Varicocele and male infertility: current concepts and future perspectives

This Special Issue of Asian Journal of Andrology is fully dedicated to the thematic area of Varicocele, which has been one of the most controversial issues in the field of Urology, Andrology, and Reproductive Medicine. Recognized as a clinical entity for over a century, varicocele from Latin: varix (dilated vein) and from Greek: kele (tumor) still elicits heated debate among scientists and clinicians on an arguable negative effect on male fertility and gonadal function and has fueled thousands of scholarly articles since its first report in the 18^th century.Varicocele and Male Infertility: Current Concepts and Future Perspectives contains the seminal work of renowned scientists and clinicians from 15 countries on five continents. In 29 chapters, comprehensive reviews on the pathophysiology,1,2,3 epidemiology,4 diagnosis,5,6,7,8 and management9,10,11,12,13,14,15,16,17,18,19,20 of varicocele are presented; they dissect our current knowledge about varicocele from a multitude of angles. Among them, two systematic reviews critically summarize the clinical practice guidelines and best practice statements for diagnosis and management of varicocele in adults and adolescents.17,18 Moreover, three meta-analyses summarize the evidence on the effect of varicocele on semen parameters7 and the role of repairing varicoceles in men with azoospermia19 and in the male partners of infertile couples that will be subjected to assisted reproductive technology (ART).20 One of these meta-analyses is of particular interest to all health care providers and scientists alike because it revisits the effect of varicocele on conventional semen parameters in the face of the latest (fifth) edition of the World Health Organization (WHO) manual for the laboratory examination of human semen.7 As readers may be well aware of, the newest WHO manual not only changed the reference values for interpreting semen analysis results but also updated the methods for conducting such analyses.Marmar, whose seminal work on subinguinal microsurgical varicocelectomy lead to a paradigm shift in the way we now treat varicoceles, compiled a historical review of varicocele surgery.10 Two original articles were included; one presenting novel findings of an association between proteomics signatures in infertile men with clinical varicocele and sperm mitochondrial dysfunction,3 and another commenting on the usefulness of antegrade scrotal sclerotherapy as an alternative method for varicocele treatment to the commonly used open surgical repair.12 In addition, six commentary articles written by experts with vast clinical experience discuss challenging clinical conditions faced by health care practitioners dealing with males with varicocele.21,26 Furthermore, opportune is the review of Chiles and Schlegel, which provides a critical appraisal of the cost-effectiveness of varicocele surgery in the era of ART.27This Special Issue of Asian Journal of Andrology includes a multinational authoritative review, including 19 institutions across 12 countries about how to track research impact by selecting the appropriate metrics.28 In the years to come, it will be interesting to learn how these various bibliometrics reflect the impact of this Special Issue of Asian Journal of Andrology. Equally interesting will be to know if the predictions of Lamb and Lipshultz''s group come true with regards to the future use of molecular biomarkers for the diagnosis and management of adolescents and adults with varicocele.29We are very fortunate indeed that Thomas Jr. accepted our invitation to write the foreword.30 His humbleness and gentle manners hide a giant who contributed greatly to the field of male infertility, including varicocele and microsurgery. Tony Thomas has taught a legion of young doctors from so many different places and countries for so long, making it impossible to measure by any scientific means the impact of his work.We as guest editors are grateful to the Chief Editor and the Editorial staff of the Asian Journal of Andrology for their impeccable support. Ms. Danqing (Dan) Ren (Scientific Editor), who was in-charge of our Special Issue, was one of the best editorial professionals we could have asked for. She was diligent, organized, hardworking, and a very understanding individual. We would like to thank her and the members of her team for their enormous dedication in compiling this Special Issue. This Special Issue is recommended to students and researchers in the biological and medical sciences and clinicians involved in the management of infertile couples, including urologists, andrologists, gynecologists, embryologists, and reproductive specialists interested in following the exponential growth in the knowledge of varicocele. Due to the multidisciplinary nature of varicocele as a cause of male infertility, unsolved problems present themselves and the opportunities for advancement continue to expand. We hope our readers will appreciate this Special Issue of Asian Journal of Andrology and share our excitement in the study of varicocele.     

New therapies for relapsed castration-resistant prostate cancer based on peptide analogs of hypothalamic hormones

It is a pleasure to contribute our presentation at the International Prostate Forum of the Annual Meeting of the American Urological Association (AUA) to this special issue of the Asian Journal of Andrology.We are gratified that the method developed in our laboratories1 based on agonistic analogs of hypothalamic luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, which was discovered and characterized by one of us (AVS) in the 1970s,2,3,4,5,6 has been used since the early 1980s for the treatment of hormone-dependent prostate cancer.7,8,9,10,11 Since that time our laboratory has been trying to develop therapies for relapsed androgen-independent, castration-resistant prostate cancer (CRPC). These new therapies are also based on various analogs of hypothalamic hormones and are sorely needed when the patients with hormone-dependent prostate cancer undergo loss of effect of androgen deprivation therapy and relapse. New drugs such as abiraterone, enzalutamide (MDV 3100), cabazitaxel, sipuleucel-T, zoledronic acid, and radium-22312,13,14,15,16,17 are welcome additions to the oncological-urological armamentarium but after an initial response, resistance to most of these agents appears to develop.Consequently, in our view, synthetic antagonistic analogs of peptides such as growth hormone-releasing hormone (GHRH), LHRH, bombesin/gastrin releasing peptide (BN/GRP) that inhibit growth factors such as epidermal growth factor, vascular endothelial growth factor, insulin-like growth factor-I, II or analogs with cytotoxic moieties, which can target receptors on tumors, must be developed.8,9,10,18,19,20As we know, therapies for metastatic hormone-sensitive prostate cancer, as introduced by Huggins and Hodges21 and others include: orchiectomy, estrogens, adrenalectomy, corticosteroids, hypophysectomy, and anti-androgens. Each can induce palliation in advanced prostate cancer; however, each has its pros and cons, morbidity and mortality, and limited long-term efficacy. Our laboratory many years ago introduced LHRH agonists, which in chronic application downregulate pituitary LHRH receptors. In turn, this downregulation of LHRH receptors leads to an inhibition of the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), producing a suppression of androgen and estrogen levels in blood.1,7,8,9,10,22 The treatment of patients with prostate cancer has been greatly facilitated by the introduction of sustained delivery systems10,22 as the administration of microcapsules containing the agonist can be performed only every 3–6 months.Following elucidation of the effects of LHRH agonists on prostate cancer and recognition of its associated effects, we turned our attention to LHRH antagonists. We and others synthesized antagonists of LHRH that block pituitary receptors for LHRH and produce an immediate cessation of secretion of LH, FSH and sex steroids.8,9,10 Early LHRH antagonists had some in edematogenic activities due to histamine release. In the LHRH antagonist, cetrorelix, developed by us, these activities were greatly reduced, and it was possible to carry out clinical studies in patients with prostate cancer and benign prostatic hyperplasia.8,9,10,23 Modern LHRH antagonist, degarelix, developed by Ferring, is the current drug of choice in this category.24,25,26,27 Degarelix has no serious adverse effects and avoids the flare phenomenon of LHRH agonists. Degarelix provides fast and effective control of testosterone, prostate specific antigen, LH, and FSH levels. It produces lower FSH levels than leuprolide, eliminates microsurges of testosterone, and leads to fewer cardiovascular and metabolic consequences than the LHRH agonists.24,25,26,27Luteinizing hormone-releasing hormone analogs provide effective palliative therapy for patients with advanced prostate carcinomas resulting in objective stable disease, partial remission and occasionally long-term complete remission.8,9 However, all hormonal therapies aimed at androgen deprivation, including orchiectomy, anti-androgens, LHRH agonists or antagonists, with or without anti-androgens, usually provide remissions of only limited duration.8,9 Most patients who live long enough with advanced prostatic carcinoma relapse. The prognosis of these patients with androgen-independent prostate cancer is very poor.8,9 The latest therapeutic drugs for prostate cancer, like abiraterone, extend the survival only by a few months.12,15,16Continuing our studies, it became clear that some effects of LHRH analogs are exerted directly, rather than indirectly, on prostate cancer cells.8,9,10,28 We were able to demonstrate the presence of high levels of receptors for LHRH, BN/GRP, and somatostatin, as well as mRNAs for their receptor subtypes, in human prostate cancer specimens.8,9,10,28 In experimental studies on human prostate cancer lines xenografted into nude mice, analogs of LHRH,10 analogs of somatostatin,29 and analogs of GRP30 each inhibited prostate tumors growth and in vitro reduced their proliferation.8,9,10,28 In vitro effects demonstrated a direct effect of these analogs on tumors.10 Following the example with Estracyt (estramustine) consisting of nitrogen mustard coupled to carrier estrogen, we developed cytotoxic analogs of LHRH, somatostatin, and GRP which actively target respective receptors on prostate cancers.18,19,20,31,32,33,34,35,36,37 Thus, we have synthesized a targeted cytotoxic LHRH analog, denoted AN-152 (commercially AEZS-108, zoptarelin-doxorubicin), which combines a D-Lys-6 LHRH agonist moiety (necessary for binding to LHRH receptors on cancer cell surfaces) with the cytotoxic doxorubicin.19 This analog delivers doxorubicin to only those cells with LHRH receptors on the cell membrane, thus avoiding cytotoxic side effects in normal cells. We found that after binding to LHRH receptors, AN-152 (AEZS-108) is internalized into the tumor cells.18,19,32,37AN-152 (AEZS-108) was extensively tested in vitro and also in vivo in nude mice with xenografted human cancer lines expressing LHRH receptors.8,9,37 This drug inhibited the growth of a wide range of carcinomas (including kidney, prostate, urothelium) and sarcomas. These included DU-145 human androgen-independent prostate cancer as well as HT-1376, J82, RT-4 and HT-1197 bladder cancer lines.8,9,37,38,39 The administration of AN-152 (AEZS-108) produced a powerful inhibition of tumor growth, greater than that induced by doxorubicin alone. The hybrid was found to be more efficacious and less toxic than doxorubicin.37 These studies were followed by Phase I and II human trials in women with endometrial and ovarian cancer expressing LHRH receptors.40,41Dose escalation studies established that the maximum tolerated dose of AEZS-108 is 267 mg m⁻². Dose-limiting leukopenia and neutropenia were observed at the highest dose.40 Liu, Pinski et al. also subjected AN-152 (AEZS-108) to Phase II trials in patients with CPRC resistant to taxane.42 AEZS-108 is currently in Phase III trials in USA and Europe in women with endometrial cancer. We have great expectations for it.Another class of new and important antitumor peptides that could inhibit CRPC consists of antagonists of GHRH.43,44,45,46 The story behind these compounds is most interesting. One of us (AVS) was among the investigators who discovered GHRH in hypothalami of animals in the 1960s.43 Because only extremely small quantities of GHRH are present in the hypothalamus, it was not possible to characterize GHRH structurally until the early 1980s.43 At that time, the clinicians became aware of cases of paraneoplastic acromegaly in some patients with pancreatic carcinoma. These tumors were actually producing GHRH, which then induced GH release from the pituitary. Thus, GHRH can be produced by tumors themselves, and it thus functions in an autocrine/paracrine fashion as a growth factor. Samples of these tumors were used for the isolation and structural elucidation of GHRH, which was then synthesized.43,44,45,46 Over the past 30 years, we have been investigating the role of GHRH in tumor growth and found that many tumors produced GHRH and had GHRH receptors.43,44,45,46 We determined that human prostate cancer specimens and human prostatic cell lines express GHRH and GHRH receptors.47 We also demonstrated the expression of splice variants of these receptors.47,48,49 This presence of GHRH receptors provides the basis for a new approach to the treatment of CRPC based on antagonists of GHRH.8,9,43 Thus, over the past 20 years we produced nearly 2000 synthetic antagonistic analogs of GHRH, with each step improving their potency and half-life.43,44,45,46,50 We substituted some of the natural (coded) L-amino acids in the N-terminal 29 amino acid sequence of GHRH that has all the biological activity either with their “D” isomers or with totally synthetic amino acids.43,44,45,46,50 The structure of one of our GHRH antagonists, MIA-602, the one we have chosen for clinical development, is shown in 43,44,45,46,51,52,53,54,55,56,57,58,69 We showed that MIA-602 and our other GHRH antagonists inhibited growth of PC-3 and 22Rv1 human androgen-independent prostate cancer cell lines and also hormone-dependent prostate cancer lines.58,59,60,61,62 Our GHRH antagonists also suppressed prostate, kidney, urothelial, breast, triple-negative breast, ovary, astrocytoma, melanoma, ENT tumors, esophagus, stomach, colon, lung, adrenal cortical, pheochromocytoma, uterus, osteosarcomas and multiple lymphoma types. In addition to their inherent effects on cancer, we found that the GHRH antagonists also potentiated the effects of cytotoxic chemotherapy without enhancing the toxicity!70

Table 1

Structure of growth hormone-releasing hormone antagonist, MIA-602Open in a separate windowThe side effect/toxicity profile of GHRH analogs is minimal. Similarly, LHRH agonists and antagonists also have little or no toxicity, and it is really their anti-androgenic effect, not the drugs themselves that cause some adverse effects.71,72     

Regulation of sperm capacitation and the acrosome reaction by PIP2 and actin modulation

Actin polymerization and development of hyperactivated (HA) motility are two processes that take place during sperm capacitation. Actin polymerization occurs during capacitation and prior to the acrosome reaction, fast F-actin breakdown takes place. The increase in F-actin during capacitation depends upon inactivation of the actin severing protein, gelsolin, by its binding to phosphatydilinositol-4, 5-bisphosphate (PIP₂) and its phosphorylation on tyrosine-438 by Src. Activation of gelsolin following its release from PIP₂ is known to cause F-actin breakdown and inhibition of sperm motility, which can be restored by adding PIP₂ to the cells. Reduction of PIP₂ synthesis inhibits actin polymerization and motility, while increasing PIP₂ synthesis enhances these activities. Furthermore, sperm demonstrating low motility contained low levels of PIP₂ and F-actin. During capacitation there was an increase in PIP₂ and F-actin levels in the sperm head and a decrease in the tail. In spermatozoa with high motility, gelsolin was mainly localized to the sperm head before capacitation, whereas in low motility sperm, most of the gelsolin was localized to the tail before capacitation and translocated to the head during capacitation. We also showed that phosphorylation of gelsolin on tyrosine-438 depends upon its binding to PIP₂. Stimulation of phospholipase C, by Ca²⁺-ionophore or by activating the epidermal-growth-factor-receptor, inhibits tyrosine phosphorylation of gelsolin and enhances enzyme activity. In conclusion, these data indicate that the increase of PIP₂ and/or F-actin in the head during capacitation enhances gelsolin translocation to the head. As a result, the decrease of gelsolin in the tail allows the maintenance of high levels of F-actin in this structure, which is essential for the development of HA motility.To acquire the ability to fertilize the egg, mammalian spermatozoa must undergo several biochemical and morphological changes in the female reproductive tract, collectively called capacitation. These changes include cAMP/PKA activation, cholesterol efflux from the plasma membrane, PKA-dependent protein tyrosine phosphorylation, actin polymerization and the development of HA motility.1,2 In a recent study we suggested a mechanism by which the Ser/Thr targeting PKA can lead to Tyr phosphorylation of proteins in the capacitation process. We showed that PKA activates Src which, in turn, inhibits the phosphatase PP1, leading to CaMKII activation, which activates Pyk2 to phosphorylate phosphatidyl-inositol-3-kinase on tyr-458.3We have shown elsewhere that actin polymerization must take place in order to capacitate spermatozoa while very fast depolymerization of F-actin occurs prior to the acrosome reaction.4 It has been suggested that an increase in F-actin during capacitation creates a network in the sperm head between the plasma membrane and the outer acrosomal membrane, and the dispersion of this F-actin must occur to enable acrosomal exocytosis.4,5,6,7 The increase in F-actin in the sperm tail during capacitation is important for the development of HA motility.8 The latter is characterized by an increase in flagellar bending amplitude and an increase in average lateral head movement.9,10 It was shown that the efficiency of HA sperm to penetrate the egg is much higher than non-HA sperm.11 Sperm motility and HA motility are mediated by PLD-dependent actin polymerization.8 It is known that phosphatidylinositol 4,5-bisphosphate (PIP₂) is a cofactor for PLD activation in many cell types.12,13,14,15,16 PIP₂ comprises only 1% of plasma membrane phospholipids, however its extraordinary versatility puts it in the center of plasma membrane dynamics governing cell motility, adhesion, endo- and exocytosis.17,18PIP₂ serves as an effector of several proteins such as Myristoylated alanine-rich C-kinase substrate (MARCKS), gelsolin, PLD and PI3K. These proteins are present in spermatozoa19,20 and are involved in the regulation of sperm capacitation and/or the acrosome reaction. PIP₂ binds gelsolin and release it from actin filaments ends, exposing sites for actin assembly.21 We have shown that the release of bound gelsolin from PIP₂, causes rapid Ca²⁺-dependent F-actin depolymerization as well as an increased acrosome reaction.22 We have also shown that PIP₂ and gelsolin are involved in regulating sperm motility and the development of HA motility.23     

Supraspinatus and infraspinatus compartment syndrome following scapular fracture

Acute compartment syndrome occurs when pressure within a confined fascial space rises to a level impairing microvascular perfusion to surrounding tissues.[1,2,3,4,5,6,7] The majority of the reported literature is based on lower extremity compartment syndrome, but any muscle group within an osteofascial compartment has the potential to develop compartment syndrome. We report a case of a 64-year-old male who developed an acute compartment syndrome of both the supraspinatus and infraspinatus after sustaining a severely comminuted scapula fracture. Diagnosis of compartment syndrome was made after intracompartmental pressure measurements of the supraspinatus and infraspinatus revealed pressures within 30 mmHg of the diastolic blood pressure, prompting emergency decompressive fasciotomy. At final follow-up, the examination revealed full shoulder strength with near-full range of motion. There were no signs of sequelae from compartment syndrome at any point. Few case reports describe compartment syndrome of the periscapular fascial compartments. However, these cases were either retrospectively diagnosed[8,9] or diagnosed via magnetic resonance imaging (MRI) findings and lab values.[9,10] Surgical management of acute compartment syndrome of the supraspinatus has been reported in only one other case.[10] To our knowledge, we report the only case of a patient with acute compartment syndrome of both the supraspinatus and infraspinatus compartments treated with emergent decompressive fasciotomy. Due to the devastating complications and functional loss of a missed diagnosis of compartment syndrome, a high index of clinical suspicion for developing compartment syndrome must be maintained in every fracture setting, regardless of anatomic location or rarity of reported cases.     

Modified technique in treating recurrent priapism: a technique report

Recurrent ischemic priapism is a problem in clinical treatment. Most of the cases require more invasive surgery to shunt the blood stasis. We introduce a modified technique in treating recurrent ischemic priapism. The technique described is applied to acute ischaemic priapic episodes in patients with a history of stuttering priapism. It was carried out by a Winter''s shunt combined with a continuous cavernosal irrigation system. Priapism was effectively resolved on the patients without recurrence. The four patients who received this treatment recovered most sexual function after 6 months follow-up.The authors would introduce a technique in treating recurrent ischemic priapism, a Winter''s shunt that combined with continuous cavernosal irrigation. The measurement can overcome the shortcoming of Winter''s shunt and effectively resolve recurrent ischemic priapism. It can avoid the creation of a more invasive shunt or even an open surgery.Ischemic priapism is a rare emergency urological disease that is characterized by persistent penile erection continuing beyond, or unrelated to, sexual stimulation.1,2 It is a disorder of venous outflow and/or stasis.3 If it is not be treated effectively and timely, long-term impotence may result. Priapism can be treated by intracavernosal injection with a dilute solution of phenylephrine or cavernosal irrigation with saline.1,4 Some priapism cases need a less invasive shunt such as Winter''s shunt5 to create a shunt distally between the corpora cavernosal and glans of the penis with the large biopsy needle. With this method, the congested cavernosa can be drained through venous drainage of corpora spongiosum and the corporal cavernosa. However, those therapies cannot be effectively used to resolve prolonged priapism because of thrombocyte adherence and loss of contractile trabecular elements.6 Priapism still repeatedly recurred after the therapies. Recurrent ischemic priapism is a problem in clinical treatment. Most of the cases require more invasive surgery to shunt the blood stasis.7 Surgical treatment includes distal shunt (EbbehØj, Al-Ghorab) and proximal shunt (cavernospongious shunt, cavernosalsaphenous shunt). Like Winter''s shunting, EbbehØj or Al-Ghorab is to create a corporoglanular shunt with a scalpel rather than a needle.8,9,10 The proximal shunts are open surgical operations.11,12 The surgical treatments are more invasive. It is reported that proximal shunts can easily result in impotence (49% with cavernospongiosal shunts and 52% with cavernosalsaphenous shunts) and significant complication such as urethral fistula, cavernositis11 and even pulmonary embolism.13,14     

Optimal management of prostate cancer with lethal biology – state-of-the-art local therapy

Defining prostate cancer with lethal biology based upon clinical criteria is challenging. Locally advanced/High-Grade prostate cancer can be downstaged or even downgraded with cure in up to 60% of patients with primary therapy.1,2,3,4,5 However, what is known is that high-grade prostate cancers have a greater potential for recurrence and progression to metastatic disease, which can ultimately result in a patient''s death. Patients with clinical features of “high-risk” prostate cancer (cT2c, PSA >20, ≥ Gl 8 on biopsy) are more likely to harbor more aggressive pathologic findings. The optimal management of high-risk prostate cancer is not known as there are not prospective studies comparing surgery to radiation therapy (RT). Retrospective and population-based studies are subject to many biases and attempts to compare surgery and radiation have demonstrated mixed results. Some show equivalent survival outcomes6 while others showing an advantage of surgery over RT.7,8,9,10,11 Local therapy for high-risk disease does appear to be beneficial. Improved outcomes realized with local therapy have been clearly demonstrated by several prospective studies evaluating androgen deprivation therapy (ADT) alone versus ADT plus RT. The combination of local with systemic treatment showed improved disease-specific and overall survival outcomes.12,13,14 Unfortunately, primary ADT for N0M0 prostate cancer is still inappropriately applied in general practice.11 While the surgical literature is largely retrospective, it too demonstrates that surgery in the setting of high-risk prostate cancer is effective in providing durable disease-specific and overall survivals.2,3,15Whether both treatment modalities provide equivalent results is yet to be determined. In fact, many patients may benefit from a multimodality approach potentially including surgical excision, followed by postoperative radiation with or without ADT. However; when initiating therapeutic strategies, there may be certain clinical scenarios where relevant clinical findings or patient history could direct a clinician toward an optimal therapy. These decisions are typically based on inherent risks, theoretical concerns or the preponderance of evidence surrounding a single aspect of the particular clinical scenario. The following are clinical scenarios where RT or surgery may be considered as the best initial treatment for primary therapy in cTxN0M0 prostate adenocarcinoma. While this is by no means meant to be a strict guide for application of therapy, it does call to attention considerations as to appropriate clinical decision-making.     

Increased alveolar nitric oxide concentration and high levels of leukotriene B(4) and 8-isoprostane in exhaled breath condensate in patients with asbestosis

Background

Inhaled asbestos fibres can cause inflammation and fibrosis in the lungs called asbestosis. However, there are no non‐invasive means to assess and follow the severity of the inflammation. Exhaled nitric oxide (NO) measured at multiple exhalation flow rates can be used to assess the alveolar NO concentration and bronchial NO flux, which reflect inflammation in the lung parenchyma and airways, respectively. The aim of the present study was to investigate whether exhaled NO or markers in exhaled breath condensate could be used to assess inflammation in asbestosis.

Methods

Exhaled NO and inflammatory markers (leukotriene B₄ and 8‐isoprostane) in exhaled breath condensate were measured in 15 non‐smoking patients with asbestosis and in 15 healthy controls. Exhaled NO concentrations were measured at four constant exhalation flow rates (50, 100, 200 and 300 ml/s) and alveolar NO concentration and bronchial NO flux were calculated according to the linear model of pulmonary NO dynamics.

Results

The mean (SE) alveolar NO concentration was significantly higher in patients with asbestosis than in controls (3.2 (0.4) vs 2.0 (0.2) ppb, p = 0.008). There was no difference in bronchial NO flux (0.9 (0.1) vs 0.9 (0.1) nl/s, p = 0.93) or NO concentration measured at ATS standard flow rate of 50 ml/s (20.0 (2.0) vs 19.7 (1.8) ppb, p = 0.89). Patients with asbestosis had increased levels of leukotriene B4 (39.5 (6.0) vs 15.4 (2.9) pg/ml, p = 0.002) and 8‐isoprostane (33.5 (9.6) vs 11.9 (2.8) pg/ml, p = 0.048) in exhaled breath condensate and raised serum levels of C‐reactive protein (2.3 (0.3) vs 1.1 (0.2) μg/ml, p = 0.003), interleukin‐6 (3.5 (0.5) vs 1.7 (0.4) pg/ml, p = 0.007) and myeloperoxidase (356 (48) vs 240 (20) ng/ml, p = 0.034) compared with healthy controls.

Conclusions

Patients with asbestosis have an increased alveolar NO concentration and high levels of leukotriene B4 and 8‐isoprostane in exhaled breath. Measurement of exhaled NO at multiple exhalation flow rates and analysis of inflammatory markers in exhaled breath condensate are promising non‐invasive means for assessing inflammation in patients with asbestosis.Asbestosis is diffuse interstitial lung fibrosis caused by an inflammatory response to inhaled asbestos fibres.^1,2,3,4 It requires moderate or heavy exposure to asbestos and takes at least 15–20 years to develop in most cases. The diagnosis of asbestosis is based on findings of diffuse interstitial fibrosis when a history of sufficient exposure to asbestos exists and other causes of pulmonary fibrosis have been ruled out. The general features of the inflammatory reaction in asbestosis have recently been reviewed.¹ However, there are no non‐invasive tools to assess the inflammatory reaction in asbestosis, and efforts to treat the disease have not been successful.^1,2,3,4,5There is a clinical need to develop a direct means of measuring inflammation for follow‐up and diagnostic purposes in inflammatory lung diseases. Exhaled nitric oxide (NO) measurements and inflammatory markers in exhaled breath condensate have recently been introduced as non‐invasive methods for assessing lung inflammation.^6,7 NO is a gaseous signalling molecule that regulates various physiological and pathophysiological functions in the lungs and in the whole human body.^8,9 It is synthesised in small amounts by constitutive nitric oxide synthases (cNOS) in physiological conditions. In inflammation, the inducible nitric oxide synthase (iNOS) produces higher amounts of NO for prolonged periods.^10,11 The NO concentration in exhaled air is known to be increased in diseases such as asthma,^12,13,14 chronic obstructive pulmonary disease (COPD)¹⁵ and alveolitis.^14,16 According to the ERS and ATS recommendations, exhaled NO should be measured at a single exhalation flow rate of 50 ml/s.⁷ However, measurement of exhaled NO at multiple exhalation flow rates allows assessment of alveolar and bronchial NO output separately.^17,18,19,20 The multiple flow rate method is based on a mathematical model which divides the lung into two compartments—the alveolar/peripheral and bronchial/central compartments.¹⁷ The multiple exhalation flow rate method has been shown to differentiate successfully between bronchial and alveolar inflammation in asthma, COPD and alveolitis.^{14,18,19,21,22,23,24,25}Non‐gaseous markers of pulmonary inflammation can be non‐invasively sampled by collecting exhaled breath condensate, and raised levels of inflammatory mediators such as leukotriene B₄ (LTB₄) and 8‐isoprostane have been found in certain inflammatory lung diseases.²⁶In the present study we measured exhaled NO at multiple exhalation flow rates and collected exhaled breath condensate in 15 patients with asbestosis and 15 age‐ and sex‐matched healthy controls. The aim of the study was to determine whether patients with asbestosis have altered bronchial or alveolar NO output or increased concentrations of inflammatory markers LTB₄ and/or 8‐isoprostane in their exhaled breath condensate.     

Lipogenic metabolism： a viable target for prostate cancer treatment？

Cancer cells often depend on altered metabolism compared with their normal counterparts.1-4 As observed in 1924 by Otto Warburg, cancer cells show preferential glucose consumption by way of aerobic glycolysis while normal cells generally assume mitochondrial oxidative phosphorylation.4 Another metabolic hallmark of carcinogenesis is altered lipid metabolism, whereby cancer cells may adopt enhanced de novo lipid production （lipogenesis）.l-3 Enhanced lipid metabolism is also observed in individuals with metabolic syndromes potentially a consequence of increasing popularity of the Standard American Diet, composed of high levels of saturated fats and carbohydrates.5 A growing body of epidemiological data indicates a positive correlation between the occurrence of metabolic syndromes, such as cardiovascular disease, obesity, type-2 diabetes and associated hyperinsulemia, with the aggressiveness of cancer.6-9 Remarkably, it is estimated that for every 1% reduction in saturated fats, replaced by polyunsaturated, there would be a 2%-3% reduction in cardiovascular disease.10 Thus, it is conceivable that an equally remarkable attenuation in cancer progression might be achieved with such a reduction in lipid accumulation.     

Lipoma arborescens associated with osseous/chondroid differentiation in subdeltoid bursa

Lipoma arborescens (LA) is a rare benign lesion of unknown etiology. It is characterized histologically by villous proliferation of the synovial membrane and diffuse replacement of the subsynovial tissue by mature fat cells. This condition affects the knee joint most commonly. Cases involving other locations including glenohumeral joint,[1] hip,[2] elbow,[3] hand[4] and ankle[5] have been rarely described. Involvement of the subdeltoid bursa has also been reported, but to date no case has described LA with osseous/chondroid differentiation of this bursa. Another significant finding in our case was the coexistence of LA with intermuscular lipoma, SLAP lesion and labral cyst.     

Are men talking their reproductive health away?

The advent of mobile phones has revolutionized communication trends across the globe. As the popularity of mobile phone usage continues to escalate, there is now growing concern about the effects of radiofrequency electromagnetic waves (RF-EMW) exposure on biological tissues, such as the brain and testes. Researchers have sought to link the much debated decline in human sperm quality in the last decade, with increased exposure to RF-EMW, particularly through mobile phone usage. In a recent systematic review and meta-analysis on the effect of mobile phone RF-EMW radiation on sperm quality, Adams et al. 1 demonstrated an association between mobile phone exposure and reduced sperm motility and viability, with inconsistent effects on sperm concentration.1 Results from 10 pooled experimental (in vitro) and observational (in vivo)human studies (n = 1492) led these researchers to suggest that exposure to RF-EMW radiation from carrying a mobile phone in the trouser pocket negatively impacts sperm quality.Mobile phones operate within low RF bands and radiate nonionizing energy in the form of RF-EMW. Mobile phones emit RF energy when in use (talk mode) and the closer the mobile phone is to the tissue when in use, the greater the RF-EMW energy that will be absorbed. When used as a hands free device along with a wired or wireless earpiece/headset (both of which also emit a small amount of RF energy), placement of the mobile phone when in talk mode either in the trouser pocket or clipped to a belt, places the main source of the mobile phone RF-EMW energy away from the head but closer to the genital tissue.2Electromagnetic waves radiation is absorbed as it interacts with matter and transfers wave energy into the medium. The amount of RF-EMW radiation energy absorbed by human tissue depends on the frequency, intensity, polarization and duration of exposure.3 Specific absorption rate (SAR) is a measure of the relative amount of RF energy absorbed by the human body (expressed in W kg⁻¹) when using a mobile phone. SAR value for mobile phones operating at its maximum power level is limited to 1.6 W kg⁻¹ in the US, Canada and Australia, and 2.0 W kg⁻¹ in Europe.4 The SAR value varies for each type of mobile phone and can also vary greatly in any one particular model based on usage conditions.Exposure to RF-EMW radiation could potentially exert thermal and nonthermal effects on biological tissue. Heat is mostly generated from the handset, but the thermal effects of mobile phone radiation seem less probable as adverse heating effects occur at SAR values of 4.0 W kg⁻¹ and greater.5 Exposure to various environmental frequencies can induce cellular changes.6 Nonthermal effects of mobile phones on the male reproductive system include increased generation of seminal reactive oxygen species and reduction in antioxidant enzymes leading to oxidative stress, chromosomal damage and micronuclei formation, altered spermatozoal membrane potential and signal transduction (decreased calcium efflux, histone kinase and protein kinase C), altered sperm proliferative activity, increased caspase activation leading to apoptosis, suppression of testicular steroidogenesis and reduced testosterone levels, leading to decreased spermatogenesis.2,3,7,8Current literature on EMW radiation exposure and male reproduction remains controversial, with conflicting results reported in human and animal studies on the effects of RF-EMW on male fertility.2,3,7,8 In their meta-analysis, Adams et al. pooled results from 6 in vitro (n = 254–361 each) and 4 in vivo (n = 8–64 each) human studies, consisting of cohorts from the general population and those attending fertility clinics.1 Of the 10 selected studies, 9 used sperm motility as a parameter, while 5 to 6 studies had data on sperm viability and concentration as a measure of sperm quality. In vitro application of RF energy was mostly 850–900 MHz, while SAR values ranged from 1 to 2 W kg⁻¹. The source of RF-EMR was mainly commercially-available mobile phones and exposure time was mainly 60 min. Heterogeneity was high in all their meta-analyses, and was a study limitation.1On the whole, the main limitation in researching the effects of RF-EMW exposure on male reproductive health is the study design and methods applied; as those that have been used or are currently available lacks sufficient strength to reveal conclusively if EMW radiation impairs sperm quality.8 It would be ideal if experiments on mobile phones and male fertility use standardized exposure protocols such as a fixed mobile phone frequency (MHz) and intensity with minimal fluctuations in SAR, fixed exposure time (either acute, intermittent or continuous radiation) and study the same key primary outcomes of sperm quality. But then again, this is hardly the case in reality.The real difficulty lies in recreating a realistic scenario representative of actual habits of mobile phone users in the general population. Study designs may seem perfect theoretically, but when put into practice, they may prove to be less than ideal. For example, in observational studies, the amount and chronicity of exposure could be subject to recall bias. The location of mobile phone storage (shirt or pants pocket, or belt clip) and usage type (hand held or hands-free) should be noted.8 Unreported or unknown confounders that may influence study results, such as age and smoking habits need to be factored in.1 Studies on cohorts that seek fertility intervention may not be representative of the general population. Semen parameters of fertile men are also subject to variation at each sample collection.9 Studies that use purified sperm samples lack the “buffering” effects of other semen components, soft tissues and clothing that may decrease the effective SAR on human sperm.8Animal studies comes with its own limitations in projecting its data onto humans for example, in the commonly used mouse/rat model, it can be argued that these animal models have smaller-sized testes, which are able to ascend freely through the inguinal canal into the abdomen, and scrota, which are nonpendulous.8 Further, the distance between the testes and the source of the EMW radiation (the antenna) in these animal studies are varied (placed in or on the cage, approximated to the animal testes or close to the animal''s face), which prevent any direct comparisons between study results.8Accurate estimation of the amount of RF-EMW that the testes are exposed to during a mobile phone call can be tricky as the testes are protected by multiple layers of scrotal tissue. Using a two-dimensional computational model simulation of scrotal tissues and the finite difference time domain method, Mouradi''s group established that for an in vitro experimental set up to mimic real life conditions, the mobile phone emitting RF-EMW should be positioned at a distance of 0.8–1.8 cm further away than the real life model.10 The group also demonstrated that RF-EMW emitted from mobile phone located nearby the groin can penetrate testicular tissues to reach spermatozoa in the seminiferous tubules. For further in depth studies, three-dimensional modeling goes an additional step by considering the anatomical details of the male genital soft tissues. The model should also factor in the potential additional effects of clothing layers.10Prior to Adam''s study, another meta-analysis investigating the effects of mobile phone EMW radiation on sperm quality in men within the reproductive age had also demonstrated that mobile phone usage leads to detrimental effects in sperm quality. The analyses were performed on 11 studies (separated into in vitro and in vivo studies) from both the general and subfertile cohorts, and the strength of evidence obtained varied from very low to very high for the different parameters.11 Despite the results of these analyses and the large number of studies that associate mobile phone usage with a decrease in male fertility, the evidence remains inadequate at this stage. Until proven otherwise, it is recommended that those with subfertility issues or seeking assisted reproduction minimize their exposure to environmental RF-EMW radiation to alleviate its potential negative impact on sperm quality.     

Development of tissue bank

The history of tissue banking is as old as the use of skin grafting for resurfacing of burn wounds. Beneficial effects of tissue grafts led to wide spread use of auto and allograft for management of varied clinical conditions like skin wounds, bone defects following trauma or tumor ablation. Availability of adequate amount of tissues at the time of requirement was the biggest challenge that forced clinicians to find out techniques to preserve the living tissue for prolonged period of time for later use and thus the foundation of tissue banking was started in early twentieth century. Harvesting, processing, storage and transportation of human tissues for clinical use is the major activity of tissue banks. Low temperature storage of processed tissue is the best preservation technique at present. Tissue banking organization is a very complex system and needs high technical expertise and skilled personnel for proper functioning in a dedicated facility. A small lapse/deviation from the established protocol leads to loss of precious tissues and or harm to recipients as well as the risk of transmission of deadly diseases and tumors. Strict tissue transplant acts and stringent regulations help to streamline the whole process of tissue banking safe for recipients and to community as whole.KEY WORDS: Tissue banking, tissue preservation, tissue storageThe human body is the perfect example of an efficient machine. Every machine requires repair and replacement of defective components for proper functioning. Unlike machines, the spares for the human body are not available. Tissue engineering has tried to find out the answer to provide the spares but none can match the quality of natural tissues. Human tissues can be harvested from the dead, potentially dead and before the death of transplantable tissues has occurred and can be occurence of stored suitably to be used at the time of need later. This concept is the basic idea behind the development of tissue banks. Tissue banking is the activity of harvesting, processing, storage and distribution of transplantable human tissues. Tissues retrieved from the human body are used to repair and or replace the diseased or lost tissues of living human body and have saved many precious lives. The common tissues being harvested and used are cornea, skin,[1] bones, cartilage, joints, heart valves, fascia, tendons, and duramater from human cadaver.Practically any human tissue can be harvested and banked for clinical use and research. Biobanking of normal and tumor cells,[2] stem cells from bone marrow, umbilical cord, and adipose tissue,[3] are increasingly used by pathologist to maintain cell lines and bioengineering.[4] Newer applications of autologus banked tissues for future use are being regularly reported in literature viz., blood vessels,[5] testicular tissue,[6] ovarian tissue,[7] nipple areola complex,[8] sperm, penile skin,[9] cord blood, Placenta[10] etc.     

Reappraisal of glucocorticoids in castrate-resistant prostate cancer

Recent reports and discussions of .preclinical prostate cancer models have emphasized the possibility that enzalutamide resistance may be mediated by glucocorticoid receptors （GR）.In both in vitro and xenograft animal studies, it is possible to show that the GR is up-regulated in prostate cancer cell lines and that dexamethasone reverses enzalutamide induced growth inhibition. In these model systems, GR agonists can induce a subset of androgen receptor target genes including prostate-specific antigen. These investigators also report a correlation between GR expression in patient-derived prostate cancer specimens and clinical response to enzalutamide. The authors discuss the possibility that these findings have important clinical relevance. We note that the current clinical evidence for GR mediating drug resistance or disease progression in patients with castrate-resistant prostate cancer （CRPC） is very limited at best.     

Robotic radical prostatectomy in high-risk prostate cancer: current perspectives

Around 20%–30% of patients diagnosed with prostate cancer (PCa) still have high-risk PCa disease (HRPC) that requires aggressive treatment. Treatment of HRPC is controversial, and multimodality therapy combining surgery, radiation therapy, and androgen deprivation therapy have been suggested. There has been a trend toward performing radical prostatectomy (RP) in HRPC and currently, robot-assisted laparoscopic RP (RARP) has become the most common approach. Number of publications related to robotic surgery in HRPC is limited in the literature. Tissue and Tumor characteristics might be different in HRPC patients compared to low-risk group and increased surgical experience for RARP is needed. Due to the current literature, RARP seems to have similar oncologic outcomes including surgical margin positivity, biochemical recurrence and recurrence-free survival rates, additional cancer therapy needs and lymph node (LN) yields with similar complication rates compared to open surgery in HRPC. In addition, decreased blood loss, lower rates of blood transfusion and shorter duration of hospital stay seem to be the advantages of robotic surgery in this particular patient group. RARP in HRPC patients seems to be safe and technically feasible with good intermediate-term oncologic results, acceptable morbidities, excellent short-term surgical and pathological outcomes and satisfactory functional results.Prostate cancer (PCa) accounts for almost 30% of all newly diagnosed cancers in men in the United States and is the second most frequent cause of cancer death in men.1 Due to serum prostate specific antigen (PSA) screening, there is an increase in the percent of patients diagnosed with localized PCa.2 However, around 20%–30% of patients diagnosed with PCa still have high-risk, nonmetastatic disease.3In 1998, D’Amico et al. first proposed a three-group risk stratification system to predict posttreatment biochemical failure following radical prostatectomy (RP) and external-beam radiotherapy.4 This system classified nonmetastatic PCa into low-, intermediate- and high-risk PCa according to initial serum PSA, clinical T stage and biopsy Gleason score (4 On the other hand, Loeb et al. defined HRPC using two definitions including: (i) 1992 TNM of cT2b and biopsy Gleason score 8–10, or PSA ≥15 ng ml⁻¹, and (ii) those with 1992 TNM of cT3.5

Table 1

Classification of nonmetastatic PCa into risk groups by D’Amico et al. according to initial serum PSA, clinical T stage and biopsy Gleason score4Open in a separate windowAggressive treatment is required in HRPC otherwise this disease might progress and cause serious symptoms and complications and eventually patient death.6 Although treatment of HRPC is controversial, radiation therapy, androgen deprivation therapy, surgery and most importantly multimodality therapy combining surgery and radiation have been suggested in various studies7,8 meaning that RP could only cure a percentage of this patient group.9,10,11 The outcomes of the Swedish Registry Study that has been very recently published suggested that surgery seems to be superior to radiation therapy and longer cancer-specific survival (CSS) was achieved in the surgery group in patients with HRPC as per a 15-year CSS data.12 Therefore, there has been a trend toward performing RP in HRPC patients.13Although open RP (ORP) is a well-established and standard surgical technique in the surgical management of patients with PCa, robotic approach has become the most common approach for PCa surgery in USA.14 Many authors have published their outcomes related with robot-assisted laparoscopic RP (RARP) with promising results particularly in low- and intermediate-risk PCa patients with similar oncological and functional outcomes to open surgery suggesting the advantages of decreased blood loss, shorter duration of hospital stay, decreased postoperative analgesic requirement and earlier convalescence in the robotic surgery group.15,16,17,18 On the other hand, the number of publications related to the use of robotic surgery in HRPC is very limited in the literature. They mostly have limited numbers of patients and short follow-up periods. Herein, we summarized the literature on RARP and HRPC.     

Controversies in testosterone supplementation therapy

Testosterone has now become one of the most widely used medications throughout the world. The rapid growth of the testosterone market in the past 10 years is due to many factors. We currently have a worldwide aging population. In the US, the number of men 65 years old or older is increasing 2–3 times faster than the number of men younger than 65 years. In addition, poor general health and certain medical conditions such as diabetes/metabolic syndrome (MetS), cardiovascular disease (CVD), and osteoporosis have been associated with low serum testosterone levels.1,2,3 There are now fewer concerns regarding the development of prostate cancer (PCa) after testosterone therapy, making it a more attractive treatment option. Finally, the introduction of different forms of testosterone supplementation therapy (TST) with increased promotion, marketing, and direct-to-consumer advertising is also driving market growth. As the demand for TST continues to grow, it is becoming more important for clinicians to understand how to diagnose and treat patients with low testosterone.There are still several controversies associated with TST. Many clinicians are still concerned about the potential adverse effects of TST on male fertility, CVD, PCa, MetS, and benign prostatic hyperplasia (BPH). The aim of this Asian Journal of Andrology (AJA) special edition on controversies in TST is to carefully examine the literature in each of these topics and offer a better understanding of how TST truly impacts each of these conditions. This special edition also focuses on the diagnosis and management of TST as well as alternative treatment options for androgen deficiency syndrome.The diagnosis and management of TST can be challenging. For example, there are large variations in laboratory reference ranges and this is compounded by the fact that there are no universally agreed upon cut-offs for total and free testosterone for the diagnosis of hypogonadism.4,5 In addition, the signs and symptoms of hypogonadism are nonspecific and serum testosterone levels do not appear to correlate directly with symptoms in all patients.4 There are now numerous TST options available and deciding on the appropriate treatment option can be challenging. The decision of which TST formulation to use should be based on several factors including cost, compliance, convenience, and efficacy.An increasingly large number of middle-age men are seeking treatment for androgen deficiency. It is estimated that roughly 3%–8% of men in their reproductive years suffer from hypogonadism.6 There are several reasons for this including increased anabolic steroid use in younger men, increased use of opioids in younger men and the growing epidemics of diabetes and obesity that are now greatly affecting the younger population.7 TST can lead to impaired spermatogenesis, and men desiring to initiate a pregnancy in the future should be counseled appropriately before beginning therapy.8 For patients who are desiring to initiate TST and still preserve their fertility, alternative treatment options should be discussed. In these patients, increasing endogenously serum testosterone levels through stimulation of the hypothalamic-pituitary-gonadal axis is a better option. Treatment options for raising endogenous serum testosterone include the use of clomiphene citrate, anastrozole, and human chorionic gonadotropin. There are many new treatment options currently under development to raise endogenous testosterone and at the same time preserve fertility in young hypogonadal men.Despite persistent concerns, there are still no convincing data to indicate that TST increases the risk of PCa. However, to date, there are no prospective, controlled studies with adequate sample size and duration to definitively assess the relationship of TST with the risk of PCa. There continues to be a low rate of negative outcomes reported with TST.9 While further research is required to define the safety of TST in men with a history of PCa, many hypogonadal symptomatic patients are willing to accept the potential risk of PCa recurrence or progression in return for an opportunity to live a happier and fuller life with TST.For many years, TST has been thought to exacerbate BPH and lower urinary tract symptoms (LUTS). In fact, most of the package inserts of testosterone therapies state that clinicians should monitor patients with BPH for worsening of signs and symptoms, and that elderly patients treated with androgens may be at increased risk for BPH. However, recent data suggest that TST may actually improve BPH/LUTS.10,11 The exact mechanism of this improvement is still unknown, but there are several existing theories that have been established. Until more studies are completed, patients should still be counseled on the TST label regarding the risk of urinary retention and worsening LUTS.There have been several recent observational studies suggesting that the testosterone may increase the risk for CVD.12,13 However, the Food and Drug Administration in the US has reviewed these reports and found them to be seriously flawed. TST appears to have a minimal effect on cardiovascular risk factors except for a potential increase in hematocrit. In fact, several studies have found that hypogonadal men initiating TST experience improvements in cardiovascular parameters including reductions in systolic and diastolic blood pressures, reduction in resting heart rate, better endothelial cell function, and reduction in arterial plaque size.2There are still some questions associated with MetS and testosterone. Do low serum testosterone levels cause MetS? Is TST an effective treatment for MetS? Low testosterone has been shown to result in elevated fasting insulin, glucose and hemoglobin A1c levels, and possibly to predict the onset of diabetes.3 TST has been shown to result in significant changes in insulin sensitivity, weight, waist circumference, and hemoglobin A1c levels.3 The relationship of low testosterone to MetS is often considered to be bidirectional. This relationship is probably not direct, and while there may be an association between testosterone and MetS, causality cannot yet be confirmed.The purpose of this AJA special edition on hypogonadism is to address these controversies associated with TST and to increase our understanding of how TST is associated with these aforementioned different conditions. In this special issue, the diagnosis and management of hypogonadism will be first reviewed.14 Testosterone''s association with CVD15 and MetS16 will also be reviewed. Furthermore, this issue will discuss preserving fertility in the hypogonadal patient17 and alternatives to TST.18 Finally, this issue will review the effects of testosterone on the prostate including PCa19 and BPH.20 It is clear that large, randomized, placebo-controlled trials are needed to provide more definitive data regarding the efficacy and safety of TST in hypogonadal men with these conditions.     

Previous tumour as a prognostic factor in stage I non-small cell lung cancer

Objective

To evaluate the effect of comorbidity as an independent prognostic factor in lung cancer.

Method

Data on 2991 consecutive cases of lung cancer were collected prospectively from 19 Spanish hospitals between 1993 and 1997 by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB‐S). To evaluate the effect of comorbidity on survival, 1121 patients with non‐small cell lung cancer (NSCLC) in pathological stage I who underwent complete resection were selected, excluding operative mortality. The presence of specific comorbidities at the time of thoracotomy was registered prospectively.

Results

Cox regression analysis showed that tumour size (0–2, 2–4, 4–7, >7 cm) (HR 1.45 95% CI 1.08 to 1.95), 1.86 (95% CI 1.38 to 2.51), 2.84 (95% CI 1.98 to 4.08)), the presence of a previous tumour (HR 1.45 (95% CI 1.17 to 1.79)) and age (HR 1.02 (95% CI 1.01 to 1.03)) had a significant prognostic association with survival. This study excluded the presence of visceral pleural involvement or other comorbidities as independent variables.

Conclusion

The presence of a previous tumour is an independent prognostic factor in pathological stage I NSCLC with complete resection, increasing the probability of death by 1.5 times at 5 years. It is independent of other comorbidities, TNM classification and age.The presence of other associated diseases (comorbidity) has been reported in 68% of all lung cancers included in a population registry¹ and in 73% of surgical cases of lung cancer from a Spanish prospective study.² Comorbidity is considered to be a prognostic factor in cancer generally^1,3 and in the initial stages of surgically treated lung cancer.⁴ Specifically, the association between lung cancer and chronic obstructive pulmonary disease (COPD) is frequent,² the latter being an independent aetiological factor from smoking. If we evaluated COPD by conditional survival analysis, it could be considered a late onset prognostic factor 2–3 years after surgery.⁵ The presence of a past history of aerodigestive or bladder tumours is frequent in patients with lung cancer,^6,7,8,9 and is an additional risk for developing the disease. This association is thought to be a result of field cancerisation of these tumours that facilitate their multiple presence in aerodigestive epithelium, possibly due to genetic mechanisms.¹⁰A study was undertaken to evaluate prospectively the prognostic value of comorbidity in a series of consecutive patients surgically treated for lung cancer in 19 Spanish hospitals between 1993 and 1997.