Nucleotide metabolic mismatches in mammalian hearts: implications for transplantation

Introduction

Human donor organ shortages have led surgeons and scientists to explore the use of animals as alternative organ sources. Acute thrombovascular rejection (AVR) is the main hurdle in xenotransplantation. Disparities in nucleotide metabolism in the vessels of different species may contribute significantly to the microvascular component of AVR.

Methods

We evaluated the extent of nucleotide metabolism mismatch in selected organs and endothelial cells of different mammals with particular focus on the changes in activity of ecto-5’-nucleotidase (E5’N) elicited by exposure of porcine hearts or endothelial cells to human blood (ex vivo) or human plasma (in vitro).

Results

E5’N activity in the rat heart was significantly higher than in other species. We noted a significant difference (p<0.001) in E5’N activity between human and pig endothelial cell lines. Initial pig aortic endothelial E5’N activity decreased in vitro after a three-hour exposure to human and porcine plasma while remaining constant in controls. Ex vivo perfusion with fresh human blood for four hours resulted in a significant decrease of E5’N activity in both wild type and transgenic pig hearts overexpressing human decay accelerating factor (p<0.001).

Conclusions

This study provides evidence that mismatches in basal mammalian metabolic pathways and humoral immunity interact in a xenogeneic environment. Understanding the role of nucleotide metabolism and signalling in xenotransplantation may identify new targets for genetic modifications and may lead to the development of new therapies extending graft survival.     

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G(2)-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G(2)-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed "stand alone" antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors.     

Endoscopic Ultrasound Staging of Stenotic Esophageal Cancers May Be Unnecessary to Determine the Need for Neoadjuvant Therapy

Introduction

Endoscopic ultrasound (EUS) is an essential component of preoperative staging for esophageal cancer and is used to determine which patients should proceed to primary surgical resection or receive neoadjuvant therapy prior to surgery. However, when the EUS scope cannot traverse a tumor, the role of pre-dilatation is controversial due to the risk of perforation.

Methods

A retrospective review was conducted of all patients with esophageal tumor stenosis that could not accommodate the EUS scope who then proceeded with primary esophagectomy. The pathology results were classified based on the revised seventh edition American Joint Committee on Cancer staging system.

Results

A total of 27 patients met inclusion criteria. The majority of tumors were T3 (24/27, 89 %). There were no stage I tumors, 15 % (4/27) were stage II, 81 % (22/27) were stage III, and 4 % (1/27) were stage IV due to a resected solitary lung metastasis.

Conclusion

Tumors that cannot be assessed with an EUS scope due to tumor stenosis will have locally advanced disease in the majority of cases. In these situations, pre-dilatation of the tumor with EUS staging should be omitted when considering the risk of potential esophageal perforation and the patients should be referred for neoadjuvant therapy.     

Lateralized and focal clinical, EEG, and FLAIR MRI abnormalities in Creutzfeldt-Jakob disease.

OBJECTIVE: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive fatal prion disorder with typical clinical findings of dementia, motor dysfunction, and myoclonus and characteristic electroencephalographic (EEG) findings of bilateral synchronous periodic sharp waves. Advances in neuroimaging capabilities with diffusion-weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) techniques have shown promise in the non-invasive diagnosis of CJD. This series illustrates the correlation between the lateralized and focal clinical, EEG, and MRI FLAIR sequence abnormalities in 8 patients (7 men and one woman 55-73 years old) with CJD. METHODS: A case series of 8 patients, evaluated at Mayo Clinic, who had a history of rapidly progressive lateralized or focal neurologic dysfunction and laboratory findings consistent with CJD between 1996 and 1999 were identified. EEG, MRI of the head with FLAIR sequence, and cerebrospinal fluid studies were performed in all patients. RESULTS: Mean time to death from symptom onset was 4 months. Symptoms were lateralized to the left hemisphere in 5 patients and to the right hemisphere in two. One patient showed bilateral occipital lobe involvement. In all patients, the EEG showed lateralized or focal periodic sharp waves that colocalized with clinical cerebral dysfunction. FLAIR MRI images revealed increased signal in the cortical ribbon and deep gray matter corresponding to the lateralized clinical and EEG findings in 7 patients. The other patient had bilateral occipital increased signal on FLAIR MRI. CONCLUSIONS: CJD may present with lateralized or focal cortical syndromes with colocalizing EEG and MRI findings. With the appropriate clinical history and laboratory evaluation, the corresponding areas of increased signal on FLAIR MRI provide supportive evidence of the disease. SIGNIFICANCE: CJD can sometimes present with more focal or lateralized clinical findings, and the colocalizing EEG and MRI findings can help make or confirm the diagnosis of CJD.     

Outcomes of outpatient breast cancer surgery at a private breast clinic

Advances in surgical and anesthetic techniques have allowed for outpatient treatment of breast cancer. We evaluated the feasibility, safety, efficacy, and surgical outcomes of outpatient surgery in 370 patients with breast cancer who underwent breast‐conserving surgery (BCS)/axillar lymph node (ALN) management. There were no deaths or severe intraoperative complications, but 41 complications were observed and disease recurrence occurred in 18 patients. The cumulative overall survival rate was 95.2%. Outpatient surgery was well tolerated, feasible, and safe in patients receiving BCS/ALN management.