In-Vivo Biodistribution and Safety of 99mTc-LLP2A-HYNIC in Canine Non-Hodgkin Lymphoma

Theranostic agents are critical for improving the diagnosis and treatment of non-Hodgkin Lymphoma (NHL). The peptidomimetic LLP2A is a novel peptide receptor radiotherapy candidate for treating NHL that expresses the activated α4β1 integrin. Tumor-bearing dogs are an excellent model of human NHL with similar clinical characteristics, behavior, and compressed clinical course. Canine in vivo imaging studies will provide valuable biodistribution and affinity information that reflects a diverse clinical population of lymphoma. This may also help to determine potential dose-limiting radiotoxicity to organs in human clinical trials. To validate this construct in a naturally occurring model of NHL, we performed in-vivo molecular targeted imaging and biodistribution in 3 normal dogs and 5 NHL bearing dogs. 99mTc-LLP2A-HYNIC-PEG and 99mTc-LLP2A-HYNIC were successfully synthesized and had very good labeling efficiency and radiochemical purity. 99mTc-LLP2A-HYNIC and 99mTc-LLP2A-HYNIC-PEG had biodistribution in keeping with their molecular size, with 99mTc-LLP2A-HYNIC-PEG remaining longer in the circulation, having higher tissue uptake, and having more activity in the liver compared to 99mTc-LLP2A-HYNIC. 99mTc-LLP2A-HYNIC was mainly eliminated through the kidneys with some residual activity. Radioactivity was reduced to near-background levels at 6 hours after injection. In NHL dogs, tumor showed moderately increased activity over background, with tumor activity in B-cell lymphoma dogs decreasing after chemotherapy. This compound is promising in the development of targeted drug-delivery radiopharmaceuticals and may contribute to translational work in people affected by non-Hodgkin lymphoma

Cell adhesion receptors in lymphoma dissemination

Regulated lymphocyte trafficking is essential for the control and integration of systemic immune responses. This homing process disperses the immunologic repertoire, guides lymphocyte subsets to the specialized microenvironments that control their differentiation and survival, and targets immune effector cells to sites of antigenic insult. This review discusses data indicating that the adhesion receptors regulating the trafficking of normal lymphocytes are also expressed and functionally active in their malignant counterparts, the non-Hodgkin lymphomas. These "homing receptors" appear to mediate the highly tissue-specific dissemination of specific lymphoma subtypes, such as lymphomas of the mucosa-associated lymphoid tissues and lymphomas of the skin. Furthermore, as a result of their capability to enhance lymphoma dissemination and to transduce signals into the cell, promoting cell growth and survival, adhesion receptors may contribute to lymphoma aggressiveness. Taken together, the data offer a framework for understanding the dissemination routes of non-Hodgkin lymphomas and suggest that adhesion receptors, specifically those of the CD44 family, may present useful tools to predict prognosis in patients with lymphomas. (Blood. 2000;95:1900-1910

Esophageal squamous cell carcinoma 38 years after primary repair of esophageal atresia

The authors report a case of a 38-year-old man with an esophageal squamous cell carcinoma after repair of esophageal atresia with tracheoesophageal fistula. This carcinoma occurred at a young age, near to the scar of the old anastomosis, in a patient with no other apparent risk factors. It is hypothesized that stasis caused by impaired esophageal motility may be the underlying cause. A single case is not enough to unequivocally prove a possible relationship between esophageal atresia and the development of esophageal cancer. Now that the first generation of survivors of esophageal atresia is reaching middle aged adulthood, one should, however, be aware of a possible increased incidence in these patients. J Pediatr Surg 36:629-63

Cystadenomen met ovarieel stroma in lever en pancreas: aanwijzingen voor embryonale migratie van gonadaal epitheel

OBJECTIVE: To provide an embryological explanation for the presence of ovarian stroma in cystadenomas of the liver and pancreas. DESIGN: Investigation of patients and embryos. METHOD: From 1997 to 2001 in the Academic Medical Centre, Amsterdam, the Netherlands, nine women were treated for a cystadenoma with ovarian stroma, six of which were situated in the liver and three in the tail of pancreas. In one patient with a cystadenoma in the liver, malignant changes had taken place. In embryos at 5-8 weeks development, the regional differences in the morphology of the epithelium of the peritoneal cavity and the position of the gonads in relation to the embryonic liver, pancreas and spleen were examined. RESULTS: In the foetal period before the gonads begin to descend, they are situated directly dorsal to the liver, tail of pancreas and spleen, but are separated from these by the peritoneal cavity. The cells that cover the urogenital folds distinguish themselves from those elsewhere in the peritoneal cavity as they are bulging in shape as opposed to flattened. This activated morphology suggests that on physical contact with a neighbouring organ the cells covering the gonads may become detached and lodge in that organ. CONCLUSION: It is likely that cystadenomas of the liver and pancreas have their origin in the cells that cover the embryonic gonads. The anomalous morphology of these covering cells in fact suggests that they are relatively easily mobilized. They are probably comparable with inoculation metastasis in the coelomic cavity. Taking the chance of malignant transformation of a cystadenoma into account, the treatment of choice is radical resection of the abnormality

K-ras mutations in gastric stump carcinomas and in carcinomas from the non-operated stomach

Partial gastrectomy is a well-established pre-malignant condition. It is postulated that in the gastric stump an accelerated neoplastic process takes place, similar to that of (intestinal type) adenocarcinoma from the non-operated stomach. K-ras codon 12 mutation is one of the most frequent oncogenic alterations in human solid neoplasms. It is rare in conventional gastric carcinoma and has not been studied in gastric stump carcinoma. The aim of this study was to compare the prevalence of K-ras codon 12 point mutations in gastric stump carcinomas with those in conventional carcinomas from the non-operated stomach. Twenty-four gastric stump carcinomas were compared with 26 conventional gastric carcinomas. Stage, histology, and demographics were comparable in both groups. Mutations in codon 12 of the K-ras gene were examined with a polymerase chain reaction (PCR)-based method and subsequent dot blot hybridization with mutation-specific probes. The results of Helicobacter pylori infection, Epstein-Barr virus infection and p53 immunohistochemistry were partially known from a previous study. In one of the gastric stump carcinomas as well as in one of the conventional gastric carcinomas a K-ras codon 12 point mutation was found. p53 immunohistochemistry results were comparable in both groups. Interestingly, Helicobacter pylori infection rate and Epstein-Barr virus in situ hybridization for EBER1, as previously studied, appeared were significantly different in the two groups. K-ras codon 12 point mutations are rare in both gastric stump carcinomas and conventional gastric carcinomas. This supports the postulated hypothesis that the pathways of carcinogenesis in both gastric stump carcinoma and conventional gastric carcinoma share common features. However, these groups differ in infection rate of Helicobacter pylori and of Epstein-Barr virus, which suggests that some neoplastic stimuli differ as wel

Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis

Background: Crohn's disease is characterised by a chronic relapsing inflammation of the bowel in which proinflammatory cytokines play an important perpetuating role. Mitogen activated protein kinase p38 (p38 MAPK) has been established as a major regulator of the inflammatory response, especially with regard to production of proinflammatory cytokines, but its role in inflammatory bowel disease is unexplored. In this paper we describe the effects of a specific p38 MAPK inhibitor, SB 203580, in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice. Results: SB 203580 had a dichotomal effect in TNBS mice. Weight loss of TNBS mice treated with SB 203580 was significantly worse and colon weight on sacrifice was significantly increased in MAPK inhibitor treated TNBS mice (229.2 mg and 289.1 mg, respectively). However, the total number of cells in the caudal lymph node decreased to 188.8×10(4) cells in SB 203580 treated TNBS mice compared with 334×10(4) cells in vehicle treated mice. CD3/CD28 double stimulated caudal lymph node cells of SB 203580 treated mice showed decreased interferon γ production but increased tumour necrosis factor α production. The concentration of interleukin 12p70 in colon homogenates was significantly decreased in SB 203580 treated mice whereas concentrations of interleukin 12p40, tumour necrosis factor α, and interleukin 10 were similar in vehicle and SB 203580 treated TNBS mice. Conclusion: Our results reveal a dichotomy in p38 MAPK action during experimental colitis