Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Briasoulis, E.
Right arrow Articles by Pavlidis, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Briasoulis, E.
Right arrow Articles by Pavlidis, N.
The Oncologist, Vol. 6, No. 2, 153-161, April 2001
© 2001 AlphaMed Press

Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

Evangelos Briasoulis, Nicholas Pavlidis

Department of Medical Oncology, University of Ioannina, Ioannina, Greece

Correspondence: Evangelos Briasoulis, M.D., Medical Oncology Department, Ioannina University, Ioannina, 45110, Greece. Telephone and Fax: 30-651-99394; e-mail: ebriasou{at}otenet.gr.


   ABSTRACT
Top
 Abstract
Introduction
 Methods
 Anticancer Therapy-Induced...
 Conclusion
 References
 
Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The time proximity to therapy with drugs that are known to precipitate NCPE, any preceding episodes of flu-like symptoms during previous chemotherapy courses and possible response to corticosteroids may further support such a diagnosis. Cancer therapeutic agents clearly associated with NCPE are cytarabine, gemcitabine, and interleukin-2, as well as all-trans retinoic acid in acute promyelocytic leukemia patients, while a few other compounds have rarely or occasionally been implicated. The pathophysiology of lung injury in drug-induced NCPE remains unclear. There are indications suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved in its pathogenesis. By distinction to drug-induced pulmonary pneumonitis that may lead to permanent pulmonary fibrosis, NCPE if not fatal, can be reversed upon prompt recognition, following immediate discontinuation of the offensive drug and start of intensive supportive treatment and intravenous corticosteroids.

Key Words. Chemotherapy • Interleukin-2 • Pulmonary toxicity • NCPE • ARDS • Noncardiogenic pulmonary edema • Acute lung injury • Cytarabine • Gemcitabine • All-trans retinoic acid • Arsenic trioxide (As203)


   INTRODUCTION
Top
 Abstract
 Introduction
Methods
 Anticancer Therapy-Induced...
 Conclusion
 References
 
Several cancer therapeutic drugs are known to induce pulmonary damage, which may result in a variety of clinicopathologic syndromes with minor to severe clinical consequences [1]. Clinical syndromes associated with drug-induced pulmonary toxicity include pneumonitis/fibrosis, hypersensitivity lung disease, and noncardiogenic pulmonary edema (NCPE)/acute respiratory distress syndrome (ARDS). These syndromes share a similar symptomatology but differ in regard to the time-relation to cancer treatment, the radiographic findings, the duration of pulmonary damage, and the long-term outcome [2]. Non-specific symptomatology of cough, progressive dyspnea, and often a low-grade fever alert clinicians confronted with the diagnostic challenge to recognize subclinical syndromes and differentiate fully developed drug-induced pulmonary reactions from lung injuries caused by infectious, cardiac, and neoplastic causes.

The most common chemotherapy-associated lung injury is drug-induced pneumonitis. This type of pulmonary toxicity has extensively been studied and attributed to a majority of the pulmonotoxic antineoplastic agents, of which bleomycin is the prototype and nitrosoureas rank second [3-7]. Major concern with this pulmonary toxicity is the potential to progress to irreversible chronic pulmonary fibrosis.

Noncardiogenic pulmonary edema is a rarely cited and less well-recognizable pulmonotoxic syndrome of anticancer therapy. Our recent experience with NCPE that complicated gemcitabine plus docetaxel combination chemotherapy [8] prompted us to investigate existing medical literature in regard to this unusual pulmonary toxicity of anticancer therapy. To our knowledge, this is the first review on anticancer-therapy-associated noncardiogenic pulmonary edema.


   METHODS
Top
 Abstract
 Introduction
 Methods
Anticancer Therapy-Induced...
 Conclusion
 References
 
A computerized Internet PubMed search of English and non-English language medical literature was conducted by using Reference Manager Version 9.5 (ISI ResearchSoft; PA; http://www.risinc.com/RShome.html) for the period 1965 to 2000, and manually for the period 1960 to 1965. For our search, we used as all-field parameters the generic names of pharmacologic anticancer agents, the words chemotherapy, immunotherapy, and biotherapy, and the key phrases anticancer treatment and drug-induced, combined with the words or key phrases noncardiogenic or primary pulmonary edema, NCPE, pulmonary toxicity, pulmonary disease, respiratory distress syndrome, and acute lung injury.

Reports of drug-induced pulmonary disease related to anticancer treatment had to fit the most accepted definitions for NCPE and ARDS in order to be considered for this review [9-11]. NCPE, also termed as Acute Lung Injury (ALI), is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension. The term ARDS is applied to the most severe cases of acute respiratory failure. According to the criteria set by the American-European Consensus Conference on ARDS, a <=200 mmHg value of quotient PaO2/FIO2 (arterial oxygen-tension/fractional inspired-oxygen) defines ARDS, while <=300 mmHg characterizes ALI.


   ANTICANCER THERAPY-INDUCED NONCARDIOGENIC PULMONARY EDEMA
Top
 Abstract
 Introduction
 Methods
 Anticancer Therapy-Induced...
Conclusion
 References
 
Clinical Presentation—Diagnosis
NCPE is a rare but major complication of anticancer therapy. This typically presents as a sub-acute clinical syndrome characterized by severe dyspnea, cough, tachypnea, fatigue, and a low-grade fever that occurs shortly after or within a few days following the administration of the offensive pharmaceutical agent or agents [8, 12, 13]. Patients with drug-induced NCPE are usually markedly hypoxemic, with crackles on auscultation and chest radiography showing confluent alveolar consolidations almost identical to those seen in congestive heart failure, and a normal-size heart [14].

Diagnosing drug-induced NCPE is actually an exercise of exclusion, as there is no diagnostic test available. Diagnosis relies upon typical radiograph findings [15] and the documented exclusion of heart dysfunction and any infectious, metabolic, or cancer-related causes. The time proximity to administration of drugs known to precipitate NCPE, any preceding episodes of flu-like symptoms during previous chemotherapy courses, and possible response to corticosteroids may further support such a diagnosis. By distinction from drug-induced pulmonary pneumonitis that potentially may evolve to pulmonary fibrosis, NCPE if not fatal, can be fully reversed upon prompt recognition, following discontinuation of offensive drugs and immediate start of intensive support treatment and intravenous corticosteroids.

Cancer therapeutic agents that clearly precipitate NCPE are cytarabine, gemcitabine, and interleukin 2 (IL-2), and the all-trans retinoic acid and arsenic trioxide (As2O3) in acute promyelocytic leukemia patients, while a few more compounds have rarely or occasionally been implicated (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Cancer therapeutic agents associated with the development of noncardiogenic pulmonary edema
 
Biotherapeutic Agents
Among biological agents, recombinant IL-2 (rIL-2) has been clearly associated with the induction of NCPE toxicity, while there is some weak evidence for a similar pulmonotoxic potential of white blood cell growth-stimulating factors.

IL-2, a glycoprotein naturally produced by human T cells during immune response, was introduced in cancer therapeutics 15 years ago as a novel approach to the treatment of solid tumors [16, 17]. This biological response modifier is currently employed in the management of metastatic melanoma and renal cell carcinoma, alone or in combination with chemotherapy or biotherapy [18-21].

Unfortunately, the clinical development of rIL-2 has been compromised by frequently associated toxicities and a narrow therapeutic index [22-24]. Regarding pulmonary toxicity, rIL-2 given intravenously is commonly complicated by NCPE. This occurs in the context of a vascular leak syndrome, the most frequent complication of IL-2, and is mediated via a mechanism of increased microvascular permeability [25, 26]. It is now clear that rIL-2-induced pulmonary toxicity is a dose-related phenomenon that tends to resolve within a few days upon treatment discontinuation [27].

Initial clinical testing identified malaise and weight gain as the dose-limiting toxicities of systemic administration of rIL-2 [28], whereas further clinical experience revealed a significant incidence of NCPE in patients treated with high-dose intravenous rIL-2 [29]. The incidence rate as recorded in the first large cohorts of treated patients ranged from 10%-20%, with a considerable number of treated patients requiring intubation [27, 30, 31]. Interestingly, newest clinical data show a decline in rIL-2-related pulmonary toxicity, obviously due to improvement in key safety issues such as eligibility screening and optimization of therapeutic conditions. Kammula et al. reviewed safety data of high-dose bolus rIL-2 (720,000 IU/kg every 8 h) administered in 1,241 cancer patients over a 12-year period and found a clear improvement in rIL-2 safety profile with a remarkable drop from 12% to 3% in the incidence of NCPE [32]. The feasibility and the safety of long-term administration of subcutaneous rIL-2 at conventional doses of 4.5 million IU/day, three times weekly, has been well established [33] while novel locoregional administration strategies, such as the inhalation of nebulized rIL-2, are being investigated with the aim of improving its therapeutic index [34]. The more favorable toxicity profile of subcutaneous, compared with intravenous, bolus administration of rIL-2, is possibly attributed to a lower systemic absorption (30% of the injected dose) and a better pharmacokinetic profile (sustained systemic exposure and lower peak levels) associated with this route [22].

Hematopoietic growth factors G-CSF and GM-CSF have both been associated as causative or contributing factors with the development of pulmonary toxicity. G-CSF administered during bleomycin-containing chemotherapy regimens may enhance subclinical bleomycin pulmonary toxicity [35, 36], while a possible pulmonotoxic synergy has been suggested for the combination of GM-CSF with chemoradiotherapy in small cell lung cancer patients who received this treatment [37]. Regarding pulmonary edema, G-CSF and GM-CSF have occasionally been implicated with the development of true NCPE, as a small number of published case reports indicate, not all of them well documented [38-40]. It is most possible that the underlying pathophysiological machinery in NCPE cases is the same as with the capillary-leak syndrome that has more commonly been associated with the clinical use of these hematopoietic factors [41-43]. It should be recognized that a definite association of G-CSF and GM-CSF with pulmonary toxicity in most of the clinical studies is rather poorly documented, but the pulmonotoxic potential of G-CSF has been highlighted in a single preclinical study. Hierholzer et al. have shown that installing G-CSF into the lungs of rats by intratracheal injection resulted in recruitment of neutrophils, lung injury, and impaired pulmonary function [44].

Cytotoxic Drugs
Two cytotoxic antimetabolites, cytarabine, and gemcitabine, both analogues of the nucleoside cytidine, have clearly been associated with the development of pulmonary toxicity of the NCPE type. Cytarabine is used in the chemotherapy of leukemia and lymphoma, and gemcitabine is used in the chemotherapy of solid tumors. These agents compete with deoxycytidine triphosphate for incorporation into the C sites of the growing DNA strand and halt DNA synthesis in progress, inducing cell apoptosis primarily at the S phase [45, 46].

Treatment of leukemia patients with high or moderate doses of cytarabine has been associated with the development of NCPE at a relatively high rate. Andersson et al. reported a 12.5% incidence of fatal pulmonary edema in 103 relapsed leukemia patients at a median time of 16 days from the initiation of high-dose cytarabine therapy. Postmortem findings in seven patients who died of ARDS showed a massive pulmonary edema with a highly proteinaceous intra-alveolar infiltrate, and in one case diffuse alveolar damage. No inflammatory changes were detected [47]. Similar toxicity has also been seen in pediatric patients. Shearer et al. described a fatal pulmonary insufficiency in 5 of 22 pediatric patients treated with high-dose cytarabine and G-CSF support for relapsed acute myelogenous leukemia. Postmortem examination disclosed profound pulmonary edema [48]. In another study, Haupt reviewed clinical and pathologic features of 181 patients with leukemia who had been autopsied at the Johns Hopkins Hospital. They found a highly significant increase in the frequency of pulmonary edema in 51 patients (it was massive in 24 patients) who were treated with cytarabine within the last 30 days prior to their death as compared with non-cytarabine-treated patients. These investigators failed to detect any other cause possibly related to the observed pulmonary edema in 67% of the cases [49]. An interesting syndrome characterized by pulmonary edema, fever, and diarrhea was reported in 4 of 23 lymphoma patients who were treated with high-dose cytarabine. High concentrations of tumor necrosis factor-alpha and platelet activating factor activity were found in the serum of two of those patients [50]. Finally, a review of radiography findings in patients treated with cytarabine who developed pulmonary complications demonstrated diffuse consolidations of the alveolar pattern in both lungs that regressed within 3 to 7 days in the majority of patients who recovered [15].

Gemcitabine is currently employed in the treatment of solid tumors, as a drug of a particularly modest toxicity profile with a low incidence of the side effects normally associated with cytotoxics [51]. In regard to pulmonary toxicity a self-limiting dyspnea has been reported in 5%-8% of patients treated with this agent [52] while true NCPE was recorded in clinical trials at an incidence of about 0.1% [53]. Interestingly, flu-like symptoms and fever have also been reported in 20%-35%, and peripheral edema in up to 20% of the patients treated with gemcitabine [51]. Gemcitabine-induced pulmonary toxicity usually upsurges after a number of repeated drug administrations gradually building up, although occasionally it has also been reported to occur after a single-dose administration [54-56]. A small number of NCPE cases associated with the gemcitabine administration have been reported so far. In the first published report Pavlakis et al. presented three cases of cancer patients who developed NCPE/ARDS while being treated with gemcitabine. Two patients died, after being repeatedly challenged with gemcitabine despite persistent episodes of dyspnea following first chemotherapy courses. Corticosteroids provided maximum benefit in a third patient in whom they were commenced early at diagnosis and were coupled with discontinuation of gemcitabine [54]. Following this report, two fatal and three successful corticosteroid-managed cases were reported [57-60]. In most of these cases a diffuse alveolar damage consistent with acute respiratory distress syndrome was found and systemic corticosteroids seemed to help if started early at diagnosis.

There are also a few other cytotoxic compounds that have occasionally been associated with NCPE. Those are docetaxel, vinblastine and intrathecal methotrexate. Docetaxel, a novel mitotic spindle poison that acts as a microtubule stabilizer, has only infrequently been associated with the development of pulmonary toxicity, that is usually of the type of hypersensitivity pneumonitis not meeting the criteria for NCPE [61, 62]. Notably, a fluid retention syndrome is known to occur in as many as 20%-60% of nonpremedicated patients treated with the agent, but this is typically peripheral, with pleural effusions reported only occasionally [63-65]. Although no NCPE has been attributed to docetaxel as a single agent to date, several cases have been reported with its combination with gemcitabine and radiotherapy [8, 66, 67]. Vinblastine as a single agent has anecdotally been associated with the development of NCPE [68], but this toxicity seems to occur more often when combined with mitomycin [69-71].

Although the most common pulmonary disorder connected with methotrexate is a gradually developing interstitial pneumonitis in rheumatoid arthritis patients [72], three cases of NCPE have been reported that were associated with intrathecal methotrexate. The clinical course, radiology findings, and in one patient, the pathology report favor the diagnosis of NCPE in these cases [73, 74].

A high incidence of NCPE has been reported to occur in allogeneic and autologous bone marrow transplant patients in a single study. In those patients, NCPE presented in the context of a capillary leak syndrome and was accompanied by generalized organ dysfunction in many cases [75]. It is thought that induction chemotherapy may also play some role in the development of lung toxicity in these patients. Data suggest that standard-dose chemotherapy produces asymptomatic pulmonary dysfunction and inflammation, which may prime the lungs for further injury by high-dose chemotherapy. In a prospective study, high-risk breast cancer patients developed a 12.6% decrease of diffusing capacity of the lungs for carbon monoxide (DL(CO)) after three cycles of induction chemotherapy with CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) and prior to high-dose chemotherapy with autologous bone marrow or peripheral blood progenitor cell support [76].

ATRA Syndrome
The vitamin A derivative all-trans-retinoic acid (ATRA) and As203 are two drugs with the potential to induce granulocytic differentiation and promote apoptosis of leukemic promyelocytes [77-79]. Currently used in the treatment of acute promyelocytic leukemia [80, 81], these agents have both been associated with the development of NCPE/ARDS in the context of ATRA syndrome. This is a life-threatening complication that occurs in a quarter of patients with acute promyelocytic leukemia who undergo remission induction treatment with ATRA or As203, with or without chemotherapy [82, 83]. The ATRA syndrome characterizes a loosely defined constellation of signs and symptoms that primarily consist of fever and respiratory distress, but also of weight gain, peripheral edema, pleural or pericardial effusions, and hypotension [84]. The pathophysiology of the ATRA syndrome is uncertain, but in vitro data provide evidence that the induction of inflammatory cytokines in acute promyelocytic leukemia cells may play an important role in its pathogenesis [77].

Pathophysiology
The exact mechanism of lung injury in the case of NCPE related to cancer therapeutic agents varies with each class of drugs involved, but overall, it remains poorly defined. It must be emphasized that comorbidities existing in cancer patients potentially complicate the attempt to identify an unequivocal explanation for these clinical findings. Furthermore, in combination chemotherapies or high-dose chemotherapies with G-CSF support, it is quite difficult to mark out the major offensive compound, although lung toxicity can obviously be amplified when pulmonotoxic agents are used concurrently.

Regarding cytotoxic agents, a direct insult by the offensive agent to the alveolar type I pneumocytes or pulmonary vascular endothelial cells and the triggering of a cytokine-mediated inflammatory response appear to be the most frequently involved pathogenic mechanisms. Findings from leukemia patients who died of ARDS following treatment with high-dose cytarabine revealed massive edema and partly diffuse alveolar damage without inflammatory reaction, probably indicating that a direct cytocidal result was a most contributing pathogenetic mechanism in those cases [47]. The hypothesis for the involvement of a cytokine-mediated inflammatory response is suggested by the drug-related fever that occurs in almost half of the patients treated with cytarabine or gemcitabine [85] and the rapid response to corticosteroids reported by several investigators [60, 86]. Additional data provide evidence indicating the involvement of several cytokines, such as tumor necrosis factor-alpha and platelet activating factor in the development of lung injury [50, 87, 88]. Regarding a possible implication of the dosage in the development of NCPE, a dose/pulmonary-toxicity relationship has only been documented for cytarabine, while this does not seem to be the case with gemcitabine [89, 90]. Whatever the exact mechanism of pathogenesis of the lung injury in the case of chemotherapy-induced NCPE, the end-result is an increase in vascular permeability accompanied by extravasation of fluids and proteins into the air space [9]. This has been clearly documented by autopsy findings [47, 54]. Interestingly, two cancer therapeutic agents with pulmonotoxic potential are also known to induce a capillary leak syndrome [51, 91].

The pathogenesis of the lung injury that is related to intravenous administration of high doses of recombinant IL-2 has been investigated extensively. Initial preclinical studies suggested that microvasculature damage, causing a generalized increase of vascular permeability to albumin, was the basic mechanism of rIL-2-induced NCPE [25]. Subsequent studies went into more detail and associated the systemic administration of rIL-2 with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells in animals, while leukocyte or platelet activation, generation of free radicals, and activation of the complement system have also been suggested to be involved in its pathogenesis [92-97]. Despite a widening evidence of the involvement of various cytokines released by activated lymphoid cells in the pathogenesis of rIL-2-induced NCPE, the exact mechanism of the damaging events that drive this clinical syndrome remain unclear [23, 33]. Recent demonstration of functional IL-2 receptors on type II pneumocytes indicates that these cells may also become involved in the pathogenesis of rIL-2-induced NCPE [98].

Regarding NCPE that presents in the context of the ATRA syndrome (see above), activation of production of inflammatory cytokines by acute promyelocytic leukemia cells after exposure to ATRA or As203 seems to play an important role in its pathogenesis. In vitro data suggest that acute promyelocytic leukemia cells may produce an increased expression of IL-1 beta, tumor necrosis factor-alpha, IL-8, L-selectin, and intercellular adhesion molecule-1 after induction of differentiation with ATRA, an effect considered related to the progress of the differentiation [77, 99, 100]. The similarity of the clinical phenomena that characterize the ATRA syndrome with those observed after increased production or administration of exogenous cytokines, the overexpression of which has been shown in vitro to be activated after exposure of acute promyelocytic leukemia cells to ATRA, suggests a link between the ATRA syndrome/NCPE and increased production of cytokines and surface integrins during the process of induction of differentiation.

Finally, research on systemic capillary leak syndrome (SCLS) that is a distinct clinical entity characterized by attacks of a marked shift of plasma from the intravascular to the extravascular space may offer an additional theoretical basis for the interpretational approach of the pathophysiology underlining chemotherapy-related NCPE. There is evidence for a complement-mediated injury that leads to a breakdown of the endothelial barrier and plasma leakage in SCLS [101-103].

Treatment
Awareness of early recognition of evolving lung toxicity and withdrawal of the possibly offensive drug or drugs are suggested as the most important steps toward successful management of drug-induced NCPE. Intravenous corticosteroids, if started early in the course of drug-induced NCPE, diuretic therapy, and respiratory support with or without mechanical ventilation have reportedly salvaged a number of patients from this pulmonary toxicity.


   CONCLUSION
Top
 Abstract
 Introduction
 Methods
 Anticancer Therapy-Induced...
 Conclusion
References
 
It is important for practicing oncologists to realize that a number of cancer-therapeutic agents can produce, or interact with other drugs to produce, noncardiogenic pulmonary edema. Prompt evaluation of any new respiratory symptoms that occur in patients who are treated with pharmaceutical agents potentially inducing NCPE is important for early detection of this severe complication. Patients with pulmonary compromise should be hospitalized and can successfully be managed with high-dose corticosteroids, diuretics, and oxygen supplementation. Immediate discontinuation of chemotherapy is recommended upon suspicion of lung toxicity, and in disputed cases, a lung biopsy should be taken into consideration.


   REFERENCES
Top
 Abstract
 Introduction
 Methods
 Anticancer Therapy-Induced...
 Conclusion
 References
 

  1. Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncol 1992;19:508-520.[Medline]
  2. Stover DE, Kaner RJ. Pulmonary toxicity. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 5th ed. Philadelphia, PA: Lippincott-Raven, 1997:2729-2739.
  3. Simpson AB, Paul J, Graham J et al. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: a review of patients with germ cell tumours. Br J Cancer 1998;78:1061-1066.[Medline]
  4. O'Driscoll BR, Hasleton PS, Taylor PM et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med 1990;323:378-382.[Abstract]
  5. Castro M, Veeder MH, Mailliard JA et al. A prospective study of pulmonary function in patients receiving mitomycin. Chest 1996;109:939-944.[Abstract/Free Full Text]
  6. Gaetani P, Silvani V, Butti G et al. Nitrosourea derivatives-induced pulmonary toxicity in patients treated for malignant brain tumors. Early subclinical detection and its prevention. Eur J Cancer Clin Oncol 1987;23:267-271.[CrossRef][Medline]
  7. Jules-Elysee K, White DA. Bleomycin induced pulmonary toxicity. Clin Chest Med 1990;11:1-20.[Medline]
  8. Briasoulis E, Froudarakis M, Milionis H et al. Chemotherapy induced noncardiogenic pulmonary edema: case report related to gemcitabine plus docetaxel combination with G-CSF support. Respiration 2000;67:680-683.[CrossRef][Medline]
  9. Flick MR, Matthay MA. Pulmonary edema and acute lung injury. In: Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine, 3rd ed. Philadelphia, PA: W.B. Saunders Company, 2000:1575-1598.
  10. Bernard GR, Artigas A, Brigham KL et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-824.[Abstract]
  11. Rosenow EC III, Myers JL, Swensen SJ et al. Drug-induced pulmonary disease. An update. Chest 1992;102:239-250.[Free Full Text]
  12. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 1986;133:321-340.[Medline]
  13. Andersson BS, Cogan BM, Keating MJ et al. Subacute pulmonary failure complicating therapy with high-dose Ara-C in acute leukemia. Cancer 1985;56:2181-2184.[CrossRef][Medline]
  14. Reed CR, Glauser FL. Drug-induced noncardiogenic pulmonary edema. Chest 1991;100:1120-1124.[Free Full Text]
  15. Tham RT, Peters WG, de Bruine FT et al. Pulmonary complications of cytosine-arabinoside therapy: radiographic findings. Am J Roentgenol 1987;149:23-27.[Abstract/Free Full Text]
  16. Lotze MT, Robb RJ, Sharrow SO et al. Systemic administration of interleukin-2 in humans. J Biol Response Mod 1984;3:475-482.[Medline]
  17. Rosenberg SA, Lotze MT, Mule JJ. NIH conference. New approaches to the immunotherapy of cancer using interleukin-2. Ann Intern Med 1988;108:853-864.
  18. Keilholz U, Stoter G, Punt CJ et al. Recombinant interleukin-2-based treatments for advanced melanoma: the experience of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. Cancer J Sci Am 1997;3(suppl 1):S22-S28.
  19. Dutcher JP, Atkins M, Fisher R et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am 1997;3(suppl 1):S73-S78.
  20. Allen MJ, Vaughan M, Webb A et al. Protracted venous infusion 5-fluorouracil in combination with subcutaneous interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer: a phase II study. Br J Cancer 2000;83:980-985.[CrossRef][Medline]
  21. Legha SS. Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alpha and chemotherapy. Semin Oncol 1997;24:S39-S43.[Medline]
  22. Anderson PM, Sorenson MA. Effects of route and formulation on clinical pharmacokinetics of interleukin-2. Clin Pharmacokinet 1994;27:19-31.[Medline]
  23. Vial T, Descotes J. Clinical toxicity of interleukin-2. Drug Saf 1992;7:417-433.[Medline]
  24. Shulman KL, Stadler WM, Vogelzang NJ. High-dose continuous intravenous infusion of interleukin-2 therapy for metastatic renal cell carcinoma: the University of Chicago experience. Urology 1996;47:194-197.[CrossRef][Medline]
  25. Fairman RP, Glauser FL, Merchant RE et al. Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2. Cancer Res 1987;47:3528-3532.[Abstract/Free Full Text]
  26. Saxon RR, Klein JS, Bar MH et al. Pathogenesis of pulmonary edema during interleukin-2 therapy: correlation of chest radiographic and clinical findings in 54 patients. Am J Roentgenol 1991;156:281-285.[Abstract/Free Full Text]
  27. Conant EF, Fox KR, Miller WT. Pulmonary edema as a complication of interleukin-2 therapy. Am J Roentgenol 1989;152:749-752.[Abstract/Free Full Text]
  28. Lotze MT, Matory YL, Rayner AA et al. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer 1986;58:2764-2772.[CrossRef][Medline]
  29. Rosenstein M, Ettinghausen SE, Rosenberg SA. Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 1986;137:1735-1742.[Abstract]
  30. Lee RE, Lotze MT, Skibber JM et al. Cardiorespiratory effects of immunotherapy with interleukin-2. J Clin Oncol 1989;7:7-20.[Abstract]
  31. Mann H, Ward JH, Samlowski WE. Vascular leak syndrome associated with interleukin-2: chest radiographic manifestations. Radiology 1990;176:191-194.[Abstract/Free Full Text]
  32. Kammula US, White DE, Rosenberg SA. Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer 1998;83:797-805.[CrossRef][Medline]
  33. Guida M, Abbate I, Casamassima A et al. Long-term subcutaneous recombinant interleukin-2 as maintenance therapy: biological effects and clinical implications. Cancer Biother 1995;10:195-203.[Medline]
  34. Huland E, Heinzer H, Mir TS et al. Inhaled interleukin-2 therapy in pulmonary metastatic renal cell carcinoma: six years of experience. Cancer J Sci Am 1997;3(suppl 1):S98-S105.
  35. Lei KI, Leung WT, Johnson PJ. Serious pulmonary complications in patients receiving recombinant granulocyte colony-stimulating factor during BACOP chemotherapy for aggressive non-Hodgkin's lymphoma. Br J Cancer 1994;70:1009-1013.[Medline]
  36. Matthews JH. Pulmonary toxicity of ABVD chemotherapy and G-CSF in Hodgkin's disease: possible synergy [Letter]. Lancet 1993;342:988.
  37. Bunn PA Jr, Crowley J, Kelly K et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.[Abstract/Free Full Text]
  38. Kitamura S, Kinouchi K, Fukumitsu K et al. A risk of pulmonary edema associated with G-CSF pretreatment. Masui 1997;46:946-950.[Medline]
  39. Ruiz-Arguelles GJ, Arizpe-Bravo D, Sanchez-Sosa S et al. Fatal G-CSF-induced pulmonary toxicity [Letter]. Am J Hematol 1999;60:82-83.[CrossRef][Medline]
  40. Schilero GJ, Oropello J, Benjamin E. Impairment in gas exchange after granulocyte colony stimulating factor (G-CSF) in a patient with the adult respiratory distress syndrome. Chest 1995;107:276-278.[Abstract/Free Full Text]
  41. Arning M, Kliche KO, Schneider W. GM-CSF therapy and capillary-leak syndrome [Letter]. Ann Hematol 1991;62:83.[CrossRef][Medline]
  42. Emminger W, Emminger-Schmidmeier W, Peters C et al. Capillary leak syndrome during low dose granulocyte-macrophage colony- stimulating factor (rh GM-CSF) treatment of a patient in a continuous febrile state. Blut 1990;61:219-221.[CrossRef][Medline]
  43. Heitger A, Maurer K, Neu N et al. Capillary leak syndrome in a patient with septicemia and granulocyte-colony-stimulating factor (G-CSF)-induced accelerated granulopoiesis [Letter]. Med Pediatr Oncol 1998;31:126-127.[CrossRef][Medline]
  44. Hierholzer C, Kelly E, Lyons V et al. G-CSF instillation into rat lungs mediates neutrophil recruitment, pulmonary edema, and hypoxia. J Leukoc Biol 1998;63:169-174.[Abstract]
  45. Gemcitabine. In: Dollery C, ed. Therapeutic Drugs, 2nd ed. Edinburgh, UK: Churchill Livingstone, 1999:G25-G30.
  46. Cytarabine. In: Dollery C, ed. Therapeutic Drugs, 2nd ed. Edinburgh, UK: Churchill Livingstone, 1999:C373-C375.
  47. Andersson BS, Luna MA, Yee C et al. Fatal pulmonary failure complicating high-dose cytosine arabinoside therapy in acute leukemia. Cancer 1990;65:1079-1084.[CrossRef][Medline]
  48. Shearer P, Katz J, Bozeman P et al. Pulmonary insufficiency complicating therapy with high dose cytosine arabinoside in five pediatric patients with relapsed acute myelogenous leukemia. Cancer 1994;74:1953-1958.[CrossRef][Medline]
  49. Haupt HM, Hutchins GM, Moore GW. Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med 1981;70:256-261.[CrossRef][Medline]
  50. Chiche D, Pico JL, Bernaudin JF et al. Pulmonary edema and shock after high-dose aracytine-C for lymphoma; possible role of TNF-alpha and PAF. Eur Cytokine Netw 1993;4:147-151.[Medline]
  51. Aapro MS, Martin C, Hatty S. Gemcitabine—a safety review. Anticancer Drugs 1998;9:191-201.[Medline]
  52. Nelson R, Trassoff P. Dyspnea with gemcitabine is commonly seen, often disease related, transient and rarely severe. Eur J Cancer 1999;31(A):S197-S198.
  53. Roychowdhury DF, Smith CA, Peterson P et al. A report on serious pulmonary toxicity associated with gemcitabine-based therapy (36th Annual Meeting). Proc Am Soc Clin Oncol 2000;19:196a.
  54. Pavlakis N, Bell DR, Millward MJ et al. Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 1997;80:286-291.[CrossRef][Medline]
  55. Linskens RK, Golding RP, van Groeningen CJ et al. Severe acute lung injury induced by gemcitabine. Neth J Med 2000;56:232-235.[CrossRef][Medline]
  56. Ciotti R, Belotti G, Facchi E et al. Sudden cardio-pulmonary toxicity following a single infusion of gemcitabine [Letter]. Ann Oncol 1999;10:997.[Free Full Text]
  57. Tempero MA, Brand R. Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 1998;82:1800-1801.[Medline]
  58. Sauer-Heilborn A, Kath R, Schneider CP et al. Severe non-haematological toxicity after treatment with gemcitabine. J Cancer Res Clin Oncol 1999;125:637-640.[CrossRef][Medline]
  59. Marruchella A, Fiorenzano G, Merizzi A et al. Diffuse alveolar damage in a patient treated with gemcitabine. Eur Respir J 1998;11:504-506.[Abstract]
  60. Vander EN, Miller V. Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 1998;114:1779-1781.[Abstract/Free Full Text]
  61. Etienne B, Perol M, Nesme P et al. Acute diffuse interstitial pneumopathy following docetaxel (Taxotere). Apropos of 2 cases. Rev Mal Respir 1998;15:199-203.[Medline]
  62. Merad M, Le CA, Baldeyrou P et al. Docetaxel and interstitial pulmonary injury. Ann Oncol 1997;8:191-194.[Free Full Text]
  63. Schrijvers D, Wanders J, Dirix L et al. Coping with toxicities of docetaxel (Taxotere). Ann Oncol 1993;4:610-611.[Abstract/Free Full Text]
  64. Trudeau ME, Eisenhauer EA, Higgins BP et al. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol 1996;14:422-428.[Abstract/Free Full Text]
  65. Semb KA, Aamdal S, Oian P. Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol 1998;16:3426-3432.[Abstract]
  66. Dunsford ML, Mead GM, Bateman AC et al. Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma. Ann Oncol 1999;10:943-947.[Abstract/Free Full Text]
  67. Hesse K, Heinrich B, Zimmermann F et al. Combined radiochemotherapy with docetaxel in patients with unresectable locally advanced head and neck tumors. Strahlenther Onkol 2000;176:67-72.[CrossRef][Medline]
  68. Israel RH, Olson JP. Pulmonary edema associated with intravenous vinblastine [Letter]. JAMA 1978;240:1585.
  69. Hoelzer KL, Harrison BR, Luedke SW et al. Vinblastine-associated pulmonary toxicity in patients receiving combination therapy with mitomycin and cisplatin. Drug Intell Clin Pharm 1986;20:287-289.[Abstract]
  70. Konits PH, Aisner J, Sutherland JC et al. Possible pulmonary toxicity secondary to vinblastine. Cancer 1982;50:2771-2774.[CrossRef][Medline]
  71. Rao SX, Ramaswamy G, Levin M et al. Fatal acute respiratory failure after vinblastine-mitomycin therapy in lung carcinoma. Arch Intern Med 1985;145:1905-1907.[Abstract/Free Full Text]
  72. Leduc D, De VP, Lheureux P et al. Pneumonitis complicating low-dose methotrexate therapy for rheumatoid arthritis. Discrepancies between lung biopsy and bronchoalveolar lavage findings. Chest 1993;104:1620-1623.[Abstract/Free Full Text]
  73. Bernstein ML, Sobel DB, Wimmer RS. Noncardiogenic pulmonary edema following injection of methotrexate into the cerebrospinal fluid. Cancer 1982;50:866-868.[CrossRef][Medline]
  74. Hamous JE, Guffy MM, Aschenbrener CA. Fatal acute respiratory failure following intrathecal methotrexate administration. Cancer Treat Rep 1983;67:1025-1026.[Medline]
  75. Cahill RA, Spitzer TR, Mazumder A. Marrow engraftment and clinical manifestations of capillary leak syndrome. Bone Marrow Transplant 1996;18:177-184.[Medline]
  76. Bhalla KS, Wilczynski SW, Abushamaa AM et al. Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med 2000;161:17-25.[Abstract/Free Full Text]
  77. Chen ZX, Xue YQ, Zhang R et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 1991;78:1413-1419.[Abstract/Free Full Text]
  78. Puccetti E, Guller S, Orleth A et al. BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity. Cancer Res 2000;60:3409-3413.[Abstract/Free Full Text]
  79. Shao W, Fanelli M, Ferrara FF et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells. J Natl Cancer Inst 1998;90:124-133.[Abstract/Free Full Text]
  80. Tallman MS, Andersen JW, Schiffer CA et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-1028.[Abstract/Free Full Text]
  81. Niu C, Yan H, Yu T et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999;94:3315-3324.[Abstract/Free Full Text]
  82. De Botton S, Dombret H, Sanz M et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1998;92:2712-2718.[Abstract/Free Full Text]
  83. Camacho LH, Soignet SL, Chanel S et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol 2000;18:2620-2625.[Abstract/Free Full Text]
  84. Frankel SR, Eardley A, Lauwers G et al. The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med 1992;117:292-296.
  85. Pollera CF, Ceribelli A, Crecco M et al. Weekly gemcitabine in advanced or metastatic solid tumors. A clinical phase I study. Invest New Drugs 1994;12:111-119.[CrossRef][Medline]
  86. Barrios NJ, Tebbi CK, Freeman AI et al. Toxicity of high dose Ara-C in children and adolescents. Cancer 1987;60:165-169.[CrossRef][Medline]
  87. Sleijfer S, Vujaskovic Z, Limburg PC et al. Induction of tumor necrosis factor-{alpha} as a cause of bleomycin-related toxicity. Cancer 1998;82:970-974.[CrossRef][Medline]
  88. Powell BL, Zekan PJ, Muss HB et al. Ara-C syndrome during low-dose continuous infusion therapy. Med Pediatr Oncol 1986;14:310-312.[Medline]
  89. Stentoft J. The toxicity of cytarabine. Drug Saf 1990;5:7-27.[Medline]
  90. Vermorken JB, Guastalla JP, Hatty SR et al. Phase I study of gemcitabine using a once every 2 weeks schedule. Br J Cancer 1997;76:1489-1493.[Medline]
  91. Piccart MJ, Klijn J, Paridaens R et al. Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer. J Clin Oncol 1997;15:3149-3155.[Abstract]
  92. Dubinett SM, Huang M, Lichtenstein A et al. Tumor necrosis factor-alpha plays a central role in IL-2-induced pulmonary vascular leak and lymphocyte accumulation. Cell Immunol 1994;157:170-180.[CrossRef][Medline]
  93. Rabinovici R, Sofronski MD, Renz JF et al. Platelet activating factor mediates IL-2-induced lung injury in the rat. J Clin Invest 1992;89:1669-1673.
  94. Queluz TT, Brunda M, Vladutiu AO et al. Morphological basis of pulmonary edema in mice with cytokine-induced vascular leak syndrome. Exp Lung Res 1991;17:1095-1108.[Medline]
  95. Klausner JM, Paterson IS, Goldman G et al. IL-2-induced lung injury is mediated by oxygen free radicals. Surgery 1991;109:169-175.[Medline]
  96. Lissoni P, Barni S, Cattaneo G et al. Activation of the complement system during immunotherapy of cancer with IL-2: a possible explanation of the capillary leak syndrome. Int J Biol Markers 1990;5:195-197.[Medline]
  97. Welbourn R, Goldman G, Kobzik L et al. Involvement of thromboxane and neutrophils in multiple-system organ edema with IL-2. Ann Surg 1990;212:728-733.[Medline]
  98. Lesur O, Arsalane K, Berard J et al. Functional IL-2 receptors are expressed by rat lung type II epithelial cells Am J Physiol 1997;273:L495-L503.[Abstract/Free Full Text]
  99. Hsu HC, Tsai WH, Chen PG et al. In vitro effect of granulocyte-colony stimulating factor and all-trans retinoic acid on the expression of inflammatory cytokines and adhesion molecules in acute promyelocytic leukemic cells. Eur J Haematol 1999;63:11-18.[Medline]
  100. Grande A, Manfredini R, Tagliafico E et al. All-trans-retinoic acid induces simultaneously granulocytic differentiation and expression of inflammatory cytokines in HL-60 cells. Exp Hematol 1995;23:117-125.[Medline]
  101. Atkinson JP, Waldmann TA, Stein SF et al. Systemic capillary leak syndrome and monoclonal IgG gammopathy; studies in a sixth patient and a review of the literature. Medicine (Baltimore) 1977;56:225-239.[Medline]
  102. Lofdahl CG, Solvell L, Laurell AB et al. Systemic capillary leak syndrome with monoclonal IgG and complement alterations. A case report on an episodic syndrome. Acta Med Scand 1979;206:405-412.[Medline]
  103. Johansson BR, Lofdahl CG. Ultrastructure of the microvessels in skeletal muscle in a case of systemic capillary leak syndrome. Acta Med Scand 1979;206:413-416.[Medline]
  104. Jehn U, Goldel N, Rienmuller R et al. Noncardiogenic pulmonary edema complicating intermediate and high-dose Ara C treatment for relapsed acute leukemia. Med Oncol Tumor Pharmacother 1988;5:41-47.[Medline]
  105. Gerard B, Aamdal S, Lee SM et al. Activity and unexpected lung toxicity of the sequential administration of two alkylating agents—dacarbazine and fotemustine—in patients with melanoma. Eur J Cancer 1993;29A:711-719.[CrossRef]
Received August 15, 2000; accepted for publication November 30, 2000.




This article has been cited by other articles:


Home page
 BloodHome page
F. Giles, N. Vey, D. DeAngelo, K. Seiter, W. Stock, R. Stuart, D. Boskovic, A. Pigneux, M. Tallman, J. Brandwein, et al.
Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse
Blood, November 5, 2009; 114(19): 4027 - 4033.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
P. D. Cole, C. L. Schwartz, R. A. Drachtman, P. A. de Alarcon, L. Chen, and T. M. Trippett
Phase II Study of Weekly Gemcitabine and Vinorelbine for Children With Recurrent or Refractory Hodgkin's Disease: A Children's Oncology Group Report
J. Clin. Oncol., March 20, 2009; 27(9): 1456 - 1461.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
C. M. Hartford, S. Duan, S. M. Delaney, S. Mi, E. O. Kistner, J. K. Lamba, R. S. Huang, and M. E. Dolan
Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity
Blood, March 5, 2009; 113(10): 2145 - 2153.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
B. Vahid and P. E. Marik
Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumors*
Chest, February 1, 2008; 133(2): 528 - 538.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
F. Forghieri, M. Luppi, M. Morselli, L. Potenza, F. Volzone, G. Riva, A. Imovilli, E. Rivolti, and G. Torelli
Cytarabine-related lung infiltrates on high resolution computerized tomography: a possible complication with benign outcome in leukemic patients
Haematologica, September 1, 2007; 92(9): e85 - e90.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
F. Guilhot
Indications for Imatinib Mesylate Therapy and Clinical Management
Oncologist, June 1, 2004; 9(3): 271 - 281.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
A. F. Shorr, G. M. Susla, and N. P. O'Grady
Pulmonary Infiltrates in the Non-HIV-Infected Immunocompromised Patient: Etiologies, Diagnostic Strategies, and Outcomes
Chest, January 1, 2004; 125(1): 260 - 271.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
C. J. Dunton
Management of Treatment-Related Toxicity in Advanced Ovarian Cancer
Oncologist, October 1, 2002; 7(90005): 11 - 19.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Briasoulis, E.
Right arrow Articles by Pavlidis, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Briasoulis, E.
Right arrow Articles by Pavlidis, N.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS