Lobectomy vs. segmentectomy. A propensity score matched comparison of outcomes.

BACKGROUND: Segmentectomy has emerged as a lung parenchymal sparring alternative to the gold standard lobectomy in non-small cell lung cancer (NSCLC) patients. We hypothesized that there is parity between functional, local recurrence and survival outcomes. PATIENTS AND METHODS: Parenchymal sparring procedures including anatomical segmentectomies were propensity score matched 1:1 with lobectomies (n = 64). The primary outcomes included survival, functional and oncological outcomes. The oncological outcomes were: post-operative histology, clear margins and local recurrence rates. Kaplan Meier survival curves were used to compare the survival. Oncological and functional variables were assessed by Fischer exact test and t-test. RESULTS: The pre-operative performance status, ASA grade, lung function, risk factors, surgical approach and tumour histology were similar between the groups. The tumour size was significantly higher for lobectomies (32.4 ±â€¯17 vs. 24.6 ±â€¯12 mm, p = 0.01). The tumour staging in the segmentectomy group was similar to the lobectomy group (Ia; 50 vs. 34%; Ib: 29 vs. 37%; IIa 11 vs. 9.3%; IIb 5 vs. 14%; IIIa 5 vs. 4.6%, p = 0.83). The loco-regional recurrence was lower in the segmentectomy group (1.5 vs. 3.1%, p = 0.69). The up-staging and down-staging post-surgery was similar in both groups, while neo-adjuvant therapy was used in 5 lobectomy and 3 segmentectomy cases. The survival was similar at 1 year between the groups (88 vs. 92%, p = 0.65). Between 4 and 5 years, the survival reduced in the parenchymal sparing group to 39% vs. 68% in the lobectomy group (p = 0.04). CONCLUSION: Surgical selection bias could be an important confounder in the selection of patients undergoing segmentectomy. Similar up and down staging were demonstrated in the two groups. This is one of the first studies to investigate the results of segmentectomy versus lobectomy in stage II/IIIa NSCLC tumours. No significant differences were found in functional outcomes, but the survival decreased after 4 years in the segmentectomy group, which could be explained by lower survival in the stage II/IIIa tumours treated with segmentectomy.

Postoperative survival following perioperative MAGIC versus neoadjuvant OE02-type chemotherapy in oesophageal adenocarcinoma.

The optimal management of resectable oesophageal adenocarcinoma is controversial, with many centres using neoadjuvant chemotherapy following the Medical Research Council (MRC) oesophageal working group (OE02) trial and the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. The more intensive MAGIC regimen is used primarily in gastric cancer but some also use it for oesophageal cancer. A database of cancer resections (2001-2013) provided information on survival of patients following either OE02 or MAGIC-type treatment. The data were compared using Kaplan-Meier analysis. Straight-to-surgery patients were also reviewed and divided into an 'early' cohort (2001-2006, OE02 era) and a 'late' cohort (2006-2013, MAGIC era) to estimate changes in survival over time. Subgroup analysis was performed for responders (tumour regression grade [TRG] 1-3) versus non-responders (TRG 4 and 5) and for anatomical site (gastro-oesophageal junction [GOJ] vs oesophagus). An OE02 regimen was used for 97 patients and 275 received a MAGIC regimen. Those in the MAGIC group were of a similar age to those undergoing OE02 chemotherapy but the proportion of oesophageal cancers was higher among MAGIC patients than among those receiving OE02 treatment. MAGIC patients had a significantly lower stage following chemotherapy than OE02 patients and a higher median overall survival although TRG was similar. On subgroup analysis, this survival benefit was maintained for GOJ and oesophageal cancer patients as well as non-responders. Analysis of responders showed no difference between regimens. 'Late' group straight-to-surgery patients were significantly older than those in the 'early' group. Survival, however, was not significantly different for these two cohorts. Although the original MAGIC trial comprised few oesophageal cancer cases, our patients had better survival with MAGIC than with OE02 chemotherapy in all anatomical subgroups, even though there was no significant change in operative survival over the time period in which these patients were treated. The use of the MAGIC regimen should therefore be encouraged in cases of operable oesophagogastric adenocarcinoma.

A Grassroots Remote Sensing Toolkit Using Live Coding, Smartphones, Kites and Lightweight Drones.

This manuscript describes the development of an android-based smartphone application for capturing aerial photographs and spatial metadata automatically, for use in grassroots mapping applications. The aim of the project was to exploit the plethora of on-board sensors within modern smartphones (accelerometer, GPS, compass, camera) to generate ready-to-use spatial data from lightweight aerial platforms such as drones or kites. A visual coding 'scheme blocks' framework was used to build the application ('app'), so that users could customise their own data capture tools in the field. The paper reports on the coding framework, then shows the results of test flights from kites and lightweight drones and finally shows how open-source geospatial toolkits were used to generate geographical information system (GIS)-ready GeoTIFF images from the metadata stored by the app. Two Android smartphones were used in testing-a high specification OnePlus One handset and a lower cost Acer Liquid Z3 handset, to test the operational limits of the app on phones with different sensor sets. We demonstrate that best results were obtained when the phone was attached to a stable single line kite or to a gliding drone. Results show that engine or motor vibrations from powered aircraft required dampening to ensure capture of high quality images. We demonstrate how the products generated from the open-source processing workflow are easily used in GIS. The app can be downloaded freely from the Google store by searching for 'UAV toolkit' (UAV toolkit 2016), and used wherever an Android smartphone and aerial platform are available to deliver rapid spatial data (e.g. in supporting decision-making in humanitarian disaster-relief zones, in teaching or for grassroots remote sensing and democratic mapping).

Patients' attitudes to risk in lung cancer surgery: A qualitative study.

OBJECTIVES: Lung cancer surgery leads to long term survival for some patients but little is known about how patients decide whether to accept the associated surgical risks. The objective of this qualitative study was to explore patients' attitudes to the risks associated with lung cancer surgery. METHODS: Fifteen patients with resectable lung cancer, recruited via multi-disciplinary team meetings at an English tertiary referral centre, participated in semi-structured interviews to explore their attitudes to the morbidity and mortality risks associated with lung cancer surgery. Transcripts were analysed using the framework method. RESULTS: Participants reported being 'pleased' to hear that they were suitable for surgery and felt that surgery was not a treatment to be turned down because they did not see any alternatives. Participants had some knowledge of perioperative risks, including mortality estimates; however, many voiced a preference not to know these risks and to let the medical team decide their treatment plan. Some found it difficult to relate the potential risks and complications of surgery to their own situation and appeared willing to accept high perioperative mortality risks. Generally, participants were willing to accept quite severe long-term postoperative breathlessness; however, it was apparent that many actually found this possibility difficult to imagine. CONCLUSION: Patients do not necessarily wish to know details of risks associated with lung cancer surgery and may wish to defer decisions about treatment to their medical team. Investment in the doctor-patient relationship, particularly for the surgeon, is therefore important in the management of patients with lung cancer.

Lung cancer survival in England: trends in non-small-cell lung cancer survival over the duration of the National Lung Cancer Audit.

BACKGROUND: In comparison with other European and North American countries, England has poor survival figures for lung cancer. Our aim was to evaluate the changes in survival since the introduction of the National Lung Cancer Audit (NLCA). METHODS: We used data from the NLCA to identify people with non-small-cell lung cancer (NSCLC) and stratified people according to their performance status (PS) and clinical stage. Using Cox regression, we calculated hazard ratios (HRs) for death according to the year of diagnosis from 2004/2005 to 2010; adjusted for patient features including age, sex and co-morbidity. We also assessed whether any changes in survival were explained by the changes in surgical resection rates or histological subtype. RESULTS: In this cohort of 120,745 patients, the overall median survival did not change; but there was a 1% annual improvement in survival over the study period (adjusted HR 0.99, 95% confidence interval (CI) 0.98-0.99). Survival improvement was only seen in patients with good PS and early stage (adjusted HR 0.97, 95% CI 0.95-0.99) and this was partly accounted for by changes in resection rates. CONCLUSION: Survival has only improved for a limited group of people with NSCLC and increasing surgical resection rates appeared to explain some of this improvement.

MAGIC in practice: experience of peri-operative ECF/X chemotherapy in gastro-esophageal adenocarcinomas.

BACKGROUND: The MAGIC trial demonstrated the perioperative regimen of Epirubicin (E), Cisplatin (C) and 5-Fluorouracil (F) to have an overall survival benefit for patients with gastro-esophageal adenocarcinomas. We present our experience of the peri-operative regimen of ECF/ECX(X = Capecitabine) in operable gastro-esophageal adenocarcinoma. METHODS: Analysis of retrospective data of patients treated with MAGIC style therapy between May 2006 and August 2008 with potentially operable gastro-esophageal adenocarcinoma. RESULTS: One hundred patients underwent peri-operative chemotherapy according to the MAGIC protocol. Median age was 66 years, with 39% above the age of 70 years. The tumours were evenly distributed between the lower esophagus, gastro-esophageal junction and stomach. Seventy-nine percent completed all pre-operative cycles of chemotherapy and 81% proceeded to surgery, whilst 24% did not receive curative surgery. The median survival on an intention to treat analysis is 31.7 months from diagnosis. The median survival of patients who underwent resection has not yet been reached after a median follow-up of 41.4 months. CONCLUSION: Our patient population is older than the patients in the MAGIC trial (age 66 years vs. 62 years) with a much higher proportion of esophageal and GEJ tumours. Overall, curative resection rate was comparable to the MAGIC trial. Overall survival is superior to that found in the MAGIC trial.

The role of staging laparoscopy in oesophagogastric cancers.

AIMS: Selection of patients for treatment of oesophagogastric cancers rests on accurate staging. Laparoscopy has become a safe and effective staging tool in upper gastrointestinal cancers because of its ability to detect small peritoneal and liver metastases missed by imaging techniques. The aim of this study was to evaluate the role of staging laparoscopy (SL) in determining resectability of oesophagogastric cancers. METHODS: A review of 511 patients with oesophagogastric cancers referred to our centre during a 7-year period was performed. Four hundred and sixteen of them assessed to have resectable tumours after preoperative staging with CT and/or ultrasound underwent SL. The main outcome measure was the number of patients in whom laparoscopy changed treatment decision. RESULTS: Staging laparoscopy changed treatment decision in 84 cases (20.2%): locally advanced disease in 17, extensive lymph node disease in four and distant metastases (liver and peritoneum) in 63 cases. The sensitivity of laparoscopy for resectability was 88%. Eighty-one percent of patients who had combined CT scan and EUS were resectable at surgery compared with 65% of those who had CT scan alone (statistically significant with P-value<0.05). Of those patients deemed resectable by SL 8.1% were found to be unresectable at laparotomy, 16 with locally advanced disease and 11 with metastases. CONCLUSION: Staging laparoscopy avoided unnecessary laparotomy in 20.2% of our patients and was most useful in adenocarcinoma, distal oesophageal, GOJ and gastric cancers and probably not necessary in lesions of the upper two-third of the oesophagus.

Pathological determinants of survival in node-negative oesophageal cancer.

BACKGROUND: Many studies have analysed prognostic factors following oesophagectomy, but few have examined survival determinants in node-negative (N0) oesophageal cancer. The prognostic significance of a number of histological variables following surgical resection of N0 oesophageal cancer was studied. METHODS: The case notes of 219 patients undergoing potentially curative oesophagectomy for N0 squamous cell carcinoma or adenocarcinoma of the oesophagus were reviewed. Details of the patient's sex, age at operation, histological type, longitudinal tumour length, tumour (T) stage, circumferential resection margin involvement, tumour grade, presence of vascular invasion, perineural invasion, Barrett's metaplasia, and survival were noted. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Univariate analysis revealed three factors that correlated with poor prognosis: T stage (P = 0.024), adenocarcinoma (P = 0.033) and degree of differentiation (P = 0.001). Multivariate analysis revealed that all three were significant independent adverse prognostic indicators. CONCLUSION: Surgical resection of node-negative oesophageal cancer is associated with diverse long-term outcomes. This diversity of outcome is not reflected in the tumour node metastasis (TNM)-based staging system. The utility of the TNM system in predicting prognosis after surgical resection is open to question.

Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer.

The factors affecting long-term survival following oesophagectomy for oesophageal cancer are poorly understood. We examined the significance of microscopic tumour involvement at the circumferential resection margin (CRM) on postoperative survival following oesophagectomy. The case notes of 329 patients who underwent a potentially curative oesophagectomy for squamous or adenocarcinoma were reviewed retrospectively. As part of the procedure, all patients underwent an en-bloc resection of their periesophageal tissue. The presence of tumour either at, or within, 1 mm of the CRM was recorded and correlated with their TNM and survival data. A total of 67 patients (20%) were noted to have a positive CRM, of which 40 cases (12%) had tumour at the resection margin and the remainder had tumour within 1 mm of the margin. Univariate analysis showed no statistically significant association between survival and either category of CRM involvement. Multivariate analysis showed that only T-stage, nodal status and tumour grade were prognostic markers. In conclusion, the presence of microscopic tumour at the CRM following an en-bloc oesophagectomy is not a significant prognostic marker.

Preliminary findings in the neurophysiological assessment of intercostal nerve injury during thoracotomy.

OBJECTIVE: Previous work has suggested that intercostal nerve injury is a major factor in the aetiology of chronic post-thoracotomy pain. The aim of this study was to establish if there was identifiable intercostal nerve injury during thoracotomy. METHODS: Intercostal nerves were stimulated and motor evoked potentials were recorded from intercostal muscles in 13 patients undergoing thoracotomy. Measurements were taken before and after entering the pleural space, after removal of the rib retractor and after intercostal space closure. RESULTS: Intercostal nerves functioned normally before and after entering the pleural space. After the rib retractor was removed, there was a total conduction block in the nerve immediately above the incision in every patient. In the nerves above this, six had a total block, one a partial block and three had normal conduction. There was a total conduction block in the nerve immediately below the incision in all but one patient. Of the nerves below this, four had a total block, two a partial block and three had normal conduction. In the cases of total conduction block, there was either a discrete block at the level of the distal end of the rib retractor or impairment throughout the whole nerve. Intercostal space closure did not injure any previously uninjured nerve. In a solitary patient where rib retraction was not employed, there was no impairment of the intercostal nerves throughout the operation. CONCLUSIONS: This study demonstrates for the first time that intercostal nerve injury occurs routinely due to rib retraction during thoracotomy. We believe that it may be an important step toward understanding the cause of post-thoracotomy neuralgia.

Surgical treatment of para-oesophageal hiatal hernia.

The development of laparoscopic antireflux surgery has stimulated interest in laparoscopic para-oesophageal hiatal hernia repair. This review of our practice over 10 years using a standard transthoracic technique was undertaken to establish the safety and effectiveness of the open technique to allow comparison. Sixty patients with para-oesophageal hiatal hernia were operated on between 1989 and 1999. There were 38 women and 22 men with a median age of 69.5 years. There were 47 elective and 13 emergency presentations. Operation consisted of a left thoracotomy, hernia reduction and crural repair. An antireflux procedure was added in selected patients. There were no deaths among the elective cases and one among the emergency cases. Median follow-up time was 19 months. There was one recurrence (1.5%). Seven patients (12%) required a single oesophagoscopy and dilatation up to 2 years postoperatively but have been asymptomatic since. Two patients (3%) developed symptomatic reflux which has been well controlled on proton-pump inhibitors. Transthoracic para-oesophageal hernia repair can be safely performed with minimal recurrence.

Surgical aspects of chronic post-thoracotomy pain.

Chronic post-thoracotomy pain is a continuous dysaesthetic burning and aching in the general area of the incision that persists at least 2 months after thoracotomy. It occurs in approximately 50% of patients after thoracotomy and is usually mild or moderate. However, in 5% the pain is severe and disabling. No one technique of thoracotomy has been shown to reduce the incidence of chronic postthoracotomy pain. The most likely cause is intercostal nerve damage, although the precise mechanism for this is not known. Future work needs to examine surgical technique in detail. Until then, patients need to be adequately warned of this sequela of thoracotomy.

Cellular and biochemical characterization of VX-710 as a chemosensitizer: reversal of P-glycoprotein-mediated multidrug resistance in vitro.

VX-710 or (S)-N[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-piperidine-2-carboxylic acid 1,7-bis(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for its ability to reverse P-glycoprotein-mediated multidrug resistance in vitro. VX-710 at 0.5-5 microM restored sensitivity of a variety of multidrug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclitaxel, including drug-selected human myeloma and epithelial carcinoma cells, and human MDR1 cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5-2.5 microM fully restored intracellular accumulation of [14C]doxorubicin in multidrug resistant cells, suggesting that VX-710 inhibits the drug efflux activity of P-glycoprotein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azidoprazosin with EC50 values of 0.75 and 0.55 microM. Moreover, P-glycoprotein was specifically labeled by a tritiated photoaffinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50 of 0.75 microM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2- to 3-fold in a concentration-dependent manner with an apparent k(a) of 0.1 microM. These data indicate that a direct, high-affinity interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by the MDR1 gene product in multidrug resistant tumor cells.

Phase II study of mitomycin, ifosfamide and cisplatin in adenocarcinoma of the oesophagus.

We evaluated the effect of brief neoadjuvant chemotherapy in patients with apparently operable adenocarcinoma of the oesophagus. Two courses of mitomycin (6 mg/m2), ifosfamide (3 g/m2) and cisplatin (50 mg/m2;MIC) were given followed by evaluation of response by barium swallow and computed tomography scan. Of 20 patients, 17 completed both courses and 4 (20%) showed a partial response. Toxicity was generally mild and consisted principally of nausea and vomiting. Altogether, 15 patients were surgically explored; resection was completed in 12 patients, 3 of whom died in hospital (25%). Neoadjuvant therapy with MIC offers no advantage over surgery alone.

Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protein for the immunosuppressant FK506.

We have synthesized a series of non-macrocyclic ligands to FKBP12 that are comparable in binding potency and peptidyl prolyl isomerase (PPIase) inhibition to FK506 itself. We have also solved the structure of one of these ligands in complex with FKBP12, and have compared that structure to the FK506-FKBP12 complex. Consistent with the observed inhibitory equipotency of these compounds, we observe a strong similarity in the conformation of the two ligands in the region of the protein that mediates PPIase activity. Our compounds, however, are not immunosuppressive. In the FKBP12-FK506 complex, a significant portion of the FK506 ligand, its 'effector domain', projects beyond the envelope of the binding protein in a manner that is suggestive of a potential interaction with a second protein, the calcium-dependent phosphatase, calcineurin, whose inhibition by the FKBP 12-FK506 complex interrupts the T-cell activation events leading to immunosuppression. In contrast, our compounds bind within the surface envelope of FKBP12, and induce significant changes in the structure of the FKBP12 protein which may also affect calcineurin binding indirectly.

Effects of chemotherapy on ultrastructure of oesophageal squamous cell carcinoma.

Seven oesophageal squamous carcinomas, treated with pre-operative chemotherapy (mitomycin-C, ifosfamide and cisplatin-MIC), with a course finishing 21 days prior to resection, were examined by electronmicroscopy. In one treated case detailed light microscopy failed to reveal any tumour. Five of the remaining six tumours showed cytotoxic damage in that apoptosis and unusual necrotic changes were observed in almost all the neoplastic cells. These features were not seen in untreated cases. In four additional cases, who received one pulse of MIC followed by biopsy or resection within 3-6 days, apoptotic changes were very pronounced and extensive and most neoplastic cells presented unusual degeneration with characteristic derangement of the cytoskeleton, destruction of organelles and accumulation of glycogen. The ultrastructural appearance of 18 untreated resected oesophageal squamous carcinomas was studied for comparison with the treated tumours. The study has demonstrated ultrastructural changes resulting from chemotherapy. Results suggest that the regimen is more effective against squamous carcinomas than against adenocarcinomas of the oesophagus, as judged by comparison with the results of a previous study.

A phase II study of mitomycin, ifosfamide and cisplatin in operable and inoperable squamous cell carcinoma of the oesophagus.

We have evaluated the effect of mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 (MIC) in two groups of patients with squamous or undifferentiated carcinoma of the oesophagus, as either preoperative or primary treatment. Response was assessed by barium swallow, CT scan, and measurement of metastases where present. Toxicity was acceptable and there were no chemotherapy related deaths. In the operated group, five of 23 patients (22%) showed a complete response (three confirmed histologically) and nine (39%) showed a partial response following two courses of MIC. Resection was completed in 21 patients, with three hospital deaths (14%). Of the 18 patients who were discharged from hospital, eight have died at 4-24 months (median 13) from the start of treatment and 10 are alive at 5-35 months, with known recurrence in one. In the non-operated group, five of 20 patients (25%) showed a response, one complete, following one to four (mean 2.6) courses of MIC. Nineteen patients have died (at median 5 months), and one, who had a complete response, is alive and free from disease at 29 months. Neo-adjuvant therapy with MIC in squamous carcinoma of the oesophagus has shown encouraging early results, with acceptable toxicity.

Time-course of free radical activity during coronary artery operations with cardiopulmonary bypass.

Myocardial and pulmonary impairment after cardiopulmonary bypass may be caused by oxygen free radicals produced by reperfusion and by activated neutrophils. Free radical activity was assessed by assays for lipid peroxidation (thiobarbituric acid-reactive material) and phospholipid-esterified diene conjugation (18:2[9,11]/18:2[9,12] molar ratio) in 25 patients during coronary artery operations. Arterial blood samples were obtained before, during the ischemic period, and for 24 hours thereafter. There were no significant changes in free radical indices during the ischemic periods, but after cessation of bypass they increased significantly. Ten minutes after bypass thiobarbituric acid-reactive material rose from 96 (median; range 65 to 145) nmol/gm albumin to 138 (85 to 200) nmol/gm albumin (p < 0.001), and molar ratio rose from 2.23% (0.45% to 7.70%) to 2.51% (0.39% to 7.93%) (p < 0.02). Values of thiobarbituric acid-reactive material subsequently decreased, but molar ratio reached a peak at 4 hours after bypass, 2.64% (0.55% to 10.08%) (p < 0.001), thereafter returning to baseline. The postoperative increases in thiobarbituric acid-reactive material and in molar ratio were correlated (r = +0.53; p = 0.006). These increases in thiobarbituric acid-reactive material and in molar ratio were not related to age, preoperative left ventricular function, or the number of grafts performed. Increase in thiobarbituric acid-reactive material correlated with the duration of cardiopulmonary bypass (r = +0.43; p = 0.03). In 10 patients in whom cardiopulmonary bypass was performed using a bubble oxygenator, the increases in thiobarbituric acid-reactive material were significantly greater than in the 15 in whom a membrane oxygenator was used (p < 0.02). These data show that after apparently uncomplicated coronary operations with bypass there is an increase in lipid peroxidation and diene conjugation, indicating increased free radical activity. This increase varies between patients and does not relate to patient or surgical factors but may depend on the type of oxygenator employed during bypass.