Impact of lung cancer screening on surgical stage distribution and surgical practice: a regional analysis of patients operated in and out of a screening program.

OBJECTIVES: The aim of this study was to assess variations in surgical stage distribution in 2 centres within the same UK region. One centre was covered by an active screening program started in November 2018 and the other was not covered by screening. METHODS: Retrospective analysis of 1895 patients undergoing lung resections (2018-2022) in 2 centres. Temporal distribution was tested using Chi-squared for trends. A lowess curve was used to plot the proportion of stage 1A patients amongst those operated over the years. RESULTS: The surgical populations in the 2 centres were similar. In the screening unit (SU), we observed a 18% increase in the proportion of patients with clinical stage IA in the recent phase compared to the early phase (59% vs 50%, P = 0.004), whilst this increase was not seen in the unit without screening. This difference was attributable to an increase of cT1aN0 patients in the SU (16% vs 11%, P = 0.035) which was not observed in the other unit (10% vs 8.2%, P = 0.41). In the SU, there was also a three-fold increase in the proportion of sublobar resections performed in the recent phase compared to the early one (35% vs 12%, P < 0.001). This finding was not evident in the unit without screening. CONCLUSIONS: Lung cancer screening is associated with a higher proportion of lung cancers being detected at an earlier stage with a consequent increased practice of sublobar resections.

Differential effects of atrial and brain natriuretic peptides on human pulmonary artery: An in vitro study.

BACKGROUND: The prevalence of cardiovascular diseases, especially heart failure, continues to rise worldwide. In heart failure, increasing levels of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are associated with a worsening of heart failure and a poor prognosis. AIM: To test whether a high concentration of BNP would inhibit relaxation to ANP. METHODS: Pulmonary arteries were dissected from disease-free areas of lung resection, as well as pulmonary artery rings of internal diameter 2.5-3.5 mm and 2 mm long, were prepared. Pulmonary artery rings were mounted in a multiwire myograph, and a basal tension of 1.61gf was applied. After equilibration for 60 min, rings were pre-constricted with 11.21 µmol/L PGF2α (EC80), and concentration response curves were constructed to vasodilators by cumulative addition to the myograph chambers. RESULTS: Although both ANP and BNP were found to vasodilate the pulmonary vessels, ANP is more potent than BNP. pEC50 of ANP and BNP were 8.96 ± 0.21 and 7.54 ± 0.18, respectively, and the maximum efficacy (Emax) for ANP and BNP was -2.03 gf and -0.24 gf, respectively. After addition of BNP, the Emax of ANP reduced from -0.96gf to -0.675gf (P = 0.28). CONCLUSION: BNP could be acting as a partial agonist in small human pulmonary arteries, and inhibits relaxation to ANP. Elevated levels of circulating BNP could be responsible for the worsening of decompensated heart failure. This finding could also explain the disappointing results seen in clinical trials of ANP and BNP analogues for the treatment of heart failure.

Characterization of optimal resting tension in human pulmonary arteries.

AIM: To determine the optimum resting tension (ORT) for in vitro human pulmonary artery (PA) ring preparations. METHODS: Pulmonary arteries were dissected from disease free sections of the resected lung in the operating theatre and tissue samples were directly sent to the laboratory in Krebs-Henseleit solution (Krebs). The pulmonary arteries were then cut into 2 mm long rings. PA rings were mounted in 25 mL organ baths or 8 mL myograph chambers containing Krebs compound (37 °C, bubbled with 21% O2: 5% CO2) to measure changes in isometric tension. The resting tension was set at 1-gram force (gf) with vessels being left static to equilibrate for duration of one hour. Baseline contractile reactions to 40 mmol/L KCl were obtained from a resting tension of 1 gf. Contractile reactions to 40 mmol/L KCl were then obtained from stepwise increases in resting tension (1.2, 1.4, 1.6, 1.8 and 2.0 gf). RESULTS: Twenty PA rings of internal diameter between 2-4 mm were prepared from 4 patients. In human PA rings incrementing the tension during rest stance by 0.6 gf, up to 1.6 gf significantly augmented the 40 mmol/L KCl stimulated tension. Further enhancement of active tension by 0.4 gf, up to 2.0 gf mitigate the 40 mmol/L KCl stimulated reaction. Both Myograph and the organ bath demonstrated identical conclusions, supporting that the radial optimal resting tension for human PA ring was 1.61 g. CONCLUSION: The radial optimal resting tension in our experiment is 1.61 gf (15.78 mN) for human PA rings.

In Vivo Inhibition of Proteasome Activity and Tumour Growth by Murraya koenigii Leaf Extract in Breast Cancer Xenografts and by Its Active Flavonoids in Breast Cancer Cells.

Inhibition of the 26S proteasome is an attractive approach for anticancer therapy. Proteasome inhibitors are known to selectively target cancer cells and make them more sensitive to chemotherapeutic agents. Murraya koenigii is a medicinally important herb of Asian origin and a rich source of bioactive compounds such as flavonoids and alkaloids. In the present study, we investigated the proteasome inhibitory and apoptotic effect of M. koenigii leaf extract in vivo in a xenograft tumor mouse model, and also assessed the toxicity if any in normal mice. M. koenigii extract did not lead to any toxicity in mice. Analysis of extract revealed the presence of flavonoid compounds which act as proteasome inhibitors. Quercetin treatment led to the decrease in the cell viability and arrest of cells in G2/M phase. Quercetin, Apigenin, Kaempferol and Rutin; flavonoids present in the leaf extract, dose-dependently inhibited the endogenous 26S proteasome activity in MDA-MB-231 cells. Reduction in tumor growth was associated with a decrease in proteasomal enzyme activities in the treated groups. Increased caspase-3 activity and TUNEL-positive cells indicated enhanced apoptosis with Murraya leaf extract treatment. Decreased expression of angiogenic and anti-apoptotic gene markers is indicative of inhibition of angiogenesis and promotion of apoptosis in the leaf extract treated tumors.

Short- and long-term outcomes of pneumonectomy in a tertiary center.

BACKGROUND: Surgery is the most important therapeutic modality for lung cancer. Surgical outcomes are normally reported as 30-day or 90-day mortality or 5-year survival; 10-year survival is rarely mentioned in national data or international studies. METHODS: Three hundred and six patients (79% male) underwent pneumonectomy, mainly for lung cancer, from January 1998 to February 2013. Their short- and long-term outcomes up to September 2014 were analyzed retrospectively. The mean age was 64 years (range 22-82 years) and 24% were aged ≥70 years. Thoracoscore was used to calculate the risk of hospital mortality. RESULTS: Operative mortality was 4.5% whereas predicted mortality was 8%. The operative mortality for cancer patients was 3.3%; the national mortality for lung cancer is 6.5%. Only 2 patients died in hospital after a pneumonectomy in the last 5 years. Half of the patients who died in hospital were ≥70 years old; 29% (4 patients) died after urgent operations for nonmalignant disease. Overall 5- and 10-year survival was 32% and 20%. Median and mean survival was 26 and 57 months, respectively. Long-term survival was better in females aged <70 years, in left pneumonectomy patients, and in those with squamous cell lung cancer. CONCLUSION: Our mortality for pneumonectomy was 50% less than the national mortality rate and significantly lower than that predicted by the Thoracoscore for lung cancer. This confirms that pneumonectomy is still an effective modality for the treatment of lung cancer, with low operative mortality and good long-term survival, especially in younger patients.

Preventive effects of butyric acid, nicotinamide, calcium glucarate alone or in combination during the 7, 12-dimethylbenz (a) anthracene induced mouse skin tumorigenesis via modulation of K-Ras-PI3K-AKTpathway and associated micro RNAs.

Skin cancer is among the most common cancers worldwide and identifiable molecular changes for early and late stage of skin tumorigenesis can suggest the better targets for its control. In this study, we investigated the status of K-Ras-PI3K-AKTpathway followed by NF-κB, cyclin D1, MMP-9 and regulatory micro RNA during 7, 12-dimethylbenz[a]anthracene (DMBA) induced mouse skin tumorigenesis and its prevention by butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG), individually or in combination with respect to time. DMBA upregulated the K-Ras, PI3K, Akt, NF-κB, cyclin D1 and MMP-9, but downregulated the PTEN in a time dependent manner. DMBA also reduced the levels of micoRNA let-7a but induced the levels of miR-21 and miR-20a as a function of time. BA, NA and CAG were found to prevent DMBA induced changes, but they were most effective when used together in a combination. Reduced let-7a and miR-211 were correlated with the overexpression of K-Ras and MMP-9. Overexpression of miR-21 and miR-20a was correlated with the down regulation of PTEN and overexpression of Cyclin D1. Collectively, the enhanced chemopreventive potential of natural compound in combination via regulation of K-Ras-PI3K-AKTpathway along with regulatory micro RNAs provide a newer and effective mean for cancer management.

Combinatorial chemopreventive effect of butyric acid, nicotinamide and calcium glucarate against the 7,12-dimethylbenz(a)anthracene induced mouse skin tumorigenesis attained by enhancing the induction of intrinsic apoptotic events.

We explored the basis of the combinatorial chemopreventive effect of butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) on mouse skin exposed to 7,12-dimethylbenz(a)anthracene (DMBA). We studied the effects of topical application of DMBA in the presence or absence of BA, NA and CAG on the regulators of apoptosis. DMBA treatment suppressed Bax, Bax/Bcl-2 ratio, release of cyt c, Apaf1, caspase-9, -3 mediated apoptosis. Downregulation of p21 and upregulation of Bcl-2, mut p53 were also observed in only DMBA treated mice. Simultaneous application of BA, NA and CAG induced a mitochondria-mediated apoptosis, characterized by a rise in the Bax, Bax/Bcl-2 ratio, release of cyt c, upregulation of Apaf1 with down-stream activation of caspase-9, -3. Furthermore treatment with BA, NA and CAG demonstrated an upregulation of p21 and downregulation of Bcl-2, mut p53. But this effect was enhanced in the presence of all the three compounds together in combination. Chemoprevention by a combination of BA, NA and CAG by inducing the apoptosis, the natural cell death, suggest the importance of the potential combinational strategies capable of preventing skin tumor development.

Vitamin D deficiency decreases adiposity in rats and causes altered expression of uncoupling proteins and steroid receptor coactivator3.

The vitamin D endocrine system is functional in the adipose tissue, as demonstrated in vitro, in cultured adipocytes, and in vivo in mutant mice that developed altered lipid metabolism and fat storage in the absence of either 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or the vitamin D receptor. The aim of the present study was to examine the role of vitamin D and calcium on body adiposity in a diet-induced vitamin D deficient rat model. Vitamin D-deficient rats gained less weight and had lower amounts of visceral fat. Consistent with reduced adipose tissue mass, the vitamin D-deficient rats had low circulating levels of leptin, which reflects body fat stores. Expression of vitamin D and calcium sensing receptors, and that of genes involved in adipogenesis such as peroxisome proliferator-activated receptor, fatty acid synthase and leptin were significantly reduced in white adipose tissue of deficient rats compared to vitamin D-sufficient rats. Furthermore, the expression of uncoupling proteins (Ucp1 and Ucp2) was elevated in the white adipose tissue of the deficient rat indicative of higher energy expenditure, thereby leading to a lean phenotype. Expression of the p160 steroid receptor coactivator3 (SRC3), a key regulator of adipogenesis in white adipose tissue was decreased in vitamin D-deficient state. Interestingly, most of the changes observed in vitamin D deficient rats were corrected by calcium supplementation alone. Our data demonstrates that dietary vitamin D and calcium regulate adipose tissue function and metabolism.

WITHDRAWN: Is there life after the Mesothelioma and Radical Surgery trial? Does extrapleural pneumonectomy still have a role in the management of pleural mesothelioma? A 13-year, single-center experience.

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Could Thoracoscore predict postoperative mortality in patients undergoing pneumonectomy?

OBJECTIVES: Thoracoscore is incorporated in the new British Thoracic Society and National Institute of Health and clinical Excellence guidelines to evaluate the operative mortality risk of patients undergoing thoracic surgery. This study examines the accuracy of Thoracoscore in predicting postoperative mortality in patients undergoing pneumonectomy. METHODS: All patients who underwent pneumonectomy from January 1998 to March 2008 were included. Thoracoscore was calculated based on the following variables: age, sex, American Society of Anaesthesiologists' class, performance status classification, dyspnoea score, priority of surgery, procedure class, Diagnosis group and comorbidities score. RESULTS: Two hundred and forty-three patients with a mean age of 63 ± 9 years were included and 81% were male. The predicted postoperative mortality based on Thoracoscore was 8 ± 2.6% (95% confidence interval (CI) 4.56-11.43), while actual in-hospital mortality was 4.5% (11/243) (95% CI 1.87-7.12). 54% (6/11) of in-hospital mortality was of those who were >70 years old and 73% (8/11) of patients who died in hospital were male. Nine of 11 (82%) patients had pneumonectomy for malignancy. Thoracoscore was divided into four risk groups: low (0-3), moderate (3.1-5), high (5.1-8) and very high (>8). It underestimated mortality in low-risk group while overestimated in high-risk groups. The 30-day, 1-year, 2-year and 3-year observed mortalities were 5.3, 29, 43 and 55%, respectively. CONCLUSIONS: Although advanced age, the male sex and malignancy proved to be strong predictors of in-hospital mortality in our study, Thoracoscore failed to predict accurate risk of in-hospital mortality in pneumonectomy patients in this study. Further studies are required to validate the Thoracoscore in different subgroups of thoracic surgery.

Eri silkworm: a source of edible oil with a high content of α-linolenic acid and of significant nutritional value.

BACKGROUND: The study was undertaken to provide value addition to spent eri silkworm as an alternative source of edible oil for the food and feed industry by carrying out a short-term nutritional and toxicological evaluation of eri silkworm pupae oil using Wistar NIN rats. RESULTS: Growth performance of rats fed either sunflower oil (Control) or eri silkworm pupae oil (Experimental) was comparable. Histopathological examination of the various tissues showed no signs of toxicity even after feeding the eri silkworm oil for 18 weeks. Serum cholesterol and triglyceride was significantly reduced (P < 0.05) while high-density lipoprotein cholesterol was significantly increased (P < 0.05) which is attributed to the high α-linolenic acid content of eri silkworm oil. CONCLUSION: The study showed that eri silkworm pupae oil is safe and nutritionally equivalent to commonly used vegetable oils. Eri silkworm pupae can be harvested to provide a cost effective alternative edible oil that can be used to nutritional advantage in the food and feed industry. Therefore eri silkworm and its host plants offer an excellent example of multiple product crops and of sustainable agricultural practice with excellent opportunity for economic and nutritional benefits.

Dietary fatty acid composition alters 11ß-hydroxysteroid dehydrogenase type 1 gene expression in rat retroperitoneal white adipose tissue.

The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies intracellular glucocorticoid action by converting inactive glucocorticoids to their active forms in vivo. Adipose-specific overexpression of 11ß-HSD1 induces metabolic syndrome in mice, whereas 11ß-HSD1 null mice are resistant to it. Dietary trans and saturated fatty acids (TFAs and SFAs) are involved in the development of metabolic syndrome, whereas polyunsaturated fatty acids (PUFA) offer protection against this. Here, we report the effects of chronic feeding of different diets containing vanaspati (TFA rich), palm oil (SFA rich) and sunflower oil (PUFA rich) at 10%level on 11ß-HSD1 gene expression in rat retroperitoneal adipose tissue. 11ß-HSD1 gene expression was significantly higher in TFA rich diet-fed rats compared to SFA rich diet-fed rats, which in turn was significantly higher than PUFA rich diet-fed rats. Similar trend was observed in the expression of CCAAT-enhancer binding protein-α (C/EBP-α), the main transcription factor required for the expression of 11ß-HSD1. We propose that TFAs and SFAs increase local amplification of glucocorticoid action in adipose tissue by upregulating 11ß-HSD1 by altering C/EBP-α-gene expression. The increased levels of glucocorticoids in adipose tissue may lead to development of obesity and insulin resistance, thereby increasing the risk of developing metabolic syndrome.

Differentiating effortful and noneffortful swallowing with a neck force transducer: implications for the development of a clinical feedback system.

This study sought to determine whether effortful saliva swallows could be differentiated from habitual, noneffortful saliva swallows on the basis of swallow-related changes in neck circumference in humans. Gender differences in swallow-related neck circumference were examined as a secondary question. Twenty-seven healthy adults (14 females; mean age = 26.6 years, SD = 3.9 years) participated in two experimental runs (run duration = 10 min) during which they produced single trials of three visually cued tasks in random order: effortful saliva swallowing, saliva swallowing, and a control task involving repetitive apposition of the dominant thumb and index finger. Neck and ribcage circumference were simultaneously collected from the output of force transducers positioned around the neck and ribcage, respectively. The primary outcome variables were the positive and negative voltage peak amplitudes associated with changes in neck circumference during single-swallow trials. Effects of the swallowing task on positive and negative voltage peaks were examined with separate two-way analysis of variance procedures. Results indicated that both positive (F = 6.49, p < 0.05) and negative (F = 12.05, p

Chronic encapsulated mediastinal abscess presenting with remote cutaneous fistulization 12 years after redo aortic valve replacement for prosthetic valve endocarditis.

Chronic encapsulated mediastinal abscess is an unusual complication of previous open heart surgery. We report on the case of a 79 year old male who presented with epigastric fistulization of an encapsulated anterior mediastinal abscess 12 years after a redo aortic valve replacement for prosthetic valve endocarditis. The encapsulated abscess and its complex branching tracts and the cutaneous fistula were excised completely except the thin longitudinal strip of the ascending aorta which formed part of the posterior wall of the infected tract. This was covered with transposed greater omentum based on right gastroepiploic artery pedicle. Patient remains fit and well 2 years after his operation. This report is unusual on account of the length of the interval between previous heart surgery and the infective complication, the presumed dormancy of the abscess for as long as 12 years, the complex course, branching tracts and the contents of the abscess, the remote fistulization of the abscess at a distant anatomical site and, finally, the principle of successfully covering an infected tract which formed the adventia of the ascending aorta with pedicled omentum in the hope of avoiding an ascending aortic replacement in a frail 79 year old man. In the entire English language literature, this report represents the longest interval between a heart operation and a sternal or mediastinal abscess.

Can surgery for cancer accelerate the progression of secondary tumors within residual minimal disease at both local and systemic levels?

BACKGROUND: Surgical removal remains the principal treatment modality in the management of lung cancer. Our aim is to characterize the effects of tumor removal on subsequent tumor recurrence at both local and systemic levels. METHODS: C57/BL6 mice [10/group] underwent a mammary fat pad inoculation of 3LL cells [5 x 10(5)/animal] and were divided into two groups. Group 1 served as control while mice in group 2 were further subdivided into groups 2A and 2B. After 2 weeks, all mice in 2A were killed, and primary tumors and lungs were excised. At 2 weeks, primary tumors were excised completely for all mice in group 2B. These mice were then recovered and recurrent tumor growth evaluated for a further 2 weeks. Four weeks from the onset of the study, all remaining primary tumors and lungs were excised from groups 1 and 2. RESULTS: After 4 weeks undisturbed growth, primary tumors in group 1 reached a mean size of 2.85 +/- 0.33 cm. After 2 weeks growth, primary tumors in groups 2A and 2B were comparable at 1.36 +/- 0.44 m and 1.53 +/- 0.29 cm, respectively. Two weeks after primary tumor excision, recurrent tumors in group 2B had reached a mean size of 2.65 +/- 0.74 cm. Moreover, for several animals, recurrent tumors rapidly reached similar volumes to that of primary tumors in group 1. Primary tumors were typically encapsulated and nonadherent. In contrast, recurrent tumors were locally invasive and adherent to chest wall and wound. Interestingly, pulmonary metastatic burden was increased in group 2B relative to group 1. Histologic examination revealed increased mitosis in recurrent tumors when compared with primary tumors. CONCLUSIONS: Tumor removal is followed by accelerated growth of locally recurrent tumors and metastases. Moreover, recurrent tumors are more locally invasive than primary tumors. These findings strongly indicate that resection may be followed by tumor progression in residual disease.

Surgically induced accelerated local and distant tumor growth is significantly attenuated by selective COX-2 inhibition.

BACKGROUND: Even after apparently curative resection, lung cancer recurrence continues to lead to high mortality levels. The aim of this study was to assess the effects of cyclooxygenase-2 (COX-2) inhibitor on local and systemic recurrent tumor growth. METHODS: C57BL/6 mice underwent mammary fat pad inoculation with 3LL cells. After two weeks growth, flank tumors were resected completely and followed for recurrent tumor growth. Postresection mice were randomized to receive placebo alone (group 1) or the selective COX-2 inhibitor, rofecoxib (group 2), daily for two weeks by tube feeding. Recurrent tumor growth kinetics were compared for both groups. Two weeks following primary tumor excision animals were sacrificed, after which lungs were resected and pulmonary metastatic burden was assessed using the lung-body weight ratio. Apoptotic and mitotic indices were established for recurrent tumors and lungs, using hematoxylin and eosin histology. RESULTS: Two weeks postexcision of the primary tumor, recurrent tumors in the placebo group were significantly greater than the treatment group (p = 0.002). While primary tumors were typically encapsulated and not adherent, recurrent tumors in the placebo group were invasive, adherent to the chest wall and the overlying wound. In contrast, recurrent tumors in the treatment group were nonadherent to the chest wall. Moreover, postoperative pulmonary metastatic burden was significantly reduced in treated animals. Histologic examination revealed increased apoptosis as well as an increase in the apoptosis-mitosis ratio in treated animals. CONCLUSIONS: Primary tumor excision was associated with accelerated local and systemic tumor recurrence. However, these effects were significantly attenuated using selective COX-2 inhibition. The COX-2-inhibition was associated with increased levels of apoptosis. These findings endorse a role for COX-2 inhibition in the secondary prevention of lung cancer recurrence at both local and systemic levels.