Jesper Ravn

Preoperative Staging of Lung Cancer with Combined PET–CT

BACKGROUNDnFast and accurate staging is essential for choosing treatment for non-small-cell lung cancer (NSCLC). The purpose of this randomized study was to evaluate the clinical effect of combined positron-emission tomography and computed tomography (PET-CT) on preoperative staging of NSCLC.nnnMETHODSnWe randomly assigned patients who were referred for preoperative staging of NSCLC to either conventional staging plus PET-CT or conventional staging alone. Patients were followed until death or for at least 12 months. The primary end point was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who had recurrent disease or death from any cause within 1 year after randomization.nnnRESULTSnFrom January 2002 through February 2007, we randomly assigned 98 patients to the PET-CT group and 91 to the conventional-staging group. Mediastinoscopy was performed in 94% of the patients. After PET-CT, 38 patients were classified as having inoperable NSCLC, and after conventional staging, 18 patients were classified thus. Sixty patients in the PET-CT group and 73 in the conventional-staging group underwent thoracotomy (P=0.004). Among these thoracotomies, 21 in the PET-CT group and 38 in the conventional-staging group were futile (P=0.05). The number of justified thoracotomies and survival were similar in the two groups.nnnCONCLUSIONSnThe use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality. (ClinicalTrials.gov number, NCT00867412.)

Outcome of accidental hypothermia with or without circulatory arrest: experience from the Danish Præstø Fjord boating accident.

BACKGROUNDnResuscitation guidelines for the treatment of accidental hypothermia are based primarily on isolated cases. Mortality rates are high despite aggressive treatment aimed at restoring spontaneous circulation and normothermia.nnnMETHODSnThe present report is based on a boating accident where 15 healthy subjects (median age 16 (range 15-45) years) were immersed in 2 °C salt water. Seven victims were recovered in circulatory arrest with a median temperature of 18.4 °C (range 15.5-20.2 °C). They were all rewarmed with extracorporeal membrane oxygenation (ECMO) and were subsequently evaluated with advanced neuroradiological and functional testing. The remaining 7 had established spontaneous circulation without the use of ECMO. One victim drowned in the accident.nnnRESULTSnThe victims that survived the accident without circulatory arrest were predominantly females with a higher body mass index. Victims with circulatory arrest pH on arrival was a median of 6.61 (range 6.43-6.94), with ECMO being established a median of 226 (178-241)min after the accident. Magnetic resonance spectroscopy showed neuronal dysfunction in five. In five victims initial normal white matter spectra progressed to show evidence of abnormal axonal membranes. Based on the seven-level Functional Independence Measure test functional outcome was good in six circulatory arrest victims and in all without circulatory arrest. Mild to moderate cognitive dysfunction was seen in six and severe dysfunction in one circulatory arrest victim.nnnCONCLUSIONnSeven patients with profound accidental hypothermic circulatory arrest were successfully resuscitated using a management approach that included extracorporeal rewarming, followed by successive periods of therapeutic hypothermia and sedated normothermia and intensive neurorehabilitation. Seven other hypothermic victims (core temperature as low as 23 °C) that did not suffer circulatory arrest also survived the accident.

Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma

BACKGROUND AND PURPOSEnThe combination of chemotherapy, surgery, and radiotherapy has improved the prognosis for patients with malignant pleural mesothelioma (MPM). Intensity-modulated radiotherapy (IMRT) has allowed for an increase in dose to the pleural cavity and a reduction in radiation doses to organs at risk. The present study reports and analyses the incidence of fatal pulmonary toxicity in patients treated at Rigshospitalet, Copenhagen.nnnMATERIALS AND METHODSnTwenty-six patients were treated with induction chemotherapy followed by extrapleural pneumonectomy and IMRT between April 2003 and April 2006. The entire preoperative pleural surface area was treated to 50 Gy and areas with residual disease or close surgical margins were treated to 60 Gy in 30 fractions.nnnRESULTSnThe main toxicities were nausea, vomiting, esophagitis, dyspnea, and thrombocytopenia. One patient died from an intracranial hemorrhage during severe thrombocytopenia. Four patients (15%) experienced grade 5 lung toxicity, i.e. pneumonitis 19-40 days after the completion of radiotherapy. Patients with pneumonitis had a significantly larger lung volume fraction receiving 10 Gy or more (V10) (median: 60.3%, range 56.4-83.2%) compared to patients without pneumonitis (median: 52.6%, range: 25.6-80.3%) (p=0.02). Mean lung dose (MLD) was also significantly higher in patients who developed pneumonitis (median 13.9 Gy, range: 13.6-14.2 Gy) than in patients who did not (median=12.4 Gy, range: 8.4-15.4 Gy) (p=0.04).nnnCONCLUSIONSnSignificant differences in MLD and V10 for patients with fatal pulmonary toxicity compared to patients without fatal lung toxicity have been demonstrated. Based on the presented data local lung dose constraints have been modified in order to avoid unacceptable toxicity.

Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial

Background Correct mediastinal staging is a cornerstone in the treatment of patients with non-small cell lung cancer. A large range of methods is available for this purpose, making the process of adequate staging complex. The objective of this study was to describe faults and benefits of positron emission tomography (PET)-CT in multimodality mediastinal staging. Methods A randomised clinical trial was conducted including patients with a verified diagnosis of non-small cell lung cancer, who were considered operable. Patients were assigned to staging with PET-CT (PET-CT group) followed by invasive staging (mediastinoscopy and/or endoscopic ultrasound with fine needle aspiration (EUS-FNA)) or invasive staging without prior PET-CT (conventional work up (CWU) group). Mediastinal involvement (dichotomising N stage into N0–1 versus N2–3) was described according to CT, PET-CT, mediastinoscopy, EUS-FNA and consensus (based on all available information), and compared with the final N stage as verified by thoracotomy or a conclusive invasive diagnostic procedure. Results A total of 189 patients were recruited, 98 in the PET-CT group and 91 in the CWU group. In an intention-to-treat analysis the overall accuracy of the consensus N stage was not significantly higher in the PET-CT group than in the CWU group (90% (95% confidence interval 82% to 95%) vs 85% (95% CI 77% to 91%)). Excluding the patients in whom PET-CT was not performed (n=14) the difference was significant (95% (95% CI 88% to 98%) vs 85% (95% CI 77% to 91%), p=0.034). This was mainly based on a higher sensitivity of the staging approach including PET-CT. Conclusion An approach to lung cancer staging with PET-CT improves discrimination between N0–1 and N2–3. In those without enlarged lymph nodes and a PET-negative mediastinum the patient may proceed directly to surgery. However, enlarged lymph nodes on CT needs confirmation independent of PET findings and a positive finding on PET-CT needs confirmation before a decision on surgery is made. Clinical trial number NCT00867412.

Diagnostic potential of miR-126, miR-143, miR-145, and miR-652 in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is difficult to distinguish from reactive mesothelial proliferations (RMPs). It is uncertain whether miRNAs are useful biomarkers for differentiating MPM from RMPs. Thus, we screened with a quantitative RT-PCR (RT-qPCR)-based platform the expression of 742 miRNAs in formalin-fixed, paraffin-embedded, preoperative diagnostic biopsy samples, surgically resected MPM specimens previously treated with chemotherapy, and corresponding non-neoplastic pleura (NNP), from five patients. miR-126, miR-143, miR-145, and miR-652 were significantly down-regulated (≥twofold) in resected MPM and/or chemotherapy-naïve diagnostic tumor biopsy samples. The miRNA expression pattern was validated by RT-qPCR in a cohort of 40 independent MPMs. By performing binary logistic regression on the RT-qPCR data for the four miRNAs, the established four-miRNA classifier differentiated MPM from NNP with high sensitivity and specificity (area under the curve, 0.96; 95% CI, 0.92-1.00). The classifiers optimal logit(P) value of 0.62 separated NNP and MPM samples with a sensitivity of 0.95 (95% CI, 0.89-1.00), a specificity of 0.93 (95% CI, 0.87-0.99), and an overall accuracy of 0.94 (95% CI, 0.88-1.00). The level of miR-126 in MPM was inversely correlated with that of the known target, the large neutral amino acid transporter, small subunit 1 (r = -0.38; 95% CI, -0.63 to -0.06). Overall, these results indicate that these four miRNAs may be suitable biomarkers for distinguishing MPM from RMPs.

Are differentially expressed microRNAs useful in the diagnostics of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is radiologically and histologically difficult to distinguish from reactive mesothelial proliferations (RMPs), partly because proposed MPMmarkers have not shown enough specificity and reproducibility or need further validation (1–3). MicroRNAs (miRs) are small non-coding RNA-strands (~22 nt) post-transcriptionally regulating gene-expression and playing increasingly evident roles in several diseases (4). MiRs might potentially be attractive biomarkers for MPM, as MiR-expression in other cancers has shown prognostic and diagnostic significance (5). Furthermore, miRs are more stable and much smaller than mRNAs, thus they can be reliably detected in formalin-fixed paraffin-embedded (FFPE) tissues (6). However, it is unclear whether currently published miR-data may provide biomarker candidates for differentiating MPM from RMP, as it has been implied (7–11). The only study published to date comparing miR-expression in patientmatched MPM and adjacent non-neoplastic pleura (NP) samples, was based on few analyzed miRs (7). Recently, more extensive in vitro analysis compared miR-expression in normal mesothelial cell-cultures and commercially available MPM-cell-lines (8). Other comprehensive studies in vivo instead focused on miRsignatures differentiating MPM histological subtypes (epithelioid, sarcomatoid, and biphasic) or discriminating MPM from lung adenocarcinoma (9–11). For instance, Busacca et al. reported that the expression of miR-17-5p and miR-30c, already known to be related to other malignancies (5), was associated with mesothelioma subtypes (11). Others recently confirmed miR-17-5p up-regulation in MPM-cell-lines, in association with reduced expression of one of its targets, the cyclin-dependent kinase-inhibitor (CDKI) p21 (8, 12). In contrast miR-221 and -222, known negative regulators of the CDKI p27 and the tumor suppressor PTEN, were reported as down-regulated in human MPM cell lines compared to non-tumorous immortalized mesothelial cells (11). This is somehow surprising given that loss of p27 and PTEN expression is frequent and associated with poor prognosis in MPM patients (4,12,13) To test whether miR-17-5p, -30c, -221, and 222 may be useful in differentiating MPM from RMP in vivo, we quantified and compared their expression in FFPE epithelioid MPM (stages I-IV) and NP tissue-samples collected from 13 patients (11 male patients, 2 female patients, ages 49–69) (Table 1) during extra-pleural pneumonectomy preceded by 1–3 cycles of chemotherapy (vinorelbine/cisplatin or gemcitabine/carboplatin). We quantified these miRs and reference RNU6B by realtime-PCR-based TaqMan MicroRNA Assays (Applied Biosystems, Foster City, CA, USA) according to manufacturer’s instructions using 7500 Real-Time PCR System (Applied Biosystems). Threshold-cycles (Ct) were determined with related system-software (SDS v1.2.2, Applied Biosystems) and PCR-data analyzed comparatively with RNU6B as normalizer. Statistically significant (p < 0.05) differences between independent or paired groups were detected by nonparametric Mann–Whitney and Wilcoxon matched pairs tests, respectively.

Ossifying thymoma associated with refractory myasthenia gravis

Only two cases of ossifying thymoma (OT), i.e. thymoma with osseous metaplasia of the stroma, have been reported to date (1, 2). They are both described as type B1 thymoma with focal areas of stromal ossification localized within an intratumoral calcification. In one case, concomitant peripheral T lymphocytosis was observed (1); however, neither case was associated with myasthenia gravis (MG). We present a case of OT that differs from these two by predominant component of sclerosis and ossification, association with MG and the presence of type A thymoma. A 73-year-old woman presented with a 4-year history of late-onset generalized MG that became progressively refractory to treatment with anticholinesterase drugs, steroids, azathioprine and tacrolimus, and was only partially compensated by plasmapheresis. A CT scan of the chest revealed in the superior– anterior mediastinum a 5 · 7 cm large, apparently totally calcified mass (Fig. 1A), which despite no radiological evidence of tumor tissue was suspected to be a calcified thymoma, and was surgically removed because of

Oxidized resorbable cellulose (Gelita-cel) causing foreign body reaction in the mediastinum†

Different types of oxidized cellulose have been used for haemorrhage control in thoracic surgery, abdominal surgery and neurosurgery. Oxidized resorbable cellulose (Gelita-cel) is a new haemostatic agent. Once saturated with blood, it swells and makes a gelatinous mass that formats as a fibrin clot. We have performed a prospective observational cohort study of patients operated for lung cancer or suspected lung cancer using Gelita-cel as a haemostatic agent. Between October 2010 and April 2012, 477 patients were operated in our department for lung cancer. Gelita-cel was used in 200 patients due to minor intraoperative haemorrhage after lymph node resection from Stations 2 to 11. During follow-up for lung cancer, computed tomography, which was performed 4-60u2009months after the primary operation, showed enlarged lymph nodes in the mediastinum in 16 patients. Endoscopic bronchial ultrasonographic biopsies of the lymph nodes showed foreign body material and granulomatous inflammation, and no sign of lung cancer recurrence. Gelita-cel has a high risk of causing granuloma and should not be used as a haemostatic agent in thoracic surgery.

Heart and Great Vessel Injuries

Blunt trauma to the heart and great vessels is often secondary to a high-energy impact to the thorax, leading to major injuries that can be rapidly fatal in many circumstances. Those patients who arrive to the emergency room with signs of life are candidates for an immediate thoracotomy. Patients who are stable may be candidates for diagnostic imaging, including ultrasonography, computed tomography, and invasive arteriography. The initial management of all patients should follow ATLS guidelines. Following the decision to proceed to surgery, an appropriate incision that maximizes access to key structures should be chosen. Full-thickness sutures for atrial lesions will avoid tearing of this thin tissue. Pledgeted sutures may be necessary for partial-thickness sutures in the ventricles. Injury to the great vessels requires proximal (i.e., hilar clamping) and distal control, and extracorporeal membrane oxygenation (ECMO) may be required in select patients following surgical correction of bleeding. Early involvement of cardiothoracic surgeons is often beneficial to help optimize overall care.

Surgical treatment of synchronous and metachronous hepatic–and pulmonary colorectal cancer metastases —the Copenhagen experience

SummaryBackgroundThe surgical treatment of patients with isolated colorectal hepatic- or pulmonary metastases is well established with a 5-year survival in the range of 40–50xa0%. In contrast the treatment of patients with both hepatic- and pulmonary metastases remains controversial. We here present our initial results of patients who underwent both hepatic- and pulmonary resections for colorectal metastases with emphasis on post-operative complications and long-term survival.MethodsThe files of patients with metastasising colorectal cancer who underwent both hepatic- and pulmonary metastasectomy during 2003–2010 were reviewed retrospectively. Estimated overall survival and 1-, 3-, and 5-year survival rates were calculated by the method of Kaplan Meier. The log-rank test was used to compare patients survival for synchronous and metachronous metastases. A p value <u20090.05 was considered significant.ResultsNineteen patients were identified (9F/10M) with a median age of 63 years. Ten patients (53xa0%) presented with synchronous metastases and nine patients (47xa0%) with metachronous metastases. Only minor medical- and surgical complications were reported subsequent surgery. The 30-day mortality was zero. From time of resection of the primary colorectal tumour the estimated 5-year survival rate was 48.5xa0% with a median survival of 47 months. There were no difference in long-term survival between synchronous and metachronous metastases (p>u20090.05).ConclusionsThe present study has demonstrated that resection of both hepatic and pulmonary colorectal metastases is safe and good long-term outcome can be obtained for selected patients. Thus, an aggressive surgical approach to patients with synchronous or metachronous hepatic and pulmonary metastases seems justified.