Toward endobronchial Ir-192 high-dose-rate brachytherapy therapeutic optimization.

A number of patients with lung cancer receive either palliative or curative high-dose-rate (HDR) endobronchial brachytherapy. Up to a third of patients treated with endobronchial HDR die from hemoptysis. Rather than accept hemoptysis as an expected potential consequence of HDR, we have calculated the radial dose distribution for an Ir-192 HDR source, rigorously examined the dose and prescription points recommended by the American Brachytherapy Society (ABS), and performed a radiobiological-based analysis. The radial dose rate of a commercially available Ir-192 source was calculated with a Monte Carlo simulation. Based on the linear quadratic model, the estimated palliative, curative and blood vessel rupture radii from the center of an Ir-192 source were obtained for the ABS recommendations and a series of customized HDR prescriptions. The estimated radius at risk for blood vessel perforation for the ABS recommendations ranges from 7 to 9 mm. An optimized prescription may in some situations reduce this radius to 4 mm. The estimated blood perforation radius is generally smaller than the palliative radius. Optimized and individualized endobronchial HDR prescriptions are currently feasible based on our current understanding of tumor and normal tissue radiobiology. Individualized prescriptions could minimize complications such as fatal hemoptysis without sacrificing efficacy. Fiducial stents, HDR catheter centering or spacers and the use of CT imaging to better assess the relationship between the catheter and blood vessels promise to be useful strategies for increasing the therapeutic index of this treatment modality. Prospective trials employing treatment optimization algorithms are needed.

Photodynamic therapy of the intact breast.

As breast cancer is diagnosed in over a million patients a year it is a significant oncological issue. Treatment paradigms have shifted to emphasize breast preservation protocols. However, due to a lack of equipment and facilities this option is only rarely offered to poverty stricken patients and those in the developing world. Photodynamic therapy may play a role in allowing for greater breast conservation based in part on the emerging success of partial breast radiation. This paper will review the rationale behind and technical aspects for intact breast photodynamic therapy.

PD/PDT for gynecological disease: A clinical review.

The evolution of diagnostic and interventional procedures for gynecologic disease has led to organ, sexual and reproductive sparing treatments. Photodiagnosis (PD) and photodynamic therapy (PDT) may play a great role for gynecological patients as both offer the potential to achieve these goals. PD/PDT for a wide variety of diagnostic and therapeutic interventions have shown potential for excellent clinical outcomes. However, significant limitations remains, both clinically and dosimetrically, that prevent consistent results. When those limitations are resolved PD/PDT could move to the forefront of gynecological therapy. This clinical review highlights the outcomes and shortcomings of PD/PDT through the peer reviewed literature for gynecological sites.

Clinical photodynamic therapy of head and neck cancers-A review of applications and outcomes.

As local control is tantamount to cure in head and neck cancer, an aggressive regimen of surgery and radiation remains the standard of care for most patients. Despite significant technical advances, these treatments are highly morbid. Further, patients who fail treatment have limited salvage options. Photodynamic therapy (PDT) and photodiagnosis (PD) of head and neck cancer offer significant potential for improved outcomes in a myriad of clinical indications ranging from in situ to recurrent disease. However, despite promising results, these modalities remain at the fringe of head and neck treatment options. Photofrin(®), Photosan and Foscan(®) are photosensitizers used clinically in head and neck PD/PDT. In addition, aminolevulinic acid (ALA), which gives origin to Protoporphyrin IX, an endogeneous photosensitizer, is also used for PD/PDT. We review the clinical literature on these photosensitizers to assist in the integration of these important modalities into the mainstream of head and neck oncological therapy.

Photodynamic therapy for chest wall recurrence from breast cancer.

Breast cancer is common with over 230,000 new cases diagnosed each year in North America alone. While great strides have been made to achieve excellent cancer control and survival, a significant minority of patients fail locally. While initial salvage to regain disease control is of the utmost importance, it is not universally successful. This leads to a therapeutic quagmire. Additional surgery, radiation and chemo-hormonal therapy are possible, but they are usually highly morbid with low success rates. Photodynamic therapy appears to be an underutilized salvage modality for this unfortunate patient population. This report analyzes and reviews the role of photodynamic therapy for patients with chest wall re-recurrence from breast cancer.

Pulmonary arteriovenous malformation.

Pulmonary arteriovenous malformations (PAVM) are rare pulmonary vascular anomalies. Although most patients are asymptomatic, PAVMs can cause dyspnoea from right-to-left shunt. Because of paradoxical emboli, various central nervous system complications have been described including stroke and brain abscess. There is a strong association between PAVM and hereditary haemorrhagic telangiectasia. Chest radiography and contrast enhanced computed tomography are essential initial diagnostic tools but pulmonary angiography is the gold standard. Contrast echocardiography is useful for diagnosis and monitoring after treatment. Most patients should be treated. Therapeutic options include angiographic embolisation with metal coil or balloon occlusion and surgical excision.

Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis.

Alveolar proteinosis (AP) is characterized by excessive surfactant accumulation, and most cases are of unknown etiology. Standard therapy for AP is whole-lung lavage, which may not correct the underlying defect. Because the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for normal surfactant homeostasis, we evaluated the therapeutic activity of GM-CSF in patients with idiopathic AP. Fourteen patients received 5 microg/kg/d GM-CSF for 6 to 12 wk with serial monitoring of the alveolar-arterial oxygen gradient ([A-a]DO2), diffusing capacity of carbon monoxide, computed tomographic scans, and exercise testing. Patients not responding to 5 microg/kg/d GM-CSF underwent stepwise dose escalation, and responding patients were retreated at disease recurrence. Stored pretreatment sera were assayed for GM-CSF-neutralizing autoantibodies. According to prospective criteria, five of 14 patients responded to 5 microg/kg/d GM- CSF, and one of four patients responded after dose escalation (20 microg/kg/d). The overall response rate was 43% (mean improvement in [A-a]DO2 = 23.2 mm Hg). Responses lasted a median of 39 wk, and were reproducible with retreatment. GM-CSF was well-tolerated, with no late toxicity seen. The only treatment-related factor predictive of response was GM-CSF-induced eosinophilia (p = 0.01). Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM- CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.

Cholelithoptysis. A complication following laparoscopic cholecystectomy.

A 59-year-old woman who underwent laparoscopic cholecystectomy for symptomatic cholecystitis presented four months later with fever, malaise, anorexia, hemoptysis and lithoptysis. Chemical analysis of the expectorated lithes revealed them to be gallstones. Ultrasound studies of the right upper quadrant demonstrated both supradiaphragmatic and subdiaphragmatic fluid collections containing echogenic fragments. ERCP failed to demonstrate retained ductal stones or fistula formation. To our knowledge, this is the first reported case of cholelithoptysis and demonstrates an unusual complication of gallstone retention following laparoscopic cholecystectomy.

Interleukin-2 directly increases albumin permeability of bovine and human vascular endothelium in vitro.

The direct effects of interleukin-2 (IL-2) on albumin permeability of cultured bovine pulmonary artery endothelial cell (BPAEC) and human arterial endothelial cell (HAEC) monolayers were studied. BPAEC were exposed to IL-2 (500 to 25,000 U/ml) for 4 h. The steady-state transfer rate of [125I]albumin across the BPAEC monolayer was 3.3 +/- 0.4%/h (n = 10) in control BPAEC (diluent alone), was significantly increased in BPAEC exposed to 500 U/ml of IL-2 (72 +/- 3% above control values, n = 6, P less than 0.02), and further increased in BPAEC exposed to 5,000 U/ml (60 +/- 2% increase above 500 U/ml values, n = 5, P less than 0.02). No further increase was noted after exposure to 25,000 U/ml of IL-2. Additionally, no further increase in [125I]albumin transfer rates was noted in BPAEC exposed to 5,000 U/ml of IL-2 for 24 versus 4 h. Similar changes were found using HAEC. Preincubation of HAEC with an anti-IL-2 low-affinity receptor antibody (anti-IL-2R alpha) inhibited the IL-2-induced permeability increase. Expression of IL-2R alpha receptors in HAEC incubated with 5,000 U/ml of IL-2 for 4 h was also found. Thus, IL-2 appears to have a direct effect on cultural arterial endothelial monolayers not requiring the presence of other cell types or serum proteins. IL-2-induced increases in endothelial macromolecular permeability may play an important role in the pathogenesis of the IL-2-induced vascular leak syndrome seen in vivo.

Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation.

To study the effects of relatively long-term interaction of antibodies with surface antigens of lung endothelium, rabbits were intravenously injected for a maximum of 4 d with goat anti-rabbit lung angiotensin-converting enzyme (Gt anti-RbACE) antibodies. On day 1 69%, on day 2 13%, and on days 3 and 4 of injection none of the rabbits developed lethal pulmonary edema. By immunofluorescence microscopy, deposits of GtIgG, frequently in association with RbC3, were found along the endothelium of alveolar capillary walls in all rabbits studied on day 1, in 57% on day 2, in 33% on day 3, and in none of them on day 4. While in vitro anti-ACE antibodies bound in a linear pattern to the lung endothelium, the binding pattern in vivo was distinctly granular. The in vivo interaction of antibodies with ACE also redistributed ACE in a granular pattern along capillary walls. In contrast to the granular deposition of injected anti-ACE IgG and F(ab')2 fragments of anti-ACE IgG, Fab fragments of anti-ACE IgG localized, without fixing C3, in a linear pattern along the endothelium of lung capillaries and did not modify the normal distribution of ACE. However, when the injection of Fab fragments of Gt anti-RbACE IgG was followed by an injection of Rb anti-GtIgG serum, granular deposits of Gt Fab fragments, RbIgG and RbC3 were seen along alveolar capillary walls. Biochemical measurement of ACE activity in lung homogenates provided data in agreement with those obtained by immunofluorescence microscopy, showing diminished activity to none on day 4, with some return of ACE activity on day 5, 24 h after the last injection of antibody, and normal values on day 21. The results obtained indicate that divalent antibodies to an antigen expressed on the plasma membrane of rabbit lung endothelial cells promotes a rapid redistribution of antigenic receptors, fixation of complement and, in surviving rabbits, disappearance of the antigen from the endothelial cells that are no longer susceptible to immune injury. In vivo "immunologic enzymectomy" induced by a ligand-surface antigen interaction is an example of antigenic modulation. These events may have an important role in the pathogenesis of inflammatory lesions induced by antibodies reacting with antigens expressed on the plasma membrane of cells in the lung and in other organs.