John Keech

O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

A Prospective Study of Chronic Pain after Thoracic Surgery

Background: The goal of this study was to detect the predictors of chronic pain at 6 months after thoracic surgery from a comprehensive evaluation of demographic, psychosocial, and surgical factors. Methods: Thoracic surgery patients were enrolled 1 week before surgery and followed up 6 months postsurgery in this prospective, observational study. Comprehensive psychosocial measurements were assessed before surgery. The presence and severity of pain were assessed at 3 and 6 months after surgery. One hundred seven patients were assessed during the first 3 days after surgery, and 99 (30 thoracotomy and 69 video-assisted thoracoscopic surgery, thoracoscopy) patients completed the 6-month follow-up. Patients with versus without chronic pain related to thoracic surgery at 6 months were compared. Results: Both incidence (P = 0.37) and severity (P = 0.97) of surgery-related chronic pain at 6 months were similar after thoracotomy (33%; 95% CI, 17 to 53%; 3.3 ± 2.1) and thoracoscopy (25%; 95% CI, 15 to 36%; 3.3 ± 1.7). Both frequentist and Bayesian multivariate models revealed that the severity of acute pain (numerical rating scale, 0 to 10) is the measure associated with chronic pain related to thoracic surgery. Psychosocial factors and quantitative sensory testing were not predictive. Conclusions: There was no difference in the incidence and severity of chronic pain at 6 months in patients undergoing thoracotomy versus thoracoscopy. Unlike other postsurgical pain conditions, none of the preoperative psychosocial measurements were associated with chronic pain after thoracic surgery.

Erratum: O2 ⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate (Cancer Cell (2017) 32 (2)(268) (S1535610817300624) (10.1016/j.ccell.2017.02.018))

Joshua D. Schoenfeld1, Zita A. Sibenaller1, Kranti A. Mapuskar1, Brett A. Wagner1, Kimberly L. Cramer-Morales1, Muhammad Furqan2, Sonia Sandhu2, Thomas L. Carlisle2, Mark C. Smith1, Taher Abu Hejleh2, Daniel J. Berg2, Jun Zhang2, John Keech3, Kalpaj R. Parekh3, Sudershan Bhatia1, Varun Monga2, Kellie L. Bodeker1, Logan Ahmann1, Sandy Vollstedt1, Heather Brown1, Erin P. Shanahan Kauffman2, Mary E. Schall2, Ray J. Hohl2, Gerald H. Clamon2, Jeremy D. Greenlee4, Matthew A. Howard4, Michael K. Shultz5, Brian J. Smith6, Dennis P. Riley7, Frederick E. Domann1, Joseph J. Cullen3, Garry R. Buettner1, John M. Buatti1, Douglas R. Spitz1,*,#, and Bryan G. Allen1,* 1Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, 52242, USA

Exposure of Difficult Left Hilum in Bilateral Sequential Lung Transplantation

Left hilar exposure can be challenging during bilateral sequential lung transplantation, particularly in patients with idiopathic pulmonary fibrosis due to the overlying heart and limited space. We describe a cost-effective technique that has been used in off-pump cardiopulmonary bypass to retract the heart away from the left hilum, without causing hemodynamic instability, thereby allowing implantation of the left lung without the use of cardiopulmonary bypass.

Lobar versus sub-lobar surgery for pulmonary typical carcinoid, a population-based analysis

Background The optimal surgery for resectable pulmonary typical carcinoid (TC), e.g., lobar resection (L-R) vs. sub-lobar resection (SL-R), is controversial. This is further explored in this population-based study. Methods The Surveillance, Epidemiology, and End Results (SEER) Program was used to select patients ≥66 years old, and diagnosed between 2000 and 2012 with pulmonary TC. A similar cohort was developed using the SEER-Medicare database (diagnosed from 2000-2007) to identify chemotherapy (CTX) use and co-morbidity. Five-year survival was calculated using univariate and multivariate analysis. Results A total of 1,506 and 512 patients were identified from SEER and SEER-Medicare, respectively. In the SEER cohort, 49%, 29% and 21% received L-R, SL-R, and no surgery (NS), respectively. Those who received NS were older (P<0.001), had a higher stage (P<0.001), greater comorbidity (P<0.001), and were more likely to receive radiotherapy (XRT) (P<0.001) and CTX (P<0.001). Relative survival was nearly 100% for those who received L-R or SL-R as opposed to 72% for those who received NS (P<0.001). Cox models showed no survival difference for L-R vs. SL-R (HR 1.1, P=0.663), but worse survival for those who received NS vs. L-R or SL-R (HR 3.6, P<0.001). XRT in NS cohort was associated with increased risk of death (HR 2.3, P=0.017). Conclusions SL-R was better than NS, and similar to L-R in terms of survival. SL-R should be considered over NS if L-R is unfeasible. Role of adjuvant CTX and XRT is unclear as these did not improve survival in this study.

Screening Patients with Esophageal Cancer to Determine Eligibility for Adjuvant Treatment Trials

Background: The tolerability of adjuvant chemotherapy in esophageal cancer is unclear. Patients and Methods: This was a phase II trial of adjuvant paclitaxel in patients with esophageal cancer after trimodality treatment. Patients with residual viable tumor after resection were eligible for study inclusion. Treatment was 80 mg/m2 paclitaxel intravenously on days 1, 8, and 15 every 28 days for total of two cycles. The primary objective was to determine whether 75% or more of the patients would tolerate 240 mg/m2 or more of paclitaxel, which corresponded to 50% or more of the total planned dose. Results: Eleven out of the 12 enrolled patients (92%, 95% confidence interval (CI)=62-100%) were able to complete at least 50% of the planned paclitaxel dose. Median progression-free survival was 7 months (95% CI=2-28 months). Median overall survival was 28 months (95% CI=12-36 months). Only one patient experienced a grade 4 adverse event. Conclusion: Screening patients with esophageal cancer after trimodality treatment might improve completion of adjuvant trials.

Prolonged Air Leak After Lung Resection and Emphysema

M IS C E L L A N E O U S the prolapsed posterior leaflet, it is important to place expanded polytetrafluoroethylene neochordae on both the prolapsed leaflet and papillary muscles. The advantage of the authors’ repair technique is that it avoids systolic anterior motion that may occur by anterior shift of the coaptation point [2]. In most cases of posterior leaflet prolapse, the prolapse is segmental but not wide. In addition, systolic anterior motion can occur only when the edge of the large posterior leaflet is adjusted to that of the anterior leaflet at the same level to achieve coaptation. The leaflet portion 1.5 cm away from the annulus can be adjusted to the leaflet coaptation level by tightening the neochordae that hold the free edge of the large prolapsed leaflet during saline tests, so the remnant tissue of the large leaflet is located below the real coaptation and closer to the papillary muscle (Fig 1). As a result, the anterior (remnant) portion of the large leaflet becomes the upper part of the neochordae. The repaired posterior leaflet does not cause systolic anterior motion, and the leaflet suture knots are placed below the coaptation. In cases of the posterior leaflet prolapse, the affiliated posterior papillary muscle head is frequently too narrow and weak to hold the neochordae sutures. The neochordae sutures should be fixed to the thick base of the anterior papillary muscle head as a mattress suture with a pledget (Fig 1) or to the groove between the anterior and posterior papillary muscle heads. The location and direction of the neochordae are important for coaptation and smooth motion of the posterior leaflet.

Response to “Editorial on pain following thoracic surgery”

We appreciate Holm et al.’ s interest in our paper (1). By design, our study was not powered to answer each secondary result. This point was already acknowledged in the limitations section. The primary outcome variable of our study was the incidence of chronic pain, at 6 months, for any patient undergoing thoracic surgery. We tested the primary hypothesis of whether variables from preoperative evaluation can predict chronic pain after thoracic surgery. Based on our data from 99 patients who were followed for 6 months, the answer was no. Acute postsurgical pain was the only covariate associated with the presence of chronic pain.

Response to “VATS vs. thoracotomy regarding postoperative chronic pain”

The first point made by the commentary was related with “The definition of the primary endpoint (chronic pain after 6 months in relation to what?)”. The International Association for the Study of Pain (1) defines chronic postsurgical pain as pain persisting at least 3 months after surgery. The primary outcome variable of our study was chronic pain related to thoracic surgery (yes/no) at 6 months after surgery, based on the following question: “Do you currently have pain related to your thoracic surgery?” Those patients with chronic pain related to thoracic surgery at 6 months after surgery were compared to those patients without such pain at that time.