Is There a Role for Percutaneous Ablation for Early Stage Lung Cancer? What Is the Evidence?

PURPOSE OF REVIEW: For patients with early stage non-small-cell lung cancer (NSCLC), thermal ablation (TA) has become in the least two decades an option of treatment used worldwide for patients with comorbidities who are not surgical candidates. Here, we review data published with different TA techniques: radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation. This paper reviews also the comparison that has been made between TA and stereotactic radiotherapy (SBRT). RECENT FINDINGS: A majority of retrospective studies, the absence of comparative studies, and the variety of techniques make difficult to get evident data. Nevertheless, these stand-alone techniques have demonstrated local efficacy for tumors less than 3 cm and good tolerance on fragile patients. Many recent reviews and database analyses show that outcomes after TA (mainly RFA and MWA) are comparable to SBRT in terms of survival rates. For patients who are unfit for surgery, TA has demonstrated interesting results for safety, benefits in overall survival, and acceptable local control.

Percutaneous thermal ablation of lung tumors - Radiofrequency, microwave and cryotherapy: Where are we going?

Main indications of percutaneous pulmonary thermal ablation are early stage non-small cell lung carcinoma (NSCLC) for patients who are not amenable to surgery and slow-evolving localized metastatic disease, either spontaneous or following a general treatment. Radiofrequency ablation (RFA) is the most evaluated technique. This technique offers a local control rate ranging between 80 and 90% for tumors <3cm in diameter. Other more recently used ablation techniques such as microwaves and cryotherapy could overcome some limitations of RFA. One common characteristic of these techniques is an excellent tolerance with very few complications. This article reviews the differences between these techniques when applied to lung tumors, indications, results and complications. Future potential associations with immunotherapy will be discussed.

Percutaneous thermal ablation of primary lung cancer.

Percutaneous ablation of small-size non-small-cell lung cancer (NSCLC) has demonstrated feasibility and safety in nonsurgical candidates. Radiofrequency ablation (RFA), the most commonly used technique, has an 80-90% reported rate of complete ablation, with the best results obtained in tumors less than 2-3cm in diameter. The highest one-, three-, and five-year overall survival rates reported in NSCLC following RFA are 97.7%, 72.9%, and 55.7% respectively. Tumor size, tumor stage, and underlying comorbidities are the main predictors of survival. Other ablation techniques such as microwave or cryoablation may help overcome the limitations of RFA in the future, particularly for large tumors or those close to large vessels. Stereotactic ablative radiotherapy (SABR) has its own complications and carries the risk of fiducial placement requiring multiple lung punctures. SABR has also demonstrated significant efficacy in treating small-size lung tumors and should be compared to percutaneous ablation.

Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53.

The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1(+/-) mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.

HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation.

Che-1/AATF is an RNA polymerase II-binding protein that is involved in the regulation of gene transcription, which undergoes stabilization and accumulation in response to DNA damage. We have previously demonstrated that following apoptotic induction, Che-1 protein levels are downregulated through its interaction with the E3 ligase HDM2, which leads to Che-1 degradation by ubiquitylation. This interaction is mediated by Pin1, which determines a phosphorylation-dependent conformational change. Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation. HIPK2 interacts with Che-1 and, upon genotoxic stress, phosphorylates it at specific residues. This event strongly increases HDM2/Che-1 interaction and degradation of Che-1 protein via ubiquitin-dependent proteasomal system. In agreement with these findings, we found that HIPK2 depletion strongly decreases Che-1 ubiquitylation and degradation. Notably, Che-1 overexpression strongly counteracts HIPK2-induced apoptosis. Our results establish Che-1 as a new HIPK2 target and confirm its important role in the cellular response to DNA damage.

Effects of acute blood volume expansion on respiratory mechanics in the rat.

BACKGROUNDS: The effects of acute blood volume expansion (BVE) on the respiratory mechanics of normal animals have been not extensively studied. The subject is of both theoretical and practical interest since BVE is a frequent medical intervention, and the associated increase in cardiac output may occur in different physiopathological situations. OBJECTIVES: To describe the changes in the parameters of respiratory mechanics occurring as an effect of acute BVE and the related increase in cardiac output. METHODS: We applied the end-inflation occlusion method in normal, positive pressure-ventilated rats to measure the respiratory mechanics under control and BVE conditions. RESULTS: Under BVE conditions, we found a statistically significant increase in static respiratory system elastance (E(st,rs)), ohmic airway resistance plus resistance of respiratory system tissues to movement (R(min,rs)), and overall resistance including pendelluft and stress relaxation effects (R(max,rs)). Under BVE conditions, the resistive component due to sole stress relaxation and pendelluft (R(visc,rs)) increased almost significantly while a significant increment in mean respiratory system hysteresis surface area (Hy(rs)) was also found. CONCLUSIONS: Increasing pulmonary blood flow by BVE increases the mechanical work of breathing because of the effects on E(st,rs), R(min,rs) and R(max,rs), and because of the increase in Hy(rs).

Anesthesia and myotonic dystrophy (Steinert's syndrome). The role of total intravenous anesthesia with propofol, cisatracurium and remifentanyl. Case report.

Anesthesia for patients with Steinert's syndrome (myotonic dystrophy, MD) is a challenge for the anaesthetist. MD is a multisystemic disease and the neuromuscular symptoms can be associated with sleep apnea, endocrine disorders (diabetes, hypogonadism, hypothyroidism), cardiac, gastroenteric or cognitive disorders (mental deficiency, attention disorders). The diagnosis is facilitated when one or more of these symptoms are associated with the neuromuscular symptoms; however, the latter are not always present at the onset, which makes the diagnosis of MD a difficult and often late one. The choice of drugs and the choice of anesthesia in these patients can be very challenging for many reasons. A myotonic crisis can be triggered by several factors including hypothermia, shivering and mechanical or electrical stimulation. These patients are very sensitive to the usual anesthetics such as hypnotics and paralyzing agents (both depolarizing and nondepolarizing). The following case report describes pathophysiological considerations and a technique for anaesthesia during thoracic surgery that has been able to assure hemodynamic peroperative stability, early extubation and prolonged respiratory autonomy in a patient affected by this genetic disorder.

Evaluation of two anesthetic techniques for hemodynamic control during carotid surgery. Preliminary results.

BACKGROUND: To evaluate two anesthetic techniques for hemodynamic control during carotid TEA surgery and early post-surgery. METHODS: Two study groups treated by carotid surgery were compared; the Fentanyl group consisted of 7 patients in ASA class 3, the Remifentanil-Sevoflorane group included 12 patients in ASA class 3. The double product was monitored on entry to the operating room, at 5, 15, 30 min after induction of anesthesia and tracheal intubation, and at 30 min after extubation. Time of extubation, re-awakening and attention levels during early post-surgery, and myocardial ischemia markers were monitored for 48 h after surgery in the Remifentanil group. RESULTS: Statistical analysis using Student's "t"-test for paired data showed that the double product indicated better hemodynamic stability in the patients who received Remifentanil-Sevoflorane than in those who received Fentanyl. CONCLUSIONS: Compared with anesthesia using Fentanyl and with locoregional techniques, anesthesia with Remifentanil-Sevoflorane in carotid surgery provides a valuable alternative and secures good hemodynamic stability.

Cardiac output measurement by the thermodilution method: an in vitro test of accuracy of three commercially available automatic cardiac output computers.

OBJECTIVE: To describe the accuracy and the reproducibility of the thermodilution flow measurements obtained using 3 commercially available cardiac output computers commonly used in intensive care units. DESIGN: An experimental "in vitro" study. Twelve different values of control flow (Qctr) were measured (Qmsr) using 3 different cardiac output computers (Abbott Critical Care System, Oximetrix 3 SvO2/CO Computer, Baxter Oximeter/Cardiac Output Computer SAT-1; American Edwards Laboratories, 9520 A Cardiac Output Computer). Standard equipment and techniques were employed, taking account of the specific weight and heat of warm water relative to blood. In addition, separate sets of measurements were performed in order to investigate the effect on Qmsr of some variables which may influence the "indicator" loss (time for injection, depth of immersion of the catheter, temperature of the injected fluid). SETTING: Our laboratory, inside the intensive care unit. MEASUREMENTS AND RESULTS: The analysis of the linear regression of Qmsr versus Qctr (r values between 0.992 and 0.984; residual standard deviation values comprised between 0.24 and 0.49 l/min; intercepts and slopes not significantly different from identity line), the values of the percentage errors (PE = [Qctr-Qmsr].100/Qctr; PE mean values 7.9, 5.0 and 13.1), and those of the coefficients of variability (CV = standard deviation mean value, %; CV mean values 5.4, 5.8 and 4.6), show a good level of accuracy and reproducibility of the measurements. Our data confirm previously reported results. Furthermore, the cumulative effect of variables capable of influencing the "indicator" loss, even if corrected according to the "calculation constant" the manufacturers provide, was found to result in statistically significant changes of Qmsr. CONCLUSION: The accuracy and reproducibility of the automatic cardiac computers tested is sufficient for practical clinical purpose. It may also depend on the modality of injection of the cooling bolus, which may significantly influence the effective "indicator" losses.