- Email: [email protected]
Inhaled insulin for the early detection of lung cancer
Correspondence Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou Street, Byzantio 551 33,
615 Thessaloniki, Greece Tel.: +30 2310 892238; fax: +30 2310 992794 E-mail address: [email protected] (J. Kountouras)
doi:10.1016/j.mehy.2008.05.007
Inhaled insulin for the early detection of lung cancer Early lung cancer detection may save lives but is controversial [1]. Recently a study appeared documenting improved survival of early lung cancer detected with spiral CT [2]. Biochemical methods of early lung cancer detection have been developed. For example, measurement of an autoantibody response to one or more tumor-associated antigens in an optimized panel assay provides a sensitive and specific blood test to aid the early detection of lung cancer [3]. Early lung cancer can also be detected by obtaining fluid and tissue samples. Respiratory tract material, including sputum or bronchial fluid or other pulmonary tissue or thoracic cells or regional lymph nodes, is assayed with monoclonal antibodies for antigens whose enhanced presence correlates with the development of lung cancer [4]. Surface enhanced laser desorption/ionization (SELDI) mass spectrometry has been used to identify five distinct potential lung cancer serum biomarkers with high sensitivity and specificity [5]. Very small malignant lung tumors might be detected by allowing the subject to inhale powdered insulin, preceded and followed by measurement of circulating hormones, growth factors, and receptor proteins in the blood, particularly those that lung tumors are known to produce: Antidiuretic hormone (ADH) is ordinarily produced in the hypothalamus and secreted from the posterior lobe of the pituitary gland. Lung tumors produce ADH. This hormone is involved in the maintenance of the extracellular fluid environment by reducing free water clearance [6]. Adrenocorticotrophic hormone (ACTH) is the most common ectopic hormone that lung tumors produce. Like ADH, increased serum levels of ACTH in patients with lung cancer are frequent and may be detectable in up to 50% of cases [6].
Atrial natriuretic peptide is another hormone produced ectopically by lung cancer cells, which affects renal salt and water handling. In individual patients, increased levels of atrial natriuretic peptide may contribute to hyponatremia by causing natriuresis [6]. Parathyroid hormone (PTH) and parathyroid hormone related protein (PTHRp) are produced by malignant lung tumors [6] and can lead to hypercalcemia, most commonly in squamous cell carcinomas. Insulin is a growth factor and causes tumor stimulation. Increased serum insulin levels are associated with an increased incidence of prostate cancer, and also a poor prognosis in prostate and breast cancer [7–9]. Moreover, Pfizer Inc. reported an increase in lung cancer among patients who used its discontinued inhaled insulin Exubera. A review of clinical trial data found there were six cases of lung cancer among 4740 patients using Exubera, compared with one of 4292 who did not take Exubera. All cases were in former cigarette smokers [10]. To diagnose lung cancer, inhaled insulin would be used to stimulate lung tumor cells to produce increased blood levels of hormones and other lung cancer markers. Subjects would undergo venepuncture, have blood collected, and receive a single dose or multiple doses of inhaled insulin. After the last insulin dose, blood would be obtained by venepuncture and measurement made of Antidiuretic hormone, Adrenocorticotrophic hormone, Atrial natriuretic peptide, parathyroid hormone, parathyroid hormone related protein, and other lung cancer serum markers. The levels of the hormones and markers would be compared pre and post insulin inhalation. If there had been a significant elevation of one or more hormones or markers after insulin inhalation, as compared to the results from controls without lung cancer, subjects would be sent for further evaluation with spiral CT scanning.
616 A second use of the inhaled insulin test would be to determine if a candidate for inhaled insulin therapy might be prone to develop lung cancer.
References [1] Marshall E. Medicine A bruising battle over lung scans. Science 2008;320(5876):600–3. [2] Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355(17):1763–71. [3] Chapman CJ, Murray A, McElveen JE, Sahin U, Luxemburger O, Tureci O. Autoantibodies in lung cancer: possibilities for early detection and subsequent cure. Thorax 2008;63(3): 228–33. [4] Mulshine JL, Scott F, Zhou J, Avis I, I, Vos M, Miller MJ. Development of molecular approaches to early lung cancer detection. Semin Radiat Oncol 1996;6(2):72–5. [5] Xiao XY, Tang Y, Wei XP, He DC. A preliminary analysis of non-small cell lung cancer biomarkers in serum. Biomed Environ Sci 2003;16(2):140–8.
Correspondence [6] Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest 2003;123(Suppl. 1):97S–104S. [7] Hammarsten J, Hogstedt B. Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer 2005;41(18):2887–95. [8] Hede K. Doctors seek to prevent breast cancer recurrence by lowering insulin levels. J Natl Cancer Inst 2008;100(8): 530–2. [9] Lehrer S, Diamond EJ, Stagger S, Stone NN, Stock RG. Serum insulin level, disease stage, prostate specific antigen (PSA) and Gleason score in prostate cancer. Br J Cancer 2002;87(7):726–8. [10] Johnson A. Exubera runs into more woes. Wall Street J 2008;D2.
Steven Lehrer 30 W 60th Street 5M, New York, NY 10023, United States E-mail address: [email protected]
doi:10.1016/j.mehy.2008.05.019
Can Helicobacter pylori infection be proven beneficial to patients with b-thalassaemia major? Beta-thalassaemia major is characterized by a hereditary defect in the synthesis of b-chains of haemoglobin leading to ineffective erythropoiesis. Conventional management of b-thalassaemia requires regular blood transfusions and systematic use of iron-chelation agents. Inexorable iron accumulation leads to serious organic dysfunction, mainly in heart, liver and endocrine glands, causing even fatal clinical complications [1]. On the other hand, Helicobacter pylori infection has long been associated with iron deficiency anaemia, even in the absence of overt bleeding [2]. Anaemia is unresponsive to iron treatment, or is responsive but exacerbated when supplementary iron is stopped, whereas it is improved by eradication of the bacteria. Patients with b-thalassaemia major are in greater risk for infectious diseases due to multiple causative factors and infections constitute the second most common cause of mortality in thalassaemia [3]. In order to determine the prevalence of H. pylori infection among asymptomatic patients with b-thalassaemia, we assessed 40 thalassaemic patients (24 F, 16 M, mean age: 27.2 ± 9.7
years) and 30 sex- and age-matched controls for the presence of anti-Helicobacter pylori antibodies in serum using a commercial qualitative and quantitative immunoassay (VarelisaÒ H. pylori IgG Antibodies, PhadiaÒ, Upsala, Sweden). No significant difference in the prevalence of H. pylori seropositiveness was observed in patients with b-thalassaemia (6/40, 15%) compared to controls (6/30, 20%). As expected, a significant higher mean age and a higher incidence of splenectomy were observed in thalassaemic patients being seropositive to H. pylori. Surprisingly, serum ferritin concentrations were significantly lower in seropositive to H. pylori patients compared to seronegative ones (969.8 ± 677 lg/L vs 2069.5 ± 1250 lg/L, p = 0.008). Iron-chelation regimens and reported compliance to treatment were equivalent in all patients. In a recent study [4], a prevalence of as high as 68% of H. pylori infection was recorded among thalassaemic patients with recurrent abdominal pain; however, not significantly increased compared to controls (60%) with same symptomatology. In this study, no difference in
615 Thessaloniki, Greece Tel.: +30 2310 892238; fax: +30 2310 992794 E-mail address: [email protected] (J. Kountouras)
doi:10.1016/j.mehy.2008.05.007
Inhaled insulin for the early detection of lung cancer Early lung cancer detection may save lives but is controversial [1]. Recently a study appeared documenting improved survival of early lung cancer detected with spiral CT [2]. Biochemical methods of early lung cancer detection have been developed. For example, measurement of an autoantibody response to one or more tumor-associated antigens in an optimized panel assay provides a sensitive and specific blood test to aid the early detection of lung cancer [3]. Early lung cancer can also be detected by obtaining fluid and tissue samples. Respiratory tract material, including sputum or bronchial fluid or other pulmonary tissue or thoracic cells or regional lymph nodes, is assayed with monoclonal antibodies for antigens whose enhanced presence correlates with the development of lung cancer [4]. Surface enhanced laser desorption/ionization (SELDI) mass spectrometry has been used to identify five distinct potential lung cancer serum biomarkers with high sensitivity and specificity [5]. Very small malignant lung tumors might be detected by allowing the subject to inhale powdered insulin, preceded and followed by measurement of circulating hormones, growth factors, and receptor proteins in the blood, particularly those that lung tumors are known to produce: Antidiuretic hormone (ADH) is ordinarily produced in the hypothalamus and secreted from the posterior lobe of the pituitary gland. Lung tumors produce ADH. This hormone is involved in the maintenance of the extracellular fluid environment by reducing free water clearance [6]. Adrenocorticotrophic hormone (ACTH) is the most common ectopic hormone that lung tumors produce. Like ADH, increased serum levels of ACTH in patients with lung cancer are frequent and may be detectable in up to 50% of cases [6].
Atrial natriuretic peptide is another hormone produced ectopically by lung cancer cells, which affects renal salt and water handling. In individual patients, increased levels of atrial natriuretic peptide may contribute to hyponatremia by causing natriuresis [6]. Parathyroid hormone (PTH) and parathyroid hormone related protein (PTHRp) are produced by malignant lung tumors [6] and can lead to hypercalcemia, most commonly in squamous cell carcinomas. Insulin is a growth factor and causes tumor stimulation. Increased serum insulin levels are associated with an increased incidence of prostate cancer, and also a poor prognosis in prostate and breast cancer [7–9]. Moreover, Pfizer Inc. reported an increase in lung cancer among patients who used its discontinued inhaled insulin Exubera. A review of clinical trial data found there were six cases of lung cancer among 4740 patients using Exubera, compared with one of 4292 who did not take Exubera. All cases were in former cigarette smokers [10]. To diagnose lung cancer, inhaled insulin would be used to stimulate lung tumor cells to produce increased blood levels of hormones and other lung cancer markers. Subjects would undergo venepuncture, have blood collected, and receive a single dose or multiple doses of inhaled insulin. After the last insulin dose, blood would be obtained by venepuncture and measurement made of Antidiuretic hormone, Adrenocorticotrophic hormone, Atrial natriuretic peptide, parathyroid hormone, parathyroid hormone related protein, and other lung cancer serum markers. The levels of the hormones and markers would be compared pre and post insulin inhalation. If there had been a significant elevation of one or more hormones or markers after insulin inhalation, as compared to the results from controls without lung cancer, subjects would be sent for further evaluation with spiral CT scanning.
616 A second use of the inhaled insulin test would be to determine if a candidate for inhaled insulin therapy might be prone to develop lung cancer.
References [1] Marshall E. Medicine A bruising battle over lung scans. Science 2008;320(5876):600–3. [2] Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355(17):1763–71. [3] Chapman CJ, Murray A, McElveen JE, Sahin U, Luxemburger O, Tureci O. Autoantibodies in lung cancer: possibilities for early detection and subsequent cure. Thorax 2008;63(3): 228–33. [4] Mulshine JL, Scott F, Zhou J, Avis I, I, Vos M, Miller MJ. Development of molecular approaches to early lung cancer detection. Semin Radiat Oncol 1996;6(2):72–5. [5] Xiao XY, Tang Y, Wei XP, He DC. A preliminary analysis of non-small cell lung cancer biomarkers in serum. Biomed Environ Sci 2003;16(2):140–8.
Correspondence [6] Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest 2003;123(Suppl. 1):97S–104S. [7] Hammarsten J, Hogstedt B. Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer 2005;41(18):2887–95. [8] Hede K. Doctors seek to prevent breast cancer recurrence by lowering insulin levels. J Natl Cancer Inst 2008;100(8): 530–2. [9] Lehrer S, Diamond EJ, Stagger S, Stone NN, Stock RG. Serum insulin level, disease stage, prostate specific antigen (PSA) and Gleason score in prostate cancer. Br J Cancer 2002;87(7):726–8. [10] Johnson A. Exubera runs into more woes. Wall Street J 2008;D2.
Steven Lehrer 30 W 60th Street 5M, New York, NY 10023, United States E-mail address: [email protected]
doi:10.1016/j.mehy.2008.05.019
Can Helicobacter pylori infection be proven beneficial to patients with b-thalassaemia major? Beta-thalassaemia major is characterized by a hereditary defect in the synthesis of b-chains of haemoglobin leading to ineffective erythropoiesis. Conventional management of b-thalassaemia requires regular blood transfusions and systematic use of iron-chelation agents. Inexorable iron accumulation leads to serious organic dysfunction, mainly in heart, liver and endocrine glands, causing even fatal clinical complications [1]. On the other hand, Helicobacter pylori infection has long been associated with iron deficiency anaemia, even in the absence of overt bleeding [2]. Anaemia is unresponsive to iron treatment, or is responsive but exacerbated when supplementary iron is stopped, whereas it is improved by eradication of the bacteria. Patients with b-thalassaemia major are in greater risk for infectious diseases due to multiple causative factors and infections constitute the second most common cause of mortality in thalassaemia [3]. In order to determine the prevalence of H. pylori infection among asymptomatic patients with b-thalassaemia, we assessed 40 thalassaemic patients (24 F, 16 M, mean age: 27.2 ± 9.7
years) and 30 sex- and age-matched controls for the presence of anti-Helicobacter pylori antibodies in serum using a commercial qualitative and quantitative immunoassay (VarelisaÒ H. pylori IgG Antibodies, PhadiaÒ, Upsala, Sweden). No significant difference in the prevalence of H. pylori seropositiveness was observed in patients with b-thalassaemia (6/40, 15%) compared to controls (6/30, 20%). As expected, a significant higher mean age and a higher incidence of splenectomy were observed in thalassaemic patients being seropositive to H. pylori. Surprisingly, serum ferritin concentrations were significantly lower in seropositive to H. pylori patients compared to seronegative ones (969.8 ± 677 lg/L vs 2069.5 ± 1250 lg/L, p = 0.008). Iron-chelation regimens and reported compliance to treatment were equivalent in all patients. In a recent study [4], a prevalence of as high as 68% of H. pylori infection was recorded among thalassaemic patients with recurrent abdominal pain; however, not significantly increased compared to controls (60%) with same symptomatology. In this study, no difference in