Modified oxygen mask to induce target levels of hyperoxia and hypercarbia during radiotherapy: A more effective alternative to carbogen

Purpose: Carbogen has long been under investigation as an adjuvant to radiotherapy of tumors. A major factor confounding its evaluation is its inconsistency in raising blood partial pressure of CO₂ (pCO₂). We investigated whether a new partial rebreathing method would provide better control of pCO₂ than carbogen.

Methods and materials: We compared the efficacy of each method in 10 healthy volunteers. Volunteers breathed 1.5, 3 and 5% carbogen in 5-min stages via the usual non-rebreathing circuit. All the volunteers then breathed 100% O₂ through a commercial sequential gas delivery (SGD) circuit modified by attaching a reservoir to its exhalation port. Hypercarbia was induced by step reductions in oxygen flow to the SGD circuit. We monitored minute ventilation and end-tidal pCO₂ (ETpCO₂) as a surrogate for its arterial value.

Results: Inhalation of 1.5 and 3% carbogen did not increase ETpCO₂ from baseline (40 ± 1.5 mmHg); 5% carbogen increased ETpCO₂ to 45 ± 1.6 mmHg (p < 0.001). With the SGD circuit, reducing O₂ flow to 4.3 ± 0.7 l/min increased ETpCO₂ in all subjects from 41 ± 2.0 mmHg (baseline) to 46 ± 2.1 mmHg (p < 0.001). Voluntary hyperventilation reduced ETpCO₂ with 5% carbogen but not with SGD (p = 0.379).

Conclusions: We confirm previous observations that carbogen inhalation does not result in a predictable rise in ETpCO₂ and suggest that a precise and stable target ETpCO₂ can instead be induced by simply controlling O₂ flow into a modified SGD circuit. We hoped that the reliable control of pCO₂ will enable studies that address first, the efficacy of raising ETpCO₂ on specific tumor blood flow, and eventually, its benefit as an adjuvant to radiotherapy.     

Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia

Liver diseases and regeneration are associated with hemodynamic changes denoting pathological alterations. Determining and monitoring physiological and pathological liver changes is essential for diagnostic and therapeutic objectives. Our aim was to determine the feasibility of functional magnetic resonance imaging (fMRI) during hypercapnia and hyperoxia for monitoring liver pathology. Liver fMRI images were acquired in rodents following acute bleeding, partial hepatectomy, and fibrosis. Results were quantitated and confirmed by histology. Changes induced by hyperoxia and hypercapnia following hemorrhage significantly correlated with the percentage of blood loss, reflecting lower liver perfusion and diminished vessel responsiveness to gas saturation. Hepatectomy resulted in an early decline in signal intensity changes due to hyperoxia, suggesting a decrease in liver perfusion and blood content. Following hepatectomy, signal intensity changes due to hypercapnia increased, signifying a change in liver perfusion from a mainly portal to a more arterial source. Two weeks after induction of fibrosis, signal intensity changes due to hypercapnia became much lower and those due to hyperoxia were much higher than those in normal livers, reflecting the increased perfusion due to the inflammatory process as confirmed by histologic analysis. With fibrosis progression, signal intensity changes induced by hypercapnia and hyperoxia were gradually attenuated, indicating structural and functional alterations of the liver vasculature during fibrosis. CONCLUSION: In various liver pathologies, fMRI response to hypercapnia and hyperoxia is sensitive to changes in liver hemodynamic status involved in hepatic damage or recovery; thus, this technique may offer an additional noninvasive diagnostic tool for evaluation and follow-up of liver diseases by means of examining perfusion-related alterations.     

Reply to ‘Indication bias or protopathic bias?’

Aim

The aim of the study was to characterize the extent of indication bias resulting from the excessive use of NSAIDs on the days preceding a spontaneous abortion to relieve pain.

Methods

We used data from a retrospective cohort study assessing the risk for spontaneous abortions following exposure to NSAIDs. Three definitions of exposure for cases of spontaneous abortions were compared, from the first day of pregnancy until the day of spontaneous abortion and until 3 and 2 days before a spontaneous abortion. Statistical analysis was performed using multivariate time programmed Cox regression.

Results

A sharp increase was observed in the dispensation of indomethacin, diclofenac and naproxen, and a milder increase was found in the use of ibuprofen during the week before a spontaneous abortion. Non- selective COX inhibitors in general and specifically diclofenac and indomethacin were found to be associated with spontaneous abortions when the exposure period was defined until the day of spontaneous abortion (hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04, 1.28; HR 1.31, 95% CI 1.08, 1.59 and HR 3.33, 95% CI 2.09, 5.29, respectively). The effect disappears by excluding exposures occurring on the day before the spontaneous abortion for non-selective COX inhibitors and on the last week before the spontaneous abortion for indomethacin. In general, decreasing HRs were found with the exclusion of exposures occurring on the days immediately before the spontaneous abortion.

Conclusions

The increased use of NSAIDs during the last few days that preceded a spontaneous abortion to relieve pain associated with the miscarriage could bias studies assessing the association between exposure to NSAIDs and spontaneous abortions.     

Effects of lovastatin therapy on LDL receptor activity in circulating monocytes and on structure and composition of plasma lipoproteins

The effect of lovastatin therapy on LDL-receptor activity in fresh monocytes and on the structure and composition of lipoproteins was determined in 9 patients with familial hypercholesterolemia (FH) and 8 patients with non-familial hypercholesterolemia (NFH). Lovastatin reduced LDL-cholesterol levels by 34.8 and 47.5%, respectively, in the 2 groups of patients, and plasma apo B levels by 33.3 and 42.5%. LDL receptor activity in fresh monocytes increased by 53% and 86% respectively. HDL-cholesterol and plasma apo A-I levels increased only in the NFH group, by 10.2 and 7.1%. Lipoproteins were separated by centrifugation on a zonal rotor. Except for the intermediate density lipoprotein (IDL) fraction, no changes were observed in the structure and composition of the various lipoproteins. The investigations thus demonstrated that lovastatin therapy is associated with a measurable and significant increase of LDL-receptor activity in circulating monocytes that may contribute to the lipid lowering action of the drug.     

Successful splenectomy in May-Hegglin anomaly: report of a case with platelet kinetic studies

Bleeding diathesis is not necessarily one of the conspicuous and serious characteristics of the macrothrombocytopenic syndromes, which include the May-Hegglin anomaly. Nevertheless, occasionally prolonged bleeding time may endanger organs or even life. We report a case of a young girl with severe thrombocytopenia due to May-Hegglin anomaly, who was facing blindness because of intraocular haemorrhages. Being unable to intervene in the pathogenesis of the disease, we performed splenectomy after proving splenic sequestration of platelets. This procedure allowed the performance of a successful bilateral vitrectomy.     

Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2

Ovarian carcinoma patients are initially responsive to platinum-based therapy, but eventually become refractory to treatment due to the development of platinum chemoresistance. Elevated levels of interleukin-6 (IL-6) in the sera and ascites of these patients predict poor clinical outcome. Our goal was to analyze the interaction between cisplatin and cisplatin-resistant ovarian cancer cells, and to identify means of circumventing platinum resistance. We studied ovarian carcinoma cell lines and cells drawn from ovarian carcinoma patients. Gene array analyses were performed on ovarian carcinoma cells upon treatment with cisplatin, and the results were validated by ELISA and Western blotting (WB). Cytotoxicity assays were performed on anti-IL-6 Ab-, IL-6-, and cellular inhibitor of apoptosis 2 (cIAP-2) siRNA-treated cells, following cisplatin addition. Our results revealed a highly significant increase in IL-6 and cIAP-2 mRNA and protein levels upon treatment with cisplatin. WB analysis of cisplatin-treated cells exhibited decreased cIAP-2 expression level following anti-IL-6 Ab addition. Furthermore, IL-6 by itself, significantly increased cIAP-2 levels in ovarian carcinoma cells. Finally, cytotoxicity assays showed sensitization to cisplatin following the addition of IL-6 and cIAP-2 inhibitors. In conclusion, cisplatin treatment of ovarian carcinoma cells upregulates IL-6 and cIAP-2 levels while their inhibition significantly sensitizes them to cisplatin. Here, we present cIAP-2 as a novel inducer of platinum resistance in ovarian carcinoma cells, and suggest an axis beginning with an encounter between cisplatin and these cells, mediated sequentially by IL-6 and cIAP-2, resulting in cisplatin resistance. Consequently, we propose that combining IL-6/cIAP-2 inhibitors with cisplatin will provide new hope for ovarian carcinoma patients by improving the current treatment.     

Novel Method for Real Time Co‐Registration of IVUS and Coronary Angiography

Objectives

We present our experience with a novel method for real time co‐registration of intravascular ultrasound (IVUS) and coronary angiography.

Background

A major limitation of the current practice of concomitant use of coronary angiography and IVUS is that the locations of the acquired IVUS images are not correlated with their exact locations on the vessel roadmap obtained by coronary angiography.

Methods

Phantoms simulating the coronary tree were used to test the accuracy and potential of co‐registration. Subsequently we examined patients who underwent IVUS during cardiac catheterization. Analysis and feasibility were performed in 42 arteries of 36 patients.

Results

The statistical validation in phantoms resulted in a co‐registration accuracy of 1.12 mm. The length measurement on an angiogram resulted in an accuracy of 0.38 mm. Co‐registration in patients was successful in all cases and four categories were assisted by 1(bad) to 5 (good) grading. Accuracy (the co‐registration precision in pointing at the exact corresponding location): 4.8±0.41; Ease of use and workflow: 4.74±0.44; Stent landing zone detection and evaluation: 4.58±0.5; Stent landing zone length and diameter measurement: 4.94±0.23. The co‐registration error was estimated as no more than 1 mm.

Conclusion

In this pilot study, we found that the novel IVUS and coronary angiography co‐registration method is accurate, easy to use, fast and user‐friendly. This method precludes the need to use motorized automated pull back device. (J Interven Cardiol 2016;29:225–231)