Coupling of lactose molecules to the carrier protein hinders the spleen and bone marrow uptake of doxorubicin conjugated with human albumin.

Several attempts have been made to enhance doxorubicin (DOXO) concentrations in tumour cells by drug conjugation with human albumin (HSA). HSA-DOXO has the drawback of causing DOXO accumulation in spleen and bone marrow, with a consequent leucopoenia not produced when lactose molecules are coupled to the carrier protein. In the present experiments we demonstrated that the effect of HSA lactosamination is not a consequence of a more rapid disappearance from the bloodstream of the lactosaminated conjugate (L-HSA-DOXO), which is rapidly internalized by the liver through the asialoglycoprotein receptor, but is due to a hindered uptake by spleen and bone marrow cells caused by the coupled lactose molecules. Experiments in vitro showed that HSA-DOXO produced an inhibition of murine macrophage proliferation not caused by L-HSA-DOXO. This result can be explained by higher amounts of the former conjugate entering in these cells and suggests macrophages as the cell type responsible for the spleen and bone marrow internalization of HSA-DOXO hindered by lactose coupling. Importantly, lactosamination of HSA did not reduce the marked uptake of HSA-DOXO by chemically induced rat hepatocellular carcinoma. L-HSA-DOXO, by avoiding DOXO accumulation in bone marrow is an attractive candidate for clinical trials against tumors which were found to actively internalize this conjugate in laboratory animals, such as hepatocellular carcinoma.     

Inhibition of [3H]thymidine incorporation into DNA of rat regenerating liver by 2',2'-difluorodeoxycytidine coupled to lactosaminated poly-L-lysine

The expression of asialoglycoprotein receptor (ASGP-R) on human hepatocarcinoma cells might be exploited to reduce the extrahepatic toxicity of DNA synthesis inhibitors by their conjugation with galactosyl- terminating peptides. We conjugated 2',2'-difluorodeoxycytidine (dFdC), an inhibitor of DNA synthesis active on solid tumors, with lactosaminated poly-L-lysine (L-poly(LYS)). In experiments in vitro, L-poly(LYS)-dFdC inhibited proliferation of Hep G2 cells, a human hepatocarcinoma cell line which maintains the ASGP-R. Inhibition was rescued by asialofetuin. To study the pharmacological action of the conjugate in vivo, we used rats 18-24 hr after 2/3 hepatectomy and observed that regenerating hepatocytes expressed ASGP-R on their surface and internalized L-poly(LYS)-dFdC. Conjugate uptake by bone marrow, spleen, and intestine was negligible. We also found that L-poly(LYS)-dFdC inhibited [3H]thymidine incorporation into DNA of regenerating liver. These results indicated that hepatectomized rats were a suitable animal model to study the pharmacological action, on DNA-synthesizing hepatocytes, of conjugates binding to ASGP-R and carrying inhibitors of DNA synthesis. L-poly(LYS)-dFdC also inhibited [3H]thymidine incorporation in bone marrow, spleen, and intestine. Evidence was obtained that inhibition of DNA synthesis in extrahepatic tissues was a consequence of drug release from hepatocytes into blood-stream after the bond with the carrier has been broken down within liver cells. Possible ways of reducing the exit of dFdC from liver cells, thereby obtaining an inhibition of DNA synthesis restricted to dividing hepatocytes, were discussed.     

Can gangrenous cholecystitis be prevented?: a plea against a "wait and see" attitude

BACKGROUND/AIMS: A delay in recognizing and treating an inflamed gallbladder may increase the risk of a necrotic evolution and represent a critical factor affecting the progression of the inflammatory process. Aim of the study is to assess the therapeutic attitude in patients with histologically proved gangrenous cholecystitis, to find out whether it could play a role in the progression of the inflammatory condition. METHODOLOGY: Twenty-seven patients with gangrenous cholecystitis at histology were compared with a matched-control group with phlegmonous cholecystitis. RESULTS: Age, gender, ASA score, and concomitant diseases did not differ significantly in both groups. WBC was significantly higher (P = 0.026) in patients with gangrene. Ultrasounds were unhelpful in identifying the severity of the disease. Patients with gangrenous gallbladder showed a significantly increased (P = 0.0006) admission delay compared with controls (104.3+/-15.3 hours vs. 59.7+/-7.7 hours). Surgeon's delay, morbidity and mortality were not different in both groups. CONCLUSION: Patient's delay before hospitalization may represent a crucial factor in the progression toward a more severe disease in acute cholecystitis. The time between symptoms onset and hospital admission (and consequently surgery) was significantly longer in patients with gangrenous cholecystitis, further emphasizing the need for an early (if not urgent) surgical treatment in acute cholecystitis, even with mild symptoms.     

The role of cholecystectomy in renal transplantation

INTRODUCTION: We reviewed our clinical experience to assess the role of cholecystectomy transplant candidates pre- and posttransplantation. METHODS: Between April 1986 and December 2003, 57 (6.8%) candidates among 839 kidney transplants were found during routine pretransplant screening to show gallstones. RESULTS: Thirty nine (68.4%) symptomatic patients underwent cholecystectomy before transplantation. Among 18 (31.6%) asymptomatic patients monitored after transplantation, the 7 (39%) who developed biliary tract symptoms underwent laparoscopy or minilaparocholecystectomy without postoperative morbidity, mortality, or graft loss. CONCLUSIONS: Symptomatic gallstones have to be treated using the laparoscopic cholecystectomy or minilaparotomy technique. In asymptomatic cholelithiasis prophylactic cholecystectomy is only reserved for patients with biliary "intrinsic" risk factors. An early diagnosis and prompt surgical treatment yields good results.     

Coupling of 5-fluoro 2'-deoxyuridine to lactosaminated poly-l-lysine: an approach to a regional, non-invasive chemotherapy of liver micrometastases

Nucleoside analogs conjugated with galactosyl-terminating peptides selectively enter liver cells and after intracellular release from the carrier partly exit into bloodstream, resulting in higher concentrations in liver blood than in systemic circulation. The aim of the present experiments was to ascertain whether, in mice injected with non-toxic doses of a 5-fluoro 2'-deoxyuridine (FUdR) conjugate with lactosaminated poly-L-lysine (L-poly(LYS)), the drug was released by hepatic cells in high enough amounts to be pharmacologically active on neoplastic cells infiltrating the liver. We observed that L-poly(LYS)-FUdR inhibited the growth of hepatic metastases induced by intrasplenic administration of murine colon carcinoma C-26 cells. L-poly(LYS)-FUdR was not toxic for C-26 cells in vitro, was selectively taken up by mouse liver, and was stable in mouse blood, indicating that the effect on the metastases was due to FUdR (and/or its active metabolites) released in liver blood after the conjugate was taken up by the hepatic cells. These results suggest that L-poly(LYS)-FUdR might be useful in adjuvant chemotherapy of tumors giving liver metastases. The drug released from hepatic cells into liver blood following conjugate administration via the peripheral venous route might accomplish a locoregional, non-invasive treatment of micrometastases nourished by liver sinusoids.     

Kidney preservation with university of Wisconsin and Celsior solution: a prospective multicenter randomized study

BACKGROUND: Although the University of Wisconsin (U.W.) solution continues to be the most commonly used for intra-abdominal organs, a new solution, Celsior, already used for heart and lungs, has been proposed for kidney and liver preservation. The aim of this research was to assess the effect of Celsior as compared with U.W. on immediate graft function and a 2-year follow-up of kidney transplants. METHODS: A prospective multicenter randomized study was designed to evaluate the efficacy of the Celsior solution in the clinical preservation of the kidney. In this report, we present the data collected as of September 2000. One hundred donors were included in the trial resulting in 187 renal transplants. Ninety-nine kidneys were stored in Celsior solution and 88 in U.W. solution. The groups were comparable with regard to donor and recipient characteristics. RESULTS: Delayed graft function occurred in 31.3% of the Celsior group and in 33.9% of the U.W. group (P=n.s.). Mean serum creatinine levels and mean daily urinary output were also comparable. Two year graft survival in kidneys preserved with Celsior was 84% as compared with 75% for U.W.-preserved kidneys without any significant statistical difference. CONCLUSIONS: Our data show that the preservation of kidneys in Celsior solution in a clinical setting is equivalent to that of U.W. solution. When using Celsior during multiple-organ donor harvesting it would be possible to perform an in situ flush of all intra-abdominal and intrathoracic organs with a single cold storage solution.     

Non-Hodgkin's lymphoma. Extranodal localizations in the head and neck. Clinical and therapeutic evaluations

The staging, therapy and course of 91 patients with extranodal NHL of the head and neck treated between 1970 and 1985, were analyzed. The sites involved were: Waldeyer's ring 71 patients, tonsil 59, nasopharynx 12 and extralymphatic sites 20 patients (larynx 6, paranasal sinus 5, orbit 5, oral cavity 3, salivary gland 1). Sixty-three patients had unfavourable histology with 22 patients in stage I; 33 in II; 21 in III; 15 in IV. Chemotherapy plus radiotherapy was used in 43 patients and 34 obtained Complete Remission (CR). Chemotherapy alone was used in 30 patients and in 11 CR was achieved, radiotherapy alone in 18 patients and 11 obtained CR. The actuarial survival rate was 55% and recurrence-free survival, evaluated only in those patients who achieved complete remission, was 80%. Results, as survival and freedom from recurrence, are analyzed in relation to main prognostic factors and therapy, and patterns of recurrence are reported. The present study confirmed the view that radiotherapy combined with chemotherapy represents the best treatment for NHL of the head and neck.     

Hygiene precautions and the transmission of infections in radiology

Healthcare-associated infections are a critical challenge for the public health sector. Most are acquired through contact, predominantly with the hands of health care personnel. Hand hygiene, therefore, is the single most effective measure for preventing and controlling infectious diseases. Recently, cases of acute hepatitis C occurred in patients who had undergone contrast-enhanced computed tomography. This was probably related to inadequate handling by health care staff. Rigorous compliance with standard precautions is therefore compulsory even in radiology, a setting traditionally considered at low risk for the transmission of pathogens. Adherence to standard precautions is still poor and the persistence of inappropriate practices responsible for preventable incidents is very common in radiology, often owing to underestimation of risk. Radiology units must promote compliance with correct hand hygiene through appropriate education programmes and provision of adequate areas and hand hygiene products. The evidence base to support the use of alcohol-based hand rub is demonstrating that these formulations are effective in improving hand hygiene compliance and preventing infections.