The IASLC Lung Cancer Staging Project: Proposals for Revision of the Classification of Residual Tumor after Resection for the Forthcoming (9th) Edition of the TNM Classification of Lung Cancer.

The goal of surgical resection is to completely remove a cancer; it is useful to have a system to describe how well this was accomplished. This is captured by the residual tumor (R) classification, which is separate from the TNM classification that describes the anatomic extent of a cancer independent of treatment. The traditional R-classification designates as R0 a complete resection, as R1 a macroscopically complete resection but with microscopic tumor at the surgical margin, and as R2 a resection that leaves gross tumor behind. For lung cancer, an additional category encompasses situations in which the presence of residual tumor is uncertain. This paper represents a comprehensive review of evidence regarding these R categories and the descriptors thereof, focusing on studies published after the year 2000 and with adjustment for potential confounders. Consistent discrimination between complete, uncertain, and incomplete resection is demonstrated with respect to overall survival. Evidence regarding specific descriptors is generally somewhat limited and only partially consistent; nevertheless, the data suggests retaining all descriptors but with clarifications to address ambiguities. Based on this review, the R-classification for the 9th edition of stage classification of lung cancer is proposed to retain the same overall framework and descriptors, with more precise definitions of descriptors. These refinements should facilitate application as well as further research.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented. METHODS: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability. RESULTS: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer. CONCLUSIONS: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex.

Low-dose X-ray radiation induces an adaptive response: A potential countermeasure to galactic cosmic radiation exposure.

Space exploration involves many dangers including galactic cosmic radiation (GCR). This class of radiation includes high-energy protons and heavy ionizing ions. NASA has defined GCR as a carcinogenic risk for long-duration space missions. To date, no clear strategy has been developed to counter chronic GCR exposure. We hypothesize that preconditioning cells with low levels of radiation will be protective from subsequent higher radiation exposures. H9C2 cells were pretreated with 0.1 to 1.0 Gy X-rays. The challenge radiation exposure consisted of either 8 Gy X-rays or 75 cGy of GCR, using a five-ion GCRsim protocol. A cell doubling time assay was used to determine cell viability. An 8 Gy X-ray challenge alone significantly (P < 0.05) increased cell doubling time compared to the no-radiation control group. Low-dose radiation pre-treatment ameliorated the 8 Gy X-ray-induced increases in cell doubling time. A 75 cGy GCR challenge alone significantly increased cell doubling time compared to the no-radiation group. Following the 75 cGy challenge, only the 0.5 and 1.0 Gy pre-treatment ameliorated the 75 cGy-induced increases in cell doubling time. DNA damage or pathological oxidant stress will delay replicative functions and increase cell doubling time. Our results suggested that pretreatment with low-dose X-rays induced an adaptive response which offered a small but significant protection against a following higher radiation challenge. Although perhaps not a practical countermeasure, these findings may serve to offer insight into cell signalling pathways activated in response to low-dose irradiation and targeted for countermeasure development.

An initiative to assess and improve the resources and patient care processes used among Chest Wall Injury Society collaborative centers (CWIS-CC2).

BACKGROUND: Over the last two decades, the acute management of rib fractures has changed significantly. In 2021, the Chest Wall injury Society (CWIS) began recognizing centers who epitomize their mission as CWIS Collaborative Centers (CWIS-CC). The primary aim of this study was to determine the resources, surgical expertise, access to care, and institutional support that are present among centers. METHODS: A survey was performed including all CWIS-CC evaluating the resources available at their hospital for the treatment of patients with chest wall injury. Data about each Chest Wall Injury Center (CWIC) care process, availability of resources, institutional support, research support, and educational offerings were recorded. RESULTS: Data was collected from 20 trauma centers resulting in an 80% response rate. These trauma centers were made up of 5 international and 15 US based trauma centers. Eighty percent (16/20) have dedicated care team members for the evaluation and management of rib fractures. Twenty-five percent (5/20) have a dedicated rib fracture service with a separate call schedule. Staffing for chest wall injury clinics consists of a multidisciplinary team: with attending surgeons in all clinics, 80%(8/10) with APPs and 70%(7/10) with care coordinators. Forty percent(8/20) of centers have dedicated rib fracture research support and 35%(7/20) have SSRF-related grants. Forty percent (8/20) of centers have marketing support and 30%(8/20) have a web page support to bring awareness to their center. At these trauma centers, a median of 4(1-9) surgeons perform surgical stabilization of rib fractures (SSRF). In the majority of trauma centers the trauma surgeons perform SSRF. CONCLUSIONS: Considerable similarities and differences exist within these CWIS collaborative centers. These differences in resources are hypothesis generating in determining the optimal CWIC. These findings may generate several patient care and team process questions to optimize patient care, patient experience, provider satisfaction, research productivity, education, and outreach. LEVEL OF EVIDENCE: IV Economic & Value-Based Evaluations.

Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. Methods: The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Measurements and Main Results: Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively (P = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) (P = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) (P = 0.023). One serious adverse event was reported in the VATS arm. Conclusions: This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).

Chest Wall Injury Society recommendation for surgical stabilization of nonunited rib fractures to decrease pain, reduce opiate use, and improve patient reported outcomes in patients with rib fracture nonunion after trauma.

BACKGROUND: Rib fractures are common injuries which can be associated with acute pain and chronic disability. While most rib fractures ultimately go on to achieve bony union, a subset of patients may go on to develop non-union. Management of these nonunited rib fractures can be challenging and variability in management exists. METHODS: The Chest Wall Injury Society's Publication Committee convened to develop recommendations for use of surgical stabilization of nonunited rib fractures (SSNURF) to treat traumatic rib fracture nonunions. PubMed, Embase, and the Cochrane database were searched for pertinent studies. Using a process of iterative consensus, all committee members voted to accept or reject the recommendation. RESULTS: No identified studies compared SSNURF to alternative therapy and the overall quality of the body of evidence was rated as low. Risk of bias was identified in all studies. Despite these limitations, there is lower-quality evidence suggesting that SSNURF may be beneficial for decreasing pain, reducing opiate use, and improving patient reported outcomes among patients with symptomatic rib nonunion. However, these benefits should be balanced against risk of symptomatic hardware failure and infection. CONCLUSION: This guideline document summarizes the current CWIS recommendations regarding use of SSNURF for management of rib nonunion. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Costal margin injuries and trans-diaphragmatic intercostal hernia: Presentation, management and outcomes according to the Sheffield classification.

BACKGROUND: Costal margin rupture (CMR) injuries are under-diagnosed and inconsistently managed, while carrying significant symptomatic burden. We hypothesized that the Sheffield Classification system of CMR injuries would relate to injury patterns and management options. METHODS: Data were collected prospectively between 2006 and 2023 at a major trauma center in the United Kingdom. Computed tomography scans were interrogated and injuries were categorized according to the Sheffield Classification. Clinical, radiologic, management and outcome variables were assessed. RESULTS: Fifty-four patients were included in the study. Intercostal hernia (IH) was present in 30 patients and associated with delayed presentation ( p = 0.004), expulsive mechanism of injury (i.e. such as occurs with coughing, sneezing, or retching), higher body mass index ( p < 0.001), and surgical management ( p = 0.02). There was a bimodal distribution of the level of the costal margin rupture, with IH Present and expulsive mechanism injuries occurring predominantly at the ninth costal cartilage, and IH Absent cases and other mechanisms at the seventh costal cartilage ( p < 0.001). There were correlations between the costal cartilage being thin at the site of the CMR and the presence of IH and expulsive etiology ( p < 0.001). Management was conservative in 23 and surgical in 31 cases. Extrathoracic mesh IH repairs were performed in 3, Double Layer Mesh Repairs in 8, Suture IH repairs in 5, CMR plating in 8, CMR sutures in 2, and associated Surgical Stabilization of Rib Fractures in 11 patients. There was one postoperative death. There were seven repeat surgical procedures in five patients. CONCLUSION: The Sheffield Classification is associated statistically with presentation, related chest wall injury patterns, and type of definitive management. Further collaborative data collection is required to determine the optimal management strategies. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Interobserver agreement for the Chest Wall Injury Society taxonomy of rib fractures using computed tomography images.

BACKGROUND: In 2020, a universal nomenclature for rib fractures was proposed by the international Chest Wall Injury Society taxonomy collaboration. The purpose of this study is to validate this taxonomy. We hypothesized that there would be at least moderate agreement, regardless of the observers' background. METHODS: An international group of independent observers evaluated axial, coronal, and sagittal computed tomography images on an online platform from 11 rib fractures for location (anterior, lateral, or posterior), type (simple, wedge, or complex), and displacement (undisplaced, offset, or displaced) of rib fractures. The multirater κ and Gwet's first agreement coefficient (AC1) were calculated to estimate agreement among the observers. RESULTS: A total of 90 observers participated, with 76 complete responses (84%). Strong agreement was found for the classification of fracture location ( κ = 0.83 [95% confidence interval (CI) 0.69-0.97]; AC1, 0.84 [95% CI, 0.81-0.88]), moderate for fracture type ( κ = 0.46 [95% CI, 0.32-0.59]; AC1, 0.50 [95% CI, 0.45-0.55]), and fair for rib fracture displacement ( κ = 0.38 [95% CI, 0.21-0.54], AC1, 0.38 [95% CI, 0.34-0.42]). CONCLUSION: Agreement on rib fracture location was strong and moderate for fracture type. Agreement on displacement was lower than expected. Evaluating strategies such as comprehensive education, additional imaging techniques, or further specification of the definitions will be needed to increase agreement on the classification of rib fracture type and displacement as defined by the Chest Wall Injury Society taxonomy. LEVEL OF EVIDENCE: Diagnostic Test or Criteria; Level IV.

Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.

BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), the use of postoperative radiotherapy (PORT) has been controversial since 1998, because of one meta-analysis showing a deleterious effect on survival in patients with pN0 and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many changes have occurred in the management of patients with NSCLC, the role of three-dimensional (3D) conformal PORT warrants further investigation in patients with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT should be part of their standard treatment. METHODS: Lung ART is an open-label, randomised, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC with complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients aged 18 years or older, with an WHO performance status of 0-2, were recruited from 64 hospitals and cancer centres in five countries (France, UK, Germany, Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the PORT or no PORT (control) groups via a web randomisation system, and minimisation factors were the institution, administration of chemotherapy, number of mediastinal lymph node stations involved, histology, and use of pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30 daily fractions, on five consecutive days a week. Three dimensional conformal radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted in centres with expertise. The primary endpoint was disease-free survival, analysed by intention to treat at 3 years; patients from the PORT group who did not receive radiotherapy and patients from the control group with no follow-up were excluded from the safety analyses. This trial is now closed. This trial is registered with ClinicalTrials.gov number, NCT00410683. FINDINGS: Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly staged with 18F-fluorodeoxyglucose (18F-FDG) PET (456 [91%]; 232 (92%) in the PORT group and 224 (90%) in the control group), were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51) without PORT, and the median disease-free survival was 30·5 months (95% CI 24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients (11%) in the PORT group versus 12 (5%) in the control group. Two patients died from pneumonitis, partly related to radiotherapy and infection, and one patient died due to chemotherapy toxicity (sepsis) that was deemed to be treatment-related, all of whom were in the PORT group. INTERPRETATION: Lung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using (18F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC. FUNDING: French National Cancer Institute, Programme Hospitalier de Recherche Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK, Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer Research Foundation, Swiss Cancer League.

COVID-19 and the multidisciplinary care of patients with lung cancer: an evidence-based review and commentary.

Delivering lung cancer care during the COVID-19 pandemic has posed significant and ongoing challenges. There is a lack of published COVID-19 and lung cancer evidence-based reviews, including for the whole patient pathway. We searched for COVID-19 and lung cancer publications and brought together a multidisciplinary group of stakeholders to review and comment on the evidence and challenges. A rapid review of the literature was undertaken up to 28 October 2020, producing 144 papers, with 113 full texts screened. We focused on new primary data collection (qualitative or quantitative evidence) and excluded case reports, editorials and commentaries. Following exclusions, 15 published papers were included in the review and are summarised. They included one qualitative paper and 14 quantitative studies (surveys or cohort studies), with a total of 2295 lung cancer patients data included (mean study size 153 patients; range 7-803). Review of current evidence and commentary included awareness and help-seeking; lung cancer screening; primary care assessment and referral; diagnosis and treatment in secondary care, including oncology and surgery; patient experience and palliative care. Cross-cutting themes and challenges were identified using qualitative methods for patients, healthcare professionals and service delivery, with a clear need for continued studies to guide evidence-based decision-making.

G6PD activity contributes to the regulation of histone acetylation and gene expression in smooth muscle cells and to the pathogenesis of vascular diseases.

We aimed to determine 1) the mechanism(s) that enables glucose-6-phosphate dehydrogenase (G6PD) to regulate serum response factor (SRF)- and myocardin (MYOCD)-driven smooth muscle cell (SMC)-restricted gene expression, a process that aids in the differentiation of SMCs, and 2) whether G6PD-mediated metabolic reprogramming contributes to the pathogenesis of vascular diseases in metabolic syndrome (MetS). Inhibition of G6PD activity increased (>30%) expression of SMC-restricted genes and concurrently decreased (40%) the growth of human and rat SMCs ex vivo. Expression of SMC-restricted genes decreased (>100-fold) across successive passages in primary cultures of SMCs isolated from mouse aorta. G6PD inhibition increased Myh11 (47%) while decreasing (>50%) Sca-1, a stem cell marker, in cells passaged seven times. Similarly, CRISPR-Cas9-mediated expression of the loss-of-function Mediterranean variant of G6PD (S188F; G6PDS188F) in rats promoted transcription of SMC-restricted genes. G6PD knockdown or inhibition decreased (48.5%) histone deacetylase (HDAC) activity, enriched (by 3-fold) H3K27ac on the Myocd promoter, and increased Myocd and Myh11 expression. Interestingly, G6PD activity was significantly higher in aortas from JCR rats with MetS than control Sprague-Dawley (SD) rats. Treating JCR rats with epiandrosterone (30 mg/kg/day), a G6PD inhibitor, increased expression of SMC-restricted genes, suppressed Serpine1 and Epha4, and reduced blood pressure. Moreover, feeding SD control (littermates) and G6PDS188F rats a high-fat diet for 4 mo increased Serpine1 and Epha4 expression and mean arterial pressure in SD but not G6PDS188F rats. Our findings demonstrate that G6PD downregulates transcription of SMC-restricted genes through HDAC-dependent deacetylation and potentially augments the severity of vascular diseases associated with MetS.NEW & NOTEWORTHY This study gives detailed mechanistic insight about the regulation of smooth muscle cell (SMC) phenotype by metabolic reprogramming and glucose-6-phosphate dehydrogenase (G6PD) in diabetes and metabolic syndrome. We demonstrate that G6PD controls the chromatin modifications by regulating histone deacetylase (HDAC) activity, which deacetylates histone 3-lysine 9 and 27. Notably, inhibition of G6PD decreases HDAC activity and enriches H3K27ac on myocardin gene promoter to enhance the expression of SMC-restricted genes. Also, we demonstrate for the first time that G6PD inhibitor treatment accentuates metabolic and transcriptomic reprogramming to reduce neointimal formation in coronary artery and large artery elastance in metabolic syndrome rats.

Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716.

OBJECTIVES: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM. MATERIALS AND METHODS: Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response. RESULTS: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks. CONCLUSIONS: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

Testing the clinical validity of the Bemelman Rib Fracture Management Guideline.

Whilst surgical stabilization of rib fractures (SSRF) results in better outcomes, selection algorithms are lacking. We aimed to validate the Rib Fracture Management Guideline proposed by Bemelman. From a cohort of 792 patients with multiple rib fractures, 2 sequential cohorts were selected: 48 patients who underwent SSRF and 48 patients who managed conservatively. Admission computed tomography scans and records were reviewed by an investigator blinded to the SSRF outcome. Adherence to the Bemelman guideline, revised to take account of consensus rib fracture definitions, was tested. Fifty-seven patients had multiple rib fractures only, and 39 patients also had a flail segment. Thirty-nine patients with flail segment underwent SSRF, and 18 patients were managed conservatively. Of the patients that the guideline predicted should have received surgery, 87% did. Of those that it predicted should not receive SSRF, 98% did not. The guideline displayed a sensitivity (95% confidence interval) and specificity for predicting the fixation of 0.98 (0.89-0.9995) and 0.83 (0.70-0.93), respectively. The positive and negative predictive values for surgical fixation were 0.87 (0.76-0.92) and 0.98 (0.85-0.99), respectively. The Bemelman guideline was thus a good predictor of SSRF in retrospective cohort but should be used in conjunction with clinical judgement. Further validation is indicated in a prospective study.

Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity.

Children surviving cancer and chemotherapy are at risk for adverse health events including heart failure that may be delayed by years. Although the early effects of doxorubicin-induced cardiotoxicity may be attributed to a direct effect on the cardiomyocytes, the mechanisms underlying the delayed or late effects (8-20 yr) are unknown. The goal of this project was to develop a model of late-onset doxorubicin-induced cardiotoxicity to better delineate the underlying pathophysiology responsible. The underlying hypothesis was that doxorubicin-induced "late-onset cardiotoxicity" was the result of mitochondrial dysfunction leading to cell failure and death. Wistar rats, 3-4 wk of age, were randomly assigned to vehicle or doxorubicin injection groups (1-45 mg/kg). Cardiovascular function was unaltered at the lower dosages (1-15 kg/mg), but beginning at 6 mo after injection significant cardiac degradation was observed in the 45 mg/kg group. Doxorubicin significantly increased myocardial mitochondrial DNA (mtDNA) damage. In contrast, in isolated c-kit left ventricular (LV) cells, doxorubicin treatment did not increase mtDNA damage. Biomarkers of senescence within the LV were significantly increased, suggesting accelerated aging of the LV. Doxorubicin also significantly increased LV histamine content suggestive of mast cell activation. With the use of flow cytometry, a significant expansion of the c-kit and stage-specific embryonic antigen 1 cell populations within the LV were concomitant with significant decreases in the circulating peripheral blood population of these cells. These results are consistent with the concept that doxorubicin induced significant damage to the cardiomyocyte population and that although the heart attempted to compensate it eventually succumbed to an inability for self-repair.

The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor Descriptors for Non-Small Cell Lung Cancer.

OBJECTIVE: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). METHODS: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. RESULTS: In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobe-specific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for R0, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases. CONCLUSIONS: R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.

Determining the clinical significance of the Chest Wall Injury Society taxonomy for multiple rib fractures.

BACKGROUND: The Chest Wall Injury Society (CWIS) proposals for standardized nomenclature for multiple rib fracture (MRF) classifications were derived by international expert Delphi consensus. This study aimed to validate the CWIS taxonomy using a single-instituion clinical database. METHODS: Computed tomography (CT) scans, of 539 consecutive patients with MRFs admitted to a regional major trauma center over a 33-month period, were reviewed (blinded for clinical outcomes). Every rib fracture in every patient was assessed according to each of the CWIS criteria (the degree of displacement, characterization of the fracture line, location of each fracture, and the relationship to neighboring fractures). The clinical significance of the proposed CWIS definitions were determined from independently coded, routinely collected Hospital Episodes Statistics data. RESULTS: The radiologic aspects of 3,944 individual rib fractures were assessed. Indicators of injury severity (severe displacement greater series length, and flail segment) were positively associated with other fractures (p < 0.001), hemopneumothorax (p < 0.001), pulmonary complications (p = 0.002), adverse outcomes (p = 0.006), mechanical ventilation (p < 0.001) and prolonged hospital and intensive therapy unit length of stay (p = 0.006, p = 0.007 respectively). Four of the CWIS-proposed definitions were correlated with pulmonary complications and adverse outcomes: the categories of displacement, the definition of individual fracture characterization, the presence of a flail segment. Two definitions for which there was CWIS consensus were not correlated with clinical outcomes: the definition of a series to describe associated fractures on neighboring ribs, the inclusion of a paravertebral sector for fracture localization. CONCLUSION: The CWIS rib fracture taxonomy demonstrates clinical relevance. There were associations between the severity of category groups within three of the proposed definitions, based on the clinical outcomes observed. Clinical outcome assessment proved inconclusive for four agreed definitions. Comprehensive, multiinstitutional data collection would be required to provide validation for all the CWIS-proposed definitions. LEVELS OF EVIDENCE: Level IV.