaging (LSI) technique is evaluated for its ability to capture and generate blood flow images during endoscopic surgery. STUDY DESIGN/MATERIALS AND METHODS: Investigations are detailed in an in-vitro blood flow model simulating physiological properties of vascularized tissue, and in-vivo in rabbit joint capsule tissue. RESULTS: In-vitro measurements showed a linear response of the instrument to blood flow in the range of 0-800 microl/minute, where data points were significantly correlated with an r(2) value of 0.96. In-vivo measurements showed a 58.7% decrease to the medial collateral ligament during occlusion of the femoral artery. CONCLUSIONS: Blood flow images demonstrate that the endoscopic LSI technique is capable of measuring relative tissue blood flow changes at high resolutions and rapid response times and incorporates well with endoscopic surgeries.     

Laser Doppler imaging of burn scars: a comparison of wavelength and scanning methods

Laser Doppler perfusion imaging (LDI) is a useful tool for the early clinical assessment of burn depth and prognostic evaluation of injuries that may require skin grafting. We have evaluated two commercially available laser Doppler imagers for the perfusion measurement of normal and burn scar tissue. METHODS: A single wavelength (635 nm), step-wise scanning LDI and a dual wavelength (633 and 780 nm), continuous scanning LDI were used. Twenty patients with hypertrophic burn scars (time since injury: 1 month-8 years) were recruited and the color and elevation of the scar was clinically assessed using a modified Vancouver Burn Scar Scale. Perfusion of each scar region was measured using both imagers. A symmetric contralateral region of unburned skin was also imaged to record baseline perfusion. RESULTS: Comparisons of wavelength and scanning technique were made using perfusion values obtained from 22 burn scars. Highly significant positive correlation was observed in all comparisons. In addition, output from both instruments was strongly and significantly correlated with the clinical grading of the scar. SIGNIFICANCE: Both LDI scanners perform similar perfusion measurements. The results also indicate that red and near-infrared (NIR) wavelength photons provide similar blood flow information. The faster, continuous scanning method provides a clinical advantage without a significant loss of blood flow information. However, a critical evaluation of both instruments suggests that caution must be exercised when using these optical diagnostic techniques and that some knowledge of light-tissue interaction is required for the proper analysis and interpretation of clinical data.     

Synthesis and anticonvulsant activity of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones

The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones (4a--l, 5a--j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anticonvulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED(50)=44.7 mg x kg(-1) i.p.) 1-[2-hydroxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED(50)=72 mg x kg(-1) i.p.) and 1-[2-hydroxy-3-imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED(50)=79 mg x kg(-1) i.p.) were also found to have maximum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).     

Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro

Mechanisms of antibiotic resistance of bacteria include efflux pumps which extrude the antibiotic prior to reaching its target. Phenothiazines inhibit the activity of some efflux pumps thereby altering the susceptibility of bacteria. This study demonstrated that chlorpromazine and thioridazine reduce the susceptibility of methicillin-resistant strains (MRSA) but not that of methicillin-susceptible Staphylococcus aureus (MSSA) strains to oxacillin (MIC of oxacillin reduced from >500 to 10 mg/l). Reserpine, an inhibitor of antibiotic efflux pumps also reduced the resistance of MRSA strains to oxacillin suggesting the presence of an efflux pump that contributes to antibiotic resistance of MRSA strains.     

Use of a phage display library to identify oligopeptides binding to the lumenal surface of polarized endothelium by ex vivo perfusion of human umbilical veins

Human endothelial-specific targeting peptides were identified by biopanning within freshly-obtained human umbilical cords. Umbilical veins were cleaned in situ and M13 phage display libraries were passed through the cords. Tightly bound phage were recovered following isolation of endothelial cells by collagenase digestion and homogenisation, allowing production of enriched phage libraries for subsequent rounds of panning. After five rounds of biopanning, five promising sequences were selected and the binding of the corresponding phage clones was compared in perfused umbilical veins. Each of these peptides showed substantial binding, although the clone encoding the heptapeptide KPSGLTY showed the greatest, some 89-times greater than insertless phage. Binding of this phage clone was examined to cells in vitro, where it demonstrated at least five-times greater binding to isolated human umbilical vein endothelial cells than to 911, SKOV3, B16F10 and Cos7 cells. These initial peptides may prove useful targeting agents for endothelial-selective delivery, and this powerful approach should be readily applicable to biopanning in a broad range of human vessels ex vivo.