Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

Transcapillary fluid balance consequences of missing initial lymphatics studied in a mouse model of primary lymphoedema

To investigate the phenotypic consequences of a deranged lymphangiogenesis in relation to tissue fluid accumulation and the possible role of inflammation in the pathogenesis of lymphoedema, we measured determinants of transcapillary fluid filtration and inflammatory mediators in the interstitial fluid in genetically engineered Chy mice, a model for primary congenital lymphoedema (Milroy's disease). Although initial lymphatics were not present in dermis in any of the areas studied (fore paw, hind paw, thigh and back skin) interstitial fluid pressure ( P _if), measured with micropipettes, and tissue fluid volumes were significantly increased only in the areas with visible swelling – the fore and hind paw, whereas interstitial colloid osmotic pressure (COP_if) was increased in all the skin areas examined. A volume load of 15% of body weight resulted in a more pronounced increase in P _if as well as a four-fold increase in interstitial fluid volume in Chy relative to wild-type (wt) mice, showing the quantitative importance of lymphatics for fluid homeostasis during acute perturbations. A similar level of proinflammatory markers in interstitial fluid in early established lymphoedema (3–4 months) in Chy and wt suggests that inflammation does not have a major pathogenetic role for the development of lymphoedema, whereas a reduced level of the immunomodulatory cytokine interleukin (IL)-4 may result in a reduced immunological defence ability and thus lead to the increase in inflammatory cytokines IL-2 and IL-6 observed at a later stage (11–13 months). Our data suggest that primary lymphoedema results in a high interstitial fluid protein concentration that does not induce an interstitial inflammatory reaction per se , and furthermore shows the paramount importance of the initial lymphatics in tissue fluid homeostasis, especially during perturbations of transcapillary fluid balance.     

Vertebroplasty and Kyphoplasty in Spinal Trauma

Abstract Kyphoplasty and vertebroplasty have become recognized procedures for the treatment of vertebral fractures, especially in patients with osteoporosis. In most cases of osteoporotic spinal vertebral fracture in elderly patients, polymethylmethacrylate (PMMA) cement is used to fill the defect and stabilize the vertebral body. The techniques of vertebroplasty and kyphoplasty differ in the possibility of realignment and reconstruction of the vertebral body and spinal column. Long-term results in terms of integration of the cement and bioreactivity of the vertebral body are still lacking; so, these procedures are still no options in the treatment of younger patients. Vertebroplasty and kyphoplasty show different success in the management of fresh traumatic spine fractures. The acute traumatic vertebral fracture has to be classified sensitively, to find the right indication for cement augmentation. Mild acute compression fractures can be treated by vertebroplasty or kyphoplasty, severe compression and burst fractures by combination of internal fixation and kyphoplasty. The indications for use of biological or osteoinductive cement in spinal fracture management must still be regarded as restricted owing to the lack of basic biomechanical research data. Such cement should not be used except in clinical studies.     

Posttraumatisches septisches Abdomen

Abdominal infection has the fifth highest incidence of all posttraumatic infections but has the second highest mortality rate with 25%,pneumonia,with 29%, being the only posttraumatic infection that is more frequently lethal.Posttraumatic abdominal sepsis, on the other hand, has a mortality rate of almost 50%.This rate cannot be reduced except by prompt identification of the correct diagnosis of the underlying injury or complication.This means that delayed laparotomy is strikingly detrimental in these patients, with 46% mortality as opposed to 11% in patients who undergo laparotomy promptly. In parallel with this, the mortality of fresh-onset and localized peritonitis is 14%,whereas that of diffuse purulent peritonitis is up to a devastating 42%.     

Small cell lung cancer in Norway. Should more patients have been offered surgical therapy?

OBJECTIVE: The final outcome of patients with small cell lung cancer (SCLC) is poor with an overall 5-year survival rate of less than 10%. Therefore, the question of surgery in patients with a technically-operable solitary tumor has been raised. The purpose of this study was to identify the proportion of patients with operable SCLC and to assess the prognosis of different treatment strategies. For patients who were operated, we compared the resection specimens from patients with more than 5-year survival with those with shorter survival to see whether the specimens belonged to different subclasses of SCLC. METHODS: In Norway all clinical and pathologic departments submit reports on cancer patients to the Cancer Registry. The Registry also has a law-regulated authority to collect supplemental information regarding diagnosis, treatment and outcome for all cancer patients from the hospitals in charge. All reports on patients diagnosed as having SCLC in limited disease or unknown stage during the time interval 1993-1999 were reviewed. Patients with a T2-tumor, in whom a pneumonectomy would have to be performed, were classified as potentially operable. Five-year relative survival was calculated for patients diagnosed in 1993-1997. RESULTS: During the actual period 2442 individuals with SCLC were identified. The majority was treated with conventional chemotherapy or concurrent chemoradiotherapy while 38 underwent surgical therapy. Following reclassification of 697 patients reported to have limited disease or unknown stage 180 were judged to be in stage I. In addition to the 38 resected patients 14 were considered fit for surgery technically and medically while 97 were found to be potentially operable treatment modalities apart from surgery yielded a 5-year survival rate <7%. For stage I (N=96) the rate was 11.3% in conventionally treated patients compared to 44.9% for those who underwent surgical resection. By pathological review of surgical specimens a diagnosis of SCLC was confirmed in all patients treated by surgery in the groups with long and short survival. CONCLUSION: This investigation demonstrates that patients with SCLC having a peripherally located tumor should be referred to surgery, as long time survival is far better than for conventionally treated patients.     

Structure and Function of Plasmid pColD157 of Enterohemorrhagic Escherichia coli O157 and Its Distribution among Strains from Patients with Diarrhea and Hemolytic-Uremic Syndrome

In this study, pColD157, a 6.7-kb colicinogenic plasmid of enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain CL40cu, was characterized by restriction mapping and determination of its complete nucleotide sequence. The sequence consists of 6,675 bp and shows a high degree of similarity to the nucleotide sequence of colicinogenic plasmids pColD-CA23 and pColK. Seven potential genes were located on pColD157, three of which were closely related (>97.9%) to the colicin D structural gene and the corresponding immunity and lysis genes of plasmid pColD-CA23, and these were therefore designated cda, cdi, and cdl, respectively, using the reference extension -CL40 for differentiation. The adjacent 3′ region is related to the origin of replication of pColD-CA23. In contrast, the remaining part of the plasmid harbors a cluster of genes, closely related to the mobilization genes of pColK, which is followed by a 0.3-kb stretch homologous to the pColK resolution function. These determinants were designated mbdA, mbdB, mbdC, and mbdD and cdr, respectively. Southern blot analysis was performed with a probe specific for the cda gene of pColD157 and two groups of EHEC O157:H7 isolates from patients with diarrhea or hemolytic-uremic syndrome resident in Germany. Whereas 16 of 46 E. coli O157 strains isolated between 1987 and 1991 harbored plasmid pColD157, only 1 of 50 strains isolated during 1996 carried this plasmid. In addition, all strains harboring plasmid pColD157 were shown to have colicinogenic activity.