Ran Kremer

A nanomaterial-based breath test for short-term follow-up after lung tumor resection

UNLABELLED In this case study, we demonstrate the feasibility of nanomaterial-based sensors for identifying the breath-print of early-stage lung cancer (LC) and for short-term follow-up after LC-resection. Breath samples were collected from a small patient cohort prior to and after lung resection. Gas-chromatography/mass-spectrometry showed that five volatile organic compounds were significantly reduced after LC surgery. A nanomaterial-based sensor-array distinguished between pre-surgery and post-surgery LC states, as well as between pre-surgery LC and benign states. In contrast, the same sensor-array could neither distinguish between pre-surgery and post-surgery benign states, nor between LC and benign states after surgery. This indicates that the observed pattern is associated with the presence of malignant lung tumors. The proof-of-concept presented here has initiated a large-scale clinical study for post-surgery follow-up of LC patients. FROM THE CLINICAL EDITOR Monitoring for tumor recurrence remains very challenging due to post-surgical and radiation therapy induced changes in target organs, which often renders standard radiological identification of recurrent malignancies inaccurate. In this paper a novel nanotechnology-based sensor array is used for identification of volatile organic compounds in exhaled air that enable identification of benign vs. malignant states.

Heparanase is overexpressed in lung cancer and correlates inversely with patient survival.

Heparanase is an endo‐β‐D‐glucuronidase that is capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size (approximately 5‐7 kDa). Heparanase activity has been detected frequently in several cell types and tissues. Heparanase activity correlates with the metastatic potential of tumor‐derived cells, a correlation that has been attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the extracellular matrix barrier.

Low Integrated DNA Repair Score and Lung Cancer Risk

DNA repair is a prime mechanism for preventing DNA damage, mutation, and cancers. Adopting a functional approach, we examined the association with lung cancer risk of an integrated DNA repair score, measured by a panel of three enzymatic DNA repair activities in peripheral blood mononuclear cells. The panel included assays for AP endonuclease 1 (APE1), 8-oxoguanine DNA glycosylase (OGG1), and methylpurine DNA glycosylase (MPG), all of which repair oxidative DNA damage as part of the base excision repair pathways. A blinded population-based case–control study was conducted with 96 patients with lung cancer and 96 control subjects matched by gender, age (±1 year), place of residence, and ethnic group (Jews/non-Jews). The three DNA repair activities were measured, and an integrated DNA repair OMA (OGG1, MPG, and APE1) score was calculated for each individual. Conditional logistic regression analysis revealed that individuals in the lowest tertile of the integrated DNA repair OMA score had an increased risk of lung cancer compared with the highest tertile, with OR = 9.7; 95% confidence interval (CI), 3.1–29.8; P < 0.001, or OR = 5.6; 95% CI, 2.1–15.1; P < 0.001 after cross-validation. These results suggest that pending validation, this DNA repair panel of risk factors may be useful for lung cancer risk assessment, assisting prevention and referral to early detection by technologies such as low-dose computed tomography scanning. Cancer Prev Res; 7(4); 398–406. ©2013 AACR.

Aberrant right subclavian artery- suggested mechanism for esophageal foreign body impaction: Case report

Aberrant right subclavian artery (ARSA) is asymptomatic in most cases. This variant anatomy can cause dysphagia in elderly patients. Impaction of foreign body in the esophagus is rarely the presenting symptom of ARSA. We present an eighty four years old patient who first presented with esophageal foreign body impaction and was diagnosed with an aberrant right subclavian artery compressing the esophagus just below the site of impaction.We assume that the exact place of impaction was not incidental and that a relative narrowing of the esophagus caused by the vascular anomaly is responsible for this specific presentation.

Enzymatic MPG DNA repair assays for two different oxidative DNA lesions reveal associations with increased lung cancer risk.

DNA repair is a major mechanism for minimizing mutations and reducing cancer risk. Here, we present the development of reproducible and specific enzymatic assays for methylpurine DNA glycosylase (MPG) repairing the oxidative lesions 1,N6-ethenoadenine (εA) and hypoxanthine (Hx) in peripheral blood mononuclear cells protein extracts. Association of these DNA repair activities with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean MPG-εA in case patients was 15.8 units/μg protein (95% CI 15.3-16.3), significantly higher than in control subjects-15.1 (14.6-15.5), *P = 0.011. The adjusted odds ratio for lung cancer associated with a one SD increase in MPG-εA activity (2.48 units) was significantly bigger than 1 (OR = 1.6, 95% CI = 1.1-2.4; *P = 0.013). When activity of OGG1, a different DNA repair enzyme for oxidative damage, was included in the model, the estimated odds ratio/SD for a combined MPG-εA-OGG1 score was 2.6 (95% CI 1.6-4.2) *P = 0.0001, higher than the odds ratio for each single assay. The MPG enzyme activity assays described provide robust functional risk biomarkers, with increased MPG-εA activity being associated with increased lung cancer risk, similar to the behavior of MPG-Hx. This underscores the notion that imbalances in DNA repair, including high DNA repair, usually perceived as beneficial, can cause cancer risk. Such DNA repair risk biomarkers may be useful for risk assessment of lung cancer and perhaps other cancer types, and for early detection techniques such as low-dose CT.

Development of APE1 enzymatic DNA repair assays: low APE1 activity is associated with increase lung cancer risk

Summary We developed radioactivity-based and fluorescence-based assays for the DNA repair enzyme APE1 and showed that its decreased activity is associated with increased lung cancer risk. This suggests that ‘bad DNA repair’ rather than ‘bad luck’ is involved in cancer etiology.

The Role of Pain Catastrophizing in the Prediction of Acute and Chronic Postoperative Pain

Background and Objectives: Despite the established association between greater pain catastrophizing and enhanced postoperative pain, it is still unclear: (i) what is the relative contribution of each of the pain catastrophizing scale (PCS) dimensions in the prediction of acute and chronic postoperative pain; and (ii) whether PCS scores mediate the association between acute and chronic postoperative pain intensity. Methods: The current prospective, observational study was conducted at Rambam Health Care Campus, Haifa, Israel. PCS was obtained in 48 pain-free patients a day before an elective thoracotomy in response to tonic heat pain. Acute postthoracotomy pain (APTP) was assessed during rest, including general pain (Rest general ), and incision-related pain (Rest incision ), and in response to provoked physical activity, including hand elevation (Provoked hand ) and cough (Provoked- cough ). Chronic postthoracotomy pain (CPTP) was assessed after 4.5±2.3 months. Results: Of the PCS subscales, only rumination: (i) was correlated with Rest general scores (r=0.337, P=0.027); and (ii) predicted chronic postthoracotomy pain in a regression analysis (P=0.001). General PCS and its subscales mediated the correlation between Rest general and chronic postthoracotomy pain intensity (Ps<0.006). Conclusions: Findings may elucidate the unique role of the rumination subscale in reflecting an individuals postoperative acute and chronic pain responsiveness. The transition from acute to chronic postoperative pain seems to be facilitated by enhanced pain catastrophizing.

Lower lung cancer rates in Jewish smokers in Israel and the USA

Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non‐Jews in Israel and in the United States. Data were derived from a population‐based, case–control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case–control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non‐Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90–7.31 and OR = 2.10, 1.36–3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34–10.90 and OR = 8.50, 5.94–12.17) but were significantly higher in Israeli non‐Jewish men (OR = 12.96, 4.83–34.76) and US non‐Jewish men and women (OR = 11.33, 9.09–14.12 and OR = 12.78, 10.45–15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non‐Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non‐Jewish smokers in different areas of the world.

C-Reactive Protein Predicts Pleurodesis Success in Malignant Pleural Effusion Patients

Dear Editor: Malignant pleural effusions (MPEs) often cause debilitating symptoms that result in impaired quality of life. The limited clinical success of pleurodesis necessitates MPE management advancement. The clinical predictive value of objective markers, such as pH and adenosine deaminase, is still debated. The goal of the current study was to explore an objective indicator attesting to whether or not an MPE patient would benefit from talc pleurodesis. We hypothesized that C-reactive protein (CRP) levels in the intrapleural fluid would predict the clinical improvement in the patient’s condition after talc installation objectively, as reflected by chest x-ray (CXR), and subjectively, via reports of respiratory symptoms, both evaluated one month posttreatment. The underlying rationale was that CRP levels represent an existing inflammation, and therefore the attempt to further induce a local inflammatory reaction via the installation of a chemical agent in the pleural space would be clinically constructive. The current prospective study included 63 consecutive patients with symptomatic MPE, 35 of whom were included in the final analyses. Four grams of talc mixed in 150 ml of saline were administered after complete drainage of the pleural effusion. Based on posttreatment CXR evaluations, pleurodesis was successful in 19 patients (54.29%). Based on subjective reports, pleurodesis was successful in 17 patients (48.58%). The subjective success criterion was in excellent agreement with the objective success criterion (j = 0.942). Of age, gender, CRP, pH, total protein, and lactate dehydrogenase, logistic regression analyses indicated that CRP was the sole predictor for the success of the pleurodesis procedure assessed objectively by CXR (P = 0.018), while CRP and age were the sole predictors for pleurodesis success assessed subjectively (P = 0.042). CRP levels in the patients who underwent a successful pleurodesis versus unsuccessful pleurodesis were different, based on posttreatment evaluations, both objective (CXR; P = 0.021) and subjective (individual reports; P = 0.039). MPE patients with CRP levels ‡ 30 mg/L will most probably undergo a successful pleurodesis procedure, as assessed both objectively by CXR and subjectively by individual reports (P < 0.0001). Due to the pleurodesis failure and high complication rates, it is reasonable to determine the patients in whom the pleurodesis procedure will succeed. Pleurodesis success rates among malignant pleural effusion patients may be as low as 47%. However, of the 10 malignant pleural effusion patients of the current study, who demonstrated CRP levels greater than the critical threshold of 30 mg/L, 9 patients (90%) were successfully treated by pleurodesis. Bielsa and colleagues reported that malignant effusions specifically due to lung cancer are particularly prone to a failed procedure. In the current study group, of the six lung cancer patients, five (83.3%) demonstrated a successful pleurodesis using the aforementioned CRP threshold value. In conclusion, pleural effusion CRP levels may reliably predict pleurodesis success and symptomatic failure among MPE patients. Therefore, it may be advantageous when selecting patients for pleurodesis to incorporate in the clinic routine tests of pleural fluid CRP levels.

Patient derived xenografts (PDX) predict an effective heparanase-based therapy for lung cancer

Heparanase, the sole heparan sulfate (HS) degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby facilitating cell invasion and regulating the bioavailability of heparin-binding proteins. HS mimicking compounds that inhibit heparanase enzymatic activity were examined in numerous preclinical cancer models. While these studies utilized established tumor cell lines, the current study utilized, for the first time, patient-derived xenografts (PDX) which better resemble the behavior and drug responsiveness of a given cancer patient. We have previously shown that heparanase levels are substantially elevated in lung cancer, correlating with reduced patients survival. Applying patient-derived lung cancer xenografts and a potent inhibitor of heparanase enzymatic activity (PG545) we investigated the significance of heparanase in the pathogenesis of lung cancer. PG545 was highly effective in lung cancer PDX, inhibiting tumor growth in >85% of the cases. Importantly, we show that PG545 was highly effective in PDX that did not respond to conventional chemotherapy (cisplatin) and vice versa. Moreover, we show that spontaneous metastasis to lymph nodes is markedly inhibited by PG545 but not by cisplatin. These results reflect the variability among patients and strongly imply that PG545 can be applied for lung cancer therapy in a personalized manner where conventional chemotherapy fails, thus highlighting the potential benefits of developing anti-heparanase treatment modalities for oncology.