Rationale: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. Objectives: We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion. Methods: Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessed in CBDL versus sham rats (n 5 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(1) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n 5 10 per group). Measurements and Main Results: CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(1) macrophages (nuclear factor-kB1) accumulated in HPS pulmonary arteries, drawn by elevated levels of plasma endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. Conclusions: HPS results from intravascular accumulation of CD68 (1) macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.Keywords: liver transplantation; arteriovenous malformations; clodronate; cirrhosis; portopulmonary hypertension Hepatopulmonary syndrome (HPS), characterized by hypoxemia and intrapulmonary shunting, occurs in 5 to 32% of patients with liver disease (1). HPS significantly increases mortality and worsens functional status and quality of life in patients with cirrhosis (2). The major pathological abnormalities in HPS include alveolar capillary dilatation and pulmonary arteriovenous malformations (3). Clinically, patients with HPS present with hypoxemia and signs of a hyperdynamic circulatory state that include low systemic vascular resistance, low pulmonary vascular resistance (PVR), and high cardiac output (CO) (1). The pathogenesis of HPS is unclear, and currently there are no effective medical therapies. Orthotopic liver transplantation is the only available treatment (1). It is noteworthy that some patients with cirr...

We have investigated the dose-response relationships for the incidence of salivary gland tumors in a cohort of 2945 individuals who were irradiated as children between 1939-1962. Most of the patients were treated to reduce the size of their tonsils and adenoids. The mean dose to the salivary glands (+/-SD) was 4.2 +/- 1.7 Gy. Eighty-nine patients developed 91 salivary gland neoplasms; 22 had single malignancies, 64 had single benign neoplasms, 2 developed two separate benign neoplasms, and 1 developed a single neoplasm but did not have surgery. The majority (81 of 89) of the patients developed neoplasms in the parotid glands. Mucoepidermoid carcinomas were the most common malignancy and mixed (pleomorphic) adenomas were the most common benign neoplasm. For all salivary gland tumors, the excess relative risk per gray (ERR/Gy) was 0.82; however, the 95% confidence interval was wide (0.04, upper bound indeterminate). The trend was determined principally by benign tumors, as there was no dose-response relationship for salivary gland cancer, although there were too few cases to draw definitive conclusions. Overall, our study provides support for an association between salivary gland tumors and radiation exposure. Although most salivary gland tumors are benign and are usually readily detected, they may cause morbidity, and people who have been irradiated in the area should be monitored for their occurrence.

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The most common secondary neoplasms which occur following cranial radiation therapy are sarcoma and meningioma. The occurrence of glioblastoma multiforme following radiation and chemotherapy in acute lymphocytic leukaemia (ALL) is rare. We report 3 cases of glioblastoma multiforme in children developing 11–72 months following completion of chemotherapy/radiotherapy for ALL. The exact cause for the development of glioblastoma multiforme following therapy for ALL is not clear. A genetic predisposition may be essential for the occurrence of such a highly malignant primary brain tumour in leukaemia patients, irrespective of radiation and/or chemotherapy. The pathogenesis and surgical management are discussed, and the literature on the subject is reviewed.

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